Azasilanes have excellent bioactivities; however, asymmetric synthesis of azasilinan-6-one with a substitution at the second potion has been investigated very little. In this paper, (R)-2-[3-(methoxymethoxy)propyl] -3,3-diphenyl-1-tosyl-1,3-azasilinan-6-one was successfully synthesized.
Trang 1This paper is available online at http://stdb.hnue.edu.vn
ASYMMETRIC SYNTHESIS OF
(R)-2-[3-(METHOXYMETHOXY)PROPYL]-3,3-DIPHENYL-1-TOSYL-1,3-AZASILINAN-6-ONE
Duong Quoc Hoan1 and Scott McN Sieburth2
1Faculty of Chemistry, Hanoi National University of Education
2Department of Chemistry, Temple University, the United States of America
Abstract. Azasilanes have excellent bioactivities; however, asymmetric
synthesis of azasilinan-6-one with a substitution at the second potion has
been investigated very little In this paper, (R)-2-[3-(methoxymethoxy)propyl]
-3,3-diphenyl-1-tosyl-1,3-azasilinan-6-one was successfully synthesized The
chiral center of silylsulfinamide was prepared by the addition of silyl lithium
to (R)-Davis’ chiral sulfinimine Cyclization of δ-amino carboxylic acid gave
1,3-azasilinan-6-one that can be an important product to synthesize 2-substituted
1,3-azasilinan rings Structures of all new compounds were confirmed by IR,1H
and13C-NMR, along with the exact mass
Keywords: Synthesis,
(R)-2-[3-(methoxymethoxy)propyl]-3,3-diphenyl-1-tosyl-1,3 azasilinan-6-one, IR,1H and13C-NMR
1 Introduction
Nitrogen-containing heterocycles constitute structural frameworks in a plethora
of pharmaceuticals and alkaloids and are essential components of the pharmacophore [2, 3, 6] In recent years, there has been an interest in the preparation of heterocycles
in which one of the ring carbons has been replaced by silicon atoms A few bioactive silicon-nitrogen heterocycles have thus far been synthesized and screened for bioactivity
For example, the dopamine receptor antagonist silahaloperidol 1 (Figure 1) displays
improved selectivity compared to haloperidol Furthermore, its metabolic fate in human liver microsomas does not produce a silicon analogue of the neurotoxic metabolite HPP+ (Hereditary pyropoikilocytosis), which is responsible for the severe side effects of haloperidol [4] Other heterocyclic sila analogues have been prepared, including a class
of spirocyclic acceptor ligands, such as 2 [5] the neurotropic tetrahydroisoquino-line sila
Received January 2, 2014 Accepted August 15, 2014.
Contact Duong Quoc Hoan, e-mail address: hoanqduong@gmail.com
Trang 2analogue 3 [5] and the silicon analogue 4 [9] of the anti-depressive agent dimetracrine
(Figure 1) Another important compound in the biorganosilicon area is a sila analogue of
proline prepared enantioselectively by Vivet et al [8].
Figure 1 Examples of bioactive silicon-nitrogen heterocycles
Annaliese K Franz et al have a detail review of advantages gained when carbons
are replaced by silicon for bio-activities and medicinal properties of silicon containing compounds Because it is larger than carbon, the silicon plays an important role in increasing lipophilicity, and flexibilities of organosilicon molecules often enhances cell and tissue penetration and alter the potency and selectivity of the silicon structure relative
to the carbon structure [1]
Scheme 1 Retrosynthesis of 1,3-azasilinan-6-one (5)
