On the stereoselective bicyclization of aminodienes catalyzed by chelating diamide complexes of the group 3 metals. A direct comparison of Sc(iii) and Y(iii) bis(amide)s with an application to the synthesis of alkaloid 195F

Article abstract of DOI:10.1039/c1cc15399d

Highly diastereoselective bicyclizations of aminodienes catalyzed by chelating diamide complexes of Sc(iii) and Y(iii) that lead to pyrrolizidines and indolizidines are described. This bis(annulation) procedure has been utilized in a concise synthesis of the pyrrolizidine alkaloid 195F.

Full text of DOI:10.1039/c1cc15399d

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COMMUNICATION
On the stereoselective bicyclization of aminodienes catalyzed by chelating
diamide complexes of the group 3 metals. A direct comparison of Sc(III)
and Y(III) bis(amide)s with an application to the synthesis of alkaloid 195Fw
Tao Jiang, Tom Livinghouse* and Helena M. Lovick
Received 30th August 2011, Accepted 9th October 2011
DOI: 10.1039/c1cc15399d
Highly diastereoselective bicyclizations of aminodienes catalyzed
by chelating diamide complexes of Sc(III) and Y(III) that lead to
pyrrolizidines and indolizidines are described. This bis(annulation)
procedure has been utilized in a concise synthesis of the pyrrolizidine
alkaloid 195F.
(Scheme 2).2a The aminodienes 2a–e that were utilized in this
study were prepared as described previously2c by the sequential
alkylation of 5-hexene-2-one-N,N-dimethylhydrazone (5) [(1a)
n-BuLi, THF; (1b) RCHQCHCH2Cl 6] followed by hydrolysis
(HCl/H2O) and reductive amination (Scheme 1).
Exposure of 2a to the more reactive and selective chelating
diamide complex of yttrium 1a2e,3 (10 mol%) in toluene-D8 at
23 1C gave rise to an exceptionally rapid monocyclization
event (r9 min) to provide 3trans and 3cis as an 18 : 1 mixture
(by 1H NMR spectroscopy). Subsequent heating of the reaction
mixture to 60 1C (3 h) subsequently furnished 4a (91%, NMR)
with 3cis remaining unreacted. As previously reported, catalyst
1b (10 mol%) proved exceptionally stereoselective, albeit less
reactive, furnishing 3a [trans/cis = 49 : 1, (10 1C, 12 h)] and
ultimately pyrrolizidine 4a (3 h, 60 1C). Aminodienes 2b–e
were subsequently subjected to bicyclization catalyzed by 1a
and 1b respectively. The results of these studies are presented
in Table 1.
The catalytic hydroamination/cyclization of aminoalkenes
constitutes a synthetic route to azacycles that is endowed with
exceptional atom economy. Although main-group metal complexes
have recently been used as catalysts for alkene hydroamination,1a
the most general cases for the synthesis of amines and their
derivatives involve transition metal catalysis using complexes
of rhodium,1b–d ruthenium,1e–f nickel,1g–i palladium,1j–p and
gold1q–s as well as the group 32a–o and group 42p–z metals. The
group 3 metallocenes developed by Marks and coworkers2 for
this important reaction have more recently been supplemented
by a variety of nonmetallocene complexes of the group 3 and
group 4 metals as viable catalysts. We have previously
disclosed that chelating diamido complexes of the group 3
metals (particularly Y, Nd, and Sc) are potent catalysts for
intramolecular alkene hydroamination2e and, in certain in-
stances, aminodiene bicyclizations.2c,d In this communication
we present our most recent observations on the stereoselectivities
and rates associated with the bicyclization of a series of
electronically differentiated aminodienes catalyzed by chelating
diamide complexes of the type 1a,b.
