Stereoselective and Regioselective Preparation of C-Pentopyranosides and Formal Synthesis of Omarigliptin

Article abstract of DOI:10.1002/ejoc.201601074

A readily available intermediate obtained from d-arabinose was identified as a versatile starting material for the stereoselective synthesis of C-pentopyranosides in one pot. For two of the C-pentopyranosides, subsequent epoxide ring formation and a regioselective opening process was proven to be a robust approach to 3-deoxy C-pentopyranosides in two to four steps. A key intermediate used in the preparation of omarigliptin was obtained in four steps. Most of the conversions were high-yielding and proceeded with high selectivities on a multigram scale.

Full text of DOI:10.1002/ejoc.201601074

A Journal of
Accepted Article
Title: Stereoselective and Regioselective Preparations of C-Pentopyranosides and
Formal Synthesis of Omarigliptin
Authors: Tongchao Liu; Jian Hou; Wuchen Xie; You Li; Huanming Ren; Jianpeng
Liang; Bing Xiong; Guohua Chen; Maosheng Cheng; Dongmei Zhao; Jingkang
Shen; Yue-Lei Chen
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601074
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601074
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European Journal of Organic Chemistry
10.1002/ejoc.201601074
COMMUNICATION
DOI: 10.1002/ejoc.200
Stereoselective and Regioselective Preparations of C-Pentopyranosides and Formal
Synthesis of Omarigliptin
Tongchao Liu[a,b] †, Jian Hou[c] †, Wuchen Xie[b,d], You Li[b,d], Huanming Ren[b,d], Jianpeng Liang[b],
Bing Xiong [b], Guohua Chen[d], Maosheng Cheng[a], Dongmei Zhao*[a], Jingkang Shen*[b] , and
Yue-Lei Chen*[b]
Keywords: C-glycoside / glycosylation / omarigliptin / epoxide / stereoselective synthesis
Readily available intermediate ent-8 from D-arabinose was identified as a versatile starting material for stereoselective C-
pentopyranoside synthesis, leading to C-pentopyranosides 11a-e in one pot. From compounds 11a and 11e, the following epoxide ring
formation and regioselective opening process was proved as a robust approach to 3-deoxy C-pentopyranosides 18, 21 or 23 in 2-4 steps.
From compound 23, the key intermediate 7 for Omarigliptin was prepared in 4 steps. Most of the conversions were of high yield and
selectivity at multi-gram scales.
____________
[a]
Tongchao Liu, Dr. Maosheng Cheng, Dr. Dongmei Zhao
Shenyang Pharmaceutical University, 103 Wenhua Lu, Shenyang 110016, P. R.
China.
[b]
Tongchao Liu, Wuchen Xie, You Li, Huanming Ren, Jianpeng Liang, Dr. Bing
Xiong, Dr. Jingkang Shen, Dr. Yue-Lei Chen
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203;
University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing
100049, P. R. China
E-mail: chenyuelei@gmail.com
[c]
Dr. Jian Hou
Shanghai Shynedec Pharmaceutical Co.,Ltd. 378 Jianlu Road, Shanghai
200137,P.R.China.
[d]
Wuchen Xie, You Li, Huanming Ren, Dr. Guohua Chen
School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang,
Nanjing 210009, P. R. China.
†
T. L. and J. H. contributed equally.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/ejoc.xxxxxxxxx.
Scheme 1. Some natural products and bioactive structures containing C-
pentopyranoside motif.
Introduction
The syntheses of these C-pentopyranosides have been tackled
with different approaches. For example, compound 2 was prepared
C-Pentopyranoside is a common motif in natural products and
bioactive structures. To name a few (Scheme 1), carlinoside 1 was
found to alleviate liver damage.[1] Neodysiherbaine A 2 was
isolated as an excitatory amino acid. [2] Pro-xylane 3 is a marketed
cosmetic ingredient. [3] 3-Deoxygenated C-pentopyranoside is also
a priviledged module in bioactive compounds. For example,
structure 4 is present in compounds with different biological
activities.[4] Spiroacetal 5 is a highly active herbicidal compound. [5]
The new DPPIV inhibitor Omarigliptin 6, [6] a useful drug against
diabetic mellitus, features a unique 2,3-dideoxy 2-amino C-
pentopyranoside skeleton 7, too. [7] The preparation of Omarigliptin
has been disclosed by Merck and us, with 2,3-dideoxy 2-amino C-
pentopyranoside 7 as the key intermediate. [8]
[2]
from acetylated D-glucal. Stucture 4 was often prepared from
[4]
glucose diacetonides.
Compound 7 was made by two routes.
