Biomass derived furfural-based facile synthesis of protected (2S)-phenyl-3-piperidone, a common intermediate for many drugs

Article abstract of DOI:10.1039/c4cc02645d

An efficient synthetic route towards tosyl-protected (2S)-phenyl-3- piperidone, a common intermediate for many drugs, has been developed in 5 steps in 54% yield from biomass derived furfural. The synthetic utility of the piperidone core structure was demonstrated with the synthesis of a NK ₁ receptor antagonist. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc02645d

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Biomass derived furfural-based facile synthesis of
protected (2S)-phenyl-3-piperidone, a common
intermediate for many drugs†
Cite this: Chem. Commun., 2014,
50, 8324
Received 10th April 2014,
Accepted 1st May 2014
P.-F. Koh,a P. Wang,a J.-M. Huangab and T.-P. Loh*ac
DOI: 10.1039/c4cc02645d
www.rsc.org/chemcomm
An efficient synthetic route towards tosyl-protected (2S)-phenyl-3-
We envisioned that the xylan content present in rice straw
piperidone, a common intermediate for many drugs, has been could be used as a feedstock to produce furfural which can then
developed in 5 steps in 54% yield from biomass derived furfural. be efficiently transformed into a tosyl-protected (2S)-phenyl-3-
The synthetic utility of the piperidone core structure was demon- piperidone core structure 2 which allows facile access to numerous
strated with the synthesis of a NK1 receptor antagonist.
neurokinin-1 (NK1) receptor antagonists (Fig. 1). These potent NK1
receptor antagonists showed promising biological activities which
The sustained increase in the consumption of finite fossil fuel may offer novel cures to disorders such as depression, anxiety and
resources has painted a bleak global energy outlook for the 21st emesis.5 Various protected 2-phenyl-3-piperidones have been
century. This has also attracted considerable research attention to synthesized by Merck and other research groups with low overall
various renewable resources such as biomass, which has the yields (o40%) over a minimum of 6 steps.6,7 The advantages of
potential to serve as a renewable source of energy and organic this strategy include the use of a cheap and renewable biomass-
carbon.1 Furfural 1 is a platform chemical which can be derived derived starting material, being a short synthetic route with only a
from biomass2a,b and annually about 300 000 tonnes of agricul- single silica gel column chromatography step, and obtaining
tural raw materials are dehydrated to form furfural. It is notable product in a higher yield than existing methods with almost no
that a recent report suggests a possible significant reduction in loss of optical purity.
furfural production costs2c which highlights the potential for lower
Modification of a previously reported synthesis of furfural 1
costs when utilizing furfural as a carbon source. The inclusion of from corn cobs8 to rice straw with hourly removal of DCM from
furfural as one of the top ‘‘biobased product opportunities’’3a
emphasizes its usefulness in various domains such as fuels,3b
solvents,3c natural product synthesis3d–i and more recently as chiral
inducers.3j Annual world production of rice exceeds 500 million
tonnes4a and its associated agricultural waste, rice straw, is
produced in large quantities in Asian countries such as China
(110 Mt per year), India (97 Mt per year), Thailand (22 Mt per year)
and the Philippines (11 Mt per year).4b,c Currently rice straw is
largely left uncollected in the field or is disposed of through open-
field burning which causes air pollution and health hazards.4
a Division of Chemistry & Biological Chemistry, Nanyang Technological University,
50 Nanyang Avenue, Singapore 639798, Singapore
b School of Chemistry and Chemical Engineering, South China University of
Technology, Guangzhou, Guangdong, 510640, China
c Hefei National Laboratory for Physical Sciences at the Microscale and
Department of Chemistry, University of Science and Technology of China,
Hefei, 230026, P. R. China. E-mail: teckpeng@ntu.edu.sg
† Electronic supplementary information (ESI) available: Additional text with full
experimental details, characterization and crystallographic data, chromatograms
Fig. 1 Construction of the piperidone core structure from furfural to
access various potent NK1 receptor antagonists.
and NMR spectra. CCDC 917485–917489. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c4cc02645d
8324 | Chem. Commun., 2014, 50, 8324--8327
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
ChemComm
Scheme 1 Synthesis of furfural from rice straw.
Fig. 3 ORTEP drawing of 7.
Scheme 2 Facile synthesis of piperidone 2 from biomass-derived furfural.