We have previously shown2j that 5-amino-1,8-nonadiene (2a)
undergoes efficient monocyclization to provide 3a with 13 : 1
trans/cis selectivity in the presence of Y[N(TMS)2]3 (2.7 mol%) at
10 1C (18 h), and subsequent stereospecific bicyclization to 4a at
70 1C (18 h), wherein the minor cis-isomer 3acis remained
unreacted. We subsequently demonstrated that catalyst 1b is
vastly more stereoselective, furnishing 3a (trans/cis = 49 :1) with
ultimate conversion to pyrrolizidine 4a.2d The stereospecific
conversion of 3a to 4a is consistant with a mechanism involving
syn-addition of the metal-nitrogen bond to the CQC p-bond
As is evident from these results, and as would be expected,
the rate and stereoselectivity of monocyclization to pyrroli-
dines 3b–f is metal dependent, but invariant with respect to the
structure of the 7-aryl(ethenyl) substituent. The stereochemical
consequences of the subsequent bicyclizations of 3b–f are
stereospecific, in accord with our earlier observations for
3a.2j Under the indicated reaction conditions using 1a,
3bcis–3fcis (ca. 5.3%) were resistant toward further cyclization
and only pyrrolidines 3btrans–3ftrans underwent bicyclization.
Gratifyingly, 3bcis–3fcis were easily separated from 4b–4f by
column chromatography. Cyclizations catalyzed by 1b provided
exclusively 3btrans–3ftrans (as observed by 1H NMR spectroscopy)
which subsequently underwent stereospecific cyclization to
provide pyrrolizidines 4b–4f.
Department of Chemistry and Biochemistry,
Montana State University, Bozeman, MT 59717, USA.
E-mail: Livinghouse@chemistry.montana.edu; Fax: (406) 994-5407;
Tel: (406) 994-5408
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc15399d
Scheme 1 Synthesis of aminodienes 2a–f.
c
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Chem. Commun., 2011, 47, 12861–12863 12861

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stereospecific bicyclization to secure indolizidine 10 (95%). As
expected, monocyclization catalyzed by 1a (10 mol%) was
very rapid (23 1C, r9 min) to furnish 9 (95%, trans :cis= 18:1),
from which 9trans was lethargically converted to 10 [60 1C, 144 h,
(80%)] (Scheme 3).
It is of preparative significance that aminodiene bicyclizations
catalyzed by the more stereoselective scandium complex 1b
were readily achievable on Z 1 mmol scale with a catalyst
loading of 2 mol%. To this end, aminodienes 2a, 2b and 8 were
converted to azabicycles 4a, 4b and 10 in 98%, 74% and 98%
isolated yields, respectively.4
Scheme 2 Catalytic bicyclizations of aminodienes 2a–f.
Table 1 Bicyclization of aminodienes 2a–2f
Complex Substrate 1C t1
3trans : 3cis t2 (h) %NMR 4 (%isol.
)
c
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
2a
2a
2b
2b
2c
2c
2d
2d
2e
2e
2f
23 9 mina 18 : 1
10 12 h 49 : 1
23 9 mina 18 : 1
10 12 h 49 : 1
23 9 mina 18 : 1
10 12 h 49 : 1
23 9 mina 18 : 1
10 12 h 49 : 1
23 9 mina 18 : 1
10 12 h 49 : 1
23 9 mina 18 : 1
10 12 h 49 : 1
3
3
44
26
11
6
95
95
87
90
91
90
70
86
84
90
82
91
(98)d
(98)e
(73)
(85)
(81)
(70)
(64)
(71)
(75)
(84)
(74)
(71)
Scheme 3 Catalytic bicyclizations leading to indolizidine 10.
48b
36
30
24
60
17
The pyrrolizidine defense alkaloid 195F (11) was isolated
from the whole-body extract of the Madagascar arthropod
Paratrechina amblyops in 2005.5 Access to this natural product
as its trifluoroacetate salt was readily achieved in 64% isolated
yield by reductive desulfurization of 4f via RANEYs Ni in
EtOH and subsequent treatment with TFA. This represents
the first total synthesis for this natural product (Scheme 4).6
2f
a
Time span from the addition of the aminodiene to aquisition of the
b
1H NMR spectrum. Reaction conducted at 120 1C. Integration
relative to p-xylene as an internal standard. Isolated as the trifluoro-
c
d
acetate salt, contains 5.3% 3cisÁTFA. e Isolated as the trifluoroacetate salt.
In contrast, the relative rates for bicyclization were markedly
influenced by the nature of the aryl(alkenyl) substituent.
Marks and coworkers have shown that turnover numbers
for representative cyclization/hydroaminations of amino-
alkynes catalyzed by rare-earth metallocenes are strongly coupled
to the electronic characteristics of the alkyne substituent.3 In that
study, electron-rich alkynes were found to facilitate ring closure
involving the electron-deficient metallocene amide intermediates.