According to Merck’s report, initially it was acquired by non-
stereoselective reactions and the desired isomers were resolved by
chiral-HPLC. [6] Later, from non-carbohydrate starting materials, a
multistep synthesis including a key Ru-catalyzed DKR reaction
was developed for the manufacture of 7. [7,8a] In search of robust
[9]
routes to C-pentopyranosides with lower costs,
we considered
lactone 8 [10] as a promising starting point. According to Fleet et al,
compound 8 was prepared efficiently (ca. 68% yield) from
inexpensive L-arabinose 9 in 3 steps (Scheme 2). [10,11] This also
made ent-8 an easily accessible starting material, since D-arabinose
is a bulk material.
Scheme 2. Lactone 8 and ent-8 as readily available building blocks.
Submitted to the European Journal of Organic Chemistry
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European Journal of Organic Chemistry
10.1002/ejoc.201601074
Herein, we report a versatile and efficient route from compound
ent-8, leading to C-pentopyranosides and 3-deoxy C-
pentopyranosides, via highly stereoselective C-glycosylation,
efficient epoxide formation, and highly regioselective epoxide
opening. Using one of the products from this new route, the key
intermediate 7 of Omarigliptin was readily prepared in a few steps,
too.
Results and Discussion
From sugar lactone, typical C-glycoside synthesis involves
carbanion addition and Lewis-acid mediated silane reduction. [12]
Although lactone 8 accepts the addition of MeLi, [10a] the second
reduction step leading to a C-glycoside was never found in
literature. We surmised that both O-TBS and acetonide protection
could interfere with the Lewis-acid mediated reduction step. Thus,
we decided to extend the scope of nucleophilic reagents in the first
addition step, and then explore the hitherto unknown second
reduction step (Scheme 3).
Scheme 3. Preparation of C-pentopyranosides from lactone ent-8. Reaction
conditions: a) lithiated 12a-e, n-BuLi, THF, -78 oC or ether, -90 oC; b) crude
10a-e, TMSOTf, Et3SiH, DCM, -78 oC; c) Yield was determined after flash
chromatography, and anomeric stereochemistry was determined by NMR.
Initially, we used lithiated 12a and 12b for the nucleophilic
addition to ent-8, and the conversions to intermediate 10a and 10b
was satisfactory. Next, since the recent success in SGLT-2
inhibitors rendered aryl C-glycosides highly attractive, [13] we used
bromobenzene derivatives 12c and 12d to prepare the lithium
reagent for the nucleophilic addition to ent-8. Again, the Br-Li
From structure 11, we attempted to utilize the differently
protected 2- and 3,4- hydroxyls and prepare the 2,3-epoxides,
which could lead to further structural variations of C-
pentopyranosides via epoxide ring opening. Derivatization of 2,3-
epoxide on 3,4-aceto-O-pentopyranosides has been demonstrated a
o
exchange and the nucleophilic addition went smoothly at -78 C.
[15]
versatile (Scheme 4) strategy in carbohydrate synthesis.
Although compound 12e, a starting material in Omarigliptin
synthesis, [6,7,8a] could be a poor substrate for Br-Li exchange due to
the fluoride elimination, it was still tested with n-BuLi. Indeed the
experimental observation accorded with the expectation: Using
similar conditions as that for substrates 12c and 12d, usually no
desired intermediate 10e could be found. Thus, we performed
extensive condition screening, and identified that ether is a key
solvent for the Br-Li exchange and the following nucleophilic
addition. Using ether as the solvent, with careful tuning of the ratio
of substrates, we were able to reach a spot-to-spot conversion from
ent-8 to intermediate 10e at a scale larger than 10 grams. It is also
interesting to notice that, except for 12e, all other substrates (12a-d)
required THF solvent for successful conversion, indicating that
substrate-solvent pair was highly important in the nucleophilic
addition step.
However, this does not imply that other glycosides are suitable for
this epoxide approach. For example, S-glycoside, was not a good
substrate for this approach, according to very rare literature report
[15c]
[16]
and our own experience.
Meanwhile, C-Glycosides
remained an even more obscure, yet more interesting material for
this epoxide approach. [17]
Scheme 4. Typical epoxide ring formation and opening approach on O-
pentopyranosides. Reaction conditions: a) acidic removal of acetonide, then
epoxide formation under basic condition; b) nucleophile.
After some experimentation, to our pleasure, the known epoxide
formation methods [15d,e] used for O-glycosides worked smoothly on
C-glycoside analogues, including synthetically useful dithiane
glycoside 11a and aryl glycoside 11e, and gave epoxide sugars 17
and 20 with good yields. Next, we explored conditions to open the
epoxide ring with metal hydrides. Epoxide ring opening with
hydrides on pyranosides have shown variable regioselectivity. [18]
However in the cases of C-pentopyranoside epoxide 17 and 20, a
simple LAH reduction in THF showed complete regioselectivity
and led to high yields of 3-deoxy C-pentopyranosides 18 and 21,
respectively. More interestingly, it was even possible to oxidize the
free hydroxyl on compound 20, and then open the epoxide under a
very mild condition [19] to give ketone 23 with 89% yield. In this
way, the 2,4-dihydroxyls on the C-pentopyranoside 21 was
efficiently differentiated (Scheme 5).
