Asymmetric synthesis of (-)-(R)-sitagliptin

Article abstract of DOI:10.1016/j.tetlet.2012.04.025

The asymmetric synthesis of (-)-(R)-sitagliptin was achieved in seven steps from commercially available starting materials using the highly diastereoselective conjugate additions of either lithium (R)-N-benzyl-N- (α-methylbenzyl)amide or lithium (R)-N-benzyl-N-(α-methyl-p- methoxybenzyl)amide to tert-butyl 4-(2′,4′,5′-trifluorophenyl) but-2-enoate to install the correct stereochemistry. Subsequent sequential acid-catalysed hydrolysis of the resultant β-amino esters, HOBt/EDC mediated coupling with the triazolopyrazine fragment, and hydrogenolysis gave (-)-(R)-sitagliptin in 43% and 42% overall yields, respectively.

Full text of DOI:10.1016/j.tetlet.2012.04.025

Tetrahedron Letters 53 (2012) 3052–3055
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric synthesis of (ꢀ)-(R)-sitagliptin
⇑
Stephen G. Davies , Ai M. Fletcher, Linlu Lv, Paul M. Roberts, James E. Thomson
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric synthesis of (ꢀ)-(R)-sitagliptin was achieved in seven steps from commercially available
starting materials using the highly diastereoselective conjugate additions of either lithium (R)-N-benzyl-
Received 29 February 2012
Revised 26 March 2012
Accepted 4 April 2012
Available online 12 April 2012
N-(a-methylbenzyl)amide or lithium (R)-N-benzyl-N-(a-methyl-p-methoxybenzyl)amide to tert-butyl
4-(20,40,50-trifluorophenyl)but-2-enoate to install the correct stereochemistry. Subsequent sequential
acid-catalysed hydrolysis of the resultant b-amino esters, HOBt/EDC mediated coupling with the triazolo-
pyrazine fragment, and hydrogenolysis gave (ꢀ)-(R)-sitagliptin in 43% and 42% overall yields, respectively.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Sitagliptin
Lithium amide
Conjugate addition
Asymmetric synthesis
Fluorinated b-amino acid motifs have appeared in a variety of
medicinally valuable molecules over recent years.1 For example,
Taxol (paclitaxel) and Taxotere (docetaxel) have become the most
widely used drugs in cancer chemotherapy.2 Studies on fluorinated
analogues, especially of the b-amino acid moieties within both
Taxol and Taxotere, have been actively pursued and have revealed
interesting biological activities.3 Another important fluorinated
b-amino acid derivative, (ꢀ)-(R)-sitagliptin (JANUVIA™) 1,4 has
recently been developed by Merck and has been marketed as the
first potent and selective orally active dipeptidyl peptidase IV
(DPP-4) inhibitor for the treatment of type 2 diabetes (Fig. 1).5
Recently, Merck’s three generations of syntheses for manufac-
turing (ꢀ)-(R)-sitagliptin 1 were highlighted6 to showcase how
process chemistry could overcome challenges such as reducing
chemical waste by increasing atom efficiency, reducing cost by
employing a recyclable biocatalyst instead of expensive transition
metal catalysts, and achieving efficient target syntheses moving
towards ‘greener’ chemical processes. In all three generations of
syntheses, the key steps to install the correct configuration for
(ꢀ)-(R)-sitagliptin 1 relied on asymmetric reductions: in the first
generation synthesis a ruthenium-catalysed chemo- and stereo-
selective hydrogenation of a b-ketoester was followed by an EDC
coupling/Mitsunobu reaction sequence; in the second generation
synthesis a rhodium-catalysed asymmetric hydrogenation of an
enamine was conducted under high pressure; and in the third gen-
eration synthesis a biocatalytic asymmetric reductive amination of
a b-ketoamide was employed. On a laboratory scale, there have
ammonium salt derivatives) reported.7,8 Among them, an elegant
approach was demonstrated by the research groups from Merck
and Takasago International Corporation, where they developed a
ruthenium-catalysed direct asymmetric reductive amination pro-
tocol employing ammonium salicylate as a ‘nitrogen’ source.9 In
this synthesis the readily available b-ketoamide 2 was treated with
ammonium salicylate under high pressure hydrogen in the pres-
ence of the chiral ruthenium complex Ru(OAc)2[(R)-dm-segphos]
to give enantiomerically pure (R)-sitagliptin salicylate 3 in 91%
yield and 99.5% ee (Scheme 1).
We have previously established the highly diastereoselective
conjugate addition of a variety of enantiopure secondary lithium
amides (derived from
a-methylbenzylamines) to a range of a,b-
unsaturated esters and amides.10 This methodology has been em-
ployed in numerous applications, including the total syntheses of
natural products,11 molecular recognition phenomena12 and reso-
lution protocols,13 and has been reviewed.14 As part of our ongoing
research programme in this area we, as have others,8 anticipated
that (ꢀ)-(R)-sitagliptin 1 would be an ideal synthetic target to
demonstrate the utility of this versatile and efficient methodology.
Herein, the further application of this lithium amide conjugate
addition protocol to facilitate an efficient and concise synthesis
of (ꢀ)-(R)-sitagliptin 1 is delineated.
Commercially available 2,4,5-trifluorobenzaldehyde
4 was
homologated by Wittig reaction with the ylid derived from
[MeOCH2PPh3]+[Cl]ꢀ to give the corresponding enol ether 5 as a
55:45 [(E)/(Z)] mixture of geometric isomers. After treatment of 5
with 4.0 M HCl in 1,4-dioxane for 6 h, Wadsworth–Emmons reac-
tion of the resultant aldehyde with tert-butyl diethylphosphono-
been
a
few other syntheses of (ꢀ)-(R)-sitagliptin
1 (or its
acetate (promoted by MeMgBr)15 gave
a,b-unsaturated ester 6 as
a single product in 74% isolated yield (from 4) after purification.
Two alternative N-protecting group strategies were next
⇑
Corresponding author.
E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.025

