Asymmetric Synthesis of the Tetraponerine Alkaloids

Article abstract of DOI:10.1021/acs.joc.7b00837

The asymmetric syntheses of all eight tetraponerine alkaloids (T1-T8) were achieved using the diastereoselective conjugate additions of lithium amide reagents in the key stereodefining steps. Conjugate addition of either lithium (R)-N-allyl-N-(α-methylbenzyl)amide or lithium (R)-N-(but-3-en-1-yl)-N-(α-methylbenzyl)amide to tert-butyl sorbate was followed by ring-closing metathesis of the resultant N-alkenyl β-amino esters, reduction to the corresponding aldehydes, and reaction with tert-butyl (triphenylphosphoranylidene)acetate. Subsequent conjugate addition of the requisite antipode of lithium N-benzyl-N-(α-methylbenzyl)amide to the resultant α,β-unsaturated esters gave a range of diamines for elaboration to T1-T8 via a sequence involving reduction of the ester moiety to give the corresponding aldehyde, olefination, tandem hydrogenation/hydrogenolysis, and cyclization upon reaction with 4-bromobutanal to give the tricyclic skeleton.

Full text of DOI:10.1021/acs.joc.7b00837

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Article
Asymmetric Synthesis of the Tetraponerine Alkaloids
Stephen G. Davies, Ai M. Fletcher, Ian T. T. Houlsby, Paul M. Roberts, and James E. Thomson
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 24 May 2017
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The Journal of Organic Chemistry
Asymmetric Synthesis of the Tetraponerine Alkaloids
Stephen G. Davies,* Ai M. Fletcher, Ian T. T. Houlsby
Paul M. Roberts, and James E. Thomson
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Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
Mansfield Road, Oxford, OX1 3TA, U.K.
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steve.davies@chem.ox.ac.uk
23 The asymmetric syntheses of all eight tetraponerine alkaloids (T1–T8) were achieved using the
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diastereoselective conjugate additions of lithium amide reagents in the key stereodefining steps. Conjugate
addition of either lithium (R)-N-allyl-N-(α-methylbenzyl)amide or lithium (R)-N-(but-3-en-1-yl)-N-(α-
methylbenzyl)amide to tert-butyl sorbate was followed by ring-closing metathesis of the resultant N-alkenyl
β-amino esters, reduction to the corresponding aldehydes, and reaction with tert-butyl
(triphenylphosphoranylidene)acetate. Subsequent conjugate addition of the requisite antipode of lithium N-
benzyl-N-(α-methylbenzyl)amide to the resultant α,β-unsaturated esters gave a range of diamines for
elaboration to T1–T8 via a sequence involving reduction of the ester moiety to give the corresponding
aldehyde, olefination, tandem hydrogenation/hydrogenolysis, and cyclisation upon reaction with 4-
bromobutanal to give the tricyclic skeleton.
Introduction
Tetraponerines 1–8 (which are also known as T1–T8, respectively) are a series of tricyclic aminals
first isolated from the paralyzing venom of the New Guinean pseudomyrmecine ant Tetraponera sp.1 These
54 alkaloids represent the major constituents of the contact poison secreted by host ants as a defence against
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enemy colonies: when smeared with the contact poison enemies display signs of paralysis and ultimately
death, presumably by inhibition of nicotinic acetylcholine receptors.2 The structures of the tetraponerine
alkaloids are based on either a decahydrodipyrrolo[1,2-a:1',2'-c]pyrimidine skeleton 1 (for tetraponerines 1,
2, 5 and 6) or a decahydro-5H-pyrido[1,2-c]pyrrolo[1,2-a]pyrimidine skeleton 2 (for tetraponerines 3, 4, 7
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and 8), with a C(5)-alkyl substituent being present in all cases. Within each heterocyclic series, the alkaloids
differ in their configurations at C(5) and also in the identity of the C(5)-alkyl substituent (Fig. 1). (+)-
Tetraponerine 8 is the only member of this family for which an X-ray crystal structure has been obtained to
confirm both its gross structure and relative configuration.1 The absolute configurations of tetraponerines 3–
8 have been established by separate chemical syntheses and comparison of the specific rotations for the
natural and synthetic material.3–5 Synthetic samples of (+)-tetraponerine 1 and (+)-tetraponerine 2 have also
been prepared,5,6 although the absolute configurations of the natural materials have not been unambiguously
established as only very small amounts were obtained from natural sources.4,7 The unusual tricyclic aminal
structure of the tetraponerine alkaloids, as well as their potent insecticidal activity, has meant that they have
become popular targets for total synthesis. Since their isolation in 1987, there have been several syntheses of
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21 these alkaloids in both racemic8 and enantiopure3–6,9 form.10,11 Herein, we report total syntheses of all eight
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tetraponerine alkaloids using our diastereoselective lithium amide conjugate addition methodology12 in the
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key stereodefining steps.
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FIGURE 1. The structures of the tetraponerine alkaloids T1–T8.
Our divergent synthetic strategy towards the tetraponerine alkaloids involved two iterative lithium
amide conjugate additions to install the requisite stereochemistry. In the first instance, conjugate addition of
either lithium (R)-N-allyl-N-(α-methylbenzyl)amide (R)-4 (n = 1) or lithium (R)-N-(but-3-en-1-yl)-N-(α-
methylbenzyl)amide (R)-5 (n = 2) to tert-butyl sorbate 3,13–15 followed by ring-closing metathesis of the
resultant N-alkenyl β-amino ester 6 (n = 1 or 2) and homologation would give the key α,β-unsaturated ester 7
(n = 1 or 2). Subsequent conjugate addition of the requisite antipode of lithium N-benzyl-N-(α-
methylbenzyl)amide 8 to α,β-unsaturated ester 7 (n = 1 or 2) would then provide a range of diamines 9 and
10 (n = 1 or 2 in both cases) for elaboration. In each case, a sequence involving reduction of the ester moiety
to the corresponding aldehyde, olefination, and tandem hydrogenation/hydrogenolysis would produce the
corresponding diamines 11 or 12 (n = 1 or 2 in both cases), which have previously been converted into the
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tetraponerine alkaloids by Gonzalez-Gomez et al.6,9d upon reaction with 4-bromobutanal (Fig. 2). As part of
their study, Gonzalez-Gomez et al. proposed that the configuration at the aminal functionality within each of
the tetraponerine alkaloids is susceptible to equilibration via the corresponding iminium ion and that the
natural products may therefore possess the most thermodynamically favourable relative configurations with
respect to epimerisation at the aminal centre.
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FIGURE 2. Proposed synthetic strategy to access all eight tetraponerine alkaloids.
Results and Discussion
The tetraponerine alkaloids based upon a decahydro-5H-pyrido[1,2-c]pyrrolo[1,2-a]pyrimidine
skeleton 2 (i.e., tetraponerines 3, 4, 7 and 8) were targeted initially. Tetrahydropyridine 14 was prepared via
a known sequence of reactions,13,14 involving conjugate addition of lithium (R)-N-(but-3-en-1-yl)-N-(α-
methylbenzyl)amide (R)-5 to tert-butyl sorbate 3,16 which gave β-amino ester 13 as a single diastereoisomer
(>99:1 dr) in 69% yield. Subsequent ring-closing metathesis of 13 gave tetrahydropyridine 14 in 83%
yield.13,14 A superior overall yield of 14 from tert-butyl sorbate 3 was obtained by omitting the purification
of the intermediate β-amino ester 13; following this sequence, tetrahydropyridine 14 was isolated in 73%
yield (from 3) and >99:1 dr. Reduction of 14 with LiAlH4 gave the corresponding alcohol 15 in 94% yield as
a single diastereoisomer. Swern oxidation of primary alcohol 15 followed by Wittig reaction of the resultant
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aldehyde with Ph3P=CHCO2 Bu gave a 93:7 mixture of diastereoisomeric products 16 and 17, respectively.
Purification of the crude reaction mixture gave the major product 16 in 46% yield and >99:1 dr [(E):(Z)], and
the minor product 17 in 3% yield and >99:1 dr [(Z):(E)]. However, a superior yield of 16 was obtained from
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the reduction of β-amino ester 14 with DIBAL-H followed by in situ Wittig reaction of the intermediate
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aldehyde with Ph3P=CHCO2 Bu, which gave an 80:20 mixture of 16 and 17, respectively, from which 16
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was isolated in 72% yield and >99:1 dr [(E):(Z)], and 17 was isolated in 14% yield and >99:1 dr [(Z):(E)]
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(Scheme 1).
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SCHEME 1. Preparation of tetrahydropyridine 16
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The inherent level of substrate control offered by chiral α,β-unsaturated ester 16 upon reaction with a
lithium amide reagent was probed upon conjugate addition of lithium N-isopropyl-N-benzylamide 18, which
we have previously employed as an achiral model for the conjugate addition of either antipode of
enantiopure lithium N-benzyl-N-(α-methylbenzyl)amide 8.17 Reaction of 16 with the achiral lithium amide
reagent 18 gave a 50:50 mixture of the diastereoisomeric β-amino ester adducts 19 and 20, which were
isolated in 96% combined yield. This result suggests that α,β-unsaturated ester 16 elicits essentially no
diastereoselectivity in the conjugate addition reaction, and is consistent with the low levels of substrate
control observed upon conjugate addition of lithium amides to substrates bearing remote stereogenic
centres.18 The conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide (R)-8 to α,β-unsaturated
ester 16 gave β-amino ester 21 in >95:5 dr, and conjugate addition of lithium (S)-N-benzyl-N-(α-
methylbenzyl)amide (S)-8 to 16 gave β-amino ester 22 in >95:5 dr. Following purification of the crude
reaction mixtures, 21 was isolated in 97% yield and >99:1 dr, and 22 was isolated in 94% yield and >99:1 dr
(Scheme 2). The configurations of the newly formed stereogenic centres within 21 and 22 were assigned on
the assumption that conjugate addition proceeds under the dominant stereocontrol of the lithium amide
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reagent 8 (given the total lack of substrate control observed upon conjugate addition of lithium N-isopropyl-
N-benzylamide 18 to α,β-unsaturated ester 16), and is consistent with the formation of 21 and 22 as single
diastereoisomers in both cases. These stereochemical assignments were later confirmed upon derivatisation
to the target tetraponerine alkaloids.
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SCHEME 2. Conjugate additions to 16
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The elaboration of 21 to (+)-tetraponerine 4 (27) was achieved via reduction of the ester moiety
within 21 with DIBAL-H followed by Wittig reaction of the resultant aldehyde with Ph3P=CH2, which gave
olefin 23 in 62% and >99:1 dr. Tandem Pd-mediated hydrogenation/hydrogenolysis of 23 in a mixture of
MeOH, H2O and AcOH gave diamine 25 in 73% isolated yield and >99:1 dr. Finally, reaction of 25 with 4-
bromobutanal and K2CO3 in CH2Cl2, according to the literature protocol,6,9d gave (+)-tetraponerine 4 (27) in
68% yield and >99:1 dr. The spectroscopic data and specific rotation for this sample of (+)-tetraponerine 4
(27) were in good agreement with literature values {[]2D5 +90.8 (c 1.0 in CHCl3); lit.4 for a sample isolated
from the natural source []2D0 +94 (c 0.2 in CHCl3); lit.9b []D20 +96 (c 2.0 in CHCl3)}, thereby confirming
the assigned configurations of the synthetic precursors 21, 23 and 25. Repetition of this
hydrogenation/hydrogenolysis and ring-closure reaction sequence, but omitting the purification of the
intermediate diamine 25, gave (+)-tetraponerine 4 (27) in 54% overall yield (from 23), representing a
marginal improvement over the stepwise protocol (i.e., 50% overall yield from 23). (+)-Tetraponerine 8 (28)
was also prepared from 21 in a directly analogous manner: one-pot reduction/Wittig reaction of 21 gave
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olefin 24 in 62% yield and >95:5 dr [(Z):(E)].19 Subsequent tandem hydrogenation/hydrogenolysis of 24
gave diamine 26 (although in this case only it was necessary to re-subject the hydrogenation/hydrogenolysis
reaction using Pd(OH)2 as the catalyst to effect complete N-debenzylation). Diamine 26 was then
immediately converted into (+)-tetraponerine 8 (28) upon treatment with 4-bromobutanal.6,9d Following
purification of the crude reaction mixture, (+)-tetraponerine 8 (28) was isolated as a single diastereoisomer
(>99:1 dr) in 67% yield from 24 (Scheme 3). The spectroscopic data, melting point and specific rotation for
this sample of (+)-tetraponerine 8 (28) were all in good agreement with literature values {mp 38–40 °C; lit.5
mp 40 °C; []2D5 +93.0 (c 1.0 in CHCl3); lit.4 for a sample isolated from the natural source []D20 +102 (c 0.2
in CHCl3); lit.9b []D20 +101 (c 2.0 in CHCl3)}, thereby confirming the assigned configurations of the
synthetic precursors 21, 24 and 26. The asymmetric syntheses of (+)-tetraponerine 4 (27) and (+)-
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from commercially available starting materials.
SCHEME 3. Preparation of (+)-tetraponerine 4 and (+)-tetraponerine 8
Elaboration of the diastereoisomeric substrate 22 to (+)-tetraponerine 3 (33) and (+)-tetraponerine 7
(34) was also evaluated. Reduction of 22 with DIBAL-H followed by Wittig reaction of the resultant
aldehyde with the requisite ylid reagent Ph3P=CHR gave either 29 (R = H) or 30 (R = Et); after
chromatographic purification of the crude reaction mixtures, 29 was isolated in 54% yield as a single
diastereoisomer and 30 was isolated in 47% yield and >95:5 dr [(Z):(E)].20 Tandem
hydrogenation/hydrogenolysis of 29 and 30 gave the corresponding diamines 31 and 32, which were
immediately reacted with 4-bromobutanal6,9d to give (+)-tetraponerine 3 (33) and (+)-tetraponerine 7 (34) in
60 and 44% yield, respectively, as single diastereoisomers (>99:1 dr) in each case (Scheme 4). The
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spectroscopic data and specific rotations for these samples of (+)-tetraponerine 3 (33) and (+)-tetraponerine
7 (34) were in good agreement with literature values {for (+)-tetraponerine 3 (33): []2D5 +30.9 (c 1.0 in
CHCl3); lit.4 for a sample isolated from the natural source []2D0 +27 (c 0.07 in CHCl3); lit.5 []2D0 +31 (c 3.1
in CHCl3); lit.9d []D20 +35 (c 0.49 in CHCl3); for (+)-tetraponerine 7 (34): []D25 +30.4 (c 0.8 in CHCl3); lit.4
for a sample isolated from the natural source []2D0 +30 (c 0.22 in CHCl3); lit.9b []D20 +29.5 (c 2.2 in CHCl3)},
thereby confirming the assigned configurations of the synthetic precursors 22 and 29–32. The asymmetric
syntheses of (+)-tetraponerine 3 (33) and (+)-tetraponerine 7 (34) were therefore achieved in 14.6 and 9.3%
overall yield, respectively, in eight steps from commercially available starting materials.
