Asymmetric allylic alkylation in combination with ring-closing metathesis for the preparation of chiral N-heterocycles

Article abstract of DOI:10.1021/ol101944j

Asymmetric copper-catalyzed allylic substitution with methylmagnesium bromide is employed in combination with ring-closing olefin metathesis or ene - yne metathesis to achieve the synthesis of chiral, unsaturated nitrogen heterocycles. The resulting six-

Full text of DOI:10.1021/ol101944j

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4658-4660
Asymmetric Allylic Alkylation in
Combination with Ring-Closing
Metathesis for the Preparation of Chiral
N-Heterocycles
Johannes F. Teichert, Suyan Zhang, Anthoni W. van Zijl, Jan Willem Slaa,
Adriaan J. Minnaard, and Ben L. Feringa*
Stratingh Institute for Chemistry, UniVersity of Groningen, Nijenborgh 4, 9747 AG,
Groningen, The Netherlands
b.l.feringa@rug.nl
Received August 17, 2010
ABSTRACT
Asymmetric copper-catalyzed allylic substitution with methylmagnesium bromide is employed in combination with ring-closing olefin metathesis
or ene-yne metathesis to achieve the synthesis of chiral, unsaturated nitrogen heterocycles. The resulting six- to eight-membered chiral
heterocycles are accessible in high yields and with excellent enantioselectivities.
Nitrogen-containing heterocycles are ubiquitous in naturally
occurring compounds, such as alkaloids, but are also key
structural features in many biologically active products.1-4
Among these, nitrogen heterocycles with various ring sizes
bearing stereogenic centers are frequently observed.5-10 For
example, poisonous frogs produce a variety of biologically
active chiral piperidines featuring methyl substituents at the
stereocenters.11,12 These structures represent interesting
targets for synthesis,13-16 imposing particular challenges with
regard to the construction of the stereogenic centers with
high selectivity. One approach that has been frequently
exploited is the use of ring-closing metathesis for the
construction of N-heterocycles,14,17-19 which has among
(1) Fattorusso, E.; Taglialatela-Scafati, O. Modern Alkaloids: Structure,
Isolation, Synthesis and Biology; Wiley-VCH: Weinheim, 2007
(2) Michael, J. P. Nat. Prod. Rep. 2005, 22, 603–626
.
.
(3) Mitchinson, A.; Nadin, A. J. Chem. Soc., Perkin Trans. 1 2000,
2862–2892
.
(11) Daly, J. W.; Noimai, N.; Kongkathip, B.; Kongkathip, N.; Wilham,
J. M.; Garraffo, H. M.; Kaneko, T.; Spande, T. F.; Nimit, Y.; Nabhitabhata,
(4) Ohagan, D. Nat. Prod. Rep. 1997, 14, 637–651
(5) Boger, D. L.; Turnbull, P. J. Org. Chem. 1997, 62, 5849–5863
.
.
J.; Chan-Ard, T. Toxicon 2004, 44, 805–815.
(6) Martin, S. F.; Liao, Y. S.; Wong, Y. L.; Rein, T. Tetrahedron Lett.
1994, 35, 691–694
(12) Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68,
.
1556–1575
.
(7) Pilli, R. A.; de Oliveira, M. D. C. F. Nat. Prod. Rep. 2000, 17, 117–
(13) Alibes, R.; Figueredo, M. Eur. J. Org. Chem. 2009, 2421–2435
(14) Arisawa, M.; Nishida, A.; Nakagawa, M. J. Organomet. Chem.
.
127
.
(8) Sakai, R.; Higa, T. J. Am. Chem. Soc. 1986, 108, 6404–6405
(9) Smith, A. B.; Cho, Y. S.; Pettit, G. R.; Hirschmann, R. Tetrahedron
.
2006, 691, 5109–5121
(15) Laschat, S.; Dickner, T. Synthesis 2000, 1781–1813
(16) Naito, T. Chem. Pharm. Bull. 2008, 56, 1367–1383
(17) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199–2238
.
.
2003, 59, 6991–7009
.
.
(10) Wipf, P.; Spencer, S. R. J. Am. Chem. Soc. 2005, 127, 225–235
.
.
10.1021/ol101944j  2010 American Chemical Society
Published on Web 09/23/2010

