Efficient Routes to a Diverse Array of Amino Alcohol-Derived Chiral Fragments

Article abstract of DOI:10.1021/acscombsci.6b00050

Efficient syntheses of chiral fragments derived from chiral amino alcohols are described. Several unique scaffolds were readily accessed in 1-5 synthetic steps leading to 45 chiral fragments, including oxazolidinones, morpholinones, lactams, and sultams. These fragments have molecular weights ranging from 100 to 255 Da and are soluble in water (0.085 to >15 mM).

Full text of DOI:10.1021/acscombsci.6b00050

Research Article
pubs.acs.org/acscombsci
Efficient Routes to a Diverse Array of Amino Alcohol-Derived Chiral
Fragments
Sina Haftchenary,†,‡,∇ Shawn D. Nelson, Jr.,†,‡ Laura Furst,† Sivaraman Dandapani,† Steven J. Ferrara,†
†,‡
Zarko V. Boskovic, Samuel Figueroa Lazu,† Adrian M. Guerrero,† Juan C. Serrano,†
̌
̌
́
́
DeMarcus K. Crews,† Cristina Brackeen,† Jeffrey Mowat,§ Thomas Brumby,§ Marcus Bauser,§
Stuart L. Schreiber,*,†,‡,⊥ and Andrew J. Phillips*,#,¶
#Center for the Development of Therapeutics, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, United States
†Center for the Science of Therapeutics, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, United States
‡Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United
States
§Bayer Pharma AG, Drug Discovery, Mullerstraße, 178, 13353 Berlin, Germany
̈
⊥Howard Hughes Medical Institute, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, United States
S
* Supporting Information
ABSTRACT: Efficient syntheses of chiral fragments derived from chiral amino alcohols are described. Several unique scaffolds
were readily accessed in 1−5 synthetic steps leading to 45 chiral fragments, including oxazolidinones, morpholinones, lactams,
and sultams. These fragments have molecular weights ranging from 100 to 255 Da and are soluble in water (0.085 to >15 mM).
KEYWORDS: amino alcohols, fragment-based lead discovery, chiral fragments, drug discovery
proportion of sp3-hybridized atoms may be beneficial.3,4 Here,
INTRODUCTION
■
we describe initial efforts to access sp3-rich chiral fragments
Fragment-based ligand discovery (FBLD) has emerged as a
from chiral amino alcohols, a class of starting materials
valuable complement to high-throughput screening over the
advantaged by commercial availability, diversity of additional
past decade and has produced clinical-stage candidates (Figure
functional groups, and well-understood reactivity with electro-
1), as well as the FDA-approved drugs vemurafenib and
philes.
venetoclax.1−3 The rise of FBLD has been underpinned by
methodological advances in the discovery of fragments hits by
biophysical screening methods such as nuclear magnetic
RESULTS AND DISCUSSION
■
resonance (NMR), surface plasmon resonance (SPR), calorim-
etry, mass-spectrometry (MS) and X-ray crystallography. In
contrast, the chemical features and optimal properties of
fragments remain an area of debate and unresolved challenges.2
For instance, some fragments available from commercial
vendors are limited by their poor solubility in water and lack
of appropriate functionality for rapid fragment growth. Many
commercial fragment collections are enriched in aromatic and
heteroaromatic compounds, therefore expanding existing frag-
ment chemical space by making compounds with a higher
We synthesized low molecular weight 5-, 6- and 7-membered
cyclic scaffolds from 1,2-amino alcohols and measured their
aqueous solubilities to evaluate their potential for use in FBLD.
Since thousands of enantioenriched 1,2-amino alcohols are
already commercially available or easily obtained through
modern asymmetric synthesis,5−9 chemical pathways and
Received: April 6, 2016
Revised: July 18, 2016
© XXXX American Chemical Society
A
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Figure 1. Representative examples of clinical-stage and approved compounds originating from FBLD.
a
solubility data reported in this article will encourage the
production of more diverse and larger sub-libraries.
Scheme 1
A representative selection of nine amino alcohols (Figure 2)
were selected to pilot the synthesis of diverse skeletons. Amino
Figure 2. Structures of the representative chiral (or spiro) amino
alcohol building blocks.
alcohols 1-4 were chosen to explore the effects of both aliphatic
and aromatic substituents on the carbon atom alpha to the
amine or alcohol across all scaffolds. Amino alcohols 5-710
explore the role of secondary amines while 8 and 911 represent
simple amino alcohols that can result in polar spirocyclic
fragments with additional heteroatoms. The goal of this study
was to “de-risk” the chemistry involved in accessing various
scaffolds with a limited set of amino alcohols and to evaluate
the suitability of the resulting fragments for FBLD by
experimentally determining their aqueous solubilities.
