Stereochemical and skeletal diversity arising from amino propargylic alcohols

Article abstract of DOI:10.1021/ol100914b

(Figure presented) An efficient synthetic pathway to the possible stereoisomers of skeletally diverse heterocyclic small molecules is presented. The change in shape brought about by different intramolecular cyclizations of diastereoisomeric amino propargy

Full text of DOI:10.1021/ol100914b

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2822-2825
Stereochemical and Skeletal Diversity
Arising from Amino Propargylic Alcohols
Daniela Pizzirani,‡ Taner Kaya,† Paul A. Clemons,† and Stuart L. Schreiber*,†
Howard Hughes Medical Institute, Broad Institute of HarVard and MIT, 7 Cambridge
Center, Cambridge, Massachusetts 02142, and Department of Chemistry and Chemical
Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
stuart_schreiber@harVard.edu
Received April 21, 2010
ABSTRACT
An efficient synthetic pathway to the possible stereoisomers of skeletally diverse heterocyclic small molecules is presented. The change in
shape brought about by different intramolecular cyclizations of diastereoisomeric amino propargylic alcohols is quantified using principal
moment-of-inertia (PMI) shape analysis.
Human genetics and physiology are increasingly revealing
the root causes of human disorders, yet many of the
relevant targets and processes are considered difficult to
modulate with small molecules.1,2 At least part of the
difficulty is associated with the candidate small molecules
that populate screening collections.3 We describe an effort
to address this shortcoming by applying a build/couple/pair
strategy in organic synthesis.4,5 The synthetic pathway we
describe focused on the goal of synthesizing stereoisomers
of skeletally diverse compounds so that stereochemistry-
based structure-activity relationships (SARs) can be derived
directly from small-molecule screening. Small-molecule
probe-development efforts are significantly enhanced when
“hits” from screens can be prioritized and optimized using
Figure 1. Stereochemical and skeletal diversity.
stereochemistry-based SARs, and we imagine that drug
discovery efforts might similarly be facilitated in the future.
We envisioned that densely functionalized chiral amino
propargylic alcohols 1a-d could be synthesized as a complete
matrix of stereoisomers using simple coupling reactions and
readily available building blocks. These coupling products
undergo intramolecular cyclization reactions to generate diverse
heterocyclic skeletons in 1-2 steps (Figure 1).
† Broad Institute of Harvard and MIT.
‡ Harvard University. Current address: Department of Drug Discovery
and Development, Italian Institute of Technology (IIT), Via Morego 30,
16163 Genova, Italy.
(1) Schreiber, S. L. ChemBioChem 2009, 10, 26–29
(2) Schreiber, S. L. Nature 2009, 153–154
.
.
(5) For recent examples, see: (a) Kumagai, N.; Muncipinto, G.; Schreiber,
S. L. Angew. Chem. Int. Ed 2006, 45, 3635–3638. (b) Spiegel, D. A.;
Schroeder, F. C.; Duvall, J. R.; Schreiber, S. L. J. Am. Chem. Soc. 2006,
128, 14766–14767. (c) Uchida, T.; Rodriquez, M.; Schreiber, S. L. Org.
Lett. 2009, 11, 1559–1562.
(3) Payne, D. J.; Gwynn, M. N.; Holmes, D. L.; Pompliano, D. L. Nat.
ReV. Drug DiscoVery 2007, 6, 29–40.
(4) Nielsen, T. E.; Schreiber, S. L. Angew. Chem., Int. Ed. 2008, 47,
48–56
.
10.1021/ol100914b  2010 American Chemical Society
Published on Web 05/18/2010

We initiated our study with the preparation of densely
functionalized amides 2a,b6 starting from commercial (R)- and
(S)-phenylalanine.7 The 2-nitrobenzensulphonyl (Ns) group was
chosen both to modulate the pKa of the attached nitrogen to
facilitate subsequent allylation8 and to introduce an additional
chemical handle for the “pair phase” of the pathway.
In the couple phase, an alkynyl moiety was incorporated
by triethylsilylacetylide addition to amides 2a,b, generating
the corresponding R,ꢀ-acetylenic ketones 3a,b in good yield
and without racemization, when temperature and reaction
time were optimized (Scheme 1). Reactions that enable
achieved by reagent- and substrate-controlled site-selective
activation of different pairs of functional groups, strategically
placed on the linear template 1a (Scheme 2). We first
Scheme 2
.
Skeletal Diversty through Functional Group Pairing
Reactions
Scheme 1
.
