In dian Jou rnal of Chemi stry Vol. 42 8 , April 2003, pp. 863-872 Synthesis of optically active benzocyclobutene and biphenylene based unusual a-amino acid derivatives Sa mbas iva rao Kotha* & Somnath Halder Department of Chemi stry, Indian In stitute of Techn ology-B ombay, Mumbai, 400 076, Indi a Phone: +9 1-22-257671 60, Fax: +9 1-22-25723480, Email : srk @chem.iit h.ac. in Received 12 August 2002: accepted 28 October 2002 Opti call y ac ti ve be nzocyclobutene and biphenylene based unu sual a-amino acid deri vati ves have been prepared via a six step sequ ence usin g Scholl kopf chi ra l aux ili ary in a very high diastereoselective mann er. Benzocyclobutene 1 (BCB) and its derivatives repre­ butenyl glycine and simil ar deri vati ves were sy nthe­ sent a unique class of reacti ve molecules because of sized in connection with CNS depressants.5 In view of thermodynami c stability associated with the aromati c diverse applications of BCBs in organi c synthes is and system and the kineti c reactivity of the strained polymer synthes is it occurred to us th at amin o ac ids cycl obutene ring. They are useful building bl ocks in containing BCB unit (e.g. 3-6) may prov id e an unique orga ni c sy nth es is because of th eir ability to isomeri ze opportunity for post-translational peptide modifica­ to o-x ylylene upon th ermal ac tivation (Eqn 1). 1 The ti ons via the Di els-Alder meth odology. 6 Here we de­ temperature required fo r electrocycli c ring opening scribe the full detail s for the preparati on of va ri ous reacti on depend s on the nature of substituents on the optically pure BCB based a -amino acid (AA A) de­ cyclobutene moiety. o-Xylylene 2 can be trapped by ri vatives related to 3.7 vari ous di enophiles in Di els-Aider fas hi on either by Retrosyntheti c analysis of 3 indicates (Figure 1) intermolec ul ar or intramolecul ar process (Eqn 2). eight viabl e routes for its preparati on. Strateg ica ll y Thi s strategy has been used in the literature to co n­ these routes can be classified into fo ur categori es. In stru ct va ri ous polycyc il c and heterocycli c systems." the first category the phenyl alanin e deri va ti ves can be Recentl y BCB s are also used to prepare conducting extended to th e required BCB derivati ve 3 by se lec­ polymers and crosslinking agents. 3 Several BCB de­ ti ve C-C bond formation reacti ons (path a and b) or 4 ri vatives are used to fun cti onali ze C60 . 1-Benzocyclo- via benzyn e intermediate (path c). The second strat­ egy involves cyclobutene deriv ati ves as starting mate­ ri als and the benzene rin g is constructed by cycloaddi­ Eqn I ti on approach (path f and g) . Altern ati ve ly, both be n­ [al zene and cyclobutene moieti es can be assembl ed via a 2 [2+2+2] cycloaddition approach as shown in path e. Finall y, 3 can be prepared starting with preformed benzocyclobutene system (path d and h). Path d can be reali zed by repl acing hydroxy group of serin e with OC? suitably substituted BCB derivati ves . The other route COOH 864 INDIAN J. CHEM., SEC B, APRIL 2003 H,N ECOOH . ac:fJ ~ )QD Figure 1- Retrosynthetic analysis of BCB based AAA deri vati ve (path h) in vo lves asy mmetri c deri va ti zati on of glyc ine di ffi cult th an anti cipated. Initi al attempts to prepare deriva ti ve with BCB moiety . bromo derivati ve 9 under PBr3/ether/pyridine Since asy mmetri c deriv ati zati on of glyc in e is we ll conditions gave the rin g-opened product along with known in th e literature, we have chosen path h in the min or amount of the bro mo deri vati ve 9. Later on, prese nt study. 