Bespoke SnAP reagents for the synthesis of c-substituted spirocyclic and bicyclic saturated N-heterocycles

Article abstract of DOI:10.1021/acs.orglett.5b00618

The precise placement of C-substituents on bicyclic and spirocyclic N-heterocycles is readily achieved by the combination of aldehydes and new SnAP reagents. The substituted SnAP reagents are readily prepared from simple starting materials and couple with

Full text of DOI:10.1021/acs.orglett.5b00618

Letter
pubs.acs.org/OrgLett
Bespoke SnAP Reagents for the Synthesis of C‑Substituted
Spirocyclic and Bicyclic Saturated N‑Heterocycles
Kimberly Geoghegan and Jeffrey W. Bode*
Laboratorium fur Organische Chemie, Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir Prelog Weg 3,
̈
̈
CH-8093 Zurich, Switzerland
̈
S
* Supporting Information
ABSTRACT: The precise placement of C-substituents on bicyclic
and spirocyclic N-heterocycles is readily achieved by the
combination of aldehydes and new SnAP reagents. The substituted
SnAP reagents are readily prepared from simple starting materials
and couple with a variety of aromatic and heteroaromatic aldehydes
at room temperature under operationally simple conditions to
deliver substituted morpholine and piperazine products.
Scheme 1. Synthesis of SnAP Reagents 3−5
ull exploration of chemical space in the design and
1
Fdevelopment of small-molecule drugs requires the rapid
Scheme 2. Synthesis of SnAP Reagents 9 and 10
Figure 1. Unsubstituted and substituted bis-amino spirocycles.
assembly of suitable frameworks from readily available
components. In recent years, medicinal chemists have recognized
the distinct advantages of saturated N-heterocycles,2 which were
represented in 42% of all small-molecule new molecular entities
introduced between 2009 and 2013. Looking forward,
considerable attention is focused on spirocyclic and bicyclic
scaffolds,3 as these constructs provide even greater opportunities
for the fine-tuning of substituent groups while still providing a
rigid, metabolically robust framework with low molecular
weight.4
commercially available examples, typically by amide formation or
other C−N bond-forming reactions.6 The true potential of
spirocycles for precise positioning of substituents on a rigid
scaffold requires a means of incorporating substituent groups
onto one of the carbon atoms (Figure 1). The introduction of a
single C-substituent dramatically increases the number of
At the present time, the use of spirocyclic and bicyclic
Received: March 1, 2015
Published: March 30, 2015
scaffolds5,13,14 is largely limited to the derivatization of a few
© 2015 American Chemical Society
1934
DOI: 10.1021/acs.orglett.5b00618
Org. Lett. 2015, 17, 1934−1937

Organic Letters
Letter
a
Scheme 3. Synthesis of Spirocyclic Morpholines from SnAP Reagents
a
All reactions were performed using 1 equiv of SnAP reagent, 1 equiv of Cu(OTf)2, 1 equiv of 2,6-lutidine in 4:1 CH2Cl2/HFIP at rt for 15 h. Yields
shown are of isolated, analytically pure products following column chromatography. MS = molecular sieves. HFIP = 1,1,1,3,3,3-hexafluoro-2-
1
propanol. [a] Diastereomeric ratio (dr) was determined by H NMR analysis of purified products.
potential structures, but the lack of effective synthetic methods
has hampered the implementation of this seductive approach to
drug development. Exciting methodologies for derivatizing
saturated N-heterocycles by radical and C−H functionalization
reactions promise to provide new entries,7 but the current
approaches have either not been extended to spirocyclic systems
Figure 2. Additional custom SnAP reagents prepared by analogous
methods (see Supporting Information for details).
or require the use of N-substituents that limit the utility of the
resulting products.8
As part of our efforts to provide a cross-coupling approach to
the rapid construction of substituted, saturated N-heterocycles,
1935
DOI: 10.1021/acs.orglett.5b00618
Org. Lett. 2015, 17, 1934−1937