Synthesis of Diastereoisomeric Amino Propargylic
Alcohols
a Ratio endo/exo ) 10:1.5 was determined by 1H NMR. b Single
stereoisomer. c Intramolecular enyne metathesis product 13a was also
obtained as minor product in 38% yield.
a ee was determined by SFC analysis. b dr was determined by 1H NMR
analysis of the inseparable mixture of the two diastereomers.
investigated enyne metathesis to access a substituted vinyl
tetrahydropyridine-type skeleton, which is poised for further
diversification. We determined that syn-amino propargylic
alcohol (2R,3S)-1a in the presence of second generation
Hoveyda-Grubbs catalyst (5 mol %) under ethylene atmo-
sphere undergoes endo-mode selective cyclization forming
the corresponding cycloheptadiene 5a as the major regioi-
somer (endo:exo selectivity ) 10:1.5).13 Noting the size of
the newly formed ring and the presence of nonsubstituted
alkenyl and alkynyl groups in the substrate,14 we determined
that this unusual result was influenced by the free hydroxyl
group at the propargylic position. Protection of the alcohol
as acetate 6a resulted in exo-mode ring closure to form six-
membered ring diene 7a as the only product. We speculate
that in the latter case the endo-mode RCM is disfavored as
a result of the formation of a sterically hindered alkylidene,
compared to the exo-mode RCM intermediate. Under the
same reaction conditions, the anti-diastereomer (2R,3R)-1b
controlled access to all possible diastereomers are especially
valuable in diversity-oriented synthesis.9 After extensive
experimentation, we determined that the carbonyl diaste-
reotopic faces in (R)-3a and (S)-3b can be differentiated
efficiently by the chirality of CBS-Me-oxazaborolidine,10
overriding the influence of the adjacent nitrogen-substituted
stereogenic center. The reduction of chiral ynone (R)-3a
(98% ee) using the stoichiometric complex (R)-Me-CBS-
oxazaborolidine/BH3THF in dry THF at -78 °C delivered
the syn-amino propargylic alcohol (2R,3S)-4a in excellent
yield and good diastereoselectivity (diasteroisomeric ratio
dr ) 91:9). When (R)-3a was instead reduced with (S)-Me-
CBS-oxazaborolidine/BH3THF, the corresponding anti-
amino propargylic alcohol (2R,3R)-4b was obtained in
comparable yield and diastereoselectivity. Reduction of (S)-
3b (96% ee) under the same reaction conditions provided
(2S,3S)-4c and (2S,3R)-4d, respectively (Scheme 1). In
contrast, reduction of (R)-3a with NaBH4 in MeOH afforded
a 5:1 mixture of anti/syn diastereoisomeric alcohols. Desi-
lylation with a 1:1 molar ratio of TBAF/AcOH efficiently
delivered the key intermediates of the pathway 1a-d.11 The
diastereoisomeric ratio for the anti-products (2R,3R)-1b and
(2S,3S)-1c was increased to 97:3 after a single crystallization.
We next explored a series of intramolecular cyclization
reactions using the syn- and anti-diastereomers 1a,b12 (based
on symmetry, we expect that the same reactions would work
analogously on enantiomers 1c,d, providing products in all
stereochemical combinations). Skeletal diversification was
(6) Experimental procedures to amide derivatives 2a,b are reported in
Supporting Information.
(7) D’Aniello, F.; Mann, A. J. Org. Chem. 1996, 61, 4870–4871.
(8) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36,
6373–6374.
(9) For examples, see: (a) Taylor, M. S.; Jacobsen, E. N. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5368–5373. (b) Balskus, E. P.; Jacobsen, E. N.
Science 2007, 317, 1736–1740. (c) Liu, X.; Henderson, J. A.; Sasaki, T.;
Kishi, Y. J. Am. Chem. Soc. 2009, 131 (46), 16678–16680.
(10) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986–
2012.
(11) Yohannes, D.; Danishefsky, S. J Tetrahedron Lett. 1992, 33, 7469–
7462.
(12) Structures and stereochemistry of all the reported compounds were
determined by detailed spectroscopic analysis, including X-ray structures
of compounds 11a, 13a, and 14a (see Supporting Information).
1
(13) Endo:exo products ratio was determined by H NMR analysis of
the inseparable mixture of the two regioisomers.
