Stereoselective synthesis of 2-dienyl-substituted pyrrolidines using an η4-dienetricarbonyliron complex as the stereodirecting element: Elaboration to the pyrrolizidine skeleton

Article abstract of DOI:10.1021/ol061132l

Primary amines react with keto-aldehyde functionality located in the side-chain of an η⁴-dienetricarbonyliron complex to provide the corresponding pyrrolidines in excellent diastereoselectivity. Two of the pyrrolidine products, 1i and 1k, have been elaborated into pyrrolizidines using a 1,5-C-H insertion and radical cyclization strategy, respectively.

Full text of DOI:10.1021/ol061132l

ORGANIC
LETTERS
2006
Vol. 8, No. 20
4389-4392
Stereoselective Synthesis of
2-Dienyl-Substituted Pyrrolidines Using
an
η
4-Dienetricarbonyliron Complex as
the Stereodirecting Element:
Elaboration to the Pyrrolizidine Skeleton
Iwan Williams,† Benson M. Kariuki,† Keith Reeves,‡ and Liam R. Cox*,†
School of Chemistry, UniVersity of Birmingham, Edgbaston, Birmingham B15 2TT,
U.K., and Sandwich Laboratories, Pfizer Limited, Sandwich, Kent CT13 9NJ, U.K.
l.r.cox@bham.ac.uk
Received May 9, 2006
ABSTRACT
Primary amines react with keto-aldehyde functionality located in the side-chain of an
pyrrolidines in excellent diastereoselectivity. Two of the pyrrolidine products, 1i and 1k, have been elaborated into pyrrolizidines using a
1,5-C H insertion and radical cyclization strategy, respectively.
η
4-dienetricarbonyliron complex to provide the corresponding
−
Unsymmetrically substituted η4-dienetricarbonyliron com-
plexes exhibit planar chirality and are readily prepared in
enantiomerically pure form. As a consequence, this class of
organometallic has become an important chiral auxiliary for
stereoselective synthesis.1 The steric blocking capability of
the Fe(CO)3 unit ensures that an external reagent approaches
a side-chain functional group in a predictable fashion,
attacking the diastereotopic face that is remote from the iron
unit (Scheme 1). Providing the pendant functional group
adopts a single reactive conformation, levels of diastereo-
selectivity can be excellent. The reaction of nucleophiles with
pendant ketone functionality in η4-diene2sand related3s
complexes provides a paradigm. In these cases, the stereo-
chemical outcome of the reaction can be rationalized by
assuming nucleophilic addition proceeds opposite the bulky
Fe(CO)3 group on the s-cis conformer of the ketone.2,3
Our interest in 2-dienyl-substituted nitrogen heterocycles
for potential application in natural product synthesis led us
to propose a novel route to this framework using η4-
dienetricarbonyliron complexes (Scheme 1).4 Starting from
keto-aldehyde complex 4, a first reductive amination on the
more electrophilic aldehyde would generate secondary amine
3. Subsequent cyclization on to the proximal ketone, to afford
a second iminium species 2, followed by a second reductive
amination, would then generate the corresponding pyrrolidine
† University of Birmingham.
‡ Pfizer Limited.
(2) (a) Gonza´lez-Blanco, O.; Branchadell, V.; Gre´e, R. Chem. Eur. J.
1999, 5, 1722-1727. (b) Franck-Neumann, M.; Chemla, P.; Martina, D.
Synlett 1990, 641-642. (c) Clinton, N. A.; Lillya, C. P. J. Am. Chem. Soc.
1970, 92, 3058-3064.
(3) (a) Ley, S. V.; Cox, L. R.; Meek, G.; Metten, K.-H.; Pique´, C.;
Worrall, J. M. J. Chem. Soc., Perkin Trans. 1 1997, 3299-3313. (b) Ley,
S. V.; Cox, L. R. J. Chem. Soc., Perkin Trans. 1 1997, 3315-3325.
(4) For a novel application of this type of building block in the synthesis
of elaeokanine C, see: Sato, Y.; Saito, N.; Mori, M. Tetrahedron 1998,
54, 1153-1168.
