Rifamycin S, synthesis

Z)-awh-4-Hydroxy-l-aIkenyl carbamates 363, when subjected to substrate-directed, vanadyl-catalysed epoxidation , lead to diastereomerically pure epoxides of type 364 (equation 99)247,252,269 qqjggg epoxides are highly reactive in the presence of Lewis or Brpnsted acids to form -hydroxylactol ethers 366 in some cases the intermediate lactol carbamates 365 could be isolated . However, most epoxides 364 survive purification by silica gel chromatography . The asymmetric homoaldol reaction, coupled with directed epoxidation, and solvolysis rapidly leads to high stereochemical complexity. Some examples are collected in equation 99. The furanosides 368 and 370, readily available from (/f)-0-benzyl lactaldehyde via the corresponding enol carbamates 367 and 369, respectively, have been employed in a short synthesis of the key intermediates of the Kinoshita rifamycin S synthesis . 1,5-Dienyl carbamates such as 371, obtained from 2-substituted enals, provide a facile access to branched carbohydrate analogues . 

The Nozaki-Hiyama reactions are applied mainly to coupling reactions between aldehydes and unsaturated halides. For example, an intermediate of antibiotics rifamycin S synthesis is shown in eq. (13.54) [86,86a]. 

Tarara G, Hoppe D. Total synthesis of protected D-altro-3,6-dideoxy-3-C-methylhexose and D-galacto-3,6-dideoxy-3-C-methyUiexose-key intermediates of a rifamycin S synthesis. Synthesis 1989 (2) 89-92. 

A reiterative application of a two-carbon elongation reaction of a chiral carbonyl compound (Homer-Emmonds reaction), reduction (DIBAL) of the obtained trans unsaturated ester, asymmetric epoxidation (SAE or MCPBA) of the resulting allylic alcohol, and then C-2 regioselective addition of a cuprate (Me2CuLi) to the corresponding chiral epoxy alcohol has been utilized for the construction of the polypropionate-derived chain ]R-CH(Me)CH(OH)CH(Me)-R ], present as a partial structure in important natural products such as polyether, ansamycin, or macro-lide antibiotics [52]. A seminal application of this procedure is offered by Kishi s synthesis of the C19-C26 polyketide-type aliphatic segment of rifamycin S, starting from aldehyde 105 (Scheme 8.29) [53]. 

Polypropionate chains with alternating methyl and hydroxy substituents are structural elements of many natural products with a broad spectrum of biological activities (e.g. antibiotic, antitumor). The anti-anti stereotriad is symmetric but is the most elusive one. Harada and Oku described the synthesis and the chemical desymmetrization of meso-polypropionates [152]. More recently, the problem of enantiotopic group differentiation was solved by enzymatic transesterification. The synthesis of the acid moiety of the marine polypropionate dolabriferol (Figure 6.58a) and the elaboration of the C(19)-C(27) segment of the antibiotic rifamycin S (Figure 6.58b) involved desymmetrization of meso-polypropionates [153,154]. 

Fig. 3. Stepwise synthesis of rifaximin (from De Angelis [39]). The reaction of rifamycin S (I) with pyridine perbro-mide (II) in 2-propanol/chloroform (70/30) mixture at 0°C gives 3-bromorifamycin S (III), which is then condensed with 2-amino-4-methyl-pyridine (IV) at 10°C. The o-quinonimic compound (V) is then obtained. This compound is finally reduced with ascorbic acid to rifaximin. 

Among the syntheses of complicated natural products, the total synthesis of rifamycin S (44) is another example that shows how a complicated structure can be constructed by applying the concept of double asymmetric synthesis (see Section 1.5.3 for double asymmetric synthesis). Rifamycin S is one of the an-samycin antibiotics, characterized by a distinct structural feature a macro-... 

The total synthesis of rifamycin S was one of Kishi s many achievements in organic synthesis.6 Kishi recognized that a certain type of (Z)-olefin such as 51 tends to take a conformation in which C-l, C-2, C-3, and H-3 are nearly co-... 

This chapter has introduced the asymmetric synthesis of several types of natural products erythronolide A, 6-deoxyerythronolide, rifamycin S, prostaglandins and baccatin III, the polycyclic part of taxol, as well as the taxol side chain. The... 

This reaction played a key role in a highly stereocontrolled synthesis of the aliphatic segment 1 of the antibiotic rifamycin S (2),2 as formulated in equation (III). In each of the two Cr(II) mediated reactions, the desired aldol is essentially the only product isolated. Further studies3 indicate that the 2,3-stereoselectivity is sensitive to the large substituent a to the aldehyde. A cyclic acetal group appears to play a specific role in contrast to an acyclic group, but the factors controlling stereoselectivity are not well understood. 

BouzBouz, S. Cossy, J. Efficient strategy for the synthesis of stereopentad subunits of scytophydn, rifamycin S, and discodermolide. Org. Lett. 2001, 3, 3995-3998. 

In order to apply tartrate ester-modified allyl- and crotylboronates to synthetic problems,23 Roush and Palkowitz undertook the stereoselective synthesis of the C19-C29 fragment 48 of rifamycin S, a well-known member of the ansamycin antibiotic group24 (Scheme 3.1u). The synthesis started with the reaction of (S,S)-43E and the chiral aldehyde (S)-49. This crotylboration provided the homoallylic alcohol 50 as the major component of an 88 11 1 mixture. Compound 50 was transformed smoothly into the aldehyde 51, which served as the substrate for the second crotylboration reaction. The alcohol 52 was obtained in 71% yield and with 98% diastereoselectivity. After a series of standard functional group manipulations, the alcohol 53 was oxidized to the corresponding aldehyde and underwent the third crotylboronate addition, which resulted in a 95 5 mixture... 