Different approaches have been developed to prepare such heterocyclic systems containing silicon and nitrogen [1, 8] However, few syntheses have targeted 2-substituted 1,3-azasilaheterocycles These include the reaction of a bishaloalkylsilane with a primary amine and a nonregioselective aminomercuration which yielded a 2-substituted azasilinane as a by-product [1] In this paper, a flexible and efficient approach to the stereo controlled synthesis of a 2-substituted-1,3-azasilinan-2-one is reported The synthetic
route is outlined in Scheme 1, whereby the azasilaheterocycle 5 can be formed by an intra
Trang 3molecular cyclization, respectively The substrates 6 would be prepared from sulfinimine
7 and silyl lithium would be made from lithiation of 8, a strategy recently and successfully
developed by Sieburth’s group
2 Content
2.1 Experiment
All IR spectra were recorded on a Mattson 4020 GALAXY series FT-IR (Germany) NMR spectra were studied on 400 Bruker and Avance III 500 spectrometers (Germany) The Perkin Elmer Model 341 Polarimeter was used to obtain optical rotations
* 3-(Diphenylsilyl)propan-1-ol (8)
To a solution of diphenylsilane (9) (10.0 g, 54.3 mmol) in heptane (150 mL) was
added allylic alcohol (5.5 mL, 65.2 mmol), tert-dodecylmercaptan (1.2 mL, 5.4 mmol)
and AIBN (0.44 g, 0.26 mmol) The resulting mixture was heated to 75◦C for 19 h, and then concentrated in vacuo Flash column chromatography using a gradient eluent (100:1
to 95:5 hexane and ethyl acetate) gave alcohol 8 (11.2 g, 80%) as a colorless oil Rf = 0.6 (hexane/ethyl acetate 6:1) Rf = 0.30 (4: 1 hexane/ethyl acetate) IR (neat) 3337 (broad),
2931, 2119, 1428 cm−1;1H-NMR (400 MHz, CDCl3) 7.54 - 7.59 (m, 4H), 7.34 - 7.43
(m, 6H), 4.88 (t, J = 3.8 Hz,1H), 3.64 (t, J = 6.5 Hz, 2H), 1.67 - 1.76 (m, 2H), 1.27 (br,
1H), 1.14 - 1.21 (m, 2H);13C-NMR (125 MHz, CDCl3) 135.1, 134.2, 129.7, 128.1, 64.9, 27.5, 8.1
* (R)-N-1-[(3-hydroxypropyl)diphenylsilyl]-4-(methoxymethoxy)butyl-4-methylbenzene sulfonamide (6)
To a mixture of lithium (1.73 g, 247 mmol) in THF (20 mL) at 0◦C in dry argon gas
was added by-compound 8 (3.0 g, 12.4 mmol) The mixture was stirred at 0◦C until the reduction was completed The progress of reaction was monitored by NMR The solution then was cooled to -78◦C, transferred via a cannula to a solution of sulfinimine 7 (0.73
g, 4.1 mmol) in THF (10 mL) at -78 ◦C for more than 15 min The resulting solution was stirred at -78◦C for 5 hr, gradually warmed up to room temperature and stirred for overnight The reaction was quenched by water (100 mL), and extracted by ethyl acetate (3× 30 mL) The organic combination phase was washed by water (3 × 50 mL), and then
dried over with Na2SO4, concentrated in vacou Flash column chromatography gave crude
sulfinamide 11 (1.3 g, 76%) The sulfinamide 11 (1.3 g, 3.1 mmol) was dissolved in DCM
(20 mL) at 0◦ C was added 77% m-CPBA (0.83 g, 3.72 mmol) The progress of reaction was monitored by TLC The excess m-CPBA was quenched by saturated Na2SO3 The mixture was extracted with DCM (3× 30 mL) Combination of organic phases was dried
over with Na2SO4, concentrated in vacou Flash column chromatography gave sulfone
6(1.45 g, 89%) as a colorless oil Rf = 0.58 (hexane/ethyl acetate 1:2); [α]20D = +9.4 (c
0.085, CHCl3); IR: 3289, 3068, 2926, 2874, 1598, 1540, 1155, 1111, 702 cm−1;1H-NMR