Organic Letters
Letter
morpholine) (4) and SnAP 2-spiro-(4-piperdine) morpholine
(5), both containing a cyclic moiety on the 3-position of the
SnAP skeleton, were prepared via the corresponding amino
alcohols.16
The regioisomeric SnAP reagent 9, SnAP 2-spiro-(4-
piperdine) morpholine, could be accessed from N-Boc
piperidone 6 (Scheme 2). Cyanohydrin formation (93% yield)
followed by nitrile reduction and trityl protection of the resulting
primary amine afforded compound 8 (77% isolated yield from
cyanohydrin 7). Alkylation using our standard conditions
provided N-trityl-protected SnAP 9 in 96% yield. In this
synthetic route, amine protection was necessary as N-alkylation
is a competitive reaction. Deprotection was effected using a
mixture of CH2Cl2/TFE/AcOH to provide SnAP reagent 9 in
76% yield. The identical synthetic route was applied to the
synthesis of the five-membered ring SnAP 2-Spiro-(2-Pyr) M
(10), starting from N-Boc pyrrolidinone (5 steps, 52% yield).
With the new SnAP reagents in hand, we examined their use in
the formation of C-substituted spirocycles with a range of
aldehydes. Pleasingly, the standard conditions used for SnAP
cyclization (1 equiv of Cu(OTf)2, 1 equiv of 2,6-lutidine,
CH2Cl2/HFIP) gave the desired spirocyclic morpholine
products in moderate to excellent yields (Scheme 3). No special
precautions were necessary for the reaction setup, and all
experiments were performed using identical reaction conditions
without substrate-specific optimization. Aldehydes containing
functional groups including esters (11a, 13b, 14a, 15a, and 15c),
aldehydes (14d), and aryl halides (11d) enable the production of
scaffolds suitable for further elaboration. The tolerance of aryl
MIDA ester (20d) is noteworthy, as these substrates could
potentially undergo oxidation in the presence of copper. When
SnAP reagent 10 was employed, the resulting products were
isolated as a mixture of diastereomers.17 SnAP reagents 3, 9, and
10 contain a Boc-protected nitrogen atom within the appended
ring, providing an additional exit vector for subsequent
modification.5b,18 The ability to construct regioisomeric
products, such as 11a and 14a, where the piperidine ring has
been shifted along the ethylene backbone demonstrates the
suitability of these reagents for structure−activity relationship
studies since they readily enable the subtle modification of the
substituent spatial arrangements.6a,b
Oxetanes have become a popular functional group for drug
discovery and have proven useful as surrogates for carbonyl and
gem-dimethyl groups.19 SnAP 3-SpirOx M (4) allows rapid
access to oxetane-containing compounds (12a,b) in good yields.
The protected diol in SnAP reagent 5 offers access, in good yield,
to morpholines 13a and 13b, which are poised for further
elaboration.
Similar approaches were used for the preparation of
piperazine-forming SnAP reagent 16 and bicyclo-forming
reagents 17 and 18 (Figure 2). These custom SnAP reagents
were coupled with aldehyde partners to give spirocyclic
piperazines (19a,b) and bicyclic morpholines (20 and 21)
(Figure 3). When SnAP reagent 17 was employed, the
diastereomeric ratio of the resulting products varied depending
on the aldehyde used; in all cases, the major isomer could be
identified as the structures shown in Figure 3 based on X-ray
crystallographic analysis of compound 20a. Diastereomerically
pure bicycles (21a−d, dr >20:1) could be obtained using
enantiomerically pure SnAP reagent 18. A ketone was also a
viable substrate and provided tetracycle 21e, albeit in somewhat
diminished yield.
Figure 3. Synthesis of piperazines and bicyclic compounds. All reactions
were performed using 1 equiv of SnAP reagent, 1 equiv of Cu(OTf)2, 1
equiv of 2,6-lutidine in 4:1 CH2Cl2/HFIP at rt for 15 h. Yields shown are
of isolated, analytically pure products following column chromatog-
raphy. The dr was determined by H NMR analysis of unpurified
reaction mixtures.
1
we have introduced SnAP (stannyl (Sn) amine protocol)
reagents for the one-step conversion of aldehydes and ketones
into N-unsubstituted thiomorpholines,9 morpholines, pipera-
zines,10 diazepanes,11 and related heterocyclesincluding
unsubstituted spirocycles.12−14 These SnAP reagents serve as
cross-coupling surrogates for the parent N-heterocycles and can
be easily prepared in a few steps; several are commercially
available. We envisaged the preparation of more elaborate SnAP
reagents that could be used as cross-coupling partners with
aldehydes to form C-substituted bicyclic and spirocyclic
structures. In this communication, we report eight such SnAP
reagents and their application to the one-step preparation of
substituted bicyclic and spirocyclic morpholines and piperazines.
At the outset of our studies, we identified two initial targets,
SnAP reagent 3 and its regioisomer 9, which would form two
distinct spirocyclic morpholines joined to a N-Boc-protected
piperidine. Our first customized SnAP reagent 3 was derived
from amino alcohol 2, which could be prepared from the
commercially available amino acid 1 (Scheme 1). Alkylation of
the amino alcohol (ICH2SnBu3/NaH) afforded SnAP 2-spiro-
(4-piperdine) morpholine (3) in 95% isolated yield. The
alkylation reaction was successfully carried out in the presence
of an unprotected primary amine. Two other structurally related
SnAP reagents, SnAP 3-SpirOx M (SnAP 3-spiro-oxetane
1936
DOI: 10.1021/acs.orglett.5b00618
Org. Lett. 2015, 17, 1934−1937

