Regioselective and stereoselective copper(I)-Promoted allylation and conjugate addition of N -Boc-2-lithiopyrrolidine and N -Boc-2-lithiopiperidine

Article abstract of DOI:10.1021/jo100415x

Copper salts have been screened for transmetalation and electrophilic quench of N-tert-butoxycarbonyl-2-lithiopyrrolidine (N-Boc-2-lithiopyrrolidine) and N-Boc-2-lithiopiperidine, formed by deprotonation of N-Boc-pyrrolidine and N-Boc-piperidine, respectively. Transmetalation with zinc chloride then (lithium chloride solubilized) copper cyanide followed by allylation typically gives mixtures of regioisomers (S_N2 and S_N2′ products), whereas transmetalation with copper iodideTMEDA then allylation occurs regioselectively (S_N2 mechanism). Addition to an enone or α,β-unsaturated ester occurs by 1,4-addition. Asymmetric deprotonation of N-Boc-pyrrolidine or dynamic resolution in the presence of a chiral ligand of N-Boc-2-lithiopiperidine followed by the zinc/copper chemistry was successful and gave the allylated pyrrolidine and piperidine products with good enantioselectivity, although use of the copper iodide chemistry resulted in some loss of enantiopurity. The chemistry provides formal syntheses of (+)-allosedridine, (+)-lasubine II, and (+)-pseudohygroline and has been used for the synthesis of (+)-coniine, (-)-pelletierine, (+)-coniceine, (-)-norhygrine, and the ant extract alkaloids cis- and trans-2-butyl-5- propylpyrrolidine.

Full text of DOI:10.1021/jo100415x

pubs.acs.org/joc
Regioselective and Stereoselective Copper(I)-Promoted
Allylation and Conjugate Addition of N-Boc-2-lithiopyrrolidine
and N-Boc-2-lithiopiperidine
Iain Coldham* and Daniele Leonori
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, U.K.
i.coldham@sheffield.ac.uk
Received March 5, 2010
Copper salts have been screened for transmetalation and electrophilic quench of N-tert-butoxycar-
bonyl-2-lithiopyrrolidine (N-Boc-2-lithiopyrrolidine) and N-Boc-2-lithiopiperidine, formed by dep-
rotonation of N-Boc-pyrrolidine and N-Boc-piperidine, respectively. Transmetalation with zinc
chloride then (lithium chloride solubilized) copper cyanide followed by allylation typically gives
mixtures of regioisomers (SN2 and SN20 products), whereas transmetalation with copper iodide
3
TMEDA then allylation occurs regioselectively (SN2 mechanism). Addition to an enone or R,β-
unsaturated ester occurs by 1,4-addition. Asymmetric deprotonation of N-Boc-pyrrolidine or
dynamic resolution in the presence of a chiral ligand of N-Boc-2-lithiopiperidine followed by the
zinc/copper chemistry was successful and gave the allylated pyrrolidine and piperidine products with
good enantioselectivity, although use of the copper iodide chemistry resulted in some loss of
enantiopurity. The chemistry provides formal syntheses of (þ)-allosedridine, (þ)-lasubine II, and
(þ)-pseudohygroline and has been used for the synthesis of (þ)-coniine, (-)-pelletierine, (þ)-
coniceine, (-)-norhygrine, and the ant extract alkaloids cis- and trans-2-butyl-5-propylpyrrolidine.
Introduction
transmetalation of these species to, for example, organo-
zinc3-6 or organocopper7-14 species can provide organome-
tallic compounds with different nucleophilicities that open
up wider synthetic transformations.
The formation of carbon-carbon bonds is a fundamental
process in synthetic chemistry and often involves the direct
interaction of nucleophilic intermediates with electrophilic
partners. Organolithium compounds have emerged as very
attractive nucleophilic intermediates, and their reactions
have been studied extensively.1,2 In many cases, these orga-
nolithiums give poor results with electrophiles such as
Michael acceptors, allylic and aryl halides. However, the
(5) Klein, S.; Marek, I.; Normant, J.-F. J. Org. Chem. 1994, 59,
2925.
(6) Yus, M.; Ortiz, R. Eur. J. Org. Chem. 2004, 3833.
(7) Erdik, E. Tetrahedron 1984, 40, 641.
(8) Kocienski, P.; Wadman, S.; Cooper, K. J. Am. Chem. Soc. 1989, 111,
2363.
(9) Breit, B.; Schmidt, Y. Chem. Rev. 2008, 108, 2928.
(10) Ortiz, R.; Yus, M. Tetrahedron 2005, 61, 1699.
(11) Haubrich, A.; van Klaveren, M.; van Koten, G.; Handke, G.;
Krause, N. J. Org. Chem. 1993, 58, 5849.
(1) Clayden, J. Organolithiums: Selectivity for Synthesis; Pergamon:
Oxford, 2002.
(2) Rappoport, Z.; Marek, I. The Chemistry of Organolithium Com-
pounds; Wiley: Chichester, 2004.
(3) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117.
(4) Uchiyama, M.; Nakamura, S.; Furuyama, T.; Nakamura, E.;
Morokuma, K. J. Am. Chem. Soc. 2007, 129, 13360.
(12) Pastor, I. M.; Yus, M. Tetrahedron 2001, 57, 2371.
(13) Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH:
Weinheim, 2002.
(14) The Chemistry of Organocopper Compounds; Rappoport, Z., Marek,
I., Eds.; Wiley: Chichester, 2009.
DOI: 10.1021/jo100415x
r
Published on Web 05/14/2010
J. Org. Chem. 2010, 75, 4069–4077 4069
2010 American Chemical Society

Coldham and Leonori
JOCArticle
SCHEME 1. Related Results by Dieter and Co-workers (Boc =
CO2 Bu)
TABLE 1. Screen of Copper(I) Salts for Allylation
t
entry
Cu(I) salt
CuCN 2LiCl
CuCl
yield (%)
1
2
3
4
5
52
35
41
39
67a
3
CuBr SMe2
3
CuI
ZnCl2 then CuCN 2LiCl
3
a38% yield using diethyl allyl phosphate.
SCHEME 3. Zinc-copper-Based Reactions of N-Boc-2-
lithiopiperidine
SCHEME 2. Formation of N-Boc-2-allylpiperidine 2a
Recently, we showed that N-Boc-2-lithiopiperidine reacts
with electrophiles either directly or via transmetalation to the
corresponding organozinc reagent.27-30 In order to expand
the range of electrophiles amenable to this versatile reagent,
we decided to study various copper(I) salts and electrophiles.
We hoped to find a system that would allow regioselective
allylation and reaction, using an enantioenriched organo-
lithium, without loss of enantioselectivity. The results of
these efforts are described in this paper, together with the
application of this chemistry to the synthesis of a selection of
simple 2-substituted pyrrolidine- and piperidine-containing
natural products.
The organolithiums formed by deprotonation in the 2-
position of N-tert-butoxycarbonyl-2-lithiopyrrolidine (N-Boc-
pyrrolidine) and N-Boc-piperidine with sec-BuLi/TMEDA,
developed by Beak and co-workers,15 are important reagents
due to the presence of pyrrolidines and piperidines in many
natural products and pharmaceutical compounds.16-18 Addi-
tion of these organolithiums to allyl halides results in low
yields (if any) of the 2-allylated cyclic amine products.
