Organolanthanide-catalyzed hydroamination/cyclization. Efficient allene- based transformations for the syntheses of naturally occurring alkaloids

Article abstract of DOI:10.1021/ja984305d

The total syntheses of the pyrrolidine alkaloid (+)-197B (1) and pyrrolizidine alkaloid (+)-xenovenine (2) are described. The strategy involves enantioselective syntheses of the aminoallene, (5S,8S)-5-amino- trideca-8,9-diene (3), and the aminoallene-alkene, (5S)-5-amino-pentadeca- 1,8,9-triene (4), which then undergo regio- and stereoselective cyclohydroamination catalyzed by the organolanthanide precatalysts Cp'₂LnCH(TMS)₂ and Me₂SiCp''((t)BuN)LnN(TMS)₂ (Cp' = η⁵-Me₅C₅; Cp'' = η⁵-Me₄C₅; Ln = lanthanide; TMS = Me₃Si). These reactive organolanthanide complexes efficiently mediate highly diastereoselective intramolecular hydroamination/cyclization (IHC) reactions under mild conditions. The turnover-limiting step in these catalytic cycles is proposed to be intramolecular insertion into the Ln-N bond of the proximal allenic C=C linkage, followed by rapid protonolytic cleavage of the resulting Ln-C bond. The rate and selectivity of the insertion process is highly sensitive to the steric demands of the substrate.

Full text of DOI:10.1021/ja984305d

J. Am. Chem. Soc. 1999, 121, 3633-3639
3633
Organolanthanide-Catalyzed Hydroamination/Cyclization. Efficient
Allene-Based Transformations for the Syntheses of Naturally
Occurring Alkaloids
Victor M. Arredondo, Shun Tian, Frank E. McDonald,* and Tobin J. Marks*
Contribution from the Department of Chemistry, Northwestern UniVersity, EVanston, Illinois 60208-3113
ReceiVed December 14, 1998
Abstract: The total syntheses of the pyrrolidine alkaloid (+)-197B (1) and pyrrolizidine alkaloid (+)-xenovenine
(2) are described. The strategy involves enantioselective syntheses of the aminoallene, (5S,8S)-5-amino-trideca-
8,9-diene (3), and the aminoallene-alkene, (5S)-5-amino-pentadeca-1,8,9-triene (4), which then undergo regio-
and stereoselective cyclohydroamination catalyzed by the organolanthanide precatalysts Cp′2LnCH(TMS)2 and
Me2SiCp′′(tBuN)LnN(TMS)2 (Cp′ ) η5-Me5C5; Cp′′ ) η5-Me4C5; Ln ) lanthanide; TMS ) Me3Si). These
reactive organolanthanide complexes efficiently mediate highly diastereoselective intramolecular hydroamination/
cyclization (IHC) reactions under mild conditions. The turnover-limiting step in these catalytic cycles is proposed
to be intramolecular insertion into the Ln-N bond of the proximal allenic CdC linkage, followed by rapid
protonolytic cleavage of the resulting Ln-C bond. The rate and selectivity of the insertion process is highly
sensitive to the steric demands of the substrate.
Introduction
of unsaturated C-C bonds. The regioselective, catalytic intra-
molecular hydroamination/cyclization (IHC) of aminoalkenes2
and aminoalkynes3 allows efficient construction of mono- and
polycyclic organonitrogen frameworks (e.g., pyrrolidines, pyr-
rolizidines, indolizidines, and quinolizidines) using organolan-
thanide complexes of the type Cp′2LnCH(TMS)2 and Me2-
SiCp′′2LnCH(TMS)2 (Cp′ ) η5-Me5C5, Cp′′ ) η5-Me4C5; Ln
) La, Sm, Y, Lu; TMS ) Me3Si; shown below)
The discovery and implementation of new synthetic reagents
and transformations offers the opportunity to explore new, more
efficient and selective synthetic strategies for the total synthesis
of complex natural products. In the past decade, several broad
classes of organolanthanide catalysts1 were developed in this
and other laboratories which effectively and selectively mediate
a variety of transformations, including hydroamination,2,3
hydrogenation,4 oligomerization/polymerization,5 silanolytic
chain transfer in olefin polymerization,6 hydrosilylation,7 hy-
drophosphination,8 hydroboration,9 and reductive cyclization10
(1) For recent organolanthanide reviews, see: (a) Anwander, R.; Herr-
mann, W. A. In Topics in Current Chemistry; Springer-Verlag: Berlin, 1996;
Vol. 179, pp 1-32. (b) Edelmann, F. T. In Topics in Current Chemistry;
Springer-Verlag: Berlin, 1996; Vol. 179, pp 247-276. (c) Edelmann, F.
T. Angew. Chem., Int. Ed. Engl. 1995, 34, 2466-2488. (d) Schumann, H.;
Meese-Marktscheffel, J. A.; Esser, L. Chem. ReV. 1995, 95, 865-986. (e)
Schaverien, C. J. AdV. Organomet. Chem. 1994, 36, 283-362.
(2) (a) Molander, G. A.; Dowdy, E. D. J. Org. Chem. 1998, 63, 8983-
8988. (b) Roesky, P. W.; Stern, C. L.; Marks, T. J. Organometallics 1997,
16, 4705-4711. (c) Giardello, M. A.; Conticello, V. P.; Brard, L.; Gagne´,
M. R.; Marks, T. J. J. Am. Chem. Soc. 1994, 116, 10241-10254. (d) Gagne´,
M. R.; Stern, C. L.; Marks, T. J. J. Am. Chem. Soc. 1992, 114, 275-294.
(e) Gagne´, M. R.; Brard, L.; Conticello, V. P.; Giardello, M. A.; Stern, C.
L.; Marks, T. J. Organometallics 1992, 11, 2003-2005. (f) Gagne´, M. R.;
Nolan, S P.; Marks, T. J. Organometallics 1990, 9, 1716-1718.
(3) (a) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1998, 120, 1757-1771.
(b) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1996, 118, 9295-9306. (c) Li,
Y.; Marks, T. J. Organometallics 1996, 15, 3770-3772. (d) Li, Y.; Marks,
T. J. J. Am. Chem. Soc. 1996, 118, 707-708. (e) Li, Y.; Fu, P.-F.; Marks,
T. J. Organometallics 1994, 13, 439-440.
as precatalysts in both single and sequentially coupled multistep
processes. We recently reported the first organolanthanide-
catalyzed regio- and diastereoselective IHC of disubstituted
aminoallenes, which affords the corresponding mono- and
disubstituted pyrrolidines and piperidines bearing an R-alkene
functionality.11 Such structures offer unique opportunities for
(7) (a) Molander, G. A.; Retsch, W. H. Organometallics 1995, 14, 4570-
4575. (b) Fu, P.-F.; Brard, L.; Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1995,
117, 7157-7168. (c) Molander, G. A.; Julius, M. J. Org. Chem. 1992, 57,
6347-6351. (d) Sakakura, T.; Lautenschlager, H.-J.; Tanaka, M. J. Chem.
