Syntheses of stereochemically diverse nine-membered ring-containing biaryls

Article abstract of DOI:10.1021/ol048273c

(Chemical Equation Presented) A library of nine-membered, biaryl-containing rings has been synthesized in parallel on polystyrene macrobeads. Dimeric medium rings were shown to be accessible via a regio- and stereoselective double cyclization.

Full text of DOI:10.1021/ol048273c

ORGANIC
LETTERS
2004
Vol. 6, No. 22
4021-4024
Syntheses of Stereochemically Diverse
Nine-Membered Ring-Containing Biaryls
Shyam Krishnan and Stuart L. Schreiber*
Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute,
HarVard UniVersity, and the Broad Institute of HarVard and MIT,
Cambridge, Massachusetts 02138
stuart_schreiber@harVard.edu
Received August 28, 2004
ABSTRACT
A library of nine-membered, biaryl-containing rings has been synthesized in parallel on polystyrene macrobeads. Dimeric medium rings were
shown to be accessible via a regio- and stereoselective double cyclization.
Small molecules and small-molecule screening can illuminate
cell circuitry and disease biology.1 A promising approach
to the creation of effective small-molecule modulators
involves the use of diversity-oriented synthesis (DOS).2 Here
we report the generation of stereochemically diverse small
molecules using DOS.
molecules using chemical genetic assays. An example is 2,
a modulator of zebrafish cardiovascular development.4b,c
Our earlier studies resulted in the split-pool synthesis of
a library of (mostly) 10-membered ring-containing com-
pounds. With the goal of increasing the rigidity of the
resultant small molecules while maintaining the axially
dissymmetric nature of the biaryl moiety, we embarked on
the synthesis of a library of nine-membered rings. We
We were stimulated by the stereochemically complex
ellagitannin family of natural products, a representative
member of which is tellimagrandin I (1) (Figure 1). The
rigidity of these compounds is due to the presence of an
axially dissymmetric biaryl moiety implanted in a medium
ring. The structural preorganization induced by biaryl bond
formation may enhance the potential for selective recognition
of protein targets, as suggested by the cellular activity
displayed by ellagitannins.3 This line of reasoning was
supported by stereoselective copper-mediated syntheses of
“ellagitannin-like” biaryl medium rings by adaptation of a
protocol published by Lipshutz and co-workers4a and sub-
sequent discovery of several biologically active small
(1) Schreiber, S. L. Chem. Eng. News 2003, 81, 51-61. See also http://
www-schreiber.chem.harvard.edu.
(2) (a) Schreiber, S. L. Science 2000, 287, 1964-1968. (b) Burke, M.
D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46-58.
(3) Quideau, S.; Feldman, K. S. Chem. ReV. 1996, 96, 475-503.
Figure 1. Natural (1, tellimagrandin I) and nonnatural (2, modula-
tor of zebrafish cardiovascular development) biaryl-containing
medium-ring compounds.
10.1021/ol048273c CCC: $27.50
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presence of tri-n-butylphosphine and N,N,N′,N′-tetramethyl-
azodicarboxamide (TMAD)6 resulted in complete conversion
to 6. The stereochemistry of 6 resulted from retention of
configuration at the center bearing the benzylic hydroxyl,
presumably due to the involvement of an aziridinium ion
intermediate7 formed by anchimeric assistance from the
tertiary amine â to the reacting center. Cyclization to the
medium ring 7 was achieved by (i) magnesium-bromine
exchange using i-PrBu2MgLi,8 (ii) magnesium to copper
transmetalation using a solution of CuCN‚2LiBr, and (iii)
oxidation of the resulting cuprate with a solution of 1,3-
dinitrobenzene. The greater rigidity of the nine-membered
ring framework relative to a 10-membered ring results in 7
exhibiting configurational stability about the biaryl axis even
though one of the ortho substituents on the biaryl nucleus is
a pyridine nitrogen.9 The relative stereochemistry of 7 was
confirmed by NOE analysis and characteristic coupling
constants10 observed for protons on the amino alcohol
backbone.
Scheme 1. Synthesis of Nine-Membered Biaryl Rings on
