Self‐Regeneration of Stereocenters (SRS)—Applications, Limitations, and Abandonment of a Synthetic Principle
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For example the diastereoselective formation of such organometallic derivatives has been demonstrated with Li‐dithianes such asI(“Umpolung of the Reactivity of Carbonyl Compounds Through Sulfur‐Containing Reagents”:B.‐T.Gröbel D.Seebach Synthesis1977 357–402;
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We believe that an aggregate of the achiral enolate and the chiral enolate (shown in Scheme 2a) may be responsible for the observed effect:D.Wasmuth Dissertation No. 7033 ETH Zürich 1982.
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One of the first applications of this principle was independently published byG.Fráter[42] and by us [43].
Initially we used the term “self‐reproduction of chirality” or “of stereogenic centers” [45–48]. Our colleague Vladimir Prelog has however convinced us that the term “self‐reproduction” should be reserved only for living organisms.
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2 2‐Disubstituted 1 3‐dioxolanones have been prepared from lactic acid mandelic acid and alkyl aryl and other unsymmetrical ketones by using acid catalysis [51] or Ru catalysis [52]. However reactions of the resulting enolates tend to occur albeit not unexpectedly in a not particularly stereoselective fashion [51]. On the other hand the diastereoselectivity of Michael additions to dioxinones remains high even when the acetal center is substituted by both atBu and a Me group or when the six‐membered ring derived from menthone is the substituent on the acetal center. See the work of Lange et al. [160–162] and of Kaneko et al. [238] and ref. [302].
See Schemes 2c–e and the refs. [212–218].
BASF kindly donated large quantities of pivalaldehyde to us over many years. We thank them for their generosity.
Shell Chemicals is a source of large quantities of pivalaldehyde.
It is highly likely that transformations previously described in the literature have followed the principles of self‐regeneration of stereocenters; however we know of no example where this synthetic principle was recognized explicitly formulated and systematically used before our own work.
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The acid‐catalyzed cyclization of the appropriate alanine derivative to give imidazolidinone1(RA=tBu R = Me × = Y = NH) results in a 1:1 mixture of thecisandtransproducts. As thecisisomer can betert‐butoxycarbonylated at N1 under mild conditions while thetransisomer remains unprotected they can be easily separated: see Section 7 and ref. [235].
Beck A. K., 1988, Chimia, 42, 142
For the preparations and reactions of dioxolanones derived from chiral α‐hydroxy acids and ucetaldehye isobutyraldehyde benzaldehyde cyclohexane‐carboxaldehyde acetone 2‐hexanone acetophenone or pivalophenone see refs. [51 52 76–79].
The selectivity with regard to the configuration of the newly formed stereogenic center at the 1′‐position (addition to aldehydes and Michael acceptors) is generally low. For highly diastereoselective reactions of chiral glycinederived enolates with concomitant formation of two new stereogenic centers see Section 9.3 and Scheme 29e.
The use of the SRS principle is not necessary in the case of hydroxyproline as this amino acid contains a second stereogenic center.
See also the discussion in Sections 9.2 and 9.4 and Schemes 28 and 33 which relate to this particularly problematic case.
see also ref. [131]. For the formation of products of typeXIIIandXIVfrom reactions of dioxolanone carboxylic ester enolates such asXandXIand for related reactions of cyclopentane carboxylic ester enolates which interestingly may proceedcisto the neighboring substituent at the stereogenic center see refs. [62 93–98]. The enolateXIhas a relatively high tendency to decompose by β‐elimination (see the discussion in the text and the legends of Scheme 6 and Schemes 29 b and 32 c and also the review in ref. [36]).
Seebach D., 1988, Chimia, 42, 176
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The eliminations depicted in Scheme 6e cannot proceed along the optimal trajectory (Bürgi‐Dunitz rules) and to use a different terminology are “Baldwin‐forbidden retro‐5‐endo‐trigprocesses”: (a)J. E.Baldwin J. Chem. Soc. Chem. Commun.1976 734–736;
(b)J. E.Baldwin J.Cutting W.Dupont L. I.Kruse L.Silberman R. C.Thomas J. Chem. Soc. Chem. Commun.1976 736–738;
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In a similar fashion a thiolactic acid derivativeXVIIImay be alkylated (→XIX) at the α‐carbonyl carbon and due to the presence of a sulfoxide center a nonracemic product results. R. Breitschuh Dissertation. No. 9654 ETH Zürich 1992.
