Free Radical Reactions in Synthetic Organic Chemistry

Transcription

1 Free adical eactions in ynthetic rganic Chemistry C549.M. Williams Free radical intermediates have been utilized with varying degrees of success in the stereocontrolled formation of C-C bonds. Among the potential problems with free radical intermediates is the possibility for bond rotation (resulting in loss of stereochemical integrity), quenching of the radical prior to C-C bond formation, side reactions (such as reactions with adventitious oxygen or other radical traps), and the possibility of homo-coupling (dimerization). In addition, carbon-centered free radicals are generally highly reactive species and methods to tame their selectivity have been a challenging endeavor. owever, judicious choices of substrate structure and reaction conditions can often lead to synthetically useful transformations. Primarily through the work of Walling, Ingold, Beckwith, Barton, Julia, Giese, tork and Curran, many methods now exist for the generation of radical species have been realized. A few examples are illustrated below. The Barton eaction The Barton reaction is a radical-based method to remotely functionalize an unactivated C- bond as shown below: The general reaction involves the formation and photochemical rearrangement of a nitroxyl intermediate that tautomerizes to an oxime; hydrolysis affords the corresponding aldehyde of ketone hn 3. 3 hn - 3 oxime Initially designed for the remote functionalization of carbon atoms in steroids as shown by the example below, the Barton reaction has also been put to advantage in natural products total syntheses. Ac hn 3. 3 An example of the latter application is a synthesis of grandisol (the boll weevil pheromone) by obbs and Magnus as shown below. C Ac

2 = 1. hn, n-hexane 2% aq. 2. i-pr, D Et 2, acetone 51% overall 3 P=C 2 Ac 67% 2, 20% Pd-C 90% ( 2 CC) 2 B, TF; a, 2 2 Ac 95% C hn, ac 3 obbs, P.D.; Magnus, P.D., J. Am. chem. oc. 1976, 98, 4594 The Barton-McCombie Deoxygenation eaction 1. Ac 2, py. 2. P 3, py. 59% Ac Ac 1. h( 3 P) 3 2. LA 60% 75% Cr 3 -py 41% grandisol Barton & McCombie have devised a useful synthetic method for the radical-based deoxygenation of alcohols. The method involves the formation of thiohydroxamates or xanthates which upon reaction with a trialkyltin hydride, leads to the net replacement of the alcohol group with a hydrogen atom. The general reaction is shown below: 1 Z X X n-bu 3 n tol., D 1 2 The mechanism of the Barton-McCombie deoxygenation reaction is illustrated below on the 2,4,6- trichlorothionocarbonate species py., 1 2 nn-bu 3 n-bu 3 n tol., D 1 2 nn-bu 3 n-bu 3 n 2 1 nn-bu3 Xanthates can also be used in this reaction and are the easiest to prepare and are the least expensive. 1. C 2, a 2 2. I n-bu 3 n tol., D 1 2 xanthate Three specific examples are shown below:

3 n- 3 n, AIB toluene /reflux (81%) 3 steps 40% BBu 2 ~1:25 C 2 2 /-78 C 53% 2, Pd 2 Et-TF n-bu 2 BTf, Et 3 C 2 2 /0 C 2 C 2 C a(i 3 ) 2 TF -78 C Æ T 38% Williams,.M.; Im, M-.; Cao, J., J.Am.Chem.oc., 1991, 113, 6976~6981 (6-hydroxymethyl-2,6-diaminopimelic acid, a natural antibiotic from Micromonospora chalcea) C % Br, D 2. Et, D 91% 2 C 2 6-MDAP C 2 2 4% a, C 2 2, C 2, I 3 n, AIB toluene /reflux 1. 2, Pd 2 Et-TF 2. Et, reflux 2 C 2 C 2 2 Williams,.M.; Yuan, C., J. rg. Chem., 1992, 57, TB Ac 1. C n 4, Et 2 2. Ac 2, py. 54% Ac 1. Jones ox a 91% Ac 1. s 4, M n-bu 3 n, AIB 74% C 2 Ac 1. BP, Et 3 C 2 allyl 2. ( 3 P) 4 Pd 53% Uno,.; Baldwin, J.E.; ussell, A.T., J.Am.Chem.oc., 1994, 116, 2139~2140. The Barton Thiohydroxamic Ester Chemistry Ac 1. 2, Pd-C,, 2. Et 3 i, py., Ac % F, C 70% lactacystin Barton has also exploited the facile homolysis of thiohydroxamic esters to generate caron-centered free radicals that can be trapped by a variety of agents forming new functionality. The general mechanism is shown below: C 2 Ac