Solid Phase
With the aim of deriving the diversity of the biaryl medium
rings from readily available amino alcohols, aldehydes and
2-bromophenols, we selected building blocks individually
on the basis of the success of their incorporation (>80%
purity by NMR and LC-MS) with a chosen substrate under
generalized reaction conditions. Figure 2 illustrates all the
building blocks selected for use in a parallel library
synthesis.11 Amino alcohols with primary as well as second-
ary amines12 (building blocks B1-13) could be used but were
restricted to those that could undergo regioselective displace-
ment with bromophenols in the subsequent Mitsunobu
reaction. Several aliphatic aldehydes were suitable building
blocks for the reductive alkylation of polymer-supported
secondary amines (C1-6). Aromatic aldehydes were not
used at this stage due to the reduced rate of the subsequent
Mitsunobu reaction, a feature observed even in substrates
in solution phase. This is presumably due to the increased
steric hindrance around the carbinol carbon. While we tested
a number of bromophenols for the Mitsunobu reaction, we
chose building blocks D1 and D2 for incorporation in a
library synthesis.
a NOEs indicated by arrows.
decided to use parallel solid-phase synthesis with the aim
of generating 1-5 mg of each library member.
Our synthetic plan is depicted in Scheme 1. Polystyrene
macrobeads functionalized with a silyl linker5 were loaded
with 2-bromo-5-hydroxybenzaldehyde via an intermediate
silyl triflate. The polymer-supported aldehyde 3 was soaked
in a solution of excess amino alcohol in trimethylorthofor-
mate to form a Schiff base that was reduced using NaBH3-
CN in acidic solution to form the amino alcohol 4 (>90%
purity by NMR and HPLC). The reductive alkylation of 4
was achieved by initial formation of an oxazolidine with a
solution of excess hydrocinnamaldehyde in trimethylortho-
formate; the resulting oxazolidine was reduced with NaBH3-
CN in acidic solution to form the amino alcohol 5 (>90%
purity by NMR and HPLC). Amino alcohol 5 was trans-
formed to the cyclization precursor 6 under Mitsunobu
conditions. Reaction of 5 with 2-bromo-3-pyridinol in the
In the reductive alkylation of secondary amines, it was
found that building block B6 was not compatible with C3,
C4, and C5.13 The tertiary amine derived from building block
B9 underwent Mitsunobu displacement with phenols D1 and
(6) Tsunoda, T.; Otsuka, J.; Yamamiya, Y.; Ito, S. Chem. Lett. 1994, 3,
539-542.
(7) For Mitsunobu reactions proceeding via aziridinium ion intermediates,
see: (a) Freedman, J.; Vaal, M. J.; Huber, E. W. J. Org. Chem. 1991, 56,
670-672. (b) Okuda, M.; Tomioka, K. Tetrahedron Lett. 1994, 35, 4585-
4586. (c) Poelert, M. A.; Hulshof, L. A.; Kellogg, R. M. Recl. TraV. Chim.
Pays-Bas 1994, 113, 355-364.
(8) Kitagawa. K.; Inoue, A.; Shinokubo, H.; Oshima, K. Angew. Chem.,
Int. Ed. 2000, 39, 2481-2483. (b) Inoue, A.; Kitagawa, K.; Shinokubo,
H.; Oshima, K. J. Org. Chem. 2001, 66, 4333-4339.
(9) 10-Membered rings with nitrogen and sulfur as ortho substituents
show no evidence of restricted rotation around the biaryl bond.
(10) See Supporting Information.
(11) A complete list of building blocks tested for each step is included
in the Supporting Information.
(12) Reductive aminations of secondary amines could be carried out with
a modification of the procedure for primary amines, by initial formation of
an oxazolidine, followed by reduction.
(4) (a) (i) Lipshutz, B. H.; Kayser, F.; Liu, Z.-P. Angew. Chem., Int. Ed.
1994, 33, 1842-1844. (ii) Lipshutz, B. H.; Kayser, F.; Maullin, N.
Tetrahedron Lett. 1994, 35, 815-818. (iii) Lipshutz, B. H.; Liu, Z.-P.;
Kayser, F. Tetrahedron Lett. 1994, 35, 5567-5570. (b) Spring, D. R.;
Krishnan, S.; Schreiber S. L. J. Am. Chem. Soc. 2000, 122, 5656-5657.
(c) Spring, D. R.; Krishnan, S.; Blackwell, H. E.; Schreiber S. L. J. Am.
Chem. Soc. 2002, 124, 1354-1363.
(5) Tallarico, J. A.; Depew, K. M.; Pelish, H. E.; Westwood, N. J.;
Lindsley, C. W.; Shair, M. D.; Schreiber, S. L.; Foley, M. A. J. Comb.
Chem. 2001, 3, 312-318.
4022
Org. Lett., Vol. 6, No. 22, 2004