However, Dieter and co-workers have reported the transme-
talation of N-Boc-2-lithiopyrrolidine and N-Boc-2-lithiopi-
Results and Discussion
peridine with CuCN 2LiCl and have studied the reactivity of
Initially, we chose N-Boc-2-lithiopiperidine as the nucleo-
phile and studied a selection of conditions for allylation.26,31-33
The results of addition of various Cu(I) salts to this organo-
lithium followed by allyl bromide are shown in Scheme 2 and
3
these cuprate reagents with a range of different electro-
philes.19-24 Addition of allyl bromide or propargyl bromide
to the dialkylcopper lithium species generated from enantio-
merically enriched N-Boc-2-lithiopyrrolidine [enantiomer
ratio (er) ∼97:3 (S/R), formed by asymmetric deprotonation
Table 1. The use of CuCN 2LiCl (1.1 equiv in comparison
3
with the organolithium) gave the desired compound 2a in
52% yield (yield based on the piperidine 1). With copper
halides, inferior results were obtained. Organozinc cuprates
have been shown to be good nucleophiles,34-37 and we were
pleased to find an increase in the yield of 2a when ZnCl2 was
with sec-BuLi/(-)-sparteine]25 and CuCN 2LiCl (0.5 equiv)
3
gave, respectively, N-Boc-2-allylpyrrolidine with some loss
of enantiopurity (er 89:11) or N-Boc-2-allenylpyrrolidine
with more significant loss of enantiopurity (er 75:25)
(Scheme 1).26 No substituted allyl halides were reported, so
the regioselectivity issue was not addressed. In addition, no
allylation reactions (racemic or asymmetric) have been re-
ported with N-Boc-2-lithiopiperidine.
added prior to CuCN 2LiCl (Table 1, entry 5). Lower yields
3
of the product 2a were obtained using substoichiometric
amounts of CuCN 2LiCl or using diethyl allyl phosphate
3
instead of allyl bromide as the electrophile.
Based on these preliminary results, we developed the strategy
illustrated in Scheme 3. Deprotonation of N-Boc-piperidine
(15) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109.
(16) Rubiralta, M.; Giralt, E.; Diez, A. Piperidine: Structure, Preparation,
Reactivity and Synthetic Applications of Piperidine and Its Derivatives; Else-
vier: Amsterdam, 1991.
(27) Coldham, I.; Patel, J. J.; Raimbault, S.; Whittaker, D. T. E. Chem.
Commun. 2007, 4534.
(17) O’Hagan, D. Nat. Prod. Rep. 2000, 435.
(18) Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693.
(19) Dieter, R. K.; Lu, K. J. Org. Chem. 2002, 67, 847.
(20) Li, S. J.; Dieter, R. K. J. Org. Chem. 2003, 68, 969.
(21) Dieter, R. K.; Chen, N.; Yu, H.; Nice, L. E.; Gore, V. K. J. Org.
Chem. 2005, 70, 2109.
(22) Dieter, R. K.; Sharma, R. R. Tetrahedron Lett. 1997, 38, 5937.
(23) Dieter, R. K.; Topping, C. M.; Nice, L. E. J. Org. Chem. 2001, 66,
2302.
(28) Coldham, I.; O’Brien, P.; Patel, J. J.; Raimbault, S.; Sanderson, A. J.;
Stead, D.; Whittaker, D. T. E. Tetrahedron: Asymmetry 2007, 18, 2113.
(29) Coldham, I.; Raimbault, S.; Chovatia, P. T.; Patel, J. J.; Leonori, D.;
Sheikh, N. S.; Whittaker, D. T. E. Chem. Commun. 2008, 4174.
(30) Coldham, I.; Leonori, D. Org. Lett. 2008, 10, 3923.
(31) Dieter, R. K.; Velu, S. E.; Nice, L. E. Synlett 1997, 1114.
(32) Dieter, R. K.; Gore, V. K.; Chen, N. Org. Lett. 2004, 6, 763.
(33) Stead, D.; O’Brien, P.; Sanderson, A. J. Org. Lett. 2005, 7, 4459.
(34) Papillon, J. P. N.; Taylor, R. J. K. Org. Lett. 2002, 4, 119.
(35) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390.
(24) Dieter, R. K.; Lu, K.; Velu, S. E. J. Org. Chem. 2000, 65, 8715.
(25) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc. 1994, 116,
3231.
(26) Dieter, R. K.; Oba, G.; Chandupatla, C.; Topping, C. M.; Lu, K.;
Watson, R. T. J. Org. Chem. 2004, 69, 3076.
(36) Yus, M.; Gomis, J. Eur. J. Org. Chem. 2003, 2043.
(37) Dieter, R. K.; Watson, R. T.; Goswami, R. Org. Lett. 2004, 6, 253.
4070 J. Org. Chem. Vol. 75, No. 12, 2010

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TABLE 3. Racemic Reactions of N-Boc-2-lithiopiperidinea
TABLE 2. Racemic Reactions of N-Boc-2-lithiopiperidinea
aConditions as shown in Scheme 4. bdr 1:1.
SCHEME 5. Zinc-Copper-Promoted Reactions of N-Boc-2-
lithiopyrrolidine
aConditions as shown in Scheme 3. b2c dr 1:1. c2f dr 4:1. d2h dr 1:1.
eFor an alternative method, see Table 3.
SCHEME 4. Copper Iodide Promoted Reactions of N-Boc-2-
lithiopiperidine
This methodology was unsuccessful for reaction with alkyl
halides or with the classical Michael acceptors such as
acrylonitrile, cyclohexenone, or methyl propiolate. How-
ever, methyl acrylate gave the desired compound 2k in mod-
est yield. The addition of I2 to the organozinc reagent (no
copper salt) gave N-Boc-tetrahydropyridine 2q (Scheme 3) in
84% yield.
To study the problem of SN2/SN20 attack, we tested
different Cu(I) salts with prenyl bromide as the electrophile.
This was aided by the ease of purification of the regioiso-
in Et2O at -78 °C for 3 h using 1.2 equiv of TMEDA and 1.2
equiv of sec-BuLi was followed by addition of ZnCl2 (1.3
equiv) in THF then CuCN 2LiCl (1.2 equiv) in THF. After
3
30 min at -78 °C, the electrophile was added and the results
are summarized in Table 2. The reactions of this new mixed
zinc cuprate reagent with allyl bromides and chlorides
proceeded in good yields. Unfortunately, for unsymmetrical
allylic halides mixtures of SN2 and SN20 products were
usually obtained.38-41 The regioisomers from the reaction
with prenyl bromide (Table 2, entry 3) could be separated by
column chromatography. Interestingly, the use of 3-chloro-
but-1-ene and 1-bromobut-2-yne (Table 2, entries 6 and 7)
gave only the SN20 product (2b and 2i, respectively).
meric products (2d and 2e). The use of CuCN 2LiCl or CuCl
with or without ZnCl2, or CuTC,42 gave 1:1 mixtures of
regioisomers. The presence of additives BF3 OEt2 or TMSCl
3
3
also resulted in a mixture of isomers.43-46 We were pleased to
find, however, that the use of Cu(I) iodide TMEDA
3
complex47 (prepared from 1.1 equiv of CuI and 1.15 equiv
(42) Woodward, S. Angew. Chem., Int. Ed. 2005, 44, 5560.
(43) Sakata, H.; Kuwajima, I. Tetrahedron Lett. 1987, 28, 5719.
(44) Matsuzawa, S.; Horiguchi, Y.; Nakamura, E.; Kuwajima, I. Tetra-
hedron 1989, 45, 349.
(38) Goering, H. L.; Seitz, E. P.; Tseng, C. C. J. Org. Chem. 1981, 46,
5304.
(39) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1984, 25, 3063.
(40) Yoshikai, N.; Zhang, S.-L.; Nakamura, E. J. Am. Chem. Soc. 2008,
130, 12862.
(45) Yamamoto, Y. Angew. Chem., Int. Ed. 1986, 25, 947.
(46) Ibuka, T.; Tanaka, M.; Nishii, S.; Yamamoto, Y. J. Am. Chem. Soc.
1989, 111, 4864.
(41) Streitwieser, A.; Jayasree, E. G.; Hasanayn, F.; Leung, S. S.-H.
J. Org. Chem. 2008, 73, 9426.
(47) Taylor, R. J. K. Organocopper Reagents: A Practical Approach;
Oxford University Press: Oxford, 1994.
J. Org. Chem. Vol. 75, No. 12, 2010 4071

Coldham and Leonori
JOCArticle
TABLE 4. Asymmetric Reactions of N-Boc-2-lithiopyrrolidinea
aConditions as shown in Scheme 5. ber of each regioisomer 94:6. cer for 3d 95:5, for 3e 94:6.
of TMEDA in THF) with or without TMSCl as addit-
ive gave only the SN2 product (2d) in reasonable yield
(51-53%).
