Total synthesis of pinnamine and anatoxin-a via a common intermediate. A caveat on the anatoxin-a endgame

Article abstract of DOI:10.1021/jo0506682

This paper describes the total synthesis of the naturally occurring alkaloids pinnamine (1) and anatoxin-a (2) from a common enantiomerically pure intermediate (7) easily available from pyroglutamic acid. The synthesis of enantiopure pinnamine proceeded in 10 steps and 4.8% overall yield, and the route was flexible enough to allow stereocontrolled access to a non-natural congener (5-epi-pinnamine) of the natural product. Intramolecular reaction of an N-acyl iminium ion was a key step in the synthesis of both pinnamine and anatoxin-a. However, in stark contrast to literature precedent, complete racemization was observed during the reaction of the N-acyliminium ion leading to the latter alkaloid.

Full text of DOI:10.1021/jo0506682

Total Synthesis of Pinnamine and Anatoxin-a via a Common
Intermediate. A Caveat on the Anatoxin-a Endgame
Thomas Hjelmgaard, Inger Søtofte, and David Tanner*
Department of Chemistry, Buildings 201 and 207, Technical University of Denmark, Kemitorvet,
DK-2800 Kgs. Lyngby, Denmark
dt@kemi.dtu.dk
Received April 5, 2005
This paper describes the total synthesis of the naturally occurring alkaloids pinnamine (1) and
anatoxin-a (2) from a common enantiomerically pure intermediate (7) easily available from
pyroglutamic acid. The synthesis of enantiopure pinnamine proceeded in 10 steps and 4.8% overall
yield, and the route was flexible enough to allow stereocontrolled access to a non-natural congener
(5-epi-pinnamine) of the natural product. Intramolecular reaction of an N-acyl iminium ion was a
key step in the synthesis of both pinnamine and anatoxin-a. However, in stark contrast to literature
precedent, complete racemization was observed during the reaction of the N-acyliminium ion leading
to the latter alkaloid.
Introduction
Pinnamine 1 and anatoxin-a 2 are two potent alka-
loidal toxins possessing the unusual 9-azabicyclo[4.2.1]-
nonane skeleton. Pinnamine (shown in Figure 1 using
the numbering used in the literature) was isolated from
the Okinawan bivalve Pinna muricata and characterized
in 2000,1 and a 16-step total synthesis of the naturally
occurring enantiomer appeared the following year.2 This
alkaloid shows characteristic toxic symptoms, resembling
those of anatoxin-a,1a,2 such as acute toxicity against mice
with a LD99 (intraperitoneal, mouse) of 0.5 mg/kg result-
ing in death within 5 min, and can be regarded as a
conformationally constrained version of anatoxin-a.3
Anatoxin-a was reported in 1977,4 and the structure
was established by X-ray crystallographic analysis.5 It
FIGURE 1. Pinnamine 1 (numbering as in the literature)1a,2
and anatoxin-a 2.
is a potent neurotoxin produced by certain strains of the
freshwater blue green alga Anabena flos-aquae and has
been responsible for fatal poisoning of wildlife in North
America. Anatoxin-a is also known as “Very Fast Death
Factor” and causes death by respiratory paralysis with
an LD50 (intraperitoneal, mouse) of 0.2 mg/kg.6 The
alkaloid mimics the neurotransmitter acetylcholine and
therefore acts as a potent agonist for the nicotinic
acetylcholine receptor nAChR.7 As acetylcholine defi-
ciency is implicated in diseases such as Alzheimer’s,
analogues of anatoxin-a possessing lower levels of toxicity
may have potential in the treatment of brain disorders.8
The combination of unusual structure and significant
biological properties has prompted much synthetic inter-
* Corresponding author. Tel: + 45 45 25 21 88. Fax: + 45 45 93 39
86.
(1) (a) Takada, N.; Iwatsuki, M.; Suenaga, K.; Uemura, D. Tetra-
hedron Lett. 2000, 41, 6425. (b) Kuramoto, M.; Arimoto, H.; Uemura,
D. Mar. Drugs 2004, 1, 39.
(2) Kigoshi, H.; Hayashi, N.; Uemura, D. Tetrahedron Lett. 2001,
42, 7469.
(3) Schwarz, S.; Ka¨mpchen, T.; Tilotta, M. C.; Gu¨ndisch, D.; Seitz,
G. Pharmazie 2003, 58, 295.
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X. ACS Symp. Ser. 1990, 418, 107.
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R. K.; Stavric, B. Can. J. Chem 1977, 55, 1367.
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Tetrahedron 2000, 56, 309.
10.1021/jo0506682 CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/15/2005
5688
J. Org. Chem. 2005, 70, 5688-5697

Total Synthesis of Pinnamine and Anatoxin-a
SCHEME 1. Retrosynthetic Analysis of Protected
Pinnamine A1 and Protected Anatoxin-a A4a
SCHEME 2a
a P ) CO2Me. Key: (a) TsCl, Et3N, DMAP, CH2Cl2, rt, 98%; (b)
allylmagnesium chloride, THF/Et2O 1:1, 0 °C to rt, 51%; (c) n-BuLi,
ClCO2Me, THF, -78 to 0 °C, 91%; (d) NaBH4, little H2SO4, EtOH,
-20 °C; then excess H2SO4, EtOH, 0 °C; (e) O3, CH2Cl2, -78 °C;
then PPh3, CH2Cl2, -78 °C to rt, two steps, 68%.
Results and Discussion
The synthesis of pinnamine started with the conversion
of 3 to tosylate 4 in 98% yield (Scheme 2).13 Next, the
allyl group was installed, yielding alkene 5. Although the
yield was moderate (51%), this method is very direct and
could be reproduced without difficulty on a multigram
scale. It is noteworthy that the direct displacement14 of
the tosylate by allylmagnesium chloride in a 1:1 THF/
Et2O mixture was far superior to protocols employing Cu
a P ) protecting group.
est and numerous total syntheses of racemic and enan-
tiomerically pure anatoxin-a have appeared.9 In this
paper, we present total syntheses of both pinnamine and
anatoxin-a from a common chiral intermediate (Scheme
1). As will become apparent, this plan provided an
unpleasant surprise en route to the latter alkaloid.
The combined retrosynthetic scheme for both N-pro-
tected pinnamine A1 and N-protected anatoxin-a A4 is
shown in Scheme 1. The key idea for the synthesis of A1
was to obtain the dihydropyrone A2 by an asymmetric
hetero-Diels-Alder reaction between aldehyde A3 and
an appropriate silyloxydiene. Generation of an iminium
ion followed by cyclization would then yield the protected
pinnamine derivative A1. Aldehyde A3 could be derived
from alkene A6 which in turn could be synthesized from
the commercially available and enantiomerically pure
pyroglutamic acid derivative 3. Aldehyde A3 would be
the branching point for the syntheses of A1 and A4 since
similar intermediates have been used previously in both
enantiomerically pure (P ) Ts)10 and racemic (P )
CO2Me)11 form for the synthesis of anatoxin-a. Thus, for
both A1 and A4 the final ring-closure step was projected
to involve N-acyliminium ion intermediates.12
catalysis: use of CuI,15 CuBr‚DMS,16 or Li2CuCl4 to-
17
gether with the Grignard reagent gave complex mixtures
and/or incomplete reactions. The use of stoichiometric
copper reagents derived from allylzinc iodide by trans-
metalation with CuCN‚2LiCl or CuBr‚DMS also proved
fruitless. Protection18 of the lactam as the carbomethoxy
derivative 6 then proceeded in excellent yield. The
carbomethoxy species was chosen since (i) the protecting
group would have to survive the strongly acidic conditions
(methanol saturated with HCl) later required to cyclize
A5 via the corresponding iminium ion to the protected
anatoxin-a A4,10,11 (ii) it was expected to be easily cleaved
in the final step, and (iii) this group enhances the
electrophilicity of iminium ions.11 The iminium ion
precursor12 was obtained by reduction of 6 with NaBH4
in EtOH in the presence of H2SO4 followed by in situ
ethanolysis.11,19 The crude product obtained after aqueous
workup and drying was then subjected to ozonolysis11,20
(12) For some recent reviews, see: (a) Speckamp, W. N.; Hiemstra,
H. Tetrahedron 1985, 41, 4367. (b) Speckamp, W. N.; Moolenaar, M.
J. Tetrahedron 2000, 56, 3817. (c) Maryanoff, B. E.; Zhang, H.-C.;
Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. Rev. 2004, 104,
1431.
(13) (a) Holmes, A. B.; Smith, A. L.; Williams, S. F.; Hughes, L. R.;
Lidert, Z.; Swithenbank, C. J. Org. Chem. 1991, 56, 1393. (b) Naka-
gawa, Y.; Matsumoto, K.; Tomioka, K. Tetrahedron 2000, 56, 2857.
(14) (a) Taber, D. F.; Deker, P. B.; Gaul, M. D. J. Am. Chem. Soc.
1987, 109, 7488. (b) Mart´ın, A.; Salazar, J. A.; Sua´rez, E. J. Org. Chem.
1996, 61, 3999. (c) Taber, D. F.; Green, J. H.; Geremia, J. M. J. Org.
Chem. 1997, 62, 9342.
(9) For a recent review on synthetic routes to anatoxin-a, see:
Mansell, H. L. Tetrahedron 1996, 52, 6025. For more recent syntheses,
see: (a) Ferguson, J. R.; Lumbard, K. W.; Scheinmann, F.; Stachulski,
A. V.; Stjernlo¨f, P.; Sundell, S. Tetrahedron Lett. 1995, 36, 8867. (b)
Parsons, P. J.; Camp, N. P.; Underwood, J. M.; Harvey, D. M.
Tetrahedron 1996, 52, 11637. (c) Oh, C.-Y.; Kim, K.-S.; Ham, W.-H.
Tetrahedron Lett. 1998, 39, 2133. (d) Aggarwal, V. K.; Humphries, P.
S.; Fenwick, A. Angew. Chem., Int. Ed. 1999, 38, 1985. (e) Trost, B.