others been employed for the synthesis of non-natural amino
acids.20,21
We have developed the asymmetric Cu-catalyzed allylic
substitution of allylic bromides with Grignard reagents,
employing chiral ferrocene-based bisphosphine ligands
(Scheme 1).22-26 This catalytic process is especially suited
The N-substituted allylic bromides 1 and 5 (Tables 1 and
3) of various chain lengths are available in a few steps from
commercially available compounds.31
Table 1. Asymmetric Allylic Alkylation of Allylic Bromides 1
Scheme 1
.
Cu-Catalyzed Allylic Alkylation of Cinnamyl
Bromide
entry
n
branched (2)/linear (3) yield (%) (for 2) ee (%)
1
2
3
1 (1a)
2 (1b)
3a (1c)
95:5
98:2
92:8
74 (2a)
84 (2b)
72 (2c)
99
90
98
a 6.00 mol % of CuBr·SMe2 and 8.00 mol % of L1 were used.
for the introduction of chiral methyl substituents, a structural
motif frequently observed in naturally occurring com-
pounds.27 One major advantage of this methodology is that
it furnishes terminal olefinic bonds, which represent ideal
starting points for further modifications. This concept has been
successfully applied in the synthesis of chiral allylic esters,
which are important building blocks for the preparation of chiral
lactones.28 Similar approaches have been reported for the
synthesis of chiral carbocycles by combination of allylic
substitution followed by ring-closing metathesis.29,30
We anticipated that the Cu-catalyzed asymmetric allylic
alkylation would serve as an ideal basis for the synthesis of
nitrogen-containing heterocycles of various ring sizes, when
combined with olefin or ene-yne ring-closing metathesis.
When starting off from allylic bromides substituted with
protected amine and terminal olefin or alkyne substituents,
the obtained chiral products could subsequently be trans-
formed to the correspoding unsaturated piperidines, azepanes
or azocanes. One important feature of this approach is the
fact that the resulting compounds bearing olefins or dienes
are well-suited chiral building blocks for further modifica-
tions.
When allyl bromides 1 with terminal olefin substituents
were subjected to allylic alkylation conditions (3.0 mol %
of CuBr·SMe2, 4.0 mol % of L1 (Taniaphos32-34 ), 1.2 equiv
of MeMgBr in CH2Cl2 at -80 °C), the desired chiral products
2 were obtained in good yields and up to excellent enanti-
oselectivities (reaching 99% ee, Table 1, entry 1). Further-
more, the product distribution of branched (2) to linear (3)
was very good, exceeding 92:8 favoring the branched
products. To reach full conversion of 1c (n ) 3) (Table 1,
entry 3), a higher catalyst loading of 6.0 mol % of CuBr·SMe2
and 8.0 mol % of L1 was required.
Chiral compounds 2 were subsequently transformed to the
corresponding N-heterocycles 4 by ring-closing metathesis
(Table 2). With 5.0 mol % of Hoveyda-Grubbs second-
Table 2. Ring-Closing Metathesis of Olefinic Substrates 2
(18) Felpin, F. X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693–3712
(19) Pandit, U. K.; Overkleeft, H. S.; Borer, B. C.; Bieraugel, H. Eur.
J. Org. Chem. 1999, 959–968.
.
entry
n
yield (%)
ee (%)
1
2
3
1 (2a)
2 (2b)
3 (2c)
54 (4a)36
61 (4b)
77 (4c)
99
90
98
(20) Hassan, H. M. A.; Brown, F. K. Chem. Commun. , 46, 3013–3015
(21) Rutjes, F. P. J. T.; Schoemaker, H. E. Tetrahedron Lett. 1997, 38,
.
677–680
.
(22) Harutyunyan, S. R.; den Hartog, T.; Geurts, K.; Minnaard, A. J.;
Feringa, B. L. Chem. ReV. 2008, 108, 2824–2852
(23) Lo´pez, F.; van Zijl, A. W.; Minnaard, A. J.; Feringa, B. L. Chem.
Commun. 2006, 409–411
(24) van Zijl, A. W.; Lo´pez, F.; Minnaard, A. J.; Feringa, B. L. J. Org.
Chem. 2007, 72, 2558–2563
(25) van Zijl, A. W.; Szymanski, W.; Lo´pez, F.; Minnaard, A. J.; Feringa,
B. L. J. Org. Chem. 2008, 73, 6994–7002
(26) Alexakis, A.; Ba¨ckvall, J. E.; Krause, N.; Pa`mies, O.; Die´guez, M.
.
generation catalyst,35 the six- to eight-membered rings were
obtained in moderate to good yields. The best result was
found for the eight-membered unsaturated azocane 4c (77%,
.
.
.
Chem. ReV. 2008, 108, 2796–2823
.
(31) For the synthetic routes, see the Supporting Information.
(32) Ireland, T.; Grossheimann, G.; Wieser-Jeunesse, C.; Knochel, P.
(27) ter Horst, B.; Feringa, B. L.; Minnaard, A. J. Chem. Commun. 2010,
46, 2535–2547.
Angew. Chem., Int. Ed. 1999, 38, 3212–3215
(33) Fukuzawa, S.; Yamamoto, M.; Hosaka, M.; Kikuchi, S. Eur. J.
Org. Chem. 2007, 5540–5545
(34) Ireland, T.; Grossheimann, G.; Wieser-Jeunesse, C.; Knochel, P.
Angew. Chem., Int. Ed. 2008, 47, 3666
(35) Grubbs, R. H. Angew. Chem., Int. Ed. 2006, 45, 3760–3765.
.
(28) Geurts, K.; Fletcher, S. P.; Feringa, B. L. J. Am. Chem. Soc. 2006,
128, 15572–15573.
.
(29) Alexakis, A.; Croset, K. Org. Lett. 2002, 4, 4147–4149
.
(30) Giacomina, F.; Riat, D.; Alexakis, A. Org. Lett. 2010, 12, 1156–
.
1159
.
Org. Lett., Vol. 12, No. 20, 2010
4659

