Synthesis of 1-aminopyrrolizidine alkaloid (-)-absouline by stereoselective aminoconjugate addition

Article abstract of DOI:10.1016/j.tetlet.2012.06.028

The diastereoselective aminoconjugate addition of benzylamine and lithiobenzylamine to both E and Z-configured vinylogous proline derivatives has been investigated. The results from this study have enabled the stereoselective synthesis of the 1-aminopyrrolizidine alkaloid (-)-absouline.

Full text of DOI:10.1016/j.tetlet.2012.06.028

Tetrahedron Letters 53 (2012) 4644–4647
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Synthesis of 1-aminopyrrolizidine alkaloid (ꢀ)-absouline by stereoselective
aminoconjugate addition
⇑
Emily J. Eklund, Robert D. Pike, Jonathan R. Scheerer
Department of Chemistry, The College of William & Mary, PO Box 8795, Williamsburg, VA 23187, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The diastereoselective aminoconjugate addition of benzylamine and lithiobenzylamine to both E and
Z-configured vinylogous proline derivatives has been investigated. The results from this study have
enabled the stereoselective synthesis of the 1-aminopyrrolizidine alkaloid (ꢀ)-absouline.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 16 May 2012
Revised 4 June 2012
Accepted 6 June 2012
Available online 18 June 2012
Keywords:
(ꢀ)-Absouline
Pyrrolizidine alkaloids
Horner–Wadsworth–Emmons olefination
Heteroconjugate addition
Alkaloid synthesis
Pyrrolizidine alkaloids are prevalent secondary metabolites that
are isolated from plants, insects, bacteria, and fungi.1 The complete
family of [3.3.0]-azabicyclic alkaloids features an impressive vari-
ety of biological activities. Derivatives bearing hydroxylmethyl
substitution at C1 (or esters thereof) are the most abundant pyrr-
olizidines. As a simple example, supinidine (1) is hepatotoxic and
believed to play a role in feeding deterrence.2 Polyhydroxylated
a new route centered on incorporation of the 1-amino substituent
through heteroconjugate addition to an ,b-unsaturated carbonyl
a
electrophile (e.g., 12a, Scheme 1). We anticipated that this ap-
proach would be direct and has several features that could be
exploited in order to control stereoselectivity of the aminoconju-
gate addition. We selected 4 as our ultimate synthetic target in or-
der to validate the identity of our product by comparison to the
spectroscopic data for both natural and synthetic materials.
Reports concerning the conjugate addition of amines13 or metal
variants have garnered recent interest due to their
a-glucosidase
inhibitory activity3 and representative pyrrolizidines 2 and 3 are
lead candidates for the treatment of cancer, diabetes, and viral
infection.4
amides13d,14 to
a,b-unsaturated esters bearing a c-stereogenic cen-
ter were encouraging from a reactivity standpoint; however, 1,2-
induction from these examples generally predicted that addition
would occur opposite to the desired sense.15 Nonetheless, we set
In contrast to the family in general, 1-aminopyrrolizidines are
not widespread and the three known natural products in this sub-
class are illustrated (4–6, Fig. 1). Absouline5 (4) and laburnamine6
(5) differ at the C1 amide substituent and exhibit modest anti-pro-
liferative activities. Loline (6) is produced by mutualistic fungal
endophytes living on turfgrasses.7 The insecticidal and antifeedant
properties of 3 and related derivatives protect the host plant from
insect herbivory. In addition to natural aminopyrrolizidine struc-
tures, several synthetic derivatives possess bioactivity including
oxime 7 and hydrazone 8, which show cardiotonic activity,8 and
SC52246 (9), a selective 5HT3 serotonin receptor antagonist.9
As part of our program into the synthesis of aminopyrrolizidine
alkaloids,10 we desired a short synthetic route to enantioenriched
10. Although two racemic11 and three asymmetric12 syntheses
intercept 10, the overall length of these sequences led us to pursue
OH
OH
OH
HO
H
N
H
N
H
N
OH
OH
OH
OH
(+)-supinidine (1)
(–)-hyacinthacine A1 (2)
(+)-alexine (3)
O
O
HN
HN
H
N
H
Me
Me
N
OMe
(+)-absouline (4)
(+)-laburnamine (5)
O
OMe
R
N
NHMe
HN
H
N
H
N
O
N
NH2
SC-52246 (9)
Cl
R = OH (7)
R = NH2 (8)
(+)-loline (6)
⇑
Corresponding author. Tel.: +1 11 757 221 2551; fax: +1 11 757 221 2715.