M.; Oslob, J. D. J. Am. Chem. Soc. 1999, 121, 3057. (f) ref 8. (g) Wegge,
T.; Schwarz, S.; Seitz, G. Tetrahedron: Asymmetry 2000, 11, 1405. (h)
Mori, M.; Tomita, T.; Kita, Y.; Kitamura, T. Tetrahedron Lett. 2004,
45, 4397. (i) Brenneman, J. B.; Machauer, R.; Martin, S. F. Tetrahedron
2004, 60, 7301. (j) Brenneman, J. B.; Martin, S. F. Org. Lett. 2004, 6,
1329.
(15) Sibi, M. P.; Rutherford, D.; Sharma, R. J. Chem. Soc., Perkin
Trans. 1 1994, 1675.
(16) Kant, J. J. Org. Chem. 1993, 58, 2296.
(17) Schlosser, M.; Bossert, H. Tetrahedron 1991, 47, 6287.
(18) Bach, T.; Brummerhop, H.; Harms, K. Chem. Eur. J. 2000, 6,
3838.
(19) Hubert, J. C.; Wijnberg, J. B. P. A.; Speckamp, W. N. Tetra-
hedron 1975, 31, 1437.
(20) (a) Hiemstra, H.; Sno, M. H. A. M.; Vijn, R. J.; Speckamp, W.
N. J. Org. Chem. 1985, 50, 4014. (b) Dinsmore, A.; Doyle, P. M.; Steger,
M.; Young, D. W. J. Chem. Soc., Perkin Trans. 1 2002, 613.
(10) Somfai, P.; A° hman, J. Tetrahedron Lett. 1992, 33, 3791.
(11) Melching, K. H.; Hiemstra, H.; Klaver, W. J.; Speckamp, W.
N. Tetrahedron Lett. 1986, 27, 4799.
J. Org. Chem, Vol. 70, No. 14, 2005 5689

Hjelmgaard et al.
SCHEME 3. Hetero-Diels-Alder Reaction between
Aldehyde 7 and Silyloxydiene 8, Yielding
Pyranone 9a
SCHEME 5a
a P ) CO2Me. Key: (a) 8, (S)-(+)-BINOL, (S)-(+)-H8-BINOL,
Ti(OiPr)4, toluene, rt; then H2SO4, EtOH/THF, rt, 52%. The
subsequent cyclization was unsuccessful.
considerable improvement over the previous route.24 The
synthesis of silyloxydiene 8 was completed by reaction
of 11 with TMSOTf and Et3N in 72% yield.23f
a P ) CO2Me.
SCHEME 4a
For the following asymmetric hetero-Diels-Alder reac-
tion of aldehyde 7 with silyloxydiene 8 we decided to use
the catalyst system (S)-(+)-BINOL/(S)-(+)-H8-BINOL/
Ti(OiPr)4, since it was reported22 to give excellent yields
and stereoselectivity and uses commercially available
ligands. The published method uses TFA in Et2O to
quench the reaction and generate the desired dihydro-
pyrone system but since our product contains the acid-
sensitive ethoxycarbamate functionality we opted to
perform the quenching and generation of dihydropyrone
with H2SO4 in EtOH/THF. In this way, the desired enone
9 was obtained in 52% yield as shown in Scheme 5.
We did not establish the absolute configuration of the
new stereogenic center at this point, but only the 1:1
mixture of isomers of the ethoxycarbamate functionality
could be seen on TLC and in NMR, indicating that the
cycloaddition had proceeded with high stereoselectivity.
Unfortunately, we were not able to cyclize the enone 9
to the protected pinnamine 12. Attempts to perform the
cyclization directly on 9 with TiCl4/CH2Cl2/0 °C,25 TiCl4/
iPr2NEt/CH2Cl2/0 °C,26 Sn(OTf)2/iPr2NEt/CH2Cl2/0 °C,27
HCOOH/0 °C to rt,28 TFA/0 °C to rt or HCl/MeOH/-50
to 0 °C29 gave at best only rise to isolation of starting
material and/or a crude product in which the ethoxycar-
bamate functionality had been exchanged for a hydroxy-
carbamate. The latter result implied that the iminium
ion must have been generated, but still no cyclization
occurred. We then attempted to synthesize the silyl
enolate using previously described conditions TMSOTf/
Et3N/Et2O, 0 °C23f but this resulted in a complex mixture.
Attempts to generate the lithium enolate of the enone
funcionality with LDA/THF/-78 °C also failed.
a Key: (a) (1) NaOMe (2.0 equiv), MeOCHO (2.5 equiv), Et2O,
0 °C to rt, 50%; (b) AcCl, MeOH/c-hexane, 0 °C; then p-TsOH,
MeOH/c-hexane, ∆, 43%; (c) TMSOTf, Et3N, Et2O, 0 °C, 72%.
followed by reductive workup yielding aldehyde 7 in 68%
yield for the two steps as a 1:1 mixture of the two
21
stereoisomers. Performing the reduction with LiBH4
instead of NaBH4/H2SO4 reduced the yield for the two
steps to 43% overall. The synthesis of the key “branching
point” aldehyde 7 was thus completed in five steps with
31% overall yield.
With the enantiopure aldehyde 7 in hand, the next key
step was planned to be a stereoselective hetero-Diels-
Alder reaction between 7 and silyloxydiene 8 yielding
dihydropyrone 9 as shown in Scheme 3. It was our
intention to control the absolute configuration at the new
stereogenic center generated in the cycloaddition by use
of a chiral catalyst22 since we considered the stereocenter
in the substrate to be too far removed from the site of
reaction to provide useful levels of stereocontrol.
The synthesis of the requisite silyloxydiene 8, derived
from enone 11, is shown in Scheme 4 and is based on
modification of literature procedures.23 Our method for
preparation of 11, 21% overall from 2-pentanone in a
convenient reaction sequence, which avoids use of car-
cinogenic agents such as benzene and Me2SO4, is a
At this point, we decided to revise the route to
pinnamine, while still wishing to take advantage of key
intermediate A3 (Scheme 6).
We envisioned that cyclization of the â-diketone A7
onto an in situ generated iminium ion would be a
plausible alternative to the unsuccessful enone/iminium
ion cyclization. The subsequent reduction of the C-5
ketone (pinnamine numbering) would be expected to give
the desired stereochemistry via reaction on the less
hindered face of the molecule. For the synthesis of
(21) Macdonald, S. J. F.; Clarke, G. D. E.; Dowle, M. D.; Harrison,
L. A.; Hodgson, S. T.; Inglis, G. G. A.; Johnson, M. R.; Shah, P.; Upton,
R. J.; Walls, S. B. J. Org. Chem. 1999, 64, 5166.
(22) Long, J.; Hu, J.; Shen, X.; Baoming, J.; Ding, K. J. Am. Chem.
Soc. 2002, 124, 10.
(23) (a) Sugasawa, S.; Yamada, S.-i.; Narahashi, M. J. Pharm. Soc.
Jpn. 1951, 71, 1345; Chem. Abstr. 1952, 46, 8034. (b) Arth, G. E.; Poos,
G. I.; Lukes, R. M.; Robinson, F. M.; Johns, W. F.; Feurer, M.; Sarett,
L. H. J. Am. Chem. Soc. 1954, 76, 1715. (c) Gupta, R. C.; Larsen, D.
S.; Stoodly, R. J. J. Chem. Soc., Perkin Trans. 1 1989, 739. (d) Clive,
D. L. J.; Bergstra, R. J. J. Org. Chem. 1991, 56, 4976. (e) Hoffman, J.
M.; Wai, J. S.; Thomas, C. M.; Levin, R. B.; O’Brien, J. A.; Goldman,
M. E. J. Med. Chem. 1992, 35, 3784. (f) Myles, D. C.; Bigham, M. H.
Org. Synth. 1992, 70, 231. (g) Miyashita, M.; Yamasaki, T.; Shiratani,
T.; Hatakeyama, S.; Miyazawa, M.; Irie, H. Chem. Commun. 1997,
1787.
(24) Lock, R.; Waldmann, H. Chem. Eur. J. 1997, 3, 143.
(25) Shono, T.; Matsumura, Y.; Tsubata, K. J. Am. Chem. Soc. 1981,
103, 1172.
(26) Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M.
T. J. Am. Chem. Soc. 1990, 112, 8215.
(27) Nagasaka, T.; Nishida, S.; Sugihara, S.; Kawahara, T.; Adachi,
K.; Hamaguchi, F. Heterocycles 1994, 39, 171.
(28) Esch, P. M.; de Boer, R. F.; Hiemstra, H.; Boska, I. M.;
Speckamp, W. N. Tetrahedron 1991, 47, 4063.
(29) Skrinjar, M.; Nilsson, C.; Wistrand, L.-G. Tetrahedron: Asym-
metry 1992, 3, 1263.
5690 J. Org. Chem., Vol. 70, No. 14, 2005

Total Synthesis of Pinnamine and Anatoxin-a
SCHEME 6. Revised Retrosynthesis of Protected
Pinnamine A1 from Branching-Point Aldehyde A3
SCHEME 8. Two Possible Products from
Cyclization of 14 (Pinnamine Numbering)a
SCHEME 7a
a P ) CO2Me.
a P ) CO2Me. Key: (a) 11, iPr2NH, n-BuLi, THF, -78 °C, 87%;
(b) (COCl)2, DMSO, CH2Cl2, -78 °C; then Et3N, CH2Cl2, -78 to
-10 °C, 78%.
-78 °C.26,34 Although these conditions gave exclusively
the 4S-isomer 15, we were not able to obtain yields over
30% (entries 3 and 4). It was, however, using this system
that the optimal quenching method was found. The
products were found to be very sensitive to acidic and
basic conditions and all products decomposed when
quenching was performed by simply pouring the reaction
mixture into water or adding a Et3N/methanol mixture
at -78 °C. Eventually, it was discovered that pouring
the reaction mixture very slowly into a stirred saturated
aqueous solution of NaHCO3 caused the least amount of
product loss, and this procedure remained our preferred
method.