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SCHEME 4. Preparation of (+)-tetraponerine 3 and (+)-tetraponerine 7
The remaining tetraponerine alkaloids in the series, based on a decahydrodipyrrolo[1,2-a:1',2'-
c]pyrimidine scaffold 1 (i.e., tetraponerines 1, 2, 5 and 6), were targeted next. Dihydropyrrole 36 was
prepared via a known sequence of reactions,13,15 involving conjugate addition of lithium (R)-N-allyl-N-(α-
methylbenzyl)amide (R)-4 to tert-butyl sorbate 3,16 which gave β-amino ester 35 in 89% yield as a single
diastereoisomer (>99:1 dr). Subsequent ring-closing metathesis of 35 gave dihydropyrrole 36 in 86% yield
and >99:1 dr.13,15 In this case, it was found that hydrogenation of 36 with Wilkinson’s catalyst
[RhCl(PPh3)3]13,15a,b to give pyrrolidine 37 was necessary to avoid oxidative side reactions, leading to
various pyrrole containing species, in the subsequent steps.21 Reduction of the ester moiety within
pyrrolidine 37 with DIBAL-H followed by in situ Wittig reaction of the corresponding aldehyde with
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Ph3P=CHCO2 Bu gave a 75:25 mixture of 38 and 39, respectively. Following purification of the crude
reaction mixture, an 86:14 mixture of 38 and 39, respectively, was isolated in 66% combined yield in
addition to a 9:91 mixture of 38 and 39 in 13% combined yield. Upon repetition of the reaction sequence,
hydrogenation of dihydropyrrole 36 followed by immediate reduction of the crude reaction mixture with
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DIBAL-H and Wittig reaction of the resultant aldehyde gave 38 in 50% yield (from 36) and 98:2 dr (Scheme
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SCHEME 5. Preparation of pyrrolidine 38
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The inherent level of substrate control offered by α,β-unsaturated ester 38 (98:2 dr [(E):(Z)]) was
probed upon conjugate addition of lithium N-isopropyl-N-benzylamide 18, which gave a 50:50 mixture of
the diastereoisomeric β-amino ester adducts 40 and 41. Following purification of the crude reaction mixture,
40 and 41 were isolated as a 50:50 mixture in 70% combined yield. This result suggests that α,β-unsaturated
ester 38 elicits essentially no diastereoselectivity in the conjugate addition reaction, as was also the case for
the homologous tetrahydropyridine containing substrate 16, and is again consistent with the low levels of
substrate control observed upon conjugate addition of lithium amides to other substrates bearing remote
stereogenic centres.18 The conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide (R)-8 to
α,β-unsaturated ester 38 (98:2 dr [(E):(Z)]) gave β-amino ester 42 in 98% yield and >99:1 dr, whereas
conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide (S)-8 to 38 (98:2 dr [(E):(Z)]) gave β-
amino ester 43 in 92% isolated yield and >99:1 dr (Scheme 6). The configurations of the newly formed
54 stereogenic centres within the conjugate addition products 42 and 43 were assigned, as before, on the
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assumption that conjugate addition proceeds under the dominant stereocontrol of the lithium amide reagent
in both cases; these assignments were later confirmed upon derivatisation to the target alkaloids. Conjugate
addition of lithium amide (R)-8 to an 86:14 mixture of (E)-38 and (Z)-39, respectively, gave an 86:14
mixture of β-amino ester 42 and a species which was tentatively assigned as the corresponding β,γ-
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1
unsaturated derivative 44; there was no evidence of either (E)-38 or (Z)-39 in the H NMR spectrum of the
crude reaction mixture. As β-amino ester 42 and β,γ-unsaturated ester 44 were only partially separable upon
attempted chromatographic purification, this result confirmed that it was necessary to enrich the
diastereoisomeric purity of the α,β-unsaturated ester prior to attempting the conjugate addition reaction.
SCHEME 6. Conjugate additions to 38
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Reduction of 42 with DIBAL-H followed by Wittig reaction of the resultant aldehyde with the
requisite ylid reagent Ph3P=CHR gave either 45 (R = H) or 46 (R = Et); after chromatographic purification
of the crude reaction mixtures, 45 was isolated in 76% yield and >99:1 dr, and 46 was isolated in 75% yield
and >95:5 dr [(Z):(E)].20 Tandem hydrogenation/hydrogenolysis of 45 and 46 gave the corresponding
diamines 47 and 48, which were immediately reacted with 4-bromobutanal6,9d to give (+)-tetraponerine 2
(49) and (+)-tetraponerine 6 (50) in 37 and 54% yield, respectively, as single diastereoisomers (>99:1 dr) in
each case (Scheme 7). For (+)-tetraponerine 2 (49), the specific rotation was consistent with literature values
{
[]2D5 +44.2 (c 1.0 in CHCl3); lit.5 []D20 +36 (c 1.79 in CHCl3); lit.6 []2D0 +47 (c 0.232 in CHCl3)}; however,
for (+)-tetraponerine 6 (50) the specific rotations of our synthetic samples were consistently larger than
literature values {[]2D5 +66.3 (c 1.0 in CHCl3); lit.4 for a sample isolated from the natural source []D20 +35
(c 0.15 in CHCl3); lit.6 []D20 +40 (c 0.75 in CHCl3)}. Despite this discrepancy,22 the spectroscopic data for
both samples of (+)-tetraponerine 2 (49) and (+)-tetraponerine 6 (50) were in good agreement with literature
values, thereby confirming the assigned configurations of the synthetic precursors 42 and 45–48. The
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asymmetric syntheses of (+)-tetraponerine 2 (49) and (+)-tetraponerine 6 (50) were therefore achieved in 9.6
and 13.8% overall yield, respectively, in nine steps from commercially available starting materials.
SCHEME 7. Preparation of (+)-tetraponerine 2 and (+)-tetraponerine 6
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Reduction of the diastereoisomeric substrate 43 with DIBAL-H followed by Wittig reaction of the
resultant aldehyde with the requisite ylid reagent Ph3P=CHR gave either 51 (R = H) or 52 (R = Et); after
chromatographic purification of the crude reaction mixtures, 51 was isolated in 40% yield as a single
diastereoisomer and 52 was isolated in 48% yield and >95:5 dr [(Z):(E)].20 Tandem
hydrogenation/hydrogenolysis of 51 and 52 gave the corresponding diamines 53 and 54, which were
immediately reacted with 4-bromobutanal6,9d to give (+)-tetraponerine 1 (55) and (+)-tetraponerine 5 (56) in
15 and 14% yield, respectively, as single diastereoisomers (>99:1 dr) in each case (Scheme 8). The
spectroscopic data and specific rotations for these samples of (+)-tetraponerine 1 (55) and (+)-tetraponerine
5 (56) were in good agreement with literature values {for (+)-tetraponerine 1 (55): []2D5 +14.4 (c 0.13 in
CHCl3); lit.5 []D20 +11 (c 0.14 in CHCl3); lit.6 []D20 +14 (c 0.498 in CHCl3); for (+)-tetraponerine 5 (56):
[]2D5 +12.4 (c 0.13 in CHCl3); lit.4 for a sample isolated from the natural source []D20 +10 (c 0.2 in CHCl3);
lit.5 []2D0 +10 (c 0.24 in CHCl3); lit.6 []2D0 +14 (c 1.6 in CHCl3)}, thereby confirming the assigned
configurations of the synthetic precursors 43 and 51–54. The asymmetric syntheses of (+)-tetraponerine 1
(55) and (+)-tetraponerine 5 (56) were therefore achieved in 1.9 and 2.2% overall yield, respectively, in nine
steps from commercially available starting materials.
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SCHEME 8. Preparation of (+)-tetraponerine 1 and (+)-tetraponerine 5
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Conclusion
In conclusion, the conjugate addition of either lithium (R)-N-allyl-N-(α-methylbenzyl)amide or
lithium (R)-N-(but-3-en-1-yl)-N-(α-methylbenzyl)amide to tert-butyl sorbate was followed by ring-closing
metathesis of the resultant N-alkenyl β-amino esters and homologation. Subsequent conjugate addition of the
requisite antipode of lithium N-benzyl-N-(α-methylbenzyl)amide to the resultant α,β-unsaturated esters gave
a range of diamines for elaboration to all eight tetraponerine alkaloids (T1–T8) via a sequence involving
reduction of the ester moiety to the corresponding aldehyde, olefination, tandem
hydrogenation/hydrogenolysis, and reaction with 4-bromobutanal to give the tricyclic skeleton. In each case,
the target alkaloids were isolated enantiomerically pure as single diastereoisomers in nine steps or fewer
from commercially available sorbic acid.
Experimental Section
General experimental details. All reactions involving organometallic or other moisture-sensitive
reagents were carried out under a nitrogen atmosphere using standard vacuum line techniques and glassware
that was flame dried and cooled under nitrogen before use. Solvents were dried according to the procedure
outlined by Grubbs and co-workers.23 BuLi was purchased as a solution in hexanes and titrated against
diphenylacetic acid before use. All other reagents were used as supplied without prior purification. Organic
layers were dried over Na2SO4. Thin layer chromatography was performed on aluminium plates coated with
60 F254 silica. Plates were visualised using UV light (254 nm), 1% aq KMnO4 or Dragendorff’s reagent.
Flash column chromatography was performed on Kieselgel 60 silica. Melting points are uncorrected.
Specific rotations are reported in 10−1 deg cm2 g−1 and concentrations in g/100 mL. IR spectra were recorded
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using an ATR module. Selected characteristic peaks are reported in cm–1. NMR spectra were recorded in the
deuterated solvent stated. Spectra were recorded at rt unless otherwise stated. The field was locked by
1
2
3
4
5
1
external referencing to the relevant deuteron resonance. H−1H COSY, 1H−13C HMQC, and 1H−13C HMBC
6
7
8
9
analyses were used to establish atom connectivity. Accurate mass measurements were run on a TOF
spectrometer internally calibrated with polyalanine.
10
11
12
13
14
15
16
17
18
19
20
tert-Butyl (E,E)-hexa-2,4-dienoate [tert-butyl sorbate] 3. Condensed isobutylene (180 mL) at –78
°C was added to a stirred solution of sorbic acid (30.0 g, 268 mmol) and conc aq H2SO4 (3.00 mL) in
CH2Cl2 (600 mL) at 0 °C, and the resultant mixture was allowed to warm to rt and stirred at rt for 48 h. The
reaction mixture was washed with satd aq NaHCO3 (5 × 300 mL) and the combined aqueous washings were
extracted with CH2Cl2 (2 × 300 mL). The combined organic extracts were washed with brine (500 mL), then
21 dried and concentrated in vacuo to give 3 as a pale yellow oil (41.1 g, 91%, >99:1 dr);13 δH (400 MHz,
22
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30
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32
33
34
35
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37
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39
40
41
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CDCl3) 1.48 (9H, s, CMe3), 1.84 (3H, d, J 5.9, C(6)H3), 5.70 (1H, d, J 15.4, C(2)H), 6.04–6.21 (2H, m,
C(4)H, C(5)H), 7.15 (1H, dd, J 15.4, 10.0, C(3)H).
tert-Butyl (3S,αR,E)-3-[N-(but-3'-en-1'-yl)-N-(α-methylbenzyl)amino]hex-4-enoate 13. BuLi (2.3
M in hexanes, 2.00 mL, 4.61 mmol) was added dropwise to a stirred solution of (R)-N-(but-3-en-1-yl)-N-(α-
methlbenzyl)amine (833 mg, 4.76 mmol, >99:1 er) in THF (5 mL) at –78 °C and the resultant mixture was
stirred at –78 °C for 30 min. A solution of 3 (500 mg, 2.97 mmol, >99:1 dr) in THF (2 mL) at
–78 °C was added via cannula and the resultant mixture was stirred at –78 °C for 2 h. Satd aq NH4Cl (2 mL)
was added and the reaction mixture was allowed to warm to rt, then concentrated in vacuo. The residue was
partitioned between CH2Cl2 (10 mL) and 10% citric acid (10 mL), and the organic layer was washed with
satd aq NaHCO3 (10 mL) and brine (10 mL), then dried and concentrated in vacuo to give 13 in >95:5 dr.
Purification via flash column chromatography (eluent 30–40 °C petrol/Et2O, 20:1) gave 13 as a pale yellow
[]2D5
[]2D0
–14.6 (c 1.0 in CHCl3)}; δH (400
oil (708 mg, 69%, >99:1 dr);13
–15.4 (c 2.0 in CHCl3); {lit.14
MHz, CDCl3) 1.36 (3H, d, J 6.7, C(α)Me), 1.40 (9H, s, CMe3), 1.69 (3H, d, J 5.0, C(6)H3), 1.96–2.08 (2H,
m, C(2')H2), 2.28 (1H, dd, J 14.1, 8.2, C(2)HA), 2.40 (1H, dd, J 14.1, 6.6, C(2)HB), 2.44–2.58 (2H, m,
C(1')H2), 3.75–3.81 (1H, m, C(3)H), 3.93 (1H, q, J 6.7, C(α)H), 4.86–4.94 (2H, m, C(4')H2), 5.45–5.58 (2H,
m, C(4)H, C(5)H), 5.64 (1H, ddt, J 17.0, 10.3, 6.8, C(3')H), 7.17–7.23 (1H, m, Ph), 7.25–7.30 (2H, m, Ph),
7.32–7.37 (2H, m, Ph).
tert-Butyl (2'S,αR)-2-[N(1')-(α-methylbenzyl)-1',2',5',6'-tetrahydropyridin-2'-yl]acetate 14.
