Indian Journal of Chemistry Vol. 41B, August 2002, pp. 1 666- 1 669

Synthesis of novel chiral auxiliaries

S Narasimhan*, S Swamalakshmi, R Balakumar & S Velmathi

Centre for Natural Products, SPIC Science Foundation, Chennai 600 032, India and

Department of Chemistry, Guru Nanak College, Chennai 600 042, India Received 25 November 1999; accepted (revised) 29 December 2001

A simple and easy route for the preparation of the higher homologue of oxazaborolidine namely dihydrooxazaborin has been reported. Also, the preparations of new bicyclic oxazaborolidines are reported.

Nature has provided us with a number of naturally occurring chiral compounds, which can be suitably modified to get potential chiral auxiliaries. Amino acids, which are naturally occurring chiral compounds, have been extensively used by scientists over the past several decades in preparing various chiral auxiliaries. Oxazaboroldines, developed by Itsunol and explored in detail by Corey

2 are one such

chiral auxiliary which are occupying a prominent place in the field of asymmetric synthesis. The amino acid proline was used for the preparation of the oxazaborolidines. Proline was subjected to an organometallic reaction to get an amino alcohol, which was then treated, with borane to yield the oxazaborolidines with a five membered ring containing a nitrogen, boron and oxygen in it. Now in this paper we report the synthesis of the higher homologue of these oxazaborolidines with a nitrogen, boron and oxygen in a six membered ring. Also, in the reported oxazaborolidines the acid end of the amino acid has been used up for the construction of the oxazaborolidine ring. In our present approach we wished to maintain the acid end of the amino acid intact and constructed the oxazaborin ring. The

existing oxazaborolidine along with the modification we desired is represented in Figure 1

Retrosynthetic analysis (Figure 2) showed two possibilities for the construction of the oxazaborolidine ring and we chose salicylaldehyde, as it is expected to offer more rigidity to the chiral auxiliary and also could participate in the stacking effect during the course of the asymmetric reductions.

The compounds are easily prepared through simple reactions and in good yields. The amino acids valine, leucine, iso-leucine and phenyl alanine have been used for the preparation of these chiral auxiliaries. The reaction sequence is present in Scheme I. Salicylaldehyde and the amino acid ester were reacted in benzene solvent to obtain the imine ester 1. The imine

R' H "''-- /

R :-(," " " R

HN, 0 B/ H

Itsuno Corey Modification

Figure 1 fH2CHO + H2NyHCOOR CH20H R r r /

CNHHCHCOOR C NHCHCOOR ��> OH � Figure 2

�CHO I + .0 OH

NARASIMHAN et al.: SYNTHESIS OF NOVEL CHIRAL AUXILIARIES 1667

(}CHO 1 .0 + OH

R

�NCHR �_. 'cOOCH3 OH

1

THi Bu,NBH, . CC� ��OCH3

.0 O,B'H 0 1 eq . . reflux C("'=:: NHCHR

h OH 'cOOCH3

3 2

Where R=2a : iso-propyl, 2b : iso-butyl, 2c : sec-butyl , 2d : benzyl Scheme I

ester is selectively reduced by tetrabutyl-ammonium borohydride to the corresponding amine ester.

The chiral precursor, 2 has been characterized by 10 and 20 NMR experiments and by GC and GC-MS experiments. The two benzylic protons remain stereochemically non equivalent as seen in the IH NMR spectrum [8 4. 1 ppm (d, I H, 1=1 3.5 Hz), 3.6 ppm (d, I H, 1=1 3.5 Hz)] which can be attributed to the conformational locking achieved by hydrogen bonding. Homocosy showed the direct geminal coupling of the two benzylic protons while heterocosy confirmed the connectivity of two benzylic protons to the same carbon.

These evidences support the conformational locking expected through hydrogen bonding between NH protons and carbonyl oxygen and phenolic hydrogen and nitrogen as shown in Figure 3. Also, the shift of ester carbonyl stretching absorption to a lower wave number 1735 cm-I in IR spectrum indicated the intramolecular hydrogen bonding between . ester carbonyl group and NH group. The IH NMR and l 3C NMR data are presented in Table I.