8 The required bromo derivative 9 was attempts to prepare the tosyl deri vative from 8 under prepared in a fo ur-step sequence startin g fro m a ­ vari ous reacti on conditi ons were unsuccessful. After chl oro-o-xy lene as show n in Scheme I. Thus, fl as h considerabl e amount of ex perimentati on, we fo und vac uum pyrolys is of a -chl oro-o-xy lene at 780 °C (0.3 th at treatment of hydroxy deriva ti ve 8 with mm/H g) gave the benzocyclobutene contamin ated NaBr/BF30 Et2 in acetonitril e at 0 "C gave th e bromo with the startin g materi al, whi ch was treated with the de ri vative 9 in 70% isolated yield as a low melt ing 13 excess amount of powdered KOH in presence of solid . Then, the bromo derivative 9 was treated with 14 DMSO to eliminate the starting materi al and then mono-ani on of Schollkopf's bis-l actim ether 12a at usual work up and di still ati on under redu ced pressure - 78°C and th e reaction mixture was qu enched wi th gave th e pure BCB 1.9 Under Vil smeier formylati on water to give 10 in 73 % yield after sili ca gel flas h conditions (POCI3/DM F), BCB 1 did not give th e re­ column chromatograph y. The diastereoselec ti vity of quired aldehyde 7.10 However, formylati on of 1 with the C-C bond fo rmati on step is very hi gh. Du ring th e CI2CHOMe in presence of TiCI4 in dry di chl oro­ purificati on of 10 we were abl e to isolate the min or meth ane at 0 °C gave the required aldehyde 7 in 34% di astereomer in an impure fo rm (~: 2 % ). The structure y.te ld . I I of 10 was in full agreement wi th i t~ spectral data. The Redu cti on of th e aldehyde 7 was achi eved by IR spectrum of 10 showed a strong absorpti on at 1694 1 treatment with NaBH4 in presence of dry meth anol at em·' due to C=N stretching. ln th e H NMR spectru m 0°C to give hydroxy deri va ti ve 8 (8 5% yield, mp 59- two doublets at 8 0.6 1, and 0.95 (2d, 1=6.9 Hz) are 600C).1 2 Co nversion of hydroxy compound 8 to the due to two meth yl groups of CHMe2. The two sin glets correspondin g bromo derivati ve 9 proved to be more at 8 3.68 and 3.71 are due to two methoxy gro ups. KOTHA et a/.: BENZOCYCLOBUTENE & BIPHE YLENE BASED a -AMINO ACID DERIVATIVES 865 1~ 6n _._..(iii) OHC~ ~ OH t(iv) (vi) ,Q9 (v) MeO~N Brr©9 ~0 ~ OMe (i) FVP, 780 OC/0.3Hg 111111 (ii) TiCI4, CI CHOCH3 (iii) NaBH4, MeOH 2 (iv) NaB r, BF30 Et2, CH 3CN (v) n-BuLi, chiral auxiliary, THF (vi) 0.1 N HCI Scheme I The 18-line 13C NMR spectrum of 10 resonating at 8 firmed the structural fo rmulation of 11. Two other 16.5, 19.1 , 29.2, 29.4, 3 1.3, 40.6, 52.2, 52.4, 56.9, alkylated products 13 and 14 were hydrolyzed under 60.3, 12 1.8 , 124.1, 128.6, 135.9, 143.6, 145.2, 162.7, similar reacti on conditions to give the amino ester 163.8 delineated its structure. The mass spectrum at derivatives 15 and 16 (Table 1), verifies the generality mlz 300 amu for C1 8H24N20 2 further supported of this method. molecul ar formulation of 10. Two other chiral Biphenylne-based unusual a -amino acid auxi li aries (12b and 12c) were alkylated wi th bromo derivatives derivative 9 to give the corresponding coupling Biphenylene (BP) 17 is dibenzo derivati ve of products 13 and 14 (Table 1). All the products were cyclobutadiene 18 having 4n electrons and expected characterized on the basis of spectral data. to show anti-aromatic behavior. BP is normally stable It is well known in the literature that electrophile and behave like aromatic compound. BP has five can­ enters from the opposite side of the isopropyl group nonical or Kekule forms in which the structure 17 15 during alkylation step. The homogeneity of the major represents the purely covalent fo rm. BP 17 is a diastereomer formed here has been establi shed by 13 C unique molecule because of the presence of a formal NMR spectral data. Hydrolysis of 10 with 0.1 N HCl cyclobutadiene unit. In the beginning, ring structure, at RT gave the amino ester 11. The structure of 11 reactivity, and other properties are the major driving was fully established on the basis of spectral data. The forces for the development of BP chemistry. IR spectrum showed absorpti on bands at 3378 and 1 1737 cm· due to amine and ester functional groups 1 respectively. The H NMR spectrum with three I [D] si nglets at 8 2. 13, 3. 13 and 3.72 due to amine, OD17 18 cyclobutene ring and ester methyl groups respec­ tively . It ex hibited a part of a doublet of 1/2 ABq at 8 Recently, several derivatives of 17 have been 2.82 (1=8, 13.