â-diketone A7 we planned to use an aldol reaction
between enone 11 and aldehyde A3 followed by an
oxidation (Scheme 6).
Thus, aldehyde 7 was reacted with the lithium enolate
of 11 to give 13 as a mixture of two diastereomeric
alcohols (Scheme 7).30 The following oxidation to give
â-diketone 14 proved rather troublesome. Whereas some
commonly used methods such as TPAP/NMO/4Å MS/
CH2Cl2/MeCN/rt, pyridine‚SO3/Et3N/DMSO/rt,31 and PCC/
CH2Cl2/rt32 resulted only in decomposition of starting
material, use of Dess-Martin periodinane/CH2Cl2/rt
seemed promising as judged by TLC of the reaction
mixture. Unfortunately, and surprisingly, the product did
not survive the conditions of workup (quenching with
aqueous Na2S2O4 followed by treatment with aqueous
NaHCO3). Swern oxidation,33 however, proved to be the
solution and initially the â-diketone 14 could be obtained
in variable yields in the range of 39-58%. It was found
that by allowing the reaction mixture to warm to no more
than -10 °C and quenching with ice-water gave repro-
ducible yields of around 78%. With the â-diketone 14 in
hand, we were now ready to perform the key cyclization
which could give rise to two products, the 4S-isomer 15
and the 4R isomer 16 (pinnamine numbering) as shown
in Scheme 8.
Several different Lewis acids, bases, and solvents were
screened on a small scale (up to ca. 0.1 mmol 14), and it
quickly became clear that even minor changes in solvent
composition had a major impact on the product distribu-
tion. The results obtained are listed in Table 1. Charac-
terization of the two products as the 4S or 4R isomer was
not possible directly from NMR of the two compounds,
but the absolute stereochemistry could be established at
a later stage (vide infra).
As can be seen in Table 1, use of Sn(OTf)22,27 as Lewis
acid quickly stood out as giving the highest yield and
highest selectivity between the two possible cyclized
isomers under different conditions. Thus, reaction of 14
with Sn(OTf)2 (2.2 equiv) and N-ethylpiperidine (1.5
equiv) in THF at 0 °C gave, apart from starting material,
exclusively the 4S-isomer 15 in 46% yield (entry 14),
whereas when the reaction was performed in CH2Cl2
(entry 13) the 4R-isomer 16 was isolated in 32% yield
along with traces of 4S-isomer 15. We therefore decided
to continue optimizing the reaction using Sn(OTf)2 as
Lewis acid, and the results are listed in Table 2.
As seen in Table 2, performing the reaction in CH2Cl2
(entries 7 and 8) required much lower temperatures, -78
to -35 °C, than when the reaction was performed in THF
(entries 1-4) where temperatures below 0 °C resulted
in a very slow reaction. For these solvents, warming the
reaction mixture above -30 or 0 °C, respectively, resulted
in decomposition (entry 3 vs 1 and entry 5 vs 7).
Interestingly, use of the solvents CH2Cl2 (entries 7 and
8) and MeCN (entry 16) was optimized to give the 4R-
isomer 16 as the major product (57-61% yield) and the
4S-isomer 15 as the minor product (21-24%), whereas
THF (entry 1) as mentioned earlier gave the 4S-isomer
15 as the only product along with some starting material.
Other solvents (entries 19-24) gave lower yields, so
further work was concentrated on CH2Cl2, MeCN, and
THF.
Initially, much attention was devoted to performing the
cyclization using TiCl4 or (OiPr)TiCl3/iPr2NEt/CH2Cl2 at
Since the 4R-isomer 16 could be obtained in relatively
good yield (entries 7, 8, and 16) further optimization was
concentrated on conditions leading selectively to the 4S-
isomer 15. Increasing the amount of base (entry 2) or
(30) (a) Reiter, M.; Ropp, S.; Gouverneur, V. Org. Lett. 2004, 6, 91.
(b) Hjelmgaard, T.; Persson, T.; Rasmussen, T. B.; Givskov, M.; Nielsen,
J. Bioorg. Med. Chem. 2003, 11, 3261.
(31) Evano, G.; Schaus, J. V.; Panek, J. S. Org. Lett. 2004, 6, 525.
(32) Chackalamannil, S.; Fett, N.; Kirkup, M.; Afonso, A.; Ganguly,
A. K. J. Org. Chem. 1988, 53, 450.
(33) Agami, C.; Couty, F.; Evano, G.; Darro, F.; Kiss, R. Eur. J. Org.
Chem. 2003, 2062.
(34) Solsona, J. G.; Romea, P.; Urp´ı, F.; Vilarrasa, J. Org. Lett. 2003,
5, 519.
J. Org. Chem, Vol. 70, No. 14, 2005 5691

Hjelmgaard et al.
TABLE 1. Obtained Results from Performing the Cyclization of 14 To Yield 4S-Isomer 15 and 4R-Isomer 16 (Pinnamine
Numbering) under Different Conditions
entry
Lewis acid (equiv)
base (equiv)
iPr2NEt (1.0)
solvent
CH2Cl2
T (°C) (time (h))
product composition
1a
TMSOTf (2.0)
BF3‚OEt2 (1.0)
TiCl4 (1.1-5.0)
(OiPr)TiCl3 (1.1)
Cu(OTf)2 (2.2)
Cu(OAc)2 (2.3)
Sc(OTf)3 (1.2-2.4)
Sc(OTf)3 (1.2-2.4)
AlCl3 (1.5)
0 (1)
0 (1)
6% 15
2a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
CH2Cl2
CH2Cl2
THF
complex mixturec
<30% 15
3a
iPr2NEt (0-2.1)
iPr2NEt (1.1)
iPr2NEt (1.5)
iPr2NEt (1.5)
iPr2NEt (1.1)
iPr2NEt (1.1-2.2)
-78 (1)
-78 (2)
0 to rt (3)
0 to rt (3)
0 (2)
4a
<22% 15
5b
16 major isomer; 14 majorc
no reactionc
6b
7b
15/16 ca. 1:1; 14 majorc
trace 15c
8b
0 (3)
9a
-78 to 0 (2.5)
-78 (1)
-30 to rt (3)
-78 to 0 (2)
0 (2)
complex mixturec
12% 15
10a
11a
12a
13a
14a
SnCl4 (2.5)
SnCl4 (2.1)
iPr2NEt (1.5)
trace 15c
ZnCl2 (2.0)
iPr2NEt (1.5)
THF/CH2Cl2
CH2Cl2
THF
no reactionc
Sn(OTf)2 (2.2)
Sn(OTf)2 (2.2)
N-ethylpiperidine (1.5)
N-ethylpiperidine (1.5)
32% 16, trace 15
46% 15
0 (3.5)
a 0.08-0.12 mmol 14 scale. b 0.05 mmol 14 scale. c As judged by TLC.
TABLE 2. Sn(OTf)2-Mediated (2.2 equiv) Cyclization of 14 to 4S-Isomer 15 and 4R-Isomer 16 (Pinnamine Numbering)
under Different Conditions
entry
base (equiv)
solvent
T (°C) (time (h))
15 (4S)
16 (4R)
14
1a
N-ethylpiperidine (1.5)
N-ethylpiperidine (2.1)
N-ethylpiperidine (1.5)
n-BuLi (1.1)
THF
THF
THF
THF
0 (3.5)
46
38
29
NIc
NIc
NIc
45
2a
0 (2.5)
3a
rt to 30 (1.75)
-78 to rt (3.5)
0 (2)
4a
NIc (major)
5a
N-ethylpiperidine (1.5)
N-ethylpiperidine (1.5)
iPr2NEt (1.5)
CH2Cl2
33
42
61
57
36
NIc
19
6a
CH2Cl2
-78 to -50 (2)
-78 to -35 (2.5)
-78 to -35 (2.5)
-35 to -30 (2 h)
0 (3.5)
27
21
24
30
48
41
53
36
48
46
24
26
28
trace
7a
CH2Cl2
8b
iPr2NEt (1.5)
CH2Cl2
9a
iPr2NEt (1.5)
CH2Cl2/THF 17:1
CH2Cl2/THF 9:1
CH2Cl2/THF 9:1
CH2Cl2/THF 3:1
CH2Cl2/THF 3:1
CH2Cl2/THF 1:1
CH2Cl2/THF 1:5
MeCN
24
10a
11b
12a
13b
14a
15a
16a
17a
18a
19a
20a
21a
22a
23a
24a
N-ethylpiperidine (1.5)
N-ethylpiperidine (1.5)
N-ethylpiperidine (1.5)
N-ethylpiperidine (1.5)
N-ethylpiperidine (1.5)
N-ethylpiperidine (1.5)
iPr2NEt (1.5)
NIc
20
0 (2.5)
0 (3.5)
NIc
26
0 (3.5)
trace
0 (3.5)
NIc
NIc
0 (3.5)
0 (0.5)
58
56
29
iPr2NEt (1.5)
MeCN/THF 17:1
MeCN/THF 9:1
Et2O
-35 to -30 (2)
-35 to -30 (2h)
0 (3.5)
NIc
15
iPr2NEt (1.5)
iPr2NEt (1.5)
NIc (major)
NIc (only)
NIc (major)
49
iPr2NEt (1.5)
DMF
0 to rt (8)
0 to 60 (7)
0 (3)
iPr2NEt (1.5)
NMP
trace
34
21
24
trace
iPr2NEt (1.5)
DME
iPr2NEt (1.5)
dioxane
10 to rt (1.25)
-30 to 0 (2.5)
6
2
26
trace
iPr2NEt (1.5)
toluene
a 0.10-0.12 mmol 14 scale. b 0.80 mmol 14 scale. c Not isolated.
changing the base to n-BuLi (entry 4) did not improve
the yields. It was, however, found that using a CH2Cl2/
THF mixture as solvent (entries 9-15)sand to a much
lesser degree a MeCN/THF mixture (entries 17 and 18)s
provided a useful way of controlling the selectivity of the
reaction. Thus, on a small scale (0.10-0.12 mmol 14) the
optimal solvent composition was found to be CH2Cl2/THF
1:3 which gave 4S-isomer 15 in an improved 53% yield
(entry 12). However, it was later found that a high
content of THF in scaled-up reactions (0.80 mmol 14)
apparently had a detrimental effect on the yields due to
product decomposition during quenching of the reaction
(entry 13 vs 12). Therefore, we opted for a solvent
composition with less THF, CH2Cl2/THF 1:9, which when
scaled up gave the 4S-isomer 15 in an acceptable 41%
yield along with 19% 4R-isomer 16 and 20% 14 (entry
11).
tion, almost complete epimerization to 15 but in only 31%
yield. On the basis of the results presented above, we
suggest that the cyclization reaction of 14 in THF (slower
reaction) is under thermodynamic control, while the
reaction in CH2Cl2 (faster reaction) is under kinetic
control, although we have not performed experiments to
verify this.
