Scope and limitations of the alkylidene carbene 1,5-CH insertion reactions of α-amino acid-derived substrates

Article abstract of DOI:10.1016/S0040-4039(02)00585-3

A range of α-amino acid-derived cyclisation precursors were synthesised from suitably protected α-amino esters, via a Dibal-H/Wittig/catalytic hydrogenation strategy and each of these was subjected to alkylidene carbene-forming conditions (lithio(trimethy

Full text of DOI:10.1016/S0040-4039(02)00585-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3541–3542
Scope and limitations of the alkylidene carbene 1,5-CH insertion
reactions of a-amino acid-derived substrates
Renameditswe Mapitse and Christopher J. Hayes*
The School of Chemistry, The University of Nottingham, University Park, Nottingham NG7 2RD, UK
Received 14 August 2001; revised 13 March 2002; accepted 21 March 2002
Abstract—A range of a-amino acid-derived cyclisation precursors were synthesised from suitably protected a-amino esters, via a
Dibal-H/Wittig/catalytic hydrogenation strategy and each of these was subjected to alkylidene carbene-forming conditions
(lithio(trimethylsilyl)diazomethane, THF). The cyclisations proceeded in poor to good yield, with the best cyclisations occurring
to produce spirocyclic products. © 2002 Published by Elsevier Science Ltd.
The asymmetric construction of quaternary stereocen-
tres continues to be an interesting and challenging area
of organic chemistry.1 Of the synthetic approaches
available, selective CH-insertion into an existing ter-
tiary stereocentre offers a particularly direct solution to
the problem and under the correct conditions this can
be achieved with a high degree of selectivity.2
examine the alkylidene carbene CH-insertion reaction
of a range of other a-amino acid derived substrates,
and we now wish to report our preliminary findings.
In order to study the effects of a variety of amino acid
side chains on the alkylidene carbene CH-insertion
reaction, a range of cyclisation precursors was synthe-
sised. The desired materials were elaborated readily
from suitably protected versions of the parent amino
acids, proline, threonine, glycine, alanine, leucine and
phenyl alanine using the DIBAL-H/Wittig/reduction
sequence outlined below (Scheme 2).4
We have recently reported a method for the asymmetric
construction of nitrogen-bearing quaternary stereocen-
tres using an alkylidene carbene 1,5-CH insertion reac-
tion as a key step, and that this methodology can be
used for a,a-dialkyl-a-amino acid synthesis (Scheme
1).3 Due to this initial success, we extended our work to
With a range of ketone precursors in hand, we were
now in a position to examine the key alkylidene car-
bene CH-insertion reaction. A cold (−78°C) solution of
lithio(trimethylsilyl)diazomethane (LTDM)5 in THF
was treated with each of the ketones (Scheme 2) to
generate the corresponding diazoalkenes. Upon warm-
ing from −78 to 0°C, nitrogen was expelled and the
alkylidene carbenes were generated (c.f. 2, Scheme 1).
The results of the subsequent cyclisation reactions are
summarised below (Scheme 3).
O
Boc
H
TMSCHN2, BuLi,
N
O
O
THF, -78oC to 0oC
62%
N
Boc
1
2
1,5-CH
insertion
Both the proline- and threonine-derived precursors 6
and 8 cyclised to produce the desired spirocyclic prod-
ucts in acceptable yield (53 and 45%, respectively).
Pleasingly, both chiral GC (b-cyclodextrin, 100°C) and
1H NMR showed that 18 was produced with >95%
retention of stereochemistry at the nitrogen bearing
stereocentre.6 We were expecting the rather simple
glycine-derived ketone 10 to perform similarly well in
the cyclisation reaction, but we were a little disap-
pointed to find that the corresponding cyclopentene 19
was only produced in 29% yield. Following this finding,
Boc
BocHN
HO2C
steps
N
O
3
4
Scheme 1.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00585-3