The dihydrooxazaborin 3 has been prepared by stirring 2 with borane-THF for 1 .5 hr. The l iB NMR of the formed dihydrooxazaborin gave a signal at

=CO OCH3 .......... .f N " .

c(tH . r '-': H " H : '" I O-� R �

Figure 3

8 = 24 ppm indicating the formation of the chiral auxiliary.

Alternatively, a novel bicyc1ic oxazaborolidine 5 was also synthesized from 1 . The reaction scheme is presented in Scheme II. The imine ester has been completely reduced to the phenolic amino alcohol 4 using zirconium borohydride under room temperature stirring and further stirred with borane-THF to get the novel chiral auxiliary.

The amine alcohol 4 has been characterized by 10, 20 NMR experiments and GC-MS experiments. In all these chiral precursors, the two benzylic proton signals appear as a singlet while methylene protons of the primary alcoholic group appear individually as doublet at 8 3.75 ( I H, dd 1 = 1 1 Hz, 5.6 Hz) exhibiting the stereochemical non equivalence of the methylene protons while the two methylene protons showed direct

CH(CH3>2

1 I I • 0= CH2NHCHCH(CH3>2 BH3 / THF

.0 OH CHpH D. 1 .5 hr cx:�j 4 5

Where R = 4a : iso-propyl, 4b : iso-butyl, 4c : sec-butyl , 4d : benzyl Scheme II

1668 INDIAN J. CHEM., SEC B, AUGUST 2002

Table I - Spectral data of chiral precursors for the formation of oxazaborolidine Compd IH NMR I3C NMR

Methyl-2-(N-2' -hydroxybenzyl)amino-3-methylbutanoate, 2a

Methy 1-2-(N-2' -hydrox ybenzy l)amino-4-methylpentanoate, 2b

Methy 1-2-(N-2' -hydroxybenzy I )amino-3-methylpentanoate, 2c

Methy 1-2-(N-2' -hydroxy benzy I )amino-3-phenylpentanoate, 2d

2-[N-2' -hydroxybenzylJ amino-3-methyl- l butanol, 4a

2-[N-2'-hydroxybenzyIJ amino-4-methyl- lpentanol, 4b

2-[N-2' -hydroxybenzylJ amino-3-methyl- l pentanol, 4c

2-[N-2'-hydroxybenzyIJ amino-3-phenyl- l propanol, 4d

2-[N-2'-hydroxybenzyIJ amino- I , I diphenyl-3-methyl butanol, 6

0.9 (d, 6H, J=8 Hz ), 2.0 (m, l H), 3.2(d, lH, 1 8.0, 1 9.2, 3 1 .2, 5 1 .4, 5 1 .7, 65.8, 1 16.3, J=8 Hz), 3.6(d, I H, J=1 3.5 Hz), 3.75 (5, 1 19.2, 1 22.2, 1 28.5, 1 28.9, 1 57.7, 174.0 3H), 4. 1 (d, lH, J=1 3.5Hz), 6.7-7.0 (m, 3H), 7.3 (t, I H, J=8 Hz)

1 .0 (d, 6H), 2.0 (m, lH), 3.2(t, IH, J=8 Hz), 18 . 1 , 1 9.2, 27.5, 3 1 .2, 5 1 .4, 5 1 .7, 65.8, 3.6(d, IH, J=1 3.5 Hz}, 3.75 (5, 3H), 4. 1 (d, 1 16.3, 1 19.2, 1 22.2, 128.9, 157.4, 174.0 l H, J=13.5Hz), 6.7-7.0 (m, 3H), 7.3 (t, l H, J=8 Hz)