Oxazolidinones 10a−g (Scheme 1) were straightforward to
prepare by previously reported approaches or modifications
thereof.12−18 In general, amino alcohols could be treated with
carbonyldiimidazole and triethylamine (Et3N), followed by
heating at 60 °C overnight to afford the desired compounds in
low to high yields (28−85%). Alternatively, oxazolidinones 10a
and 10b were obtained in high yields (84%) by treatment of the
neat amino alcohol with diethylcarbonate and a substoichio-
metric amount of sodium ethoxide at temperatures between
135 and 150 °C. Morpholinones 11a−f were synthesized by a
similarly direct process in which the amino alcohols were
treated with sodium hydride and ethyl chloroacetate at room
temperature overnight to afford the morpholinone analogs in
variable yields (19−82%).19 Morpholinones 11g and 11h were
a
Reaction conditions: (A) CDI, Et3N, THF, 60 °C, 24 h, 27−85%;
(B) NaH; ethyl chloroacetate, THF, rt, 24 h, 19−82%; (C) (i) Boc2O,
Et3N, DCM, 0 °C, rt, 24 h, 83-99%; (ii) SOCl2, imidazole, Et3N,
DCM, −40 °C, 2 h; then at rt for 2 h, 55−94%; (iii) RuCl3, NaIO4,
MeCN:H2O (1:1), 0 °C to rt, 3 h, 31−95%; (iv) TFA, DCM, rt, 24 h,
66−90%; (D) (i) ClCH2SO2Cl, Et3N, DCM, 0 °C to rt, 6 h, 34-84%;
(ii) PMB-Br, K2CO3, DMF, rt, 1 h, 17−89%; (iii) Cs2CO3, DMF, 80
°C, 24 h, 55−78%; (iv) CAN, MeCN:H2O (9:1), rt, 24 h, 24−78%;
(E) (i) Boc2O, Et3N, DCM, 0 °C, rt, 24 h, 83−99%; (ii) t-butyl
acrylate, Cs2CO3, t-BuOH, 24 h, 75−99%; (iii) 4.0 M HCl in dioxane,
24 h, 97−99%; (iv) T3P, Et3N, dioxane, 24 h, rt, 33−86%; (F) (i)
TBS-Cl, Et3N, DCM, 0 °C to rt, 24 h, 71−95%; (ii) chloroethane
sulfonyl chloride, Et3N, 0 °C to rt, 2 h, 75−95%; (iii) MeI, K2CO3,
MeCN, 72 h, 70−90%; (iv) TBAF, THF, 2 h, 38−91%.
prepared using an alternative methodology in which the amino
alcohols were treated with chloroacetyl chloride at room
temperature, followed by intramolecular cyclization with
sodium hydride at temperatures between 65 and 80 °C (18−
22%).20 Conveniently, morpholinones 11c, 11d, 11f, and 11g,
were transformed to morpholines 11i−l in low to good yields
(23−75%) by direct reduction of the lactam with lithium
aluminum hydride at room temperature (those not shown were
not attempted or were readily commercially available).21,22
B
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Figure 3. Readily prepared pilot collection of 45 chiral amino alcohol-derived fragments presented with overall yields and solubility data (nd = not
determined). Compounds with >0.50 mM solubilities were exposed to an assay with a 0.50 mM upper limit (see Supporting Information). (a)
Amino alcohol 7 was explored solely for the 7-membered lactam family of compounds.
Sulfamidates 12a, 12b, and 12d were obtained by a four step
sequence as outlined in Scheme 1.23,24 Protection of the amine
as the t-butoxycarbonyl (Boc) carbamate and reaction with
thionyl chloride in the presence of imidazole and triethylamine
at −40 °C afforded the desired cyclic sulfamidite in modest to
high yields (55−94%). The sulfamidite was subsequently
oxidized using catalytic ruthenium(III) chloride and an excess
of sodium periodate in acetonitrile to afford the protected
sulfamidates. Removal of the Boc protecting group with
trifluoroacetic acid afforded the desired sulfamidates (12a,
12b, and 12d) in good to high yields (66−90%). The N-
benzylated sulfamidate 12c was prepared with an analogous
approach in modest yields (40%) by treatment of the N-benzyl
amino alcohol with thionyl chloride, imidazole, and triethyl-
amine at −40 °C, followed by oxidation with catalytic
ruthenium(III) chloride and sodium periodate in acetonitrile
(products derived from amino alcohols 1, 2, 7, 8, and 5 were
not investigated).
Our initial efforts to synthesize low molecular weight sultams
commenced with the straightforward preparation of the α-
chlorosulfonamide by treatment of amino alcohols with
chloromethanesulfonyl chloride under basic conditions (20−
84%). In accordance with previous observations on analogous
systems by Borcard and colleagues,25 we observed that direct
cyclization attempts from this intermediate were ineffective and
resulted in poor conversion and polymeric products. These
synthetic challenges were readily overcome by selective
protection of the sulfonamide nitrogen with a p-methoxybenzyl
(PMB) group (17−98%) and subsequent cyclization under
basic conditions (55−87%). The PMB protecting group was
readily removed by ceric ammonium nitrate (CAN) in a 9:1
mixture of acetonitrile and water to produce 13a-g in low to
C
DOI: 10.1021/acscombsci.6b00050
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a
Scheme 2. Synthetic Route to Expanded Product Library Derived from 11c as a Representative Example
a
Reaction conditions: (i) Lawesson’s reagent, THF, 55 °C, 3 h, 78%; (ii) RCONHNH2, t-BuOH, 135 °C, 24 h, 39-63%. Aqueous solubility data is
show in parentheses.
good yields (24−78%); 2,3-dichloro-5,6-dicyano-p-benzoqui-
none (DDQ) was wholly ineffective for this deprotection.