Method A (from 13): Grubbs I catalyst (301 mg, 0.366 mmol) was added to a stirred, degassed solution of 13
(3.14 g, 9.14 mmol, >99:1 dr) in anhydrous CH2Cl2 (EtOH stabilised, 300 mL) at rt. The resultant mixture
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was stirred at rt for 16 h, then concentrated in vacuo. Purification via flash column chromatography (eluent
1
2
3
30–40 °C petrol/Et2O/NH4OH, 100:10:1) gave 14 as a pale yellow oil (2.30 g, 83% from 13, >99:1 dr);13
4
5
[]2D5 +41.5 (c 1.0 in CHCl3); {lit.13
+41.8 (c 1.5 in CHCl3)}; δH (400 MHz, CDCl3) 1.38 (3H, d, J 6.6,
[]2D5
6
7
8
9
C(α)Me), 1.48 (9H, s, CMe3), 1.66–1.75 (1H, m, C(5')HA), 2.04–2.16 (1H, m, C(5')HB), 2.37 (1H, dd, J 14.2,
6.8, C(2)HA), 2.43–2.50 (1H, m, C(6')HA), 2.59 (1H, dd, J 14.2, 7.3, C(2)HB), 2.84 (1H, ddd, J 13.9, 9.5, 4.7,
C(6')HB), 3.70–3.77 (1H, m, C(2')H), 3.89 (1H, q, J 6.6, C(α)H), 5.62–5.67 (1H, m, C(3')H), 5.78–5.85 (1H,
m, C(4')H), 7.20–7.34 (5H, m, Ph).
10
11
12
13
14
15
16
17
18
19
20
Method B (from 3) – Step 1: BuLi (2.3 M in hexanes, 20.0 mL, 46.1 mmol) was added dropwise to a stirred
solution of (R)-N-(but-3-en-1-yl)-N-(α-methylbenzyl)amine (8.33 g, 47.6 mmol, >99:1 er) in THF (70 mL)
at –78 °C and the resultant mixture was stirred at –78 °C for 30 min. A solution of 3 (5.00 g, 29.7 mmol,
21 >99:1 dr) in THF (10 mL) at –78 °C was then added and the resultant mixture was stirred at –78 °C for 2 h.
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51
52
53
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55
56
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60
Satd aq NH4Cl (20 mL) was added and the reaction mixture was allowed to warm to rt, then concentrated in
vacuo. The residue was partitioned between CH2Cl2 (50 mL) and 10% citric acid (50 mL), and the organic
layer was washed with satd aq NaHCO3 (50 mL) and brine (50 mL), then dried and concentrated in vacuo to
give 13 in >95:5 dr.
Method B (from 3) – Step 2: Grubbs I catalyst (854 mg, 1.04 mmol) was added to a stirred, degassed solution
of the residue of 13 from the previous step in anhydrous CH2Cl2 (EtOH stabilised, 900 mL) at rt. The
resultant solution was stirred at rt for 16 h, then concentrated in vacuo. Purification via flash column
chromatography (eluent 30–40 °C petrol/Et2O/NH4OH, 100:10:1) gave 14 as a pale yellow oil (6.55 g, 73%
[]25
from 3, >99.1 dr);
+44.8 (c 0.8 in CHCl3).
D
(2'S,αR)-2-[N(1')-(α-Methylbenzyl)-1',2',5',6'-tetrahydropyridin-2'-yl]ethan-1-ol 15. LiAlH4 (2.4
M in THF, 3.18 mL, 7.63 mmol) was added to a stirred solution of 14 (2.30 g, 7.63 mmol, >99:1 dr) in THF
(70 mL) at 0 °C. The resultant mixture was allowed to warm to rt and stirred at rt for 16 h. 2.0 M aq NaOH
(7 mL) was then added and the resultant mixture was stirred at rt for 3 h. The reaction mixture was filtered
through Celite® (eluent CH2Cl2), then concentrated in vacuo to give 15 as a pale yellow oil (1.66 g, 94%,
[]25
>99:1 dr);
–3.9 (c 1.0 in CHCl3); νmax (ATR) 3393 (O–H), 3026, 2970, 2839, (C–H), 1454 (C=C); δH
D
(400 MHz, CDCl3) 1.49 (3H, d, J 6.6, C(α)Me), 1.73–1.88 (2H, m, C(2)HA, C(5')HA), 1.88–1.97 (1H, m,
C(2)HB), 2.04–2.14 (1H, m, C(5')HB), 2.34 (1H, app dt, J 13.4, 4.5, C(6')HA), 3.02 (1H, ddd, J 13.4, 8.9, 4.7,
C(6')HB), 3.59–3.66 (1H, m, C(2')H), 3.85–3.96 (2H, m, C(1)H2), 4.05 (1H, q, J 6.6, C(α)H), 5.50–5.56 (1H,
m, C(3')H), 5.84–5.97 (1H, m, C(4')H), 6.36 (1H, br s, OH), 7.24–7.39 (5H, m, Ph); δC (100 MHz, CDCl3)
21.3, 21.4 (C(5'), C(α)Me), 32.9 (C(2)), 40.0 (C(6')), 56.2 (C(2')), 57.6 (C(α)), 63.0 (C(1)), 126.4 (C(4')),
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127.4 (p-Ph), 127.8, 128.5 (o,m-Ph), 128.5 (C(3')), 142.6 (i-Ph); m/z (ESI+) 232 ([M + H]+, 100%); HRMS
(ESI+) m/z: [M + H]+ Calcd for C15H22NO+ 232.1696; Found 232.1696.
1
2
3
4
5
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7
8
9
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19
20
tert-Butyl (2'S,αR,E)-4-[N(1')-(α-methylbenzyl)-1',2',5',6'-tetrahydropyridin-2'-yl]but-2-enoate
16 and tert-Butyl (2'S,αR,Z)-4-[N(1')-(α-methylbenzyl)-1',2',5',6'-tetrahydropyridin-2'-yl]but-2-enoate
17. Method A (from 15): DMSO (0.61 mL, 8.65 mmol) was added to a stirred solution of (COCl)2 (0.37 mL,
4.32 mmol) in CH2Cl2 (50 mL) at –78 °C. After 20 min, 15 (500 mg, 2.16 mmol, >99:1 dr) was added and
the resultant mixture was stirred at –78 °C for 40 min, then Et3N (1.81 mL, 13.0 mmol) was added. The
t
reaction mixture was allowed to warm to rt, Ph3P=CHCO2 Bu (814 mg, 2.16 mmol) was added, and the
resultant mixture was stirred at rt for 16 h. Satd aq K2CO3 (300 mL) was then added and the reaction mixture
was extracted with CH2Cl2 (3 × 300 mL). The combined organic extracts were washed with brine (500 mL),
21 then dried and concentrated in vacuo to give a 93:7 mixture of 16 and 17, respectively. Purification via flash
22
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26
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28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
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47
48
49
50
51
52
53
54
55
56
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59
60
column chromatography (eluent 30–40 °C petrol/Et2O/NH4OH, 100:10:1) gave 17 as a pale yellow oil (19
[]25
mg, 3%, >99:1 dr);
+57.4 (c 1.0 in CHCl3); νmax (ATR) 2975, 2931 (C–H), 1712 (C=O), 1639 (C=C);
D
δH (400 MHz, CDCl3) 1.34 (3H, d, J 6.8, C(α)Me), 1.47 (9H, s, CMe3), 1.84–1.94 (1H, m, C(5')HA), 1.96–
2.05 (1H, m, C(5')HB), 2.23 (1H, ddd, J 12.1, 7.2, 5.7, C(6')HA), 2.65–2.73 (1H, m, C(4)HA), 2.92 (1H, app
dt, J 12.1, 5.6, C(6')HB), 3.16–3.26 (2H, m, C(4)HB, C(2')H), 4.00 (1H, q, J 6.8, C(α)H), 5.46–5.51 (1H, m,
C(3')H), 5.73 (1H, d, J 11.4, C(2)H), 5.73–5.78 (1H, m, C(4')H), 6.30 (1H, app dt, J 11.4, 7.5, C(3)H), 7.17–
7.34 (5H, m, Ph); δC (100 MHz, CDCl3) 20.9 (C(α)Me), 24.3 (C(5')), 28.4 (CMe3), 32.1 (C(4)), 40.8 (C(6')),
54.9 (C(2')), 57.1 (C(α)), 80.1 (CMe3), 122.0 (C(2)), 126.5 (C(4')), 126.9 (p-Ph), 128.1, 128.1 (o,m-Ph),
130.1 (C(3')), 142.6 (i-Ph), 146.7 (C(3)), 166.4 (C(1)); m/z (ESI+) 328 ([M + H]+, 100%); HRMS (ESI+) m/z:
+
[M + H]+ Calcd for C21H30NO2 328.2271; Found 328.2273. Further elution gave 16 as a yellow oil (322 mg,
[]25
46%, >99:1 dr);
+65.9 (c 1.0 in CHCl3); νmax (ATR) 2979, 2932 (C–H), 1713 (C=O), 1651 (C=C); δH
D
(400 MHz, CDCl3) 1.38 (3H, d, J 6.7, C(α)Me), 1.49 (9H, s, CMe3), 1.82–1.93 (1H, m, C(5')HA), 2.03–2.15
(1H, m, C(5')HB), 2.36–2.55 (3H, m, C(4)H2, C(6')HA), 2.88 (1H, ddd, J 12.7, 7.8, 4.8, C(6')HB), 3.23–3.31
(1H, m, C(2')H), 3.95 (1H, q, J 6.7, C(α)H), 5.53–5.58 (1H, m, C(3')H), 5.77 (1H, d, J 15.5, C(2)H), 5.77–
5.83 (1H, m, C(4')H), 6.90 (1H, ddd, J 15.5, 8.0, 6.7, C(3)H), 7.21–7.35 (5H, m, Ph); δC (100 MHz, CDCl3)
21.4 (C(α)Me), 23.9 (C(5')), 28.3 (CMe3), 35.9 (C(4)), 40.7 (C(6')), 54.6 (C(2')), 57.9 (C(α)), 80.1 (CMe3),
124.3 (C(2)), 126.5 (C(4')), 127.0 (p-Ph), 127.9, 128.3 (o,m-Ph), 129.5 (C(3')), 143.4 (i-Ph), 145.9 (C(3)),
+
166.1 (C(1)); m/z (ESI+) 328 ([M + H]+, 100%); HRMS (ESI+) m/z: [M + H]+ Calcd for C21H30NO2
328.2271; Found 328.2271.
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Method B (from 14): DIBAL-H (1.0 M in PhMe, 7.30 mL, 7.30 mmol) was added dropwise to a stirred
solution of 14 (2.00 g, 6.64 mmol, >99:1 dr) in PhMe (20 mL) at –78 °C and the resultant mixture was
1
2
3
4
5
t
stirred at –78 °C for 1 h. MeOH (1.34 mL, 33.2 mmol) and Ph3P=CHCO2 Bu (2.50 g, 6.64 mmol) were
6
7
8
9
added sequentially, and the resultant mixture was allowed to warm to rt and stirred at rt for 16 h. The
reaction mixture was then concentrated in vacuo to give an 80:20 mixture of 16 and 17, respectively.
Purification via flash column chromatography (eluent 30–40 °C petrol/Et2O/NH4OH, 100:10:1) gave 17 as a
pale yellow oil (313 mg, 14%, >99:1 dr); []2D5 +60.2 (c 0.5 in CHCl3). Further elution gave 16 as a yellow
oil (1.57 g, 72%, >99:1 dr); []2D5 +63.4 (c 1.0 in CHCl3).
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11
12
13
14
15
16
17
18
19
20
tert-Butyl
(3R,2'S,αR)-3-[N-benzyl-N-isopropylamino]-4-[N(1')-(α-methylbenzyl)-1',2',5',6'-
tetrahydropyridin-2'-yl]butanoate and tert-butyl (3S,2'S,αR)-3-[N-benzyl-N-isopropylamino]-4-[N(1')-
21 (α-methylbenzyl)-1',2',5',6'-tetrahydropyridin-2'-yl]butanoate 19 and 20. BuLi (2.3 M in hexanes, 0.44
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
mL, 1.00 mmol) was added dropwise to a stirred solution of N-benzyl-N-isopropylamine (155 mg, 1.04
mmol) in THF (2 mL) at –78 °C and the resultant mixture was stirred at –78 °C for 30 min. A solution of 16
(212 mg, 0.647 mmol, >99:1 dr) in THF (1 mL) at –78 °C was added via cannula and the resultant mixture
was stirred at –78 °C for 2 h. Satd aq NH4Cl (0.5 mL) was added and the reaction mixture was allowed to
warm to rt, then concentrated in vacuo. The residue was partitioned between CH2Cl2 (10 mL) and 10% citric
acid (10 mL), and the organic layer was washed with satd aq NaHCO3 (10 mL) and brine (10 mL), then
dried and concentrated in vacuo to give a 50:50 mixture of 19 and 20 as a colourless oil (296 mg, 96%). Data
for 19: δH (400 MHz, CDCl3) 1.05–1.11 (6H, m, NCHMe2), 1.35 (3H, d, J 6.5, C(α)Me), 1.36–1.63 (2H, m,
C(4)HA, C(5')HA), 1.50 (9H, s, CMe3), 1.84–1.98 (1H, m, C(4)HB), 2.04–2.17 (1H, m, C(5')HB), 2.42–2.57
(3H, m, C(2)H2, C(6')HA), 2.72–2.84 (1H, m, C(6')HB), 2.91–3.02 (1H, m, NCHMe2), 3.32–3.43 (1H, m,
C(2')H), 3.52–3.61 (1H, m, C(3)H), 3.65 (1H, d, J 14.5, NCHAHBPh), 3.73 (1H, d, J 14.5, NCHAHBPh), 3.84
(1H, q, J 6.5, C(α)H), 5.33–5.43 (1H, m, C(3')H), 5.69–5.79 (1H, m, C(4')H), 7.19–7.43 (10H, m, Ph). Data
for 20: δH (400 MHz, CDCl3) 1.05–1.11 (6H, m, NCHMe2), 1.35 (3H, d, J 6.5, C(α)Me), 1.36–1.63 (2H, m,
C(4)HA, C(5')HA), 1.46 (9H, s, CMe3), 1.68 (1H, app dt, J 14.2, 5.2, C(4)HB), 2.04–2.17 (1H, m, C(5')HB),
2.29 (1H, dd, J 13.7, 6.2, C(2)HA), 2.40–2.57 (2H, m, C(2)HB, C(6')HA), 2.72–2.84 (1H, m, C(6')HB), 2.91–
3.02 (1H, m, NCHMe2), 3.32–3.43 (1H, m, C(2')H), 3.52–3.61 (1H, m, C(3)H), 3.66 (2H, s, NCH2Ph), 3.84
(1H, q, J 6.5, C(α)H), 5.49–5.55 (1H, m, C(3')H), 5.69–5.79 (1H, m, C(4')H), 7.19–7.43 (10H, m, Ph). Data
for mixture of 19 and 20: νmax (ATR) 3024, 2967, 2931, 2837 (C–H), 1724 (C=O), 1602 (C=C); δC (100
MHz, CDCl3) 20.2, 20.4, 20.8, 20.9, 21.1, 21.8, 22.7, 23.0, 28.3, 28.3, 36.5, 37.4, 39.8, 39.9, 40.2, 40.4,
47.8, 49.3, 49.4, 50.0, 51.2, 51.9, 52.4, 53.9, 58.0, 58.2, 80.0, 80.1, 125.4, 125.7, 126.6, 126.6, 126.8, 126.8,
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127.5, 127.6, 128.1, 128.1, 128.3, 128.3 ,128.5, 129.0, 129.8, 130.2, 141.8, 142.3, 145.9, 146.2, 172.3,
1
2
3
+
172.6; m/z (ESI+) 477 ([M + H]+, 100%); HRMS (ESI+) m/z: [M + H]+ Calcd for C31H45N2O2 477.3476;
4
5
Found 477.3471.