1 .0 (d, 6H), 1 .75 (m, 2H), 1 .9 (m, l H), 3.2 12 . 1 , 1 6. 1 , 27.0, 38.5, 52.0, 52. 1 , 65.3, (d, I H, J=8 Hz), 3.6 (d, I H, J=1 3.5 Hz), 1 16.8, 1 19.6, 122.7, 1 29.0, 129.4, 158.2, 3.75 (5, 3H), 4. 1 (d, lH, J=1 3.5Hz), 6.7-7.0 174.5 (m, 3H), 7.3 (t, I H, J=8 Hz)

3.2 (t, l H, J=7.9 Hz), 3.6 (d, lH, J=1 3.5 39.0, 5 1 .0, 53.3, 6 1 .7, l I6.4, 1 19 . 1 , 122.0, Hz), 3.75 (5, 3H), 4.0 (d, I H, J=1 3.5Hz), 5.5 125.7, 1 27.0, 128.2, 128.5, 1 28.9, 136.2, (5, 2H), 5.7-6.9 (m, 4H), 7 . 1 -7.25 (m, 5H). 157.7, 178.6 l . l (6H, 2d, J = 7.9 Hz), 2 (m, I H), 2.5 (q, 1 8.7, 1 9. 1 , 28.0, 50.8, 60.9, 64.0, 1 16.3, l H, J= 7.9 Hz), 3.65 (dd, l H, J=l l , 5.6 Hz), 1 19.0, 1 23.2, 128.2, 128.6, 1 58.0 3.75 (dd, l H, J=l l , 3.5 Hz), 6.7-7.0 (m, 3H), 7.3 (t, l H, J=8 Hz)

0.9 (6H, 2d), 1 .6 (m, 2H), 2.9 (m, I H), 2.5 1 8.7, 1 9. 1 , 23.0, 28.0, 50.9, 60.8, 64.0, (m, l H), 3.65 (dd, l H), 3.75 (dd, l H), 4.0 (5, 1 16.3, 1 19.0, 1 23.0, 128. 1 , 1 28.7, 157.9 2H), 6.7-7.0 (m, 3H), 7.3 (t, l H)

l . l (2d, 6H), 1 .5 (m, 2H), 2.0 (m, I H), 2.4 1 8.7, 1 9. 1 , 25.0, 28.0, 50.8, 60.2, 64.0, (q, l H), 3.6 (dd, l H, J=l I , 5.6 Hz), 3.75 1 16.0, 1 19. 1 , 1 23.0, 128.2, 1 28.8, 1 58.0 (dd, l H, J=l l , 5.6 Hz), 4.0 (5, 2H), 6.7-7.0 (m, 3H), 7.3 (t, l H, J=8 Hz)

2.8 (d, 2H), 3.0 (m, l H), 3.6 (dd, I H, J=l l , 37.3, 50.3, 59.6, 62.6, 1 16.5, 1 19. 1 , 1 19.5, 3.5Hz), 3.8 (dd, I H, J=l 1 , 3.5 Hz), 4.5 (5, 1 22.8, 1 26.6, 1 27.0, 1 28.2, 128.7, 129. 1 , 2H), 6.7-6.9 (m, 4H), 7 . 1 -7.25 (m, 5H) 1 38.0, 1 58.0

0.77 (d, 3H, J=7Hz), 0.97 (d, 3H, J=7Hz), 16.9, 24.0, 28.8, 54.3, 68.0, 8 1 .9, 1 16.2, 1 .95 (m, I H), 3.47 (d, lH, J= I lHz), 3.25 1 19. 1 , 1 19.5, 1 23.5, 125.5, 1 26.9, 127. 1 , (d, I H, J=13 Hz), 3.63 (d, l H, J=13 Hz), 1 28.4, 1 45.2, 1 57.5 6.62 (m, 3H), 7.44 (m, 4H).

geminal coupling and by vicinal coupling by the hydrogen attached to the adjacent chiral carbon as seen in the homocosy experiment. Heterocosy confirmed the connectivity of two methylene protons to the same carbon. Analogously, a diphenyl derivative of the phenolic amino alcohol was prepared (Scheme III). The crystal structure of 6 (Figure 4) indicated the intramolecular hydrogen bonding between the phenolic hydrogen and nitrogen as proposed for the structure 2 shown in Figure 3.