Soc., Chem. Commun. 1991, 40-41.
(8) Giardello, M. A.; King, W. A.; Nolan, S. P.; Porchia, M.; Sishta, C.;
Marks, T. J. In Energetics of Organometallic Species; Martinho Simoes, J.
A., Ed.; Kluwer: Dordrecht, 1992; pp 35-51.
(9) (a) Harrison, K. N.; Marks, T. J. J. Am. Chem. Soc. 1992, 114, 9220-
9221. (b) Bijpost, E. A.; Duchateau, R.; Teuben, J. H. J. Mol. Catal. 1995,
95, 121-129.
(4) (a) Roesky, P. W.; Denninger, U.; Stern, C. L.; Marks, T. J.
Organometallics 1997, 16, 4486-4492. (b) Molander, G. A.; Hoberg, J. O.
J. Org. Chem. 1992, 57, 3266-3268. (c) Jeske, G.; Lauke, H.; Mauermann,
H.; Swepston, P. N.; Schumann, H.; Marks, T. J. J. Am. Chem. Soc. 1985,
107, 8111-8118. (d) Evans, W. J.; Bloom, I.; Hunter, W. E.; Atwood, J.
L. J. Am. Chem. Soc. 1983, 105, 1401-1403.
(5) (a) Yang, X.; Seyam, A. M.; Fu, P.-F.; Marks, T. J. Macromolecules
1994, 27, 4625-4626. (b) Watson, P. L.; Parshall, G. W. Acc. Chem. Res.
1985, 18, 51-56. (c) Jeske, G.; Schock, L. E.; Swepston, P. N.; Schumann,
H.; Marks, T. J. J. Am. Chem. Soc. 1985, 107, 8103-8110.
(6) Fu, P.-F.; Marks, T. J. J. Am. Chem. Soc. 1995, 117, 10747-10748.
(b) Koo, K.; Fu, P.-F.; Marks, T. J. Macromolecules 1999, 32, 981-988.
(10) (a) Molander, G. A.; Retsch, W. H. J. Am. Chem. Soc. 1997, 119,
8817-8825. (b) Molander, G. A.; Nichols, P. J. J. Am. Chem. Soc. 1995,
117, 4415-4416. (c) Molander, G. A.; Hoberg, J. O. J. Am. Chem. Soc.
1992, 114, 3123-3125.
(11) Arredondo, V. M.; McDonald, F. E.; Marks, T. J. J. Am. Chem.
Soc. 1998, 120, 4871-4872.
10.1021/ja984305d CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/02/1999

3634 J. Am. Chem. Soc., Vol. 121, No. 15, 1999
Arredondo et al.
Scheme 1
applying this methodology to natural product synthesis,12 which
will be described herein.
and Kibayashi23 obtained 1 from C2-symmetric diepoxides
derived from D-mannitol. On the other hand, Lhommet et al.24
and Momose et al.25 reported the asymmetric synthesis of 2
from (S)-pyroglutamic acid and from D-alanine, respectively.
Both syntheses relied on the reductive annulation of a cyclic
aminocarbonyl compound.
A variety of substituted pyrrolidines13 and pyrrolizidines14
are found in the venom of ants15 of the genus Solenopsis and
Monomorium, and play biological roles ranging from protective
and pheromonal functions to necrotic, hemolytic, and allergenic
reactions.16 These alkaloids also occur in trace amounts in
amphibian skins where they serve as a chemical defense.17
However, the frogs themselves produce none of the alkaloids.
Instead, they are taken up from dietary arthropods (including
ants and beetles), and are sequestered unchanged into secretory
skin glands.18 Examples of these structures include (+)-
pyrrolidine 197B (1), [(2S,5S)-trans-2-butyl-5-pentylpyrroli-
dine], which was detected in skin extracts of Dendrobates
histronicus,19 and (+)-xenovenine (2), [(3S,5R,8S)-3-heptyl-5-
methylpyrrolizidine], isolated from Solenopsis xenoVeneum in
1980.20
On the basis of these reports, we decided to explore a com-
pletely different and potentially general stereoselective synthetic
approach via organolanthanide-catalyzed ring closure processes
involving N-H additions to C-C multiple bonds. We wish to
report here the enantioselective total syntheses of (+)-pyrrolidine
197B26 (1) and (+)-xenovenine27 (2) implementing the IHC
reaction as catalyzed by organolanthanide complexes.
Retrosynthesis. A retrosynthetic analysis is presented in
Scheme 1. Our synthetic strategy includes three key stereogenic
elements: (a) enantioselective formation of a primary amine
adjacent to a chiral carbon center, (b) diastereoselective IHC
of substrate 3, and (c) tandem intramolecular hydroamination/
bicyclization of substrate 4. This overall strategy is based on
our recent finding that the carbon atom bearing the amine
functional group dictates the stereochemical course of this type
of aminoallene cyclization process.11
Results and Discussion
Construction of Cyclization Substrates. The present syn-
thetic strategy requires enantioselective construction of the
cyclization precursors 3 and 4 (Scheme 1). As an entry point
to aminoallene precursor 3, we prepared enantiomerically pure
Previous asymmetric syntheses of these pyrrolidine and pyr-
rolizidine alkaloids were performed using chiral synthons
derived from the natural chiral pool.21 For example, Momose
et al.22 described the asymmetric synthesis of 1 by an intramo-
lecular amidomercuration of R-butyl-4-pentenylcarbamate which
was in turn prepared from L-norleucine, whereas Machinaga
(19) (a) Daly, J. W.; Spande, T. F.; Whittaker, N.; Highet, R. J.; Feigl,
D.; Nishimori, N.; Tokuyama, T.; Myers, C. W. J. Nat. Prod. 1986, 49,
265-280. It has also been detected in the alkaloidal venoms of fire ants:
(b) Jones, T. H.; Blum, M. S.; Fales, H. M. Tetrahedron 1982, 38, 1949-
1958. (c) Pedder, D. J.; Fales, H. M.; Jaouni, T.; Blum, M.; MacConnell,
J.; Crewe, R. M. Tetrahedron 1976, 32, 2275-2279.
(20) Jones, T. H.; Blum, M. S.; Fales, H. M.; Thompson, C. R. J. Org.
Chem. 1980, 45, 4778-4780.
(21) For discussion of the asymmetric synthesis of pyrrolizidine alkaloids,
see: (a) Provot, O.; Lhommet, G.; Ce´lerier, J.-P. J. Heterocyclic Chem.
1998, 35, 371-376. (b) Dai, W.-M.; Nagao, Y. Heterocycles 1990, 30,
1231-1261.
(22) Takahata, H.; Takehara, H.; Ohkubo, N.; Momose, T. Tetrahe-
dron: Asymmetry 1990, 1, 561-566.
