Spirocyclic amino alcohol building blocks prepared via a Prins-type cyclization in aqueous sulfuric acid

Article abstract of DOI:10.1016/j.tetlet.2016.06.054

A convenient Prins cyclization of various azacycloalkanones with homoallylic alcohol was achieved in aqueous sulfuric acid. The formal four-center, three-component reaction provides a facile and flexible entry into a range of spirocyclic amino alcohols wh

Full text of DOI:10.1016/j.tetlet.2016.06.054

Accepted Manuscript
Spirocyclic Amino Alcohol Building Blocks Prepared via a Prins-Type Cycli-
zation in Aqueous Sulfuric Acid
Alexey Lukin, Darya Bagnyukova, Natalya Kalinchenkova, Nikolay Zhurilo,
Mikhail Krasavin
PII:
S0040-4039(16)30723-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.06.054
TETL 47781
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 May 2016
6 June 2016
13 June 2016
Please cite this article as: Lukin, A., Bagnyukova, D., Kalinchenkova, N., Zhurilo, N., Krasavin, M., Spirocyclic
Amino Alcohol Building Blocks Prepared via a Prins-Type Cyclization in Aqueous Sulfuric Acid, Tetrahedron
Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.06.054
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Spirocyclic Amino Alcohol Building Blocks Prepared via a Prins-
Type Cyclization in Aqueous Sulfuric Acid
Alexey Lukin, Darya Bagnyukova, Natalya Kalinchenkova, Nikolay Zhurilo, and Mikhail
Krasavin*

Spirocyclic Amino Alcohol Building Blocks Prepared via a Prins-
Type Cyclization in Aqueous Sulfuric Acid
Alexey Lukin,a Darya Bagnyukova,a Natalya Kalinchenkova,a Nikolay Zhurilo,a and Mikhail
Krasavin*,b
a
Lomonosov Institute of Fine Chemical Tehnologies, Moscow Technological University, 86
Vernadskogo Prospekt, Moscow, 117571 Russian Federation
b Saint Petersburg State University, Saint Petersburg, 199034 Russian Federation
* Corresponding author; phone: + 7 931 3617872, fax: +7 812 428 6939.
E-mail: m.krasavin@spbu.ru
Abstract
A convenient Prins cyclization of various azacycloalkanones with homoallylic alcohol was
achieved in aqueous sulfuric acid. The formal four-center, three-component reaction provides a
facile and flexible entry into a range of spirocyclic amino alcohols which are valuable, ‘high-
Fsp3’ motifs for drug design.
Keywords
Prins spirocylization, amino alcohols, bifunctional building blocks, high-Fsp3 scaffolds,
privileged structures.
Spirocyclic motifs are valuable tools in drug design and their use in constructing small molecule
bioactive compounds has delivered numerous advanced leads and clinically used compounds in
diverse biotarget and therapeutic areas.1 The privileged character2 of spirocycles can be
intuitively linked to the more pronounced three-dimensionality of spirocyclic scaffolds compared
to their flat aromatic counterparts. The more ‘shapely’ character of small molecules intended to
modulate a biological target is likely to result in more efficient complementary interaction
between the two. This, in turn, leads to higher affinity of the future drug to its target, better
efficacy (lower dose required to achieve therapeutic effect) and lower toxicity (off-target)
profile.3 Being more saturated (i.e. containing a higher fraction of sp3-hybridized atoms or Fsp3),
compared to flat aromatic scaffolds, spirocycles are also more attractive from a drug
development perspective. This has to do not only with the higher solubility of compounds based

on high-sp3 cores (due to the absence of - crystal packing). The number of aromatic rings in
the molecule was also shown to correlate with a compound’s advanced properties, including
serum albumin binding, cytochrome P450 and hERG channel inhibition.4 Collectively, these are
likely reasons explaining the tendency of compounds to become more saturated as they progress
through the development cycle (according to a statistical analysis published by Wyeth).5
Our recent interest in designing new antidiabetic agonists of free fatty acid receptor 1 (FFA1 or
GPR40)6 led us to consider one of Eli Lilly’s advanced compounds, LY2881835 (1)7 as a lead
for a new series (2), containing a similar spirocyclic amine periphery (Figure 1) with potential
affinity to the receptor.
Figure 1. FFA1 agonist series 2 containing a basic scaffold and a spirocyclic periphery inspired
by LY2881835 (1).
Lewis (LA) or Brønsted (BA) acid-promoted Prins cyclization of cyclic ketones with homoallyl
alcohol conveniently delivers spirocyclic tetrahydropyrans 3. In the latter, the substituent in
position 4 of the tetrahydropyran ring results from interception of intermediate carbocation 4 by
the acidic catalyst’s counterion (X = I,8 Br,9 F,10 OMs11) or water (X = OH).12 Alternatively,
carbocation 4 can be trapped in an intermolecular fashion by a nucleophilic nitrile molecule13 or
an electron-rich arene14 via Ritter and Friedel-Crafts reactions, respectively (Scheme 1).
Scheme 1. The Prins cyclization of cyclic ketones and homoallyl alcohol.

