Short synthesis of skeletally and stereochemically diverse small molecules by coupling petasis condensation reactions to cyclization reactions

Article abstract of DOI:10.1002/anie.200600497

(Chemical Equation Presented) An efficient synthetic pathway to skeletally and stereochemically diverse molecules is described. Densely functionalized amino alcohols were readily synthesized through a Petasis three-component, boronic acid Mannich reaction

Full text of DOI:10.1002/anie.200600497

Angewandte
Chemie
Multicomponent Reactions
DOI: 10.1002/anie.200600497
Short Synthesis of Skeletally and Stereochemically
Diverse Small Molecules by Coupling Petasis
Condensation Reactions to Cyclization
Reactions**
Naoya Kumagai, Giovanni Muncipinto, and
Stuart L. Schreiber*
Herein, we report a short and efficient synthetic pathway that
uses intramolecular cyclization reactions of readily synthe-
sized and densely functionalized amino alcohols. The research
illustrates the implementation of a strategy that enables the
synthesis, in only three to five steps, of a diverse collection of
single-isomer small molecules whose members have over 15
different types of skeleton. In the future, this research should
also enable the consequences of the unique structural features
of the compounds in small-molecule screens to be deter-
mined.[1,2]
We used the Petasis three-component, boronic acid
Mannich reaction[3] followed by an amine propargylation to
yield b-amino alcohols 1. These compounds bear polar
(amino, hydroxy, ester) and nonpolar (alkene, alkyne, cyclo-
propane) functionalities strategically placed as handles for
subsequent skeletal diversification reactions (Scheme 1).
The Petasis reaction of (S)-lactol 2a (from l-phenyllactic
acid), l-phenylalanine methyl ester (3a), and (E)-2-cyclo-
propylvinylboronic acid (4) proceeded smoothly under ambi-
ent conditions in EtOH to afford the anti diastereomer 5aa
exclusively in 85% yield.[4] The same conditions but with (R)-
lactol 2b afforded the corresponding (2R,3S) isomer 5ba
exclusively (Scheme 2). These reactions indicate that the
secondary hydroxy group adjacent to the intermediate imines
directs the stereochemical outcome of the reaction, over-
riding any directing effects of the stereocenter in 3a.[3b] These
[*] Prof. Dr. S. L. Schreiber
Broad Institute of Harvard and MIT
Howard HughesMedical Institute
Department of Chemistry and Chemical Biology
Harvard University
12 Oxford Street, Cambridge, MA 02138 (USA)
Fax: (+1)617-495-0751
E-mail: stuart_schreiber@harvard.edu
Dr. N. Kumagai, G. Muncipinto
Department of Chemistry and Chemical Biology
Harvard University
12 Oxford Street, Cambridge, MA 02138 (USA)
[**] The NIGMS-sponsored Center of Excellence in Chemical Method-
ology and Library Design (Broad Institute CMLD) enabled this
research. We thank Nilesh Kumar and Drs. Paul Clemons, Ryan
Looper, Xiang Wang, and Damian Young for helpful discussions.
G.M. is a visiting PhD student from the Dipartimento Farm-
acochimico, University of Bari (Italy). S.L.S. is an Investigator with
the Howard HughesMedical Institute.
Supporting information for thisarticle isavailable on the WWW
under http://www.angewandte.org or from the author.
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clic compound 10aa. The stereochemistry of the only
isolated isomer 10aa results from the dienophile approach-
ing the side opposite to the substituent on the pyrroline ring
of 9aa. Electrophilic activation of the alkyne functionality in
1aa with NaAuCl4 in MeOH led to the intramolecular
cyclization of the hydroxy group followed by incorporation
of MeOH to provide a morpholine skeleton 11aa as a single
diastereomer,[9] likely because of an anomeric effect. Treat-
ment of 1aa with NaH at room temperature gave lactone
12aa in 88% yield without epimerization. Lactone 12aa was
subjected to the same reaction conditions
Scheme 1. The Petasis reaction followed by amine propargylation to yield b-amino
alcohols 1.
as those for template 1aa to furnish the
corresponding bicyclic triene 13aa, fused
tricyclic [5+2] product 14aa, fused tricyclic
enone 15aa, and bicyclic diene 16aa in
good yield. Diene 16aa was further con-
verted into fused tetracyclic compound
17aa by a Diels–Alder reaction using the
same conditions as before. Transforma-
tions of lactone 12aa also proceeded with
high diastereoselectivity to afford each
product as a single detectable diastereo-
mer.
