Tetrahedron
Volume 59, Issue 33,
11 August 2003
, Pages 6147-6212
This review is dedicated to Professors E. J. Corey and D. Seebach for their seminal contributions to 2-lithio-1,3-dithianes
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Introduction
The normal reactivity of a carbonyl compound (I) is as an a1-reagent (II) and the temporary reversal of the characteristic pattern of reactivity of a functional group is described by the term umpolung which was introduced by Corey and Seebach and widely accepted in the scientific community. 2-Lithio-1,3-dithiane derivatives (IV) are the most successful sulfur-stabilised acyl anion equivalents (V), having been widely used as masked nucleophilic acylating agents (as well as carbanions VI by final sulfur–hydrogen exchange) since the pioneering work of Corey and Seebach.1 These systems (also called d1-reagents following Seebach's nomenclature2) are easily prepared by deprotonation with alkyllithiums of the corresponding dithiane (III)1 and show reverse reactivity of the carbonyl group. The dithioacetal moiety could be hydrolysed after reaction with an electrophile to provide the corresponding ketone (VIII) or it could be reductively removed to yield the compound IX. In the case of R=H, a second deprotonation of the dithiane VII would lead to a new 2-lithio-1,3-dithiane compound X, which, after reaction with a second electrophile and final hydrolysis or reduction of the dithiane unit, would give a difunctionalised ketone XII or a methylene derivative XIII (through dithiane XI), respectively. Through this strategy, the dithiane compound acted as an equivalent of the formaldehyde dianion (XIV) or the methylene dianion (XV) (Scheme 1).
2-Lithio-1,3-dithiane derivatives are quite stable species, other intermediates containing different cations than lithium (for instance, sodium, potassium, magnesium3 and copper) being less employed because of the lack of general methodologies for the introduction of the metal into the dithiane unit and their low reactivity. The stability of 2-lithio-1,3-dithiane is due to the effect of the sulfur atoms on adjacent carbanions4 by electron back-donation into vacant sulfur d-orbitals.5
The 1,3-dithiane ring can be introduced in an organic molecule following two general approaches. The reaction of the anion of 1,3-dithiane, with or without substitution at the C(2) position, with different electrophilic reagents is the method most commonly used and thioacetalisation of a carbonyl group, using Lewis or Brönsted acid catalysis,3., 6. is the other methodology. The dithioacetal group is also suitable for the protection of carbonyl groups because it is stable towards acidic and basic conditions. When dithiane is used as an acyl anion equivalent, it must be hydrolysed at some stage during a synthesis to reveal the carbonyl group which was originally masked. Deprotection has often been extremely difficult to achieve, especially for complex and sensitive derivatives, and many procedures have therefore been developed3., 7., 8., 9., 10., 11., 12., 13., 14. and there is not a single method that can be generally applied.
For all of the former reasons, synthetic organic chemists have found 1,3-dithianes to be versatile systems of great applicability, natural products being the main targets in organic synthesis. This review will try to survey and update published material on the use of 2-lithio-1,3-dithianes in the synthesis of natural products, paying special attention to the types of reaction in which they are involved. Other reviews regarding the synthetic uses of the 1,3-dithiane group have been reported earlier, covering the literature until 1990, and so in this review we will mainly consider total synthesis involving dithiane chemistry from 1990 up to now.3., 6., 15., 16.
Section snippets
C–C Bond-forming reactions
As mentioned above, 2-lithio-1,3-dithiane derivatives are usually prepared by deprotonation with n-BuLi in THF at low temperatures2 and the anionic species obtained are able to react with many types of electrophiles. For 2-substituted-1,3-dithianes, however, deprotonation should sometimes be performed with t-BuLi and the reaction with electrophiles should be done in the presence of HMPA or TMEDA, the most important processes probably involving C–C bond formation.