Intramolecular interception of the cationic center in 4 by a judiciously positioned nucleophilic
moiety such as hydroxyalkyl,15 aryl,16 alkenyl17 or arylsulfonylamino18 leads to rapid buildup of
the product’s molecular complexity. However, the trapping of carbocation 4 sometimes
competes with E1-type elimination leading to a mixture of olefinic products, which complicates
the isolation of the desired functionalized spirocycle 4.12f, 11a
We reasoned that if a suitably protected amine functionality was positioned within the structure
of a cyclic ketone, the Prins cyclization with homoallylic alcohol would furnish the desired
spirocyclic framework while the additional functionality handle (X) could be used for fine-
tuning the GPR40 agonist activity and lipophilicity profile19 during a medicinal chemistry
optimization. Among the possible variants of X, the hydroxyl group was viewed as the most
suitable functionality as it could be conveniently used for introducing further modifications
either directly or via oxidation to the respective ketone (a similar strategy was exploited to
optimize spirocyclic  opioid receptor ligands, also amenable by Prins chemistry).12a However,
examples of using azacycloalkanones in Prins cyclization were scarce in the literature and
appeared to be limited to those synthesized in the form of their respective mesylates (X = OMs)
by Ghosh and co-workers via methanesulfonic acid-promoted reaction in dichloromethane.11a
The literature protocol was found to be scalable to tens of grams of the starting material (ESI)
and the mesyl group could in principle be removed either with MeMgBr or LAH as
demonstrated for N-benzyl-4-piperidone-derived product 5 (Scheme 2). However, the modest
overall yield of alcohol 6 and the inconvenience associated with the use of the metal-based
reagents encouraged us to seek methods to directly prepare spirocyclic amino alcohols akin to 6.
Scheme 2. Preparation of mesylate 5 according to Ghosh and co-workers11a and subsequent
removal of the mesyl group.

The direct literature protocols toward spirocyclic 4-hydroxytetrahydropyrans included the use of
75% sulfuric acid,12a-b phosphomolybdic acid,12c cellulose-sulfonic acid,12d and indium(III)12e or
mercury(II)12f triflates. Among these, the method employing inexpensive sulfuric acid appeared
to be the most convenient and environmentally friendly. However, the presence of a basic
nitrogen atom in our starting material initially made us skeptical about the prospects of applying
the strong mineral acid-based method toward azacycloalkanones.
To our delight, when we tested the reaction of N-benzyl-4-piperidone with homoallyllic alcohol
in sulfuric acid of varying concentration, we found the reaction to work quite well at
concentrations above 60%, with the best conversion achieved in 70% H2SO4. These conditions
were not optimized further and were used for all Prins-type spirocyclizations described below.
Interestingly, reducing the H2SO4 concentration to 50% led to no conversion (Figure 2), as
1
determined by the unchanged presence of the characteristic signals in the H NMR spectrum of
the reaction, ascribed to the piperidone starting material.
Figure 2. Conversionsa for the reaction of N-benzyl-4-piperidone with homoallylic alcohol using
various concentrations of sulfuric acid.
a
1
Determined by integration of the H NMR signals relative to the internal standard (DMAP)
which was added to the organic phase containing the crude product following reaction workup.
Once our ability to achieve the Prins spirocyclization of azacycloalkanones in a strong mineral
acid medium was demonstrated, the same protocol (Scheme 3)20 was applied to a range of
ketones, some of which were not basic in nature, and the respective spirocyclic products were
obtained in good yields (Table 1). Gratifyingly, for compounds 11-12 the spirocyclization

reaction was completely diastereoselective and only a single diastereomer was obtained. In
contrast, compound 14 was obtained as a 1:1 mixture of diastereomers.
Scheme 3. Preparation of spirocyclic 4-hydroxytetrahydropyrans 6-20 from various
azacycloalkanones in 70% sulfuric acid.
Table 1. 4-Hydroxytetrahydropyrans 6-20 synthesized in this work.
Isolated
yield (%)
Product
70
65
54
63
63
6
7
8
9
10
44a
63a
11
12
61
55b
51
13
14
15