(23) Machinaga, N.; Kibayashi, C. J. Org. Chem. 1991, 56, 1386-1393.
(24) Provot, O.; Ce´le´rier, P.; Petit, H.; Lhommet, G. J. Org. Chem. 1992,
57, 2163-2166.
(12) For catalytic and synthetic organic applications of organolanthanide
complexes, see: (a) Molander, G. A. Chemtracts: Org. Chem. 1998, 11,
237-263. (b) Taube, R. In Applied Homogeneous Catalysis with Organo-
metallic Complexes; Cornils, B., Herrmann, W. A, Eds.; VCH: Weinheim,
1996; Vol. 2, pp 507-521. (c) Imamoto, T. Lanthanides in Organic
Synthesis; Academic Press: San Diego, CA, 1994. (d) Molander, G. A.
Chem. ReV. 1992, 29, 9-68.
(13) Pinder, A. R. Nat. Prod. Rep. 1992, 9, 17-23.
(14) (a) Liddell, J. R. Nat. Prod. Rep. 1996, 13, 187-193. (b) Robins,
D. J. Nat. Prod. Rep. 1994, 11, 613-619. (c) Mattocks, A. R. Chemistry
and Toxicology of Pyrrolizidine Alkaloids; Academic Press: Orlando, FL,
1986.
(15) Attygalle, A. B.; Morgan, D. E. Chem. Soc. ReV. 1984, 13, 245-
278.
(25) Takahata, H.; Bandoh, H.; Momose, T. J. Org. Chem. 1992, 57,
4401-4404.
(16) Brown, K. S.; Trigo, J. R. in The Alkaloids; Cordell, G. A., Ed.;
Academic Press: San Diego, CA, 1995; Vol. 47, pp 227-354.
(17) (a) Daly, J. W. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 9-13. (b)
Daly, J. W. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: San
Diego, CA, 1998; Vol. 50, pp 141-169. (c) Daly, J. W.; Garraffo, H. M.;
Spande, T. F. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: San
Diego, CA, 1993; Vol. 44, pp 189-256.
(26) For racemic syntheses, see: (a) Ba¨ckvall, J.-E.; Schink, H. E.; Renko,
Z. D. J. Org. Chem. 1990, 55, 826-831. (b) Gessner, W.; Takahashi, K.;
Brossi, A.; Kowalski, M.; Kaliner, M. A. HelV. Chim. Acta 1987, 70, 2003-
2010.
(27) For an asymmetric synthesis of 2 containing 12% of another
diastereomeric product, see: (a) Arseniyadis, S.; Huang, P. Q.; Husson,
H.-P. Tetrahedron Lett. 1988, 29, 1391-1394. For racemic syntheses, see:
ref 20 and (b) Vavrecka, M.; Janowitz, A.; Hesse, M. Tetrahedron Lett.
1991, 32, 5543-5546.
(18) Daly, J. W.; Garraffo, H. M.; Spande, T. F.; Jaramillo, C.; Rand,
A. S. J. Chem. Ecol. 1994, 20, 943-955.

Organolanthanide-Catalyzed Cyclohydroamination
J. Am. Chem. Soc., Vol. 121, No. 15, 1999 3635
allene-aldehyde 5 from 4-pentyn-1-ol (7) in five steps.11,28
Enantioselective addition of di-butylzinc29 to 5 in the presence
of bissulfonamide catalyst 930 affords the (R)-secondary alcohol
8 in 70% yield (94% enantiomeric excess (ee), Scheme 2). Azide
displacement of the free hydroxyl group under Mitsunobu
conditions,31 followed by LAH reduction to the amine, com-
pletes preparation of the desired aminoallene substrate 3 with
inversion of configuration.
to afford aldehyde 6. The sp3-chiral center is set via the
enantioselective addition of bis(3-butenyl)zinc33 to aldehyde 6
in the presence of chiral catalyst 9 to furnish the hydroxy-ene-
allene 13, which is stereospecifically converted to the (S)-amine
substrate 4 in 57% yield as described above for 8.
Cyclization and Synthesis Completion. The key step in the
synthesis of 1 involves the regio- and diastereoselective IHC
of 3 (Scheme 4). Thus, the catalytic ring closure of 3 is effected
Scheme 2
Scheme 4
The synthesis of aminoallene-alkene 4 is shown in Scheme
3. Treatment of 10 with n-butyllithium in tetrahydrofuran at
-78 °C, followed by quenching with hexanal, provides the
racemic propargylic alcohol 11. Conversion of 11 to allenic
alcohol 12 is accomplished in 74% yield (two steps) using the
procedure of Myers and Zheng,32 followed by Swern oxidation
by organolanthanide complex 14 in pentane solution at 23 °C,
yielding the expected trans-pyrrolidine 18 bearing an exocyclic
carbon-carbon double bond with excellent Z selectivity.
Hydrogenation with Pd(OH)2/C led to pyrrolidine 197B (1) in
88% yield (two steps), [R]23D +6.1° (c 0.83, CHCl3) [lit.23 [R]27
D
+5.8° (c 0.79, CHCl3)]. Comparison of the spectral properties
of 1 to those reported in the literature22,23 confirms the identity.
In contrast to the facile ring closure of 3 to form 18, the
stereoselective catalytic hydroamination/bicyclization of ami-
noallene-alkene 4 to (+)-xenovenine (2) proved more difficult
to achieve (Scheme 5). For instance, 4 undergoes rapid reaction
in the presence of precatalyst Cp′2LaCH(TMS)2 (15) at 23 °C
yielding exclusively the corresponding monocyclic pyrrolidine
Scheme 3
Scheme 5
(28) See Supporting Information for experimental details.
(29) Noller, C. R. Organic Syntheses, 1942; Vol. II, pp 184-187.
(30) (a) Knochel, P. Chemtracts: Org. Chem. 1995, 8, 205-221. (b)
Takahashi, H.; Kawakita, T.; Yoshioka, M.; Kobayashi, S.; Ohno, M.
Tetrahedron Lett. 1989, 30, 7095.
(31) Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K. Tetrahedron
Lett. 1977, 18, 1977-1980.
(32) Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492-4493.
(33) Seebach, D.; Beck, A. K.; Schmidt, B.; Wang, Y. M. Tetrahedron
1994, 50, 4363-4384.

3636 J. Am. Chem. Soc., Vol. 121, No. 15, 1999
Arredondo et al.