S. G. Davies et al. / Tetrahedron Letters 53 (2012) 3052–3055
3053
O
O
AcO
HO
OH
OH
O
O
tBuO
PhO
NH
O
NH
O
O
O
RF
O
O
RF
OAc
OAc
HO
O
HO
O
OH
OH
O
O
Ph
Ph
Taxol analogues
e.g. RF = CF3, p-F-C6H4
Taxotere analogues
e.g. RF = CF3, p-F-C6H4
F
F
NH2
O
N
N
N
F
N
CF3
(−)-(R)-sitagliptin 1
Figure 1. Fluorinated analogues of Taxol and Taxotere, and the structure of (ꢀ)-(R)-sitagliptin 1.
CO2
OH
F
F
F
F
F
F
O
O
NH3
O
(i)
N
N
N
N
N
N
N
N
CF3
CF3
2
3, 91%, 99.5% ee
Scheme 1. Reagents and conditions: (i) Ru(OAc)2[(R)-dm-segphos], ammonium salicylate, H2 (435 psi), MeOH, 75 °C, 7 h.
envisaged: the conjugate additions of both lithium (R)-N-benzyl-
N-( -methylbenzyl)amide and lithium (R)-N-benzyl-N-(
F
F
F
F
a
7
a-
F
F
methyl-p-methoxybenzyl)amide 8 to a,b-unsaturated ester 6 were
undertaken so that alternative N-deprotection step(s)16 could be
investigated for compatibility with the 20,40,50-trifluorophenyl
(i)
CHO
OMe
Ph
group. Thus,
a,b-unsaturated ester 6 was treated with either
(R)-7 or (R)-8 to give the corresponding b-amino esters 9 and 10
with excellent diastereoselectivity (>95:5 dr in each case), in 87%
and 86% isolated yield, respectively, and >99:1 dr in each case after
chromatographic purification (Scheme 2).
4
5, 55:45 dr [(E):(Z)]
R
N
Li
Ph
7, R = Ph
8, R = PMP
(ii), (iii)
N-Benzyl-N-a-methylbenzyl protected b-amino ester 9 was
R
N
treated with 2.0 M aq HCl at reflux to give the corresponding car-
boxylic acid hydrochloride salt 11. Subsequent HOBt/EDC medi-
ated amide coupling of 11 with triazolopyrazine 1217 gave amide
13 in 70% yield over two steps. Finally, removal of the N-protecting
groups by hydrogenolysis in the presence of Pearlman’s catalyst
[Pd(OH)2/C] gave (ꢀ)-(R)-sitagliptin 1 in 96% yield. Interestingly,
it was noted that defluorination was not observed under these con-
ditions (Scheme 3). The spectroscopic data obtained for this sample
of (ꢀ)-(R)-sitagliptin 1 were in excellent agreement with those
CO2t Bu
CO2t Bu
F
F
(iv)
F
F
F
F
9, R = Ph, 87%, >99:1 dr
10, R = PMP, 86%, >99:1 dr
6, 74% (3steps), >99:1 dr
for the sample previously reported in the literature {½a D25
ꢀ23.3
ꢁ
Scheme 2. Reagents and conditions: (i) [MeOCH2PPh3]+[Cl]ꢀ, tBuOK, THF, rt, 48 h;
(ii) 4.0 M HCl in 1,4-dioxane, rt, 6 h; (iii) MeMgBr, tert-butyl diethylphosphono-
acetate, THF, reflux, 15 h; (iv) (R)-7 or (R)-8, THF, ꢀ78 °C, 2 h. [PMP = p-
methoxyphenyl].
(c 1.0, CHCl3); lit.8
½
a 2D6
ꢁ
ꢀ22.8 (c 1.0, CHCl3)}.
Similarly, N-benzyl-N-a-methyl-p-methoxybenzyl protected b-
amino ester 10 was hydrolysed by treatment with 2.0 M aq HCl
to give the corresponding carboxylic acid hydrochloride salt 14,
during which the acid-labile
was also removed. Subsequent HOBt/EDC mediated coupling of
a
-methyl-p-methoxybenzyl group
14 with triazolopyrazine 12 afforded amide 15 in 73% yield
over two steps, and N-debenzylation of 15 under high pressure

