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A facile synthesis ofEnantiopure γ-Amino-And γ-Hydroxy-β-KetosulfonesSaumitra Sengupta a , Debarati SenSarma a &Somnath Mondal aa Department of Chemistry, Jadavpur University,Calcutta, 700032, INDIAPublished online: 23 Aug 2006.
To cite this article: Saumitra Sengupta , Debarati SenSarma & Somnath Mondal(1998) A facile synthesis of Enantiopure γ-Amino-And γ-Hydroxy-β-Ketosulfones,Synthetic Communications: An International Journal for Rapid Communication ofSynthetic Organic Chemistry, 28:23, 4409-4417, DOI: 10.1080/00397919808004476
To link to this article: http://dx.doi.org/10.1080/00397919808004476
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SYNTHETIC COMMUNICATIONS, 28(23), 4409-44 17 (1998)
A FACILE SYNTHESIS OF ENANTIOPURE y-AMINO- AND y-HYDROXY-P-KETOSULFONES
Saumitra Sengupta,* Debarati Sen S a m and Somnath Mondal
Department of Chemistry, Jadavpur University, Calcutta 700 032 INDIA
Abstract: Enantiopure y-amino and y-hydroxy-P-ketosulfones have been synthesized in high yields from a-diazoketones derived from the a-amino and a- hydroxy acid chiral pools.
Recently, we became interested in the chemistry of enantiopure y-amino- and y-
hydroxy-0-ketosulfones which, by virtue of having a chiral center adjacent to a
reactive 0-ketosulfone moeity,' appeared to hold much promise in asymmetric
synthesis. For example, these educts via an a-akylation-desulfonation sequence
promised a conceptually new synthetic route towards enantiopure a-amino and a-
hydroxy ketones2 whereas via appropriate variations of the Julia-protocols, they
can either lead to non-racemic 2' ally1 amines(alcoho1s) or to the y-amino(hydr0xy)
* To whom correspondence should be addressed
4409
Copyright 0 1998 by Marcel Dekker, Inc. www.dekker.com
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4410 SENGUPTA, SEN SARMA, AND MONDAL
vinyl sulfones3 which are interesting chiral probes of much importance in EPC
synthesis.
However, till now, little attention has been paid to such y-chiral-P-ketosulfones.
Thus. apart from a couple of reports on enantiopure y-amino-P-ketosulfones that
have been used in dipeptide isostere synthesis4 and less than a handful of y-
hydroxy(a1koxy)-P-ketosulfones that have served as intermediates in some total
synthesis of natural products,5 nothing especially is known on the synthetic utility
of these compounds. Hence, with a view to broaden the scope of these chiral
synthons, we embarked upon a program on their synthesis and reactivity studies
and as initial results towards these ends, describe a facile synthesis of a series of
enantiopure y-amino and y-hydroxy-P-ketosulfones starting from the a-amino and
a-hydroxy acid chiral-pools,6 respectively.
y-Amino and y-hydroxy(alkoxy)-P-ketosulfones, reported till date, have all been
synthesized via low temperature reaction of excess a-lithio methyl phenyl sulfone
with a-amino and a-hydroxy e ~ t e r s . ~ ’ ~ Our strategy, on the other hand, is pivoted
on the reactions of chiral-pool derived enantiopure y-amino- and y-acetoxy-a-
diazoketones which, in recent years, are receiving increasing attention as chiral
group transfer reagent^.^ In the event, the N-CO2Et protected amino acids 1A(a-
d) were converted to the corresponding a-diazoketones 2A(a-d) in good
The latter upon treatment with 47% HBr in ether at 0’ smoothly gave rise to the
corresponding a-bromoketones which, without further purifcation, were subjected
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y-AMINO- AND y-HYDROXY-PKETOSULFONES 441 1
to bromide displacement with NaSOzTol in DMF thus producing the y-amino$-
ketosulfones 3A(a-d) in high overall yields (Scheme 1, Tablel).