E-mail address: jrscheerer@wm.edu (J.R. Scheerer).
Figure 1. Representative pyrrolizidine alkaloids.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.028

E. J. Eklund et al. / Tetrahedron Letters 53 (2012) 4644–4647
4645
H
O
12a
H
H2NR
CO2Me
N
Ot-Bu
=
hetero-conjugate
addition
HWE
E-selective
NBoc
MeO2C
H
NHR
H
NH2
CO2Me
NBoc
13
H
N
CO2Me
H2NR
(–)-4
A(1,3) minimized
NBoc
11
H
H
HWE
10
Z-selective
N
MeO C
=
12b
O
2
CO2Me
N
Boc
Ot-Bu
Scheme 1. Retrosynthesis of aminopyrrolizidine 10 and (ꢀ)-absouline (4).
out to evaluate the inherent stereoselectivity of the aminoconju-
gate addition to both E- and Z-vinylogous proline derivatives 12a
and 12b, both of which could be easily prepared from a stereodi-
vergent Horner–Wadsworth–Emmons (HWE) olefination. Addi-
tionally, if unsatisfactory results were observed for both
geometric isomers, we anticipated that we could enhance the
selectivity by resorting to the addition of lithiated homochiral ben-
zyl amine derivatives.16 Although 12a and 12b (and derivatives
with different protecting group compositions) have been prepared
numerous times17 and used extensively, the conjugate addition of
an amine to these substrates had not been reported. In fact, we
were unable to identify any intermolecular heteroconjugate addi-
tion to an unsaturated pyrrolidine substrate, although several
intramolecular cases have been recently disclosed.18,10
literature
H
H
H
precedent25
1
1
OH
b
[3,3];
NBoc
N
16
N
1:1
cyclization
O
O
15a
17
CO2Et
our results
H
H 1
N
H
dr 9:1
a
c
12b
NBoc
N
OH
Boc
O
15b
18
16
Scheme 2. Claisen rearrangement to probe facial bias of 15a and 15b: (a) Dibal-H,
CH2Cl2, ꢀ70 °C (80% yield); (b) MeC(OEt)3, 5% EtCO2H, 140 °C; (c) TFA, CH2Cl2, Me2S;
EtOH, NEt3, 80 °C (51% yield, 2 steps).
were chromatographically separated to afford 46% isolated yield of
12b over the two steps.
In comparing 12a and 12b, we anticipated that the Z-alkene iso-
mer 12b would present a greater bias for addition of the amine to
With both of the isomeric unsaturated esters in hand, we
wanted to evaluate our hypothesis regarding a conformational
preference for greater facial selection of the Z-isomer relative to
the E-isomer. Because the Johnson orthoester Claisen rearrange-
ment of E-allylic alcohol 15a was known, affording after subse-
quent cyclization an equal mixture of 16 and 17 (no face
selection),25 we performed the complementary experiment with
Z-allylic alcohol 15b (Scheme 2). Claisen rearrangement of 15b
selectively afforded product 18 (dr 9:1). The structure and diaste-
reoselectivity for the reaction was were determined by conversion
of 18 into the rigid bicyclic lactam 16. The favorable selectivity for
[3,3]-rearrangement of 15b validated our conformational predic-
tions and reflects the greater facial bias the Z-alkene enforces
through A1,3-strain.26
the desired alkene
a-face due to the conformational restrictions
resulting from allylic non-bonding interactions (A1,3-strain). Given
our conformational predictions, the size and nature of the proline
nitrogen protecting group appeared relevant to alkene facial dis-
crimination; accordingly, we selected the largest carbamate func-
tion (Boc). In order to test our hypothesis, we prepared both
isomers 12a and 12b through HWE olefination on the derived alde-
hyde of 13.19
Reduction of proline 13 provided the intermediate carboxalde-
hyde, which was submitted directly to the HWE reaction.20 The
soft enolization conditions originally discovered by Masamune
and Roush were exploited in order to avoid epimerization of the
a
-stereogenic center of the derived aldehyde.21 Several phospho-
noacetate derivatives and reaction conditions were investigated
in order to improve the stereoselectivity for the formation of 12a
and 12b. The results of this screen are summarized in Table 1.