Limited literature precedent exists for the synthesis of 7-
membered chiral lactams from amino alcohols.26 Treatment of
amino alcohols with acryloyl chloride followed by intra-
molecular oxa-conjugate addition has been studied for accessing
7-membered lactams but this approach is plagued by ineffective
cyclizations and poor yields.27,28 Here, we report an efficient
route that furnishes the desired analogues, 14a−f, 14h, and 14i
in four-steps. After N-Boc protection of the amino alcohols,
treatment with t-butyl acrylate and cesium carbonate (Cs2CO3)
in t-butanol (t-BuOH) at 50 °C yielded the desired conjugate
addition products in good to high yields (75−99%). Next, a
global deprotection was performed using hydrochloric acid
(HCl) in dioxane to afford the amine hydrochloride salts in
high yields yields (97−100%). The intermediate salts were
surveyed for optimal intramolecular amidation conditions
which were achieved upon treatment with propylphosphonic
anhydride (T3P) in dioxane and stirring at room temperature
for 24 h. As such, analogs 14a−f, 14h, and 14i were prepared in
modest to high yields (33−83%). Compared to existing
methods for accessing these 7-membered rings that require
high heat and pressure,29 the T3P-mediated cyclization
reported here proceeds at ambient conditions and hence
represents an advance. Given the mild conditions, we anticipate
broader substrate scope for the T3P-mediated access to 7-
membered ring lactams.
We then investigated the utility of our chiral fragments as
starting points for further diversification. For example,
compound 11c was transformed into an array of extended
triazole products via thiolactam intermediates (Scheme 2).
Following a modified procedure from Wishka and Walker,33
two thiolactams 16 and 17 were obtained in 78 and 48% yield,
respectively, upon treatment with Lawesson’s reagent. Con-
version of 16 into triazoles 18−20 was accomplished by heating
in an excess of the appropriate hydrazide in t-BuOH for 24 h
(39-63%).34
CONCLUSION
■
In conclusion, we have developed facile and convenient
synthetic routes to several families of unique and water-soluble
amino alcohol-derived chiral fragments. A total of 45
compounds including chiral morpholines, lactams, sultams,
and sulfamidates were synthesized in 1-5 synthetic steps. These
chiral fragments are characterized by low molecular weights
(100−255 Da) and aqueous solubilities in the range of 0.085 to
>15 mM which are important criteria among compounds useful
for FBLD.35
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscombs-
ci.6b00050.
The 7-membered sultams (Scheme 1, 15a−h) were
synthesized by a modified protocol in accord with the
precedent of Zhou and colleagues.30,31 After protection of the
alcohol as the t-butyldimethylsilyl (TBS) ether, treatment with
2-chloroethanesulfonyl chloride in the presence of excess Et3N
yielded the vinyl sulfonamide intermediates in good to high
yields (60−98%). In order to promote intramolecular
cyclization, all secondary vinyl sulfonamides were methylated
to afford N-Me-sulfonamides (70-90%). Lastly, intramolecular
cyclizations were achieved in a one-pot fashion via tetra-n-
butylammonium fluoride (TBAF) promoted TBS cleavage,
followed by hetero-conjugate addition to afford the desired
sultams 15a−h in low to high yields (37−97%). No reaction
was observed with secondary sulfonamides. We postulate the
favorable s-trans conformation of the secondary sulfonamides
hinders the cyclization reaction.
Overall, we prepared a library of 50 (Figure 3, Schemes 1 and
2) chiral amino alcohol-derived fragments using the method-
ologies described above and amino alcohols chosen from the
set shown in Figure 1. All of the prepared compounds were
evaluated in an aqueous solubility assay using either LC-MS/
MS or UV for quantification.32 As displayed in Figure 3 and
Scheme 2, the aqueous solubilities ranged from 0.085 to >15
mM.
Information on compound synthesis, characterization,
detailed results, experimental procedures, and spectra
(PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: stuart_schreiber@harvard.edu.
*E-mail: aphillips@c4therapeutics.com.
■
Present Addresses
∇S.H.: GlaxoSmithKline, 7333 Mississauga Road, Mississauga,
Ontario, L5N 6L4, Canada
¶A.J.P.: C4 Therapeutics, Inc., 675 West Kendall Street,
Cambridge, Massachusetts 02142, United States
Author Contributions
S.H. and S.D.N. contributed equally. The manuscript was
written through contributions of all authors.
Funding
Support of this research was provided by the NIGMS
(GM038627), NSERC Canada (postdoctoral fellowship
awarded to S.H), and Bayer Pharma AG. S.L.S. is an
Investigator at the Howard Hughes Medical Institute
̌
(HHMI) and Z.V.B. is an HHMI Postdoctoral Associate.
S.D.N. is funded in part by Harvard University’s Graduate Prize
D
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors are grateful for contributions from Ursula Krenz
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■
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DOI: 10.1021/acscombsci.6b00050
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