The additive TMSCl is often used to enhance reactions of
organocopper reagents, and although it may not be neces-
sary, we opted to include TMSCl in further allylations under
these conditions.48 It is not clear why the use of the organo-
diastereomers (Table 3, entry 5, dr 1:1). Using acrylonitrile, a
mixture (ratio 2:1) of the protonated 2m and silylated 2n
conjugate addition products was isolated. Methyl acrylate
was a suitable electrophile, and the reaction provided the
desired addition product 2k in good yield (74%). This yield
was a significant improvement over that obtained using the
zinc cuprate reagent (Table 2, entry 8) or using the dialkyl-
copper lithium species (which requires 2 equiv of the
organolithium).24 The reaction with methyl propiolate gave
the trans isomer 2o in good yield, together with a small
amount of the ketene 2p (single diastereomer by NMR
spectroscopy).
A significant aspect of this chemistry that needs addressing
is the extent of asymmetric induction using the enantiomeri-
cally enriched organometallic species. This was probed for
both N-Boc-2-lithiopyrrolidine and N-Boc-2-lithiopiperi-
dine. Enantiomerically enriched N-Boc-2-lithiopyrrolidine
(er ∼97:3) can be prepared by asymmetric deprotonation
using the methodology of Beak and co-workers using sec-
butyllithium and (-)-sparteine.25 This procedure is not
amenable to the corresponding six-membered ring.28,50,51
However, we have previously found that dynamic resolution
of the organolithium under thermodynamic control in the
presence of a diaminoalkoxide ligand can provide good
levels of asymmetric induction after electrophilic quench
(er ∼85:15 using ligand 4).29,52 We therefore used these
copper reagent derived from using CuI TMEDA should be
3
more regioselective, although a π-allyl CuIII intermediate,
which has been shown to favor SN2 reaction, may be
involved.49 Using these reaction conditions, the same types
of electrophiles were tested (Scheme 4, Table 3). The use of
crotyl bromide or cinnamyl bromide gave only the SN2
products (entries 2 and 4), in accordance with the result
using prenyl bromide. In general, the yields of the allyla-
ted products (2a, 2b, 2d, 2g) were slightly lower than those
using the zinc-copper method given in Scheme 3; however,
only a single regioisomer was observed in each case using the
copper iodide TMEDA complex. The generation of N-Boc-
2-lithiopiperidine by tin-lithium exchange27 gave an impro-
vement in terms of the yield of the allylated product (e.g., 2g,
68%) without altering the regioselectivity. In addition to
regioselective reaction with allyl bromides, we were pleased
to find that this new organocuprate reagent reacted with
various Michael acceptors. With cyclohexenone, the trime-
thylsilyl enol ether 2l was formed in good yield as a mixture of
(48) Linderman, R. J.; Griedel, B. D. J. Org. Chem. 1991, 56, 5491.
(49) Bartholmew, E. R.; Bertz, S. H.; Cope, S.; Murphy, M.; Ogle, C. A.
J. Am. Chem. Soc. 2008, 130, 11244.
(50) Bailey, W. F.; Beak, P.; Kerrick, S. T.; Ma, S.; Wiberg, K. B. J. Am.
Chem. Soc. 2002, 124, 1889.
(51) McGrath, M. J.; Bilke, J. L.; O’Brien, P. Chem. Commun. 2006, 2607.
4072 J. Org. Chem. Vol. 75, No. 12, 2010

Coldham and Leonori
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SCHEME 6. Copper Iodide Promoted Prenylation of N-Boc-2-
lithiopyrrolidine
SCHEME 7. Asymmetric Allylation of N-Boc-2-lithiopiperidine
processes to test the ability to form the enantiomerically
enriched 2-allylpyrrolidines and 2-allylpiperidines.
We were pleased to find that addition of zinc chloride then
CuCN 2LiCl to enantiomerically enriched N-Boc-2-lithio-
3
pyrrolidine (prepared using sec-butyllithium and (-)-
sparteine) followed by allyl bromide gave N-Boc-2-allylpyr-
rolidine with good yield and enantioselectivity (Scheme 5
and Table 4). This represents an improvement to the direct
desired N-Boc-2-allylpiperidine 2a in moderate yield and
with er 78:22. When CuCN 2LiCl alone (no zinc chloride)
3
was used, the product 2a was formed with er 71:29, and using
CuI TMEDA gave 2a with er 62:38. Hence, some loss of
3
addition of CuCN 2LiCl to the organolithium (which results
3
enantiopurity occurs during this process, but proceeding
through the zinc-copper complex can minimize the loss.
In the same way, dynamic resolution of N-Boc-2-lithio-
piperidine with ligand 4, followed by formation of the
zinc-copper complex and addition of prenyl bromide, gave
the products 2d and 2e (39% yield) in a ratio of 1.5:1. The
enantiomer ratio of the SN2 product 2d was determined by
chiral GC analysis (er 74:26). Using 3-chlorobut-1-ene, only
the SN20 product 2b was formed (31% yield), but as a mixture
of E and Z isomers (E:Z 63:37), with enantiomer ratios E-2b
er 79:21 and Z-2b er 73:27. With the electrophile 1-bromo-2-
butyne, the product 2i was formed (29% yield) with an ena-
ntiomer ratio 79:21.
in some loss of enantiopurity, Scheme 1). The chemistry was
suitable for a selection of allyl halide electrophiles to give
products 3a-g (Table 4). Using the unsymmetrical electro-
phile prenyl bromide, a mixture of regioisomeric products
(3b and 3c) was formed, each with high enantioselectivity.
Using 3-chlorobut-1-ene and propargyl halides resulted in
only the SN20 products (entries 3-5), also with high enantio-
selectivity. In each case, the enantiomer ratio was determined
by chiral GC analysis. The major enantiomer for the product
3a (and by analogy for the products 3b-g) is that shown ((R)-
N-Boc-2-allylpyrrolidine) (vide infra) and is derived from the
known S-N-Boc-2-lithiopyrrolidine by reaction with reten-
tion of configuration. Unfortunately, the electrophile methyl
acrylate gave the product 3h as a racemic mixture (entry 6).
This is, however, in line with that found by Dieter and co-
workers without the ZnCl2.26
Dynamic resolution of N-Boc-2-lithiopiperidine with lig-
and 4 followed by formation of the zinc-copper species and
electrophilic quench with 2-(chloromethyl)allyltrimethylsilane
gave the product 2j (34% yield, er 77:23); however, methyl
acrylate gave none of the product 2k. Using methyl propio-
late as the electrophile gave the desired product 2o (31%
yield) but with zero optical rotation [lit.53 for S-enantiomer:
[R]D -90.1 (1.0, CHCl3)], suggesting that the racemic pro-
duct had been formed.
Addition of copper iodide TMEDA complex to (S)-N-
Boc-2-lithiopyrrolidine gave good selectivity for the SN2
products, but with some reduction in the enantiomer ratio.
Hence, addition of prenyl bromide to this enantioenriched
organocopper species gave predominantly the product 3b
with er 85:15 (Scheme 6). Use of allyl bromide gave 3a with er
82:18, suggesting that the zinc-copper method (Scheme 5,
Table 4), was preferable to avoid loss of enantiopurity. With
the electrophile 3-chlorobut-1-ene only the SN20 products (3d
and 3e, ratio 62:38) were formed, each with low enantios-
electivity (er ∼57:43).
With the results described above in hand, we were keen to
demonstrate their use in total synthesis. Several simple
substituted cyclic amine alkaloids were targeted. Wacker
oxidation of the 2-allylpyrrolidine 3a (er 95:5) gave the
ketone 5 (Scheme 8). Synthesis of the ketone 5 represents a
formal synthesis of (þ)-pseudohygroline.54 The specific rota-
tion of 5, [R]21 þ29.5 (0.44, CHCl3), matched that in the liter-
In a similar way to the reactions of enantiomerically
enriched N-Boc-2-lithiopyrrolidine, we screened the extent
of asymmetric induction with N-Boc-2-lithiopiperidine.
