A versatile, readily accessible triad of 2-enoxy silane synthons derived from furan,

pyrrole, and thiophene is presented. These heterocycles, in reacting with carbonyl and carbonyl-

related acceptors, act as vinylogous nucleophile modules, giving rise to diverse, functionality-

rich, γ-substituted α,β-unsaturated carbonyl constructs. These, in turn, are invaluable

platforms onto which further functional elements and chirality may be introduced. A

couple of appealing applications—the variable construction of a repertoire of carbasugars

and a library of annonaceous acetogenin segments—have been chosen to illustrate the viability

of this vinylogous aldol approach

Casiraghi, Giovanni

Rassu, Gloria Maria Rita

Zanardi, Franca

English

UnissResearch

Pure Appl. Chem., Vol. 72, No. 9, pp. 1645–1648, 2000.
© 2000 IUPAC
1645
Vinylogous aldol reaction of heterocyclic 
silyloxy dienes. Application in synthesis*
Giovanni Casiraghi†, Franca Zanardi, and Gloria Rassu
Dipartimento Farmaceutico dell’Università, I-43100 Parma, Italy and Istituto per
l’Applicazione delle Tecniche Chimiche Avanzate ai Problemi Agrobiologici del
CNR, I-07100 Sassari, Italy
Abstract: A versatile, readily accessible triad of 2-enoxy silane synthons derived from furan,
pyrrole, and thiophene is presented. These heterocycles, in reacting with carbonyl and car-
bonyl-related acceptors, act as vinylogous nucleophile modules, giving rise to diverse, func-
tionality-rich, γ-substituted α,β-unsaturated carbonyl constructs. These, in turn, are invalu-
able platforms onto which further functional elements and chirality may be introduced. A
couple of appealing applications—the variable construction of a repertoire of carbasugars
and a library of annonaceous acetogenin segments—have been chosen to illustrate the via-
bility of this vinylogous aldol approach.
INTRODUCTION
Vinylogy, the transmission of electronic effects through a conjugate system, thoroughly permeates
organic and bioorganic chemistry with a number of synthetic and biosynthetic events being guided by
this concept. Owing to the intrinsic polar nature of its mechanism, the aldol reaction—a cornerstone of
synthetic and biosynthetic organic chemistry—is a prime candidate for vinylogous extension. In the
vinylogous version of this construction (Scheme 1), a carbonyl framework is connected to the γ-carbon
of a dienolate synthon, generating a vinylogous aldol motif (i.e., a δ-hydroxy-α,β-unsaturated carbonyl
structure). Here, the precious functionality of the common aldols is flanked by a reactive conjugated
double bond, which can easily undergo further manipulation. Thus, the remarkable increase in educt
complexity qualifies the vinylogous aldol reaction and its close variants (imino-aldol, Mannich, nitro-
aldol, etc.) as strategic maneuvers in the multistep synthesis of a variety of functional molecular frame-
works and targets [1].
*Lecture presented at the 13th International Conference on Organic Synthesis (ICOS-13), Warsaw, Poland, 1–5 July 2000. Other
presentations are published in this issue, pp. 1577–1797.
†Corresponding author
Scheme 1
Decisive evolution of the aldol addition has been pioneered by Mukaiyama, who first found that
stable enoxy silanes quickly react with carbonyl acceptors in the presence of Lewis acids to give aldol
and aldol-related products. The aim of this account is to highlight the merits of the vinylogous version
of this basic process, as applied to a unique triad of vinylogous enoxy silane synthons, the five-mem-
bered heterocycles denoted as A in Scheme 2.
Here, densely functionalized adducts of type C are simply traced to A (a d4 donor) and B (an a1
acceptor) via the regio- and stereoselective vinylogous Mukaiyama aldolization. The wide assortment
of variables within the donor and acceptor molecules, the high functionalization potential of carbons
1–4 within C, and the flexibility with which chirality can be established, imply that, at least in theory,
a wide assortment of natural and synthetic compounds may be assembled by adopting this chemistry.
In truth, the heterocyclic enoxy silanes in this account did not fall short of our expectations, and their
use in vinylogous aldolization has evolved into an elegant platform for notable ventures in organic syn-
thesis [2].
APPLICATION IN SYNTHESIS
Carbasugars and relatives
Carbasugars, also known as pseudo-sugars, are a family of sugar analogs that are currently attracting
great interest among organic and medicinal chemists. Owing to close topological resemblance to the
parent furanoses and pyranoses (the sugar ring oxygen is here replaced by a methylene), it is not sur-
prising that their basic biological function may be attributed to the inhibition of glycoside processing
enzymes.
G. CASIRAGHI et al.
© 2000 IUPAC, Pure and Applied Chemistry 72, 1645–1648
1646
Scheme 2
Scheme 3
To access the carbasugar constructs of both 5a and 4a ring structures, we addressed the flexible
retrosynthetic plan contemplated in Scheme 3, where carbapyranoses A or carbafuranoses I were
assembled by conjoining two complementary subunits, the butyric acid-based α,γ-dianion E' and mal-
ondialdehyde- F' or glyoxal-related fragment F". Here, two common retrons, the enoxy silane E and
the chiral glyceraldehyde-related unit F, are envisioned as synthetic equivalents of dianion E' and
dialdehydes F' or F", respectively. The route we hoped to pursue involves formation of the divergent