(1) For reviews, see: (a) Kno¨lker, H.-J. Curr. Org. Synth. 2004, 1, 309-
331. (b) Ong, C. W.; Lai, M. C. Trends Organomet. Chem. 2002, 4, 47-
58. (c) Donaldson, W. A. Curr. Org. Chem. 2000, 4, 837-868. (d) Kno¨lker,
H.-J. Chem. ReV. 2000, 100, 2941-2961. (e) Kno¨lker, H.-J. Chem. Soc.
ReV. 1999, 28, 151-157. (f) Cox, L. R.; Ley, S. V. Chem. Soc. ReV. 1998,
27, 301-314. (g) Iwata, C.; Takemoto, Y. Chem. Commun. 1996, 2497-
2504. (h) Gre´e, R.; Lellouche, J.-P. AdVances in Metal-Organic Chemistry
1995, 4, 129-273. (i) Gre´e, R. Synthesis 1989, 341-355. (j) Franck-
Neumann, M. Pure Appl. Chem. 1983, 55, 1715-1732.
10.1021/ol061132l CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/09/2006

carrying out this reaction under a CO2 atmosphere led to a
substantial increase in the rate of reaction.7 Reaction of the
Grignard reagent prepared from commercially available
3-chloropropan-1-ol,8 with amide 6, proceeded smoothly to
afford keto-alcohol 7 in excellent yield, and thence keto-
aldehyde cyclization precursor 4 after Swern oxidation.9
Although double reductive amination strategies have been
successfully employed in pyrrolidine ring synthesis,5 yields
of the desired product are often compromized by a competing
Paal-Knorr reaction, which provides the corresponding
pyrrole.5d,f,10 Thus when keto-aldehyde 4 was treated with
BnNH2 (1.2 equiv) in the presence of either NaCNBH311 or
NaBH(OAc)312 and AcOH (1 equiv), it was unsurprising to
find that the rather labile pyrrole product (60%) predomi-
nated, although the desired pyrrolidine 1a was obtained in
21% yield. Fortunately, by removing the acid, pyrrole
formation was efficiently suppressed, allowing the target
pyrrolidine 1a to be isolated in good yield. More signifi-
cantly, the stereoselectivity of the reaction was excellent with
only one diastereoisomer being observed upon analysis of
the crude reaction mixture by 300 MHz 1H NMR. THF and
1,2-dichloroethane proved equally effective solvents for the
reaction, and since similar yields of pyrrolidine were obtained
with NaCNBH3 and NaBH(OAc)3, the lower toxicity issues
associated with the latter, made NaBH(OAc)3 the reagent
of choice.
Scheme 1. Retrosynthetic Analysis for 2-Dienyl-Substituted
Pyrrolidines Employing a Double Reductive Amination and an
η4-Dienetricarbonyliron Complex as the Stereocontrolling
Element
Extending this cascade double reductive amination to a
range of primary amines showed this route to be a general
approach to 2-dienyl-substituted pyrrolidines (Table 1). In
1 in one step.5 The dienetricarbonyliron group would not
only control the facial selectivity of the second reductive
amination in this cascade sequence, but also ensure that
reaction proceeds preferentially on a single conformer, which
we predicted in this case would be the s-trans conformer,
since this minimizes steric interactions between the diene
ligand and appended functionality (Scheme 1).6 We now
report the successful realization of this strategy.
Table 1. Diastereoselective Synthesis of Pyrrolidines 1
The synthesis of the keto-aldehyde complex 4 is sum-
marized in Scheme 2. Treatment of ethyl sorbate with [Fe2-
Scheme 2. Synthesis of Cyclization Precursor 4
a The reaction is generally stirred overnight, although it is often complete
in 4-6 h. b Numbers in parentheses refer to the isolated % yield of the
corresponding pyrrole byproduct. c 1:1 mixture of diastereoisomers obtained.
d The pyrrole product decomposed readily. e AcOH was used to reduce the
reaction pH to ∼6. f Isolated yield of the TBDMS-protected product (two
steps). g E/Z ratio ∼ 5:1.
