Valence tautomerism in titanium enolates: Catalytic radical haloalkylation and application in the total synthesis of neodysidenin

Article abstract of DOI:10.1021/ja910154f

(Chemical Equation Presented) A direct ruthenium-catalyzed radical chloroalkylation of N-acyl oxazolidinones capitalizing on valence tautomerism of titanium enolates has been developed. The chloroalkylation method served as the centerpiece in the enantioselective total synthesis of trichloroleucine-derived marine natural product neodysidenin.

Full text of DOI:10.1021/ja910154f

Published on Web 01/15/2010
Valence Tautomerism in Titanium Enolates: Catalytic Radical Haloalkylation
and Application in the Total Synthesis of Neodysidenin
Ste´phane Beaumont, Elizabeth A. Ilardi, Lucas R. Monroe, and Armen Zakarian*
Department of Chemistry and Biochemistry, UniVersity of California, Santa Barbara, California 93106-9510
Received December 1, 2009; E-mail: zakarian@chem.ucsb.edu
Among more than 4000 halogenated natural products identified to
date,1 neodysidenin and other trichloroleucine-derived marine me-
tabolites comprise a unique group.2 For the majority of chlorinated
natural products, a reasonable biosynthetic pathway involving an
electrophilic chlorination can be proposed.3 On the other hand, the
trichloromethyl group in neodysidenin and related compounds arises
from a remarkable direct chlorination of the pro-R methyl group of
L-leucine carried out by nonheme FeII halogenases requiring oxygen,
chloride, and R-ketoglutarate for their activity.4 In contrast, availability
of synthetic methods for stereoselective trichloromethylation is highly
limited,5 whereas chlorinated natural products are attracting increasing
attention as targets for chemical synthesis.6
likely to be substantially more stable than a carbon-centered radical
(such as D) expected from a radical addition to silyl enol ethers or
other enolates. Reduction of Ru(III) species with the Ti(III) intermediate
should regenerate the catalyst and provide the initial product as a Ti(IV)
chelate E. In addition, the chelated nature of the titanium enolates
ensures conformational rigidity required for stereocontrol.14
In this communication we describe a practical, efficient method
for highly stereoselective direct chloroalkylation of titanium enolates
and its application in the total synthesis of neodysidenin that can
be readily adopted for the synthesis of other bioactive natural
products in this class.7 Guided by an extension of the classic
Kharasch reaction8 described by Eguchi and co-workers,9 our early
efforts involved Ru(II)-catalyzed10 redox trichloromethylation of
trimethylsilyl enol ethers generated from chiral N-acyl oxazolidi-
nones such as 1 (Scheme 1).11 Although encouraging results were
obtained with silyl ketene acetals (∼50% yields, ds 3:1), the recent
characterization of valence tautomerism in titanium enolates
provided a conceptual foundation for the development of a direct
radical chloroalkylation of N-acyl oxazolidinones.12,13
Next, a series of experiments were carried out to evaluate the scope
of N-acyl oxazolidinone and of chloroalkylating components in this
Ru-catalyzed process. Table 1 illustrates that functionalized N-acyl
oxazolidinones are excellent substrates. Different Evans-type chiral
auxiliaries can be used without loss of stereoselectivity, but the highest
yields are achieved with the 5,5-dimethyl oxazolidinones.16 Aromatic,
heterocyclic, and ethereal substituents are compatible with the reaction
conditions. As evident from entry 5, a direct competition with Kharasch
reaction reveals that the more sterically demanding titanium enolate
is a superior trichloromethyl radical acceptor than a terminal double
bond. With 3 equiv of BrCCl3, the bis-trichloromethylation product
was isolated in a virtually quantitative yield. The stereoselectivity is
generally very high; in no case were we able to observe or isolate the
minor diastereomer.
The scope of the haloalkylating reagent investigated in this study
is illustrated in Table 2. For most of these examples, the more active
commercially available ATRP redox catalyst Cp*Ru[PPh3]2Cl was
required to attain optimal yields.15 Since a number of chlorinated
natural products contain a 5,5-dichloroleucine subunit, it is notable
that a direct dichloromethylation can be performed in useful yields
using bromodichloromethane (Table 2, entry 2). A range of other
functionalized haloalkylating reagents proved to be suitable with this
catalyst, including dichloro- and trichloroacetates, 1,1,1-trichloroethane,
1-chloro-1-bromo-2,2,2-trifluoroethane, and Cl3CCH2OCO2Bn. The