Reaction with trimethylphosphonoacetate (entry 1, 14a) affor-
ded a 3:1 mixture of alkene products favoring the E-isomer
(12a). By employing either arylphosphonate 14b (Ando22) or trif-
luoroethylphosphonate 14c (Still-Gennari23), the selectivity trend
could be reversed, slightly favoring the Z-isomeric product. Further
improvements were achieved by varying the base and additive.
Ultimately, a 2:1 ratio of Z-12b:E-12a could be obtained using
DBU with NaI in THF (entry 4).24 The Z- and E-isomeric substrates
With new confidence in our conformational predictions, we
sought to evaluate the aminoconjugate addition to isomeric
a,b-unsaturated esters 12a and 12b and prepare the desired 1-
aminopyrrolizidine core. As we began to probe this intermolecular
reaction, we initially noted that conjugate addition with each iso-
mer did not replicate the notable selectivity difference that we ob-
served for the model intramolecular Claisen rearrangement.
Addition of benzylamine in THF at reflux to Z-alkene 12b or
E-alkene 12a produced an identical 3:1 ratio of products 19 and
20 (Table 2; entries 1, 5). The reaction rate was slow, requiring
3 days at elevated temperatures (66 °C) to fully consume the start-
ing material. The resulting addition products 19 and 20 were
inseparable by chromatography and the product ratio could not
be determined conveniently by NMR due to carbamate rotamers.
As such, the product ratio and structure determination was
achieved by conversion of the mixture into pyrrolizidines 21 and
22 (see Scheme 3). The exocyclic or endocyclic amine function in
21 and 22 is structurally and spectroscopically distinct which per-
mitted separation of the diastereomers. The structure of 21 was
verified by single crystal X-ray analysis on the derived HCl salt.
Table 1
Preparation of vinylogous proline derivatives by HWE reaction
1. Dibal-H
H
H
CO2Me
PhMe, –60°C
13
NBoc
N
CO2Me
2.
(R)2P
Conditions
O
O
Boc
12b
14a-c
12a
OMe
Entry
R
Conditions
Ratio 12a:12b Yield (%)
During the course of reactions in THF with Z-a,b-unsaturated
1
2
3
4
14a MeO
14b PhO
14c CF3CH2O LiCl, DBU, MeCN
14b PhO NaI, DBU, THF
LiCl, i-Pr2NEt, MeCN 3:1
LiCl, i-Pr2NEt, MeCN 4:5
72 (12a–b)
36 (12b)
nd
ester 12b, isomer 12a was apparent by TLC. Several trials were
not run to full conversion and in these cases 12a was verified by
1H NMR from the unpurified reaction mixture. The presence of
12a, coupled with the nearly identical results observed for reaction
2:3
1:2
46 (12b)

4646
E. J. Eklund et al. / Tetrahedron Letters 53 (2012) 4644–4647
Table 2
Aminoconjugate addition to vinylogous proline derivatives
(E)-12a
NHBn
NHBn
H
N
H
N
or
(Z)-12b
hetero-
conjugate
addition
CO2Me
CO2Me
H
or
(E)-24
H
Boc
Boc
O
19
20
CO2t-Bu
NHBn
23
N
NBoc
Boc
Entry
Starting material
Reaction conditions
Product (ratio)a
Yieldb (%)
1
2
3
4
5
6
7
8
9
12a
12a
12a
12a
12b
12b
12b
12b
24
H2NBn, THF, 66 °C (3 d)
H2NBn, EtOH, 88 °C (2 d)
H2NBn neat, 25 °C (2 d)
LiNHBn, THF, ꢀ40 °C (2 h)
H2NBn, THF, 66 °C (3 d)
H2NBn, EtOH, 80 °C (2 d)
H2NBn neat, 25 °C (2 d)
LiNHBn, THF, ꢀ40 to 25 °C
LiNHBn, THF, ꢀ40 to 25 °C
19:20 (3:1)
19:20 (1:1)
19:20 (2:1)
23
19:20 (3:1)
19:20 (7:2)
19:20 (1:1)
nr
73
47
62
36
69
92
73
0
nr
0
a
Product ratio determined by conversion of the mixture of 19 and 20 to 21 and 22 (see Scheme 3).