2 was efficiently synthesized in an overall yield of 54% over 5 steps
from rice straw-derived furfural 1.
the Dean Stark trap gave a yield of 8.1 wt% without optimiza-
The optical rotation obtained for 7 is [a]2D1 = +123 (c = 1.32,
tion (Scheme 1). The crude product obtained was found to be CH2Cl2) for 97% ee while that reported in the literature7c is
sufficiently pure without the need for further purification [a]2D0 = À145 (c = 0.3, CH2Cl2), and the optical rotation obtained
and could be transformed into imine 4 in the presence of for 2 is [a]2D3 = À10.0 (c = 1.01, CH2Cl2) for 97% ee while that
4-methylbenzenesulfonamide and a Lewis acid catalyst with a reported in the literature7c is [a]D20 = +5 (c = 0.2, CH2Cl2). The
recrystallization yield of 75% (Scheme 2). Imine 4 was then absolute structure of 7 was determined using single-crystal
subjected to a rhodium-catalyzed asymmetric arylation metho- X-ray crystallography11 (Fig. 3), and further HPLC analysis of
dology developed by Hayashi’s group9 to afford furylamine 5 the particular single-crystal used in the X-ray crystallography as
with 97% yield and 99% enantiomeric excess (ee) after column well as the batch of crystals submitted for analysis showed
chromatography. In view of the efficiency of this step, subse- retention times and an elution order that were in agreement
quent reactions were not subjected to chromatographic purifi- with those of experimentally obtained values (see ESI† for more
cation and crude 5 was able to undergo the aza-Achmatowicz details). This rules out the possibility that the structure
rearrangement10 with N-bromosuccinimide (NBS) as the oxidant obtained from the single-crystal X-ray crystallography is the
to yield hemiaminal 6 as a cis diastereomer, as determined by minor enantiomer and hence it can be concluded that the
NMR analysis and single-crystal X-ray crystallography11 (Fig. 2), experimentally obtained 7 is indeed the desired (S)-2-phenyl-1-
probably as a result of an anomeric effect. The phenyl substi- tosyl-1,6-dihydropyridin-3(2H)-one. This conclusion can be
tuent at the chiral centre in rac-6 adopts a pseudoaxial orienta- further extended to assign the absolute configuration of 2 as
tion due to A1,3-strain12 with the tosyl protecting group. The (S)-2-phenyl-1-tosylpiperidin-3-one. The loss of ee was subse-
aza-Achmatowicz rearrangement is a variation of the Achmatowicz quently determined to be due to the inherent acidity of the
rearrangement where the former involves an amine functional silica gel chromatography; pre-treatment of silica gel with 1%
group as a nucleophile and the latter an alcohol. Crude 6 was triethylamine also resulted in a loss of ee while recrystallization
able to be immediately reduced13 without further purification to attempts proved to be futile. The acid and base sensitivity of 2
give 7 in 72% yield and 97% ee over 3 steps from 4. 7 was and 7 may be attributed to the lability of the a-hydrogen at the
hydrogenated using Pd/C in a quantitative conversion to yield chiral centre.
tosyl-protected (2S)-phenyl-3-piperidone 2. Thus, key intermediate
NK1 receptor antagonist 3 was synthesized to illustrate the
synthetic utility of piperidone 2 (Scheme 3). Rac-2 was able to
undergo a Grignard reaction and subsequent TMS deprotection
step to form rac-8, which was immediately subjected to Searles–
14
´
Crabbe homologation conditions without further purification to
transform the alkyne moiety to an allene rac-9 in 69% yield over
3 steps. The relative stereochemistry in rac-8 was established using
single-crystal X-ray crystallography11 where the alkyne is trans to the
phenyl substituent. The preference for the pseudoaxial orientation
of the phenyl substituent in rac-2 gives rise to a single diastereomer
in the Grignard reaction due to the steric hindrance imposed by the
phenyl substituent on one face of the carbonyl group.
Au-catalyzed cycloisomerisation15 of rac-9 constructed the
spirocycle rac-10 in 85% yield and rac-10 was analyzed with
Fig. 2 ORTEP drawing of rac-6.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 8324--8327 | 8325

View Article Online
ChemComm
Communication
reaction. This synthetic strategy has the advantage of being a
shorter route with only a single silica gel chromatography step,
generating product in higher yield with almost no loss of
optical purity, and originating from a renewable source, thus
improving its sustainability and alleviating the problems
caused by the open-field burning of rice straw. Most impor-
tantly, 2 allows facile access to numerous biologically active
compounds and its synthetic usefulness has been demon-
strated with the synthesis of rac-3.
This research was supported financially by Nanyang Tech-
nological University (New Initiative Funding) and the National
Environment Agency (NEA-ETRP Project Ref. No. 1002 111). The
authors would like to thank Dr Ganguly (NTU) and Dr Li (NTU)
for their assistance with the single-crystal X-ray crystallography.
Notes and references
Scheme 3 Synthesis of rac-3 using a Searles–Crabbe homologation,
´
1 (a) E. E. Hood, P. Nelson and R. Powell, Plant Biomass Conversion,
Wiley-Blackwell, Chichester, 2011; (b) G. Centi and R. A. v. Santen,
Catalysis for renewables: from feedstock to energy production, Wiley-
VCH, Weinheim, 2007; (c) D. L. Klass, Biomass for renewable energy,
fuels, and chemicals, Academic Press, San Diego, 1998.