intermediary adduct D via implementation of the C1–C2 juncture before the annulation processes (C
→ B or G → H; C4-C5 or C3–C4 junctures), which ultimately produce pseudopyranoses A or pseu-
dofuranoses I. Two formal [3+3] or [3+2] cycloadditive maneuvers featuring a sequential vinylogous
cross aldolization-cycloaldolization protocol are central to these constructions. This project was then
put into practice in the form of stereocontrolled synthesis of a diverse repertoire of chiral, nonracemic
carbasugars, including pseudo-β-D-gulopyranose, pseudo-β-D-xylofuranose, 1-deoxy-1-amino-pseudo-
β-D-gulopyranose, and 1-deoxy-1-amino-pseudo-β-D-xylofuranose.
Annonaceous acetogenins and variants thereof
The annonaceous acetogenins are a class of C35 or C37 plant metabolites isolated, as to date, only from
the archaic family of the Annonaceae. The relevance of this compound class mainly resides in their
spectacular citotoxicity against a variety of human tumor cell lines, as well as antitumor activity.
© 2000 IUPAC, Pure and Applied Chemistry 72, 1645–1648
Vinylogous aldol reaction of heterocyclic silyloxy dienes 1647
Scheme 4
The structural hallmark of the majority of annonaceous acetogenins is an oxygenated core con-
sisting of one or two adjacent tetrahydrofuran rings, carrying two alkyl chains. The synthesis of these
chiral constructs and their analogs provides a challenging application for the vinylogous aldolization
using the heterocyclic silyl dienol ethers of this report. As shown in the plan delineated in Scheme 4,
disconnection of the generic C37 binuclear acetogenin A along the bonds C11–C12 and C25–C26
defines the subtarget lactone C as the basic scaffold of the C12–C25 core backbone, which contains the
two adjacently linked heterocycles. Attachment of the methyl butenolide frame and the saturated
aliphatic chain at the north and south orthogonally masked termini (or vice-versa) guarantees formation
of the acetogenin targets. Installation of the lactone moiety within C may arise via a vinylogous junc-
ture of the silyloxy furan TBSOF to the “anomeric” carbon of the binuclear intermediate D. The
C16–C25 unit D, in turn, originates from E, an intermediate common to the synthesis of mononuclear
annonaceous acetogenins of type B. Disconnection of E along the bond C19–C20 reveals the mononu-
clear lactol-type synthon F, which, in the forward sense, leads to E via vinylogous coupling with one
of the three silyloxy diene heterocycles TBSOF, TBSOP, or TBSOT. Lactol F readily traces back to G,
which may derive from the vinylogous Mukaiyama aldol addition between glyceraldehyde H and one
of the silyloxy diene modules already mentioned.
On the whole, this synthesis, which exploits a readily available triad of four-carbon modules and
uses a uniform and reiterative chemistry, outlines the stepwise elongation of the easily accessible three-
carbon “chiron” H via three sequential vinylogous additions. The choice of the heteroatoms combined
in the first and the second vinylogous aldol couplings, the chirality of the chosen aldehyde starter H (R
vs S) and the chirality transmittal during the molecular growth (erythro vs threo, cis vs trans) all ensure
the generation of ample chemical diversity during this synthesis.
The realization of this uniformed plan allowed us to assemble a library of advanced bis-tetrahy-
drofuran, pyrrolidine, and thiolane scaffolds encompassing the core portion of a variety of annonaceous
acetogenins and their nitrogen and sulfur analogs. In practice, the utility of this construction was
demonstrated by the preparation of eight bis-tetrahydrofuran units, two bis-pyrrolidine units, and four
bis-thiolane units of type C, along with a number of intermediary subunits of type E.
CONCLUSION
Here, the vinylogy concept perceived by Claisen more than 70 years ago [3], has been adapted to the
aldol reaction and has set the foundations for the heterocyclic dienoxy silanes to become an emblemat-
ic and valuable reactant ensemble. For reasons of concision, the synthetic examples illustrated herein
have been somewhat limited, and thus the reader might not be able to fully savor this chemistry.
Nonetheless, several recent articles, extensively covering this subject matter, are available (ref. 2).  On
the whole, although much progress has been made by us and other groups over the past ten years, it can
be seen that the major contribution has come from asymmetric syntheses based on the chiron concept.
Instead, the catalytic asymmetric executions of this vinylogous aldolization, as well as the vinylogous
additions to Michael acceptors (a rare example of a double vinylogous reaction), remain only margin-
ally explored.
In the years to come, we hope to see this vinylogous aldolization involving 2-silyloxy dienes
being both exploited by an ever-growing number of organic synthesis practitioners, and applied to the
chemical synthesis of increasingly important constructs.
REFERENCES
1. G. Casiraghi, F. Zanardi, G. Appendino, G. Rassu. Chem. Rev. 100, 1929–1972 (2000).
2. G. Rassu, F. Zanardi, L. Battistini, G. Casiraghi. Chem. Soc. Rev. 29, 109–118 (2000).
3. L. Claisen. Ber. 59, 144–153 (1926).
G. CASIRAGHI et al.
© 2000 IUPAC, Pure and Applied Chemistry 72, 1645–1648
1648


Vinylogous aldol reaction of heterocyclic silyloxy dienes. Application in synthesis

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