The unconventional biradical character of titanium enolates de-
scribed by Moreira and co-workers suggests that these intermediates
should be efficient radical acceptors.12 Indeed, when the Ti enolate
derived from 114 was treated with BrCCl3 in the presence of
[Ph3P]3RuCl2 as a readily available redox catalyst (7 mol %), product
2 was obtained in an essentially quantitative yield with exquisite
stereocontrol (Scheme 1). The mechanistic hypothesis in Scheme 1 is
based on the well-established redox activity of [Ph3P]3RuCl2 widely
used in atom-transfer radical polymerization (ATRP)15 and is similar
to that proposed by Eguchi for a related process with silyl enol ethers.9
A major advantage, however, is that the radical addition product should
be stabilized by electron delocalization onto titanium, not feasible with
silyl enol ethers. Thus, in the first step of the process, the CCl3 radical
is formed upon an electron transfer from the Ru(II) complex to BrCCl3.
Addition of the electrophilic radical to biradical B should be particularly
favorable because the product is a titanium(III) complex C, which is
Scheme 1. Biradical Character of Titanium Enolates in Radical
Addition Reactions Catalyzed by Ruthenium(II)
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1482 J. AM. CHEM. SOC. 2010, 132, 1482–1483
10.1021/ja910154f  2010 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Enantioselective Total Synthesis of Neodysidenin
Table 1. Radical Trichloromethylation: N-Acyloxazolidinone
Scopea
enantioselective total synthesis of trichloroleucine-derived marine
natural product neodysidenin.
Acknowledgment. Support was provided by Eli Lilly, NIGMS
(R01 GM077379), and NSF (CHE-0836757, undergraduate summer
support to L.R.M.). We thank Dr. Wu (UCSB) for X-ray analysis,
and Professor Molinski (UCSD) for helpful discussions.
Supporting Information Available: Experimental procedures and
1
copies of H and 13C NMR spectra. This information is available free
of charge via the Internet at http://pubs.acs.org.
a See Supporting Information for experimental details. b All yields are
of isolated products; dr determined by 500 MHz 1H NMR of the crude
mixture of products. c 1.0 equiv of BrCCl3 was used, with 3 equiv of the
double addition product isolated in 97% yield (dr >98:2).
References
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Table 2. Radical Haloalkylation: Haloalkylating Agent Scope
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a All reported yields are of isolated products; dr was determined by
(10) First application of a Ru(II) complex for the generation of CCl3 radicals:
Matsumoto, H.; Nakano, T.; Nagai, Y. Tetrahedron Lett. 1973, 14, 5147–5150.
(11) Besides the control of stereoselectivity, an important function of the chiral
auxiliary is to suppress elimination of HCl in products in avoidance of
A1,3-strain. The HCl elimination is a common problem in related methods
(refs 9, 5).
500 MHz H NMR. b At the indicated stereocenter.
1
remainder of the mass balance for the reactions in Table 2 is the
substrate, with all yields based on recovered starting material exceeding
90%.
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(19) Both diastereomers at C13 of neodysidenin have been prepared. Physical
data for only the 13S isomer fully matched those reported for the natural
product, resulting in the reassignment of configuration at C13 [natural:
[a]D23-52.1° (0.165 CHCl3) ref 2a; 13R: [a]D23 +26.1° (0.50, CHCl3); 13S:
[a]D23-62.3° (0.20 CHCl3)]. Thus, neodysidenin and pseudodysidenin
appear to be identical: Jime´nez, J. I.; Scheuer, P. J. J. Nat. Prod. 2001, 64,
200–203. See Supporting Information for details.
On the basis of this methodology, the total synthesis of
neodysidenin through the intermediacy of (2S,4S)-5,5,5-trichloro-
leucine was accomplished (Scheme 2). Imide 2 was advanced to
Ellman-type N-sufinimine 4 in 5 steps.17 Sc-Catalyzed Strecker
synthesis with Me3SiCN followed by hydrolysis delivered (2S,4S)-
5,5,5-trichloroleucine (82%, dr 94:6).18 Using this modular ap-
proach, all stereoisomers of 5,5-di- or 5,5,5-trichloroleucine may
be accessed in a straightforward manner. Subsequent N-acylation
of the amino acid with reagent 5, also derived from nitrile 3, readily
afforded dipeptide 6, which has been advanced to neodysidenin in
one additional amidation step (EDC, HOAt, THF, 86% yield).19
In summary, a direct ruthenium-catalyzed radical chloroalkylation
capitalizing on the valence tautomerism of titanium enolates has
been developed. This method served as the centerpiece in the
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