4 pypy a hn or D C 2 radical trap The driving forces for the Barton thiohydroxamate system are: (1) enthalpic gain in converting the weaker thiocarbonyl group into a carbonyl group (C 2 ); (2) aromatization of the pyridine nucleus; (3) the gain in entropy in forming three components from a single molecular entity. -X -Br - BrC 3 C n-bu 3 n or t-bu 3 C-I ee e Intramolecular traps can be used for this reaction as in the cyclization reaction shown below: -I hn 82% Another utility of the Barton thiohydroxamate chemistry is in the setting of a modification of a unsdiecker reaction as illustrated below. The net result is an oxidative decarboxylation reaction. C 2 DCC, DMAP BrC 3, D (Barton-modified unsdiecker) 34~43% BrC 3 Br 1 equiv. a, 0 o C ~2:1 spirotryprostatin B 12-epi-spirotryprostatin B ebahar, P..; Williams,.M., J. Am. Chem. oc. 2000, 122, 5666~5667

5 Perhaps the greatest utility of free radical reactions has been realized in cyclization reactions and cyclization reaction cascades. ere, the conformational rigidity of the substrate can be exploited to tame the intrinsically high reactivity of the free radical instermediates. In general, the formation of five- and sixmembered rings has proven the most successful based on entropic considerations. P 5 C 4 dihydroagarofuran isodihydroagarofuran 3 : 7 (67%) n-bu 3 n, hn, D AIB, cyclohexane (20%) 6-exo-trig Büchi, G..; Wüest,., J. rg. Chem. 1979, 44, 546 Like virtually all radical reactions, we can understand the presence of the undesired (reduced) uncyclized product by a careful accounting of the mechanism. adical reactions typically occur in three stages: (1) initiation (2) propagation (3) termination In accord with this mechanism, the amount of uncyclized product increases with increasing tin hydride concentration which serves as the ultimate -atom donor. nbu 3 termination AIB = C C free radical initiator D - 2 initiation 2 C nbu 3 C nbu 3 cyclization nbu 3 propagation A solution to the poor facial selectivity of the above system was found by altering the intramolecular trap functionality to give a vinylsilane intermediate. n-bu 3 n, hn, D 6-exo-dig AIB, cyclohexane 72% TM nbu 3 pts = TM 92% dihydroagarofuran Büchi, G..; Wüest,., J. rg. Chem. 1979, 44, 546

6 tork has reported an elegant example of free radical-based cyclization reaction in the total synthesis of prostaglandin F2a as shown below. Et Et I Et Et 0.1 eq. n-bu 3 n Bu 3 n TM 2 eq. acb 3, hn C 5 11 TB TB TB TB TM C TM C 5 11 Et TM 140 o C Et Pd(Ac) 2, C Et C 5 11 TB C 5 11 (Brook rearrangement) TB C 5 11 TM (aegusa oxidation) TB 1. ()-BIAL-, TF, -100 o C (oyori asymmetric reduction) 2., TF, 2 C P C 2 PGF2a C 5 11 tork, G.; her, P.M.; Chen,.-L., J. Am. Chem. oc. 1986, 108, 6384 Thiols, sulfoxides and sulfones all readily eliminate when situated b- to a radical forming olefins. This was nicely illustrated by Boger and Coleman in their approach to CC-1065 as shown below. Br 2 n-bu 3 n, AIB Bn, D Bn 2 Bn - Bn CC-1065 Boger, D.L.; Coleman,.., J. Am. Chem. oc. 1988, 110, 4796 Arylselenides can also be utilized as substrates for the generation of free radical species. A particularly impressive example is the total synthesis of tunicamycin reported by Myers, et al. as shown below:

7 TB BM Ac BC e i n-bu 3 n, Et 3 B tol. 0 o C TB BM Ac i BC 7-endo-trig TB BM Ac i BC (C 3 ) 2 C(C 2 ) 9 5 steps Ac tunicamycin V Myers, A.G.; Gin, D.Y.; Widdowson, K.L., J. Am. Chem. oc. 1991, 113, 9661 ne of the first examples of a tandem radical cyclization cascade was reported by tork in the synthesis of a butenolide as shown below: Br n-bu 3 n 5-exo-dig 5-exo-trig AIB,, D n-bu 3 n 1. a o, TF, 3 (l) 2. PCC, C DBU tork, G.; Mook,., J. Am. Chem. oc. 1983, 105, 6765 This concept has since been extensively exploited by many workers in the synthesis of fused and spirocyclic carbocycles. Another example is the synthesis of hirsutene by Curran as shown below: 13 steps I n-bu 3 n. AIB, D 5-exo-trig 5-exo-dig n-bu 3 n hirsutene Curran, D.P.; akiewicz, D.M., J.Am.Chem. oc., 1985, 107, 1448