6
7
8
9
tert-Butyl (3R,2'S,αR,α'R)-3-[N-benzyl-N-(α-methylbenzyl)amino]-4-[N(1')-(α'-methylbenzyl)-
1',2',5',6'-tetrahydropyridin-2'-yl]butanoate 21. BuLi (2.3 M in hexanes, 0.58 mL, 1.33 mmol) was added
dropwise to a stirred solution of (R)-N-benzyl-N-(α-methylbenzyl)amine (289 mg, 1.37 mmol, >99:1 er) in
THF (2 mL) at –78 °C and the resultant mixture was stirred at –78 °C for 30 min. A solution of 16 (280 mg,
0.855 mmol, >99:1 dr) in THF (1 mL) at –78 °C was added and the resultant mixture was stirred at –78 °C
for 2 h. Satd aq NH4Cl (0.5 mL) was added and the reaction mixture was allowed to warm to rt, then
concentrated in vacuo. The residue was partitioned between CH2Cl2 (5 mL) and 10% citric acid (5 mL), and
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21 the organic layer was washed with satd aq NaHCO3 (5 mL) and brine (5 mL), then dried and concentrated in
22
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26
27
28
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vacuo to give 21 in >95:5 dr. Purification via flash column chromatography (eluent 30–40 °C
[]25
petrol/Et2O/NH4OH, 100:10:1) gave 21 as a pale yellow oil (449 mg, 97%, >99:1 dr);
+23.8 (c 1.0 in
D
CHCl3); νmax (ATR) 3025, 2973, 2931, 2837 (C–H), 1722 (C=O), 1618 (C=C); δH (400 MHz, CDCl3) 1.28
(3H, d, J 6.8, C(α')Me), 1.29 (3H, d, J 6.9, C(α)Me), 1.32 (9H, s, CMe3), 1.39–1.50 (2H, m, C(4)HA,
C(5')HA), 1.90–2.00 (1H, m, C(4)HB), 2.06 (1H, dd, J 14.1, 7.7, C(2)HA), 2.03–2.19 (1H, m, C(5')HB), 2.18
(1H, dd, J 14.1, 5.4, C(2)HB), 2.48 (1H, app dd, J 13.8, 5.3, C(6')HA), 2.81 (1H, ddd, J 13.8, 11.0, 4.7,
C(6')HB), 3.47–3.59 (2H, m, C(3)H, C(2')H), 3.58 (1H, d, J 14.7, NCHAHBPh), 3.83 (1H, d, J 14.7,
NCHAHBPh), 3.84 (1H, q, J 6.8, C(α')H), 3.92 (1H, q, J 6.9, C(α)H), 5.40–5.47 (1H, m, C(3')H), 5.71–5.77
(1H, m, C(4')H), 7.17–7.43 (15H, m, Ph); δC (100 MHz, CDCl3) 20.5 (C(α)Me), 20.9 (C(5')), 22.9
(C(α')Me), 28.2 (CMe3), 38.3, 38.5 (C(2), C(4)), 40.3 (C(6')), 50.4 (NCH2Ph), 50.9 (C(2')), 52.7 (C(3)), 58.2
(C(α')), 58.6 (C(α)), 80.1 (CMe3), 125.7 (C(4')), 126.6, 126.8, 127.0 (p-Ph), 127.6, 128.2, 128.2, 128.3,
128.3, 128.6 (o,m-Ph), 129.6 (C(3')), 142.1, 144.2, 146.2 (i-Ph), 172.1 (C(1)); m/z (ESI+) 539 ([M + H]+,
+
100%); HRMS (ESI+) m/z: [M + H]+ Calcd for C36H47N2O2 539.3632; Found 539.3648.
tert-Butyl (3S,2'S,αS,α'R)-3-[N-benzyl-N-(α-methylbenzyl)amino]-4-[N(1')-(α'-methylbenzyl)-
1',2',5',6'-tetrahydropyridin-2'-yl]butanoate 22. BuLi (2.3 M in hexanes, 0.64 mL, 1.47 mmol) was added
dropwise to a stirred solution of (S)-N-benzyl-N-(α-methylbenzyl)amine (318 mg, 1.51 mmol, >99:1 er) in
THF (2 mL) at –78 °C and the resultant mixture was stirred at –78 °C for 30 min. A solution of 16 (308 mg,
0.941 mmol, >99:1 dr) in THF (1 mL) at –78 °C was added and the resultant mixture was stirred at –78 °C
for 2 h. Satd aq NH4Cl (0.5 mL) was added and the reaction mixture was allowed to warm to rt, then
concentrated in vacuo. The residue was partitioned between CH2Cl2 (5 mL) and 10% citric acid (5 mL), and
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the organic layer was washed with satd aq NaHCO3 (5 mL) and brine (5 mL), then dried and concentrated in
vacuo to give 22 in >95:5 dr. Purification via flash column chromatography (eluent 30–40 °C
petrol/Et2O/NH4OH, 100:10:1) gave 22 as a pale yellow oil (476 mg, 94%, >99:1 dr); []2D5 +68.1 (c 1.0 in
CHCl3); νmax (ATR) 3064, 3025, 2973, 2932 (C–H), 1722 (C=O), 1609 (C=C); δH (400 MHz, CDCl3) 1.28
(3H, d, J 6.6, C(α')Me), 1.40 (3H, d, J 6.9, C(α)Me), 1.44 (9H, s, CMe3), 1.55–1.73 (3H, m, C(4)H2,
C(5')HA), 2.03–2.14 (1H, m, C(5')HB), 2.17 (1H, dd, J 14.4, 6.6, C(2)HA), 2.30 (1H, dd, J 14.4, 6.6, C(2)HB),
2.41 (1H, app dd, J 13.7, 3.5, C(6')HA), 2.76 (1H, ddd, J 13.7, 10.4, 4.8, C(6')HB), 3.28–3.35 (1H, m,
C(2')H), 3.55–3.63 (1H, m, C(3)H), 3.63 (1H, d, J 15.0, NCHAHBPh), 3.76 (1H, d, J 15.0, NCHAHBPh), 3.82
(1H, q, J 6.6, C(α')H), 4.01 (1H, q, J 6.9, C(α)H), 5.55–5.61 (1H, m, C(3')H), 5.71–5.77 (1H, m, C(4')H),
7.17–7.39 (15H, m, Ph); δC (100 MHz, CDCl3) 19.6 (C(α)Me), 21.5 (C(5')), 22.5 (C(α')Me), 28.3 (CMe3),
1
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21 36.6 (C(4)), 39.8, 39.9 (C(2), C(6')), 49.8 (NCH2Ph), 52.9 (C(2')), 54.3 (C(3)), 58.1 (C(α')), 58.9 (C(α)), 80.0
22
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47
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57
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60
(CMe3), 125.3 (C(4')), 126.6, 126.8, 126.9 (p-Ph), 127.7, 128.1, 128.2, 128.3, 128.3, 128.5 (o,m-Ph), 130.4
(C(3')), 141.9, 143.9, 145.7 (i-Ph), 172.3 (C(1)); m/z (ESI+) 539 ([M + H]+, 100%); HRMS (ESI+) m/z: [M +
+
H]+ Calcd for C36H47N2O2 539.3632; Found 539.3631.
(2S,2'S,αR,α'R)-1-[N(1')-(α-Methylbenzyl)-1',2',5',6'-tetrahydropyridin-2'-yl]-2-[N-benzyl-N-
(α'-methylbenzyl)amino]pent-4-ene 23. DIBAL-H (1.0 M in PhMe, 0.20 mL, 0.20 mmol) was added
dropwise to a stirred solution of 21 (100 mg, 0.19 mmol, >99:1 dr) in PhMe (2 mL) at –78 °C and the
resultant mixture was stirred at –78 °C for 1 h. MeOH (38 μL, 0.93 mmol) and Ph3P=CH2 (0.31 M in
PhMe/THF, 6.58 mL, 2.04 mmol)24 were added sequentially, and the resultant mixture was allowed to warm
to rt and stirred at rt for 16 h, then concentrated in vacuo. The residue was dissolved in Et2O (10 mL) and the
resultant solution was filtered through a short plug of Celite® (eluent Et2O) and concentrated in vacuo.
Purification via flash column chromatography (eluent 30–40 °C petrol/Et2O/NH4OH, 100:5:1) gave 23 as a
[]25
colourless oil (54 mg, 62%, >99:1 dr);
+28.2 (c 1.0 in CHCl3); νmax (ATR) 3358, 2961 (C–H), 1596
D
(C=C); δH (400 MHz, CDCl3) 1.26 (3H, d, J 6.4, C(α)Me), 1.37 (3H, d, J 6.9, C(α')Me), 1.46–1.57 (2H, m,
C(1)HA, C(5')HA), 1.89–2.01 (2H, m, C(3)HA, C(1)HB), 2.05–2.16 (2H, m, C(3)HB, C(5')HB), 2.49 (1H, app
dd, J 14.0, 5.2, C(6')HA), 2.86 (1H, ddd, J 14.0, 11.2, 4.6, C(6')HB), 3.12 (1H, app quintet, J 6.4, C(2)H),
3.38–3.46 (1H, m, C(2')H), 3.73 (1H, d, J 14.7, NCHAHBPh), 3.82 (1H, q, J 6.4, C(α)H), 3.84 (1H, d, J 14.7,
NCHAHBPh), 3.96 (1H, q, J 6.9, C(α')H), 4.85–4.93 (2H, m, C(5)H2), 5.46–5.52 (1H, m, C(3')H), 5.59 (1H,
ddt, J 17.0, 10.2, 7.0, C(4)H), 5.72–5.79 (1H, m, C(4')H), 7.18–7.34 (11H, m, Ph), 7.36–7.41 (2H, m, Ph),
7.42–7.46 (2H, m, Ph); δC (100 MHz, CDCl3) 17.9 (C(α')Me), 20.6 (C(5')), 22.9 (C(α)Me), 36.4 (C(3)), 37.9
(C(1)), 40.2 (C(6')), 50.3 (NCH2Ph), 51.3 (C(2')), 53.8 (C(2)), 57.3 (C(α')Me), 58.1 (C(α)Me), 115.3 (C(5)),
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125.5 (C(4')), 126.5, 126.6, 126.6 (p-Ph), 127.4, 127.9, 128.1, 128.2, 128.2, 128.5 (o,m-Ph), 130.0 (C(3')),
137.9 (C(4)), 142.2, 144.7, 146.1 (i-Ph); m/z (ESI+) 465 ([M + H]+, 100%); HRMS (ESI+) m/z: [M + H]+
1
2
3
4
5
+
Calcd for C33H41N2 465.3264; Found 465.3258.
6
7
8
9
(2S,2'S,αR,α'R,Z)-1-[N(1')-(α-Methylbenzyl)-1',2',5',6'-tetrahydropyridin-2'-yl]-2-[N-benzyl-N-
(α'-methylbenzyl)amino]hept-4-ene 24. DIBAL-H (1.0 M in PhMe, 0.53 mL, 0.53 mmol) was added
dropwise to a stirred solution of 21 (260 mg, 0.483 mmol, >99:1 dr) in PhMe (4 mL) at –78 °C and the
resultant mixture was stirred at –78 °C for 1 h. MeOH (98 μL, 2.41 mmol) and Ph3P=CHCH2CH3 (0.31 M in
PhMe/THF, 15.6 mL, 4.83 mmol)25 were added sequentially, and the resultant mixture was allowed to warm
to rt and stirred at rt for 16 h, then concentrated in vacuo. The residue was dissolved in Et2O (20 mL) and the
resultant solution was filtered through a short plug of Celite® (eluent Et2O) and concentrated in vacuo.
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17
18
19
20
21 Purification via flash column chromatography (eluent 30–40 °C petrol/Et2O/NH4OH, 100:5:1) gave 24 as a
22
23
[]25
pale yellow oil (148 mg, 62%, >95:5 dr [(Z):(E)]);
+36.5 (c 1.0 in CHCl3); νmax (ATR) 3024, 2931,
D
24
25
26
27
28
29
30
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32
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34
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58
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60
2838 (C–H), 1580, 1493, 1453 (C=C); δH (400 MHz, CDCl3) 0.91 (3H, t, J 7.5, C(7)H3), 1.26 (3H, d, J 6.4,
C(α')Me), 1.36 (3H, d, J 6.9, C(α)Me), 1.46–1.58 (2H, m, C(1)HA, C(5')HA), 1.89–2.16 (6H, m, C(1)HB,
C(3)H2, C(6)H2, C(5')HB), 2.49 (1H, dd, J 14.0, 5.2, C(6')HA), 2.87 (1H, ddd, J 14.0, 11.2, 4.7, C(6')HB),
3.06 (1H, app quintet, J 6.4, C(2)H), 3.40–3.47 (1H, m, C(2')H), 3.73 (1H, d, J 14.8, NCHAHBPh), 3.81 (1H,
q, J 6.4, C(α')H), 3.86 (1H, d, J 14.8, NCHAHBPh), 3.98 (1H, q, J 6.9, C(α)H), 5.10–5.19 (1H, m, C(4)H),
5.25–5.33 (1H, m, C(5)H), 5.44–5.50 (1H, m, C(3')H), 5.71–5.78 (1H, m, C(4')H), 7.19–7.35 (11H, m, Ph),
7.37–7.41 (2H, m, Ph), 7.42–7.46 (2H, m, Ph); δC (100 MHz, CDCl3) 14.3 (C(7)), 18.5 (C(α)Me), 20.8
(C(5')), 20.9 (C(6)), 23.0 (C(α')Me), 29.6 (C(3)), 38.3 (C(1)), 40.3 (C(6')), 50.5 (NCH2Ph), 51.6 (C(2')), 54.5
(C(2)), 57.7 (C(α)), 58.2 (C(α')), 125.5 (C(4')), 126.5, 126.7, 126.7 (p-Ph), 127.6 (o,m-Ph), 128.0 (C(4)),
128.0, 128.2, 128.3, 128.3, 128.6 (o,m-Ph), 130.2 (C(3')), 131.9 (C(5)), 142.6, 145.2, 146.3 (i-Ph); m/z
+
(ESI+) 493 ([M + H]+, 100%); HRMS (ESI+) m/z: [M + H]+ Calcd for C35H45N2 493.3577; Found 493.3568.