R
X A C O z H i or ii, iii X b+Nz-xb S02T0l
0 0 1A,B 2A,B 3A,B
A: X = NHC02Et B: X = OAc
R = Me, i-Pr, i-Bu, Bn, Ph
Scheme 1. i) (COC1)2 ,cat. DMF, CH2C12 , g0 to 250 (for X = NHCOzEt) ii) SOCh, Bz, reflux (for X = OAc); iii) excess CH 2N2,ether,0° iv) 47% HBr, ether, 0; v) NaSOzTol, DMF, 250.
The L-proline derived a-diazoketone 49 similarly gave rise to the corresponding
enantiopure P-ketosulfone 5 in 72% overall yield (Scheme 2).
4 5 (72%)
Scheme 2. i) 47% HBr, ether, 00; ii) NaS02To1, DMF, 25
The same sequence was next applied for the synthesis of enantiopure y-acetoxy-P-
ketosullbnes. For this purpose, the required a ' -acetoxy-a-diazoketones 2B(b-e)
were prepared from the respective (S)-a-acetoxy acids 1B(b-e)6b via acid chloride
formation (SOC12, Bz) and treatment with excess diazomethane in ether. Once in
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4412 SENGUPTA, SEN SARMA, AND MONDAL
Table 1. Preparation of a-Diazoketones 2A,B and b-Ketosulfones 3A,B (Scheme 1).
-
R
Me
i-Pr
i-Bu
Bn
i-Pr
i-Bu
Bn
Pha -
x
NHC02Et
11
,
OAc 37
9
2N2B
2Aa
2Ab
2Ac
2Ad
2Bb
2Bc
2Bd
2Be
Yield %
58
62
60
64
75
77
70
60
3N3B
3Aa
3Ab
3Ac
3Ad
3Bb
3Bc
3Bd
3Be
Yield %
71
73
75
71
70
73
93
73
a racemic
hand, these diazoketones 2B(b-e) were treated with 47% HBr in ether followed by
NaSOzTol in DMF to give the corresponding y-acetoxy-P-ketosulfones 3B(b-e)
also in high overall yields (Scheme 1, Table 1).
In summary, a facile new chiral-pool synthesis of enantiopure y-amino- and y-
hydroxy-P-ketosulfones has been developed. Synthetic uses of these hitherto
neglected chiral educts are currently under investigation.
Experimental
All melting points are uncorrected. IR Spectra were taken on a Perkin Elmer-297
spectrometer. 'H NMR spectra were recorded on Varian EM-360, JEOL FX- 100
and Varian XL-200 instruments. Optical rotations were measured on a JASCO
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y-AMINO- AND y-HYDROXY-PKETOSULFONES 4413
D1P-360 polarimeter at 25°C. The following compounds were prepared according
to literature procedures : lB(b-d),"b 2A(a-d)x'9 and 4.q
General procedure for the preparation of a ' -acetoxy-a-diazoketones 2B(b-
e): SOC12 (12 mmol) was added to the a-acetoxy acid 1B(b-e) (6 mmol) dissolved
in benzene (10 ml) and the solution heated under retlux for 3h. The solvent and
excess SOC12 were then removed under vacuo and twice azeotroped with benzene
to remove the last traces of SOC12. The a-acetoxy acid chloride thus obtained was
dissolved in CH2C12 (5 ml) and was added dropwise to a solution of diazomethane
[prepared from nitrosomethyl urea (18 mmol), KOH (54 mmol) in water (8 ml)] in
ether (25 ml) at 0". After being left overnight, the solution was washed with satd.
NaHC03 solution and dried (Na2S04). Removal of solvent followed by silica-gel
chromatography (20% EtOAc in pet. ether) gave the a ' -acetoxy-a-diazoketones
2B(b-e) as viscous oils. Their physical characteristics are reported in Table 2. In
addition, correct elemental (CHN) analyses (within k 0.4% of the theoretical
values) were obtained for each compounds.
