Macrocycloadditions leading to conformationally restricted small molecules

Article abstract of DOI:10.1021/ol0604724

The Cu(I)-catalyzed cycloaddition of alkynes and azides (click reaction) provides a robust method for the construction of macrocyclic small molecules via an intramolecular macrocycloaddition. A three-subunit system has been used to explore the tolerance o

Full text of DOI:10.1021/ol0604724

ORGANIC
LETTERS
2006
Vol. 8, No. 10
2063-2066
Macrocycloadditions Leading to
Conformationally Restricted Small
Molecules
Ryan E. Looper, Daniela Pizzirani, and Stuart L. Schreiber*
Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology,
HarVard UniVersity, Broad Institute of HarVard and MIT,
Cambridge, Massachusetts 02138
stuart_schreiber@harVard.edu
Received February 23, 2006
ABSTRACT
The Cu(I)-catalyzed cycloaddition of alkynes and azides (click reaction) provides a robust method for the construction of macrocyclic small
molecules via an intramolecular macrocycloaddition. A three-subunit system has been used to explore the tolerance of this macrocycloaddition
to variations of stereochemistries and substituents.
Restricting conformational freedom in small molecules1 can
lead to significant changes in assay performance, as was
quantitated in a recent study using multidimensional screen-
ing.2 For the class of compounds investigated, the presence
of a macrocycle and the stereochemistry of substituents on
the macrocycle were primary determinants of the observed
global activity patterns. Elucidating these relationships is part
of a larger effort to correlate chemical descriptors of small
molecules to assay measurement outcomes.3
the current research with the idea that the substantial
enthalpic gains associated with forming an aromatic triazole
(∆Hf ) 60 kcal/mol) might provide a useful means for
synthesizing macrocycles from substrates that vary in ster-
eochemistry and substitution patterns.5 We were also attracted
to the mild conditions reported for the Cu-catalyzed cy-
cloaddition of azides with alkynes (click reaction) that yields
this functionality.6 This strategy has previously proven
successful in the head-to-tail cyclodimerization of peptides,7
polysaccharides,8 and carbohydrate/amino acid hybrids.9 An
The preparation of macrocyclic compounds in library
syntheses can be challenging, often requiring either the
incorporation of conformational biasing elements or the
empirical optimization of reaction conditions.4 We initiated
(5) Williams, C. I.; Whitehead, M. A. THEOCHEM 1997, 393, 9-24.
(6) (a) Tornoe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
67, 3057-3064. (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem., Int. Ed. 2002, 41, 2596-2599. (c) Pe´rez-Balderas,
F.; Ortega-Mun˜oz, O.; Morales-Sanfrutos, J.; Herna´ndez-Mateo, F.; Calvo-
Flores, F. G.; Calvo-As´ın, J. A.; Isac-Garcia´, J.; Santoyo-Gonza´les, F. Org.
Lett. 2003, 5, 1951-1954.
(1) (a) Burger, M. T.; Bartlett, P. A. J. Am. Chem. Soc. 1997, 119,
12697-12698 and references therein. (b) For a review in the context of
peptides, see: Davies, J. S. J. Pept. Sci. 2003, 9, 471-501.
(2) Kim, Y.-K.; Arai, M. A.; Arai, T.; Lamenzo, J. O.; Dean, E. F.;
Patterson, N.; Patterson, N.; Clemons, P. A.; Schreiber, S. L. J. Am. Chem.
Soc. 2004, 126, 14740-14745.
(3) Schreiber, S. L. Nat. Chem. Biol. 2005, 1, 64-66.
(4) Lee, D.; Sello, J. K.; Schreiber, S. L. J. Am. Chem. Soc. 1999, 121,
1, 106480-10649 and references therein.
(7) (a) Punna, S.; Kuzelka, J.; Wang, O.; Finn, M. G. Angew. Chem.,
Int. Ed. 2005, 44, 2215-2220. (b) van Maarseveen, J. H.; Horne, W. S.;
Ghadiri, M. R. Org. Lett. 2005, 7, 4503-4506.
(8) Bodine, K. D.; Gin, D. Y.; Gin, M. S. J. Am. Chem. Soc. 2004, 126,
1638-1639.
(9) Billing, J. F.; Nilsson, U. J. J. Org. Chem. 2005, 70, 4847-4850.
10.1021/ol0604724 CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/11/2006