With the two isomers 15 and 16 now available, but still
with undetermined stereochemistry at this point, the
next step was the stereoselective reduction of the C-5
ketones (Scheme 9). Whereas attempts to use DIBALH35
or LiBH4 gave complex mixtures, the desired products
could be obtained in good yields by reduction with NaBH4
in CH2Cl2/EtOH 1:1 at 0 °C followed by quenching and
cyclization with excess H2SO4. Interestingly, the reduc-
tion of 15 required 3 h whereas reduction of 16 was
complete within 15 min. A crystalline product, 18, was
Subjecting 16 to conditions yielding 15 as the major
product (Sn(OTf)2 (2.2 equiv)/N-ethylpiperidine (1.5 equiv)
in CH2Cl2/THF 1:9 at 0 °C) gave, apart from decomposi-
(35) Hiyama, T.; Reddy, G. B.; Minami, T.; Hanamoto, T. Bull. Chem.
Soc. Jpn. 1995, 68, 350.
5692 J. Org. Chem., Vol. 70, No. 14, 2005

Total Synthesis of Pinnamine and Anatoxin-a
SCHEME 9a
SCHEME 10a
i
a P ) CO2Me. Key: (a) (MeO)2P(dO)CH2C(dO)CH3, Pr2NEt,
LiCl, MeCN, rt, 88%; (b) HCl, MeOH, -50 °C to rt; (c), DBU,
toluene, reflux, two steps, 51% overall; (d) TMSI, MeCN, 0 °C to
rt, 65%.
the less-hindered â face of C-5, as required for pinnamine,
but we were left with the problem of incorrect stereo-
chemistry at C-4. Fortunately, it was found that com-
plete epimerization at C-4 occurred during removal of
the carbomethoxy protecting group with TMSI36 giving
pinnamine in 81% yield directly from 17. The synthesis
of enantiopure pinnamine thus comprises 10 steps from
3 in 4.8% overall yield, and our method of isolation (see
the Experimental Section) provides the free amine as
colorless crystals (mp ) 47-51 °C). The trifluoroacetate
salt of 1 (isolated as a yellowish oil) showed physical and
spectral data in full accordance with those reported in
the literature.1a,2 Subjecting 18 to the same deprotection
conditions as for pinnamine yielded 4R-5S-epi-pinnamine
19 in 78% yield (5.7% overall in 10 steps from 3). In
contrast to pinnamine, which appears to be a relatively
stable substance, 19 decomposed rapidly even when kept
at -20 °C, a fact which has so far precluded any biological
testing of this compound.
a P ) CO2Me. Key: (a) NaBH4, CH2Cl2/EtOH 1:1, 0 °C; then
H2SO4, CH2Cl2/EtOH, -50 °C to rt, 15 f 17: 70%, 16 f 18: 63%
(pinnamine numbering); (b) TMSI, MeCN, 0 °C to rt, 17 f 1: 81%,
18 f 19: 79%.
With a successful route to pinnamine in hand via
aldehyde 7, we then turned our attention to the synthesis
of anatoxin-a. As mentioned above, racemic 7 has been
used previously for the synthesis11 of racemic anatoxin-
a, and we decided to simply adopt this method for the
seemingly straightforward endgame expected to deliver
the enantiomerically pure alkaloid. Thus, a Horner-
Wadsworth-Emmons reaction11,37 of aldehyde 7 with
dimethyl (2-oxopropyl)phosphonate under Masamune-
Roush conditions gave the desired enone 20 in excellent
yield (Scheme 10). Cyclization of 20 (which was a single
stereoisomer at C-5) in methanol saturated with HCl
followed by refluxing the crude product mixture in the
presence of DBU yielded 21 in 51% yield.11,37b At this
point, however, we were unpleasantly surprised to find
that the product was completely racemic, a result which
was reproducible using different batches of 20. This was
all the more unexpected in view of an earlier report10
describing an identical reaction sequence leading to
enantiopure product from the N-tosyl analogue of 20
(with a methoxy rather than an ethoxy group in the
R-position). Other related cyclizations29 have also been
FIGURE 2. X-ray structure of 18.
isolated after workup of the reaction of 16 and was
assigned the 4R/5S configuration on the basis of NMR
spectroscopy: H-4 signal: δ 2.48, 1H, dd, J ) 5.8, 0.5
Hz, which corresponded well to expected values.2 Final
proof was obtained by X-ray crystallography (Figure 2).
This showed that reduction had occurred exclusively
from the R face of 16, an unexpected result which may
be due to a conformational preference of the substrate
induced by the exocyclic enone moiety. The other diketone
isomer, 15, must have the 4S-configuration, and the
NMR spectrum of the product, 17, obtained after reduc-
tion and cyclization showed the following H-4 signals, due
to rotamers, δ 3.05 and 2.93, 0.48H and 0.52H, 2 × dd,
J ) 5.8, 5.8 Hz, which again corresponded well to
expected values.2 Since H-4 did not possess a coupling
constant in the range 10.5-11.2 Hz which would be
required if the product had the trans-configuration,2 we
have assigned the 4S/5R-cis-configuration to 17 (Scheme
9). Reduction of 15 had thus occurred, as expected, on
(36) Manfre´, F.; Kern, J.-M.; Biellmann, J.-F. J. Org. Chem. 1992,
57, 2060.
(37) (a) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183. (b) Gauthier, I.; Royer, J.; Husson, H.-P. J. Org. Chem. 1997,
62, 6704.
J. Org. Chem, Vol. 70, No. 14, 2005 5693

Hjelmgaard et al.
SCHEME 11. Proposed Mechanism for
Racemization during Cyclization of Enantiopure
20 To Yield Racemic 21a
Experimental Section
(S)-5-(Toluene-4-sulfonyloxymethyl)pyrrolidin-2-one
(4). To a solution of 3 (5.00 g, 43.3 mmol) and TsCl (10.0 g,
52.5 mmol) in CH2Cl2 (160 mL) at rt under N2 were added
Et3N (12.0 mL, 86.1 mmol) and DMAP (531 mg, 4.35 mmol).
The mixture was then stirred for 20 h at rt. The reaction
mixture was diluted with CH2Cl2 (100 mL), poured into water
(250 mL), and acidified with concd HCl (3.0 mL). The organic
phase was isolated, the aqueous phase was extracted with
CH2Cl2 (2 × 75 mL), and the combined organic phases were
dried over MgSO4 and filtered. Silica gel (13.5 g) was added
to the filtrate, and the suspension was concentrated and dried
in vacuo. The silica gel mixture was added to the top of a short
silica gel column and the product was passed through using
EtOAc/MeOH 20:1 as eluent, yielding 4 (11.5 g, 98%) as a
colorless solid: Rf (EtOAc/MeOH 20:1) ) 0.34; mp ) 128-130
°C (lit.13 mp ) 125-126 °C); [R]20D 20.3 (c 0.99, CHCl3) (lit.13b
[R]20 20.4 (c 1.05, CHCl3)); H and 13C NMR and IR spectra
1
D
were in full accordance with those reported in the literature.13
Anal. Calcd for C12H15NO4S: C, 53.52; H, 5.61; N, 5.20; S,
11.91. Found: C, 53.26; H, 5.52; N, 5.24; S, 11.69.
a P ) CO2Me.
(S)-5-(But-3-enyl)pyrrolidin-2-one (5). To a suspension
of 4 (10.8 g, 40.1 mmol) in Et2O/THF 5:3 (400 mL) at 0 °C
under N2 was added 2 M allylmagnesium chloride in THF (100
mL, 200 mmol) over 25 min. Stirring was then continued for
5 h at rt. The reaction mixture was poured into satd NH4Cl
(500 mL), and CH2Cl2 (1000 mL) was added. The organic phase
was isolated, and the aqueous phase was extracted with
CH2Cl2 (2 × 500 mL). The combined organic phases were dried
over Na2SO4, filtered, and concentrated. Flash chromatography
(CH2Cl2/MeOH 20:1) of the residue yielded impure 5 (4.33 g)
as a yellow-orange oil. Flash chromatography (EtOAc/MeOH
20:1) of the isolated oil yielded pure 5 (2.86 g, 51%) as a pale
reported to occur without loss of enantiopurity, in sharp
contrast to the present results. While we have no good
explanation for these discrepancies, we propose that the
racemization occurring in our hands goes via hydride
abstraction by the iminium ion as shown in Scheme 11,
and we note that Tietze38 has recently made similar
observations regarding iminium ion-induced 1,5-hydride
shifts. (We did not observe any spirocyclic products
which could be expected from cyclization of the pre-
sumably much less reactive39 iminium ion 22, Scheme
11.)
yellowish oil: Rf (CH2Cl2/MeOH 20:1) ) 0.31; Rf (EtOAc/MeOH
1
20:1) ) 0.31; [R]20 14.5 (c 1.00, EtOH); H NMR (300 MHz,
D
CDCl3) δ 6.15 (1H, br s), 5.80 (1H, dddd, J ) 17.0, 10.2, 6.8
Hz), 5.06 (1H, m, J ) 17.0 Hz), 5.00 (1H, m, J ) 10.2 Hz),
3.65 (1H, dddd), 2.42-2.19 (3H, m), 2.12 (2H, m), 1.81-1.50
(3H, m); 13C NMR (75.4 MHz, CDCl3) δ 178.5 (C), 137.4 (CH),
115.3 (CH2), 54.1 (CH), 35.7 (CH2), 30.2 (CH2), 30.2 (CH2), 27.1
(CH2); IR (neat) 3203 (s), 3089 (s), 1698 (s), 1641 (m). Anal.