Using ligand 4, enantiomerically enriched S-N-Boc-2-lithio-
piperidine was formed by dynamic resolution under thermo-
dynamic control (er 85:15).29,52 This was achieved by
deprotonation of N-Boc-piperidine (1), addition of ligand 4
(which was prepared from the alcohol by deprotonation with
sec-butyllithium), and equilibration at -30 °C for 1 h
(Scheme 7). The mixture was cooled to -78 °C, and then
zinc chloride and copper cyanide-lithium chloride complex
in THF were added. Addition of allyl bromide gave the
ature,54 [R]23 D þ31.6 (2.5, CHCl3), thereby demonstrating
D
that the allylation of S-N-Boc-2-lithiopyrrolidine occurs with
retention of configuration. Acid-promoted removal of the
N-Boc group gave (remarkably) the first total synthesis of
the natural product (-)-norhygrine (as its trifluoracetate
salt) using only three steps from commercial N-Boc-pyr-
rolidine.55,56 In addition to the synthesis of (-)-norhygrine,
ꢀ
ꢀ
(53) Sanchez-Sancho, F.; Herradon, B. Tetrahedron: Asymmetry 1998, 9,
1951.
(54) Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Smith, A. D.
Tetrahedron 2009, 65, 10192.
(55) Pomilio, A. B.; Gonzalez, M. D.; Eceizabarrena, C. C. Phytochem-
istry 1996, 41, 1393.
(56) Baxter, G.; Melville, J. C.; Robins, D. J. Synlett 1991, 359.
(52) Coldham, I.; Raimbault, S.; Whittaker, D. T. E.; Chovatia, P. T.;
Leonori, D.; Patel, J. J.; Sheikh, N. S. Chem. Eur. J. 2010, 16, 4082.
J. Org. Chem. Vol. 75, No. 12, 2010 4073

Coldham and Leonori
SCHEME 9. Synthesis of 2-Butyl-5-propylpyrrolidinesa
JOCArticle
SCHEME 8. Synthesis of Norhygrine and Coniceinea
aKey: (i) s-BuLi, Et2O, (-)-sparteine, -78 °C, 6 h, then ZnCl2, THF,
then CuCN 2LiCl, THF, then allyl bromide, 3a 81%, er 95:5; (ii) PdCl2,
3
CuCl2, DMF, H2O, heat, 2 h, 56%; (iii) TFA, CH2Cl2, rt, 100%; (iv) H2
(35 bar), CO (35 bar), ByPhePhos, dicarbonylacetylacetonato rhodium-
(I), THF, 60 °C, 24 h, 89%; (v) TFA, CH2Cl2 rt, then H2 (10 bar),
Pd(OH)2, MeOH, rt, 24 h, 67%.
aKey: (i) s-BuLi, Et2O, (-)-sparteine, -78 °C, 6 h, then ZnCl2, THF,
then CuCN 2LiCl, THF, then allyl bromide, 3a 81%, er 95:5; (ii) PtO2,
H2 (10 bar), MeOH, rt, 24 h, 87%; (iii) s-BuLi, TMEDA, Et2O, -78 °C,
3
3 h, then ZnCl2, THF, then CuCN 2LiCl, THF, then 3-chlorobut-1-ene,
3
we carried out hydroformylation of the 2-allylpyrrolidine 3a
(er 95:5) to give the aldehyde 6 (Scheme 8).57 Removal of the
N-Boc group with trifluoroacetic acid followed directly by
hydrogenation over palladium hydroxide gave (þ)-coni-
ceine.53,58-60 The spectroscopic data matched those in the
32%, dr 1.8:1 (trans/cis); (iv) PtO2, H2 (10 bar), MeOH, rt, 24 h, 96%; (v)
TFA, CH2Cl2, rt, 100%.
N-Boc group gave the desired trans- and cis-2-butyl-5-pro-
pylpyrrolidines (10 and 11) as their trifluoroacetate salts,
which were washed with NaOH to give the free bases. The
trans and cis isomers 10 and 11 were separated by column
chromatography. This approach represents the first asym-
metric synthesis of these alkaloids. The major isomer (trans)
(10) was assigned by analogy of the NMR spectra to related
trans- and cis-disubstituted pyrrolidines.63 The absolute
configurations are expected to be those shown in Scheme 9,
although the absolute configurations of the natural products
are unknown.
literature, including the specific rotation [R]21 þ9.1 (1.15,
D
EtOH), which compared well with the value reported in the
literature,61 [R]23D þ9.3 (1.77, EtOH).
Recently, several new alkaloids including both trans- and
cis-2-butyl-5-propylpyrrolidine (10 and 11, respectively)
were isolated from extracts of the ant Myrmicaria melano-
gaster.62 The authors state that one enantiomer was pre-
sumed to be naturally occurring (although no specific rotation
data was recorded) and these compounds have been pre-
pared only as their racemates.62 An asymmetric synthesis of
one enantiomer of each diastereomer was devised, as shown
in Scheme 9. Zinc-copper-promoted allylation of (S)-N-
Boc-2-lithiopyrrolidine gave the 2-allylpyrrolidine 3a (er
95:5) (see Scheme 5). Reduction of the alkene gave N-Boc-
2-propylpyrrolidine (7). A second metalation (with sec-bu-
tyllithium and TMEDA) followed by zinc-copper-promoted
allylation with 3-chlorobut-1-ene gave the pyrrolidines 8 as a
mixture of stereoisomers. Only the SN20 allylation product
was formed. Recovered starting material 7 was obtained on
attempted use of sec-butyllithium and (-)-sparteine (in place
of TMEDA) for this second metalation. Hydrogenation of
the alkene gave the pyrrolidines 9. No loss of enantioselec-
tivity should occur during the metalation-quench process,
and the stereoisomers of the products should have high er.
Chiral GC analysis of the mixture of stereoisomers of the 2,5-
disubstituted pyrrolidines 9 showed that the major (trans)
diastereomer had er 97:3 (the minor diastereomer did
not resolve on a β-cyclodextrin GC column). Removal of the
The syntheses of (-)-norhygrine, (þ)-coniceine, and trans-
and cis-2-butyl-5-propylpyrrolidine illustrate the versatility
of enantioenriched N-Boc-2-allylpyrrolidine. In a similar way,
N-Boc-2-allylpiperidine was converted to two natural pro-
ducts (Scheme 10). Dynamic resolution under thermody-
namic control of N-Boc-2-lithiopiperidine followed by
zinc-copper-promoted allylation with allyl bromide
gave enantioenriched N-Boc-2-allylpiperidine (2a), er 78:22
(Scheme 7). Hydrogenation of the alkene gave the piperidine
12, and removal of the N-Boc group gave the alkaloid (þ)-
coniine.60,64-69 This was formed in high yield without loss of
enantiopurity, as judged by its specific rotation [R]23D þ4.2
(1.2, EtOH) which compared well with the literature,68 [R]25
D
þ7.4 (1.0, EtOH). Although the enantiomer ratio (er 78:22) is
not very high, this represents an extremely short (three-step)
asymmetric synthesis of this alkaloid. Alternatively, Wacker
oxidation of the allylpiperidine 2a gave the ketone 13 (which
€
(63) Backvall, J.-E.; Schink, H. E.; Renko, Z. D. J. Org. Chem. 1990, 55,
826.
(64) Hande, S. M.; Kawai, N.; Uenishi, J. J. Org. Chem. 2009, 74, 244.
(65) Lauzon, S.; Tremblay, F.; Gagnon, D.; Godbout, C.; Chabot, C.;
Mercier-Shanks, C.; Perreault, S.; DeSeve, H.; Spino, C. J. Org. Chem. 2008,
73, 6239.
(57) Cuny, G. D.; Buchwald, S. L. Synlett 1995, 519.
(58) Hjelmgaard, T.; Gardette, D.; Tanner, D.; Aitken, D. J. Tetrahedron:
Asymmetry 2007, 18, 671.
(59) Dieter, R. K.; Chen, N.; Watson, R. T. Tetrahedron 2005, 61, 3221.
(60) Takahata, H.; Kubota, M.; Takahashi, S.; Momose, T. Tetrahedron:
Asymmetry 1996, 7, 3047.