(CO)9] in Et2O generated the corresponding diene complex,
and acid 5 after saponification. Reaction of 5 with carbonyl
diimidazole (CDI) and H2NMe(OMe)Cl furnished the cor-
responding Weinreb amide 6 in excellent yield. Interestingly,
4390
Org. Lett., Vol. 8, No. 20, 2006

all cases only one configuration at the newly formed
stereocenter was observed. Significantly, pyrrolidines 1c and
1l, which were formed from enantiomerically pure amines,
(S)-R-methylbenzylamine and (S)-phenylalaninol, respec-
tively, were obtained as a 1:1 mixture of diastereoisomers,
which clearly shows that the planar chirality of the diene
complex overrides the chirality of the amine. The standard
reaction conditions proved suitable for all substrates apart
from particularly basic amines such as methylamine and
ethanolamine, where the high reaction pH (>10) led to
exclusive pyrrole formation. In these cases, reducing the
reaction pH to 6 solved this problem and allowed the desired
pyrrolidine (1d, 1f) to be obtained in good yield.10 It proved
impossible to access the free pyrrolidine directly: the use
of NH3 led to a complex mixture of products, and when NH4-
HCO2 was employed, only the pyrrole was obtained.5e
However the free pyrrolidine 8 was readily accessed by
deallylation of 1h (Scheme 3).13
same, and in line with our hypothesis that the second
reductive amination proceeds on the iminium intermediate
in an s-trans conformation, with “hydride” attack from the
face remote from the bulky tricarbonyliron group.
Having established an efficient and highly stereoselective
route to 2-dienyl-substituted pyrrolidines, we were keen to
explore the possibility of employing the vinyl bromide
functionality present in 1i and 1k as an entry into the
biologically important pyrrolizidine skeleton.14
In the case of 1k, Cu(II)-mediated decomplexation af-
forded pyrrolidine 10 in 70% yield.15 While we expected a
vinyl radical formed from bromide 10 would cyclize
preferentially on to the pendant diene in a 5-exo-trig fashion,
the stereoselectivity of this cyclization and regioselectivity
in the subsequent H-abstraction step, could still afford a host
of isomeric products. It was therefore pleasing to observe
that reaction of 10 with Bu3SnH in the presence of AIBN,
provided pyrrolizidine 13 as a >10:1 mixture of vinylsilane
stereoisomers. The fact that the stereochemistry of the
vinylsilane in the major product is opposite to that in the
starting material is in accord with the known configurational
instability of vinyl radicals.16 The diastereoselectivity of the
reaction is consistent with cyclization proceeding on vinyl
radical 11 through the transition state shown in Scheme 4.
Scheme 3. Deallylation of 1h Followed by Acylation of the
Free Pyrrolidine Provided a Crystalline Product
Scheme 4. Formation of the Pyrrolizidine Skeleton through a
Radical Cyclization
Confirmation of the stereochemical outcome of the cy-
clization reactions came from crystal structures (see the
Supporting Information) of the pyrrolidine (Z)-1i and amide
9, formed from 1h after deallylation and acylation (Scheme
3). In both cases, the observed diastereoselectivity was the
(5) For some recent successful applications of this approach to pyrro-
lidines, see: (a) Laventine, D. M.; Davies, M.; Evinson, E. L.; Jenkins, P.
R.; Cullis, P. M.; Fawcett, J. Tetrahedron Lett. 2005, 46, 307-310. (b)
Gravier-Pelletier, C.; Maton, W.; Bertho, G.; Le Merrer, Y. Tetrahedron
2003, 59, 8721-8730. (c) Trost, B. M.; Schroeder, G. M.; Kristensen, J.