(2S,2'R)-1-(Piperidin-2'-yl)-2-aminopentane 25. Palladium black (15 mg, 20% w/w) was added to
a stirred, degassed solution of 23 (75 mg, 0.16 mmol) in MeOH/H2O/AcOH (10:1:1, 2 mL). The resultant
mixture was stirred under an atmosphere of H2 (5 atm) at rt for 48 h. The reaction mixture was then filtered
through a short plug of Celite® (eluent MeOH/H2O/AcOH, 10:1:1) and concentrated in vacuo. Purification
via flash column chromatography (eluent CHCl3/MeOH/NH4OH 10:1:1) gave 25 as a colourless oil (20 mg,
[]25
73%, >99:1 dr);
–3.3 (c 1.0 in CHCl3); νmax (ATR) 3292 (N–H), 2930, 2860 (C–H); δH (400 MHz,
D
CDCl3) 0.89 (3H, t, J 6.9, C(5)H3), 1.02–1.13 (1H, m, C(3')HA), 1.17–1.46 (8H, m, C(1)H2, C(3)H2, C(4)H2,
C(4')HA, C(5')HA), 1.53–1.68 (2H, m, C(3')HB, C(4')HB), 1.72–1.80 (1H, m, C(5')HB), 2.55–2.66 (2H, m,
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C(2')H, C(6')HA), 2.75–2.82 (1H, m, C(2)H), 3.01–3.07 (1H, m, C(6')HB); δC (100 MHz, CDCl3) 14.3 (C(5)),
19.2 (C(4)), 25.0 (C(5')), 26.7 (C(4')), 33.4 (C(3')), 42.1 (C(3)), 45.5 (C(1)), 47.1 (C(6')), 49.9 (C(2)), 56.1
1
2
3
4
5
+
(C(2')); m/z (ESI+) 171 ([M + H]+, 100%); HRMS (ESI+) m/z: [M + H]+ Calcd for C10H23N2 171.1856;
6
7
Found 171.1856.
8
9
(5S,6aR,11aS)-5-Propyldecahydro-5H-pyrido[1,2-c]pyrrolo[1,2-a]pyrimidine [(+)-tetraponerine
4] 27. Method A (from 25): K2CO3 (88 mg, 0.63 mmol) and 4-bromobutanal (64 mg, 0.42 mmol) were added
to a stirred solution of 25 (36 mg, 0.21 mmol, >99:1 dr) in CH2Cl2 (2 mL) at rt, and the resultant mixture
was stirred at rt for 2 h. H2O (2 mL) and satd aq NaHCO3 (10 mL) were added, and the resultant mixture
was extracted with CH2Cl2 (3 × 5 mL), then dried and concentrated in vacuo. Purification via flash column
chromatography (eluent 30–40 °C petrol/Me2CO/NH4OH, 100:10:1) gave (+)-tetraponerine 4 (27) as a
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22
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[]25
colourless oil (32 mg, 68% from 25, >99:1 dr);
+90.8 (c 1.0 in CHCl3); {lit.4 for a sample isolated
D
from the natural source []D20 +94 (c 0.2 in CHCl3); lit.9b []2D0 +96 (c 2.0 in CHCl3)}; νmax (ATR) 2933, 2855,
2793 (C–H);26 δH (400 MHz, C6D6) 0.89 (3H, t, J 7.1, C(3')H3), 1.13–1.29 (2H, m, C(9)HA, C(2')HA), 1.30–
1.56 (9H, m, C(2)HA, C(6)H2, C(7)H2, C(8)HA, C(1')H2, C(2')HB), 1.59–1.77 (7H, m, C(1)H2, C(2)HB,
C(6a)H, C(8)HB, C(9)HB, C(10)HA), 2.02 (1H, dd, J 16.3, 8.6, C(3)HA), 2.11 (1H, ddd, J 14.6, 7.4, 3.6,
C(5)H), 2.31 (1H, dd, J 7.8, 5.6, C(11a)H), 2.80–2.85 (1H, m, C(10)HB), 3.13 (1H, app td, J 8.6, 2.2,
C(3)HB); δC (100 MHz, C6D6) 14.8 (C(3')), 18.7 (C(2')), 20.2 (C(2)), 25.1 (C(9)), 26.3 (C(8)), 29.7 (C(1)),
33.0 (C(7)), 36.9 (C(1')), 38.0 (C(6)), 49.0 (C(3)), 51.6 (C(10)), 61.1 (C(5)), 62.7 (C(6a)), 85.6 (C(11a)); m/z
+
(ESI+) 223 ([M + H]+, 100%); HRMS (ESI+) m/z: [M + H]+ Calcd for C14H27N2 223.2169; Found 223.2169.
Method B (from 23): Palladium black (24 mg, 20% w/w) was added to a stirred, degassed solution of 23 (121
mg, 0.26 mmol, >99:1 dr) in MeOH/H2O/AcOH (10:1:1, 2 mL). The resultant mixture was stirred under an
atmosphere of H2 (5 atm) at rt for 48 h. The reaction mixture was then filtered through a short plug of
Celite® (eluent MeOH/H2O/AcOH, 10:1:1), and concentrated in vacuo. The residue was dissolved in CH2Cl2
(2 mL), then K2CO3 (108 mg, 0.78 mmol) and 4-bromobutanal (79 mg, 0.52 mmol) were added to the
resultant solution. The reaction mixture was stirred at rt for 2 h, then H2O (2 mL) and satd aq NaHCO3 (10
mL) were added. The reaction mixture was then extracted with CH2Cl2 (3 × 5 mL) and the combined organic
extracts were dried and concentrated in vacuo. Purification via flash column chromatography (eluent 30–40
°C petrol/Me2CO/NH4OH, 100:10:1) gave (+)-tetraponerine 4 (27) as a colourless oil (31 mg, 54% from 23,
[]25
>99:1 dr);
+88.6 (c 1.0 in CHCl3).
D
(5S,6aR,11aS)-5-Pentyldecahydro-5H-pyrido[1,2-c]pyrrolo[1,2-a]pyrimidine [(+)-tetraponerine
8] 28. Palladium black (26 mg, 20% w/w) was added to a stirred, degassed solution of 24 (130 mg, 0.26
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mmol, >95:5 dr) in MeOH/H2O/AcOH (10:1:1, 2 mL). The resultant mixture was stirred under an
atmosphere of H2 (5 atm) at rt for 48 h. The reaction mixture was then filtered through a short plug of
Celite® (eluent MeOH/H2O/AcOH, 10:1:1) and concentrated in vacuo. The residue was dissolved in
MeOH/H2O/AcOH (10:1:1, 2 mL) and the resultant solution was degassed. Pd(OH)2/C (65 mg, 50% w/w)
was added and the resultant mixture was stirred under an atmosphere of H2 (5 atm) at rt for 24 h. The
reaction mixture was then filtered through a short plug of Celite® (eluent MeOH/H2O/AcOH, 10:1:1) and
concentrated in vacuo. The residue was dissolved in CH2Cl2 (2 mL), then K2CO3 (110 mg, 0.792 mmol) and
4-bromobutanal (80 mg, 0.53 mmol) were added to the resultant solution. The reaction mixture was stirred at
rt for 2 h, then H2O (2 mL) and satd aq NaHCO3 (10 mL) were added. The reaction mixture was then
extracted with CH2Cl2 (3 × 5 mL) and the combined organic extracts were dried and concentrated in vacuo.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21 Purification via flash column chromatography (eluent 30–40 °C petrol/Me2CO/NH4OH, 100:10:1) gave (+)-
22
23
24
25
26
27
28
[]25
5
tetraponerine 8 (28) as a white solid (44 mg, 67% from 24, >99:1 dr); mp 38–40 °C; {lit. mp 40 °C};
D
+93.0 (c 1.0 in CHCl3); {lit.4 for a sample isolated from the natural source []D20 +102 (c 0.2 in CHCl3); lit.9b
[]2D0 +101 (c 2.0 in CHCl3)}; νmax (ATR) 2931, 2857, 2780 (C–H);26 δH (400 MHz, C6D6) 0.90 (3H, t, J 7.0,
29
30
C(5')H3), 1.16–1.67 (17H, m, C(2)HA, C(6)H2, C(7)H2, C(8)H2, C(9)H2, C(1')H2, C(2')H2, C(3')H2, C(4')H2),
31
32
1.68–1.78 (5H, m, C(1)H2, C(2)HB, C(6a)H, C(10)HA), 2.04 (1H, app dd, J 16.3, 8.5, C(3)HA), 2.12 (1H, app
33
34
ddd, J 14.6, 7.3, 3.6, C(5)H), 2.31 (1H, dd, J 7.9, 5.7, C(11a)H), 2.81–2.86 (1H, m, C(10)HB), 3.15 (1H, app
35
36
td, J 8.5, 2.2, C(3)HB); δC (100 MHz, C6D6) 14.4 (C(5')), 20.2 (C(2)), 23.2 (C(4')), 25.2 (C(9)), 25.2 (C(2')),
37
38
26.3 (C(8)), 29.7 (C(1)), 32.8 (C(3')), 33.0 (C(7)), 34.6 (C(1')), 38.0 (C(6)), 49.0 (C(3)), 51.6 (C(10)), 61.4
39
40
(C(5)), 62.7 (C(6a)), 85.6 (C(11a)); m/z (ESI+) 251 ([M + H]+, 100%); HRMS (ESI+) m/z: [M + H]+ Calcd
41
42
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46
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52
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60
+
for C16H31N2 251.2482; Found 251.2472.
(2R,2'S,αS,α'R)-1-[N(1')-(α-Methylbenzyl)-1',2',5',6'-tetrahydropyridin-2'-yl]-2-[N-benzyl-N-
(α'-methylbenzyl)amino]pent-4-ene 29. DIBAL-H (1.0 M in PhMe, 0.78 mL, 0.78 mmol) was added
dropwise to a stirred solution of 22 (383 mg, 0.711 mmol, >99:1 dr) in PhMe (6 mL) at –78 °C and the
resultant mixture was stirred at –78 °C for 1 h. MeOH (144 μL, 3.55 mmol) and Ph3P=CH2 (0.31 M in
PhMe/THF, 22.9 mL, 7.11 mmol)24 were added sequentially, and the resultant mixture was allowed to warm
to rt and stirred at rt for 16 h, then concentrated in vacuo. The residue was dissolved in Et2O (30 mL) and the
resultant solution was filtered through a short plug of Celite® (eluent Et2O) and concentrated in vacuo.
Purification via flash column chromatography (eluent 30–40 °C petrol/Et2O/NH4OH, 100:5:1) gave 29 as a
[]25
pale yellow oil (180 mg, 54%, >99:1 dr);
+52.5 (c 1.0 in CHCl3); νmax (ATR) 3061, 3025, 2933, 2836
D
(C–H), 1601, 1492, 1452 (C=C); δH (400 MHz, CDCl3) 1.26 (3H, d, J 6.6, C(α)Me), 1.34 (3H, d, J 6.9,
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C(α')Me), 1.58–1.76 (3H, d, C(1)H2, C(5')HA), 1.90–1.99 (1H, m, C(3)HA), 2.00–2.15 (2H, m, C(3)HB,
C(5')HB), 2.46 (1H, ddd, J 13.4, 5.4, 2.6, C(6')HA), 2.83 (1H, ddd, J 13.4, 9.9, 4.7, C(6')HB), 2.93 (1H, app
quintet, J 6.2, C(2)H), 3.24–3.30 (1H, m, C(2')H), 3.73 (1H, d, J 14.8, NCHAHBPh), 3.81 (1H, d, J 14.8,
NCHAHBPh), 3.82 (1H, q, J 6.6, C(α)H), 3.96 (1H, q, J 6.9, C(α')H), 4.86–4.88 (1H, m, C(5)HA), 4.89–4.92
(1H, m, C(5)HB), 5.54–5.65 (2H, m, C(4)H, C(3')H), 5.72–5.77 (1H, m, C(4')H), 7.18–7.37 (13H, m, Ph),
7.42–7.46 (2H, m, Ph); δC (100 MHz, CDCl3) 18.2 (C(α')Me), 22.2 (C(5')), 22.5 (C(α)Me), 36.8 (C(1)), 37.1
(C(3)), 40.1 (C(6')), 50.1 (NCH2Ph), 53.1 (C(2')), 55.1 (C(2)), 57.6 (C(α')), 58.3 (C(α)), 115.2 (C(5)), 125.2
(C(4')), 126.6, 126.8, 126.8 (p-Ph), 127.7, 128.1, 128.3, 128.3, 128.3, 128.5 (o,m-Ph), 130.6 (C(3')), 138.1
(C(4)), 142.3, 144.4, 145.5 (i-Ph); m/z (ESI+) 465 ([M + H]+, 100%); HRMS (ESI+) m/z: [M + H]+ Calcd for
1
2
3
4
5
6
7
8
9
10
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60
+
C33H41N2 465.3264; Found 465.3259.
