SmI2-mediated reduction of α-functionalised amides: Highly enantiospecific access to an atropisomeric amide

Article abstract of DOI:10.1055/s-1998-1838

SmI₂ or SmI₂-LiCl mixtures can be used to reduce α-functionalised amides in yields of up to 85% depending upon the amide structure. The method has been applied to the synthesis of an atropisomeric anilide system in highly enantioenriched form, starting with (S)-O-acetyl lactic acid.

Full text of DOI:10.1055/s-1998-1838

September 1998
SYNLETT
967
SmI2-Mediated Reduction of α-Functionalised Amides: Highly Enantiospecific Access to an
Atropisomeric Amide
Adam D. Hughes and Nigel S. Simpkins*
Department of Chemistry, The University of Nottingham, University Park, Nottingham, NG7 2RD, UK
Fax (0115) 9513564; e-mail Nigel.Simpkins@Nottingham.ac.uk
Received 20 June 1998
Abstract: SmI or SmI -LiCl mixtures can be used to reduce
group, which furnished the two separable atropisomeric products 9a and
9b. At this point it was not possible to assign the relative
stereochemistry of the aryl-C–N axis, which was deduced following
subsequent transformations.
2
2
6
α-functionalised amides in yields of up to 85% depending upon the
amide structure. The method has been applied to the synthesis of an
atropisomeric anilide system in highly enantioenriched form, starting
with (S)-O-acetyl lactic acid.
In 1994
a
report from Curran’s group described the powerful
1
stereodirecting potential of certain types of axially twisted amides. For
example, atropisomeric amide 1 and the related maleimide 2 were
shown to undergo cycloaddition reactions with excellent levels of
diastereocontrol, i.e. the formation of products having asymmetric
carbon atoms is controlled by the chiral aryl-C–N axis in the starting
material. Related studies have shown that the chiral axis present in
naphthamide 3 controls the stereochemistry of reactions involving the
2
R’ group (e.g. additions to carbonyls, etc.).
Our own interest in this area lay in the possibility of using such
atropisomeric amides in enolate chemistry, and we found that high
selectivity can be achieved, e.g. in the alkylation of 4 to give 5, if a
coordinating group (i.e. MEM) is incorporated onto the amide
Scheme 1
3
nitrogen.
Clearly, in order to transform compound 9a into 4 (and 9b into the
enantiomer of 4), a deoxygenation is required. Whilst the Taguchi
approach requires acetate hydrolysis, alcohol activation, selenide
displacement and selenoxide syn-elimination (to give an acrylamide
related to 1), we anticipated that a more direct deoxygenation should be
possible. SmI has been used extensively in such reactions, but mainly
2
involving α-heteroketones, and we were surprised to find that this
7
reagent has not been previously applied to amide reductions.
Initial reactions of amides 9 with SmI under standard conditions were
2
somewhat sluggish, and only by adopting the recently reported
8
protocol, involving addition of LiCl to the reaction mixture, were
acceptable yields obtained, Scheme 2.
Although these results show some potential for such amides in
asymmetric synthesis, most of the work reported to date uses racemic
derivatives, and access to atropisomeric intermediates in
enantiomerically enriched form poses a problem. Quite recently Taguchi
and co-workers have described a chiral pool approach to this problem,
including the synthesis of relatives of 1 starting from (S)-O-acetyl lactic
Scheme 2
4
acid. Independently, we have pursued a similar strategy and herein
describe our preliminary results, which involve the use of a new type of
At this point it was possible to determine the enantiomeric excess of
SmI reduction that can be generally applied to most types of amide.
2
these amides to be ≥93%, indicating that only a slight loss of
Acetylation of commercially available L-(+)-lactic acid (ca. 98% ee)
gave the O-acetyl derivative 7, which was then coupled with 2-tert-
9
stereochemical integrity had occurred during the synthetic sequence.
5
The absolute configurations shown were assigned following the
conversion of 4a into a known alcohol 11, as indicated in Scheme 3.
butylaniline using established peptide coupling techniques, Scheme 1.
As reported by Taguchi, we found the yields of anilide 8 to be modest
using many methods, the use of 3-ethyl-1-(3-(dimethylamino)-
propyl)carbodiimide hydrochloride (EDC·HCl) giving the best results
(in related work the pyBOP reagent also gave good results). Anilide 8
was then N-alkylated with MEMCl in order to install the required MEM
Thus alkylation of 4a (93% ee) as described before gave product anilide
with a very high degree of atroposelectivity (>25:1). Reduction then
gave the alcohol 11 of known absolute configuration and with specific
rotation data in accord with our expectation of ca. 93% ee for this