For the second reduction step, typical BF3 etherate mediated
reduction with Et3SiH was tested, [12] however either no conversion
or complete decomposition of 10 was observed. TMSOTf [14] was
found as a superior Lewis acid for the reduction. Although at -40
oC it partially removed acid labile protections on intermediate 10,
futher lowering the reaction temperature to -78 oC completely
suppressed the side reactions. Without further condition
optimization, products 11a-e were isolated with 65-95% yields,
and showed homogeneous alpha-configuration. The excellent
stereoselectivity may partially be attributed to the bulky 2-OTBS
protection and the rigid conformation locked by the acetonide
protection. [14]
Submitted to the European Journal of Organic Chemistry
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European Journal of Organic Chemistry
10.1002/ejoc.201601074
Thus, we sought more reliable methods to incorporate 2-NH2
group. To this end, compound 24 was oxidized to ketone 28 with
90% yield, and the possibilities of reductive amination were next
inspected. It was found that the best nitrogen source was
ammonium acetate, and other organic amines were of low
reactivity for the desired conversion. Hence, compound 28 was
mixed with ammonium acetate, and NaBH3CN was added to
reduce the slowly-formed imine intermediate. The direct reductive
amination products with free 2-amino group were inseparable
diastereomeric mixture by regular chromatography methods, and
Boc protection was immediately applied to yield compounds 29
and 30, which were readily purified by flash chromatography on
silica gel. The stereochemical course of this reductive amination
was influenced strongly by the substrate structure, as fine tuning of
the reagents and conditions has little effect on the outcome of C-2
chirality. That is to say, although compound 30 would be the
thermodynamically favoured product, a strong shielding effect by
the difluorophenyl moiety [20] could prevent the reducing reagent
approaching from the same side, rendering more compound 29
formation in reality. Eventually we got diastereomeric ratio of 1.1 :
1 for the products 29 and 30. The following oxidative deprotection
of the dithiolane on compound 30 was sensitive to reaction media,
and MeCN was found the solvent to end the game, along with a
typical hypervalent iodine reagent phenyliodine bis(trifluoroacetate)
(PIFA), to yield compound 7 with 79% yield (Scheme 7).
Scheme 5. Highly efficient epoxide ring formation and regioselective epoxide
ring opening approach on C-pentopyranosides. Reaction conditions: a) TBAF,
THF, rt, then MsCl, TEA, DCM, 77% to 16, 85% to 19; b) H2SO4, aqueous
acetone, then NaOMe in MeOH, 63% to 17, 92% to 20; c) LAH, THF, -78 oC to
-10 C, 90% to 18, 94% to 21; d) Dess-Martin periodinane, DCM, 92%; e) NaI,
HOAc, NaOAc, acetone, 89%.
o
In above-described work, a short route to C-pentopyranosides
and 3-deoxy C-pentopyranosides with high stereo- and regio-
selectivity was developed from ent-8. Next, we looked for the
application of the products. We noticed that the new diabetes drug
Omarigliptin 6 is a challenging synthetic target, which embraces a
masked 3-deoxy C-pentopyranoside. To date, only Merck has
developed two routes for the key intermediate 7, which could be
converted to Omariglitin 6 in two steps. The first laboratory route
with low selectivity produced different stereoisomers and might be
suitable for the early phase of drug discovery. [6] The latter 10-steps
synthesis was highly efficient for the manufacture of 7, but
tolerated little structural variation on the 3-deoxy C-
pentopyranoside skeleton. [7,8a] We now describe the third route to
compound 7, from the carbohydrate materials obtained above
(Scheme 6).
Scheme 7. A new method leading to the key intermediate 7 for the synthesis of
Omarigliptin. Reaction conditions: a) Dess-Martin periodinane, DCM, 90%; b)
NH4OAc, NaBH3CN, MeOH, then Boc2O, 35% to 29, 32% to 30; c) PIFA,
MeCN, water, 79%.
Initially, we expected that the 2-amino group could be installed
by displacement of 2-OH on compound 23. In this way, the
chirality on C-2 would correspond well to that on Omarigliptin.
Thus, Compound 23 was protected with dithiolane to compound 24
and then converted to mesylate 25. The yield of mesylation was
only 52%, much lower than our expectation. Furthermore, the
displacement of the mesylate was rather difficult, and no useful
yields could be obtained. We suspected that the dithiolane
protection on C-4 posed strong steric interference to the chemistry
on C-2. Consequently, compound 23 was protected with
olefination to give compound 26, which underwent a facile
mesylation to compound 27. Nevertheless, we found again
difficulty in displacing the 2-OMs group on compound 27 with
different nucleophiles. With more forcing reaction conditions, only
elimination products were isolated (Scheme 6).