(2R,2'S,αS,α'R,Z)-1-[N(1')-(α-Methylbenzyl)-1',2',5',6'-tetrahydropyridin-2'-yl]-2-[N-benzyl-N-
(α'-methylbenzyl)amino]hept-4-ene 30. DIBAL-H (1.0 M in PhMe, 0.77 mL, 0.77 mmol) was added
dropwise to a stirred solution of 22 (377 mg, 0.700 mmol, >99:1 dr) in PhMe (6 mL) at –78 °C and the
resultant mixture was stirred at –78 °C for 1 h. MeOH (142 μL, 3.50 mmol) and Ph3P=CHCH2CH3 (0.31 M
in PhMe/THF, 22.6 mL, 7.00 mmol)25 were added sequentially, and the resultant mixture was allowed to
warm to rt and stirred at rt for 16 h, then concentrated in vacuo. The residue was dissolved in Et2O (30 mL)
and the resultant solution was filtered through a short plug of Celite® (eluent Et2O) and concentrated in
vacuo. Purification via flash column chromatography (eluent 30–40 °C petrol/Et2O/NH4OH, 100:5:1) gave
[]25
30 as a pale yellow oil (162 mg, 47%, >95:5 dr [(Z):(E)]);
+59.2 (c 1.0 in CHCl3); νmax (ATR) 2970
D
(C–H), 1493, 1453 (C=C); δH (400 MHz, CDCl3) 0.90 (3H, t, J 7.5, C(7)H3), 1.26 (3H, d, J 6.6, C(α)Me),
1.34 (3H, d, J 6.9, C(α')Me), 1.60–1.80 (3H, m, C(1)H2, C(5')HA), 1.91 (2H, app quintet, J 7.5, C(6)H2), 1.97
(2H, app t, J 6.8, C(3)H2), 2.04–2.15 (1H, m, C(5')HB), 2.47 (1H, ddd, J 13.1, 5.3, 3.1, C(6')HA), 2.80–2.92
(2H, m, C(2)H, C(6')HB), 3.20–3.26 (1H, m, C(2')H), 3.73 (1H, d, J 14.8, NCHAHBPh), 3.81 (1H, d, J 14.8,
NCHAHBPh), 3.83 (1H, q, J 6.6, C(α)H), 3.98 (1H, q, J 6.9, C(α')H), 5.12–5.19 (1H, m, C(4)H), 5.25–5.32
(1H, m, C(5)H), 5.56–5.61 (1H, m, C(3')H), 5.71–5.77 (1H, m, C(4')H), 7.17–7.44 (15H, m, Ph); δC (100
MHz, CDCl3) 14.3 (C(7)), 18.3 (C(α')Me), 20.9 (C(6)), 22.3 (C(α)Me), 22.6 (C(5')), 30.0 (C(3)), 36.8 (C(1)),
40.2 (C(6')), 50.0 (NCH2Ph), 53.2 (C(2')), 55.5 (C(2)), 57.6 (C(α')), 58.2 (C(α)), 125.1 (C(4')), 126.6, 126.7,
126.8 (p-Ph), 127.8, 128.0 (o,m-Ph), 128.1 (C(4)), 128.2, 128.2, 128.3, 128.5 (o,m-Ph), 130.8 (C(3')), 131.8
(C(5)), 142.4, 144.7, 145.2 (i-Ph); m/z (ESI+) 493 ([M + H]+, 100%); HRMS (ESI+) m/z: [M + H]+ Calcd for
+
C35H45N2 493.3577; Found 493.3565.
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(5R,6aR,11aS)-5-Propyldecahydro-5H-pyrido[1,2-c]pyrrolo[1,2-a]pyrimidine
[(+)-
1
2
3
4
5
6
7
8
9
tetraponerine 3] 33. Palladium black (23 mg, 20% w/w) was added to a stirred, degassed solution of 29
(115 mg, 0.25 mmol, >99:1 dr) in MeOH/H2O/AcOH (10:1:1, 2 mL). The resultant mixture was stirred
under an atmosphere of H2 (5 atm) at rt for 48 h. The reaction mixture was then filtered through a short plug
of Celite® (eluent MeOH/H2O/AcOH, 10:1:1) and concentrated in vacuo. The residue was dissolved in
CH2Cl2 (2 mL), then K2CO3 (102 mg, 0.741 mmol) and 4-bromobutanal (75 mg, 0.49 mmol) were added to
the resultant solution. The reaction mixture was stirred at rt for 2 h, then H2O (2 mL) and satd aq NaHCO3
(10 mL) were added. The reaction mixture was then extracted with CH2Cl2 (3 × 5 mL) and the combined
organic extracts were dried and concentrated in vacuo. Purification via flash column chromatography (eluent
30–40 °C petrol/Me2CO/NH4OH, 100:10:1) gave (+)-tetraponerine 3 (33) as a colourless oil (33 mg, 60%
10
11
12
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[]25
from 29, >99:1 dr);
+30.9 (c 1.0 in CHCl3); {lit.4 for a sample isolated from the natural source
D
[]D20 +27 (c 0.07 in CHCl3); lit.5 []D20 +31 (c 3.1 in CHCl3); lit.9d []2D0 +35 (c 0.49 in CHCl3)}; νmax (ATR)
2954, 2928, 2859, 2802 (C–H);26 δH (400 MHz, C6D6) 0.95 (3H, t, J 7.2, C(3')H3), 1.09 (1H, app dt, J 12.7,
1.9, C(6)HA), 1.15–1.28 (1H, m, C(9)HA), 1.27–1.48 (5H, m, C(7)H2, C(1')HA, C(2')H2), 1.48–1.84 (9H, m,
C(1)H2, C(2)H2, C(8)H2, C(9)HB, C(10)HA, C(1')HB), 1.91 (1H, ddd, J 12.7, 11.9, 5.3, C(6)HB), 1.99–2.07
(1H, m, C(6a)H), 2.72–2.86 (3H, m, C(3)HA, C(5)H, C(10)HB), 3.17 (1H, app q, J 7.5, C(3)HB), 3.30 (1H,
app t, J 3.5, C(11a)H); δC (100 MHz, C6D6) 14.5 (C(3')), 20.7 (C(2')), 22.2 (C(2)), 25.3 (C(9)), 26.6 (C(8)),
30.6 (C(1)), 32.2 (C(6)), 33.4 (C(1')), 34.3 (C(7)), 50.6 (C(3)), 51.0 (C(10)), 53.0 (C(5)), 56.7 (C(6a)), 75.4
+
(C(11a)); m/z (ESI+) 223 ([M + H]+, 100%); HRMS (ESI+) m/z: [M + H]+ Calcd for C14H27N2 223.2169;
Found 223.2168.
(5R,6aR,11aS)-5-Pentyldecahydro-5H-pyrido[1,2-c]pyrrolo[1,2-a]pyrimidine [(+)-tetraponerine
7] 34. Palladium black (22 mg, 20% w/w) was added to a stirred, degassed solution of 30 (108 mg, 0.22
mmol, >95:5 dr) in MeOH/H2O/AcOH (10:1:1, 2 mL). The resultant mixture was stirred under an
atmosphere of H2 (5 atm) at rt for 48 h. The reaction mixture was then filtered through a short plug of
Celite® (eluent MeOH/H2O/AcOH, 10:1:1) and concentrated in vacuo. The residue was dissolved in CH2Cl2
(2 mL), then K2CO3 (91 mg, 0.66 mmol) and 4-bromobutanal (66 mg, 0.44 mmol) were added to the
resultant solution. The reaction mixture was stirred at rt for 2 h, then H2O (2 mL) and satd aq NaHCO3 (10
mL) were added. The reaction mixture was then extracted with CH2Cl2 (3 × 5 mL) and the combined organic
extracts were dried and concentrated in vacuo. Purification via flash column chromatography (eluent 30–40
°C petrol/Me2CO/NH4OH, 100:10:1) gave (+)-tetraponerine 7 (34) as a colourless oil (24 mg, 44% from 30,
>99:1 dr); []2D5 +30.4 (c 0.8 in CHCl3); {lit.4 for a sample isolated from the natural source []D20 +30 (c 0.22
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in CHCl3); lit.9b []D20 +29.5 (c 2.2 in CHCl3)}; νmax (ATR) 2928, 2856, 2790 (C–H);26 δH (400 MHz, C6D6)
0.93 (3H, t, J 6.9, C(5')H3), 1.13 (1H, app dt, J 12.9, 1.9, C(6)HA), 1.17–1.86 (19H, m, C(1)H2, C(2)H2,
C(7)H2, C(8)H2, C(9)H2, C(10)HA, C(1')H2, C(2')H2, C(3')H2, C(4')H2), 1.93 (1H, ddd, J 12.9, 11.9, 5.4,
C(6)HB), 2.02–2.09 (1H, m, C(6a)H), 2.74–2.86 (3H, m, C(3)HA, C(5)H, C(10)HB), 3.15–3.21 (1H, m,
C(3)HB), 3.33 (1H, app t, J 3.6, C(11a)H); δC (100 MHz, C6D6) 14.4 (C(5')), 22.2 (C(2)), 23.2 (C(4')), 25.3
(C(8)), 26.6 (C(9)), 27.4 (C(2')), 30.6 (C(1)), 31.1 (C(1')), 32.3 (C(6)), 32.5 (C(3')), 34.3 (C(7)), 50.7 (C(3)),
51.0 (C(10)), 53.3 (C(5)), 56.7 (C(6a)), 75.5 (C(11a)); m/z (ESI+) 251 ([M + H]+, 100%); HRMS (ESI+) m/z:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
+
[M + H]+ Calcd for C16H31N2 251.2482; Found 251.2480.
tert-Butyl (3S,αR,E)-3-[N-allyl-N-(α-methylbenzyl)amino]hex-4-enoate 35. BuLi (2.30 M in
hexanes, 14.0 mL, 32.3 mmol) was added dropwise to a stirred solution of (R)-N-benzyl-N-(α-
21 methylbenzyl)amine (5.36 g, 33.3 mmol, >99:1 er) in THF (30 mL) at –78 °C and the resultant mixture was
22
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60
stirred at –78 °C for 30 min. A solution of 3 (3.50 g, 20.8 mmol, >99:1 dr) in THF (10 mL) at –78 °C was
added dropwise via cannula and the resultant mixture was stirred at –78 °C for 2 h. Satd aq NH4Cl (10 mL)
was added and the reaction mixture was allowed to warm to rt, then concentrated in vacuo. The residue was
partitioned between CH2Cl2 (100 mL) and 10% aq citric acid (100 mL), and the organic layer was washed
with satd aq NaHCO3 (100 mL) and brine (100 mL), then dried and concentrated in vacuo to give 35 in
>95:5 dr. Purification via flash column chromatography (eluent 30–40 C petrol/EtOAc, 20:1) gave 35 as a
[]2D5
[]2D0
–4.7 (c 1.0 in CHCl3)};
pale yellow oil (6.10 g, 89%, >99:1 dr);15b
–3.5 (c 2.0 in CHCl3); {lit.15c
δH (400 MHz, CDCl3) 1.36 (3H, d, J 6.8, C(α)Me), 1.40 (9H, s, CMe3), 1.69 (3H, d, J 5.3, C(6)H3), 2.26 (1H,
dd, J 14.2, 8.4, C(2)HA), 2.40 (1H, dd, J 14.2, 6.4, C(2)HB), 3.10–3.14 (2H, m, C(1')H2), 3.78–3.85 (1H, m,
C(3)H), 4.00 (1H, q, J 6.8, C(α)H), 4.99 (1H, dd, J 10.3, 1.6, C(3')HA), 5.07 (1H, dd, J 17.0, 1.6, C(3')HB),
5.43–5.58 (2H, m, C(4)H, C(5)H), 5.77 (1H, ddt, J 17.0, 10.3, 6.3, C(2')H), 7.17–7.22 (1H, m, Ph), 7.25–
7.31 (2H, m, Ph), 7.35–7.39 (2H, m, Ph).
tert-Butyl (2'S,αR)-2-[N(1')-(α-methylbenzyl)-2',5'-dihydro-1H-pyrrol-2'-yl]acetate 36. Grubbs I
catalyst (230 mg, 0.36 mmol) was added to a stirred, degassed solution of 35 (3.00 g, 9.11 mmol, >99:1 dr)
in anhydrous CH2Cl2 (EtOH stabilised, 300 mL) at rt. The resultant mixture was stirred at rt for 16 h, then
concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL), then P(CH2OH)3 (4.52 g, 36.4 mmol)
and Et3N (2.54 mL, 18.2 mmol) were added sequentially. The resultant mixture was stirred at rt for 5 min,
then excess silica gel (10 g) was added and the resultant mixture was stirred at rt for 12 h before being
concentrated in vacuo. Purification via flash column chromatography (eluent 30–40 °C petrol/Et2O/NH4OH,
[]2D5
100:10:1) gave 36 as a pale yellow oil (2.25 g, 86%, >99:1 dr);15a
+99.0 (c 1.0 in CHCl3); {lit.15b for
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ent-36: []2D4 –132.0 (c 0.99 in CHCl3)}; δH (400 MHz, CDCl3) 1.43 (3H, d, J 6.7, C(α)Me), 1.46 (9H, s,
CMe3), 2.33 (1H, dd, J 14.5, 8.9, C(2)HA), 2.59 (1H, dd, J 14.5, 4.0, C(2)HB), 3.34–3.41 (1H, m, C(5')HA),
3.57–3.63 (1H, m, C(5')HB), 3.85 (1H, q, J 6.7, C(α)H), 4.10–4.18 (1H, m, C(2')H), 5.68–5.76 (2H, m,
C(3')H, C(4')H), 7.19–7.34 (5H, m, Ph).