Trang 4(400 MHz, CDCl3): δ 7.66 (d, J = 7.4 Hz, 2H), 7.5 - 7.3 (m, 10H), 7.2 (d, J = 8.0 Hz, 2H), 3.56 - 3.50 (m, 1H), 3.46 (t, J = 6.5 Hz, 2H), 3.25 - 3.20 (m, 2H), 3.21 (s, 3H), 2.4
(s, 3H), 1.87 (br, 1H), 1.72 - 1.62 (m, 1H), 1.5 - 1.3 (m, 5H), 1.0 (m, 2H);13C-NMR (100 MHz, CDCl3): δ 143.2, 138.7, 135.7, 135.5, 132.6, 131.9, 130.1, 129.6, 128.3, 127.2,
96.2, 67.3, 65.2, 55.2, 42.0, 29.8, 29.1, 27.3, 26.6, 21.6, 7.45 Exact mass: [M - Na]+
calcd for [C28H37NNaO5SSi]+ 550.2054, found 550.2035
* (R)-3-[4-(Methoxymethoxy)-1-(4-ethylphenylsulfonamido)butyl] diphenylsilyl propa noic acid (22)
To a solution of sulfonamide 6 (1.0 g, 1.9 mmol) in a mixture of solvent
DCM/CH3CN/ water (1/1/1, 50 mL) was added RuCl3 (3.9 mg, 0.019 mmol), and then NaIO4 (1.6 g, 7.6 mmol) The resulting solution was stirred at room temperature for
an hour The progress of reaction was monitored by TLC The mixtures reaction was extracted with DCM (3× 30 mL), then the combination of organic phase was dried over
Na2SO4, concentrated in vacou Flash column chromatography gave acid 22 (0.7 g, 68%)
as a colorless oil Rf = 0.4 (tail) (hexane/ethyl acetate 2/1) [α]20
D = +12.0 (c 0.05, CHCl3) IR: 3205 - 2560 (br), 3284, 3070, 2883, 1705, 1592, 1111, 734 cm−1;1H-NMR (500 MHz, CDCl3): δ 7.66 (d, J = 8.2 Hz, 2H), 7.5 - 7.3 (m, 10H), 7.2 (d, J = 7.8 Hz, 2H), 4.56 (d,
J = 9.4 Hz, 1H), 4.44 (s, 3H), 3.57 - 3.51 (m, 1H), 3.17 - 3.19 (m, 2H), 3.22 (s, 3H), 2.3
(s, 3H), 2.22 - 2.17 (m, 1H), 1.71 - 1.62 (m, 1H), 1.46 - 1.40 (m, 1H), 1.37 (dd, J = 8.6,
4.2 Hz, 1H), 1.36 - 1.30 (m 3H); 13C-NMR (125 MHz, CDCl3): δ 179.5, 143.4, 138.6,
135.6, 135.5, 131.7, 131.1, 130.4, 129.7, 128.5, 127.1, 96.2, 67.3, 55.2, 41.9, 29.1, 28.2, 27.3, 21.6, 6.5; Exact mass: [M - Na]+ calcd for [C28H35NNaO6SSi]+ 564.1847, found 564.1819
* (R)-2-[3-(Methoxymethoxy)propyl]-3,3-diphenyl-1-tosyl-1,3-azasilinan-6-one (5)
To solution of acid 22 (0.1 g, 0.18 mmol) in THF (4mL) at -20◦C was added triethyl
amine (63 µL, 0.45 mmol) followed by PivCl (22 µL, 0.18 mmol) The solution was stirred
at -20◦ C for an h, and then added LiCl (11.3 mg, 0.27 mmol) followed (S)-oxazolidione
(25.5 mg, 0.2 mmol) The mixture was stirred at the same temperature for an hour, and then at 0◦C for 2 h, quenched with saturated NH4Cl (5 mL), extracted with ethyl acetate (3 × 5 mL) The combined organic layers were washed brine (10 mL), dried over with
Na2SO4, and concentrated in vacou Column chromatography gave 5 (90 mg, 92%) R f
= 0.7 (hexane/ethyl acetate 1/1); [α]20
D = +47.0 (c 0.39, CHCl3); IR: 3070, 3012, 2926,
2883, 1694, 1591, 1343, 1107, 715 cm−1;1H-NMR (400 MHz, CDCl3): δ 7.7 (d, J = 8.0
Hz, 2H), 7.6 - 7.3 (m, 10H), 6.98 (d, J = 8.0 Hz, 2H), 4.89 - 4.84 (m, 1H), 4.5 (s, 2H),
3.48 - 3.40 (m, 2H), 3.22 (s, 3H), 2.93 - 2.79 (m, 2H), 2.3 (s, 3H), 1.86 - 1.72 (m, 3H),
1.65 (ddd, J = 15.3, 6.0, 4.0 Hz, 1H), 1.62 - 1.54 (m, 1H), 1.36 (ddd, J = 15.3, 13.3, 7.2
Hz, 1H);13C-NMR (100 MHz, CDCl3): δ 173.2, 144.2, 136.4135.2, 135.2, 132.6, 132.3,
130.7, 129.1, 128.9, 128.8, 128.6, 96.3, 67.0, 55.2, 45.2, 33.8, 30.4, 28.3, 21.7, 4.3; Exact mass: [M - Na]+calcd for [C28H33NNaO5SSi]+546.1741, found 546.1724
Trang 52.2 Synthesis, results and discussion
Alcohol 8 was synthesized from diphenylsilane (9) and allylic alcohol in 80% yield.
It is noteworthy that the synthesis of alcohol 8 can be scaled up to 100 g of diphenylsilane (9) (Scheme 2).