3054
S. G. Davies et al. / Tetrahedron Letters 53 (2012) 3052–3055
Ph
Ph
H
Cl
Ph
N
Ph
N
CO2tBu
CO2H
(i)
F
F
F
F
F
F
9, >99:1 dr
11
N
(ii)
HN
N
N
Ph
CF3
12
NH2
O
Ph
N
O
N
N
N
N
(iii)
N
N
F
N
F
N
CF3
CF3
F
F
F
F
13, 70% (2 steps), >99:1 dr
(−)-(R)-sitagliptin 1, 96%
Scheme 3. Reagents and conditions: (i) HCl (2.0 M, aq), reflux, 6 h; (ii) HOBt, EDCꢂHCl, DIPEA, CHCl3, rt, 16 h; (iii) H2 (5 atm), Pd(OH)2/C (30% w/w), MeOH, rt, 24 h.
Ph
Ph
H
N
Cl
H
F
PMP
F
N
CO2tBu
CO2H
(i)
F
F
F
F
10, >99:1 dr
14
HN
N
(ii)
N
N
N
Ph
CF3
12
H
NH2
O
O
N
N
N
N
(iii)
N
N
F
N
F
N
CF3
CF3
F
F
F
F
(−)-(R)-sitagliptin 1, 91%
15, 73% (2 steps), >99:1 dr
Scheme 4. Reagents and conditions: (i) HCl (2.0 M, aq), reflux, 6 h; (ii) HOBt, EDCꢂHCl, DIPEA, CHCl3, rt, 16 h; (iii) H2 (5 atm), Pd(OH)2/C (20% w/w), MeOH, rt, 24 h. [PMP = p-
methoxyphenyl].
hydrogen in the presence of Pearlman’s catalyst gave (ꢀ)-(R)-sitag-
liptin 1 in 91% isolated yield (Scheme 4). The spectroscopic data
obtained for this sample of (ꢀ)-(R)-sitagliptin 1 were also found
to be in excellent agreement with those for the sample originally
to be in excellent agreement with those for the sample originally
reported in the literature {½a D25
ꢁ
ꢀ75.8 (c 1.0, H2O); lit.8
½ ꢁ
a 2D0
ꢀ72.9 (c 1.0, H2O); lit.7c
[
a]
ꢀ74.4 (c 1.0, H2O)}.
D
In conclusion, two efficient and concise asymmetric syntheses
of (ꢀ)-(R)-sitagliptin 1 were accomplished in seven steps from
commercially available starting materials. Two alternative protect-
ing group strategies were evaluated which gave comparable
overall yields of (ꢀ)-(R)-sitagliptin 1 (43% overall yield employing
reported in the literature {½a D25
ꢁ
ꢀ22.0 (c 1.0, CHCl3); lit.8
½ ꢁ
a 2D6
ꢀ22.8 (c 1.0, CHCl3)}. Finally, this sample of (ꢀ)-(R)-sitagliptin 1
was converted into its phosphate salt 1ꢂH3PO4 and recrystallised
from iPrOH. The spectroscopic data for this sample were also found