We next demonstrated this diversity-
oriented synthesis (DOS) pathway using
different starting building blocks. A Peta-
sis reaction with methyl 1-amino-1-cyclo-
pentanecarboxylate (3b) afforded anti a-
mino alcohol 5ab exclusively in 84% yield
Scheme 2. a) EtOH, RT; b) propargyl bromide, NaHCO3, N,N,-dimethylformamide (DMF), 708C.
results suggest that all four of the possible anti amino alcohol
stereoisomers can be generated by appropriate combination
of stereoisomeric lactols and amino acids, thus leading to
stereochemical diversity in the final products of this pathway.
Although not explored herein, there is a reasonable assump-
tion that appendage diversification may also be achieved by
variation of the lactol building block; appendage diversifica-
tion by varying the amino component is described below. To
prepare a test substrate for subsequent skeletal diversifica-
tion, the N-selective alkylation of 5aa with propargyl bromide
afforded the template 1aa in 86% yield.
We next explored a series of skeletal diversification
reactions with 1aa (Scheme 3).[4] Cycloisomerization cata-
lyzed by [Pd(PPh3)2(OAc)2] resulted in opening of the
cyclopropyl ring to afford triene 6aa by a b-hydride elimi-
nation/reductive elimination sequence,[5] whereas cycloiso-
merization catalyzed by [CpRu(CH3CN)3PF6] (Cp = cyclo-
pentadienyl) resulted in a [5+2] reaction to afford cyclic diene
7aa by a cyclopropyl ring-opening/reductive elimination
sequence.[6] Both reactions proceeded in a diastereoselective
manner to afford single diastereomers. To the best of our
knowledge, there have been no reports on palladium-cata-
lyzed cycloisomerizations accompanied by opening of a
cyclopropyl ring to furnish a triene. A Pauson–Khand
reaction of 1aa with [Co2(CO)8] in the presence of trimethyl-
amine N-oxide[7] proceeded efficiently to provide azabicyclo-
[3.3.0] 8aa diastereoselectively (> 10:1 d.r.). Enyne meta-
thesis of 1aa using the Hoveyda–Grubbs catalyst[8] gave diene
9aa, which, following Diels–Alder reaction with 4-methyl-
1,2,4-triazolin-3,5-dione at room temperature, afforded tricy-
under modified conditions (solvent system: CH2Cl2/
1,1,1,3,3,3-hexafluoroisopropanol).[4,10] Subsequent propargy-
lation furnished 1ab in 81% yield (Scheme 4).
The cyclopentyl template 1ab was next subjected to the
same skeletal diversification reactions described above to
provide the corresponding products with a spiro ring system
(Scheme 5).[4] The reactions afforded skeletally distinct com-
pounds 6ab–20ab in good yield with high diastereoselectivity,
whereas 8ab cyclized under reaction conditions to form
lactone 15ab. The mild and chemoselective nature of these
diversification reactions allows the use of chemically complex
building blocks, such as 6-aminopenicillanic acid methyl ester
(3c). The two-step preparation of the common template 1ac
with 3c proceeded with excellent diastereoselectivity
(Scheme 4).[4] The transition-metal-catalyzed diversification
reactions worked well under the same conditions described
for the l-Phe series despite the sulfur atom in the penam
skeleton, whereas basic treatment resulted in ring opening of
b-lactam to afford lactone 21ac bearing a thiazolidine ring
(Scheme 5).
We initiated this research with the hypothesis that densely
substituted small molecules with diverse skeletons and
stereochemistries will be especially effective in small-mole-
cule screens. This new DOS pathway should enable the
further testing of this hypothesis in an effective way owing to
its ability to yield remarkably diverse, rigid, and complex
small molecules with considerable efficiency. We are encour-
aged by preliminary results that have assigned, among others,
high-feature signatures to a cluster of compounds that result
from this pathway using multidimensional, cell-based screen-
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Scheme 3. a) [Pd(PPh3)2(OAc)2] (10 mol%), benzene, 808C; b) [CpRu(CH3CN)3PF6] (10 mol%), acetone, RT; c’) [Co2(CO)8], trimethylamine N-
oxide, NH4Cl (for conditions c), benzene, RT; d) Hoveyda–Grubbs second-generation catalyst (10 mol%), CH2Cl2, reflux; e) 4-methyl-1,2,4-
triazoline-3,5-dione, CH2Cl2, RT; f) NaAuCl4 (10 mol%), MeOH, RT; g) NaH, toluene, RT; h) mCPBA, THF, ꢀ78!08C. [a] Single diastereomer;
[b] >10:1 d.r.; [c] trans/cis=6.7:1; [d] trans/cis=6.4:1; [e] from trans diene; [f] trans/cis=3:1; [g] combined yield from the trans and cis dienes.