(61) Ringdahl, B.; Pinder, A. R.; Pereira, W. E.; Oppenheimer, N. J.;
Craig, J. C. J. Chem. Soc., Perkin Trans. 1 1984, 1.
(62) Jones, T. H.; Voegtle, H. L.; Miras, H. M.; Weatherford, R. G.;
Spande, T. F.; Garraffo, H. M.; Daly, J. W.; Davidson, D. W.; Snelling, R. R.
J. Nat. Prod. 2007, 70, 160.
(66) Castro, A.; Ramirez, J.; Juarez, J.; Teran, J. L.; Orea, L.; Galindo,
A.; Gnecco, D. Heterocycles 2007, 71, 2699.
(67) Etxebarria, J.; Vicario, J. L.; Badia, D.; Carrillo, L. Tetrahedron
2007, 63, 11421.
(68) Fustero, S.; Jimenez, D.; Moscardo, J.; Catalan, S.; del Pozo, C. Org.
Lett. 2007, 9, 5283.
(69) Lebrun, S.; Couture, A.; Deniau, E.; Grandclaudon, P. Org. Lett.
2007, 9, 2473.
4074 J. Org. Chem. Vol. 75, No. 12, 2010

Coldham and Leonori
JOCArticle
SCHEME 10. Synthesis of Coniine and Pelletierinea
of peaks. Low and high resolution (accurate mass) mass spectra
were recorded using electrospray (ES).
General Procedure with Racemic ZnCl2/CuCN 2LiCl
3
(Scheme 3, Table 2). s-BuLi (1.0 mL, 1.3 mmol, 1.3 M in cyclo-
hexane) was added to the carbamate 1 (200 mg, 1.08 mmol) and
TMEDA (0.19 mL, 1.3 mmol) in dry Et2O (4.2 mL) at -78 °C.
After 3 h, ZnCl2 (190 mg, 1.4 mmol) in dry THF (1.7 mL) was
added over 10 min. After 30 min, a solution of CuCN (115 mg,
1.3 mmol) and LiCl (109 mg, 2.6 mmol, dried at 130 °C for 48 h)
in dry THF (4.3 mL) was added rapidly. The mixture was stirred
at -78 °C for 30 min, and the electrophile (3.24 mmol) was
added dropwise (if liquid) or as a 1.0 M solution in dry THF (if
solid). The mixture was allowed to warm to room temperature
slowly, and NH4OH (10 mL, 10% aqueous) was added. Et2O
(10 mL) was added, and the mixture was stirred for 20 min.
The organic layer was washed with brine, dried (Na2SO4),
filtered, and evaporated. The residue was purified by column
chromatography.
aKey: (i) Pd(OH)2, H2 (1 atm), MeOH, rt, 24 h, 84%; (ii) TFA, CH2Cl2,
rt, then NaOH, 100%; (iii) PdCl2, CuCl2, DMF, H2O, heat, 2 h, 53%;
(iv) HCl, dioxane, rt, 100%.
General Procedure with Racemic CuI TMEDA (Scheme 4,
3
represents a formal synthesis of (þ)-allosedridine and
(þ)-lasubine II).54,70 Acid-promoted removal of the N-Boc
group gave (-)-pelletierine as its HCl salt. The specific rotation
of (-)-pelletierine, [R]23D -9.2 (1.2, EtOH), matched that for
the HCl salt in the literature,71 [R]21D -18.0 (0.5, EtOH).
Table 3). s-BuLi (1.0 mL, 1.3 mmol, 1.3 M in cyclohexane) was
added to the carbamate 1 (200 mg, 1.08 mmol) and TMEDA
(0.19 mL, 1.3 mmol) in dry Et2O (4.2 mL) at -78 °C. After 3 h,
CuI (230 mg, 1.19 mmol) and TMEDA (0.19 mL, 1.24 mmol) in
dry THF (4.2 mL) were added over 10 min. The mixture was
stirred at -78 °C for 1 h, and then TMSCl (0.41 mL, 3.24 mmol)
was added rapidly. After 10 min, the electrophile (3.24 mmol)
was added dropwise (if liquid) or as a 1.0 M solution in dry THF
(if solid). The mixture was allowed to warm to room tempera-
ture slowly, and NH4OH (10 mL, 10% aqueous) was added.
Et2O (10 mL) was added, and the mixture was stirred for 20 min.
The organic layer was washed with brine, dried (Na2SO4),
filtered, and evaporated. The residue was purified by column
chromatography.
Conclusions
We have extended the reactivity of N-Boc-2-lithiopyrroli-
dine and N-Boc-2-lithiopiperidine to, in particular, allylic
halides. Transmetalation with ZnCl2/CuCN 2LiCl allows
3
subsequent reaction with allyl halides with good yields and
enantioselectivities, but mixtures of regiosiomers using un-
symmetrical allyl halides. Transmetalation with CuI TME-
3
General Procedure with ZnCl2/CuCN 2LiCl Asymmetric
3
DA provides high regioselectivity for the SN2 product for
unsymmetrical halides but with some loss of enantiopu-
rity. The chemistry has been applied to short total syntheses
of the natural products (-)-norhygrine, (þ)-coniceine,
trans- and cis-2-butyl-5-propylpyrrolidine, (þ)-coniine, and
(-)-pelletierine.
N-Boc-pyrrolidine (Scheme 5, Table 4). s-BuLi (1.2 equiv) was
added dropwise to a 0.25 M solution of (-)-sparteine (1.2 equiv)
in dry Et2O at -78 °C. After 30 min, N-Boc-pyrrolidine
(1.0 equiv) was added. After 6 h, a 0.8 M solution of ZnCl2
(1.3 equiv) in dry THF was added over 10 min. After 30 min, a
0.3 M solution of CuCN (1.2 equiv) and LiCl (2.4 equiv, dried at
130 °C for 48 h) in dry THF was added rapidly. The mixture was
stirred at -78 °C for 30 min, and the electrophile (3.0 equiv) was
added dropwise (if liquid) or as a 1.0 M solution in dry THF
(if solid). The mixture was allowed to warm slowly to room
temperature, and NH4OH (10 mL, 10% aqueous) was added.
Et2O (10 mL) was added, and the mixture was stirred for 20 min.
The organic layer was washed with brine, dried (Na2SO4),
filtered, and evaporated. The residue was purified by column
chromatography.
Experimental Section
General Experimental Methods. All reagents were obtained
from commercial suppliers and were used without further
purification unless otherwise specified. TMEDA and (-)-spar-
teine were freshly distilled from CaH2. The ligand 4 was
prepared according to a known procedure and was distilled
prior to use.29 ZnCl2, CuCN, LiCl, and CuI were flame-dried
under vacuum before use. s-BuLi was titrated before use. All of
the electrophiles were distilled prior to use. Thin-layer chroma-
tography was performed on silica plates and visualized by UV
irradiation at 254 nm or by staining with an alkaline KMnO4
dip. Column chromatography was performed using silica gel
(40-63 μm mesh). Infrared spectra were recorded on a Fourier
transform IR system. Only selected peaks are reported, and
General Procedure with CuI TMEDA Asymmetric N-Boc-
3
pyrrolidine (Scheme 6). s-BuLi (1.2 equiv) was added dropwise
to a 0.25 M solution of (-)-sparteine (1.2 equiv) in dry Et2O at
-78 °C. After 30 min, N-Boc-pyrrolidine (1.0 equiv) was added.
After 6 h, a 0.3 M solution of CuI (1.1 equiv) and TMEDA (1.15
equiv) in dry THF was added over 10 min. The mixture was
stirred at -78 °C for 1 h, and then TMSCl (3.0 equiv) was added
rapidly. After 10 min, the electrophile (3.0 equiv) was added
dropwise (if liquid) or as a 1.0 M solution in dry THF (if solid).
The mixture was allowed to warm slowly to room temperature,
and NH4OH (10 mL, 10% aqueous) was added. Et2O (10 mL)
was added, and the mixture was stirred for 20 min. The organic
layer was washed with brine, dried (Na2SO4), filtered, and eva-
porated. The residue was purified by column chromatography.