application of this chemistry to small-molecule macrocycles
as â-turn mimics has also been reported.10
Scheme 1. Preparation of the Central Sector
We have now explored a macrocycloaddition strategy in
a modular system that enables the facile variation of
stereochemistries and substituents (Figure 1). Three subunits
Figure 1. Three-subunit system for assembling macrocycles.
(A, B, and C) can be arranged to form two cyclic variants
with the interchange of subunits A and C. Likewise, two
acyclic variants can also be synthesized. A and C are
interchangeable by virtue of their having amines as the
reactive functionality. Orthogonal amine acceptors were
incorporated into subunit B so that isocyanate trapping and
peptide coupling reactions yield the acyclic triad.
Padwa and co-workers have reported reactions of iso-
mu¨nchnone dipoles with alkynes.11 In these cases, decom-
position of a diazoimide with Rh2OAc4 initiates a reaction
cascade where the carbonyl ylide undergoes [3+2] cycload-
dition to an alkyne to yield an indolizinone that then
undergoes a [4+2] cycloreversion reaction releasing an
isocyanate. This reaction provides a potentially efficient
means to diversify subunit B.
transfer afforded the R-diazo-â-imido esters 3a,b. Treatment
of 3a,b with Rh2Oct4 resulted, presumably via an intermedi-
ate ylide, in a chemoselective cycloaddition with dimethyl-
acetylene dicarboxylate without interference from the pendent
alkene or alkyne substituents. Cycloreversion of these
intermediates afforded the isocyanates that were converted
to 4a-c by the addition of (S)- or (R)-azidomethylphenyl-
alanine.14 Alternatively, the isocyanate was intercepted
with: (1) N-methyl propargylamine to give 5, (2) (S)- or
(R)-2-aminophenyl butyne to give 6a-d, or (3) the propargyl
amide of (S)- or (R)-phenylalanine to yield 7a-d.
We next examined the ability of other dipoles to participate
in the cycloaddition-cycloreversion sequence in an attempt
to expand the diversity of subunit B (Scheme 2). Decom-
position of the diazoimide 3a in the presence of ethynyl tolyl
sulfone and trapping with N-methyl propargylamine provided
8 as a single isomer in 76% yield. Methyl cyanoformate as
a dipolarophile afforded oxazole 9 in 50% yield. Methyl
propiolate is also an active participant, as reported pre-
viously.11b
To establish the stereochemistry in the subunit B, we began
with the known pyrrolidinone 1 bearing a TIPS-protected
hydroxymethyl group. This group serves to model a silylated
macrobead solid support used commonly in our laboratory
(Scheme 1).12 We adapted a one-pot procedure to access
â-imido esters by treatment of 1 first with Meldrum’s acid
in the presence of TMSCl and Et3N and then with allyl
alcohol, diisopropylcarbodiimide (DIC), and DMAP.13 Diazo
We next turned our attention to the macrocycloaddition.
Treatment of 4a with CuI in THF afforded 9 efficiently, as
judged by analysis of the reaction mixture by 1H NMR, but
in poor isolated yield (Scheme 3). The SFC-MS trace of the
(10) Angell, Y.; Burgess, K. J. Org. Chem. 2005, 70, 9595-9598.
(11) (a) Doyle, M. P.; Pieters, R. J.; Taunton, J.; Pho, H. Q.; Padwa, A.;
Hertzog, D. L.; Precedo, L. J. Org. Chem. 1991, 56, 820-829. (b) Padwa,
A.; Hertzog, D. L. Tetrahedron 1993, 49, 2589-2600.
(12) 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.
(13) Rigo, B.; Lespagnol, C.; Pauly, M. J. Heterocycl. Chem. 1988, 25,
59-63.
(14) Nantermet, P. G.; Selnick, H. G. Tetrahedron Lett. 2003, 44, 2401-
2404.
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Org. Lett., Vol. 8, No. 10, 2006