S. G. Davies et al. / Tetrahedron Letters 53 (2012) 3052–3055
3055
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N-a-methylbenzyl protection and 42% overall yield using N-a-
methyl-p-methoxybenzyl protection). In the latter case, elabora-
tion of the mono-N-protected amine intermediate 15 should allow
access to libraries of analogues.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
04.025.
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Roberts, P. M.; Thomson, J. E. Org. Lett. 2011, 13, 2544; (j) Davies, S. G.; Ichihara,
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Russell, A. J.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2007, 5, 3922; (b)
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Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Scott, P. M.; Smith, A.
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Long, M. J. C.; Morrison, R. M.; Roberts, P. M.; Smith, A. D.; Sweet, M. J.; Withey,
J. M. Org. Biomol. Chem. 2005, 3, 2762; (b) Aye, Y.; Davies, S. G.; Garner, A. C.;
Roberts, P. M.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 2195; (c)
Abraham, E.; Davies, S. G.; Docherty, A. J.; Ling, K. B.; Roberts, P. M.; Russell, A.
J.; Thomson, J. E.; Toms, S. M. Tetrahedron: Asymmetry 2008, 19, 1356; (d)
Davies, S. G.; Durbin, M. J.; Hartman, S. J. S.; Matsuno, A.; Roberts, P. M.; Russell,
A. J.; Smith, A. D.; Thomson, J. E.; Toms, S. M. Tetrahedron: Asymmetry 2008, 19,
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References and notes
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4. The phosphate monohydrate salt of (ꢀ)-(R)-sitagliptin 1 is marketed under the
name of JANUVIA™.
5. (a) Kim, D.; Wang, L.; Beconi, M.; Eiermann, G. J.; Fisher, M. H.; He, H.; Hickey,
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8. One synthesis of (ꢀ)-(R)-sitagliptin 1 employs our diastereoselective lithium
amide conjugate addition methodology, see: Liu, F.; Yu, W.; Ou, W.; Wang, X.;
Ruan, L.; Li, Y.; Peng, X.; Tao, X.; Pan, X. J. Chem. Res. 2010, 34, 230.
9. Steinhuebel, D.; Sun, Y.; Matsumura, K.; Sayo, N.; Saito, T. J. Am. Chem. Soc.
2009, 131, 11316.
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Russell, A. J.; Smith, A. D.; Toms, S. M. Org. Lett. 2008, 10, 5437.
16. For example, selective mono-N-deprotection has been developed by our group,
see: (a) Bull, S. D.; Davies, S. G.; Fenton, G.; Mulvaney, A. W.; Prasad, R. S.;
Smith, A. D. Chem. Commun. 2000, 337; (b) Bull, S. D.; Davies, S. G.; Fenton, G.;
Mulvaney, A. W.; Prasad, R. S.; Smith, A. D. J. Chem. Soc., Perkin Trans. 1 2000,
3965.
10. (a) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991, 2, 183; (b) Davies, S.
G.; Garrido, N. M.; Kruchinin, D.; Ichihara, O.; Kotchie, L. J.; Price, P. D.; Price
Mortimer, A. J.; Russell, A. J.; Smith, A. D Tetrahedron: Asymmetry 2006, 17,
1793; (c) Davies, S. G.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Russell, A. J.;
Savory, E. D.; Smith, A. D.; Thomson, J. E Tetrahedron: Asymmetry 2009, 20, 758;
(d) Davies, S. G.; Garner, A. C.; Nicholson, R. L.; Osborne, J.; Roberts, P. M.;
Savory, E. D.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2009, 7, 2604; (e)
Davies, S. G.; Mujtaba, N.; Roberts, P. M.; Smith, A. D.; Thomson, J. E. Org. Lett.
17. Triazolopyrazine 12 was prepared according to a literature procedure, see: Ref.
5a.