Abstract. Silanediols are being considered recently due to their
good biological activities, such as HIV inhibition and inhibition of
angiotensin-converting enzymes (ACE). Synthesis of silanediols needs to
have various analogs of silafurans. An asymmetric synthesis of silafuran
(S)-4-[2-(1,3-dioxolan-2-yl)ethyl]-2,2-diphenyl-2-silafuran containing a functional
group was produced successfully in this work using the chiral catalyst ferrotan. The
absolute configuration was assigned by analogy. HPLC with chiral column was use
to prove the ratio of enantiomer excess. All new compounds were characterized
with IR, NMR and MS spectra.
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JOURNAL OF SCIENCE OF HNUE
Chemical and Biological Sci., 2014, Vol. 59, No. 9, pp. 43-50
This paper is available online at
ASYMMETRIC SYNTHESIS OF A NEW SILAFURAN
Duong Quoc Hoan
Faculty of Chemistry, Hanoi National University of Education
Abstract. Silanediols are being considered recently due to their
good biological activities, such as HIV inhibition and inhibition of
angiotensin-converting enzymes (ACE). Synthesis of silanediols needs to
have various analogs of silafurans. An asymmetric synthesis of silafuran
(S)-4-[2-(1,3-dioxolan-2-yl)ethyl]-2,2-diphenyl-2-silafuran containing a functional
group was produced successfully in this work using the chiral catalyst ferrotan. The
absolute configuration was assigned by analogy. HPLC with chiral column was use
to prove the ratio of enantiomer excess. All new compounds were characterized
with IR, NMR and MS spectra.
Keywords: Silanediol, silafuran, silyl ether, ferrotan, enantiomer excess.
1. Introduction
Organisilanes are not naturally made. However, with modification of well known
biologically active compounds to silicon analogs there is a high chance of success. For
example, the design of C2 symmetry-based inhibitors that mimic the symmetry of the
human immunodeficiency virus type-1 (HIV-1) was described by Erickson et al.[3] and
Kempf et al.[7]. Based on that strategy, Merck designed a new set of pseudo C2 symmetric
inhibitors based upon L-685, 434 (IC50 = 0.23 nM), named L-700, 417 (1, IC50 = 0.67
nM). Silanediol 2 was found to have a Ki of 2.7 nM for inhibition of HIV-1, only slightly
less effective than carbon analog 1, Figure 1 [2].
Silanediol protease inhibitor 4 was assembled as an analog of Almquist’s
ketone-based Angiotensin-converting enzyme (ACE) inhibitor 3. Ketone 3 was found to
have an IC50 of 1 nM, whereas silanediol 4 was found to have an IC50 value of 3.8 nM
[8]. Silanediol 6, a metalloprotease inhibitor of thermolysin, was prepared by analogy to
the phosphinic acid inhibitor 5. Inhibition of thermolysin by silanediol 6 (Ki = 41 nM)
was comparable with that of phosphinic acid 5 (Ki = 10 nM). Both the phosphinic acid
and the silanediol hydroxyls were found to coordinate the active site zinc and by X-ray
crystallography, thus inhibit the enzyme by mimicking the transition state without being
hydrolysable.
Received October 8, 2014. Accepted November 5, 2014.
Contact Duong Quoc Hoan, e-mail address: hoanqduong@gmail.com
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Duong Quoc Hoan
Figure 1. Silanediol inhibitors
In general, the new silanediol inhibitors have a core structure like 7. It has
two chiral centers: -aminosilane and the -silyl acid. In addition, various analogs of
silanediols depend on varieties of R1 groups. To date, there are no silanediol inhibitors
with R1 containing any functional group that might be converted to various derivatives.
Controlling the -silyl acid stereogenic center of 7 depends upon the synthesis of silafuran
8 [1]. However, synthesis of 8 is a challenge. In this paper, we present the initial synthetic
results of the first asymmetric synthesis of a new silafuran containing a functional for new
synthetic silanediol inhibitor synthesis.
Figure 2. Core structure of silanediols
2. Content
2.1. Experiment
Solvents and other chemicals were purchased from Sigma-Aldrich, Gelest and TCI
and were used as received unless otherwise indicated. The 1H-NMR and 13C-NMR spectra
were recorded on a Bruker Avance 500 NMR spectrometer in CDCl3. Chemical-shift data
for each signal were reported in ppm units with tetramethylsilane (TMS) as the internal
reference, where TMS is 0 Hz. IR spectra were recorded on a Mattson 4020 GALAXY
Series FT-IR. Mass spectra were obtained from the Mass Spectrometry Facility of the
University of California at Riverside on an Agilent 6210 TOF mass spectrometer. A
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Asymmetric synthesis of a new silafuran
Perkin-Elmer Series 200 system (pump, degasser and UV/Vis Detector) was used for
HPLC.