General procedure for the preparation of y-amino- and 'y-acetoxy-P-
ketosulfones (3A,B and 5) :
47% HBr (0.14 ml, 1.2 mmol) was added dropwise to a solution of the a-
diazoketone (2A,B or 4) ( 1 .O mmol) in ether (5 d) at Oo. The mixture was stirred
for 45 min after which it was neutralized with satd. NaHCO3 soh. The ether layer
was separated, washed with water, dried (Na2S04) and the solvent removed in
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SENGUPTA, SEN SARMA, AND MONDAL
Table 2.Spectral -___I
Pdt
2Bb
2Bc
2Bd
2Be
3Ab
3Ac
3Ad
3Bb
3Bc
3Bd
3Be
mP ("C)
ail
3il
3il
ail
35-7
85-7
100-2
3il
3il
oil
118-120
ta for 2B(b-e) and 3A,B.
71.48 (5.8)
56.14 (5.5)
53.32 (8.6)
--
3.56 (2.5)
31.71 (0.7)
23.4 (1.0)
9.79 (3.0)
23.99 (4.2)
15.08 (3.5)
_-
v (cm-') (neat)
2 100,1730,1630
2100,1735,1635
21 10,1740,1635
2100,1740,1640
3320, 1715(br), 1685
3360, 1740(br), 1690
3340, 1725(br), 1690
1730,1590,1485
1720,1595,1450,
1730,1590,1485,
1740,1725,1595
6 (CDCls ) (J in Hz)
0.95 (d, 3H, J 7), 0.96 (d, 3H, J ; 7), 2.04-2.36 (m, IH), 2.12 (s , : 3H), 4.94 (d, IH, J 5), 5.44 (s,; 1 H). 0.9-1.0 (m. 6H), 1.5-1.8 (m, 3H),: 2.12 (s, 3H), 5.08 (dd, I H , J 4,8),; 5.39 (s, IH). 2.04 (s, 3H), 3.00 (dd, IH, Ji 8,12). 3.14 (dd, lH, J 4,12), 5.23:
7.3 (m, 5H). 2.18 (s, 3H), 5.40 (s, IH), 5.97 (s,; lH), 7.33-7.43 (m, 5H). 0.77 (d, 3H, J 6), 0.97 (d, 3% Jj 6), 1.24 (t, 3H, J 7), 2.28 (m, IH),; 2.44 (s, 3H), 4.00-4.48 (m, 5H),; 5.26 (br d, IH), 7.36 (d, 2H, J 8),: 7.80 (d, 2H, J 8). 0.97 (d, 6H, J 5.1), 1.26 (t, 3H, J ; 7), 1.61 (m. 3H), 2.50 (s, 3H),j 3.96-4.56 (m, 5H), 5.46 @r d,! lH), 7.40 (d, 2H, J 8), 7.83 (d,! 2H, J 8). 1.22 (t. 3H, J 7), 2.48 (s, 3H),;
(m, 4H), 4.62 (m, IH), 5.32 (br d,; IH), 7.12-7.48 (m, 7H), 7.73 (d,; 2H, J 8). 0.84 (d, 3H, J 7), 0.92 (d, 3H, J ; 7), 2.10 (s, 3H), 2.20-2.40 (m,; lH), 2.40 (s, 3H), 4.21 (ABq, 2H,i J 14), 4.98 (d, l y J 4), 7.32 (d,; 2H, J 8), 7.80 (d, 2H, J 8). 0.92- 1 .OO (m, 6H), 1.56- 1 .SO (m, i 3H), 2.14 (s, 3H), 2.46 (s, 3H),j 4.12-4.48 (m, 2H), 5.18 (dd, IH, Ji 5, 8), 7.40 (d, 2H, J 8), 7.86 (d,: 2H, J 8). 2.07 (s, 3H), 2.46 (s, 3H), 3.00; (dd, IH, J 8, 12), 3.20 (dd, IH, J! 4.4, 12), 4.17 (ABq, 2H, J 14),;
(m, 7H), 7.75 (d, 2H, J 8.4). 2.17 (s, 3H), 2.45 (s, 3H), 4.22j (ABq, 2H, J 14), 6.35 (s, 1H),j 7.30-7.45 (m, 7H), 7.77 (d, 2H, Ji 8.4).
