Electroauxiliary-assisted sequential introduction of two carbon nucleophiles on the same α-carbon of nitrogen: Application to the synthesis of spiro compounds

Article abstract of DOI:10.1021/ja028663z

The sequential introduction of two carbon nucleophiles on the same α-carbon of nitrogen by using selective oxidative cleavage of two silyl groups as electroauxilialies has been accomplished. The combination of this expedient transformation and ring-closing metathesis enables reliable and straightforward syntheses of nitrogen-containing spiro compounds, such as cephalotaxine. Copyright

Full text of DOI:10.1021/ja028663z

Published on Web 11/21/2002
Electroauxiliary-Assisted Sequential Introduction of Two Carbon Nucleophiles
on the Same r-Carbon of Nitrogen: Application to the Synthesis of Spiro
Compounds
Seiji Suga,* Mitsuru Watanabe, and Jun-ichi Yoshida*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering,
Kyoto UniVersity, Kyoto 606-8501, Japan
Received September 24, 2002
Scheme 1
Selective methods for functionalizing carbons alpha to nitrogen
are often central to the synthesis of a variety of nitrogen-containing
compounds of biological interest. There are two basic methods to
achieve this type of transformation. Oxidative introduction of a
hetero nucleophile to the R-position followed by the Lewis acid-
promoted generation of an iminium ion and subsequent reaction
with a carbon nucleophile (Scheme 1a) is efficient and useful.1 The
electronically inversed method, that is, deprotonation at the R-posi-
tion followed by reaction with a carbon electrophile (Scheme 1b)
is also powerful.2 Although these methods are widely utilized in
organic synthesis, the introduction of two organic groups on the
same R-carbon (Scheme 1c) still remains as a challenging task.
The oxidative deprotonation usually takes place at the less
substituted R-carbon.1 Therefore, the second organic group is intro-
duced to the R-carbon different from the carbon to which the first
organic group has been introduced (Scheme 1a). The base-promoted
Scheme 2
deprotonation also takes place at the less substituted R-carbon
(Scheme 1b).3 Therefore, the development of a selective method
for the introduction of two organic groups on the same carbon is
highly called for. We report here a solution to this problem.
Our approach is based on the concept of an electroauxiliary.4
Electroauxiliaries activate substrate molecules toward electrochemi-
cal,5 photochemical,6 and chemical7 electron transfer and then
by Beak’s method9 was lithiated selectively at the carbon bearing
the silyl group by sec-BuLi in Et2O with HMPA as an additive.
The treatment with TMSCl gave N-(tert-butoxycarbonyl)-2,2-bis-
(trimethylsilyl)pyrrolidine 2 in 100% regioselectivity (eq 1).10 No
2,5-bis(trimethylsilyl)substituted product was obtained. The use of
TMEDA in place of HMPA resulted in completely opposite
regioselectivity.11 Delicate balance between kinetic (steric) and
thermodynamic (stabilization of carbanion by R-silyl group) factors
seems to be responsible for these phenomena, although the detailed
mechanism is not clear.
control the reaction pathway to bias the formation of desired
products. We have already revealed that the preintroduction of an
electroauxiliary to a carbon alpha to nitrogen gives rise to selective
introduction of a nucleophile on the carbon to which the auxiliary
has been attached. In connection with our interest in extending the
utility of electroauxiliaries, we have recently expanded our focus
to use multiple electroauxiliaries.8 Thus, we envisioned that the
preintroduction of two electroauxiliaries on one carbon atom alpha
to nitrogen would lead to the introduction of two organic groups
on the same carbon (Scheme 2). Thus, pyrrolidine carbamate was
chosen as an amine derivative for study because many alkaloids of
biological interest have the pyrrolidine skeleton. The trimethylsilyl
group5 was chosen as an electroauxiliary because it is stable and
easy to handle. We envisioned that the oxidation of pyrrolidine
carbamate having two silyl groups on the same R-carbon gives
rise to the cleavage of one C-Si bond and the introduction of an
organic group. The second oxidation would lead to the cleavage
of the second C-Si bond and the introduction of the second organic
group on the same R-carbon.
Compound 2 was converted into N-methoxycarbonyl-2,2-bis-
(trimethylsilyl)pyrrolidine 3, which is more suitable for the
electrochemical oxidation, by the deprotection using TFA and the
reaction with methyl chloroformate.
Sequential introduction of two carbon nucleophiles to 3 was
studied using the electrochemical method. We employed the “cation
pool” method,12 which involves generation and accumulation of
N-acyliminium ion at low temperature and subsequent direct
reaction with carbon nucleophiles. This one-pot method has an
advantage over the conventional processes because nucleophiles
We initiated our study by searching for a straightforward method
to introduce two silyl groups on the same R-carbon of pyrrolidine
skeleton. During extensive screening, we were delighted to find
that N-(tert-butoxycarbonyl)-2-trimethylsilyl-pyrrolidine 1 prepared
* To whom correspondence should be addressed. E-mail: suga@sbchem.kyoto-
u.ac.jp; yoshida@sbchem.kyoto-u.ac.jp.
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10.1021/ja028663z CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Second Alkylation Using the Cation Pool Methoda and
Cyclization Using Metathesisb
nyl)ethyl 4-nitrobenzenesulfonate15d afforded 13. Intramolecular
Heck-type ring-closing reaction of 13 with palladium catalyst15c,16
gave 14 as a single stereoisomer. Because compound 14 is known
to be converted to 12 in four steps (75% total yield),17 a formal
total synthesis of 12 was achieved.
a After electrolysis (2.5 F/mol based on the carbamates) at -78 °C using
a divided cell, to the “cation pool” thus generated was added the carbon
nucleophile (2 equiv) to give the product. b Reaction was carried out in
benzene at room temperature using 5 mol % Grubbs catalyst (bis(tricyclo-
hexylphosphine)benzylidineruthenium (IV) dichloride).14a
In conclusion, the present strategy opens a new aspect of the
synthesis of nitrogen-containing compounds having a quaternary
carbon center, especially spiro compounds. We are currently
expanding our focus to its combinatorial aspects.
that might be otherwise oxidized during an in situ process, such as
organo magnesium, zinc, and aluminum reagents can be used
without any difficulty.12c Thus, the oxidation of 3 was carried out
at -78 °C in the absence of a nucleophile, and the resulting
2-silylpyrrolidinium ion was allowed to react with nucleophiles,
such as allyltrimethylsilane or homoallylmagnesium bromide, to
obtain the corresponding coupling products (eq 2).
Acknowledgment. The work was supported by a Grant-in-Aid
for Scientific Research from the Ministry of Education, Science,
Sports, and Culture, Japan.
Supporting Information Available: Experimental procedures and
spectroscopic and analytical data of new compounds (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
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forward access to nitrogen-containing spiro compounds.
The present approach has been successfully applied to the
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