1
2
3
4
5
6
7
8
9
tert-Butyl (R,R)-2-[N(1')-(α-methylbenzyl)pyrrolidin-2'-yl]acetate 37. RhCl(PPh3)3 (100 mg, 0.11
mmol) was added to a degassed solution of 36 (1.00 g, 3.48 mmol, >99:1 dr) in EtOAc (5 mL) and the
resultant mixture was stirred under H2 (2 atm) at rt for 16 h. The reaction mixture was then filtered through
Celite® (eluent EtOAc) and concentrated in vacuo. Purification via flash column chromatography (eluent 30–
40 °C petrol/Et2O, 10:1) gave 37 as a colourless oil (860 mg, 86%, >99:1 dr);15b []D25 +57.0 (c 1.0 in
10
11
12
13
14
15
16
17
18
19
20
[]23
CHCl3); {lit.15b for ent-37:
–56.1 (c 1.6 in CHCl3)}; δH (400 MHz, CDCl3) 1.44 (3H, d, J 6.8, C(α)Me),
D
21 1.44 (9H, s, CMe3), 1.55–1.64 (2H, m, C(3')HA, C(4')HA), 1.65–1.77 (1H, m, C(4')HB), 1.79–1.89 (1H, m,
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C(3')HB), 2.18 (1H, dd, J 14.2, 9.9, C(2)HA), 2.39 (1H, td, J 8.8, 6.9, C(5')HA), 2.58 (1H, dd, J 14.2, 3.5,
C(2)HB), 2.76–2.82 (1H, m, C(5')HB), 3.00–3.09 (1H, m, C(2')H), 3.76 (1H, q, J 6.8, C(α)H), 7.21–7.35 (5H,
m, Ph).
tert-Butyl (R,R,E)-4-[N(1')-(α-methylbenzyl)pyrrolidin-2'-yl]but-2-enoate 38. Method A (from
37): DIBAL-H (1.0 M in PhMe, 0.57 mL, 0.57 mmol) was added dropwise to a stirred solution of 37 (151
mg, 0.522 mmol, >99:1 dr) in PhMe (2 mL) at –78 °C and the resultant mixture was stirred at –78 °C for 1 h.
t
MeOH (0.11 mL, 2.61 mmol) and Ph3P=CHCO2 Bu (196 mg, 0.522 mmol) were added sequentially, and the
resultant mixture was allowed to warm to rt and stirred at rt for 16 h. The reaction mixture was then
concentrated in vacuo to give a 75:25 mixture of 38 and 39, respectively. Purification via flash column
chromatography (eluent 30–40 °C petrol/Et2O/NH4OH, 100:20:1) gave a 9:91 mixture of 38 and 39,
respectively, as a pale yellow oil (22 mg, 13%). Data for 39: δH (400 MHz, CDCl3) 1.44 (3H, d, J 6.8,
C(α)Me), 1.46–1.60 (2H, m, C(3')HA, C(4')HA), 1.50 (9H, s, CMe3), 1.65–1.77 (2H, m, C(3')HB, C(4')HB),
2.37 (1H, app q, J 8.2, C(5')HA), 2.65–2.79 (2H, m, C(4)HA, C(2')H), 2.84–2.90 (1H, m, C(5')HB), 2.94–3.03
(1H, m, C(4)HB), 3.87 (1H, q, J 6.8, C(α)H), 5.75 (1H, dt, J 11.6, 1.7, C(2)H), 6.18 (1H, dt, J 11.6, 7.2,
C(3)H), 7.21–7.37 (5H, m, Ph); δC (100 MHz, CDCl3) 22.0 (C(α)Me), 22.6 (C(4')), 28.4 (CMe3), 29.9
(C(3')), 32.6 (C(4)), 49.0 (C(5')), 58.9 (C(2')), 59.2 (C(α)), 80.1 (CMe3), 122.5 (C(2)), 126.9 (p-Ph), 128.1,
128.2 (o,m-Ph), 142.4 (i-Ph), 146.2 (C(3)), 166.2 (C(1)). Data for mixture: νmax (ATR) 2972, 2873 (C–H),
1713 (C=O), 1651 (C=C); m/z (ESI+) 316 ([M + H]+, 100%); HRMS (ESI+) m/z: [M + H]+ Calcd for
+
C20H30NO2 316.2271; Found 316.2269. Further elution (eluent 30–40 °C petrol/Et2O/NH4OH, 100:20:1)
gave an 86:14 mixture of 38 and 39, respectively, as a colourless oil (108 mg, 66%).
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Method B (from 36) – Step 1: RhCl(PPh3)3 (320 mg, 0.348 mmol) was added to a degassed solution of 36
(5.00 g, 17.4 mmol) in EtOAc (100 mL) and the resultant mixture was stirred under H2 (2 atm) at rt for 16 h.
The reaction mixture was then filtered through Celite® (eluent EtOAc) and concentrated in vacuo to give 37.
Method B (from 36) – Step 2: DIBAL-H (1.0 M in PhMe, 19.1 mL, 19.1 mmol) was added dropwise to a
stirred solution of the residue of 37 from the previous step in PhMe (70 mL) at –78 °C and the resultant
1
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5
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7
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16
17
18
19
20
t
mixture was stirred at –78 °C for 1 h. MeOH (3.57 mL, 87.0 mmol) and Ph3P=CHCO2 Bu (6.55 g, 17.4
mmol) were added sequentially, and the resultant mixture was allowed to warm to rt and stirred at rt for 16
h. The reaction mixture was then concentrated in vacuo to give a 75:25 mixture of 38 and 39, respectively.
Purification via exhaustive flash column chromatography (eluent 30–40 °C petrol/Et2O/NH4OH, 100:20:1)
[]25
gave 38 as a pale yellow oil (2.76 g, 50% from 36, 98:2 dr);
+82.7 (c 1.0 in CHCl3); νmax (ATR) 2972,
D
21 2873 (C–H), 1713 (C=O); δH (400 MHz, CDCl3) 1.44 (3H, d, J 6.8, C(α)Me), 1.48 (9H, s, CMe3), 1.48–1.81
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4H, m, C(3')H2, C(4')H2), 2.18 (1H, app dt, J 14.2, 9.0, C(4)HA), 2.40 (1H, app td, J 8.7, 7.2, C(5')HA), 2.50
(1H, dddd, J 14.2, 7.0, 3.3, 1.5, C(4)HB), 2.70–2.78 (1H, m, C(2')H), 2.80–2.86 (1H, m, C(5')HB), 3.80 (1H,
q, J 6.8, C(α)H), 5.76 (1H, dt, J 15.6, 1.5, C(2)H), 6.83 (1H, app dt, J 15.6, 7.0, C(3)H), 7.21–7.34 (5H, m,
Ph); δC (100 MHz, CDCl3) 22.2 (C(α)Me), 22.7 (C(4')), 28.3 (CMe3), 30.2 (C(3')), 37.6 (C(4)), 49.9 (C(5')),
58.7 (C(2')), 60.3 (C(α)), 80.2 (CMe3), 124.4 (C(2)), 127.0 (p-Ph), 128.0, 128.2 (o,m-Ph), 142.9 (i-Ph),
145.9 (C(3)), 166.1 (C(1)); m/z (ESI+) 316 ([M + H]+, 100%); HRMS (ESI+) m/z: [M + H]+ Calcd for
+
C20H30NO2 316.2271; Found 316.2270.
tert-Butyl
yl]butanoate
(R,R,R)-3-[N-benzyl-N-isopropylamino]-4-[N(1')-(α-methylbenzyl)pyrrolidin-2'-
and tert-butyl (3S,2'R,αR)-3-[N-benzyl-N-isopropylamino]-4-[N(1')-(α-
methylbenzyl)pyrrolidin-2'-yl]butanoate 40 and 41. BuLi (2.3 M in hexanes, 0.11 mL, 0.253 mmol) was
added dropwise to a stirred solution of N-benzyl-N-isopropylamine (38 mg, 0.25 mmol) in THF (0.5 mL) at
–78 °C and the resultant mixture was stirred at –78 °C for 30 min. A solution of 38 (50 mg, 0.159 mmol,
98:2 dr [(E):(Z)]) in THF (0.5 mL) at –78 °C was added via cannula and the resultant mixture was stirred at
–78 °C for 2 h. Satd aq NH4Cl (0.2 mL) was added and the reaction mixture was allowed to warm to rt, then
concentrated in vacuo. The residue was partitioned between CH2Cl2 (5 mL) and 10% citric acid (5 mL), and
the organic layer was washed with satd aq NaHCO3 (5 mL) and brine (5 mL), then dried and concentrated in
vacuo to give a 50:50 mixture of 40 and 41. Purification via flash column chromatography (eluent 30–40 °C
petrol/Et2O/NH4OH, 100:20:1) gave a 50:50 mixture of 40 and 41 as a colourless oil (52 mg, 70%). Data for
40: δH (400 MHz, CDCl3) 0.96–1.06 (6H, m, NCHMe2), 1.07–1.31 (2H, m, C(4)HA, C(3')HA), 1.34–1.41
(1H, m, C(3')HB), 1.39 (3H, d, J 6.7, C(α)Me), 1.45 (9H, s, CMe3), 1.48–1.62 (2H, m, C(4')H2), 1.87 (1H,
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ddd, J 13.5, 10.2, 3.8, C(4)HB), 2.10–2.18 (1H, m, C(2)HA), 2.33–2.42 (1H, m, C(5')HA), 2.64 (1H, dd, J
13.8, 3.8, C(2)HB), 2.70 (1H, ddd, J 9.2, 7.4, 3.7, C(5')HB), 2.87–2.97 (2H, m, C(2')H, NCHMe2), 3.11 (1H,
app tt, J 14.5, 3.8, C(3)H), 3.43 (1H, d, J 14.1, NCHAHBPh), 3.70 (1H, d, J 14.1, NCHAHBPh), 3.74 (1H, q, J
6.7, C(α)H), 7.17–7.40 (10H, m, Ph). Data for 41: δH (400 MHz, CDCl3) 0.96–1.06 (6H, m, NCHMe2), 1.45
(3H, d, J 6.9, C(α)Me), 1.45 (9H, s, CMe3), 1.46–1.63 (3H, m, C(4)HA, C(3')HA, C(4')HA), 1.67–1.87 (3H,
m, C(4)HB, C(3')HB, C(4')HB), 2.10–2.18 (1H, m, C(2)HA), 2.27–2.43 (3H, m, C(2)HB, C(2')H, C(5')HA),
2.82–2.97 (2H, m, C(5')HB, NCHMe2), 3.22–3.29 (1H, m, C(3)H), 3.62 (1H, d, J 14.6, NCHAHBPh), 3.75
(1H, d, J 14.6, NCHAHBPh), 3.84 (1H, q, J 6.9, C(α)H), 7.17–7.40 (10H, m, Ph). Data for mixture of 40 and
41: νmax (ATR) 3026, 2966, 2932, 2871 (C–H), 1724 (C=O); δC (100 MHz, CDCl3) 18.8, 19.8, 21.4, 21.7,
22.5, 22.8, 22.9, 23.0, 28.2, 28.2, 29.6, 30.5, 37.4, 37.8, 39.2, 40.0, 46.8, 48.7, 48.9, 49.1, 49.3, 50.4, 52.6,
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21 52.9, 57.5, 58.2, 59.4, 61.0, 80.1, 80.2, 126.6, 126.6, 126.7, 127.0, 127.9, 128.0, 128.0, 128.1, 128.1, 128.2,
22
23
24
25
26
27
128.6, 129.0, 141.1, 141.8, 142.1, 144.2, 172.4, 172.4; m/z (ESI+) 465 ([M + H]+, 100%); HRMS (ESI+) m/z:
+
[M + H]+ Calcd for C30H45N2O2 465.3476; Found 465.3475.
tert-Butyl
(R,R,R,R)-3-[N-benzyl-N-(α-methylbenzyl)amino]-4-[N(1')-(α'-
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
methylbenzyl)pyrrolidin-2'-yl]butanoate 42. Method A: BuLi (2.3 M in hexanes, 0.85 mL, 1.96 mmol)
was added dropwise to a stirred solution of (R)-N-benzyl-N-(α-methylbenzyl)amine (429 mg, 2.03 mmol,
>99:1 er) in THF (3 mL) at –78 °C and the resultant mixture was stirred at –78 °C for 30 min. A solution of
38 (400 mg, 1.27 mmol, 98:2 dr [(E):(Z)]) in THF (2 mL) at –78 °C was added and the resultant mixture was
stirred at –78 °C for 2 h. Satd aq NH4Cl (1 mL) was added and the reaction mixture was allowed to warm to
rt, then concentrated in vacuo. The residue was partitioned between CH2Cl2 (10 mL) and 10% citric acid (10
mL), and the organic layer was washed with satd aq NaHCO3 (10 mL) and brine (10 mL), then dried and
concentrated in vacuo to give 42 in >95:5 dr. Purification via flash column chromatography (eluent 30–40
[]25
°C petrol/Et2O/NH4OH, 100:20:1) gave 42 as a pale yellow oil (655 mg, 98%, >99:1 dr);
+45.1 (c 1.0
D
in CHCl3); νmax (ATR) 3027, 2971, 2932, 2872 (C–H), 1723 (C=O); δH (400 MHz, CDCl3) 1.13 (1H, ddd, J
13.7, 10.9, 2.7, C(4)HA), 1.32 (3H, d, J 7.0, C(α)Me), 1.38 (3H, obsc d, C(α')Me), 1.40 (9H, s, CMe3), 1.42–
1.50 (1H, m, C(3')HA), 1.53–1.74 (3H, m, C(3')HB, C(4')H2), 1.75–1.83 (2H, m, C(2)H2), 1.92 (1H, ddd, J
13.7, 10.8, 2.7, C(4)HB), 2.42 (1H, app q, J 8.1, C(5')HA), 2.73–2.79 (1H, m, C(5')HB), 3.10–3.18 (1H, m,
C(2')H), 3.34–3.41 (1H, m, C(3)H), 3.44 (1H, d, J 14.8, NCHAHBPh), 3.73–3.81 (2H, m, C(α)H, C(α')H),
3.87 (1H, d, J 14.8, NCHAHBPh), 7.16–7.40 (15H, m, Ph); δC (100 MHz, CDCl3) 20.8 (C(α)Me), 23.0
(C(α')Me), 23.1 (C(4')), 28.2 (CMe3), 29.8 (C(3')), 37.9 (C(2)), 38.8 (C(4)), 50.4 (NCH2Ph), 50.7 (C(5')),
51.8 (C(3)), 57.1 (C(α)), 57.5 (C(2')), 61.0 (C(α')), 80.1 (CMe3), 126.7, 126.8, 127.1 (p-Ph), 127.9, 128.2,
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128.2, 128.3, 128.4, 128.5 (o,m-Ph), 141.1, 142.5, 144.2 (i-Ph), 172.1 (C(1)); m/z (ESI+) 527 ([M + H]+,
1
2
3
+
100%); HRMS (ESI+) m/z: [M + H]+ Calcd for C35H47N2O2 527.3632; Found 527.3626.