Angew. Chem., Int. Ed. 2002, 41, 3492-3495. (d) Baxendale, I. R.; Brusotti,
G.; Matsuoka, M.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 2002, 143-
154. (e) Momotake, A.; Mito, J.; Yamaguchi, K.; Togo, H.; Yokoyama,
M. J. Org. Chem. 1998, 63, 7207-7212. (f) Boga, C.; Manescalchi, F.;
Savoia, D. Tetrahedron 1994, 50, 4709-4722.
(6) For related reactions that also proceed on iminium ions appended to
diene complexes, see: (a) Takemoto, Y.; Takeuchi, J.; Matsui, E.; Iwata,
C. Chem. Pharm. Bull. 1996, 44, 948-955. (b) Ripoche, I.; Gelas, J.; Gre´e,
D.; Gre´e, R.; Troin, Y. Tetrahedron Lett. 1995, 36, 6675-6678.
(7) Vaidyanathan, R.; Kalthod, V. G.; Ngo, D. P.; Manley, J. M.; Lapekas,
S. P. J. Org. Chem. 2004, 69, 2565-2568.
(8) Turakhia, R. H.; Fischer, G. C.; Morrow, C. J.; Maschhoff, B. L.;
Toubbeh, M. I.; Zbur-Wilson, J. L. J. Org. Chem. 1986, 51, 1955-1960.
(9) Gre´e, D. M.; Martelli, J. T.; Gre´e, R. L.; Toupet, L. J. J. Org. Chem.
1995, 60, 2316-2317.
The position of the alkene in the side-chain can then be
rationalized by assuming H-abstraction proceeds on the less
hindered end of the resulting allyl radical intermediate 12.
In an alternative elaboration strategy, we envisaged that
treating vinyl bromide 1i with base should afford a carbenoid
(10) (a) Raiman, M. V.; Pukin, A. V.; Tyvorskii, V. I.; De Kimpe, N.;
Kulinkovich, O. G. Tetrahedron 2003, 59, 5265-5272. (b) Harmata, M.;
Ghosh, S. K.; Hong, X.; Wacharasindhu, S.; Kirchhoefer, P. J. Am. Chem.
Soc. 2003, 125, 2058-2059.
(11) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc.
1971, 93, 2897-2904.
(14) Liddell, J. R. Nat. Prod. Rep. 2002, 19, 773-781 and references
therein.
(15) Thompson, D. J. J. Organomet. Chem. 1976, 108, 381-383.
(16) Vinyl radicals are known to be configurationally unstable. For a
pertinent example, see: Miura, K.; Itoh, D.; Hondo, T.; Hosomi, A.
Tetrahedron Lett. 1994, 35, 9605-9608.
(12) Abdel-Magid, A. F.; Maryanoff, C. A.; Carson, K. G. Tetrahedron
Lett. 1990, 31, 5595-5598.
(13) Lemaire-Audoire, S.; Savignac, M.; Geneˆt, J.-P.; Bernard, J. M.
Tetrahedron Lett. 1995, 36, 1267-1270.
Org. Lett., Vol. 8, No. 20, 2006
4391

intermediate, which would generate another pyrrolizidine
through a stereospecific 1,5-C-H insertion reaction.17,18
Since literature precedent suggested that this might occur
regioselectively at the more substituted carbon,18b,19 this
transformation would then provide a useful route into
challenging systems containing a defined quaternary stereo-
genic center.