57
54
16
17
65
65
18
19
44
20
a One diastereomer isolated.
b Diastereomeric mixture (1:1)
Similar to the MsOH-promoted protocol by Ghosh and co-workers (vide supra), the developed
direct amino alcohol synthesis also worked quite well on a multigram scale and was realized on a
25-gram scale using N-benzyl-4-piperidone (ESI). Without further purification, the resulting
product (6) was debenzylated and the secondary amine Boc-protected to provide, after
chromatographic purification, an excellent yield of 21, along with a small amount of
dehydroxylation product 22 (Scheme 4). This building block has been recently used in the
preparation of a library of potential GPR40 agonists, as envisioned in Figure 1.21
Scheme 4. Three-step, one-purification protocol toward Boc-protected building blocks 21-22.
In summary, we report a convenient and environmentally friendly protocol toward valuable
‘high-Fsp3’ spirocyclic amino alcohol building blocks which was applicable to a range of
azacycloalkanones. Considered to be privileged motifs in drug design,1 these building blocks are

useful for constructing potential agonists of GPR40, an important biological target in type II
diabetes mellitus. The results of these studies will be reported in due course.
Acknowledgement
This research was supported by the Russian Scientific Fund (project grant 14-50-00069).
Supporting Information
Supporting information for this article is available online at http://dx.doi.org/xxx.
References and Notes
1. Zheng, Y.; Tice, C. M.; Singh S. B. Bioorg. Med. Chem. Lett. 2014, 24, 3673-3682.
2. Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Curr. Opin. Chem. Biol. 2010, 14, 1-15.
3. Tajabadi, F. M.; Campitelli, M.; Quinn, R. J. Springer Sci. Rev. 2013, 1, 141-151.
4. Ritchie, T. J.; Macdonald, S. J. F. Drug Discov. Today 2009, 14, 101-1020.
5. Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752-6756.
6. (a) Zahanich, I.; Kondratov, I.; Naumchyk, V.; Kheylik, Y.; Platonov, M.; Zozulya, S.;
Krasavin, M. Bioorg. Med. Chem. Lett. 2015, 25, 3105-3111; (b) Krasavin, M.; Lukin, A.;
Zhurilo, N.; Kovalenko, A.; Zahanich, I.; Zozulya, S. J. Enz. Inh. Med. Chem. 2016, DOI:
10.3109/14756366.2016.1142984; (c) Krasavin, M.; Lukin, A.; Zhurilo, N.; Kovalenko, A.;
Zahanich, I.; Zozulya, S.; Moore, D.; Tikhonova, I. G. Bioorg. Med. Chem. 2016,
DOI:10.1016/j.bmc.2016.04.065.
7. Defossa, E.; Wagner, M. Bioorg. Med. Chem. Lett. 2014, 24, 2991-3000.
8. (a) Sabitha, G.; Reddy, K. B.; Bhikshapathi, M.; Yadav, J. S. Tetrahedron Lett. 2006, 47,
2807-2810; (b) Yadav, J. S.; Reddy, B. V. S.; Krishna, V. H.; Swamy, T.; Kumar, G. G. K.
S. N. Can. J. Chem. 2007, 85, 412-415; (c) Yadav, J. S.; Reddy, B. V. S.; Kumar, G. G. K.
S. N.; Reddy, G. M. Chem. Lett. 2007, 36, 426-427; (d) Liu, L.; Floreancig, P. E. Angew.
Chem., Int. Ed. 2010, 49, 5894-5897.
9. Borkar, P.; van de Weghe, P.; Reddy, B. V. S.; Yadav, J. S.; Gree, R. Chem. Commun. 2012,
48, 9316-9318.
10. (a) Bondalapati, S.; Reddy, U. C.; Kundu, D. S.; Saikia, A. K. J. Fluorine Chem. 2010, 131,
320-324; (b) Kishi, Y.; Inagi, S.; Fuchigami, T. Eur. J. Org. Chem. 2009, 103-109.