Scheme 2. Expanding the Scope of the 3-CC Reaction
Scheme 4. Partitioning between Acyclic and Cyclic Products
Cu(I)-catalyzed macrocycloaddition after 3 h was also
exceptionally promising.15 Product isolation, however, proved
difficult, possibly because of the inclusion of Cu within the
macrocycle. This was particularly problematic when the
reaction was conducted in THF or in alcoholic/aqueous
solvents using a variety of Cu(I) catalysts. Product recovery
typically gave <20% yield. The use of polymer-bound cation
scavengers failed to improve the recovery. Toluene proved
optimal for the reactions, permitting simple product recovery
after flash chromatography and a 64% yield of 10.
chemical influences within other subunits. We first synthe-
sized three CBA triads using related chemistry (Scheme 5).
Deprotection of 5 and coupling with (S)- or (R)-azidometh-
ylphenylalanine gave the macrocycloaddition precursors
14a,b. Exposure individually of the diastereomers to catalytic
CuI in toluene gave the (5S,14S) and (5S,14R) macrocycles
(15a,b) in nearly equivalent yields (64% and 68%, respec-
tively). We also note that proline can be incorporated into
the 17-membered macrocycles with similar efficiency (16).16
Scheme 3. Optimizing the Macrocycloaddition of an ABC
Triad
Scheme 5. Inverted CBA Triad
Deprotection of 4b or 4c gave acids that were coupled to
N-methyl propargylamine or to morpholine, the latter of
which cannot participate in a subsequent macrocyclization
reaction (Scheme 4). Phoshine-liganded palladium depro-
tected the allyl ester without noticeable interference by the
resident azide. The macrocycloaddition conditions afforded
both diastereomers of the ABC macrocycles 12a,b in
comparable isolated yields. The acyclic ABC constructs
13a-d were produced in good yield by acyclic coupling with
a variety of terminal alkynes.
Beginning with 6a-d, we also constructed a complete set
of diastereomeric macrocycloaddition precursors (17a-h) to
examine whether this approach would tolerate all three
subunits bearing stereogenic centers (Scheme 6). All stereo-
isomers of the acyclic azidoalkynes were shown to participate
in the macrocycloaddition reaction affording the macrocycles
In the examples above, the stereochemistry within the
macrocycles (12a,b) was largely indeterminant of the mac-
rocycloaddition outcome. Thus, we next examined stereo-
(16) Incorporation of two proline residues into macrocyclic triazoles has
recently been reported: Bock, V. D.; Perciaccante, R.; Jansen, T. P.;
Hiemstra, H.; van Maarseveen, J. H. Org. Lett. 2006, 8, 919-922.
(15) For examples, see Supporting Information. SFC ) supercritical fluid
chromatography.
Org. Lett., Vol. 8, No. 10, 2006
2065

Scheme 6. 17-Membered Macrocycles
Scheme 7. 21-Membered Macrocycles
18a-h in fair to good isolated yields. The incorporation of
a third stereogenic center appears to facilitate the formation
of a cyclodimer in some cases, albeit in low yield.
Previous reports had alerted us to the potential of a
confounding cyclodimer formation,10 so we were pleasantly
surprised by the relatively small amounts of cyclodimer
produced in the macrocycloadditions reported in this study.
For example, no cyclodimer was detected in reactions
yielding macrocycles having only one or two stereocenters.
To determine whether this result is specific to the 17-
membered macrocycles, we prepared an analogous series of
lengthened acyclic precursors 19a-d (Scheme 7). Macro-
cycloaddition of these compounds produced the 21-mem-
bered monomer 20a-d in all cases; however, significant
amounts of the cyclodimer were observed. This cyclodimer-
ization predominates in the reaction of the (5R,9S,17R)
stereotriad (20c).
The Cu(I)-catalyzed macrocycloaddition of alkynes with
azides appears to provide a reliable path for the synthesis of
macrocyclic triazoles. We have been sufficiently encouraged
by the results reported herein, especially with respect to the
macrocycloadditions’ tolerance to variations in stereochem-
istries and substituents, that we are initiating an expanded
research effort. The effort will include experiments to
determine whether control of site-site interactions in solid-
phase synthesis can be used to decrease further the yield of
cyclodimers while increasing the yield of the target macro-
cycles. Such a capability will be especially important in
expanded efforts, for example, to synthesize 21-membered
macrocycles (Scheme 7).
Acknowledgment. This research was supported by a
grant from the NIGMS supporting the Broad Institute Center
of Excellence in Chemical Methodology and Library De-
velopment (BI-CMLD). We are especially thankful to Dr.
Rui Chen for analytical assistance and Dr. Richard Staples
for X-ray crystallographic analysis. We thank Benjamin
Stanton for initial experimental assistance. R.E.L. is grateful
for an NIH postdoctoral fellowship, and D.P. thanks the
University of Bologna for support of her fellowship. S.L.S.
is an Investigator at the Howard Hughes Medical Institute.
Supporting Information Available: Characterization
data for all new compounds and X-ray crystallographic files
for 11. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0604724
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