Combined yield of 19 and 20.
b
2
To summarize our results, the aminoconjugate addition to
vinylogous proline derivatives is a marginal reaction. The approach
of the amine (or metal amide) likely encounters significant non-
i. 25% TFA,
NHBn
O
NHBn
H
N
H
8
Me2S, CH2Cl2
1
19
20
N
ii. EtOH, NEt3
1
O
bonding interactions at the c-position (the pyrrolidine ring). As a
21 22
result, elevated temperatures are required for the addition of ben-
zylamine and more reactive metal amides preferentially perform
as bases, not in the desired sense as nucleophiles. The choice of
reaction solvent has a modest effect on product ratios and, the best
overall reaction was observed with Z-12b in ethanol (entry 6, dr
7:2).
separable by
chromatography
X-ray
Structure 21•HCl
NHBn
NH2
H
H
N
a
c
Going forward with our best reaction, we prepared the desired
aminopyrrolizidine core 10 and completed the synthesis of 4, a
task requiring reduction of both the lactam and N-benzyl function
in 21. Reduction of the lactam with borane afforded the stable
intermediate pyrrolizidineꢁBH3 complex 25. We anticipated that
hydrogenolysis (in MeOH) would remove both the borane complex
and the benzyl amine.28 Toward this end, Pearlman’s catalyst
(Pd(OH)2/C) was investigated with a variety of hydrogen sources
b
21
(–)-4
[α]D = –48
(c 0.8, EtOH)
N
BH3
25
10
•2HCl
Scheme 3. Synthesis of (ꢀ)-absouline (4): (a) BH3ꢁMe2S, THF, 66 °C; (b) H2, 10% Pd/
C, MeOH, HCl; (c) DMAP, NEt3, DCC, 4-methoxycinnamic acid, CH2Cl2 (58% yield,
three steps).
ꢀ
(e.g., H2, HCO2H, NH4+HCO2 , H2NNH2) and, while the borane com-
with either 12a or 12b, support a reaction mechanism in which
isomerization of the Z-a,b-unsaturation in 12b to the E-alkene
12a is competitive with aminoconjugate addition for reactions per-
plex was easily removed, the benzyl group failed to cleave under
the conditions explored. Performing the hydrogenolysis in the
presence of strong acid proved critical for success of the operation.
Reduction with 10% Pd/C under an atmosphere of H2 at reflux in
MeOH containing 2.2 equiv of HCl efficiently cleaved the benzyl
group and decomposed the borane–amine complex. In this way,
aminopyrrolizidine 10 was reliably produced in nearly quantitative
yield. In practice, 10 was isolated as the bis-hydrochloride salt in
order to circumvent the volatility of the free amine. Largely follow-
ing precendent12a for the final reaction, amide coupling with trans-
4-methoxycinnamic acid, afforded (ꢀ)-absouline (4) in 58% yield
(three steps) from 21. The spectroscopic data for our synthetic
material agrees with previously published data.11,12 Furthermore,
the magnitude of optical rotation of 4 was consistent with preser-
vation of the stereochemical integrity at C8, the stereogenic center
derived from proline.29
In summary, we have achieved an efficient synthesis (seven
steps, four chromatographic separations) of the 1-aminopyrrolizi-
dine (ꢀ)-absouline (4) starting from a commercially available pro-
line derivative. In the course of this effort, conditions for a selective
HWE reaction were determined in order to prepare the isomeric
vinylogous proline derivatives 12a and 12b. Additionally, the ami-
noconjugate addition to both the E- and Z-unsaturated proline
derivatives was explored and optimal results were observed with
formed in THF.