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Method B: BuLi (2.3 M in hexanes, 0.22 mL, 0.50 mmol) was added dropwise to a stirred solution of (R)-N-
benzyl-N-(α-methylbenzyl)amine (109 mg, 0.52 mmol, >99:1 er) in THF (2 mL) at –78 °C and the resultant
mixture was stirred at –78 °C for 30 min. A solution of 38 and 39 (102 mg, 0.32 mmol, 86:14 dr [(E):(Z)]) in
THF (1 mL) at –78 °C was added and the resultant mixture was stirred at –78 °C for 2 h. Satd aq NH4Cl (0.5
mL) was added and the reaction mixture was allowed to warm to rt, then concentrated in vacuo. The residue
was partitioned between CH2Cl2 (5 mL) and 10% citric acid (5 mL), and the organic layer was washed with
satd aq NaHCO3 (5 mL) and brine (5 mL), then dried and concentrated in vacuo to give an 86:14 mixture of
42 and 44, respectively. Purification via flash column chromatography (eluent 30–40 °C
21 petrol/Et2O/NH4OH, 100:20:1) gave a 90:10 mixture of 42 and 44, respectively, as a pale yellow oil (143
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
mg). Data for 44: δH (400 MHz, CDCl3) [selected peaks] 2.28–2.36 (1H, m, C(5')HA) 2.85–2.95 (2H, m,
C(2')H, C(5')HB), 2.99 (1H, dd, J 15.9, 6.9, C(2)HA), 3.05 (1H, dd, J 15.9, 6.9, C(2)HB), 5.52 (1H, dd, J 15.5,
8.3, C(4)H), 5.65 (1H, app dt, J 15.5, 6.9, C(3)H); m/z (ESI+) 527 ([M(42) + H]+, 100%); 316 ([M(44) + H]+,
32%).
tert-Butyl
(3S,2'R,αS,α'R)-3-[N-benzyl-N-(α-methylbenzyl)amino]-4-[N(1')-(α'-
methylbenzyl)pyrrolidin-2'-yl]butanoate 43. BuLi (2.3 M in hexanes, 0.85 mL, 1.97 mmol) was added
dropwise to a stirred solution of (S)-N-benzyl-N-(α-methlbenzyl)amine (429 mg, 2.03 mmol, >99:1 er) in
THF (3 mL) at –78 °C and the resultant mixture was stirred at –78 °C for 30 min. A solution of 38 (400 mg,
1.27 mmol, 98:2 dr [(E):(Z)]) in THF (2 mL) at –78 °C was added and the resultant mixture was stirred at –
78 °C for 2 h. Satd aq NH4Cl (1 mL) was added and the reaction mixture was allowed to warm to rt, then
concentrated in vacuo. The residue was partitioned between CH2Cl2 (10 mL) and 10% citric acid (10 mL),
and the organic layer was washed with satd aq NaHCO3 (10 mL) and brine (10 mL), then dried and
concentrated in vacuo to give 43 in >95:5 dr. Purification via flash column chromatography (eluent 30–40
[]25
°C petrol/Et2O/NH4OH, 100:20:1) gave 43 as a pale yellow oil (615 mg, 92%, >99:1 dr);
+72.8 (c 1.0
D
in CHCl3); νmax (ATR) 3027, 2972, 2932, 2801 (C–H), 1725 (C=O); δH (400 MHz, CDCl3) 1.34 (3H, d, J
6.9, C(α)Me), 1.38 (9H, s, CMe3), 1.42 (3H, d, J 6.9, C(α')Me), 1.41–1.47 (1H, m, C(3')HA), 1.52–1.78 (4H,
m, C(4)HA, C(3')HB, C(4')H2), 1.84 (1H, ddd, J 13.0, 9.8, 2.5, C(4)HB), 1.93 (1H, dd, J 15.1, 6.6, C(2)HA),
2.10 (1H, dd, J 15.1, 5.8, C(2)HB), 2.32–2.47 (2H, m, C(2')H, C(5')HA), 2.79–2.85 (1H, m, C(5')HB), 3.31–
3.39 (1H, m, C(3)H), 3.62 (1H, d, J 14.8, NCHAHBPh), 3.75 (1H, d, J 14.8, NCHAHBPh), 3.80 (1H, q, J 6.9,
C(α')H), 3.91 (1H, q, J 6.9, C(α)H), 7.17–7.40 (15H, m, Ph); δC (100 MHz, CDCl3) 19.8 (C(α)Me), 21.9
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(C(α')Me), 22.7 (C(4')), 28.2 (CMe3), 30.9 (C(3')), 38.8 (C(4)), 39.0 (C(2)), 49.2 (C(5')), 50.4 (NCH2Ph),
53.4 (C(3)), 58.2 (C(2')), 58.6 (C(α)), 59.8 (C(α')), 80.1 (CMe3), 126.6, 126.9, 127.0 (p-Ph), 128.1, 128.1,
128.1, 128.2, 128.2, 128.5 (o,m-Ph), 141.8, 142.5, 144.1 (i-Ph), 172.1 (C(1)); m/z (ESI+) 527 ([M + H]+,
1
2
3
4
5
6
7
+
100%); HRMS (ESI+) m/z: [M + H]+ Calcd for C35H47N2O2 527.3632; Found 527.3627.
8
9
(2S,2'R,αR,α'R)-1-[N(1')-(α-Methylbenzyl)pyrrolidin-2'-yl]-2-[N-benzyl-N-(α'-
10
11
12
13
14
15
16
17
18
19
20
methylbenzyl)amino]pent-4-ene 45. DIBAL-H (1.0 M in PhMe, 0.59 mL, 0.59 mmol) was added dropwise
to a stirred solution of 42 (284 mg, 0.539 mmol, >99:1 dr) in PhMe (5 mL) at –78 °C and the resultant
mixture was stirred at –78 °C for 1 h. MeOH (109 µL, 2.70 mmol) and Ph3P=CH2 (0.31 M suspension in
PhMe/THF 17.4 mL, 5.39 mmol)24 were added sequentially, and the resultant mixture was allowed to warm
to rt and stirred at rt for 16 h, then concentrated in vacuo. The residue was dissolved in Et2O (40 mL) and the
21 resultant solution was filtered through a short plug of Celite® (eluent Et2O) and concentrated in vacuo.
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Purification via flash column chromatography (eluent 30–40 °C petrol/Et2O/NH4OH, 100:10:1) gave 45 as a
[]25
colourless oil (185 mg, 76%, >99:1 dr);
+76.9 (c 1.0 in CHCl3); νmax (ATR) 3026, 2970, 2933, 2870,
D
2803 (C–H), 1638, 1601, 1493, 1452 (C=C); δH (400 MHz, CDCl3) 1.21–1.31 (2H, m, C(1)HA, C(3')HA),
1.27 (3H, d, J 7.0, C(α')Me), 1.37 (3H, d, J 6.8, C(α)Me), 1.48–1.72 (4H, m, C(3)HA, C(3')HB, C(4')H2),
1.72–1.80 (1H, m, C(3)HB), 1.85 (1H, ddd, J 13.7, 9.9, 3.3, C(1)HB), 2.36 (1H, app q, J 8.2, C(5')HA), 2.73–
2.81 (2H, m, C(2)H, C(5')HB), 2.99–3.08 (1H, m, C(2')H), 3.57 (1H, d, J 15.0, NCHAHBPh), 3.79 (1H, q, J
6.8, C(α)H), 3.83 (1H, q, J 7.0, C(α')H), 3.92 (1H, d, J 15.0, NCHAHBPh), 4.81 (1H, d, J 17.1, C(5)HA), 4.87
(1H, d, J 10.3, C(5)HB), 5.46–5.57 (1H, m, C(4)H), 7.16–7.36 (13H, m, Ph), 7.39–7.43 (2H, m, Ph); δC (100
MHz, CDCl3) 20.8 (C(α')Me), 22.7 (C(α)Me), 22.9 (C(4')), 30.3 (C(3')), 35.9 (C(3)), 37.6 (C(1)), 50.1
(C(5')), 50.4 (NCH2Ph), 55.0 (C(2)), 57.4 (C(α')), 57.9 (C(2')), 60.5 (C(α)), 116.1 (C(5)), 126.6, 126.8, 127.0
(p-Ph), 128.1, 128.1, 128.1, 128.2, 128.4, 128.4 (o,m-Ph), 137.4 (C(4)), 141.8, 143.6, 143.7 (i-Ph); m/z
+
(ESI+) 453 ([M + H]+, 100%); HRMS (ESI+) m/z: [M + H]+ Calcd for C32H41N2 453.3264; Found 453.3259.
(2S,2'R,αR,α'R,Z)-1-[N(1')-(α-Methylbenzyl)pyrrolidin-2'-yl]-2-[N-benzyl-N-(α'-
methylbenzyl)amino]hept-4-ene 46. DIBAL-H (1.0 M in PhMe, 0.53 mL, 0.53 mmol) was added dropwise
to a stirred solution of 42 (255 mg, 0.484 mmol, >99:1 dr) in PhMe (5 mL) at –78 °C and the resultant
mixture was stirred at –78 °C for 1 h. MeOH (98 µL, 2.42 mmol) and Ph3P=CHCH2CH3 (0.31 M suspension
in PhMe/THF 15.6 mL, 4.84 mmol)25 were added sequentially, and the resultant mixture was allowed to
warm to rt and stirred at rt for 16 h, then concentrated in vacuo. The residue was dissolved in Et2O (40 mL)
and the resultant solution was filtered through a short plug of Celite® (eluent Et2O) and concentrated in
vacuo. Purification via flash column chromatography (eluent 30–40 °C petrol/Et2O/NH4OH, 100:10:1) gave
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46 as a colourless oil (174 mg, 75%, >95:5 dr [(Z):(E)]); []2D5 +78.7 (c 1.0 in CHCl3); νmax (ATR) 3061,
3026, 2966, 2932, 2872 (C–H), 1602, 1493, 1453 (C=C); δH (400 MHz, CDCl3) 0.90 (3H, t, J 7.5, C(7)H3),
1.16–1.30 (2H, m, C(1)HA, C(3')HA), 1.27 (3H, d, J 7.0, C(α')Me), 1.38 (3H, d, J 6.8, C(α)Me), 1.51–1.65
(3H, m, C(3')HB, C(4')H2), 1.72–1.95 (5H, m, C(1)HB, C(3)H2, C(6)H2), 2.39 (1H, app q, J 7.9, C(5')HA),
2.69–2.81 (2H, m, C(2)H, C(5')HB), 2.98–3.06 (1H, m, C(2')H), 3.60 (1H, d, J 15.1, NCHAHBPh), 3.80 (1H,
q, J 6.8, C(α)H), 3.86 (1H, q, J 7.0, C(α')H), 3.96 (1H, d, J 15.1, NCHAHBPh), 5.03–5.12 (1H, m, C(4)H),
5.24–5.32 (1H, m, C(5)H), 7.18–7.37 (13H, m, Ph), 7.40–7.43 (2H, m, Ph); δC (100 MHz, CDCl3) 14.3
(C(7)), 20.8 (C(6)), 21.1 (C(α')Me), 22.6 (C(α)Me), 22.8 (C(4')), 28.7 (C(3)), 30.2 (C(3')), 37.5 (C(1)), 50.0
(C(5')), 50.5 (NCH2Ph), 55.8 (C(2)), 57.8 (C(α')), 57.8 (C(2')), 60.3 (C(α)), 126.5, 126.8, 126.9 (p-Ph), 127.5
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
(C(4)), 128.0, 128.1, 128.1, 128.2, 128.3, 128.4 (o,m-Ph), 132.5 (C(5)), 142.1, 143.7, 144.3 (i-Ph); m/z
+
21 (ESI+) 481 ([M + H]+, 100%); HRMS (ESI+) m/z: [M + H]+ Calcd for C34H45N2 481.3577; Found 481.3574.
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(5S,6aR,10aS)-5-Propyldecahydrodipyrrolo[1,2-a:1',2'-c]pyrimidine [(+)-tetraponerine 2] 49.
Palladium black (37 mg, 20% w/w) was added to a stirred, degassed solution of 45 (183 mg, 0.404 mmol,
>99:1 dr) in MeOH/H2O/AcOH (10:1:1, 2 mL). The resultant mixture was stirred under an atmosphere of H2
(5 atm) at rt for 48 h. The reaction mixture was then filtered through a short plug of Celite® (eluent
MeOH/H2O/AcOH, 10:1:1) and concentrated in vacuo. The residue was dissolved in CH2Cl2 (2 mL), then
K2CO3 (168 mg, 1.21 mmol) and 4-bromobutanal (123 mg, 0.81 mmol) were added to the resultant solution.
The reaction mixture was stirred at rt for 2 h, then H2O (2 mL) and satd aq NaHCO3 (10 mL) were added.
The reaction mixture was then extracted with CH2Cl2 (3 × 5 mL) and the combined organic extracts were
dried and concentrated in vacuo. Purification via flash column chromatography (eluent 30–40 °C
petrol/Me2CO/NH4OH, 100:10:1) gave (+)-tetraponerine 2 (49) as a colourless oil (31 mg, 37% from 45,
[]2D5
>99:1 dr);
+44.2 (c 1.0 in CHCl3); {lit.5 []D20 +36 (c 1.79 in CHCl3); lit.6 []D20 +47 (c 0.232 in
CHCl3)}; νmax (ATR) 2957, 2931, 2871, 2786 (C–H);26 δH (400 MHz, C6D6) 0.92 (3H, t, J 7.2, C(3')H3),
1.27–1.83 (14H, m, C(1)H2, C(2)H2, C(6)H2, C(7)H2, C(8)H2, C(1')H2, C(2')H2), 1.83–1.97 (2H, m, C(9)HA,
C(6a)H), 2.29–2.36 (1H, m, C(3)HA), 2.39–2.46 (1H, m, C(5)H), 2.86 (1H, app t, J 5.3, C(10a)H), 2.93 (1H,
app td, J 8.5, 2.5, C(9)HB), 3.01–3.07 (1H, m, C(3)HB); δC (100 MHz, C6D6) 14.7 (C(3')), 19.3 (C(2')), 21.0
(C(2)), 21.3 (C(8)), 29.3 (C(1)), 30.6 (C(7)), 33.4 (C(6)), 37.0 (C(1')), 45.8 (C(3)), 49.2 (C(9)), 59.4 (C(5)),
64.2 (C(6a)), 83.4 (C(10a)); m/z (ESI+) 209 ([M + H]+, 100%); HRMS (ESI+) m/z: [M + H]+ Calcd for
+
C13H25N2 209.2012; Found 209.2012.
(5S,6aR,10aS)-5-Pentyldecahydrodipyrrolo[1,2-a:1',2'-c]pyrimidine [(+)-tetraponerine 6] 50.
Palladium black (31 mg, 20% w/w) was added to a stirred, degassed solution of 46 (155 mg, 0.322 mmol,
29
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