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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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(Received i n the U . S . A . 08 June 1998)

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