19 via regioselective insertion-cyclization of the allene group
1
into the Ln-N bond; no H NMR indication of reaction with
the alkene moiety was observed. Similar results were observed
with the coordinatively more open5c organolanthanide complex
Me2SiCp′′2NdCH(TMS)2 (16) at room temperature. Traces of
1
a bicyclic intermediate are detected by H NMR spectroscopy
only in cases where the reactions are conducted at 60-80 °C.34
Isolation of 19 by flash column chromatography and catalytic
hydrogenation (1 atm) using Pd(OH)2/C affords 20 in 79% yield
(two steps).35 In contrast, the “constrained geometry” organo-
lanthanide complex Me2Si(Me4C5)(tBuN)SmN(TMS)2 (17)36
efficiently catalyzes the stereoselective tandem bicyclization of
acyclic 4 to the bicyclic pyrrolizidine intermediate 21 under
mild conditions (Scheme 6).37 Finally, reduction of the exocyclic
unsaturation using Pd(OH)2/C and hydrogen (1 atm) furnishes
(+)-xenovenine (2) in 78% yield (two steps). The spectroscopic
properties of 2 (1H NMR, 13C NMR, IR, [R]23D, MS) agree in
all respects with data reported in the literature.24,25
Scheme 6
Figure 1. Simplified catalytic cycle for organolanthanide-catalyzed
IHC of aminoallenes.
Mechanistic Aspects of the IHC Reaction. On the basis of
thermochemical considerations, substituent effects, metal ion
effects, and kinetic studies of the organolanthanide-catalyzed
IHC of aminoalkenes, aminoalkynes, and aminoallenes, we
proposed a general mechanistic scenario for these transforma-
tions (e.g., Figure 1 for aminoallenes).2,3,10 Kinetic and mecha-
nistic data argue that the turnover-limiting step is intramolecular
insertion of an unsaturated C-C linkage into the Ln-N bond
(step i, Figure 1) of what is probably a labile amine-amido
complex (Cp′2LnNHR(NH2R)x).2d This insertion step is highly
sensitive to modifications in the lanthanide coordination envi-
ronment and/or to the steric demands that the unsaturated
substrate moiety imposes. Thus, for the organolanthanide-
catalyzed IHC of aminoalkenes, use of complexes with larger
metal ionic radii and more open coordination spheres (Cp′2Ln
f Me2SiCp′′2Ln) results in increased reaction rates (increased
turnover frequencies, Nt).2d However, the situation for aminoal-
lene substrates is somewhat different, because the reaction
exhibits maximum Nt values at metal ionic radii intermediate
between the largest eight-coordinate lanthanide ionic radius,
La3+ (1.160 Å) and the smallest, Lu3+ (0.977 Å).10
Figure 2. Plausible stereochemical pathway for the IHC of 3 to trans-
2-butyl-5-(1-pentenyl)pyrrolidine (18) mediated by organolanthanide
complex 14.
trans-pyrrolidine diastereoselectivity can be rationalized by
consideration of ligand-substrate nonbonded repulsions in the
proposed transition-state structures shown in Figure 2. Interest-
ingly, aminoallene-alkene substrate 4 undergoes monocyclization
to the trans-2,5-disubstituted pyrrolidine 19 in the presence of
lanthanocene precatalysts 15 and 16 (Scheme 5). The aborted
insertion of the remaining terminal alkene moiety into the Ln-N
bond (the organolanthanide hydroamination catalyst resting
state)2,3,11 is presumably due to repulsive interactions between
the substrate alkyl substituents and the catalyst ancillary ligands.
In contrast, the more open organolanthanide “constrained
geometry” complex 1736 effects rapid, diastereoselective conver-
sion to the desired bicyclic structure 21 (Scheme 6). The reaction
of 4 with the diamagnetic precatalyst Me2Si(Me4C5)(tBuN)YN-
(TMS)2 was closely monitored by 1H NMR spectroscopy at 40
°C and at constant catalyst concentration (Figure 3).38 The
kinetic data clearly show that the allene moiety reacts signifi-
cantly faster (∼20 times) than its alkene counterpart. Thus, we
The rapid reaction of aminoallene 3 with precatalyst 14
cleanly generates trans-2-butyl-5-(1-pentenyl)pyrrolidine (18)
as a 95:5 ratio of Z/E stereoisomers (Scheme 4). The observed
(34) Reactions are conveniently monitored by 1H NMR spectroscopy.
(35) (S, S)-trans-2-Butyl-5-heptylpyrrolidine is an alkaloid isolated from
Solepnosis puctaticeps, see ref 19c. For asymmetric syntheses, see: (a)
Arseniyadis, S.; Huang, P. Q.; Piveteau, D.; Husson, H.-P. Tetrahedron
1988, 44, 2457-2470. (b) Shiosaki, K.; Rapoport, H. J. Org. Chem. 1985,
50, 1229.
(36) Tian, S.; Arredondo, V. M.; Marks, T. J. Organometallics, in press.
(37) Identical results are obtained with Me2Si(Me4C5)(tBuN)YN(TMS)2.

Organolanthanide-Catalyzed Cyclohydroamination
J. Am. Chem. Soc., Vol. 121, No. 15, 1999 3637
ppm of O2). Argon (Matheson, prepurified) was purified by passage
through a MnO oxygen-removal column39 and a Davison 4A molecular
sieve column. All solvents were distilled before use under dry nitrogen
over appropriate drying agents (sodium benzophenone ketyl, metal
hydrides, Na/K alloy). Chloroform-d, benzene-d6, and toluene-d8 were
purchased from Cambridge Isotope Laboratories. Benzene-d6 and
toluene-d8 used for NMR reactions were stored in vacuo over Na/K
alloy in resealable bulbs, and were vacuum transferred immediately
prior to use. All organic starting materials were purchased from Aldrich
Chemical Co., Farchan Laboratories Inc., or Lancaster Synthesis Inc.,
and were used without further purification unless otherwise stated.
Cyclization substrates (5S,8S)-5-amino-trideca-8,9-diene (3), and (5S)-
5-amino-pentadeca-1,8,9-triene (4) were used after purification by
distillation (no drying step was required). Organolanthanide precatalysts
Cp′2LnCH(TMS)2,40 Me2SiCp′′2NdCH(TMS)25c and Me2SiCp′′(tBuN)-
LnN(TMS)2 (Ln ) Sm, Lu, Y; Cp′) η5-Me5C5; Cp′′ ) η5-Me4C5;
36
TMS ) Me3Si) were prepared by published procedures.
Physical and Analytical Measurements. NMR spectra were
1
recorded on either a Varian Gemini, VXR 300 (FT, 300 MHz, H; 75
MHz, 13C), or Unity-400 (FT, 400 MHz, 1H; 100 MHz, 13C) instrument.
Figure 3. Normalized ratio of alkene and allene functionalities to
precatalyst concentration as a function of time for the hydroamination/
bicyclization of aminoallene-alkene (4) using Me2Si(Me4C5)(tBuN)-
YN(TMS)2 in benzene-d6 at 40 °C. Lines through the data points are
drawn as a guide to the eye.
1
Chemical shifts (δ) for H and 13C are referenced to internal solvent
resonances and reported relative to SiMe4. NMR experiments on air-
sensitive samples were conducted in Teflon valve-sealed tubes (J.