Table 2 entry 3). It is important to note that the ee of the
desired product was not compromised during the reaction.
For the synthesis of chiral N-heterocycles carrying a diene
motif, the synthesis started from allylic bromides 5 bearing
terminal alkyne substituents of various chain lengths. Under
standard allylic substitution conditions, the desired chiral
products 6 were isolated in good yields (Table 3). In all cases,
Table 4. Ene-Yne Metathesis of Alkyne Substrates 6
entry
n
yield (%)
ee (%)
1
2
3
1 (6a)
2 (6b)
3 (6c)
77 (8a)
65 (8b)40
n.d.
99
99
n.d.
Table 3. Asymmetric Allylic Alkylation of Allylic Bromides 5
metathesis proceeded to the linear product 8c in moderate
yields (Scheme 2), where the alkyne moiety of 6c reacted
entry
n
branched (6)/linear (7) yield (%) for 6 ee (%)
1
2
3
1 (5a)
2 (5b)
3a (5c)
95:5
96:4
95:5
77 (6a)
53 (6b)37
82 (6c)
99
99
99
Scheme 2. Ene-Yne Metathesis of 6c
a 6.00 mol % of CuBr·SMe2 and 8.00 mol % of L1 were used.
excellent regio- and enantioselectivities were achieved (6/7
>95:5, 99% ee). As in the case of the olefinic substrates 1
(Table 1), the longest spacer length (5c, n ) 3) required a
slightly higher catalyst loading to achieve full conversion
(Table 3, entry 3).
For the ene-yne metathesis of compounds 6 to reach full
conversion, 5.0 mol % Grubbs first generation catalyst under
an ethene atmosphere was employed. The influence of ethene
was found to be essential for the reaction to proceed to 8.38,39
The resulting six- and seven-membered nitrogen-containing
rings with diene motifs 8a,b were isolated in good yields
(Table 4). Again, no loss of ee was observed in this
transformation, making this a viable pathway for the
construction of chiral nitrogen-containing heterocycles with
various ring sizes.
in an intermolecular fashion with ethene instead of intramo-
lecularly with the terminal olefin. Product 8c in turn did not
react any further to the desired ring system under the reaction
conditions.41
In summary, we have demonstrated that chiral unsaturated
heterocycles are available in excellent enantiomeric excess
and good yields via a combination of Cu-catalyzed allylic
substitution and Ru-catalyzed ring-closing metathesis. Six-
to eight-membered nitrogen-containing rings are easily
available through this short synthetic pathway. By employing
terminal olefins, singly unsaturated rings are accessible while
terminal alkynes were transformed to the corresponding
dienes in good yields and 99% ee. The obtained compounds
are ideal chiral building blocks for further functionalization
through the olefinic bonds.
The reaction of 6c under the given conditions did not
produce the desired eight-membered ring. The ene-yne
(36) Reaction reaches full conversion; one unidentified side product is
present in the reaction mixture.
(37) Reaction reaches 75% conversion; no side products were
observed.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for the reaction products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(38) Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998, 63,
6082–6083
.
(39) In the absence of an ethene atmosphere, no turnover was
observed.
(40) Reaction reaches 90% conversion; one unidentified side product
observed.
OL101944J
(41) For optimization results, see the Supporting Information.
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Org. Lett., Vol. 12, No. 20, 2010