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We have speculated in great detail about the possible reasons for the behavior of acyliminium intermediates which differs completely from that of their enolate and enoate counterparts [62]. See also refs. [187 192 194 196];
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Compare this with the modifications of serine via oxazolidine dicarboxylic acid derivatives shown in Schemes 6d 7 9 10a 11a 12 14a 15 and in Table C in the appendix.
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The decision as to whether we should include the usually catalytic process of the allylation of nucleophiles via Pd‐π‐allyl complexes such as that shown in Scheme 20 a in this discussion was not an easy one. On no account would we wish to cram an SN2 reaction that proceeds with inversion of configuration at a single stereogenic center of an enantiomerically pure substrate into the corset of the SRS principle!
Williams R. M., 1989, Synthesis of Optically Active α‐Amino Acids
If one considers the necessary steps the chiral cyclic acetals shown in Schemes 10 and 16 which are derivatives of achiral carboxylic acids and are prepared by decarboxylation (aspartic acid → dihydropyrimidinone; serine threonine cysteine → imidazoline oxazoline thiazoline) are perhaps already results of overextending the SRS principle (laborious) despite their unique reactivity!
The glycine derivative shown in Scheme 21 (top right) may also be prepared from methionine by formation of the imidazolidinone elimination via a vinylglycine derivative oxidative cleavage and finally decarboxylation [223].
Seebach D., 1980, Modern Synthetic Methods, 91
The separation of the product may also cause difficulties: for example in Schöllkopfs synthesis of amino acids via bislactim ethers derived from diketopiperazines the final step requires the separation of two amino acid esters (for a reference see Scheme 22).
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“Preparation of Optically Active 1 3‐Imidazolidin‐4‐ones as Intermediates for Optically Active Amino Acids”:D.Seebach K.Drauz M.Kottenhahn H.Lotter M.Schwarm(Degussa AG) DE‐B 4137186 1991;
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Boc‐BMI Bz‐BMI and Z‐BMI are commercially available in both enantiomeric forms from the following companies: Aldrich Chemical Company Fluka Chemie AG Interchim s. a. (France) E. Merck (Germany) Senn Chemicals AG (Switzerland) Wako Chemicals (USA).
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For example see the discussion about “flustrates” in Section 2.2 of ref. [261].
For example the addition of a cuprate to an alkylidene‐Boc‐BMI derivative is completely selective (rel. topicity 1 4‐lk) by NMR analysis even though three bonds and three trigonal centers separate the inducing and newly formed stereogenic centers (XXVII → XXVIII) [134 253]. It is even moresurprising that the reaction of the dienylideneXXIXwith dibutylcuprate leads to a single productXXX(to date of unknown configuration) although five bonds separate the stereogenic acetal center and the site of substitution in the substrate (see ref. [253] and footnote [27] therein). Stereogenic centers positioned in a 1 5‐fashion result from the 1 2‐ or 1 4‐addition of the dienolateXXXIof 2‐tert‐butyl‐6‐methyl‐1 3‐dioxin‐4‐one at the 5‐ and 1′‐position to an aliphatic aldehyde (→XXXII) or enal (→XXXIII) respectively [264 265].
Nógrádi M., 1995, Stereoselective Synthesis—A Practical Approach
Reactions of 4‐methyl and 4‐trifluoromethyldioxinones with Cu‐doped benzyl Grignard reagents (to giveXXXIVandXXXV respectively) under identical conditions. In the first case the standardtransaddition (of the benzylic C atom) occurs but the second example shows acisaddition (of theparaC atom) with concomitant formation of the quinoid system [156 157] We have previously called F‐containing reactants “flustrates” [261].
As is evident from the discussion in ref. [29] it has been accepted for many years (work of Creger and Pfeffer) that deuterolysis of an enolate produced by the use of LDA is not a reliable method for determining the degree of enolate formation.
One further equivalent of Li‐amide is produced such that the desired product of the reaction with electrophiles is now at the mercy of this strong base!