Young). Elemental analyses were performed by Midwest Microlabs,
Indianapolis, IN. Optical rotations were measured at 25 °C with an
Optical Activity Ltd. AA-100 polarimeter ((0.001) using a 0.5 dm
quartz cell. GC-MS analyses were performed using a Hewlett Packard
HP6890 instrument with a HP-5MS (5% phenylmethylsiloxane, 30 m
× 250 µm × 0.25 µm) capillary column and flame ionization detector
(FID). The conditions were as follows: detector, 150 °C; injector, 250
°C; initial oven temperature, 55 °C for 3 min; 5° min-1 to 72 °C, hold
for 0.1 min; 3° min-1 to 87 °C, hold for 0.1 min; then 40° min-1 to
270 °C. High-resolution mass spectrometry (HRMS) studies were
conducted on a VG 70-250 SE instrument with 70 eV electron impact
ionization. IR spectra were recorded using a BioRad FT S60 FTIR
instrument. Boiling points are uncorrected.
(5R,8S)-Trideca-8,9-diene-5-ol (8). A 50 mL three-necked flask
equipped with an argon inlet, a thermometer, and a septum cap was
charged with dry toluene (19 mL), Ti(OiPr)4 (21.5 g, 75.5 mmol), and
(1S,2S)-1,2-bis[(trifluoromethyl)sulfonamido]-cyclohexane (1.1 g, 3.0
mmol). The reaction mixture was heated to 40-45 °C for 0.5 h and
then cooled to -60 °C; dibutylzinc29 in toluene (17 mL) was then added,
followed after 5 min by aldehyde 528 (5.2 g, 37.8 mmol). The reaction
mixture was stirred for 2 h at -60 °C and 4 h at -20 °C. The reaction
mixture was then quenched with a 10% HCl solution and extracted
with ether. The aqueous phase was extracted twice with ether, and the
combined organic phase was washed successively with a saturated
aqueous NaHCO3 solution (2 × 100 mL) and brine (1 × 50 mL), and
was dried over MgSO4. After filtration and evaporation of the solvent,
the residual oil was purified by flash column chromatography on silica
gel (10% ether in pentane), affording 5.2 g (69% yield) of a light yellow
oil (94% ee; Mosher ester analysis). [R]23D +64.9° (c 1.6, CHCl3); IR
(KBr, thin film): νmax ) 3342, 2958, 2930, 2870, 1962, 1457, 1378,
1127, 1053 cm-1; 1H NMR (300 MHz, CDCl3): δ 5.08 (m, 2H), 3.63
(m, 1H), 2.14-2.02 (m, 2H), 1.98-1.89 (m, 2H), 1.59-1.26 (m, 11H),
0.92-0.86 (m, 6H); 13C NMR (75 MHz, CDCl3): δ 203.8, 91.2, 90.4,
71.3, 37.1, 36.5, 31.0, 27.8, 25.1, 22.7, 22.3, 14.0, 13.6; HRMS (m/z):
[M+] calcd for C13H24O, 196.18271; found, 196.18263. Anal. Calcd
for C13H24O: C, 79.53; H, 12.32. Found: C, 79.55; H, 12.49.
propose that this bicyclization reaction proceeds as depicted in
Figure 4. The first step is rapid protonolysis of the Ln-N(TMS)2
bond to generate the catalytically active lanthanide-amido
complex I and HN(TMS)2. The latter species is observed
immediately by NMR upon mixing of the substrate and
precatalyst. In principle, complex I can exist in various
energetically distinct conformations (such as I, V, and VI);
however, on the basis of the present results, conformation I is
favored for undergoing allene insertion to yield II (Figure 4).
Intra- or intermolecular protonolysis of the Ln-C bond in II
then provides the lanthanide-amido complex III, which
undergoes further insertion of the alkene moiety into the Ln-N
bond to yield IV. Finally, protonolysis of the Ln-C bond in
IV completes the catalytic cycle and furnishes 21 with the
desired observed stereochemistry.
Conclusions
The organolanthanide-catalyzed IHC reaction constitutes a
valuable new tool for regio- and stereoselective construction
of mono- and bicyclic alkaloid compounds, exemplified here
by the total syntheses of pyrrolidine 197B (1) and (+)-
xenovenine (2), respectively. The catalytic efficacy of the
organolanthanide centers is highly sensitive to the electronic
and steric characteristics of both the substrate and the catalyst.
Thus, successful and general application of this methodology
has benefited from the continued development of new, highly
reactive, and selective organolanthanide complexes. The present
results thus demonstrate that lanthanocenes are versatile pre-
catalysts for the efficient insertion of unsaturated C-C linkages
into Ln-N bonds, and thus for the construction of alkaloid
natural products. Further studies of synthetic applications of this
transformation are currently underway.
(5S,8S)-5-Amino-trideca-8,9-diene (3). To a solution of 8 (4.8 g,
24.3 mmol) in dry tetrahydrofuran (THF) (300 mL) was added PPh3
(12.8 g, 48.7 mmol), diethyl azodicarboxylate (DEAD) (8.5 g, 48.7
mmol), and diphenylphosphoryl azide (13.4 g, 48.7 mmol). The reaction
mixture was stirred for 30 min, then concentrated by rotary evaporation,
and filtered through a plug of Celite, washing with 1:1 ether/pentane.
The filtrate was concentrated by rotary evaporation and the residue
Experimental Section
Materials and Methods. All manipulations of air-sensitive materials
were carried out with rigorous exclusion of oxygen and moisture in
flame-dried Schlenk-type glassware on a dual-manifold Schlenk line
interfaced to a high-vacuum line (10-6 Torr), or in a nitrogen-filled
Vacuum Atmospheres glovebox with a high capacity recirculator (<1
(39) (a) He, M. Y.; Toscano, P. J.; Burwell, R. L.; Marks, T. J. J. Am.
Chem. Soc. 1985, 107, 641-652. (b) McIlwrick, C. R.; Phillips, C. S. G.
J. Chem. Phys., E. 1973, 6, 1208-1210.
(40) Jeske, G.; Lauke, H.; Mauermann, H.; Swepston, P. N.; Schumann,
H.; Marks, T. J. J. Am. Chem. Soc. 1985, 107, 8091-8103.
(38) Allene (CHdCdCH, δ ∼ 5.2 ppm) and alkene (CH2dCH, δ ∼
5.0 ppm) 1H resonances were normalized to the signal of the stoichiomet-
rically generated HN(TMS)2 byproduct (δ ∼ 0.1 ppm).

3638 J. Am. Chem. Soc., Vol. 121, No. 15, 1999
Arredondo et al.
Figure 4. Probable reaction mechanism and stereochemical scenario for the bicyclization of aminoallene-alkene substrate 4 mediated by precatalyst
17.
was purified by flash chromatography on silica gel (10% ether in
pentane), yielding 4.1 g (75% yield) of the azide as a light yellow oil.
Rf ) 0.88 (20% ether in pentane). IR (KBr, thin film): νmax ) 2959,
Ph3P (30.9 g, 117.9 mmol), THF (450 mL), and 11 (24.3 g, 90.7 mmol).