2 (a) K. J. Zeitsch, The Chemistry and Technology of Furfural and its
Many By-Products, Sugar Series, Elsevier, Amsterdam, 2000, vol. 13;
(b) A. Corma, S. Iborra and A. Velty, Chem. Rev., 2007, 107,
2411–2502; (c) R. Xing, W. Qi and G. W. Huber, Energy Environ.
Sci., 2011, 4, 2193–2205.
3 (a) J. J. Bozell and G. R. Petersen, Green Chem., 2010, 12, 539–554;
(b) J.-P. Lange, E. van der Heide, J. van Buijtenen and R. Price,
ChemSusChem, 2012, 5, 150–166; (c) F. W. Lichtenthaler and
S. Peters, C. R. Chim., 2004, 7, 65–90; (d) P. Srihari and Y. Sridhar,
Eur. J. Org. Chem., 2011, 6690–6697; (e) C. A. Leverett, M. P. Cassidy
and A. Padwa, J. Org. Chem., 2006, 71, 8591–8601; ( f ) M. P. Cassidy
and A. Padwa, Org. Lett., 2004, 6, 4029–4031; (g) J. M. Harris and
A. Padwa, J. Org. Chem., 2003, 68, 4371–4381; (h) J. M. Harris and
A. Padwa, Org. Lett., 2002, 4, 2029–2031; (i) M. H. Haukaas and G. A.
O’Doherty, Org. Lett., 2001, 3, 401–404; ( j) A. Kabro, E. C. Escudero-
Au-catalyzed cycloisomerisation and reductive Heck reaction.
single-crystal X-ray crystallography.11 A regio- and stereo-
selective reductive Heck reaction developed by Merck6b,c trans-
formed rac-10 to rac-11 in 56% yield. The stereoselectivity of
the reductive Heck reaction can be rationalized by the prefer-
ential approach of the arylpalladium species from the less
hindered face of the dihydrofuran moiety in rac-10, while the
regioselectivity arises due to steric considerations.16
The relative stereochemistry of rac-11 was also confirmed
using NOE analysis17 where the two benzylic protons in rac-11
were shown to have NOE correlations, in agreement with the
results reported by Merck. Rac-11 was finally subjected to
Pd-catalyzed hydrogenation and Mg-promoted tosyl deprotection
with the help of sonication to complete the synthesis of rac-3 in
51% yield over 2 steps as a white solid instead of a pale yellow oil
reported by Merck6b for the reported enantiopure form. The
single-crystal X-ray crystal11 structure of rac-3 is shown (Fig. 4).
We have demonstrated the efficiency of synthesizing tosyl-
protected (2S)-phenyl-3-piperidone 2, a common intermediate
for many drugs, from rice straw-derived furfural 1 by employing
Hayashi’s highly enantioselective rhodium-catalyzed arylation
methodology as well as the aza-Achmatowicz rearrangement
´
Adan, V. V. Grushin and P. W. N. M. van Leeuwen, Org. Lett., 2012,
14, 4014–4017.
4 (a) K. L. Kadam, L. H. Forrest and W. A. Jacobson, Biomass Bioenergy,
2000, 18, 369–389; (b) Q. Li, S. Hu, D. Chen and B. Zhu, Biomass
Bioenergy, 2012, 47, 277–288; (c) B. Gadde, C. Menke and
R. Wassmann, Biomass Bioenergy, 2009, 33, 1532–1546.
5 See ESI† for a complete list of references for the NK1 receptor
antagonists.
6 (a) P. E. Maligres, M. M. Waters, J. Lee, R. A. Reamer, D. Askin,
M. S. Ashwood and M. Cameron, J. Org. Chem., 2002, 67, 1093–1101;
(b) D. J. Wallace, J. M. Goodman, D. J. Kennedy, A. J. Davies,
C. J. Cowden, M. S. Ashwood, I. F. Cottrell, U.-H. Dolling and
P. J. Reider, Org. Lett., 2001, 3, 671–674; (c) J. J. Kulagowski,
N. R. Curtis, C. J. Swain and B. J. Williams, Org. Lett., 2001, 3,
667–670.