Kurokawa and Ohfune [71] employ i DPPA in the synthesis of the hexapeptide echinocandin D 125). As shown in Scheme 42, the cyclization of the Unear peptide 124 was accomplished by DPPA to give 125 in 50% yield. There are more applications of DPPA in the synthesis of macrocycUc natural products [72]. DEPC is relatively less commonly used than DPPA. Kishi and coworkers [73] have successfully achieved the synthesis of the macrocyclic antibiotic rifamycin S using DEPC as a macrolactamization promoter. 

In the studies of the synthesis of the ansamycin antibiotic rifamycin S (13S), Corey and Clark [76] found numerous attempts to effect the lactam closure of the linear precursor 132 to 134 uniformly unsuccessful under a variety of experimental conditions, e.g. via activated ester with imidazole and mixed benzoic anhydride. The crux of the problem was associated with the quinone system which so deactivates the amino group to prevent its attachment to mildly activated carboxylic derivatives. Cyclization was achieved after conversion of the quinone system to the hydroquinone system. Thus, as shown in Scheme 45, treatment of 132 with 10 equiv of isobutyl chloroformate and 1 eqtuv of triethylamine at 23 °C produced the corresponding mixed carbonic anhydride in 95% yield. The quinone C=C bond was reduced by hydrogenation with Lindlar catalyst at low temperature. A cold solution of the hydroquinone was added over 2 h to THF at 50 °C and stirred for an additional 12 h at the same temperature. Oxidation with aqueous potassium ferricyanide afforded the cyclic product 134 in 80% yield. Kishi and coworkers [73] gained a similar result by using mixed ethyl carbonic anhydride. 

An example of the utilization of a bridged bicyclic ketone for preparation of an acyclic moiety is the stereoselective synthesis of the C-21 to C-27 segment of rifamycin-S, a member of the ansamycin family of antibiotics (Scheme 18). Rao et alP used ketone (61), derived from furan, to prepare lactone (62). Exhaustive reduction of (62) provided the segment (63), which contains five chiral centers of lifamycin-S. 

The same sequence was used to convert the aldehyde 7 into 8. This methodology was developed in connection with a projected synthesis of rifamycin S, which contains a sequence similar to that of 8. 

Both ( )- and (Z)-crotylboronates have been used in several applications in natural product synthesis. " One application of both the allylboronate and ( )-crotylboronate reagents is found in the synthesis of the C(19)-C(29) segment of rifamycin S. The desired stereochemistry at C(25)-C(26) of the rifamycin ansa chain is set with excellent stereocontrol (>95 5) and high yield (87%) (eq 8). " ... 

Kishi and co-workers elegantly demonstrated the power of substrate-directed cro-tylation reactions in their synthesis of the C(15)-C(29) segment 83 of rifamycin S (Fig. 11-10) [61]. This synthesis utilizes two crotylation reactions with the Noza-ki-Hiyama crotylchromium reagent 8 [18, 19] and one allylation reaction using allyldichloroiodostannane [79]. 

The high syn stereoselectivity attained in zirconium enolate aldol reactions has proved useful in complex natural product synthesis. The zirconium-mediated aldol reaction of the chiral ethyl ketone (9) with a chiral aldehyde has been used by Masamune et al. to give selectively adduct (10), which was further elaborated into the ansa chain of rifamycin S (equation 1). Good enolate diastereofacial selectivity is also obtained here and leads to a predominance of one of the two possible syn adducts. A zirconium enolate aldol reaction also features in the Deslongchamps formal total synthesis of erythromycin A, where the di(cyclopentadienyl)chiorozirconium enolate from methyl propionate adds with high levels of Cram selectivity to the chiral aldehyde (11) to give the syn adduct (12 equation 2). A further example is... 

Danishefsky and coworkers employed two hetero Diels-Alder reactions in a total synthesis of the ansa bridge of rifamycin S (Scheme 52) The first cyclocondensation reaction uses the trimethylsilyloxy diene (14) and a preincubated solution of 3-(benzoyloxy)-2-methyl-1-propanal (188) with an excess of TiCU in CHCh. The product is exclusively the syn-ACF pyrone (189). Through a Ferrier rearrangement and a sequence of oxidation-reduction steps followed by functional group manipulations aldehyde (190) is obtained. 

In the second hetero Diels-Alder reaction an anti pyrone derived from Cram-Felkin addition was needed, so trimethylsilyloxy diene (14) was allowed to react with aldehyde (190) in CH2CI2 using BF.vOEt2 as the catalyst. Under these conditions, anti-CF pyrone (191) is obtained in 57% yield, accompanied by 13% of the syn-CF pyrone. Through further manipulations compound (192), a key intermediate in the Kishi synthesis of the ansa bridge of rifamycin S, was obtained. 

Studies on the total synthesis of rifamycin S (102) were initiated by Corey et al., [184] and then carried out in a complete form by Kishi et al... 

Rifamycin W (104) was isolated from a mutant strain of Norcardia mediterranei [187] and its structure was determined [188] on the basis of spectroscopic studies in comparison with rifamycin S (102). Rifamycin W (104) is transformed by the parent Norcadia strain into rifamycin S and therefore is thought to be the biosynthetic intermediate of all the rifamycins [187]. The total synthesis carried out by Tatsuta et al. has allowed the elucidation of the complete stereochemistry of compound (104) [189]. The synthesis has been accomplished by coupling the segments of the aliphatic ansa-chain (E) and the aromatic nucleus (F). 

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