11. (a) Ghosh, A. K.; Shin, D.; Schiltz, G. Heterocycles 2002, 58, 659-666; (b) Cheng, Y.;
Powers, T.; Ashton, K.; Brown, J.; Harried, S.; Hitchcock, S.; Judd, T.; Lopez, P.; Nixey, T.;
Paras, N. A.; Poon, S. F.; St. Jean, D. J.; Xue, Q.; Zhong, W. PCT Int. Appl.
2011063233A1; Chem Abstr. 2011, 155, 11774.
12. (a) Chen, X.-T.; Pitis, P.; Liu, G.; Yuan, C.; Gotchev, D.; Cowan, C. L.; Rominger, D. H.;
Koblish, M.; DeWire, S. M.; Crombie, A. L.; Violin, J. D. Yamashita, D. S. J. Med. Chem.
2013, 56, 8019-8031; (b) Yamashita, D.; Gotchev, D.; Pitis, P.; Chen, X.-T.; Liu, G.; Yuan,
C. C. K. PCT Int. Appl. WO 2012129495A1; Chem. Abstr. 2012, 157, 520309; (c) Yadav, J.
S.; Reddy B. V. S.; Kumar, G. G. K. S. N.; Aravind, S. Synthesis 2008, 395-400; (d) Reddy,
B. V. S.; Venkateswarlu, A.; Kumar, G. G. K. S.; Vinu, A. Tetrahedron Lett. 2010, 51,
6511-6515; (e) Chio, F. K.; Warne, J.; Gough, D.; Penny, M.; Green, S.; Coles, S. J.;
Hursthouse, M. B.; Jones, P.; Hassall, L.; McGuire, T. M.; Dobbs, A. P. Tetrahedron 2011,
67, 5107-5124; (f) Nishizawa, M.; Shigaraki, T.; Takao, H.; Imagawa, H.; Sugihara, T.
Tetrahedron Lett. 1999, 40, 1153-1156.
13. (a) Yadav, J. S.; Reddy B. V. S.; Aravind, S.; Kumar, G. G. K. S. N.; Madhavi, C.; Kunwar,
A. C. Tetrahedron 2008, 64, 3025-3031; (b) Yadav, J.S.; Reddy, B. V. S.; Chaya, D. N.;
Kumar, G. G. K. S. N. Can. J. Chem. 2008, 86, 769-773; (c) Yadav, J.S.; Reddy, B. V. S.;
Kumar, G. G. K. S. N.; Reddy, G. M. Tetrahedron Lett. 2007, 48, 4903-4906; (d) Reddy, B.
V. S.; Ghanty, S. Synth. Commun. 2014, 44, 2545-2554.
14. (a) Reddy, U. C.; Bondalapati, S.; Saikia, A. K. J. Org. Chem. 2009, 74, 2605-2608; (b)
Dintzner, M. R. Synlett 2013, 24, 1091-1092.
15. (a) Yadav, J. S.; Chakravarthy, P. P.; Borkar, P.; Reddy, B. V. S.; Sarma, A. V. S.
Tetrahedron Lett. 2009, 50, 5998-6000; (b) Reddy, B. V. S.; Kumar, H.; Reddy, P. S.;
Singarapu, K. K. Eur. J. Org. Chem. 2014, 4234-4238; (c) Reddy, B. V. S.; Jalal, S.; Barkar,
P.; Yadav, J. S.; Reddy, P. P.; Kunwar. A. C.; Sridhar, B. Org. Biomol. Chem. 2012, 10,
6562-6568.
16. Reddy, B. V.; Borkar, P.; Yadav, S. J.; Sridhar, B.; Gree, R. J. Org. Chem. 2011, 76, 7677-
7690.
17. (a) Reddy, B. V. S.; Yarlagadda, S.; Reddy, C. R.; Reddy, M. R.; Sridhar, B.;
Satyanarayana, D.; Jagadeesh, B. Eur. J. Org. Chem. 2015, 3076-3086; (b) Reddy, B. V. S.;
Reddy, S. G.; Durgaprasad, M.; Bhadra, M. P.; Sridhal, B. Org. Biomol. Chem. 2015, 13,
8729-8733.
18. Reddy, B. V. S.; Borkar, P.; Chakravarthy, P. P.; Yadav, J. S.; Gree, R. Tetrahedron Lett.
2010, 51, 3412-3426.
19. Waring, M. J. Expert Opin. Drug Discov. 2010, 5, 235-248.

20. General procedure for preparation of compounds 6-20: To a 0 °C vigorously stirred neat
mixture of the respective azacycloalkanone (4.42 mmol) and 3-butenol (4.86 mmol) in a 2
mL glass vial was slowly added 70% H2SO4 (1.5 mL). The stirring was continued overnight,
at which point the mixture was diluted by water (5 mL) and the pH adjusted to 9-10 using a
saturated aqueous NaOH solution. The mixture was extracted with ethyl acetate (2 x 10
mL), the combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered
and concentrated. Chromatographic purification of the residue on silica gel using 05%
MeOH in chloroform as eluent afforded analytically pure products 6-20 in the indicated
yields.
21. Lukin, A.; Krasavin, M. Manuscript in preparation.

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Prins-type spirocyclization was conducted in 70% sulfuric acid
The aqueous protocol was applied to basic substrates for the first time
The resulting building blocks are useful in antidiabetic drug design