Total synthesis of incargranine A

Article abstract of DOI:10.1039/c8ob00702k

Synthetic studies into the origins of the alkaloid incargranine A have resulted in the development of a four-step (longest linear sequence) total synthesis. This synthesis has been scaled-up to provide gram-scale quantities of material, which would alternatively require extraction of several metric-tons of dried-whole Chinese Trumpet-Creeper plants (Incarvillea mairei var. grandiflora).

Full text of DOI:10.1039/c8ob00702k

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Total Synthesis of Incargranine A
Patrick D. Brown and Andrew L. Lawrence*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Synthetic studies into the origins of the alkaloid incargranine A atoms are stereogenic. Nevertheless, we were hopeful that if
have resulted in the development of a four-step (longest linear we could gain insight into how nature synthesizes this alkaloid
sequence) total synthesis. This synthesis has been scaled-up to a step-economical biomimetic strategy could be developed.
provide gram-scale quantities of material, which would
alternatively require extraction of several metric-tons of dried- incargranine A (
whole Chinese Trumpet-Creeper plants (Incarvillea mairei var. derived C6C2 units linked together by an ornithine-derived C4N
Our biosynthetic analysis, shown in Scheme 1, reveals
1
) is likely constructed from two shikimate-
grandiflora).
unit. Our previous biomimetic studies on related
phenylethanoid alkaloids provide important clues as to the
potential origins of incargranine A (
that a network of pathways, all originating from a simple
biosynthetic precursor, diamine , could account for the
formation of several structurally distinct phenylethanoid
natural products (Scheme 2).2d In our proposal, diamine
can
1
).2 We recently proposed
In 2009 Zhang and co-workers isolated the alkaloid
incargranine A (
Bignonia plant more commonly known as the Chinese
Trumpet-Creeper plant (Scheme 1).1 Incargranine A (
) has not
1) from Incarvillea mairei var. grandiflora, a
2
1
yet succumbed to total synthesis and represents a particularly
scarce natural product, constituting just 0.0000002% by weight
of the dried whole plant. Therefore, a practical – i.e., efficient
2
participate in a pair of divergent oxidative pathways (Scheme
2; pathways 1 and 2). As shown in Scheme 2, pathway 1
3
and scalable – chemical synthesis of incargranine A (
advance a better understanding of its biological function. The
novel framework of incargranine A ( ) contains a synthetically
1) might
terminates in the formation of incarviditone
incarvilleatone (
),4 via the intermediacy of cornoside (
rengyolone (
of incargranine B (
divergent pathways could re-converge to give millingtonine
),8 via a crossed-dimerization of cornoside
, from pathway
1, and a PLP (pyridoxal phosphate) derived enamine , from
(
3
)
and
4
5
)5 and
),6 whereas pathway 2 results in the production
1
6
7
).7,2a-c It was proposed that these two
daunting bridged-cyclohexane ring, in which all six-carbon
(
8
5
9
pathway 2 (Scheme 2; pathway 3).2d The chemical feasibility of
this re-convergent pathway was demonstrated in our seven-
step biomimetic total synthesis of millingtonine (
we propose that an additional re-convergent pathway could
give rise to incargranine A ( ) (Scheme 2; pathway 4). Thus, a
Michael reaction between PLP-enamine and rengyolone (6)
8
).2d Herein,
1
9
would give an intermediate imine 11, which would ring-close
through a condensation/Mannich reaction sequence to give
incargranine A (1
).9 To investigate the feasibility of this second
re-convergent pathway, and in the hope of establishing a
practical solution to the supply problem associated with
incargranine A (1
),1 we decided to pursue the development of
Scheme 1 Structure and biosynthetic analysis of incargranine A.
a biomimetic synthetic strategy.
Condensation of 4-aminophenethyl alcohol 12 with (Z)-1,4-
dichlorobut-2-ene gave N-aryl-2,5-dihydropyrrole 13 in 87%
yield (Scheme 3).10 The primary alcohol functional group was
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Scheme 2 Proposed network of biosynthetic pathways towards a family of plant-derived phenylethanoid natural products, including incargranine A.
then protected under standard conditions as
butyldimethylsilyl ether, to give alkene 14 in 84% yield. demonstrates the viability of a crossed-dimerization between
Exposure of alkene 14 to our previously developed aminal 15 and rengyolone ( ), several issues presented
RhHCO(PPh3)3 and pyrrolidine reaction conditions gave the themselves with respect to using this strategy to access
expected aminal intermediate 15 2d,11
Due to the instability of incargranine A ( ). Firstly, rengyolone ( ) proved to be
aminal 15, and in the interests of practicality and efficiency, relatively unreactive in the crossed-dimerization, taking over a
a tert- incargranine A framework 17 (Scheme 3). Although this result
6
.
1
6
rengyolone (6), which can be readily prepared from tyrosol in 3 week to give full consumption of starting material 15, while
steps,2a was added directly to this crude reaction mixture. comparable reactions with para-quinols were generally
1
Monitoring the reaction by H NMR spectroscopy revealed it complete in 24 h.2d Furthermore, the low yield of crossed-
took 10 days at ambient temperature for aminal 15 to be dimer 16, even after these prolonged reaction times, was not a
consumed. Purification of the resulting crude reaction mixture promising start to the development of an efficient synthesis.
by column chromatography resulted in a 12% isolated yield of Finally, and most importantly, our attempts to rearrange hemi-