Reactions involving ketene dithioacetals
Ketene dithioacetals show a versatile reactivity since they can be easily converted into thioketenes, carboxylic acids or carboxylic acid derivatives.15 Their most general pattern of reactivity includes nucleophilic attack at the non-sulfur-substituted carbon atom of the double bond combined with the introduction of an electrophile at C(1). The most general method for the preparation of ketene dithioacetals includes the olefination of a carbonyl compound using the anions derived from the
Conclusions
From the chemistry described in this report we can conclude that the 1,3-dithiane unit is very useful in synthetic organic chemistry, both as an acyl anion synthetic equivalent and as protecting group for carbonyl functionalities. In the first case, functionalisation of the masked carbonyl group allows different transformations, which have been widely used in the total synthesis of complex polyfunctionalised natural compounds, as shown in this review article.
Miguel Yus was born in Zaragoza in 1947. He received the BSc (1969), MSc (1971), and PhD (1973) degrees from the University of Zaragoza. After spending 2 years as a postdoct at the Max Planck Institut für Kohlenforschung in Mülheim a.d. Ruhr, he returned to the University of Oviedo where he became Associate Professor in 1977, being promoted to Full Professor in 1987 at the same university. In 1988, he moved to a chair in Organic Chemistry at the University of Alicante. Professor Yus has been
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Citation Excerpt :
The masked aldehyde was then released by mild hydrolysis (K2CO3/CH3I) and subjected to a Still-Gennari olefination to afford predominantly (Z)-α, β-unsaturated ester 10 in 68% yield (Z/E selectivity > 12:1, J = 11.6 Hz for Z-isomer, determined by crude NMR). As a comparison, other oxidative deprotection conditions of the dithiane by such as CAN, PIFA and NBS either gave low yields or caused significant decomposition of the starting material [15]. Lactonization of the resulted (Z)-α, β-unsaturated ester using 50% aqueous trifluoroacetic acid provided the desired lactone 8 with high yield (82%) [16].
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Miguel Yus was born in Zaragoza in 1947. He received the BSc (1969), MSc (1971), and PhD (1973) degrees from the University of Zaragoza. After spending 2 years as a postdoct at the Max Planck Institut für Kohlenforschung in Mülheim a.d. Ruhr, he returned to the University of Oviedo where he became Associate Professor in 1977, being promoted to Full Professor in 1987 at the same university. In 1988, he moved to a chair in Organic Chemistry at the University of Alicante. Professor Yus has been visiting Professor at different institutions such as ETH-Zürich and the universities of Oxford, Harvard, Uppsala, Marseille, Tucson, Okayama and Paris VI. He is a member or fellow of the Chemical Societies of Argentina, England, Germany, Japan, Spain, Switzerland, and United States. He is the co-author of more than 300 papers mainly in the field of the development of new methodologies involving organometallic intermediates in synthetic organic chemistry. Among others, he has recently received the Spanish–French Prize (1999), the Japan Society for the Promotion of Science Prize (2000) and the Stiefvater Memorial Lectureship Award (2001).
Carmen Nájera was born in Nájera (La Rioja) and graduated from the University of Zaragoza in 1973, obtaining her doctorate in Chemistry from the University of Oviedo in 1979. She spent postdoctoral stays at the ETH (Zurich), at the Dyson Perrins Laboratory (Oxford), at Harvard University and at Uppsala University. She became Associate Professor in 1985 at the University of Oviedo and Full Professor in 1993 at the University of Alicante, where she is currently the Head of the Organic Chemistry Department. She is the co-author of more than 160 papers and her current research interest is focused on organometallic chemistry, sulfones, amino acids, asymmetric synthesis and peptide coupling reagents.
Francisco Foubelo was born in Carreña-Cabrales (Asturias) in 1961. He received his BSc (1984), MSc (1986), and PhD (1989) degrees in Chemistry from the University of Oviedo. After a postdoctoral stay (1989–1991) as a Fulbright fellow at Princeton University, he moved to the University of Alicante and joined the research group of Professor M. Yus where he became Associate Professor in 1995 and Full Professor in 2002. He has published more than 60 papers. His research interest has focused on the development of new synthetic methodologies for the preparation of functionalised organolithium compounds from different precursors and the application of these organometallic intermediates in organic synthesis.
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