(dd, IH, J 4,8), 5.27 (s, IH), 7.1-j
3.09 (dd, 2H, J 6,12), 4.00-4.38;
5.35 (dd, 1% J 4,8), 7.14-7.33:
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y-AMINO- AND y-HYDROXY-PKETOSULFONES 4415
CHN-Analytical Data for Unknown Conmounds t2B and 3A.B) :
2Bb:
2Bc:
2Bd:
ZBe:
Found: C, 51.87; H, 6.40; N, 14.92. CnH12N203 requires C, 52.17; H 6.52 andN, 15.21%. Found: C, 54.18; H, 7.03;N, 13.83. GH1&10? requires c'. 54.54; H, 7.04 and N, 14.14YO. Found: C, 61.68; H 5.38; N, 11 86. C&2NKh rdquirrs C, 62.07; €I, 5.17 and N, 12.07o/n. Found: C1,60.04; H, 4.73; N, 12.55. C~IHION?C)? requires C, 60.00; H, 4.S3 and N, 12.84Yo.
3Aa: Found: C, 53.63; H, 6.07; N, 4.10. c114f119NCX3 requires C, 53.67; H, 6.07 and N, 4.4096.
3Ab: Found: C, 56.12; H. 6.72; N, 4.01. C~~HZNC)~S requires C:, 56.30; H. 6.?4
3Ac: Found: C, 57.17; H, 6.94; N. 3.92. C'I$L~PJO:.S requires Cf, 57.46; H, 7.04 andN, 3.94"*.
3Ad: Found: C, 61 35; H. 6.01; N, 3.22. CBH~:NO:~S reqnires C , 61 69; H. 5.91 and N, 3.59?/b.
and N. 4.10/0.
3Bh: Found. c', 57.79, €1. 4.1 5 C I ~ H ~ O ~ S requires C, 57 69 and €I. 6 41 3Bc: Found. C. 58 50, H, 6.91 Ci6Hd20,S r x p r e s C. 58 89 and €1, 6 "41.0 3Bd: Found C', 63 16, €1 5 71 C,o€I:&)-S r~qiiire5 (', 63 3 ? and H 5 T(io'n
3Be: Found C'. 02 51. H, 5 34 <'l&@S requires C*, 62 4 ? and H 5 20%
vacuo to give the corresponding a-bromoketones. NaSOzTol (1.1 mmol) was
added to a solution of the crude a-bromoketone in DMF ( 5 ml) at room
temperature and after 30 min, the mixture was washed with satd. NaHC03
solution, extracted with CH2C12 and dried (Na2S0~). Removal of solvent in vacuo
followed by silica-gel chromatography (3Oy0 EtOAc in pet. ether) gave the
enantiopure P-ketosulfones 3A,B and 5. The physical characteristics of 3A,B are
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4416 SENGUPTA, SEN SARMA, AND MONDAL
given in Table 2. In addition, correct elemental (CHN) analysis (within k 0.4% of
the theoretical values) were obtained for each compound.
5: yield 72%; mp 66-8'; [aID -46.18 (c, 4.3, CHCl3); IR (neat): 1740 (br), 1690;
8 (CDCl3): 1.36 (3H, t, J = 6 Hz), 1.99-2.29 (4H, m), 2.52 (3H, s), 3.51-3.76
(2H, m), 4.07-4.64 (5H, m), 7.44 (2H, d, J = 8 Hz), 7.90 (2H, d, J = 8 Hz).
Found: C, 56.61; H, 6.09; N, 4.08. C ~ ~ H Z ~ N O ~ S requires C, 56.63; H, 6.19 and
N, 4.13 %.
Acknowledgements: Financial support from CSIR (0 1/137 lEMR-I1/95) is
gratefully acknowledged. D. S. S. and S. M. thank Jadavpur University for Senior
Research Fellowships.
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I-AMINO- AND */-HYDROXY-PKETOSULFONES 4417
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