* 2-(2-chloroethyl)-1,3-dioxolane (10)
To a solution of acrolein (8.4 g, 150 mmol) in CH2Cl2 (50 mL) at 0 ◦C was slowly
added trimethylsilyl chloride (21.7 g, 200 mmol). This was then added a solution of glycol
(9.31 g, 150 mL) in CH2Cl2 (50 mL). The mixture was stirred at 0 ◦C for 30 min and rt.
for 15 min, then refluxed for 4 h, and then washed with water (3 50 mL) and brine (2
15 mL). The organic was dried over MgSO4 and concentrated to give a crude product
which resembled a pale yellow oil (18.3 g, 92%). 1H-NMR (400 MHz, CDCl3): H , 4.97
(t, J = 4.6 Hz, 1H), 3.90 (m, 2H), 3.8 (m, 2H), 3.57 (t, J = 7.2 Hz, 2H), 2.06 (td, J = 7.2,
4.6 Hz, 2H).
* 2-(2-Iodoethyl)-1,3-dioxolane (11)
To a solution of the crude 2-(2-chloroethyl)-1,3-dioxolane (13.66 g, 100 mmol) in
acetone (100 mL) was added NaI (75.0 g, 500 mmol). This mixture was refluxed. The
progress of the reaction was monitored with TLC (hexane/ethyl acetate = 9/1, Rf = 0.62).
Acetone was removed in vacour to give the crude title product, which resembled a pale
yellow oil, with an 100% yield (22.8 g, 100 mmol). 1H-NMR (400 MHz, CDCl3): H ,
4.92 (t, J = 4.6 Hz, 1H), 3.95 (m, 2H), 3.87 (m, 2H), 3.20 (t, J = 7.6 Hz, 2H), 2.2 9 (td,
J = 7.7, 4.6 Hz, 2H).
* Diethyl 2-(2-(1,3-dioxolan-2-yl)ethyl)malonate (12)
To a solution of NaH (60% dispersion in mineral oil, 2.0 g, 50 mmol) in THF
(50 mL) was added diethyl malonate (10 mL, 62 mmol) at 0 ◦C over a 15 min
period of time. The mixture was stirred at 0 ◦C for 10 min, and rt. for 20 min, then
2-(2-iodoethyl)-1,3-dioxolane (11, 9.2 g, 40 mmol) was added. The reaction was refluxed
for 1 h and partitioned between water (100 mL) and ethyl acetate (50 mL). The aqueous
layer was extracted with ethyl acetate (3 10 mL). The combined organics were washed
with water (50 mL), and then brine (30 mL), and then dried over MgSO4 and concentrated
in vacuo to give a pale yellow liquid. The excess diethyl malonate was recycled with
fractional distillation at 60 ◦C (3 mmHg). Flash column chromatography (hexane/ethyl
acetate = 4/1) gave 12 (8.4 g, 81%) as a clear liquid. Rf = 0.42 (hexane/ethyl acetate =
4/1). 1H-NMR (400 MHz, CDCl3): H , 4.88 (t, J = 4.9 Hz, 1H), 4.19 (td, J = 7.7, 1.7 Hz,
4H), 3.96 (m, 2H), 3.84 (m, 2H), 3.40 (t, J = 7.7 Hz, 1H), 2.02 (m, 2H), 1.71 (m, 2H),
1.26 (t, J = 7.7 Hz, 6H); 13C-NMR (100 MHz, CDCl3): C 169.6, 104.1, 65.2, 61.7, 51.9,
31.5, 23.4, 14.4.
* Ethyl 4-(1,3-dioxolan-2-yl)-2-methylenebutanoate (13)
To a solution of diethyl 2-(2-(1,3-dioxolan-2-yl)ethyl)malonate (12, 7.0 g, 26.7
mmol) in absolute ethanol (5.0 mL) was added, over 2 h period of time, a solution of
KOH (1.5 g, 26.7 mmol) in absolute ethanol (30 mL) and then stirred for 30 h at rt..