The solution was cooled to -15 °C and DEAD (20.5 g, 117.9 mmol)
was added dropwise at -15 °C. After addition was complete, stirring
was continued for 2.5 h. To the resulting yellow solution, nitroben-
zenesulfonyl hydrazide (NBSH) (25.6 g, 117.9 mmol; dissolved in 200
mL of dry THF) was added dropwise at -15 °C. The reaction mixture
was maintained at -15 °C and stirred for 4 h, then was allowed to
warm to room temperature overnight. The resulting orange solution
was concentrated, cooled to 0 °C, and the precipitated solid was filtered
off and washed with cold ethyl acetate. Concentration of the filtrate
and purification of the residue by flash column chromatography on
silica gel (20% ether in pentane) afforded the protected allenic alcohol
as a yellow liquid (16.9 g, 74% yield). Rf ) 0.76; 1H NMR (300 MHz,
CDCl3): δ 5.07 (m, 2H), 4.56 (t, J ) 3.6 Hz, 1H), 3.88-3.81 (m, 1H),
3.79-3.71 (m, 1H), 3.51-3.36 (m, 2H), 2.08-2.01 (m, 2H), 1.99-
1.91 (m, 2H), 1.82-1.64 (m, 4H), 1.40-1.25 (m, 6H), 0.86 (t, J ) 7.0
Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 203.8, 98.8, 98.7, 91.4, 90.3,
66.9, 66.8, 62.2, 31.3, 30.7, 29.1 (2C), 28.9, 28.8, 25.6, 25.5, 22.5,
19.6, 14.1; HRMS (m/z): [M]+ calcd for C16H28O2, 252.20892; found,
252.20839. To a solution of this product (16.9 g, 67.0 mmol) in MeOH
(150 mL) was added TsOH (50 mg). The resulting mixture was stirred
at room temperature until TLC analysis (50% ether in pentane) showed
complete deprotection. Solvent was then removed in vacuo; the residue
was then diluted with ether, washed with a 10% solution of Na2CO3,
and dried over Na2SO4. Subsequent filtration and evaporation of the
solvent yielded a yellowish liquid. Flash column chromatography on
silica gel (30% ether in pentane) afforded 12 (11.1 g, 98% yield). Rf )
0.29; IR (thin film): νmax ) 3331, 2956, 2930, 2857, 1961, 1449, 1378,
2932, 2865, 2097, 1963, 1465, 1258 cm-1 1H NMR (300 MHz,
;
CDCl3): δ 5.08 (m, 2H), 3.30 (quint, J ) 6.6 Hz, 1H), 2.13-2.02 (m,
2H), 1.99-1.91 (m, 2H), 1.62-1.30 (m, 10H), 0.93-0.87 (m, 6H);
13C NMR (75 MHz, CDCl3): δ 204.1, 91.6, 89.7, 62.3, 34.1, 33.6,
31.0, 28.2, 25.3, 22.5, 22.4, 13.9, 13.6. A suspension of LiAlH4 (1.4 g,
36.5 mmol) in ether (50 mL) was stirred while a solution of this azide
(4.1 g, 18.8 mmol) in dry ether (25 mL) was added dropwise at a rate
so as to maintain a gentle reflux. When addition was complete, reflux
was continued for 24 h. The reaction mixture was then cooled to room
temperature and quenched by the sequential addition of water (1.5 mL),
a 15% solution of NaOH (1.5 mL), and water (4.5 mL). The white
precipitate which formed was filtered off and washed with ether. The
filtrate was dried over Na2SO4, filtered, the solvent evaporated, and
the product purified by vacuum distillation (bp 135-136 °C/1 mmHg),
yielding 3 as a colorless liquid (3.4 g, 92% yield). [R]23 +26.6° (c
D
2.0, CHCl3); IR (KBr, thin film): νmax ) 3373, 3303, 2958, 2929, 2859,
1962, 1465, 1378 cm-1; 1H NMR (300 MHz, CDCl3): δ 5.05 (m, 2H),
2.73 (m, 1H), 2.15-1.90 (m, 4H), 1.58-1.25 (m, 12H), 0.92-0.87
(m, 6H); 13C NMR (75 MHz, CDCl3): δ 203.8, 91.0, 90.4, 50.5, 37.7,
37.3, 31.0, 28.3, 25.6, 22.8, 22.3, 14.0, 13.6; HRMS (m/z): [M]+ calcd
for C13H25N, 195.19870; found, 196.19874. Anal. Calcd for C13H25N:
C, 79.93; H, 12.90; N, 7.17. Found: C, 79.73; H, 12.95; N, 7.13.
1-(Tetrahydropyran-2-yloxy)-undec-4-yn-6-ol (11). Compound 10
(21.1 g., 125.7 mmol) and THF (300 mL) were placed in a dried three-
necked, round-bottom flask equipped with magnetic stirrer, addition
funnel, low-temperature thermometer, and N2 inlet. The stirring solution
was cooled to -78 °C and a 1.6 M n-BuLi solution (86.4 mL, 138.3
mmol) was added dropwise while the temperature was maintained equal
to or below -70 °C. The reaction mixture was stirred at -78 °C for 1
h. Hexanal (13.2 g, 132.0 mmol) was then added dropwise at -78 °C.
After addition was complete, the mixture was stirred for an additional
15 min at -78 °C then was warmed slowly to room temperature, and
the reaction was then quenched with saturated NH4Cl solution. The
aqueous layer was separated and extracted with ether (2 × 100 mL).
The combined organic layer was dried over Na2SO4, filtered, and the
solvent removed in vacuo yielding a yellow liquid. Flash column
chromatography on silica gel (20% ether in pentane) afforded pure
1
1058 cm-1; H NMR (300 MHz, CDCl3): δ 5.08 (apparent quintet,
2H), 3.67 (t, J ) 6.5 Hz, 2H), 2.08-2.02 (m, 2H), 1.97-1.90 (m, 2H),
1.67 (quintet, J ) 7.1 Hz, 2H), 1.40-1.25 (m, 7H), 0.87 (t, J ) 6.8
Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 203.7, 91.5, 90.1, 62.2, 31.9,
31.3, 28.8 (2C), 25.1, 22.4, 14.0; Anal. Calcd for C11H20O: C, 78.51;
H, 11.98; Found: C, 78.52; H, 11.91.