Scheme 2 Radical chain hydrosilylation of allylic alcohol
In general, radical chain hydrosilylation of alkenes using R3SiH is not very helpful, since the hydrogen abstraction step is slow under standard experimental conditions; however these reactions can be promoted under milder conditions by the presence of catalytic amounts of a thiol [12] Thus, the thiol acts as the catalyst and the H transfer agent in propagation steps (Scheme 3) Under high temperature of the initiation step, AIBN (azobisisobutyronitrile) is decomposed to eliminating a molecule of nitrogen gas
to form two 2-cyanoprop-2-yl radicals (reaction 1, Scheme 3) The radical reacts with thiol XSH to yield thiyl radical (reaction 2, Scheme 3), and then the thiyl radical abstract
a hydrogen atom from the R3SiH The resulting R3Si radical adds to the double bond
to give a radical adduct, which then reacts with the thiol and gives the addition product together with ‘fresh’ XS radicals to continue the chain Chain reactions are terminated by radical-radical combination or disproportionation reactions, Scheme 3
Scheme 3 Propagation steps for radical-based hydrosilylation catalyzed by thiol
With large amount of the alcohol 8 in hand, the alcohol 8 was treated with lithium
metal at -78 ◦C in tetrahydrofuran (THF) to make (Si,O)-dianion 10 The reaction
mixture was turned in black and released hydrogen gas The addition of (Si,O)-dianion
to sulfinimine 7 gave sulfinamide 11 in 75% yield as a crude product Due to instability
of sulfinamide 11 on silica gel, it was oxidized by m-CPBA (meta-chloroperoxybenzoic
acid) to give a stable sulfonamide 6 in 89% yield, Scheme 4.
Trang 6Scheme 4 Synthesis of sulfonamide 6
Mechanism of lithium (Si, O)-dianion 10 formation and similarities is still unclear Yingjian Bo and Scott Sieburth [10] proved that the first step of the lithiation of 12
(Scheme 5, part A) is a reduction of Si-O bond and open up the ring to form (Si-O)-dianion
13 After 4 h, an asymmetric and a symmetric alcohols, hydrolysis products of (O, O)-dianion and (Si, O)-dianion, were separated by a flash column chromatography To explain the formation of these two alcohols, the either (Si)-anion or (O)-anion substitutes alkoxy of silicon following two path ways a and b and form two correlative dianions
14 , and 15 These two dianions were reduced by lithium to yield only (Si, O)-dianion
16 [13] In our case (Scheme 5, part B), Li reacted with hydroxyl group of alcohol 8
to release hydrogen gas and (O)-anion 17 then cyclized (pathway a’) to form silafuran
18 The silafuran 18 was converted to (Si, O)-dianion 10 following the same manner of
chemistry in Scheme 5, part A On the other hand, lithium reacted with both hydroxyl
group and Si-H to produce the same (Si, O)-dianion 10 (path way b’), Scheme 5, part B.
Scheme 5 Lithiation of Si-O and Si-H bond cleavages
Absolute stereochemical assignment of the major isomer was inferred by analogy
upon X-ray diffractions studies of many related single crystals such as compound 19, and
Trang 720[14-20] Both structures showed that the major isomer is the opposite isomer than the one predicted via the closed transition-state model suggested by Ellman for the majority
of organometallic additions Therefore, an open, acyclic transition state was proposed
to explain the stereochemical results where the nucleophin attacks to the lest sterically
hindered effect (Figure 2, 21).
Figure 2 Absolute stereochemical assignment of the major isomer
and proposed acyclic transition state
Alcohol 6 was oxidized by a stoichiometric amount of NaIO4and catalytic amount
of RuCl3 to give acid 22 in 68% yield Carboxylic group was activated by PivCl (Pivaloyl chloride) in basic condition of triethylamine to form 1,3-azasilinan-6-one 5 in 92% yield.
Scheme 6 Synthesis of 1,3-azasilinan-6-one
A proposed mechanism of cyclization is shown in Scheme 7 In the presence of triethyl amine, carboxylic and tosyl amine were deprotonated, therefore carboxylate reacts
easily with pivaloyl chloride (PivCl) to yield anhydride 23 following cyclization to give 1,3-azasilinan-6-one 5 in high yield.
Scheme 7 Proposed mechanism of cyclization reaction
Trang 83 Conclusion
In conclusion, (R)-2-(3-(methoxymethoxy)propyl)-3,3-diphenyl-1-tosyl-1,3- azasili
nan-6-one (5) was synthesized successfully in five linear steps in 33% yield This
is an approach for the synthesis of 1,3-azasilaheterocycles with a substituent in the 2-position as analogs of cyclic alkaloids The synthesis involves hydridosilane lithiation and sulfinimine addition with good diastereoselectivity at the silicon bearing a stereogenic center, producing the desired compounds in excellent yield This result can be applied for synthesis of a sila analogue of natural product mimics
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