The mixture was heated to 50 ◦C and filtrated to give a clear solution, concentrated in
vacuo and diluted with water (100 mL). The organic layer was extracted with ether (3
15 mL). The ethereal solution was saved to recycle diethyl-3-methoxymethoxypropyl
45
Duong Quoc Hoan
malonate. The aqueous phase was acidified with 5% HCl to pH = 5, and extracted
with ethyl acetate (3 20 mL). Combined organic layers were washed with water (3
50 mL), brine (30 mL), dried over MgSO4, and concentrated in vacuo to give crude
2-(ethoxycarbonyl)-4-(1,3-dioxolan-2-yl)butanoic acid (5.2 g, 83%).
The crude 2-(ethoxycarbonyl)-4-(1,3-dioxolan-2-yl)butanoic acid (5.2 g, 22 mmol)
was dissolved in ethyl acetate (50 mL), cooled to 0 ◦C, and added to N, N-diethyl amine
(2.65 mL, 25.4 mmol). This mixture was allowed to gradually warm to rt., added to a
portion of paraformandehyde (1.0 g, 33 mmol), and then refluxed at 90 ◦C for 2 h. The
mixture was cooled down to rt. and acidified with 5%HCl until pH = 5, and extracted with
ethyl acetate (3 10 mL). The organics were washed with water (2 50 mL), brine (2
20 mL), dried over MgSO4 and then concentrated in vacuo. Flash column chromatography
showed compound 13 (3.5 g, 80%) to be a colorless liquid. 1H-NMR (400 MHz, CDCl3):
H 6.15 (m, 1H), 5.55 (q, J = 2.7, 1.7 Hz, 1H), 4.89 (t, J = 4.6 Hz, 1H), 4.2 (q, J = 6.8
Hz, 2H), 3.96 (m, 2H), 3.85 (m, 2H), 2.43 (dd, J = 8.8, 7.4 Hz, 2H), 1.83 (m, 2H), 1.29
(t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): C 167.4, 140.5, 125.0, 104.3, 65.3,
61.0, 32.9, 26.8, 14.6.
* 4-(1,3-Dioxolan-2-yl)-2-methylenebutan-1-ol (14)
To a solution of ethyl 4-(1,3-dioxolan-2-yl)-2-methylenebutanoate (13, 4 g, 20
mmol) in THF (50 mL) was added DIBAL-H (1M in hexane, 40 mL, 40 mmol) over
a 30 min period of time at -40 ◦C. After stirring at -40 ◦C for 1 h, the mixture was allowed
to gradually warm to 0 ◦C, dropped slowly dry MeOH (10 mL), and added to a 37.5%
potassium sodium tartrate solution (20 mL) to give a biphasic solution, and then stirred
at rt. overnight. The aqueous layer was extracted with ether (3 20 mL). The combined
organics were washed with water (3 50 mL), brine (2 30 mL), dried over MgSO4 and
then concentrated in vacuo. Kugelrohr distillation (120 ◦C, 0.3 mmHg) yielded alcohol 14
(2.7 g, 85%) which appeared as a colorless liquid. Rf = 0.62 (hexane/ethyl acetate = 1/1);
1H-NMR (400 MHz, CDCl3): H 5.0 (dd, J = 0.7, 1.4 Hz, 1H), 4.88 (d, J = 1.4 Hz, 1H),
4.87 (t, J = 4.6 Hz, 1H), 4.0 (s, 2H), 3.97-3.91 (m, 2H), 3.88-3.82 (m, 2H), 2.1 (t, J = 8.0
Hz, 2H), 1.85-1.80 (m, 2H).
* [4-(1,3-Dioxolan-2-yl)-2-methylenebutanoxy]diphenylsilane (18)
To a solution of chlorodiphenylsilane (17, 2.2 g, 10.2 mmol) in ether (200 mL) was
added a mixture of 4-(1,3-dioxolan-2-yl)-2-methylenebutan-1-ol (14, 1.0 g, 6.5 mmol)
and triethyl amine (1.6 mL, 11.3 mmol) in ether (30 mL) over a 15 min period of time via
cannular at rt. and stirred at the same temperature overnight. After filtration, the mother
liquid was concentrated in vacuo, and distilled (200 ◦C, 0.3 mmHg) to give 18 (2.3 g, 68%)
which appeared as a colorless liquid. IR: 3070, 1952, 2879, 2125, 1589, 1429, 1122, 1056,
734, 689 cm−1; 1H-NMR (400 MHz, CDCl3): H 7.6-7.3 (m, 10H), 5.4 (d, J = 1.0 Hz,
1H), 5.1 (d, J = 0.8 Hz, 1H), 4.9 (s, 1H), 4.8 (t, J = 4.7 Hz, 1H), 4.2 (s, 2H), 3.97-3.91
(m, 2H), 3.88-3.82 (m, 2H), 2.1 (t, J = 8.6 Hz, 2H), 1.84-1.79 (m, 2H); 13C-NMR (100
MHz, CDCl3): C 147, 135, 134.7, 130.7, 128, 110, 104, 67, 65, 32, 27; Exact mass: [M
- H]+ calcd. for [C20H25O3Si]+ 341.1567, found 341.1568.