Organic Letters
Letter
Edwards, H.; Hunt, F.; Kindon, N.; Pairaudeau, G.; Theaker, J.; Warner,
D. J. Bioorg. Med. Chem. Lett. 2010, 20, 7458−7461.
(7) For reviews on the direct functionalization of N-heterocycles, see:
(a) Mitchell, E. A.; Peschiulli, A.; Lefevre, N.; Meerpoel, L.; Maes, B. U.
W. Chem.Eur. J. 2012, 18, 10092−10142. (b) Campos, K. R. Chem.
Soc. Rev. 2007, 36, 1069−1084.
In summary, we have demonstrated that bespoke SnAP
reagents are readily prepared and suitable for the synthesis of
substituted bicyclic and spirocyclic morpholines and piperazines.
Despite the more elaborate SnAP reagents, the key cyclization
occurs under the same standard, operationally simple conditions
previously established for monosubstituted N-heterocycles. This
work demonstrates the remarkably broad substrate scope of
SnAP chemistry, with respect not only to the aldehyde but also to
more elaborate SnAP reagents themselves. Although our strategy
does not provide access to all possible classes of bicyclic N-
heterocycles or all positional and structural isomers of C-
substituted bicyclic and spirocyclic N-heterocycles, it offers a
reliable and predictable route to a significant proportion of the
scaffolds currently in demand for modern drug development.
(8) For a recent review on the synthesis of N-heterocycles, see: Vo, C.-
V. T.; Bode, J. W. J. Org. Chem. 2014, 79, 2809−2815 and references
therein.
(9) Vo, C.-V. T.; Mikutis, G.; Bode, J. W. Angew. Chem., Int. Ed. 2013,
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(10) Luescher, M. U.; Vo, C.-V. T.; Bode, J. W. Org. Lett. 2014, 16,
1236−1239.
(11) Vo, C.-V. T.; Luescher, M. U.; Bode, J. W. Nat. Chem. 2014, 6,
310−314.
(12) Siau, W.-Y.; Bode, J. W. J. Am. Chem. Soc. 2014, 136, 17726−
17729.
ASSOCIATED CONTENT
* Supporting Information
■
(13) For examples of two-component cross-coupling reactions that
afford spirocyclic compounds, see: (a) Barroso, R.; Valencia, R. A.;
Cabal, M.-P.; Valdes, C. Org. Lett. 2014, 16, 2264−2267. (b) Reddy, B.
́
V. S.; Medaboina, D.; Sridhar, B.; Sinarapu, K. K. J. Org. Chem. 2014, 79,
2289−2295. (c) Prandi, C.; Deagostino, A.; Venturello, P.; Occhiato, E.
G. Org. Lett. 2005, 7, 4345−4348. (d) Zhou, J.; Zhou, L.; Yeung, Y.-Y.
Org. Lett. 2012, 14, 5250−5253. (e) Yin, X.-P.; Zeng, X.-P.; Liu, Y.-L.;
Liao, F.-M.; Yu, J.-S.; Zhou, F.; Zhou, J. Angew. Chem., Int. Ed. 2014, 53,
13740−13745.
(14) For another approach to the synthesis of saturated spirocycles,
see: Perry, M. A.; Hill, R. R.; Rychnovsky, S. D. Org. Lett. 2013, 15,
2226−2229.
(15) For the synthesis and uses of 1,7-diazaspiro(5.5)undecane, see:
Cordes, J.; Murray, P. R. D.; White, A. J. P.; Barrett, A. G. M. Org. Lett.
2013, 15, 4992−4995.
(16) The amino alcohol for the synthesis of SnAP reagent 4 is
commercially available. For the synthesis of amino alcohol for SnAP
S
Detailed experimental procedures, NMR spectra, X-ray analysis,
and characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: bode@org.chem.ethz.ch.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by European Research Council (ERC
Starting Grant No. 306793−CASAA and ERC Proof of Concept
Grant No. 620214−SnAP). We thank the LOC Mass
Spectrometry Service, the LOC NMR Service, and the Small
reagent 5, see: Antoni, P.; Hed, Y.; Nordberg, A.; Nystrom, D.; von
̈
Holst, H.; Hult, A.; Malkoch, M. Angew. Chem., Int. Ed. 2009, 48, 2126−
2130.
Molecule Crystallography Center of ETH Zurich for X-ray
(17) The diastereomeric ratio (dr) of these products was not easy to
assign from the 1H NMR spectra of the crude reaction mixtures, due to
rotamers. However, these diastereomers could be separated by HPLC.
(18) Rogers-Evans, M.; Knust, H.; Plancher, J.-M.; Carreira, E. M.;
̈
measurements. Guido Moller (ETH Zurich) is acknowledged for
̈
̈
amino alcohols S1 and S2.
Wuitschik, G.; Burkhard, J.; Li, D. B.; Guer
499.
́
ot, C. Chimia 2014, 68, 492−
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DOI: 10.1021/acs.orglett.5b00618
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