7 (a) J. Lee, T. Hoang, S. Lewis, S. A. Weissman, D. Askin, R. P. Volante
and P. J. Reider, Tetrahedron Lett., 2001, 42, 6223–6225;
(b) C. G. Kokotos and V. K. Aggarwal, Chem. Commun., 2006,
2156–2158; (c) X. Gaucher, M. Jida and J. Ollivier, Synlett, 2009,
´
´
´
3320–3322; (d) N. M. Garrido, M. Garcıa, M. R. Sanchez, D. Dıez and
J. G. Urones, Synlett, 2010, 387–390; (e) M. Atobe, N. Yamazaki and
C. Kibayashi, J. Org. Chem., 2004, 69, 5595–5607; ( f ) O. Calvez and
N. Langlois, Tetrahedron Lett., 1999, 40, 7099–7100; (g) K. Takahashi,
H. Nakano and R. Fujita, Tetrahedron Lett., 2005, 46, 8927–8930;
(h) P.-Q. Huang, L.-X. Liu, B.-G. Wei and Y.-P. Ruan, Org. Lett., 2003,
5, 1927–1929; (i) L.-X. Liu, Y.-P. Ruan, Z.-Q. Guo and P.-Q. Huang,
J. Org. Chem., 2004, 69, 6001–6009; ( j) S. V. Pansare and E. K. Paul,
Org. Biomol. Chem., 2012, 10, 2119–2125.
8 R. Adams and V. Voorhees, Org. Synth., 1941, 1, 280.
9 (a) N. Tokunaga, Y. Otomaru, K. Okamoto, K. Ueyama, R. Shintani and
T. Hayashi, J. Am. Chem. Soc., 2004, 126, 13584–13585; (b) G. Berthon
and T. Hayashi, Rhodium- and Palladium-Catalyzed Asymmetric
Fig. 4 ORTEP drawing of rac-3.
8326 | Chem. Commun., 2014, 50, 8324--8327
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
ChemComm
Conjugate Additions, in Catalytic asymmetric conjugate reactions,
Lett., 1995, 36, 4315–4318; (l) The mechanism for aza-Achmatowicz
rearrangement is illustrated in the ESI†.
´
ed. A. Cordova, Wiley-VCH, Weinheim, Germany, 2010, pp. 1–44.
10 (a) O. Achmatowicz Jr, P. Bukowski, B. Szechner, Z. Zwierzchowska and 11 The CIF files, ORTEP drawings and CCDC deposition numbers of
A. Zamojski, Tetrahedron, 1971, 27, 1973–1996; (b) E. A. Couladouros the crystalline compounds are provided in the ESI†.
and M. P. Georgiadis, J. Org. Chem., 1986, 51, 2725–2727; (c) Review: 12 (a) J. D. Brown, M. A. Foley and D. L. Comins, J. Am. Chem. Soc.,
M. A. Ciufolini, C. Y. W. Hermann, Q. Dong, T. Shimizu,
S. Swaminathan and N. Xi, Synlett, 1998, 105–114; (d) Y. Lefebvre,
1988, 110, 7445–7447; (b) S.-e. Yoo and S. H. Lee, J. Org. Chem., 1994,
59, 6968–6972.
Tetrahedron Lett., 1972, 13, 133–136; (e) Z.-H. Lu and W.-S. Zhou, 13 M. D. Lewis, J. K. Cha and Y. Kishi, J. Am. Chem. Soc., 1982, 104,
J. Chem. Soc., Perkin Trans. 1, 1993, 593–596; ( f ) Z. Wei-Shan, X. Wen- 4976–4978.
Ge, L. Zhi-Hui and P. Xin-Fu, Tetrahedron Lett., 1995, 36, 1291–1294; 14 S. Searles, Y. Li, B. Nassim, M.-T. R. Lopes, P. T. Tran and P. Crabbe,
(g) W.-S. Zhou, W.-G. Xie, Z.-H. Lu and X.-F. Pan, J. Chem. Soc., Perkin J. Chem. Soc., Perkin Trans. 1, 1984, 747–751.
´
Trans. 1, 1995, 2599–2604; (h) L.-X. Liao, Z.-M. Wang, H.-X. Zhang and 15 B. Gockel and N. Krause, Org. Lett., 2006, 8, 4485–4488.
W.-S. Zhou, Tetrahedron: Asymmetry, 1999, 10, 3649–3657; 16 R. F. Heck, Palladium-Catalyzed Vinylation of Organic Halides,
(i) W.-S. Zhou, Z.-H. Lu, Y.-M. Xu, L.-X. Liao and Z.-M. Wang, Tetra-
hedron, 1999, 55, 11959–11983; ( j) H.-J. Altenbach and R. Wischnat,
in Organic Reactions, ed. W. G. Dauben, John Wiley & Sons Inc,
New York, 1982, vol. 27, p. 345.
Tetrahedron Lett., 1995, 36, 4983–4984; (k) J. C. P. Hopman, E. van den 17 COSY, HMQC and nuclear Overhauser effect analyses are available
Berg, L. O. Ollero, H. Hiemstra and W. Nico Speckamp, Tetrahedron
in the ESI†.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 8324--8327 | 8327