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Asymmetric synthesis of a new silafuran
* 4-[2-(1,3-Dioxolan-2-yl)ethyl]-2,2-diphenyl-2-silafuran (20)
Non-asymmetric hydrosilylation: To a stirred solution of the Wilkinson’s catalyst
(50 mg, 54 mol) in DCM (5 mL) was added silyl ether 18 (1.0 g, 3 mmol). The reaction
was monitored using the 1H-NMR method. The mixture was concentrated in vacuo and
distilled at 230 ◦C (0.3 mmHg) to give silafuran (R/S)-20 (0.89 g, 87%) which appeared
as a colorless liquid.
Asymmetric hydrosilylation: To a stirred solution of the ferrotane catalyst 19 (8 mg,
11 mol) and triethylammonium chloride (2.8 mg, 23 mol) in DCM (6 mL) at rt. was
added silyl ether 18 (0.28 g, 0.8 mmol). Progress of the reaction was monitored using the
1H-NMR method. The mixture was diluted with hexane (v 1/1) and then passed through
Celite. The mother solution was concentrated to give silafuran (S)-20, (0.3 g, 80%) which
appeared as a colorless liquid. IR: 3061, 2948, 2879, 1589, 1558, 1429, 1116, 1043, 1043,
734, 700 cm−1; 1H-NMR (400 MHz, CDCl3): H 7.62-7.36 (m, 10H), 4.8 (t, J = 4.8 Hz,
1H), 4.29 (dd, J = 6.4, 9.2 Hz, 1H), 3.98-3.92 (m, 2H), 3.89-3.83 (m, 2H), 3.6 (t, J = 10.1
Hz, 1H), 2.36-2.24 (m, 1H), 1.82-1.79 (m, 1H), 1.76-1.70 (m, 1H), 1.66-1.60 (m, 1H), 1.5
(dd, J = 6.4, 14.8 Hz, 1H), 1.49-1.45 (m, 1H), 0.8 (dd, J = 10.4, 14.8 Hz, 1H); 13C-NMR
(100 MHz, CDCl3): C 136, 135.6, 129.8, 128.3, 104.9, 67.1, 65.1, 36.8, 30.9, 28.2, 17.4.
* (+)-4-(1,3-Dioxolan-2-yl)-2-[(triphenylsilyl)methyl]butan-1-ol (21)
To a solution of silafuran (20, 0.1 g, 0.3 mmol) in ether (5 mL) was added a 3M
ethereal phenyl magnesium bromide solution (0.3 mL, 0.9 mmol). The mixture was stirred
at rt. for 1 h and then quenched with saturated ammonium chloride solution (5 mL).
The aqueous layer was extracted with ether (3 5 mL). The combined ether layers were
washed with brine (2 5 mL), dried over Na2SO4 and concentrated in vacuo. Column
chromatography showed compound 21 (120 mg, 78%) to be a colorless oil. Rf = 0.72
(hexane/ethyl acetate = 2/1); = +4.38 (c 1.095, CHCl3); IR: 3426 (br), 3068, 2921, 2879,
1587, 1473, 1427, 1108, 727, 701 cm−1; 1H-NMR (400 MHz, CDCl3): H 7.5-7.3 (m,
15H), 4.6 (t, J = 5.2 Hz, 1H), 3.88-3.85 (m, 2H), 3.81-3.75 (m, 2H), 3.4 (t, J = 6.2 Hz,
2H), 1.8 (s, J = 5.8 Hz, 1H), 1.61-1.51 (m, 4H), 1.51-1.45 (m, 1H), 1.45-134 (m, 1H);
(100 MHz, CDCl3): C 136.0, 135.6, 129.8, 128.3, 104.9, 67.1, 65.1, 36.8, 30.8, 28.2;
Exact mass: [M - Na]+ calcd. for [C26H30NaO3Si]+ 441.1856, found 441.1854.