]
Different from both of Merck’s routes, [
our carbohydrate
6,7,8a
approach to compound 7 will allow more substitution variations on
the 3-deoxy C-pentopyranoside skeleton. Consequently, analogues
of Omarigliptin could be conveniently prepared with our method.
Conclusions
In conclusion, we demonstrated that the epoxide approach was
viable and versatile on C-glycosides. From a readily available
lactone 8, through stereoselective C-glycosylation reaction, and
regioselective epoxide ring opening approach, some valuable C-
pentopyranosides 11a-e and 3-deoxy C-pentopyranosides 18, 21,
and 23 were prepared efficiently in less than 5 steps. From
compound 23, a key synthetic intermediate 7 for Omarigliptin 6
was prepared in 4 steps. This is the first carbohydrate approach to
Omarigliptin 6. As both D- and L-arabinose are inexpensive starting
materials, not only 8 and ent-8 can both be made conveniently, but
also all enantiomers of our products can be obtained at low cost.
Experimental Section
Scheme 6. Preparation of mesylate derivatives of compound 23. Reaction
conditions: a) dithioglycol, BF3 etherate, DCM, 91%; b) MsCl, TEA, DCM,
52% to 25, 95% to 27; c) MePPh3Br, n-BuLi, THF, 90%.
Under nitrogen atmosphere, compound 12e (19.1 g, 99.19 mmol, 3.0
equiv.) was dissolved in ether (100 mL), cooled to -90 oC, and treated with
Submitted to the European Journal of Organic Chemistry
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European Journal of Organic Chemistry
10.1002/ejoc.201601074
2672. (b) K. V. Booth, F. P. da Cruz, D. J. Hotchkiss, S. F. Jenkinson, N.
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Tetrahedron: Asymmetry 2008, 19, 2417-2424.
n-BuLi (41.33 mL, 1.6 M in hexanes, 66.12 mmol, 2.0 equiv.). The mixture
was stirred at this temperature for 20 min, treated with a solution of ent-8
o
(10.0 g, 33.06 mmol, 1.0 equiv.) in ether (100 mL), and kept at -90 C for
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another hour. After the reaction was completed, sat. aq. NH4Cl was added
and the mixture was warmed to RT. The mixture was extracted with TBME
for several times. Combined organic phases were dried, coevaporated with
toluene for several times, dissolved under nitrogen into DCM (150 mL),
and cooled to -78 oC. To this cooled solution, Et3SiH (5.8 mL, 36.37 mmol,
1.1 equiv.) was added dropwise, followed by TMSOTf (7.03 mL, 36.37
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o
mmol, 1.1 equiv.). The reaction was kept at -78 C for one hour, quenched
with sat. aq. NaHCO3 and the phases were separated. The organic phase
was evaporated to dryness and the residue was purified with flash
chromatography on silica gel (10:1, 60 - 90 oC petroleum ether – EtOAc) to
afford product 11e (white solid, 12.58 g, 95%).
Supporting Information (see footnote on the first page of this article):
experimental details and copies of NMR spectra.
Acknowledgments
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This work was supported by the National Natural Science Foundation of
China (81673309, 81273368), National Science & Technology Major
Project “Key New Drug Creation and Manufacturing Program”, China
(2014ZX09507-002), and "Personalized Medicines - Molecular Signature-
based Drug Discovery and Development", Strategic Priority Research
Program of the Chinese Academy of Sciences, Grant No. XDA12020310.
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Published online: ((will be filled in by the editorial staff))
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Submitted to the European Journal of Organic Chemistry
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European Journal of Organic Chemistry
10.1002/ejoc.201601074
Entry for the Table of Contents ((Please choose one layout.))
((Key Topic))
Tongchao Liu, Jian Hou, Wuchen Xie,
You Li, Huanming Ren, Jianpeng
Liang, Bing Xiong, Guohua Chen,
*
Maosheng Cheng, Dongmei Zhao,
Jingkang Shen,* Yue-Lei Chen*
…….... Page No. – Page No.
Stereoselective and Regioselective
Preparations of C-Pentopyranosides
and Formal Synthesis of Omarigliptin
From a readily available carbohydrate chiral pool lactone 8, through stereoselective C-
glycosylation reaction and versatile epoxide approach, some valuable C-
pentopyranosides and 3-deoxy C-pentopyranosides, including the key intermediate 7
for Omarigliptin, were prepared efficiently.
Keywords: C-glycoside / glycosylation
/ omarigliptin / epoxide / stereoselective
synthesis
Submitted to the European Journal of Organic Chemistry
5
This article is protected by copyright. All rights reserved