Chiral fragments synthesis

In the synthesis of six-membered cyclic nitronates (35) by the (42 + 43) cycloaddition, facial discrimination can be achieved by introducing enantiomerically pure chiral fragments into nitro olefin (42) (147, 157) enamine (117), or enol (134). In addition, Prof. Seebach (96) and postgraduate students supervised by Prof. Denmark (158) successfully used chiral LA for facial discrimination. 

Two research groups examined the approach to the synthesis and the use of six-membered cyclic nitronates by introducing chiral inductors into the molecule of the starting a-nitroalkene. (Here, it is incorrect to use the term auxiliaries because the chiral fragment is not eliminated and is involved in the target product.)... 

Chiral Pool Reagent. (7 )-Pantolactone has been used as a source of chiral fragments for synthesis. Applications include use in the syntheses of the elfamycins (eq 12) and the bryostatins (eq IS). It has also been used to prepare potentially useful chiral epoxide synthons possessing a quaternary gem-dimethyl carbon. ... 

Chiral Cyclopentane Synthesis From Sugars Transformation of monosaccharides into enantiomerically pure penta- substituted cyclopentanes via fragmentation and nitrone-olefin dipolar cycloaddition. 

How might we obtain enantiomerically pure compounds Historically, the best answer to that question has been to isolate them from natural sources. Hence the dependence on natural product isolation for the production of enantiomerically pure pharmaceuticals. Derivatization of natural products or their use as synthetic starting materials has long been a useful tool in the hands of the synthetic chemist, but it has now been raised to an art form by practitioners of the Chiron approach to total synthesis, wherein complex molecules are dissected into chiral fragments that may be obtained from natural products [17-25]. 

In addition to their usefulness for the asymmetric addition of achiral aldehydes, it will be seen in the section 5.2.3 that the Paterson strategy is particularly useful for the aldol addition of chiral fragments such as the large, polyfunctional ketone and aldehyde fragments needed for convergent macrolide synthesis. 

Scheme 5.26. Selective coupling of two chiral fragments (double asymmetric induction) in the asymmetric synthesis of 6-deoxyerythronolide B [124,127], For a similar reaction in the synthesis of erythronolide B, see ref. [129],...

THP-Protected butyrolactone 289 is one of the chiral fragments used in the total synthesis of 2 -deoxymugineic acid (295), a metal chelator excreted from wheat root (Scheme 40) [91]. The sequence 275 —> 291 proceeds with an overall yield of 55%. 

Much of the work carried out with carbohydrates is an extension of the strategies initiated in the earlier period. The use of chiral fragments derived from D-glucose, a-D-isosaccharino-l,4-lactone and D-glucosaccharinolactone, continues in the synthesis of enantiopure AB building blocks as well as for annelation to leucoquinizarine, resulting in an anthracyclinone tetracycUc moiety with defined ring A stereochemistry. 

The target can be best disconnected into three fragments at the amide bonds. The aminopyridine can be made by the standard methods of heterocycle synthesis (chapter 30), so we are more interested in the other two chiral fragments. The middle one is an amino acid, and you should recognize it as a member of the chiral pool, (S)-glutamic acid, so this poses no problem of synthesis. (Though it will need to be appropriately protected to form the correct amide). 

The first important step was hence to judiciously design the chiral fragment, (+) (2-MA-2 -F-9,9 -SBF) (Scheme 11), which will be further involved in the porphyrin synthesis (Scheme 12) [73]. 

There have been numerous Other applications of BINOL-Ti-catalyzed ally-lation reactions in complex molecule syntheses [30, 32], In the construction of the terminal portion of mucocin, Evans documented the asymmetric addition of an allylstannane to unsaturated aldehyde 202, giving adduct 203 in 98 2 dr (Equation 14) [125]. In another example, Roush disclosed the addition of an allylstannane to aldehyde 204, en route to the synthesis of the superstolides (Equation 15) [126]. These examples underscore the Ti-cata-lyzed enantioselective allylation process as a general approach to useful, functionalized chiral fragments. 

Scheme 5 details the asymmetric synthesis of dimethylhydrazone 14. The synthesis of this fragment commences with an Evans asymmetric aldol condensation between the boron enolate derived from 21 and trans-2-pentenal (20). Syn aldol adduct 29 is obtained in diastereomerically pure form through a process which defines both the relative and absolute stereochemistry of the newly generated stereogenic centers at carbons 29 and 30 (92 % yield). After reductive removal of the chiral auxiliary, selective silylation of the primary alcohol furnishes 30 in 71 % overall yield. The method employed to achieve the reduction of the C-28 carbonyl is interesting and worthy of comment. The reaction between tri-n-butylbor-... 

An analogous solvent effect was observed upon treatment of the chiral a-alkoxy aldehyde 11 with 2-lithio-4-methylfuran in the presence of zinc bromide. This highly diastereoselective addition reaction was the key step in a synthesis of the enantiomcrically pure C-10-C-20 fragment of the immunosuppressant KK 506139. 

---