Table 1. Medium-Ring-Forming Cyclizations on Solid Phase
Figure 2. Building blocks used for the biaryl medium-ring library
with yields in parentheses.
D2 to low conversion. These building blocks were not carried
further for subsequent transformations in the library synthesis.
Representative examples of medium-ring-forming cycliza-
tions on solid support are illustrated in Table 1.
Promoting protein-protein interactions as a means of
regulating cellular processes can be achieved by using hybrid
small molecules capable of inducing protein association.16
We therefore investigated the formation of dimeric biaryl-
containing medium rings in solution (Scheme 2).
The triisopropylsilyl ether of 3-cyclopentenemethanol
(12)17 was subjected to ozonolysis and subsequent double
reductive amination with N-(2-bromobenzyl)-(1S,2R)-norephe-
202 compounds (biaryl medium rings and their intermedi-
ates) were synthesized in parallel on solid phase. Of the 202
compounds, 104 out of 124 intermediates were estimated to
be >80% pure by LC-MS and 1H NMR. Out of 78
cyclization reactions,14 57 resulted in products of >70%
purity, while 16 resulted in products that were >50% pure.
The library members were cleaved from the solid support
purified by preparative HPLC and formatted into 5 mM stock
solutions in DMSO for chemical genetic assays, as well as
1 mM stock solutions in DMF prepared for protein-binding
assays using small-molecule microarrays.15
(14) Diastereoselectivities for all cyclization reactions were not deter-
mined. We earlier observed poor diastereoselection in nine-membered ring
products derived from (S)-phenylalaninol and (S)-leucinol. In contrast, we
observed good to excellent diastereoselection in medium-ring products
bearing a phenyl substituent at C-1 of the 1,2-amino alcohol fragment (with
the presence or absence of a cis-oriented methyl group at C-2) and with a
substrate derived from trans-2-aminocyclohexanol. These results suggest a
greater role for a substituent at C-1 than a substituent at C-2 of the 1,2-
amino alcohol in influencing the atropdiastereoselection of the resulting
nine-membered ring products.
(15) Barnes-Seeman, D.; Park, S. B.; Koehler, A. N.; Schreiber, S. L.
Angew. Chem., Int. Ed. 2003, 42, 2376-2379.
(16) (a) Klemm, J. D.; Schreiber, S. L.; Crabtree, G. R. Annu. ReV.
Immunol. 1998, 16, 569-592. (b) Diver, S. T.; Schreiber, S. L. J. Am. Chem.
Soc. 1997, 119, 5106-5109.
(13) (a) rac-B6 was not combined with enantiopure C3 in order to avoid
producing an equimolar mixture of diastereomers. (b) Reaction of the
polymer-supported secondary amine derived from rac-B6 with building
blocks C4 and C5 resulted in the incorporation of a second molar equivalent
of the aldehyde, presumably via an initially formed enamine. The difficulty
of forming bicyclic oxazolidines from trans-2-aminocyclohexanol deriva-
tives has been documented. See: Rona, M.; Ben-Ishai, D. J. Org. Chem.
1961, 26, 1446-1450.
Org. Lett., Vol. 6, No. 22, 2004
4023

precursor (14). Gratifyingly, lithium-bromine exchange
followed by lithium to copper transmetalation and cuprate
oxidation delivered pseudo-C2-symmetric biaryl dimer (15)
in high diastereoselection (>20:1 M,M:P,P) as the only
doubly cyclized product.18
Scheme 2. Synthesis of Dimeric Nine-Membered Biaryl
Medium Rings in Solution
In conclusion, we have synthesized a library of nine-
membered ring, biaryl-containing compounds in parallel on
solid phase. We have also demonstrated the feasibility of
performing a double cyclization yielding a bis(macrocycle)
in solution phase. Small-molecule screening of the library
members is now underway.
Acknowledgment. We thank the NIGMS for support of
this research. We are grateful to Max Narovlyansky and
Kerry Pierce of the Broad Institute Chemical Biology
Program for macrobeads and assistance in LC-MS analysis,
respectively. S.L.S. is an Investigator at the Howard Hughes
Medical Institute at Harvard University.
Supporting Information Available: Representative ex-
perimental procedures and characterization data. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
OL048273C
a ADDP ) 1,1′-azodicarbonyldipiperidine.
(17) Prepared by silylation of the corresponding alcohol, which was
prepared as in: Olah, G. A.; Surya Prakash, G. K.; Arvanaghi M.; Anet, F.
A. L. J. Am. Chem. Soc. 1982, 104, 7105-7108.
drine to form dimeric amino alcohol (13). Further double
Mitsunobu reaction with 2-bromophenol yielded cyclization
(18) Traces of a product of single cyclization were observed (<5%) in
1
the H NMR and LC-MS analyses of crude reaction mixture.
4024
Org. Lett., Vol. 6, No. 22, 2004