As is evident from the results presented in Table 1, the relative
rates of bicyclization for both 1a and 1b follow the trend 3c (Ar =
2-(MeO)C6H4) > 3b (Ar = Ph) E 3e (Ar = 4-ClC6H4) > 3f
(Ar = 2-thienyl) > 3d (Ar = 4-(MeO)C6H4). Although it can be
asserted that 7-aryl(ethenyl) substituent of 3c benefits both from
electron donation and a possible chelation effect [arising from the
2-(MeO) group] when compared to the simple phenyl of 3b, the
unusual lethargy of 3d toward bicyclization was unexpected. It is
also noteworthy that the rates for bicyclization of 3b–f catalyzed
by 1b exceeded those exhibited by the corresponding yttrium
complex 1a in all instances. This is counter to typical reactivity
trends observed for primary aminoalkenes.
Scheme 4 Synthesis of alkaloid 195F.
In conclusion, we have shown that the neutral Sc(III)
chelating diamide complex 1b is an unusually stereoselective
precatalyst for intramolecular aminodiene bicyclization/
hydroamination leading to pyrrolizidines and the indolizidine
nucleus. Although the catalytic activity of the corresponding
Y(III) complex 1a is much higher for monocyclization, it is less
stereoselective than 1b and less effective at promoting bicyclization.
Studies utilizing chiral chelating diamido and related complexes
of the group 3 metals as catalysts for asymmetric intra-
molecular hydroamination are currently underway.
Generous financial support for this research was provided
by the National Institute of General Medical Science.
Notes and references
1 (a) M. R. Crimmin, M. Arrowsmith, A. G. M. Barrett, I. J. Casely,
M. S. Hill and P. A. Procoplou, J. Am. Chem. Soc., 2009, 131, 9670
and references cited therein; (b) S. Matsunaga, Yuki Gosei Kagaku
Kyokaishi., 2006, 64, 778; (c) A. Takemiya and J. F. Hartwig, J. Am.
Chem. Soc., 2006, 128, 6042; (d) E. B. Bauer, G. T. S. Andavan,
T. K. Hollis, R. J. Rubio, J. Cho, G. R. Kuchenbeiser,
T. R. Helgert, C. S. Letko and F. S. Tham, Org. Lett., 2008,
10, 1175; (e) J. Takaya and J. F. Hartwig, J. Am. Chem. Soc.,
2005, 127, 5756; (f) T. Knodo, T. Okada, T. Suzuki and
T. J. Mitsudo, J. Organomet. Chem., 2001, 622, 149; (g) L. Fadini
and A. Togni, Tetrahedron: Asymmetry, 2008, 19, 2555;
The indolizidine ring system is an essential subunit within
numerous naturally occurring alkaloids. Accordingly, we under-
took a brief study to ascertain the feasibility of extending the
present methodology to the elaboration of fused 6/5 rings.
Exposure of 5-amino-1,9-decadiene (8) to 1b (10 mol%) led to
efficient monocyclization (10 1C, 12 h) to give 9 [trans :cis = 49:1,
95% (NMR)]. Subsequent heating at 60 1C for 45 h induced
c
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View Article Online
(h) L. Fadani and A. Togni, Chem. Commun., 2003, 30; (i) J. Pawlas,
Y. Nakao, M. Kawatsura and J. F. Hartwig, J. Am. Chem. Soc.,
2002, 124, 3669; (j) B. M. Cochran and F. E. Michael, J. Am. Chem.
Soc., 2008, 130, 2786; (k) F. E. Michael and B. M. Cochran, J. Am.
Chem. Soc., 2006, 128, 4246; (l) U. Nettekoven and J. F. Hartwig,
J. Am. Chem. Soc., 2002, 124, 1166; (m) M. Narsireddy and
Y. Yamamoto, J. Org. Chem., 2008, 73, 9698; (n) A. R. Shaffer
and J. A. R. Schmidt, Organometallics, 2008, 27, 1259;
(o) A. I. Siriwardana, M. Kamada, I. Nakamura and
Y. Yamamoto, J. Org. Chem., 2005, 70, 5932; (p) T. Shimada and
Y. Yamamoto, J. Am. Chem. Soc., 2002, 124, 12670;
(q) R. L. LaLond, Z. J. Wang, M. Mba, A. D. Lackner and
F. D. Toste, Angew. Chem. Int. Ed. Engl., 2010, 49, 598;
(r) R. A. Widenhofer and X. Han, Eur. J. Org. Chem., 2006, 4555
and references cited therein; (s) L. Leseurre, P. V. Toullec, J. Genet
and V. Michelet, Org. Lett., 2007, 9, 4049.