Org. Lett., Vol. 12, No. 12, 2010
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yielded a mixture of decomposition products, whereas the
corresponding propargylic acetate 6b delivered 7b in moder-
ate yield as a single stereoisomer (Figure 2).15 Gratifyingly,
50% yield. In contrast, anti-diastereomer 1b rearranged to 10b
with high site- selectivity in presence of diaza-(1,3)-
bicyclo[5.4.0]undecane (DBU) in refluxing THF. When 1a was
treated with NaH in THF, the resultant alkoxide participated in
endocyclic nucleophilic aromatic substitution19 to yield the
seven-membered benzothiazepine derivative 11a. Control of the
temperature between -10 and 0 °C was needed to obtain 11a
selectively in 75% yield. In contrast, anti-diastereomer (2R,3R)-
1b only reacted at room temperature under these conditions,
generating (3R,4R)-11b in moderate yield due to lower selectiv-
ity of the ipso-substitution relative to the Smiles rearrange-
ment.20
To access wider skeletal diversity, we sought to take
advantage of the nonpolar chemical handles still available
on the benzothiazepine core 11a. An enyne metathesis
reaction yielded cross-metathesis product 12a in the presence
of ethylene gas. Intramolecular enyne metathesis product 13a
was obtained selectively in excellent yield by simply treating
the substrate with first-generation Grubbs catalyst (3 mol %)
in dichloromethane at room temperature followed by addition
of lead tetraacetate (15 mol %). The latter was added to
scavenge ruthenium and phosphine impurities.21 The structure
of the bridged ten-membered ring diene was confirmed by X-ray
analysis.12 Diastereoemer 11b only reacted in the presence of
ethylene gas providing the cross-metathesis product 12b as the
major adduct and cyclic diene 13b in combined 58% yield.
Skeletal diversification via PKR on 11a afforded bridged ten-
membered ring cyclopenten-2-enone derivative 14a in moderate
yield as a single stereoisomer. X-ray structure analysis con-
firmed the stereochemistry of this product.12 Diastereoemer 11b
did not undergo the PKR.
Figure 2. Skeletal diversity from anti-amino propargylic alcohol
a
1b. Note: single stereoisomer.
we found that catalytic InCl3 (15 mol %) promoted skeletal
reorganization16 of both syn- and anti-diastereomers 1a,b
under microwave conditions, providing the corresponding
dienes 8a,b as single products in good yield. We investigated
the Pauson-Khand reaction (PKR) as an additional alkyne-
alkene functional group-pairing reaction. After conversion
of amino propargylic alcohol 1a to acetate 6a, the Co2(CO)6
complex derived from 6a was treated with N-methylmor-
pholine N-oxide17 at room temperature to provide cyclo-
penten-2-enone derivative 9a with excellent stereoselectivity.
Similarly, diastereomer 6b formed PKR product 9b stereo-
selectively. The stereochemistry of 9a and 9b was determined
by NOE analyses.12 The benzyl substituent influenced the
diastereofacial control of cyclization, whereas the acetoxy-
substituted stereogenic center provided virtually no directing
effect.
We sought to quantify the extent to which the aforementioned
intramolecular cyclizations access different overall molecular
shapes. To obtain a simple assessment of diversity in molecular
shape among the compounds studied, we calculated normalized
principal moment-of-inertia (PMI) ratios,22 plotted as two-
dimensional characteristic coordinates (Ismall/Ilarge, Imedium/Ilarge
)
for compounds 1a and 5a-14a (Figure 3A). Points in the
resulting graph occupy an isosceles triangle defined by the
vertices (0,1), (0.5,0.5), and (1,1), corresponding to the shapes
of rod, disk, and sphere, respectively.
For 1a and 5a-14a, we observe a band covering the space
between the rod- and disk-like regions of the PMI space; 1a
is centrally located in this band, and its direct reaction
products, 5-6a, 8a, and 10-11a, span nearly the range of
rod- and disk-like shapes among all 11 compounds. However,
further cyclization of 6a to produce 7a and 9a results in the
two most disk-like of all 11 compounds, though each is
similar in shape to its precursor 6a. Further reaction of 11a
to produce 12-14a similarly results in the three most sphere-
like among the 11 compounds. In contrast to cyclization of
6a, these modifications of 11a result in relatively large overall
changes in shape.
We next examined polar/polar functional group-pairing
reactions for further skeletal diversification (Scheme 2). Treat-
ment of 1a with tetrabutylammonium fluoride (TBAF) in THF
at 0 °C provided the Smiles rearrangement18 product 10a in
(14) For the definition of endo/exo-mode selectivity in enyne RCM and
recent examples, see: (a) Hansen, E. C.; Lee, D. Acc. Chem. Res. 2006, 39,
509–519. (b) Lee, Y.-J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem.
Soc. 2009, 131, 10652–10661. (c) Hansen, E. C.; Lee, D. J. Am. Chem.
Soc. 2003, 125, 9582–9583.
(15) Experimental reaction conditions to obtain skeletons 6-13b are
reported in Supporting Information.
(19) Kleb, K. G. Angew. Chem., Int. Ed. 1968, 7, 291.
(20) Zhou, A.; Rayabarapu, D.; Hanson, P. R. Org. Lett. 2009, 11, 531–
534.
(16) (a) Lee, S. I.; Chatani, N. Chem. Commun. 2009, 371–384. (b)
Miyanohana, Y.; Chatani, N. Org. Lett. 2006, 8, 2155–2158.
(17) Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Tetrahedron Lett.
1990, 31, 5289–5292.