mCPBA=m-chloroperbenzoic acid.
ing.[11] Small molecules prepared
by this pathway are being
included in a public effort to
assess comparatively the role of
structural features in assay meas-
urements.[12] Such studies are
hoped to illuminate the variation
of assay outcomes that result
from small molecules distinct in
both their origins (natural and
non-natural) and structural fea-
tures.
Received: February 7, 2006
Published online: April 28, 2006
Keywords: amino alcohols·
.
diversity-oriented synthesis ·
multicomponent reactions·
Petasis reaction · synthesis design
Scheme 4. a) CH2Cl2/1,1,1,3,3,3-hexafluoroisopropanol=9:1, RT; b) propargyl bromide, NaHCO3, DMF,
708C; c) EtOH/1,1,1,3,3,3-hexafluoroisopropanol (9:1), RT.
Angew. Chem. Int. Ed. 2006, 45, 3635 –3638
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Communications
Scheme 5. [a] Obtained as a single diastereomer; [b] trans/cis=3:1; [c] trans/cis>13:1; [d] trans/cis=5:1; [e] combined yield from the cis and trans
dienes; [f] 3:1 d.r.; [g] >12:1 d.r.; [h] trans/cis=5.6:1; [i] from the trans diene.
c) S. Shambayati, W. E. Crowe, S. L. Schreiber, Tetrahedron Lett.
1990, 31, 5289.
[8] S. B. Garber, J. S. Kingsbury, B. L. Gray, A. H. Hoveyda, J. Am.
Chem. Soc. 2000, 122, 8168.
[1] S. L. Schreiber, Chem. Eng. News 2003, 81, 51.
[2] R. L. Strausberg, S. L. Schreiber, Science 2003, 300, 294.
[3] a) N. A. Petasis, I. A. Zavialov, J. Am. Chem. Soc. 1997, 119, 445;
b) N. A. Petasis, I. A. Zavialov, J. Am. Chem. Soc. 1998, 120,
11798.
[4] The structures and stereochemistry of all the reported com-
pounds were determined by detailed spectroscopic analyses,
including an X-ray structure of a diastereomer of 10aa prepared
from 5ba (see the Supporting Information).
[5] For a review of cycloisomerization of 1,6-enynes, see: a) B. M.
Trost, M. J. Krische, Synlett 1998, 1; b) C. Aubert, O. Buisine, M.
Malacria, Chem. Rev. 2002, 102, 813; c) G. C. Lloyd-Jones, Org.
Biomol. Chem. 2003, 1, 215.
[6] a) B. M. Trost, F. D. Toste, H. Shen, J. Am. Chem. Soc. 2000, 122,
2379; for pioneering studies of [5+2] cycloadditions, see: b) P. A.
Wender, H. Takahashi, B. Witulski, J. Am. Chem. Soc. 1995, 117,
4720.
[9] Y. Fukuda, K. Utimoto, J. Org. Chem. 1991, 56, 3729.
[10] K. K. Nanda, B. W. Trotter, Tetrahedron Lett. 2005, 46, 2025.
[11] P. A. Clemons, unpublished results; such signatures reflect both
the activity and selectivity of these compounds in a panel of 16
cell-based assays. These preliminaries studies follow the con-
cepts reported in: Y.-K. Kim, M. A. Arai, T. Arai, J. O. Lamenzo,
E. F. Dean III, N. Patterson, P. A. Clemons, S. L. Schreiber, J.
Am. Chem. Soc. 2004, 126, 14740 – 14745.
[12] This public effort (“The Forma Project”) is sponsored by the
NCI Initiative for Chemical Genetics, see: http://www.broad.
harvard.edu/chembio; all assay measurements will be made
publicly available in ChemBank.[2]
[7] a) I. U. Khand, G. R. Knox, P. L. Pauson, J. Chem. Soc. Perkin
Trans. 1 1977, 977; b) P. L. Pauson, Tetrahedron 1985, 41, 5855;
3638
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Angew. Chem. Int. Ed. 2006, 45, 3635 –3638