968
LETTERS
SYNLETT
Acknowledgements
We are grateful to the Engineering and Physical Sciences Research
Council (EPSRC) for support of A.D.H.
References and Footnotes
(1) (a) Curran, D. P.; Qi, H.; Geib, S. J.; DeMello, N. C. J. Am. Chem.
Soc. 1994, 116, 3131. (b) For a more recent contribution, see
Curran, D. P.; Hale, G. R.; Geib, S. J.; Balog, A.; Cass, Q. B.;
Degani, A. L. G.; Hernandes, M. Z.; Freita, L.C. G. Tetrahedron:
Asymmetry 1997, 8, 3955.
Scheme 3
10
product. Assignment of the configuration of the asymmetric carbon
centre in 11 allows that centre to be assigned in 10, and we can then
infer the configuration of the aryl-C–N axis as shown in 10, 4 and 9.
(2) For a listing of contributions in this area, see Ahmed, A.; Clayden,
J.; Rowley, M. Chem. Commun. 1998, 297.
Since the type of amide deoxygenation shown in Scheme 2 appeared
11
rather rare, and the application of SmI to such amide reduction was
(3) Hughes, A. D.; Price, D. A.; Shishkin, O.; Simpkins, N. S.
2
12
unprecedented, we applied the new method to a range of other amides,
Tetrahedron Lett. 1996, 37, 7607.
13
as shown in the Table.
(4) Kitagawa, O.; Izawa, H.; Sato, K.; Dobashi, A.; Taguchi, T. J.Org.
Chem. 1998, 63, 2634.
(5) Bodansky, M. Principles of Peptide Synthesis; Springer-Verlag:
New York, 1984; p 9–58.
(6) The atropisomeric amides
chromatography on silica-gel (25% EtOAc–light petroleum as
eluant), to give firstly 9b, [α]D -60 (c, 1.2 in CHCl ), followed by
9
were separated by flash
3
9a , [α]D +21 (c, 1.4 in CHCl ).
3
(7) For reviews, see (a) Molander, G. A. Org. React. 1994, 46, 211.
(b) Molander, G. A.; Harris, C. R. in Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A. Ed.; John Wiley and Sons:
1995; Vol 6, p 4428–4432. (c) Molander, G. A.; Harris, C. R.
Chem. Rev. 1996, 96, 307. (d) Kagan, H. B.; Namy, J. L.
Tetrahedron 1986, 42, 6573.
(8) Fuchs, J. R.; Mitchell, M. L.; Shabangi, M.; Flowers II, R. A.
Tetrahedron Lett. 1997, 38, 8157.
(9) Although the ee of the amides 4 could not be determined
directly, we were able to establish the enantiomeric excess of
α-methylated derivatives (from reaction of either 4a or 4b) with
LDA in THF, followed by excess MeI by HPLC using a Chiralcel
i
OD® column (1% PrOH in hexane as eluant).
(10) The sequence starting from 4a gave 10 as shown, which was then
reduced to give 11, [α]D -10 (c, 1.8 in C H ), lit. value [α]D -11(c,
6
6
2.75 in C H ) for (S)-enantiomer, see Sacha, H.; Waldmuller, D.;
6
6
Braun, M. Chem. Ber. 1994, 127, 1959. Starting with 4b gave the
expected enantiocomplementary results.
The reductions have not been fully optimised, and it is clear from the
extended reaction time of at least twenty-four hours that is required that
this is not a particularly facile process. Nevertheless, the reaction seems
fairly general for different types of tertiary amide, and effects removal
of α-bromo, α-acetoxy and α-benzyloxy functions. In general we found
it necessary to add LiCl to the reactions, although entries 4–6 show that
(11) For other examples of α-deoxygenation, see (a) Naito, T.; Kojima,
N.; Miyata, O.; Ninomiya, I.; Inoue, M.; Doi, M. J. Chem. Soc.,
Perkin Trans. 1 1990, 1271 (Ca in NH ). (b) Hirose, N.; Sohda, S.;
3
Kuriyama, S.; Toyoshima, S. Chem. Pharm. Bull. 1973, 21, 960
(Red-Al®).
debromination is rather more facile, and works well enough with SmI
(12) A very recent report describes the use of SmI to effect enamide
2
2
alone. Debromination of a secondary amide is facile (entry 6), but other
secondary amides gave either very poor yields of product (entry 9) or no
reduction at all (entry 10). In the latter case only the hydroxyamide
resulting from acetate hydrolysis was obtained (52%).
saturation; the product amide having α-oxygenation survived
intact, see Rigby, J. H.; Cavezza, A.; Heeg, M. J. J. Am. Chem.Soc.
1998, 120, 3664.
(13) Typical experimental procedure for amide reduction
A solution of LiCl (flame-dried in a round-bottomed flask under
vacuo before use) (2.76 mmol) in THF (2.8 ml) was added to a
In conclusion, we have uncovered a new type of amide reduction and
applied it to the preparation of highly enantiomerically enriched
atropisomeric amides. Further investigations of this type of
transformation, especially with cyclic amide systems, are planned.
solution of SmI , freshly prepared from Sm metal (152mg, 1.01
2
mol) and 1,2-diiodoethane (259 mg, 0.92 mmol). After 30 min a
solution of the starting amide (0.2 mmol) in THF (0.5ml) was
added and the reaction mixture stirred for 24h. Standard aqueous
work-up, followed by chromatography then gave the products in
the yields indicated.