(21) Paquette, L. A.; Schloss, J. D.; Efremov, I.; Fabris, F.; Gallou, F.;
Mendezo-Andino, J.; Yang, J. Org. Lett. 2000, 2, 1259–1261.
(22) Sauer, W. H.; Schwarz, M. K. J. Chem. Inf. Comput. Sci. 2003,
43, 987–1003.
(18) Yeom, C.-E.; Kim, H. W.; Lee, S. Y.; Kim, B. M. Synlett 2007, 1,
146–150.
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Org. Lett., Vol. 12, No. 12, 2010

We also used PMI ratio analysis to quantify the extent to
which diastereomeric products 1b and 6b-13b differ from
their counterparts 1a and 6a-13a (Figure 3B). We quantified
the PMI distance between matched pairs and observed the
largest such differences for compounds 12a,b (da-b ) 0.364),
11a,b (da-b ) 0.211), and 10a,b (da-b ) 0.116). Interestingly,
for 11 and 12, the a diastereomer is more disk-like, which
may be due to extended conformations of acyl and allyl
groups perpendicular to the rod-like structure of the molecule,
whereas b is more rod-like; the converse is true for 10, where
an opposite relationship is observed. The minimum difference
we observed was for the pair of amino propargylic alcohols
1a,b (da-b ) 0.008), which makes sense due to the short,
linear hydroxyl substituent at one of the stereocenters. A
similar trend was observed for other compounds with small
substituents, e.g., in the case of 13a,b, where only the
hydrogen atom at the bridge position is inverted.
To compare additional compounds prospectively available
from this chemistry to compounds from other sources (Figure
3C), we enumerated a virtual library of compounds that
would be obtained by substituting starting phenylalanines
with alternative amino acids to give 6 additional R-groups
(bromobenzyl, hydroxymethyl, o-TBS-ethyl, p-hydroxyben-
zyl, p-azidobenzyl, hydroxyethyl) at carbon 2. We compared
the resulting 140-compound library to 140 diverse com-
pounds selected23 from each of two sources: commercial
compounds (CC) typical of those found in many screening
collections and natural products (NP).24 We note that CC
compounds cover the left edge of the PMI space, taking
shapes intermediate between rods and discs, whereas NP
compounds distribute more evenly over the space and
populate the intermediate region between disk- and sphere-
like shapes. By comparison, the virtual products from this
chemistry also provide more broad coverage of the space
and include several products among the most sphere-like of
all compounds compared.
We initiated this research with the hypothesis that accessing
stereoisomers of skeletally diverse compounds will facilitate
small-molecule probe and drug discovery efforts. This new DOS
pathway will enable further testing of this hypothesis. This work
also provides a framework for understanding the consequences
of different synthetic decisions in the “pair phase” of build/
couple/pair synthesis strategies using PMI shape analysis to
understand changes in shape brought about by different in-
tramolecular cyclizations. The analysis of small-molecule
screening results using these compounds should enable us to
link shape analyses and synthetic decisions to biological assay
outcomes in the future.
Acknowledgment. The NIGMS-sponsored Center of Excel-
lence in Chemical Methodology and Library Development (P50-
GM069721) enabled this research. We are grateful to Dr. Peter
Muller at MIT for X-ray crystallographic analysis, and Emeline
Tissot and Christopher Johnson at the Broad Institute for help
with SFC/MS. D.P. thanks Yikai Wang and Dr. Giovanni
Muncipinto at the Department of Chemistry and Chemical
Biology (Harvard University), Dr. Manuela Rodriquez currently
at the Department of Pharmacological Sciences (University of
Salerno), and Dr. Masaaki Hirano currently at Astellas Pharma
Inc. for helpful discussions. S.L.S. is an investigator with the
Howard Hughes Medical Institute.
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.
Figure 3. Molecular shape analysis. (A) PMI plot depicting
relationships between compounds 1a and 5a-14a shown in Scheme
2. Substrate-product relationships are indicated with matched colors
between product markers and circles around substrate markers. (B)
PMI plot showing shape differences between diastereomeric pairs
a (9) and b (+) for compounds 1 and 6-13. Distances between
pairs are listed in decreasing order, and the three most distant pairs
are noted by arrows. (C) PMI plot comparing virtual library based
on the Scheme 2 (see text) with subsets of molecules of different
origins: commercial compounds (CC), natural products (NP).
OL100914B
(23) Diverse selections were made from a larger collection using the
“Diverse Molecules” component of Pipeline Pilot (Scitegic, Inc.) and the
ECFP4 molecular fingerprints.
(24) Clemons, P. A.; Bodycombe, N. E.; Carrinski, H. A.; Wilson, J. A.;
Wagner, B. K.; Koehler, A. N.; Schreiber, S. L. Manuscript submitted.
Org. Lett., Vol. 12, No. 12, 2010
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