Calcd for C8H13NO: C, 69.03; H, 9.41; N, 10.06. Found: C,
68.81; H, 9.28; N, 9.97.
Other attempts at performing the cyclization of 20 with
H2SO4/MeOH/60 °C,37b TFA/CH2Cl2/rt,40 TiCl4/CH2Cl2/-
78 °C,41 DMAP/Sn(OTf)2/CH2Cl2/0 °C to rt, or p-TsOH/
benzene/reflux did not give any useful results. The
synthesis of racemic anatoxin-a 2 was completed by
deprotection (TMSI36) in 65% yield (9% overall for nine
steps).
(S)-2-But-3-enyl-5-oxopyrrolidine-1-carboxylic Acid
Methyl Ester (6). To a solution of 5 (2.50 g, 18.0 mmol) in
THF (80 mL) under N2 at -78 °C was added dropwise 1.6 M
n-BuLi in hexanes (11.8 mL, 18.9 mmol) over 10 min. Stirring
was continued for 1 h at -78 °C whereupon freshly distilled
methyl chloroformate (1.47 mL, 21.6 mmol) was added, and
the reaction mixture was allowed to heat slowly to 0 °C over
2.5 h. The reaction mixture was poured into satd aq NH4Cl
(70 mL), and the mixture was extracted with EtOAc (3 × 90
mL). The combined organic phases were dried over MgSO4,
filtered, concentrated, and dried in vacuo. Flash chromatog-
raphy of the residue yielded 6 (3.21 g, 91%) as a pale yellowish
oil: Rf (EtOAc/heptane 1:1) ) 0.35; [R]20D -87.3 (c 1.04, EtOH);
1H NMR (300 MHz, CDCl3): δ 5.74 (1H, dddd, J ) 16.9, 10.1,
6.5 Hz), 4.99 (1H, m, J ) 16.9 Hz), 4.94 (1H, m, J ) 10.2 Hz),
4.14 (1H, m), 3.79 (3H, s), 2.56 (1H, ddd, J ) 17.8, 11.1, 9.1
Hz), 2.39 (1H, ddd, J ) 17.8, 9.4, 2.7 Hz), 2.15-1.70 (5H, m),
1.59-1.45 (1H, m); 13C NMR (75.4 MHz, CDCl3): δ 173.8 (C),
152.1 (C), 137.0 (CH), 115.3 (CH2), 57.6 (CH), 53.4 (CH3), 32.2
(CH2), 31.2 (CH2), 29.6 (CH2), 22.3 (CH2); IR (neat): 3076 (m),
1792 (s), 1750 (s), 1717 (s), 1641 (m). Anal. Calcd for C10H15-
NO3: C, 60.90; H, 7.67; N, 7.10. Found: C, 61.07; H, 7.64; N,
7.14.
Conclusion
We have demonstrated the total synthesis of enan-
tiopure pinnamine 1 in 10 steps and 4.8% overall yield
from the commercially available pyroglutamic acid de-
rivative 3. The present route is six steps shorter than
the only previously reported synthesis,2 and our meth-
odology also provides, via a stereochemically divergent
cyclization/reduction sequence, an entry to the non-
natural congener 19 (5.7% overall yield for 10 steps).
Enantiopure aldehyde 7, a key intermediate in the
pinnamine synthesis, could also be used for the total
synthesis of anatoxin-a 2 (9% overall for nine steps).
However, in complete contrast to literature precedent,
the iminium ion-induced cyclization reaction in the
anatoxin-a endgame gave rise to complete racemization,
and the present unexpected results may serve as a
caveat.
(38) Wo¨lfling, J.; Frank, EÄ .; Schneider, G.; Tietze, L. F. Eur. J. Org.
2-Ethoxy-5-(S)-(3-oxopropyl)pyrrolidine-1-carbox-
ylic Acid Methyl Ester (7). To a solution of 6 (1.48 g, 7.50
mmol) in EtOH (60 mL) at -20 °C (drying tube fitted to flask)
were added NaBH4 (851 mg, 22.5 mmol) and 5 drops of 1 M
H2SO4 in EtOH. During 6.5 h, 5 drops of 1 M H2SO4 in EtOH
were added every 15 min. 1M H2SO4 in EtOH (14.5 mL) was
Chem. 2004, 90.
(39) Kværnø, L.; Norrby, P.-O.; Tanner, D. Org. Biomol. Chem. 2003,
1, 1041.
(40) Hart, D. J. J. Org. Chem. 1981, 46, 367.
(41) Moeller, K. D.; Rothfus, S. L.; Wong, P. L. Tetrahedron 1991,
47, 583.
5694 J. Org. Chem., Vol. 70, No. 14, 2005

Total Synthesis of Pinnamine and Anatoxin-a
then added dropwise until the excess of NaBH4 had been
destroyed and pH ∼ 3. The mixture was stirred for 1.5 h at
0-2 °C and then poured into satd NaHCO3 (75 mL) and
diluted with water (45 mL). The mixture was extracted with
CH2Cl2 (3 × 120 mL), and the combined organic phases were
washed with brine (60 mL), dried over Na2SO4, filtered,
concentrated, and dried in vacuo yielding the crude product
(1.59 g) as a colorless oil. The crude product was dissolved in
CH2Cl2 (75 mL) under N2, the solution was cooled to -78 °C,
and O2 was bubbled through for a short time. O3 was then
bubbled through during 20 min until the reaction mixture
remained blue for a few minutes. PPh3 (2.16 mg, 8.24 mmol)
was added, and the reaction mixture was allowed to warm to
rt overnight while stirring under N2. The mixture was con-
centrated and dried in vacuo, and flash chromatography of the
residue yielded 7 (1.17 g, 68%) as a colorless oil: Rf (heptane/
EtOAc 3:2) ) 0.30; [R]20D -41.3 (c 1.03, EtOH); 1H NMR (300
MHz, CDCl3) δ 9.78 (1H, s), 5.45-5.20 (1H, m,), 3.98-3.79 (1H,
m), 3.71 (3H, s), 3.66-3.37 (2H, m), 2.52-2.42 (2H, m), 2.24-
1.60 (6H, m), 1.17 (3H, t, J ) 7.1 Hz); 13C NMR (75.4 MHz,
CDCl3) δ 202.0 (CH), 156.5/155.8 (C), 88.4/87.8 (CH), 62.9/62.5
(CH2), 57.5/56.8, (CH), 52.4 (CH3), 39.9 (CH2), 32.1/31.7 (CH2),
28.9/28.2 (CH2), 27.7 (CH2), 15.0 (CH3); IR (neat) 2725 (m),
1706 (s). Anal. Calcd for C11H19NO4: C, 57.62; H, 8.35; N, 6.11.
Found: C, 57.41; H, 8.23; N, 6.02.
2-Ethyl-3-oxobutanal Sodium Salt (10). To a well-stirred
suspension of NaOMe23c (10.1 g, 187 mmol) in Et2O (80 mL)
under N2 at 0 °C was added methyl formate (14.5 mL, 235
mmol) giving a thick suspension. 2-Pentanone (10.0 mL, 93.6
mmol) was then added dropwise over a period of 15 min. The
mixture was allowed to heat to rt, and stirring was continued
for 4.5 h. The precipitate was filtered off and dried in vacuo,
yielding crude 10 (6.34 g, 50%) as a pale yellow solid which
was used in the ensuing reaction without further purifica-
tion: 1H NMR (300 MHz, D2O) δ 8.88 (0.83H, s), 8.38 (0.17H,
s), 2.10 (3H, s) 2.06 (2H, q, J ) 7.5 Hz), 0.77 (3H, t, J ) 7.5
Hz); 13C NMR (75.4 MHz, D2O) δ 198.0, 182.4, 171.2, 121.0,
22.4, 15.2, 13.5.
(E)-3-(Methoxymethylene)pentan-2-one (11). Acetyl chlo-
ride (3.65 mL, 51.3 mmol) was added dropwise to MeOH (17.5
mL) at 0 °C, and the mixture was stirred for a few minutes.
The mixture was poured slowly into a suspension of the crude
sodium salt 10 (6.34 g, 46.6 mmol) in c-hexane (45 mL) and
stirring was continued for 30 min at 0 °C. The mixture was
then filtered into a 100 mL flask, rinsing the flask with
c-hexane (20 mL). p-TSA monohydrate (175 mg, 0.92 mmol)
was added to the resulting biphasic system, and the flask was
fitted with a 15 cm Vigreux column. The solvents were then
distilled off (over ca. 25 min) until ca. 55 mL distillate had
been collected and the distilling temperature had risen to ca.
81 °C. c-hexane/MeOH 2:1 (9 mL) was then added to the
reaction mixture, and further ca. 10 mL distillate was distilled
off (over ca. 10 min) until the distilling temperature had again
risen to ca. 81 °C. This was repeated one further time,
continuing the distillation until ca. 25 mL distillate had been
collected, thus concentrating the mixture volume to ca. 10 mL.
The mixture was then allowed to cool to rt, and short column
flash chromatography of the residue gave, after careful
concentration at rt, the pure product containing traces of Et2O.
Flask to flask distillation in vacuo yielded pure 11 (2.56 g, 43%)
as a pale yellowish oil: Rf (Et2O/pentane 1:1) ) 0.28. bp )
80-81 °C/14 mmHg (lit.24 bp ) 70-73 °C/13 mmHg); 1H NMR
(300 MHz, CDCl3) δ 7.18 (1H, s), 3.86 (3H, s), 2.25 (2H, q, J )
7.4 Hz), 2.20 (3H, s), 0.93 (3H, t, J ) 7.4 Hz); 13C NMR (75.4
MHz, CDCl3) δ 196.7 (C), 160.2 (CH), 124.0 (C), 61.3 (CH3),
25.2 (CH3), 16.1 (CH2), 13.1 (CH3); IR (neat) 1635 (s). Anal.