3542
R. Mapitse, C. J. Hayes / Tetrahedron Letters 43 (2002) 3541–3542
reaction. Functional group incompatibility with the
i-iii
i-iii
reaction conditions, therefore, cannot account for the
poor reactions of the acyclic precursors 12, 14 and 16.
The results presented above seem to suggest that having
some degree of conformational organisation in the
ketone precursor (cf. 1, 6 and 8) is beneficial to the
cyclisation process and that this is the major difference
between the successful and unsuccessful CH-insertions.
Careful consideration should therefore be paid to the
choice of protecting groups used for the nitrogen atom,
as this seems to have a significant impact on the course
of the alkylidene carbene 1,5-CH insertion reaction.7
We are currently examining alternative protecting
group strategies in conjunction with other methods of
carbene formation, in order to develop a useful, general
synthetic method for the formation of asymmetric
nitrogen-bearing quaternary stereocentres.
CO2Me
N
N
O
Boc
Boc
5
6
O
N
O
N
CO2Me
O
Boc
Boc
8
7
O
R
CO2Me
i-iii
R
N
Bn
Boc
N
Bn
Boc
10, R=H
9, R=H
12, R=Me
14, R=iBu
16, R=Bn
11, R=Me
13, R=iBu
15, R=Bn
Acknowledgements
Scheme 2. Reagents: (i) DIBAL-H, PhMe (56–68%); (ii)
Ph3PCHC(O)Me, CH2Cl2 (83–90%); (iii) H2/Pd (10% on C),
EtOAc (92–94%).
The authors thank The University of Botswana for the
provision of
a
Scholarship (R.M.) and also
AstraZeneca, Pfizer Central Research and the School of
Chemistry, University of Nottingham, for financial
support.
i
6
N
53%
Boc
17
References
1. For reviews on the synthesis of asymmetric quaternary
stereocentres, see: (a) Corey, E. J.; Guzman-Perez, A.
Angew. Chem., Int. Ed. 1998, 37, 388; (b) Fuji, K. Chem.
Rev. 1993, 93, 2037.
O
i
8
N
45%
Boc
2. For examples, see: (a) Taber, D. F.; Neubert, T. D. J. Org.
Chem. 2001, 66, 143; (b) Taber, D. F.; Han, Y.; Incarvito,
C. D.; Rheingold, A. L. J. Am. Chem. Soc. 1998, 120,
13285; (c) Taber, D. F.; Meagley, R. P.; Walter, R. J. Org.
Chem. 1994, 59, 6014; (d) Taber, D. F.; Meagley, R. P.;
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3. (a) Gabaitsekgosi, R.; Hayes, C. J. Tetrahedron Lett. 1999,
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4. (a) Dibal-H reduction, see: McKillop, A.; Taylor, R. K. J.;
Watson, R. J.; Lewis, N. Synthesis 1994, 31; (b) Wittig
olefinations were performed at rt with commercially avail-
able Ph3PCHC(O)Me (1.5 equiv.) in CH2Cl2 (0.25–0.5 M);
(c) catalytic hydrogenations were performed using a H2
filled balloon.
5. Ohira, S.; Okai, K.; Moritani, T. J. Chem. Soc., Chem.
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6. Although compound 17 had an [h]D −75.8 (c 1.33, CHCl3),
we were unable to determine its % ee using either chiral
GC or HPLC, and we are currently trying to determine a
suitable assay for this purpose.
7. We have performed a preliminary study on the N,N-diben-
zyl version of 10, but the results of this cyclisation were
very similar to those obtained with 10 itself. We were able
to isolate 23% of the desired cyclopentene product but this
was accompanied by a variety of unidentified products.
18
R
N
i
Bn
10, R=H
12, R=Me
14, R=iBu
16, R=Bn
Boc
19, R=H (±), 29%
20, R=Me
21, R=iBu
(10-20%)
22, R=Bn
Scheme 3. Reagents and conditions: (i) (a) TMSCHN2, BuLi,
THF, −78°C (1 h); (b) add ketone (THF solution) over 15
min, then −78°C (1 h); (c) warm −78“0°C (1 h).
we were not surprised when cyclisation of the more
hindered ketones 12, 14 and 16 proved rather difficult,
and the corresponding cyclopentenes 20, 21, and 22
could only be isolated in very low yield (10–20%). We
were unable to calculate precise yields for these three
CH-insertion reactions, as the crude reaction mixtures
contained a number of unidentifiable by-products, some
of which were inseparable from the desired
cyclopentenes.
From the successful cyclisations of 1 (62%), 6 (53%)
and 8 (45%) it can be seen that both N-Boc and
N-alkyl substituents are tolerated in the CH-insertion