4,5-Undecadienal (6). While a solution of oxalyl chloride (37.3 mL,
74.5 mmol) dissolved in CH2Cl2 (150 mL) at -78 °C was stirred,
dimethyl sulfoxide (DMSO) (10.6 mL, 149.0 mmol) dissolved in CH2-
Cl2 (20 mL) was added over a period of 20 min. After the solution
was stirred for an additional 1 h, 12 (10.9 g, 64.8 mmol) dissolved in
CH2Cl2 (30 mL) was added dropwise. The reaction mixture was stirred
at -78 °C for 1.5 h. Triethylamine (45.1 mL, 324.0 mmol) was then
added dropwise at -78 °C, the reaction mixture was stirred for an
additional 1 h, and then allowed to warm to 10 °C. Water (300 mL)
was added and the two layers separated. The aqueous layer was acidified
with 1% aqueous HCl (saturated with NaCl) and then back-extracted
with CH2Cl2 (3 × 100 mL). The combined organic layers were washed
with 1% aqueous HCl (saturated with NaCl, 6 × 100 mL) followed by
5% aqueous NaHCO3 solution (2 × 50 mL). The aqueous extracts were
back-extracted with CH2Cl2 (2 × 70 mL) and the combined organic
extracts were washed with brine and dried over Na2SO4. After filtration,
the solvent was removed by rotary evaporation to give the title
alcohol 11 (24.5 g, 88% yield). Rf ) 0.09; IR (KBr, thin film): νmax
)
3427, 2930, 2854, 2236, 1441, 1322, 1138, 990 cm-1; H NMR (300
MHz, CDCl3): δ 4.57 (t, J ) 3.4 Hz, 1H), 4.31 (tt, J ) 6.5, 1.9 Hz,
1H), 3.87-3.76 (m, 2H), 3.52-3.41 (m, 2H), 2.31 (dt, J ) 7.1, 1.9
Hz, 2H), 1.77 (quintet, J ) 6.6 Hz, 4H), 1.69-1.26 (m, 13H), 0.87 (t,
J ) 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 98.7, 84.5, 81.8,
65.8, 62.6, 62.1, 38.1, 31.4, 30.6, 28.8, 25.4, 24.9, 22.5, 19.4, 15.5,
14.0; HRMS (m/z): [M-H]+ calcd for C16H28O3, 267.1961; found,
267.1965.
1
4,5-Undecadien-1-ol (12). A 1 L Schlenk flask equipped with
magnetic stirrer and low-temperature thermometer was charged with

Organolanthanide-Catalyzed Cyclohydroamination
J. Am. Chem. Soc., Vol. 121, No. 15, 1999 3639
compound as a yellow liquid (10.6 g, 99% yield). 1H NMR (300 MHz,
CDCl3): δ 9.78 (t, J ) 1.5 Hz, 1H), 5.14 (apparent quintet, 2H), 2.52
(t, J ) 7.0 Hz, 2H), 2.33-2.25 (m, 2H), 1.96-1.90 (m, 2H), 1.38-
1.29 (m, 6H), 0.86 (t, J ) 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3):
δ 203.7, 201.9, 92.9, 89.2, 42.3, 31.2, 28.7 (2C), 22.4, 21.2, 13.9;
HRMS (m/z): [M]+ calcd for C11H18O, 166.13577; found, 166.13582.
(5R)-Pentadeca-1,8,9-triene-5-ol (13). From 2.1 g of 6, 1.0 g of
13 was obtained (36% yield) after chromatographic separation (20%
ether in pentane) using the same procedure as for 8, but with bis(3-
butenyl)zinc.33 [R]23D +2.4° (c 0.41, CHCl3); IR (KBr, thin film): νmax
1.66 (br s, 1H), 1.52-1.21 (m, 10H), 0.85 (t, J ) 6.8 Hz, 3H). 13C
NMR (75 MHz, CDCl3): δ 138.7, 133.1, 130.7, 114.4, 59.9, 57.4, 36.5,
33.1, 32.3, 32.2, 31.6, 31.4, 29.0, 22.5, 14.1 and 138.7, 133.5, 130.4,
114.4, 57.5, 54.1, 36.3, 33.4, 32.5, 31.4, 30.3, 29.5, 27.4, 14.1; HRMS
(m/z): [M]+ calcd for C15H27N, 221.21436; found, 221.21376. A
solution of 19 in MeOH (2 mL) was hydrogenated over Pd(OH)2/C (2
mg) for 2 h at 1 atm of H2 pressure. The reaction mixture was then
filtered through a short plug of Celite and washed with ether. The
solvent was removed in vacuo to yield 20 (16 mg, 93%) as a pale
yellow liquid. 1H NMR (300 MHz, CDCl3): δ 3.10 (m, 2H), 1.93 (m,
2H), 1.82 (br s, 1H), 1.34-1.21 (m, 20H), 0.89 (t, J ) 6.5 Hz, 3H),
0.88 (t, J ) 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 58.0 (2C),
37.1, 36.9, 32.5, 31.8, 30.3, 29.8, 29.5, 29.3, 27.3, 22.9, 22.7, 14.1
(2C); HRMS (m/z): [M-1]+ calcd for C13H31N, 224.23782; found,
224.23823.
) 3342, 2962, 2929, 2870, 1962, 1457, 1375, 1335, 1127, 876 cm-1
;
1H NMR (300 MHz, CDCl3): δ 5.89-5.76 (m, 1H), 5.08 (m, 2H),
5.01-4.94 (m, 2H), 3.67 (m, 1H), 2.22-2.02 (m, 4H), 1.99-1.91 (m,
2H), 1.62-1.23 (m, 11H), 0.87 (t, J ) 6.9 Hz, 3H); 13C NMR (75
MHz, CDCl3): δ 203.8, 138.6, 114.8, 91.6, 90.4, 70.9, 36.6, 36.4, 31.2,
30.1, 28.9 (2C), 25.1, 22.5, 14.1; HRMS (m/z): [M-1]+ calcd for
C15H26O, 221.19042; found, 221.19026.
(3S,5R,8S)-3-Heptyl-5-methylpyrrolizidine (2) [(+)-Xenovenine].
In the glovebox, 17 (4.7 mg, 8.8 µmol) and C6D6 (∼700 µL) were
loaded into an NMR tube equipped with a Teflon valve. On the high-
vacuum line, the tube was evacuated after the precatalyst solution was
frozen. Under a stream of Ar gas, 4 (50 mg, 226 µmol) was then
syringed in. The tube was sealed and the frozen reaction mixture was
warmed to room temperature. After the mixture was shaken, the clear
yellow solution was then warmed to 45 °C. When the reaction was
complete (overnight),34 the contents were loaded onto a short column
of silica gel and eluted with ether yielding 21 as a 1:1 mixture of Z/E
isomers. A solution of 21 in MeOH (2 mL) was next hydrogenated
over Pd(OH)2/C (2 mg) for 2 h at 1 atm of H2 pressure. The reaction
mixture was filtered through a short plug of Celite and washed with
ether. The solvent was removed in vacuo to yield 2 (39.3 mg, 78%) as
a pale yellow liquid. [R]23D +10.9° (c 0.72, CHCl3) [lit. [R]24D +11.7°
(5S)-5-Amino-pentadeca-1,8,9-triene (4). From 942.4 mg of 13,
538.7 mg of 4 was obtained (57% yield) after high-vacuum distillation
using the same procedure as for 3. [R]23 -49.4° (c 2.0, CHCl3); IR
D
(KBr, thin film): νmax ) 3373, 3303, 2957, 2926, 2871, 2855, 1961,
1
1641, 1467, 1451, 1378, 910 cm-1; H NMR (300 MHz, CDCl3): δ
5.87-5.73 (m, 1H), 5.06 (m, 2H), 4.99-4.91 (m, 2H), 2.76 (m, 1H),
2.18-1.91 (m, 6H), 1.58-1.44 (m, 2H), 1.41-1.21 (m, 10H), 0.86 (t,
J ) 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 203.7, 138.7, 114.5,
91.4, 90.5, 50.1, 37.3, 37.1, 31.3, 30.5, 28.9 (2C), 25.6, 22.5, 14.1;
HRMS (m/z): [M+1]+ calcd for C15H27N, 222.2222; found, 222.2226.