Calcd for C7H12O2: C, 65.60; H, 9.44. Found: C, 65.35; H, 9.25.
an oily red-orange lower phase was formed. The reaction
mixture was then transferred to a separatory funnel, and the
red-orange lower oily phase was separated and discarded. The
organic phase was washed with 1.0 M aqueous NaHCO3 (10
mL), and the aqueous phase was extracted with Et2O (10 mL).
The combined organic phases were dried over Na2SO4, filtered,
and concentrated under reduced pressure. Fractional distil-
lation of the residue through a 150-mm Vigreux column gave
8 (2.66 g, 72%) as a colorless oil: bp ) 79-84 °C/14 mmHg
1
(lit.24 bp ) 72-73 °C/15 mmHg); H NMR (300 MHz, CDCl3)
δ 6.45 (1H, s), 4.29 (1H, d, J ) 1.2 Hz), 4.15 (1H, d, J ) 1.2
Hz), 3.67 (3H, s), 2.19 (2H, q, J ) 7.5 Hz), 1.00 (3H, t, J ) 7.5
Hz), 0.22 (9H, s); 13C NMR (75.4 MHz, CDCl3) δ 154.7 (C),
118.1 (C), 146.6 (CH), 89.2 (CH2), 60.1 (CH3), 18.0 (CH2), 13.4
(CH3), 0.1 (3 × CH3); IR (neat) 3124 (m), 3052 (m), 1648 (s),
1593 (m). Anal. Calcd for C10H20O2Si: C, 59.95; H, 10.06.
Found: C, 59.99; H, 9.92.
Dihydropyrone (9). To solution of (S)-BINOL (23.0 mg,
0.080 mmol), (S)-H8-BINOL (24.0 mg, 0.082 mmol) and
Ti(OiPr)4 (0.024 mL, 0.081 mmol) in toluene (0.20 mL) under
N2 at rt was added 7 (367 mg, 1.60 mmol) under N2 at rt.
Freshly distilled 8 (481 mg, 2.40 mmol) was then added, and
the reaction mixture was stirred at rt for 41 h. THF (6.0 mL)
and EtOH (6.0 mL) were added followed by EtOH/H2SO4 1:1
(0.38 mL, 3.56 mmol H2SO4), and the mixture was stirred for
1 h at rt. The mixture was poured into satd NaHCO3 (10 mL),
and the resulting mixture was diluted with water (6 mL). The
mixture was then extracted with EtOAc (3 × 20 mL), and the
combined organic phases were washed with brine (10 mL),
dried over Na2SO4, filtered, concentrated, and dried in vacuo.
Flash chromatography of the residue yielded 9 (272 mg, 52%)
as a yellowish oil: Rf (heptane/EtOAc 3:2) ) 0.31; [R]20D -19.6
(c 0.76, EtOH); 1H NMR (300 MHz, CDCl3) δ 7.20 (1H, s),
5.45-5.20 (1H, m), 4.40-4.26 (1H, m), 3.97-3.76 (1H, m), 3.71
(3H, s), 3.67-3.35 (2H, m), 2.56-2.37 (2H, m), 2.27-1.46 (10H,
m), 1.17 (3H, t, J ) 7.0 Hz), 1.01 (3H, t, J ) 7.5 Hz); 13C NMR
(75.4 MHz, CDCl3) δ 192.6 (C), 159.4 (CH), 156.5/155.7 (C),
119.5 (C), 88.3/87.7 (CH), 79.0 (CH), 62.9/62.4 (CH2), 57.8/57.3
(CH), 52.4 (CH3), 41.8/41.7 (CH2), 32.3/31.8 (CH2), 31.0/30.8
(CH2), 30.3 (CH2), 29.1/28.3 (CH2), 18.5 (CH2), 15.1 (CH3), 13.7
(CH3); IR (neat) 1702 (s), 1671 (s), 1618 (s). Anal. Calcd for
C17H27NO5: C, 62.75; H, 8.36; N, 4.30. Found: C, 62.97; H,
8.21; N, 4.15.
2-Ethoxy-5-(S)-((E)-3-hydroxy-6-(methoxymethylene)-
5-oxooctyl)pyrrolidine-1-carboxylic Acid Methyl Ester
(13). iPr2NH (0.80 mL, 5.71 mmol) was dissolved in THF (3.0
mL) under N2, and the mixture was cooled to -78 °C. n-BuLi
(1.60 M) in hexanes (3.55 mL, 5.68 mmol) was added dropwise,
and the mixture was stirred for 30 min at -78 °C. A solution
of 11 (692 mg, 5.40 mmol) in THF (5.0 mL) was added
dropwise, and the mixture was stirred for 1 h further at -78
°C. A solution of 7 (1.03 g, 4.50 mmol) in THF (3.0 mL) was
then added, and stirring was continued for 1.5 h at -78 °C.
The reaction mixture was then poured into brine (30 mL) and
the mixture was extracted with Et2O (3 × 30 mL). The
combined organic phases were dried over Na2SO4, filtered,
concentrated (at rt), and dried in vacuo. Flash chromatography
of the residue yielded 13 (1.40 g, 87%) as a colorless oil: Rf
(Et2O) ) 0.28; [R]20D -34.8 (c 1.03, EtOH); 1H NMR (300 MHz,
CDCl3) δ 7.36-7.17 (1H, br s), 5.44-5.19 (1H, m), 4.13-3.99
(1H, m), 3.89/3.89 (3H, 2 × s), 3.70/3.69 (3H, 2 × s), 3.92-
3.76 (1H, m), 3.67-3.38 (2H, m), 2.90-2.64 (1H, m), 2.63-
2.41 (1H, m), 2.24 (2H, q, J ) 7.5 Hz), 2.16-1.32 (8H, m), 1.16
(3H, t, J ) 7.0 Hz), 0.93 (3H, t, J ) 7.5 Hz); 13C NMR (75.4
MHz, CDCl3) δ 199.6 (C), 161.0/160.8 (CH), 156.8/155.7 (C),
123.8 (C), 88.2/87.7 (CH), 68.1 (CH), 62.6/62.3 (CH2), 61.5
(CH3), 52.2 (CH3), 58.2/57.8 (CH), 43.0/42.3 (CH2), 32.5 (CH2),
32.2 (CH2), 32.0 (CH2), 31.7 (CH2), 31.4 (CH2), 29.2 (CH2), 28.5
(CH2), 28.3 (CH2), 16.0 (CH2), 15.0 (CH3), 13.1 (CH3); IR (neat)
3473 (m), 1697 (s), 1628 (s). Anal. Calcd for C18H31NO6: C,
60.40; H, 8.74; N, 3.92. Found: C, 60.70; H, 8.95; N, 3.65.
((E)-3-(Methoxymethylene)pent-1-en-2-yloxy)trimeth-
ylsilane (8). To a solution of 11 (2.38 g, 18.6 mmol) and Et3N
(3.40 mL, 24.4 mmol) in Et2O (20 mL) at 0 °C under N2 was
added TMSOTf (3.50 mL, 19.3 mmol) dropwise over 10 min.
Stirring was continued for 45 min at 0 °C during which time
J. Org. Chem, Vol. 70, No. 14, 2005 5695

Hjelmgaard et al.
2-Ethoxy-5-(S)-((E)-6-(methoxymethylene)-3,5-dioxo-
octyl)pyrrolidine-1-carboxylic Acid Methyl Ester (14). To
a solution of DMSO (0.64 mL, 9.02 mmol) in CH2Cl2 (10.0 mL)
under N2 at -50 °C was added dropwise oxalyl chloride (0.39
mL, 4.47 mmol). After 5 min, the temperature was cooled to
-78 °C, and a solution of 13 (1.25 g, 3.50 mmol) in CH2Cl2
(20.0 mL) was added over 5 min and stirring was continued
for 1.5 h. Et3N (2.45 mL, 17.6 mmol) was then added, and the
mixture was allowed to heat to -10 °C over 2 h. The reaction
mixture was poured into ice-water (25 mL ice-cold water +
10 g ice), and the organic phase was isolated. The aqueous
phase was extracted with CH2Cl2 (2 × 35 mL), and the
combined organic phases were washed with brine (2 × 15 mL),
dried over Na2SO4, filtered, concentrated (at rt), and dried in
vacuo. Flash chromatography of the residue yielded 14 (974
mg, 78%) as a yellowish oil: Rf (heptane/EtOAc 3:2) ) 0.30;