1
absorption maxima are given in cm-1. H NMR spectra were
recorded at 400 MHz. Chemical shifts are reported in ppm with
respect to the residual solvent peaks, with multiplicities given as
s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet,
br = broad. Coupling constants, J, are quoted to the nearest
0.5 Hz. 13C NMR were recorded at 100 MHz; 1H-1H and
1H-13C correlation spectra were run to confirm the assignment
General Procedure with ZnCl2/CuCN 2LiCl Asymmetric
3
N-Boc-piperidine (Scheme 7). N-Boc-piperidine (1.0 equiv) and
TMEDA (1.2 equiv) in dry Et2O (6 mL) were treated with
s-BuLi (1.2 equiv) at -78 °C. After 3 h, the deprotonated ligand
4 [prepared by adding s-BuLi (1.25 equiv) to a 0.25 M solution of
(70) Cheng, G.; Wang, X.; Su, D.; Liu, H.; Liu, F.; Hu, Y. J. Org. Chem.
2010, 75, 1911–1916.
(71) Carlson, E. C.; Rathbone, L. K.; Yang, H.; Collett, N. D.; Carter,
R. G. J. Org. Chem. 2008, 73, 5155.
J. Org. Chem. Vol. 75, No. 12, 2010 4075

Coldham and Leonori
JOCArticle
the prolinol29 (1.2 equiv) in Et2O at 0 °C for 30 min] was added.
The mixture was warmed to -30 °C. After 1 h, the mixture was
cooled to -78 °C, and a 0.8 M solution of ZnCl2 (1.3 equiv) in
dry THF was added over 10 min. After 30 min, a 0.3 M solution
of CuCN (1.2 equiv) and LiCl (2.4 equiv, dried at 130 °C for
48 h) in dry THF was added rapidly. After 30 min, the electro-
phile (3.0 equiv) was added dropwise (if liquid) or as a 1.0 M
solution in dry THF (if solid). The mixture was allowed to warm
slowly to room temperature, and NH4OH (10 mL, 10% aqu-
eous) was added. Et2O (10 mL) was added, and the mixture was
stirred for 20 min. The organic layer was washed with brine,
dried (Na2SO4), filtered, and evaporated. The residue was puri-
fied by column chromatography.
δ =203.4 and 202.9, 155.8, 80.8 and 79.6, 57.1, 46.7 and 46.3,
44.0, 35.5 and 34.8, 32.1 and 29.2, 28.8, 24.0 and 23.3, 19.1;
HRMS (ES) found MHþ, 242.1766, C13H24NO3 requires MHþ
242.1756; LRMS m/z (ES) 186 (100), 242 (MHþ, 10), 264
(MNaþ, 10).
(þ)-Coniceine. Trifluoroacetic acid (0.9 mL, 12.0 mmol) was
added to the carbamate 6 (300 mg, 1.2 mmol) in CH2Cl2 (12 mL)
at room temperature. After 3 h, the solvent was evaporated, dry
MeOH (5 mL) and Pd(OH)2 (30 mg) were added, and the
mixture was stirred under an atmosphere of H2 (10 bar) at room
temperature. After 24 h, the suspension was filtered on Celite,
and the solvent was evaporated to give (þ)-δ-coniceine (102 mg,
67%) as an oil: [R]21D þ9.1 (1.15, EtOH) [lit.61 [R]23D þ9.3 (1.77,
EtOH)]; 1H NMR (400 MHz, CDCl3) δ=3.16-2.87 (2H, m, 2ꢀ
CH), 2.08-1.90 (2H, m, 2 ꢀ CH), 1.87-1.59 (8H, m, 8 ꢀ CH),
1.54-1.29 (3H, m, 3 ꢀCH); 13C NMR (100 MHz, CDCl3) δ=
63.5, 61.1, 53.3, 27.1, 23.9, 21.0, 19.4, 18.5. Data as reported.53,58
tert-Butyl 2-Propylpyrrolidine-1-carboxylate 7. PtO2 (50 mg)
was added to the carbamate (R)-3a (1.0 g, 4.8 mmol) in dry
MeOH (150 mL), and the mixture was stirred under an atmo-
sphere of H2 (10 bar) at room temperature. After 24 h, the
suspension was filtered on Celite, and the solvent was evapo-
tert-Butyl 2-(2-Oxopropyl)pyrrolidine-1-carboxylate 5. To a
stirred solution of carbamate (R)-3a (er 95:5) (250 mg, 1.2 mmol)
in DMF (17 mL) and H2O (8 mL) were added PdCl2 (21 mg.
0.1 mmol) and CuCl2 (350 mg, 2.6 mmol). The dark green solu-
tion was heated under reflux for 2 h and then cooled to room
temperature. H2O (100 mL) was added, the mixture was ex-
tracted with Et2O (5 ꢀ 100 mL), and the organic layers were
washed with H2O (3 ꢀ 100 mL) and brine (100 mL), dried
(Na2SO4), filtered, and evaporated to give carbamate 5 (150 mg,
56%) as an oil: [R]21 þ29.5 (0.44, CHCl3) [lit.54 [R]21 þ31.6
rated to give the carbamate 7 (880 mg, 87%) as an oil: [R]21
D
D
D
(2.5, CHCl3)]; Rf 0.43 [petroleum ether-EtOAc (95:5)]; 1H
NMR (400 MHz, CDCl3, rotamers) δ = 4.13-3.90 (1H, m,
CH), 3.33-3.10 (2H, m, 2 ꢀ CH), 3.08-2.91 (0.6H, m, CH),
2.87-2.70 (0.4H, m, CH), 2.39-2.19 (1H, m, CH), 2.01 (3H, s,
CH3), 1.93 (1H, dd, J 12, 8 Hz, CH), 1.68 (2H, t, J 7 Hz, CH2),
1.57-1.42 (1H, m, CH), 1.32 (9H, s, t-Bu); 13C NMR (100 MHz,
CDCl3, rotamers) δ = 207.2 and 207.0, 154.2, 79.0, 53.3, 48.5
and 47.7, 46.4 and 45.9, 31.4 and 30.7, 30.4 and 30.2, 28.4, 23.4
and 22.7; HRMS (ES) found MHþ 228.1605, C12H22NO3
requires MHþ 228.1600; LRMS m/z (ES) 228 (100). Data as
reported.54
þ45.6 (0.46, CHCl3) [lit.72 [R]20 -34.1 (1.1, CHCl3)]; Rf 0.43
D
[petroleum ether-EtOAc (95:5)]; 1H NMR (400 MHz, CDCl3)
δ = 3.88-3.60 (1H, m, CH), 3.55-3.06 (2H, m, 2 ꢀ CH),
1.99-1.71 (4H, m, 2 ꢀ CH2), 1.70-1.56 (1H, m, CH), 1.46
(9H, s, t-Bu), 1.39-1.18 (3H, m, CH and CH2), 0.92 (3H, t,
J 7 Hz, CH3); 13C NMR (100 MHz, CDCl3, rotamers) δ=154.6,
78.8, 56.9, 46.4 and 45.0, 36.9 and 36.3, 30.6 and 29.8, 28.5, 23.0,
19.5, 14.1; HRMS (ES) found MHþ 214.1806, C12H24NO2
1
requires MHþ 214.1807; LRMS m/z (ES) 214 (100). H NMR
data as reported.72
tert-Butyl 2-[(E)-But-2-enyl)]-5-propylpyrrolidine-1-carboxy-
late and tert-Butyl 2-[(Z)-But-2-enyl]-5-propylpyrrolidine-1-
carboxylate 8. Using the general procedure for Scheme 3,
carbamate 7 (880 mg, 4.1 mmol), TMEDA (0.75 mL, 4.9 mmol),
s-BuLi (3.8 mL, 4.9 mmol), ZnCl2 (730 mg, 5.4 mmol), CuCN
(440 mg, 4.9 mmol), LiCl (420 mg, 9.9 mmol), and 3-chloro-1-
butene (1.2 mL, 12.4 mmol) gave, after purification by chro-
matography on silica gel, eluting with petroleum ether-EtOAc