After some optimization,20 it was found that treatment of
1i with KHMDS in 1,4-dioxane at room temperature
provided a 3:1 mixture of insertion products 14 and 15 in
55% combined yield (Scheme 5). The Fe(CO)3 group in both
tentatively suggest that the improved regioselectivity ob-
served in the 1,5-insertion reaction involving diene complex
1i is a consequence of the Fe(CO)3 group generating a
sterically more crowded methine center than is present in
free diene 16. This should result in lengthening, and
concomitant weakening, of the methine C-H bond in the
diene complex favoring insertion into this bond. Anchimeric
assistance from the iron complex also electronically activat-
ing the methine center in 1i may also be a factor in the
improved regioselectivity associated with the iron complex.1e
In summary, an η4-dienetricarbonyliron complex contain-
ing a keto-aldehyde side-chain has been used in a cascade,
double reductive amination reaction to provide the corre-
sponding 2-substituted pyrrolidine in excellent diastereose-
lectivity. The Fe(CO)3 moiety plays a crucial role in the
reaction, controlling the facial selectivity of “hydride” attack
in the second reductive amination and ensuring reaction
proceeds on a single iminium ion conformation. Since diene
complexes bearing carboxylic acid functionality, such as 5,
which is a key intermediate in our synthesis, are readily
prepared in enantiopure form, either by enzymatic resolution,22d
or through the use of chiral auxiliaries,22a-c this approach
can also be used to access the corresponding enantiomerically
pure series of N-heterocycles. The pyrrolidine products are
ripe for elaboration into pyrrolizidines, which have been
accessed in a variety of ways. Of particular note here, the
Fe(CO)3 moiety affects the regioselectivity of a 1,5-C-H
insertion with reaction favoring the pyrrolizidine containing
a stereodefined quaternary stereogenic center. Future work
will focus on using the diene that is released upon decom-
plexation in the synthesis of more complex polycyclic
frameworks.
Scheme 5. Formation of the Pyrrolizidine Skeleton through a
1,5-C-H Insertion
14 and 15 was readily removed by treatment with basic
peroxide21 to afford the free dienes, 17 and 18, respectively,
in excellent yield (Scheme 5). Interestingly, when the 1,5-
C-H insertion was performed on the free diene 16 under
our optimized conditions, the yield of insertion products, 17
and 18, improved to 86%. However, this was at the expense
of regioselectivity, which dropped to 1:1 (Scheme 5). We
Acknowledgment. We are grateful to Pfizer for an
industrial CASE studentship to I.W.
Supporting Information Available: General experimen-
tal procedures and characterization data for all new com-
pounds and X-ray crystallographic files (CIF) for compounds
(Z)-1i and 9. This material is available free of charge via
the Internet at http://pubs.acs.org.
(17) Gabaitsekgosi, R.; Hayes, C. J. Tetrahedron Lett. 1999, 40, 7713-
7716.
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50, 2557-2563. (b) Karpf, M.; Huguet, J.; Dreiding, A. S. HelV. Chim.
Acta 1982, 65, 13-25.
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1983, 48, 5251-5256.
OL061132L
(21) Franck-Neumann, M.; Heitz, M. P.; Martina, D. Tetrahedron Lett.
1983, 24, 1615-1616.
(20) LDA, LiHMDS, NaHMDS, and KHMDS were investigated in Et2O,
THF, and 1,4-dioxane at rt. The method of carbene/carbenoid generation,
including the choice of base and solvent, has been shown to influence the
regioselectivity: (a) Taber, D. F.; Christos, T. E. Tetrahedron Lett. 1997,
38, 4927-4930 and references therein. (b) Taber, D. F.; Christos, T. E.;
Neubert, T. D.; Batra, D. J. Org. Chem. 1999, 64, 9673-9678.
(22) See for example: (a) Pearson, A. J.; Chang, K.; McConville, D.
B.; Youngs, W. J. Organometallics 1994, 13, 4-5. (b) Franck-Neumann,
M.; Briswalter, C.; Chemla, P.; Martina, D. Synlett 1990, 637-640. (c) de
Montarby, L.; Tourbah, H.; Gre´e, R. Bull. Soc. Chim. Fr. 1989, 419-432.
(d) Alcock, N. W.; Crout, D. H. G.; Henderson, C. M.; Thomas, S. E. J.
Chem. Soc., Chem. Commun. 1988, 746-747.
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