2 Mg, PhBr

� dry THF cc� rY�CH3)2

.0 OH HO Ph 6

Scheme III

Experimental Section The amino acid valine has been taken as the

representative amino acid. These chiral auxiliaries are being tested for their

potential in various asymmetric reactions such as asymmetric reduction of prochiral ketones, asymmetric Michael reactions, asymmetric Diel' s-Alder reaction, asymmetric Michael-Aldol reaction etc. The results of our findings will be published subsequently.

Preparation of hydrochloride of methyl ester of valine. Valine (5.9g, 50 mmole) was stirred with 50 mL of methanol and 7.3 mL of thionyl chloride (50 mmole) for 6 hr. Excess methanol and thionyl chloride present in the reaction mixture were removed under reduced pressure. The white solid formed was dried and stored under nitrogen atmosphere (yield 90%).

NARASIMHAN et a1.: SYNTHESIS OF NOVEL CHIRAL AUXILIARIES 1669

Figure 4 - X-ray structure of compound 6

Preparation of imine ester 1a. To 5.5 mL of salicylaldehyde (50 mmole) in 50 mL of benzene was added 8.4 g of the hydrochloride of methyl ester of valine (50 mmole) and 6.3 mL of triethylamine (50 mmole) and refluxed using Dean -Stark apparatus till 0.9 mL to 1 .0 mL of water separated out. The reaction mixture was then passed through a short silica gel column to remove the triethylamine hydrochloride and the solvent benzene was removed under reduced pressure to get the aldimine ester (yield 9 1 %).

Preparation of amine ester 2a. To 5 .8g of 1a (25 mmole) in 25 mL of THF was added 3.2 g of Tetrabutylammonium borohydride ( 12.15 mmole) and stirred for 15 min. The reaction was quenched with dil. sulphuric acid and then the pH was made alkaline (PH 7-8) by adding NaOH solution. The amine ester formed was extracted in chloroform, dried over anhyd. Na2S04 and removed the solvent under reduced pressure. The tetrabutylarnmonium cation present along

with the product could be removed by passing through a short silica gel column (yield 90%).

Preparation of dihydrooxazaborin 3a. Compound 2a ( 1 .2g, 5 mmole) was refluxed with 5 mL of 1M borane THF solution (5 mmole) under N2 atmosphere for 1 .5 hr till 250 mL of H2 was evolved quantitatively.

Preparation of aminF alcohol 4a. Compound 1a ( 1 .2g, 5 mmole) in 10 tnt of dry THF was stirred with 6.6 mL of Zr(B�)4 (3M in K ), at room temperature for 2 hr under nitrogen atmosphere. The reaction was quenched with methanol . THF was removed under reduced pressure, pH was adjusted to approximately 8 by adding aq. NaOH solution and the free amine formed was extracted with chloroform. The chloroform extracts were dried over anhyd. Na2S04 and the solvent was removed under reduced pressure to yield 4a, a highly viscous liquid (yield 92%).

Preparation of bicyclic oxazaborolidine Sa. To 5 mmole of 4a, 5 mL of 1M borane THF solution (5 mmole) was added and refluxed for 1 .5 hr. The formation of Sa was monitored through the quantitative evolution of hydrogen by connecting the system to a gas burette.

Acknowledgement The authors thank Prof. TRG for his constant sup

port. SL thanks Department of Chemistry, Guru Nanak College and SV thanks CSIR, New Delhi for financial support. Thanks are due to Prof. E. Subramanian for providing us the X-ray structure of the compound 6.

References 1 Hirao A, Itsuno, Nakahama S & Yamazaki, J Chern Soc Chern

Cornrnun, 1981, 3 15. 2 Corey E J & Link J 0, Tetrahedron Lett, 31, 1990, 601 .