Anal. Calcd for C15H27N: C, 81.38; H, 12.29; N, 6.33. Found: C, 80.68;
H, 12.17; N, 6.05.
(2S,5S)-trans-2-Butyl-5-pentylpyrrolidine [(+)-Pyrrolidine 197B]
(1). In the glovebox, 14 (15 mg, 25.8 µmol) was loaded into a storage
tube equipped with magnetic stir bar and J. Young Teflon valve. At
-78 °C, pentane (1.5 mL) was vacuum-transferred onto the catalyst,
and 3 (264.5 mg, 1.35 mmol) was syringed in. The clear yellow solution
was then stirred for 1 h at ambient temperature. The reaction mixture
was next loaded onto a short column of silica gel and eluted with ether
yielding (2S,5S)-trans-2-butyl-5-(1)-pentenylpyrrolidine (18) as a 95:5
mixture of Z/E isomers. 1H NMR (300 MHz, CDCl3) Z-isomer: δ 5.36
(m, 2H), 4.01 (m, 1H), 3.18 (m, 1H), 2.52 (br s, 1H), 2.06-1.92 (m,
4H), 1.48-1.23 (m, 10H), 0.87 (t, J ) 7.2 Hz, 6H). 13C NMR (75
MHz, CDCl3): δ 133.1, 130.5, 58.2 (2C), 36.5, 33.2, 32.5 (2C), 29.5,
22.9, 22.8, 14.1, 13.8; HRMS (m/z): [M]+ calcd for C13H25N, 195.1987;
found, 195.1983. A solution of this pyrrolidine in MeOH (3 mL) was
hydrogenated over Pd(OH)2/C (10 mg) for 2 h at 1 atm of H2 pressure.
The reaction mixture was then filtered through a short plug of Celite
and washed with ether. The solvent was removed in vacuo to yield 1
(234.4 mg, 88%) as a pale yellow liquid. [R]23D +6.1° (c 0.83, CHCl3);
(c 0.69, CHCl3);25 [R]22 +6.6° (c 2.35, CHCl3)24]; IR (KBr, thin
D
film): νmax ) 2963, 2932, 2872, 1462, 1370 cm-1; 1H NMR (400 MHz,
CDCl3): δ 3.65 (m, 1H), 2.77 (m, 1H), 2.61 (m, 1H), 2.01-1.82 (m,
4H), 1.56-1.17 (m, 16H), 1.10 (d, J ) 6.6 Hz, 3H), 0.85 (t, J ) 7.0
Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 66.7, 65.1, 61.8, 36.9, 34.4,
32.4, 32.0, 31.9, 31.7, 29.8, 29.3, 27.2, 22.7, 21.7 14.1; HRMS (m/z):
[M]+ calcd for C15H29N, 223.23000; found, 223.22950.
In Situ Kinetic Study of Hydroamination/Bicyclization Reaction.
In the glovebox, the Me2SiCp′′(tBuN)YN(TMS)2 precatalyst (ca. 3.3
mg, 6.6 µmol) was weighed into an NMR tube equipped with a Teflon
valve. On the high-vacuum line, the tube was evacuated, C6D6 (700
µL) was vacuum transferred into the tube, and (5S)-5-amino-pentadeca-
1,8,9-triene (4) (18 mg, 81.3 µmol) was syringed in. The tube was
then sealed and maintained at -78 °C until kinetic measurements were
begun. The sample tube was inserted into the probe of the Unity-400
spectrometer which had been previously set to 40 °C temperature (T
( 0.2 °C; ethylene glycol temperature standard). Data were acquired
using two scans per time interval with a long pulse delay (10 s) to
avoid signal saturation. The kinetics were monitored from intensity
changes in the substrate allenic and olefinic resonances. The relative
concentration of either functional group was measured from the allenic
and olefinic peak area, standardized to the area of the free HN(TMS)2
formed as turnover commenced.
1
IR (KBr, thin film): νmax ) 3340, 2965, 2728, 1467, 1375 cm-1; H
NMR (300 MHz, CDCl3): δ 4.27 (br s, 1H), 3.17 (m, 2H), 1.93 (m,
2H), 1.53 (m, 2H), 1.56-1.24 (m, 14H), 0.83 (t, J ) 6.9 Hz, 3H), 0.81
(t, J ) 6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 58.0, 57.9, 37.1,
36.8, 32.5 (2C), 32.0, 29.5, 27.0, 22.8, 22.6, 14.1, 14.0; HRMS (m/z):
[M-1]+ calcd for C13H27N, 196.2066; found, 196.20671.
(2S,5S)-2-Butyl-5-heptylpyrrolidine (20). In the glovebox, 15 (or
16) (4.6 mg, 8.1 µmol) and C6D6 (∼700 µL) were loaded into an NMR
tube equipped with a Teflon valve. On the high-vacuum line, the tube
was evacuated when the precatalyst solution was frozen. Under a stream
of Ar gas, 4 (20 mg, 90.4 µmol) was then syringed in. The tube was
sealed and the frozen reaction mixture was warmed to room temper-
ature. After the mixture was shaken, the progress of the reaction in the
clear, colorless solution was monitored by 1H NMR spectroscopy. Upon
reaction completion (<15 min), the reaction mixture was next loaded
onto a short column of silica gel and eluted with ether affording 19
(17 mg, 85% yield) as a ∼2.5:1 mixture of Z/E isomers. 1H NMR (400
MHz, CDCl3): δ 5.87-5.73 (m, 1H), 5.54-5.32 (m, 2H), 5.02-4.89
(m, 2H), 3.97 and 3.59 (m, 1H), 3.16 (m, 1H), 2.10-1.90 (m, 6H),
Acknowledgment. Financial support by the National Science
Foundation (CHE-9618589) is gratefully acknowledged. V.M.A.
thanks Shell Oil Co. (1995-1996) and Wyeth-Ayerst (1997-
1998) for graduate fellowships, the latter administered by the
Organic Chemistry Division of the American Chemical Society.
Supporting Information Available: Detailed synthetic
procedures and analytical data for aldehyde 5 (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
JA984305D