CH2Cl2 (30 mL), and the organic phase was isolated. The
aqueous phase was extracted with CH2Cl2 (4 × 30 mL), and
the combined organic phases were dried over Na2SO4, filtered,
concentrated, and dried in vacuo. Flash chromatography of the
residue yielded 16 (141 mg, 57%) as a colorless oil. Also isolated
was 15 (59 mg, 24%). 16: Rf (heptane/EtOAc 1:2) ) 0.32; [R]20
D
1
-49.4 (c 0.50, EtOH); H NMR (300 MHz, CDCl3) δ 7.19/7.14
(1H, 2 × s), 4.76-4.38 (2H, m), 3.88/3.83 (4H, 2 × s), 4.70/
4.65 (3H, 2 × s), 3.26-3.05 (1H, m), 2.47-1.94 (6H, m), 1.76-
1.40 (3H, m), 0.93 (3H, t, J ) 7.5 Hz); 13C NMR (75.4 MHz,
CDCl3) δ 209.7/209.5 (C), 193.4 (C), 160.6/160.1 (CH), 154.7
(C), 123.5/123.2 (C), 67.1/66.8 (CH), 55.4 (CH), 54.8 (CH), 61.6
(CH3), 52.4 (CH3), 38.8/38.4 (CH2), 31.4/30.7 (CH2), 30.6/30.0
(CH2), 29.0/28.4 (CH2), 16.7 (CH2), 13.0 (CH3); IR (KBr) 1700
(s), 1628 (s); Anal. Calcd for C16H23NO5: C, 62.12; H, 7.49; N,
4.53. Found: C, 61.87; H, 7.27; N, 4.54.
[R]20 -20.5 (c 1.01, EtOH); 1H NMR (300 MHz, CDCl3) δ
D
4S,5R-epi-Pinnamine-N-carboxylic Acid Methyl Ester
(17). To a solution of 15 (124 mg, 0.401 mmol) in EtOH/CH2Cl2
1:1 (14 mL) at 0 °C in a 25 mL flask fitted with a drying tube
was added NaBH4 (45 mg, 1.190 mmol), and stirring was
continued at 0 °C for 3 h. The mixture was cooled to -50 °C,
1 M H2SO4 in EtOH (1.50 mL, 1.50 mmol H2SO4) was added
dropwise, and stirring was continued for 45 min at rt after
bubbling had ceased. The mixture was then poured into satd
NaHCO3 (15 mL), and the mixture was diluted with water (10
mL). The mixture was then extracted with CH2Cl2 (3 × 25 mL),
and the combined organic phases were washed with brine (10
mL), dried over Na2SO4, filtered, concentrated, and dried in
vacuo. Flash chromatography of the residue yielded 17 (78 mg,
7.35-7.22 (1H, br s), 5.75-5.54 (1H, m), 5.44-5.20 (1H, m),
3.90/3.84 (3H, 2 × s), 3.71/3.70 (3H, 2 × s), 3.96-3.76 (1H,
m), 3.75-3.35 (2H, m), 2.62-1.59 (10H, m), 1.24 and 1.17
(0.42H and 2.58H, 2 × t, J ) 7.0 Hz), 1.00 and 0.92 (1.96H
and 1.04H, 2 × t, J ) 7.5 Hz); 13C NMR (75.4 MHz, CDCl3) δ
204.7 (C), 195.0/193.1 (C), 185.0/183.5 (C), 156.5/155.7 (C),
124.0 (C), 117.7/116.9 (C), 162.7 (CH), 156.5 (CH), 94.6 (CH),
88.3/87.8 (CH), 62.8/62.4 (CH2), 61.7/61.3 (CH3), 52.4 (CH3),
57.8/57.2 (CH), 53.7 (CH2), 39.0 (CH2), 35.2 (CH2), 35.0 (CH2),
32.2 (CH2), 31.8 (CH2), 29.4 (CH2), 29.0 (CH2), 28.3 (CH2), 16.5/
16.2 (CH2), 15.1 (CH3), 13.4/13.0 (CH3); IR (neat) 1699 (s), 1635
(s). Anal. Calcd for C18H29NO6: C, 60.83; H, 8.22; N, 3.94.
Found: C, 60.89; H, 8.39; N, 3.92.
70%) as a colorless oil: Rf (heptane/EtOAc 2:1) ) 0.22; [R]20
D
1
114.2 (c 0.50, EtOH); H NMR (300 MHz, MeOD) δ 7.49/7.48
2-(S)-((E)-2-(Methoxymethylene)butan-1-oyl)-9-aza-
bicyclo[4.2.1]non-2-ene-9-carboxylic Acid Methyl Ester
(15). To a solution of Sn(OTf)2 (733 mg, 1.76 mmol) in THF/
CH2Cl2 1:9 (8.0 mL) at 0 °C under N2 was added N-ethyl-
piperidine (0.17 mL, 1.23 mmol), and stirring was continued
for 5 min. A solution of 14 (285 mg, 0.80 mmol) in THF/CH2Cl2
1:9 (3.5 mL) was then added dropwise, and stirring was
continued for 2.5 h at 0 °C. The reaction mixture was then
poured dropwise into vigorously stirred satd aq NaHCO3 (15
mL) at 0 °C, and stirring was continued for a few minutes.
The mixture was then diluted with cold water (20 mL) and
CH2Cl2 (30 mL), and the organic phase was isolated. The
aqueous phase was extracted with CH2Cl2 (4 × 30 mL), and
the combined organic phases were dried over Na2SO4, filtered,
concentrated (at rt), and dried in vacuo. Flash chromatography
of the residue yielded 15 (101 mg, 41%) as a colorless solid.
Also isolated were 16 (47 mg, 19%) and 14 (57 mg, 20%): Rf
(heptane/EtOAc 1:1) ) 0.37; mp ) 92-96 °C; [R]20D -152.7 (c
0.59, EtOH); 1H NMR (300 MHz, CDCl3) δ 7.35 and 7.20
(0.73H and 0.27H, 2 × s), 4.57-4.39 (2H, m), 4.37-4.29 (1H,
m), 3.93 (3H, 2 × s), 4.74/4.69 (3H, 2 × s), 2.99 (1H, ddd, J )
13.0, 13.0, 4.4 Hz), 2.55 (1H, ddd, J ) 13.0, 4.0, 4.0 Hz), 2.34-
1.65 (8H, m), 0.90 (3H, t, J ) 7.5 Hz); 13C NMR (75.4 MHz,
CDCl3) δ 209.3/209.3 (C), 195.6/195.4 (C), 162.1/161.5 (CH),
154.0/153.2 (C), 123.8 (C), 63.5/62.2 (CH), 56.1/55.9 (CH), 55.1/
54.5 (CH), 62.0/61.9 (CH3), 52.8/52.6 (CH3), 40.6/40.5 (CH2),
33.2/32.3 (CH2), 29.4/28.6 (CH2), 26.1/25.0 (CH2), 16.2/16.1
(CH2), 13.0 (CH3); IR (KBr) 1701 (s), 1623 (s). Anal. Calcd for
C16H23NO5: C, 62.12; H, 7.49; N, 4.53. Found: C, 61.88; H,
7.56; N, 4.48.
(1H, 2 × s), 4.72-4.62 (1H, m), 4.54-4.42 (1H, m), 4.34-4.24
(1H, m), 3.73/3.70 (3H, 2 × s), 3.05 and 2.93 (0.48H and 0.52H,
2 × dd, J ) 5.8, 5.8 Hz, C(dO)CH), 2.30-2.04 (5H, m), 2.00-
1.58 (5H, m), 1.02 (3H, t, J ) 7.4 Hz); 13C NMR (75.4 MHz,
CDCl3) δ 194.8 (C), 162.8/162.6 (CH), 156.2 (C), 122.2 (C), 81.5
(CH), 58.9/58.6 (CH), 55.7/55.6 (CH), 53.3/53.2 (CH3), 52.3/51.2
(CH), 33.5/32.9 (CH2), 31.3/30.6 (CH2), 28.2/28.0 (CH2), 26.8/
26.2 (CH2), 19.6 (CH2), 14.4 (CH3); IR (neat) 1698 (s), 1662
(s), 1610 (s). Anal. Calcd for C15H21NO4: C, 64.50; H, 7.58; N,
5.01. Found: C, 64.55; H, 7.39; N, 4.84.
4R,5S-epi-Pinnamine-N-carboxylic Acid Methyl Ester
(18). To a solution of 16 (108 mg, 0.349 mmol) in EtOH/CH2Cl2
1:1 (12 mL) at 0 °C in a 25 mL flask fitted with a drying tube
was added NaBH4 (20 mg, 0.529 mmol), and stirring was
continued at 0 °C for 15 min. The mixture was cooled to -50
°C, 1 M H2SO4 in EtOH (0.66 mL, 0.66 mmol H2SO4) was then
added dropwise, and stirring was continued for 30 min at rt
after bubbling had ceased. The mixture was then poured into
satd NaHCO3 (15 mL), and the mixture was diluted with water
(10 mL). The mixture was then extracted with CH2Cl2 (3 ×
25 mL), and the combined organic phases were washed with
brine (10 mL), dried over Na2SO4, filtered, concentrated, and
dried in vacuo. Flash chromatography of the residue yielded
18 (61 mg, 63%) as a colorless solid: Rf (heptane/EtOAc 1:2)
1
) 0.40; mp ) 96.5-98.5 °C; [R]20 -103.6 (c 0.55, EtOH); H
D
NMR (300 MHz, MeOD) δ 7.38 and 7.28 (0.74H and 0.26H, 2
× s), 4.83-4.74 (1H, m), 4.46-4.31 (2H, m), 3.61 and 3.48
(0.80H and 2.20H, 2 × s), 2.48 (1H, dd, J ) 5.8, 0.5 Hz, C(d
O)CH), 2.51-1.72 (9H, m), 1.60-1.48 (1H, m), 1.03/1.02 (3H,
2 × t, J ) 7.5 Hz); 13C NMR (75.4 MHz, CDCl3) δ 196.9/196.5
(C), 162.5/162.1 (CH), 156.1/155.8 (C), 120.4/119.9 (C), 80.6
(CH), 59.2 (CH), 59.1 (CH), 58.8 (CH), 58.0/57.6 (CH), 53.0/
52.5 (CH3), 35.4/34.7 (CH2), 29.3/28.7 (CH2), 28.4/27.8 (CH2),
27.0/26.9 (CH2), 19.9 (CH2), 14.1/14.0 (CH3); IR (KBr) 1702 (s),
1649 (s), 1617 (s). Anal. Calcd for C15H21NO4: C, 64.50; H, 7.58;
N, 5.01. Found: C, 64.58; H, 7.65; N, 4.96.
4-(R)-((E)-2-(methoxymethylene)butan-1-oyl)-9-aza-
bicyclo[4.2.1]non-2-ene-9-carboxylic Acid Methyl Ester
(16). To a suspension of Sn(OTf)2 (733 mg, 1.759 mmol) in
i
CH2Cl2 (8.0 mL) at 0 °C under N2 was added Pr2NEt (0.205
mL, 1.198 mmol), and stirring was continued for 5 min. The
mixture was then cooled to -78 °C, and a solution of 73 (285
mg, 0.802 mmol) in CH2Cl2 (3.5 mL) was then added dropwise.