(97:3), the carbamates 8 (360 mg, 32%), E:Z 85:15, dr of each
(-)-Norhygrine Trifluoroacetate Salt. CF3CO2H (0.25 mL,
3.3 mmol) was added to carbamate 5 (75 mg, 0.3 mmol) in
CH2Cl2 (3.0 mL) at room temperature. After 2 h, the solvent was
removed under pressure to give norhygrine trifluoroacetate salt
(73 mg, 100%) as an oil: [R]21 -14.7 (0.54, CHCl3); Rf 0.43
D
[petroleum ether-EtOAc (95:5)]; IR νmax (film)/cm-1 3470,
2955, 2865, 1670, 1420, 1380, 1310, 1270, 1135; 1H NMR
(400 MHz, CDCl3) δ = 8.37 (1H, br s, NH), 8.10 (1H, br s,
NH), 4.02-3.74 (1H, m, CH), 3.51-3.23 (2H, m, 2 ꢀ CH),
3.09-2.93 (2H, m, CH2), 2.32-2.18 (1H, m, CH), 2.15 (3H, s,
geometrical isomer 1.8:1; data for this mixture: [R]21 þ35.2
D
(0.54, CHCl3); Rf 0.52 [petrol-EtOAc (95:5)]; IR νmax (film)/
cm-1 2960, 1700, 1390, 1365, 1170, 1110; 1H NMR (400 MHz,
CDCl3, diastereomers and rotamers) δ = 5.52-5.54 (0.15 H,
m, dCH), 5.39 (0.85H, dq, J 14.5, 6 Hz, dCH), 5.33-5.19 (1H,
m, CHd), 3.86-3.49 (2H, m, 2ꢀCH), 2.59-2.23 (1H, m, CH),
2.04-1.70 (4H, m, 2 ꢀ CH2), 1.69-1.47 (5H, m, CH and 2 ꢀ
CH2), 1.40 (9H, s, t-Bu), 1.32-1.03 (3H, m, CH3), 0.85 (3H, br
t, J 7 Hz, CH3); 13C NMR (100 MHz, CDCl3, diastereomers
and rotamers) δ=154.7 and 153.7, 127.9 and 127.7, 127.3, and
127.2 and 127.0, 126.6, 125.8 and 125.6, 78.6, 58.2 and 57.3,
57.5, and 57.4 and 57.2, 37.9 and 37.1, 36.2, and 35.7 and 34.9,
28.5, 27.4 and 27.0, 26.4 and 26.1, 19.9, and 19.8 and 19.5, 17.9,
14.1 and 13.9; HRMS (ES) found MHþ, 268.2278, C16H30NO2
requires MHþ 268.2277; LRMS m/z (ES) 268 (100%).
CH3), 2.09-1.87 (2H, m, 2ꢀCH), 1.83-1.55 (1H, m, CH); 13
C
NMR (100 MHz, CDCl3, rotamers) δ=208.0, 56.2, 45.9, 44.2,
29.6, 29.3, 23.1; HRMS (ES) found MHþ 128.1073, C7H14NO
requires MHþ 128.1070; LRMS m/z (ES) 128 (100). The only
literature data available is the mass spectrum.55
tert-Butyl 2-(4-Oxobutyl)pyrrolidine-1-carboxylate 6. Fol-
lowing a literature procedure,57 a pressure reaction vessel with
a pressure coupling closure complete with gas inlet, pressure
gauge, and pressure release valve was charged with a solution of
dicarbonylacetylacetonatorhodium(I) (8.0 mg, 0.54 mol %),
biphephos (28 mg, 0.56 mol %), and carbamate R-3a (er 95:5)
(1.2 g, 5.5 mmol) in THF (10 mL). The reaction vessel was
degassed three times, filled with CO/H2 (1:1 mixture, 70 bar),
and then heated to 60 °C. After 24 h, the vessel was cooled to
room temperature, the pressure was released, and the solution
was concentrated. Purification by column chromatography on
silica gel, eluting with petroleum ether-EtOAc (87:13) gave
carbamate 6 (1.2 g, 89%) as an oil: [R]21D þ40.0 (0.45, CHCl3);
Rf 0.27 [petroleum ether-EtOAc (95:5)]; IR νmax/cm-1 2970,
trans- and cis-tert-Butyl 2-Butyl-5-propylpyrrolidine-1-car-
boxylate 9. PtO2 (18 mg) was added to the carbamates 8 (180
mg, 0.7 mmol) in dry MeOH (22 mL), and the mixture was
stirred under an atmosphere of H2 (10 bar) at room temperature.
After 24 h, the suspension was filtered on Celite, and the solvent
was evaporated to give the carbamates 9 (174 mg, 96%) as an oil;
1725, 1675; H NMR (400 MHz, CDCl3, rotamers) δ = 9.73
dr 1.8:1. Data for the mixture of diastereomers: [R]21 þ41.2
1
D
(1H, br s, CHO), 4.07-3.87 (0.4H, m, NCH), 3.72-3.49 (0.6H,
m, NCH), 3.38-3.06 (2H, m, 2 ꢀ NCH), 2.43-2.27 (2H, m,
CH2), 1.96-1.64 (6H, m, 3 ꢀ CH2), 1.62-1.41 (2H, m, CH2),
1.39 (9H, s, t-Bu); 13C NMR (100 MHz, CDCl3, rotamers)
(0.53, CHCl3); Rf 0.52 [petroleum ether-EtOAc (95:5)]; IR νmax
(film)/cm-1 2940, 1690, 1410, 1275, 1155, 1035; 1H NMR (400 MHz,
(72) Blarer, D. J.; Seebach, D. Chem. Ber. 1983, 116, 2250.
4076 J. Org. Chem. Vol. 75, No. 12, 2010

Coldham and Leonori
JOCArticle
CDCl3) δ=3.80-3.63 (1.4H, m, 2ꢀCH), 3.63-3.52 (0.6H, m,
CH), 1.96-1.70 (3H, m, CH and CH2), 1.67-1.49 (3H, m, CH
and CH2), 1.41 (9H, s, t-Bu), 1.35-1.02 (6H, m, 3 ꢀ CH2),
0.93-0.77 (6H, m, 2 ꢀ CH3); 13C NMR (100 MHz, CDCl3,
diastereomers and rotamers) δ=154.9 and 153.8, 78.5, 58.3 and
58.1, 57.5, and 57.4 and 57.2, 38.2 and 36.1, 35.6 and 34.9, 33.6
and 32.4, 29.4 and 28.9, 28.5, 27.5 and 26.6, 22.7, 19.9 and 19.5,
14.1; HRMS (ES) found MHþ 270.2432, C16H31NO2 requires
MHþ 270.2433; LRMS m/z (ES) 270 (100).
trans-2-Butyl-5-propylpyrrolidine 10 and cis-2-Butyl-5-propyl-
pyrrolidine 11. CF3CO2H (0.4 mL, 5.6 mmol) was added to the
carbamates 9 (150 mg, 0.6 mmol) in CH2Cl2 (6.0 mL) at room
temperature. After 2 h, the solvent was evaporated to give the
mixture of pyrrolidines 10 and 11 (93 mg, 100%) as an oil. Data
for the mixture of natural product as their TFA salts: 1H NMR
(400 MHz, CDCl3) δ=9.31-8.70 (2H, m, 2ꢀNH), 3.78-3.28
(2H, m, 2 ꢀ CH), 2.26-2.04 (2H, m, CH2), 1.87-1.68 (3H, m,
CH and CH2), 1.67-1.48 (3H, m, CH and CH2), 1.42-1.18
(6H, m, 3 ꢀ CH2), 0.95-0.76 (6H, m, 3 ꢀ CH3); 13C NMR
(100 MHz, CDCl3, diastereomers) δ = 60.3, 60.1, 59.8, 59.6,
34.5, 34.2, 32.1, 31.8, 30.7, 28.7, 28.5, 28.4, 22.1, 19.8, 19.7, 13.5,
13.4. This mixture was dissolved in CH2Cl2 (10 mL) and washed
with NaOH (5 mL, 2.0 M). Evaporation of the solvent gave the
free amines that were separated by column chromatography on
silica gel, eluting with petroleum ether-EtOAc-Et3N (95:5:0.5),
to give the following:
temperature. After 2 h, NaOH (10 mL, 10% aqueous solution)
was added, and the mixture was extracted with CH2Cl2 (5ꢀ10 mL).