2 (a) S. Hong and T. J. Marks, Acc. Chem. Res., 2004, 37, 673 and
references cited therein; (b) For a related bicyclization involving an
amino(allene)ene using a constrained Sm(III) metallocene catalyst,
see: V. M. Arredondo, S. Tian, F. E. McDonald and T. J. Marks,
J. Am. Chem. Soc., 1999, 121, 3633; (c) T. Jiang and T. Livinghouse,
Org. Lett., 2010, 12, 4271; (d) J. Y. Kim and T. Livinghouse, Org.
Lett., 2005, 7, 4391; (e) Y. K. Kim and T. Livinghouse, Angew.
Chem., Int. Ed., 2002, 41, 3645; (f) S. Tian, V. M. Arredondo,
C. L. Stern and T. J. Marks, Organometallics, 1999, 18, 2568;
(g) D. V. Gribkov, K. C. Hultzsch and F. Hampel, J. Am. Chem.
Soc., 2006, 128, 3748 and references cited therein; (h) J. Y. Kim,
T. Livinghouse and Y. Horino, J. Am. Chem. Soc., 2003, 125, 9560;
(i) J. Y. Kim and T. Livinghouse, Org. Lett., 2005, 7, 1737;
(j) Y. K. Kim, T. Livinghouse and J. E. Bercaw, Tetrahedron Lett.,
2001, 42, 2933; (k) F. Lauterwasser, P. G. Hayes, S. Brase,
W. E. Piers and L. L. Schafer, Organometallics, 2004, 23, 2234;
(l) J. Hannedouche, I. Aillaud, J. Collin, E. Schulz and A. Trifonov,
Chem. Commun., 2008, 3552; (m) I. Aillaud, J. Collin, C. Duhayon,
R. Guillot, D. Lyubov, E. Schulz and A. Trifonov, Chem.–Eur. J.,
2008, 14, 2189; (n) X. Yu and T. J. Marks, Organometallics, 2007,
26, 365; (o) T. J. Marks and S. Hong, J. Am. Chem. Soc., 2002,
124, 7886; (p) D. C. Leitch, P. R. Payne, C. R. Dunbar and
L. L. Schafer, J. Am. Chem. Soc., 2009, 131, 18246;
(q) A. L. Reznichenko and K. C. Hultzsch, Organometallics, 2010,
29, 24; (r) M. C. Wood, D. C. Leitch, C. S. Yeung, J. A. Kozak and
L. L. Schafer, Angew. Chem., Int. Ed., 2006, 46, 354; (s) H. Kim,
P. H. Lee and T. Livinghouse, Chem. Commun., 2005, 5205;
(t) R. K. Thomson, J. A. Bexrud and L. L. Schafer, Organometallics,
2006, 25, 4069; (u) L. E. N. Allan, G. J. Clarkson, D. J. Fox,
A. L. Gott and P. Scott, J. Am. Chem. Soc., 2010, 132, 15308;
(v) R. Kubiak, I. Prochnow and S. Doye, Angew. Chem., Int. Ed.,
2009, 48, 1153; (w) D. A. Watson, M. Chiu and R. G. Bergman,
Organometallics, 2006, 25, 4731; (x) C. Mueller, C. Loos,
N. Schulenberg and S. Doye, Eur. J. Org. Chem., 2006, 2499;
(y) J. A. Bexrud, J. D. Beard, D. C. Leitch and L. L. Schafer,
Org. Lett., 2005, 7, 1959; (z) D. L. Swartz II, R. J. Staples and
A. L. Odom, Dalton Trans., 2011, 40, 7762.
3 Y. Li and T. J. Marks, J. Am. Chem. Soc., 1996, 118, 9295.
4 Pyrrolizidine 4a and indolizidine 10 were isolated as their trifluoro-
acetate salts.
5 V. C. Clark, C. J. Raxworthy, V. Racotomalala, P. Sierwald and
B. L. Fisher, Proc. Natl. Acad. Sci. U. S. A., 2005, 102, 11617.
6 Alkaloid (Æ)-195F (11, as the free base) prepared in this manner was
spectroscopically identical to the natural product, see ref. 5.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 12861–12863 12863