The reaction mixture was then allowed to heat to -30 °C over
1.5 h, and stirring was continued at -30 to -35 °C for a further
30 min. The reaction mixture was then poured slowly into satd
aq NaHCO3 (15 mL) at 0 °C, and stirring was continued for a
few minutes. The mixture was diluted with water (20 mL) and
Crystal data: 18, M ) 279.33, orthorhombic, a ) 7.3144(5)
Å, b ) 8.3260(6) Å, c ) 23.5690(17) Å, V ) 1435.34(18) Å3, T
) 200(2) K, space group P212121, Z ) 4, Dx ) 1.293 g cm-3
,
crystal size ) 0.24 × 0.15 × 0.08 mm3, µ(Mo KR) ) 0.093
mm-1, 10266 reflections measured, 3449 unique (Rint ) 0.0255)
5696 J. Org. Chem., Vol. 70, No. 14, 2005

Total Synthesis of Pinnamine and Anatoxin-a
and 3006 reflections with I > 2σ(I) wich were used in all
calculations. The final R1 was 0.0597 (observed data) and
wR(F2) was 0.1537 (all data). The Flack x parameter is 0.3(15).
General Procedure for Deprotection of Carbomethoxy
Amides. To a solution of the carbomethoxy amide in (0.098
mmol) in MeCN (0.60 mL) under N2 at 0 °C was added TMSI
(0.0175 mL, 0.129 mmol), and the mixture was allowed to heat
to rt slowly overnight (stirred for 17-19 h). MeOH (0.50 mL)
was added, and stirring was continued for 10 min at rt. The
mixture was then concentrated and dried in vacuo. Flash
chromatography of the residue yielded the free amine.
Pinnamine (1). Deprotection of 17 (27.5 mg, 0.098 mmol)
following the general procedure yielded the free amine 1 (17.6
31.8 (CH2), 29.1/28.3 (CH2), 28.5 (CH2), 26.7 (CH3), 15.1 (CH3);
IR (neat) 1698 (s), 1680 (s), 1628 (m). Anal. Calcd for C14H23-
NO4: C, 62.43; H, 8.61; N, 5.20. Found: C, 62.20; H, 8.34; N,
5.29.
2-Acetyl-9-azabicyclo[4.2.1]non-2-ene-9-carboxylic Acid
Methyl Ester (21). MeOH (20 mL) was saturated with HCl
(g) at -50 °C, and a drying tube was fitted to the flask. A
solution of 20 (256 mg, 0.95 mmol) in MeOH (1.0 mL) was then
added, and the reaction mixture was stirred overnight while
heating slowly to rt (solution kept at -50 °C for the first hour).
The mixture was then poured slowly into stirred cold satd
NaHCO3 (100 mL), and the mixture was neutralized by slow
addition of further satd NaHCO3 (300 mL). The mixture was
then extracted with CH2Cl2 (3 × 400 mL). The combined
organic phases were dried over Na2SO4, filtered, concentrated,
and dried in vacuo. Flash chromatography of the residue
yielded a complex mixture (149 mg; Rf (heptane/EtOAc 1:1) )
0.46/0.34/0.27). This product mixture was dissolved in toluene
(25 mL) under N2 at rt, and DBU (0.20 mL, 1.34 mmol) was
added. The mixture was then refluxed for 6.5 h. After being
cooled to rt, the mixture was concentrated and dried in vacuo.
Flash chromatography of the residue yielded 21 (108 mg, 51%)
as a colorless solid: Rf (heptane/EtOAc 1:1) ) 0.27; mp ) 48-
56 °C; 1H NMR (300 MHz, CDCl3) δ 6.89-6.77 (1H, m), 5.30-
5.16 (1H, m), 4.53-4.30 (1H, m), 3.67/3.62 (3H, 2 × s), 2.52-
1.98 (5H, m), 2.29 (3H, s), 1.76-1.61 (3H, m); 13C NMR (75.4
MHz, CDCl3): δ 197.8 (C), 154.1/154.0 (C), 148.9/148.6 (C),
142.6/141.7 (CH), 55.8/55.3 (CH), 54.1/53.1 (CH), 52.2 (CH3),
31.9/31.7 (CH2), 30.8/30.6 (CH2), 29.6/28.5 (CH2), 25.4 (CH3),
24.1 (CH2); IR (neat) 1702 (s), 1660 (s), 1629 (m); HRMS
(FAB+) calcd for C12H18NO3 [M + H]+ m/z 224.1287, found
224.1289.
Anatoxin-a (2). Deprotection of 21 (31.8 mg, 0.142 mmol)
following the general procedure yielded the slightly impure
free amine 2 (20.6 mg), which was dissolved in CH2Cl2 (2.0
mL), and the mixture was poured into satd NaHCO3 (2.0 mL).
The organic phase was isolated, and the aqueous phase was
extracted with CH2Cl2 (5 × 2.0 mL). The combined organic
phases were dried over Na2SO4, filtered, concentrated, and
dried in vacuo, yielding pure 2 (15.2 mg, 65%) as a yellowish
oil: Rf (CH2Cl2/MeOH/Et3N 20:1:0.2) ) 0.21; 1H and 13C NMR
spectra were in full accordance with those reported in the
literature;29 IR (neat) 1662 (s), 1636 (m); HRMS (FAB+) calcd
for C10H16NO [M + H]+ m/z 166.1232, found 166.1237.
mg, 81%) as a colorless solid: Rf (CH2Cl2/MeOH/Et3N 20:1:
1
0.1) ) 0.15; mp ) 47-51 °C; [R]20 116.7 (c 0.63, MeOH); H
D
NMR (300 MHz, MeOD) δ 7.34 (1H, s, CdCH), 4.48 (1H, dd,
J ) 10.0, 1.3 Hz, C(dO)CHCHN), 4.30 (1H, m, J ) 13.5 Hz,
C(dO)CHCHO), 3.55 (1H, dddd, J ) 8.1, 3.3, 3.3, 0.7 Hz,
NCH), 2.28 (1H, d, J ) 13.5 Hz, C(dO)CH), 2.28-1.56 (10H,
m), 1.01 (3H, t, J ) 7.5 Hz, CCH2CH3); 13C NMR (75.4 MHz,
CDCl3) δ 195.9 (C), 161.4 (CH), 120.4 (C), 83.4 (CH), 59.1 (CH),
59.0 (CH), 52.2 (CH), 35.8 (CH2), 33.4 (CH2), 30.9 (CH2), 30.0
(CH2), 19.9 (CH2), 14.5 (CH3); IR (KBr) 1669 (s), 1616 (s);
HRMS (FAB+) calcd for C13H20NO2 [M + H]+ m/z 222.1494,
found 222.1494. A sample of the 1 was dissolved in a small
amount of MeOH, and an excess of TFA was added slowly
under stirring. The mixture was then concentrated and dried
in vacuo giving 1‚TFA as a yellowish oil: [R]20 57.4 (c 0.72,
D
MeOH) (lit.2 [R]27D 71.2 (c 0.0399, MeOH). NMR spectra were
in full accordance with those reported in the literature.1a,2
4R,5S-epi-Pinnamine (19). Deprotection of 18 (16.2 mg,
0.058 mmol) following the general procedure yielded the free
amine 19 (10.1 mg, 79%) as a colorless oil: Rf (CH2Cl2/MeOH/
Et3N 20:1:0.1) ) 0.10; 1H NMR (300 MHz, MeOD) δ 7.36 (1H,
s, CdCH), 4.82 (1H, ddd, J ) 9.0, 5.7, 0.9 Hz), 3.90 (1H, ddd,
J ) 9.1, 1.7, 1.7 Hz), 3.70 (1H, m), 2.71 (1H, dd, J ) 5.7, 1.7
Hz, C(dO)CH), 2.37-1.50 (10H, m), 1.02 (3H, t, J ) 7.5 Hz,
CCH2CH3); HRMS (FAB+) calcd for C13H20NO2 [M + H]+ m/z
222.1494, found 222.1496. Due to the instability of this
compound, further characterization was not possible.
2-Ethoxy-5-(S)-(5-oxohex-3-enyl)pyrrolidine-1-carbox-
ylic Acid Methyl Ester (20). To a suspension of LiCl (56 mg,
1.32 mmol; dried overnight in vacuo at 140 °C) in MeCN (8.5
mL) under N2 at rt were added dimethyl (2-oxopropyl)-
phosphonate (0.18 mL, 1.30 mmol), iPr2NEt (0.19 mL, 143 mg,
1.11 mmol), and then a solution of 7 (252 mg, 1.10 mmol) in
MeCN (4.5 mL). Stirring was then continued at rt under N2
for 6 h. The reaction mixture was poured into brine (40 mL),
and the mixture was extracted with CH2Cl2 (3 × 40 mL). The
combined organic phases were dried over Na2SO4, filtered,
concentrated, and dried in vacuo. Flash chromatography of the
residue yielded 20 (261 mg, 88%) as a colorless oil: Rf (heptane/
EtOAc 3:2) ) 0.26; [R]20D -35.7 (c 1.05, EtOH); 1H NMR (300
MHz, CDCl3) δ 6.81 (1H, ddd, J ) 15.8, 6.5 Hz), 6.08 (1H, d,
J ) 15.8 Hz), 5.45-5.19 (1H, m), 3.92-3.74 (1H, m), 3.70 (3H,
s), 3.65-3.35 (2H, m), 2.30-1.50 (8H, m), 2.23 (3H, s), 1.16
(3H, t, J ) 7.0 Hz); 13C NMR (75.4 MHz, CDCl3) δ 198.6 (C),
156.5/155.7 (C), 147.9/147.7 (CH), 131.3 (CH), 88.3/87.7 (CH),
62.8/62.5 (CH2), 57.7/57.2, (CH), 52.4 (C), 34.3/33.9 (CH2), 32.2/
Acknowledgment. We thank the Technical Uni-
versity of Denmark for financial support and Professor
Hideo Kigoshi for a copy of the 800 MHz 1H NMR
spectrum of pinnamine‚TFA. We also thank Bent
Petersen of the Carlsberg Research Center for providing
800 MHz NMR spectra.
Supporting Information Available: General experimen-
tal methods; 1H NMR spectra of 1, 2, 19, and 21; 13C NMR
spectra of 1, 2, and 21; COSY spectra of 1 and 19; and CIF
data for 18. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO0506682
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