The combined organic layers were dried (Na2SO4), filtered, and
evaporated to give coniine hydrochloride salt (94 mg, 100%) as
an oil: [R]23D þ4.2 (1.2, EtOH) [lit.68 [R]25D þ7.4 (1.0, EtOH)];
1H NMR (400 MHz, CDCl3) δ=3.15 (1H, br d, J 12.5 Hz, CH),
2.68 (1H, br d, J 12.5 Hz, CH), 2.58 (1H, m, CH), 2.52-2.36
(1H, m, NH), 1.75-1.56 (4H, m, 4ꢀCH), 1.52-1.00 (6H, m, 6ꢀ
CH), 0.83 (3H, t, J 7 Hz, CH3); 13C NMR (100 MHz, CDCl3)
δ = 55.7, 46.8, 39.4, 31.9, 26.2, 24.3, 18.9, 14.0. Data as
reported.73
tert-Butyl 2-(2-Oxopropyl)piperidine-1-carboxylate 13. To a
stirred solution of the carbamate 2a (200 mg, 0.9 mmol) in DMF
(13 mL) and H2O (6 mL) were added PdCl2 (16 mg. 0.09 mmol)
and CuCl2 (245 mg, 1.8 mmol). The dark green solution was
heated under reflux for 2 h and then was cooled to room
temperature. H2O (50 mL) was added, the mixture was extracted
with Et2O (5ꢀ50 mL), and the organics were washed with H2O
(3 ꢀ 50 mL) and brine (50 mL), dried (Na2SO4), filtered, and
evaporated to give the carbamate 13 (113 mg, 53%) as an oil:
[R]22D þ5.4 (1.2, CHCl3) [lit.54 [R]23D þ8.2 (2.0, CHCl3)]; Rf 0.1
[petroleum ether-EtOAc (8:2)]; IR νmax/cm-1 1705, 1680, 1625,
1585, 1525, 1475, 1410, 1365, 1265, 1160, 1050; 1H NMR (400
MHz, CDCl3) δ = 4.95-4.54 (1H, m, CH), 4.10-3.81 (1H, m,
CH), 2.79 (1H, br t, J 13 Hz, CH), 2.67 (2H, dd, J 7, 2.5 Hz,
CH2CO), 2.20 (3H, s, CH3), 1.75-1.50 (6H, m, 3 ꢀ CH2), 1.46
(9H, s, t-Bu); 13C NMR (100 MHz, CDCl3) δ = 207.6, 156.2,
80.1, 47.7, 44.8, 30.5, 30.1, 28.8, 25.7 (two CH2), 19.3; HRMS
(ES) found MHþ 242.1759, C13H24NO3 requires MHþ
242.1759; LRMS m/z (ES) 186 (40), 242 (100). Data as
reported.54
(-)-Pelletierine. HCl (0.25 mL, 1.0 mmol, 4.0 M in dioxane)
was added to the carbamate 13 (113 mg, 0.4 mmol) in CH2Cl2
(4.0 mL) at room temperature. After 16 h, the solvent was
evaporated to give (-)-pelletierine hydrochloride salt (80 mg,
97%) as an amorphous solid: mp 216-221 °C (lit.71 mp
218-219 °C); [R]23D =-9.2 (1.2, EtOH) [lit.71 for (-)-pelletier-
ine hydrochloride, er 100:0, [R]D -18.0 (0.5, EtOH)]; 1H NMR
(400 MHz, CDCl3) δ 9.43 (1H, br s, NH), 9.24 (1H, br s, NH),
3.48 (2H, d, J 12 Hz, CH2), 3.32-3.28 (1H, m, CH), 3.03-2.96
(1H, m, CH), 2.88 (1H, t, J 12 Hz, CH), 2.17 (3H, s, CH3),
1.97-1.83 (4H, m, 2ꢀCH2), 1.76-1.64 (1H, m, CH), 1.58-1.49
(1H, m, CH); 13C NMR (100 MHz, CDCl3) δ 205.0, 53.0, 46.0,
45.2, 30.7, 28.7, 22.2, 23.3; HRMS (ES) found MHþ 142.1231,
C8H16NO requires MHþ 142.1232; LRMS m/z (ES) 142 (100).
Data as reported.71
(2S,5S)-2-Butyl-5-propylpyrrolidine 10 (56 mg) as an oil:
[R]21 þ2.0 (0.5, CHCl3); Rf 0.52 [petroleum ether-EtOAc-
D
Et3N (95:5:0.5)]; IR νmax (film)/cm-1 3420, 2930, 2875, 1455,
1340, 1360, 1160, 1115; 1H NMR (400 MHz, CDCl3) δ =
3.65-3.47 (2H, m, 2 ꢀ CH), 2.27-2.11 (2H, m, 2 ꢀ CH),
1.92-1.75 (2H, m, CH2), 1.73-1.55 (4H, m, 2 ꢀ CH2),
1.48-1.20 (6H, m, 3 ꢀ CH2), 0.94 (3H, t, J 7.5 Hz, CH3), 0.90
(3H, t, J 7.5 Hz, CH3); 13C NMR (100 MHz, CDCl3) δ=59.4,
59.2, 38.7, 36.2, 31.2, 29.7, 22.9, 20.6, 14.2, 14.0; HRMS (ES)
found MHþ 170.1904, C11H24N requires MHþ 170.1909;
LRMS m/z (ES) 170 (100).
(2R,5S)-2-Butyl-5-propylpyrrolidine 11 (31 mg) as an oil:
[R]21D 0.0 (0.6, CHCl3); Rf 0.50 [petroleum ether-EtOAc-Et3N
(95:5:0.5)]; IR νmax (film)/cm-1 3415, 2930, 2870, 1455, 1340,
1365, 1165, 1115; 1H NMR (400 MHz, CDCl3) δ = 3.07-2.89
(2H, m, 2 ꢀ CH), 2.3 (1H, br s, NH), 1.94-1.76 (2H, m, CH2),
1.62-1.47 (2H, m, CH2), 1.46-1.18 (10H, m, 5 ꢀ CH2),
1.01-0.80 (6H, m, 2 ꢀ CH3); 13C NMR (100 MHz, CDCl3)
δ = 59.6, 59.3, 34.6, 32.2, 30.8, 28.5, 22.3, 19.8, 13.7, 13.6;
HRMS (ES) found MHþ 170.1903, C11H24N requires MHþ
170.1909; LRMS m/z (ES) 170 (100).
tert-Butyl 2-n-Propylpiperidine-1-carboxylate 12. Pd(OH)2
(45 mg) was added to the carbamate 2a (200 mg, 0.9 mmol) in
dry MeOH (7 mL) under an atmosphere of H2 at room temper-
ature. After 36 h, the suspension was filtered on Celite, and the
solvent was evaporated to give the carbamate 12 (165 mg, 84%).
Data as reported.73
Acknowledgment. We thank the EPSRC (Grant No. EP/
E012272/1) and the University of Sheffield for support of
this work. Mr R. J. Hanson (University of Sheffield) is
thanked for help with some of the hydrogenations.
Supporting Information Available: Experimental proce-
dures and spectroscopic data for compounds 2a-q and 3a-g,
NMR spectra for all new compounds, and GC spectra for
compounds 2a,i,j and 3a-g. This material is available free of
charge via the Internet at http://pubs.acs.org.
(þ)-Coniine. CF3CO2H (0.5 mL, 7.5 mmol) was added to the
carbamate 12 (165 mg, 0.7 mmol) in CH2Cl2 (4 mL) at room
(73) Passarella, D.; Barilli, A.; Belinghieri, F.; Fassi, P.; Riva, S.;
Sacchetti, A.; Silvani, A.; Danieli, B. Tetrahedron: Asymmetry 2005, 16, 2225.
J. Org. Chem. Vol. 75, No. 12, 2010 4077