The stereoelectronic barrier already discussed in Section 3 which protects the corresponding enolate from facile β‐elimination is nowhere near as high when the leaving group is RS−in place of RO−. When the rules for cyclization (the reverse of this elimination) were initially proposed Baldwin explicitly stated that these are only valid for cases in which no elements of the second or a higher period are involved (see also Scheme 6 and ref. [111a]).
Such adducts of RXLi and carbonyl groups appear to be involved in other reactions of Li‐enolates and possibly play a much larger role than previously thought [272]. They could for example be responsible for the 2:1 reactions of aldehydes with Li‐enolates and also possibly for the known stabilization of Li‐aldolates against elimination to give α β‐unsaturated carbonyl compounds (seeXXXVI→XXXVIIandXXXVIII→XXXIX→XL[293]).
For the first attempts at explaining a few of the observed effects see ref. [48].
See ref. [227 b].
See footnotes [41–45] in ref. [23] and the general discussion in ref. [254].
See Section 3 and Schemes 5 and 6 for references to the literature.
The alternative course of the cyclization reaction when transition metal acetalization catalysts are used has already been pointed out in Section 3 [57].
See the bicyclic azetidine carboxylic acid proline thiaproline hydroxyproline and pyroglutamic acid derivatives in Section 3 Schemes 6 and 28 Table C in the appendix and ref. [91].
See Section 3 and ref. [92] for references to the literature.
For example compare the benzylation of the dioxolane carboxylictert‐butylthioester (d.r. = 80:20 cis[93 102]) with that of theN‐formyloxazo‐lidinecarboxylic acid methyl ester (d.r. = 98.5:1.5 trans[93 100]) and also with the methylation ofN‐formylthiazolidinecarboxylic acid methyl ester (d.r. > 98:2 trans[106]). See the equations in the second line of Scheme 29 b Section 3 and Table B.
See our work on NCS reactions [133 134].
Reactions at radical centers of the heterocycle with formation of CC and CH bonds have been studied by Beckwith et al. [135]. Furthermore see the radical reactions of methylenedioxanones performed by B. Giese et al. (discussion and references in [290]).
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See ref. [178 a].
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The value of almost 20 kcal mol−1of the partial amide C = N bond corresponds to practically a third of that of the C = C bond.
For example see the data in Table 1 of both refs. [62] and [178a] and also Table 4 of ref. [143].
Following a suggestion of B. Trost during a discussion with R. W. Hoffmann the rather unfortunate expression “contrasteric” has been used in the literature for this effect [95 98].
In previous publications [93 102] we have suggested that thecisselectivity could be due to the bicyclic nature of the dioxolane carboxylic ester enolate which is attacked by the electrophile at theexoface that is cisto the existing substituent (seeXLIIIand compare the reactions of the bicyclic enolates derived from proline hydroxyproline thiaproline azetidine carboxylic acid and pyroglutamic acid Section 3 and Table (B). The chelate structure of the Li‐enolate of α‐RO‐substituted carbonyl compounds has been established by NMR analysis of the corresponding silyl enol ether [31 227].
Like the parent esters [312] chelated enolates such as those from β‐ketoesters [310] or from α‐dialkylaminoesters [311] adopt a planar arrangement.
See the examples in ref. [82] and references therein.
See also Fig. 7 in ref. [301].
Compare with the X‐ray crystal structure analysis of an alkylidene‐Boc‐BMI‐derivative in ref. [62] and the legend of Scheme 31.
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When benzaldehyde is used as the electrophile the bicyclic productXLIVis formed [99].
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Hydroxyalkylation with acetone yields the followingXLV[71]. In the reaction with aldehydes if the reaction mixture is allowed to warm to room temperature before workup the rearranged productXLVIis formed as virtually the only product [71].
A portion of the aldol product cyclizes with formation of the carbamateXLVII.
The reversal of relative topicity between the addition ofXLVIIto a “normal” aliphatic and an aromatic aldehyde [233 241] would be consistent with a chair (→XLIX) or with a boat‐type transition state (→L) (in the case of a 3‐benzyloxyaldehyde the topicity is once again reversed [365]).
K.Matsuda unpublished results (1995).
See refs. [39 227c].
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