Enantiomer analysis with HPLC: HPLC samples of () -21 and + -21 (5 mg) were
prepared in hexane/isopropanol (90/10, 0.5 mL) (note: if it can be seen with the naked eye
using a UV lamp on silica gel TLC, it is ready for HPLC analysis). These samples (20
L) were added into a Perkin-Elmer Series 200 system that was calibrated until a straight
baseline with elution of hexane/ isopropanol (90/10) was obtained. A UV-vis detector was
set in the range of 254 - 380 nm for the 20 min duration of the experiment. The flow rate
of elution was 1 mL/min.
2.2. Results and discussion
Alcohol 14 was synthesized in a straight forward fashion as shown in Scheme 1.
Acrolein 9 was selected as the starting material and reacted with ethylene glycol and
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Duong Quoc Hoan
TMSCl to give compound 10. The compound 10 did not need further purification for
the next step. A Finkelstein conversion of chloride 10 to iodide 11 was performed in
quantitative yield. Alkylation of malonate with iodide 11, saponification, decarboxylation,
formylation, elimination and reduction gave the final product 14, Scheme 1, [6].
Scheme 1. Synthesis of allyl alcohol 14
With the allylic alcohol in hand, the silicon moiety could be attached.
Chlorodiphenyl- silane (17, $205/50 g) and diphenylsilane (16, $160/100 g) are
commercially available but quite expensive. In addition, compound 16 or 17 needs
redistillation before it is used. In contrast, dichlorodiphenylsilane (15) is inexpensive
($90/2 kg, Gelest). Chlorodiphenylsilane (17) was made for 110.00/200 g including
solvent cost [5]. Dichlorodiphenylsilane 15 was slowly added to a solution of lithium
aluminum hydride (LAH) at 0 ◦C over a period of 1 h, Scheme 2. The solution was
refluxed 2 h, followed by careful work up using the Fieser & Fieser method [4].
Scheme 2. Synthesis a new silyl ether from inexpensive chlorodiphenylsilan
After removal of the ether, the mixture was diluted with pentane and held at rt.
to precipitate impurities. Filtration through a pad of Celite gave a clear solution that was
concentrated in vacuo, distilled at 70 ◦C (0.3 mmHg) to give diphenylsilane (16). CuCl2, a
brown solid, was added to the diphenylsilane (16) in catalytic amount of CuI. The reaction
was completed when the color changed from brown to white. The product 17 was distilled
with Kugelrohr (120 ◦C, 0.3 mmHg). The silyl ether 18 can now be made using the
inexpensive pathway. Asymmetric hydrosilylation (AIH) of silyl ether 18 followed the
protocol shown in [1], using catalytic ferrotane 19 (1 mol %) to give silafuran 20 in good
yield. Racemate of 20 were produced using Wilkinson’s catalyst (1 mol %), Scheme 3.
48
Asymmetric synthesis of a new silafuran
Scheme 3. Asymmetric hydrosilylation of the new silyl ether 20
It is impossible to use silafuran 20 directly on HPLC since it is not stable on silica
gel. Hence, in order to determine the ratio of enantiomer of silafuran 20, it was opened
with Grignard reagent to form alcohol 21 in excellent yield. The ratio of enantiomer of 21
is also the ratio of the silafuran. First, a chiral column on HPLC separated two enantiomers
of the racemate 20, Figure 3 (left picture) to confirm exactly the retention time on HPLC.
It was found that the first peak is at 12.83 min and the second isomer is at 16.01 min. By
the same method, HPLC separated the first one at 13.63 min and the second one at 16.23
min. Calculation showed the ratio to be 58% enantiomer excess, Figure 3. The absolute
configuration of the compound was confirmed by analogy [1], so it has S configuration.
Figure 3. Ratio of enantiomers of compound 21
3. Conclusion
A new silafuran was synthesized successfully following an inexpensive
pathway. Its synthesis has many steps that use simple purification methods
such as distillation without further purification needed. The stereogenic was
controlled with asymmetric hydrosilylation using a chiral catalyst to yield
49
Duong Quoc Hoan
4-[2-(1,3-dioxolan-2-yl)ethyl]-2,2-diphenyl-2-silafuran. Since the silafuran is unstable
on silica gel, the enantiomer excess was determined with HPLC with the product of
opening the silafuran by Grignard reagent to find 58% ee. The S absolute configuration
just was used results of its analogs. Structures were characterized with IR, NMR and high
resolution mass spectra.
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50