In order to improve the heteroconjugate addition selectivity,
the reaction solvent and conditions were varied. Reaction with
12b proceeded to completion in ethanol (2 d, 80 °C) and afforded
a 92% combined yield of 19 and 20. In ethanol, slightly greater
selectivity for the addition was observed for 12b (entry 6) relative
to the isomeric E-configured material 12a (entry 2). In the absence
of a solvent, heteroconjugate addition could be achieved at ambi-
ent temperatures, though with diminished selectivity (Table 2; en-
tries 3, 7). Additionally, the isomerization of Z-a,b-unsaturated
material 12b, was not observed for reactions performed in ethanol
or without solvent.
Attempted addition of the more reactive lithiated N-benzyl-
amine to 12a or 12b failed to afford any desired conjugate addition
products 19 or 20; rather, the Z-isomeric substrate returned only
starting material and the E-configured material afforded the benzyl
amide 23.27 Because unsaturated t-butyl esters are known to sup-
press the rate of 1,2-addition16of amide nucleophiles (in favor of
1,4-addition), 24 was prepared via an analogous HWE olefination.
Reaction of E-a,b-unsaturated t-butyl ester 24 with lithiated N-
benzylamine unfortunately failed to provide any reaction product
(entry 9).

E. J. Eklund et al. / Tetrahedron Letters 53 (2012) 4644–4647
4647
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(Z)-12b in ethanol. The selectivity observed for this reaction likely
reflects the conformational bias enforced through allylic strain. We
believe that the chemistry revealed in this synthetic exercise
makes a contribution to the rich field of heteroconjugate addition
and will hopefully enable the synthesis of related aminopyrrolizi-
dine alkaloids and b-amino acid derivatives.
15. The sense of induction is explained from a modified vinylogous polar-Felkin–
Ahn model. For explanation and general review on the topic, see: Mengel, A.;
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Acknowledgments
This work was supported in part by the Jeffress Memorial Trust.
E.J.E. gratefully acknowledges ALSAM Research Fellowship.
16. For reviews on the addition of homochiral amides, see: (a) Davies, S. G.; Smith,
A. D.; Price, P. D. Tetrahedron: Asymmetry 2005, 16, 2833–2891; (b) Krishna, P.
R.; Sreeshailam, A.; Srinivas, R. Tetrahedron: Asymmetry 2009, 65, 9657–9672.
17. Previous preparations of 12a or 12b using a Wittig or HWE reaction, though
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derivatives. None of the following reports utilize Masamune–Roush reaction
conditions: (a) Poon, C. Y.; Chiu, P. Tetrahedron Lett. 2004, 45, 2985–2988; (b)
Coz, S. L.; Mann, A.; Thareau, F.; Taddei, M. Heterocycles 1993, 36, 2073–2080;
(c) Barrett, A. G. M.; Cook, A. S.; Kamimura, A. Chem. Commun. 1998, 2533–
2534; (d) Arisawa, M.; Takezawa, E.; Nishida, A.; Mori, M.; Nakagawa, M.
Synlett 1997, 1179–1180; (e) Chappie, T. A.; Weekly, R. M.; McMills, M. C.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.06.
028. These data include MOL files and InChiKeys of the most
important compounds described in this article.
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29. The observed optical rotation for our synthetic absouline (4): ½a D25
= ꢀ48 (c 0.8,
ꢂ
11. (a) Poupat, C.; Christine, C. M.; Ikhiri, K.; Ahond, A.; Mourabit, A. A.; Potier, P.
Tetrahedron: Asymmetry 2000, 56, 1837–1850; (b) Matos, M. N.; Afonso, C. A.
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EtOH); ꢀ28 (c 1.17, CHCl3). This compares favorably with published data:
natural (+)-4 (Ref. 5) ½a D20
ꢂ
= +56 (c 1.0, EtOH); synthetic (Ref. 12a) (ꢀ)-4 ½a D20
ꢂ
= –
51 (c 0.4, EtOH); –37 (c 1.8, CHCl3); synthetic (Ref. 11a) (+)-4 ½a D20
ꢂ
= +26 (c 1.05,
CHCl3).