Carbamate chemistry has flourished since the 1980's which saw the introduction of the
carbamoyl group by Hoppe and co-workers, prominent researchers in this area, as a
suitable moiety for the activation and stabilisation of alpha-heterocarbanions which are
important intermediates in synthetic organic chemistry. This functionality increases a-CH
acidity and stabilises the a-lithiocarbanion thus generated. The versatility of the
carbamate group has spawned investigations into the numerous possibilities that exist for
the functionalisation of the carbon alpha to the carbamate group. Some of these
possibilities were explored in the present work.
The direct formation of stable benzylic carbanions alpha to an oxygen atom is not a facile
process as such lithiated species are unstable and readily undergo a 1,2-Wittig
rearrangement. However, protection of the alcohol as the carbamate enabled
functionalisation of both benzylic sites with a variety of electrophiles.
Benzyl carbamates were found to react regioselectively with a,~-unsaturated electrophiles
to afford either the 1,2- or l,4-addition products. The regioselectivity could be controlled
by the presence or absence of a silyl moiety, either a trimethylsilyl or tertbutyldimethylsilyl
moiety, attached at the benzylic position, alpha to the carbamate.
The reaction of benzyl carbamates with 2-cyclohexen-1-one and 2-butenolide afforded the
1,2-addition adducts in moderate to good yields (25-66%). The isolation of the masked ahydroxy
ketone resulting from the opening of the lactone ring on reaction of 2-butenolide
with benzyl N,N-diisopropylcarbamate was surprising, as this electrophile is known to
behave as an excellent Michael acceptor. The introduction of a silyl moiety at the benzylic
position facilitated conjugate addition, yielding the corresponding Michael addition
products.
A novel cyclisation was observed on reaction of a-silyl benzyl carbamates with methyl
acrylate to give the a,y;y-trisubstituted butanolides (y-butyrolactones). The proposed
vii
mechanism of this reaction is discussed and illustrates the migrational ability of the
carbamate functionality.
Chiral induction in benzylic systems has only been investigated by a few authors. In the
present investigation two possible routes to chiral induction at the benzylic position were
investigated using either a (-)-sparteine-mediated transformation or chiral carbamates
derived from (L)-proline. (-)-Sparteine mediated transformations were solvent dependent
with the best enantiomeric excess of 28% being obtained. The results indicated that
racemisation at the benzylic position was faster than reaction with an electrophile. The
chiral carbamates were only slightly more successful yielding the a-substituted adducts
with diastereoselectiVities of the order of 20-50%. The diastereoselectivities were found to
be enhanced by the addition of HMPA which coordinated with the transition state blocking
one of the faces to attack by the electrophile.
The 1A-addition reaction with 2-butenolide was particulary useful as it allowed the
exploration of the synthesis of lignan derivatives from benzyl carbamates. Lignans are
secondary plant metabolites and exhibit.a wide range of biological activities. Applying the
methodology developed to the synthesis of lignans resulted in the preparation of an
arylnaphthalene lignan, in 79%, and the partial synthesis of racemic fargesin, a racemic
furofuran lignan.
This natural product synthesis highlighted the difficulty in removing the carbamate
functionality and re-introducing the alcohol moiety. Thus, hydrolytic cleavage of the
benzyl carbamates was investigated using a selection of mineral acids. Depending on the
reaction conditions, the products were found to be the corresponding benzyl alkanoates or
benzylhalides. The alkanoates are derived from nucleophilic displacement of the initially
formed benzyl halide A novel deprotection of a-silyl benzyl carbamates was also observed
in which the carbamoyl group was cleaved to afford the a-silyl alkanoates and chlorides
without the loss of the silicon moiety. / Thesis (Ph.D.)-University of Natal, Pietermaritzburg, 1997.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:ukzn/oai:http://researchspace.ukzn.ac.za:10413/5766 |
| Date | January 1997 |
| Creators | Mason, Paul Henry. |
| Contributors | Ernslie, N. D. |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | English |
| Type | Thesis |
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