an unwanted crossed-dimer 16, with no detectable formation aminal 16 to give the incargranine A framework 17, via a retro-
of the desired product 17. Hemi-aminal 16 is presumably oxa-Mannich/Mannich
reaction
sequence,
were
formed via
a
domino Michael/aza-Mannich/oxa-Mannich unsuccessful.12 This prompted us to reconsider our
reaction sequence. In contrast, a final Mannich reaction biosynthetic proposal and synthetic strategy.
between C5 and C1'' would be required for formation of the
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diol-aglycone 18 spontaneously rearranges to give (±)-
incargranine A ( ) when dissolved in methanol at ambient
temperature, albeit very slowly. Ultimately, a 33% isolated
yield of (±)-incargranine A ( ) was achieved when a CD3OD
1
1
solution of diol-aglycone 18 was warmed to 40 °C for 2 days.
The chemical feasibility of our proposed biosynthetic pathway
between dia-millingtonine (10) and incargranine A (
been established. All efforts, however, to rearrange the
cyclized-aglycone 22 to give incargranine were
1) had thus
A
(1)
unsuccessful, akin to our failure to rearrange hemi-aminal 16
Scheme 3 Failed approach to synthesize incargranine A.
Scheme 4 Revised biosynthetic hypothesis for incargranine A.
(Scheme 3).12
Upon further evaluation of the incargranine
A (1)
framework it became apparent that it might instead be
derived from the syn-diastereomer of millingtonine, dia-
millingtonine (10), which we had previously identified as a
potential natural product and direct biosynthetic precursor to
The low yields and lack of selectivity achieved in the final
de-protection and rearrangement steps rendered this
synthesis unsuitable for scale-up. Alternative deprotection
conditions were therefore screened in the hope of favoring
production of diol 18, whilst avoiding formation of the
seemingly intractable ring-closed aglycone 22. Vaino and
Szarek have reported iodine in methanol as mild reaction
conditions for the cleavage of tert-butyldimethylsilyl ethers.14
Unexpectedly, however, exposure of syn-dimer 21 to iodine in
methanol did not result in the formation of diol 18, nor ring-
millingtonine (8
) (Scheme 2; pathway 3).2d Specifically, the
putative aglycone of dia-millingtonine, diol 18, could undergo
a domino retro-oxa-Mannich/oxa-Michael/Mannich reaction
sequence to give incargranine A (
pathway could be shown to be chemically feasible it would
1
) (Scheme 4).13 If this
lend further support to our proposal that dia-millingtonine (
represents an as-yet-undiscovered natural product.2d
1)
During the development of this new strategy, it was
discovered that protection of the primary alcohol in N-aryl-2,5-
dihydropyrrole 13 was not necessary for the subsequent
alkene-isomerization/hydroamination reaction. Thus, exposure
of free alcohol 13 to RhHCO(PPh3)3 and pyrrolidine gave the
expected aminal intermediate 19 (Scheme 5).2d,11 TBS-
protected para-quinol 20, which was prepared in 2 steps from
tyrosol,2a was then added directly to this crude reaction
closed aglycone 22, but instead gave (±)-incargranine A (1)
directly. Thus, in a single step, 2 new bonds, 2 new rings and 3
new stereogenic centres are formed in an impressive 84%
yield. This synthetic sequence was readily scaled-up to provide
gram-scale quantities of (±)-incargranine
A (1), which
compares very favorably to the effort required to obtain this
material from the natural source; over four metric-tons of
dried Incarvillea mairei var. grandiflora would need to be
mixture resulting in
a
kinetically-controlled crossed-
extracted to isolate one gram of natural incargranine A (
Zhang and co-workers reported an optical rotation for
natural incargranine A (
), [ꢀ]ꢂꢁꢂ = +2 (c = 0.175, CHCl3).1
1
).1
dimerization to give syn-dimer 21 in 77% yield.2d
Attention could now turn to the de-protection of crossed-
dimer 21, a synthetic equivalent of dia-millingtonine (10), and
1
However, given our biosynthetic speculation and the small
its subsequent conversion to incargranine A (1). Cleavage of
magnitude of the reported optical rotation value, we consider
the tert-butyldimethylsilyl ether using standard TBAF (tetra-n-
butylammonium fluoride) conditions gave the expected diol-
aglycone 18 in just 10% yield, alongside a cyclized-aglycone 22
in 56% yield (Scheme 5). Remarkably, it was observed that
it likely that natural incargranine A (1) exists as a racemic
mixture. Unfortunately, no authentic sample was available to
validate this hypothesis.15 In all other respects, however, the
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spectroscopic data for our synthetic material matched that
reported for natural incargranine A (
).1,15 We propose that
this successful synthesis provides new evidence in support of
Conflicts of interest
1
There are no conflicts to declare.
the proposal that dia-millingtonine
(
10
)
is
a
natural
) is only
product.2d,16 In fact, it is possible that incargranine A (
1
Acknowledgements
produced from dia-millingtonine (10) during the extraction and
We thank Prof. Wei-Dong Zhang (School of Pharmacy, Second
Military Medical University, Shanghai) for kindly providing
copies of the processed NMR spectra for natural incargranine
A. The Royal Society is thanked for the award of a Research
Grant. P.D.B. thanks the University of Edinburgh for the
provision of a studentship.
isolation process. This would not necessarily mean that
incargranine A (1) is an unimportant artifact of human
intervention.17 It is known, for example, that plants can use
glycosidic-metabolites as chemical defense systems, wherein
Notes and references
1
Y.-Q. Su, Y.-H. Shen, S. Lin, J. Tang, J.-M. Tian, X.-H. Liu and
W.-D. Zhang, Helv. Chim. Acta, 2009, 92, 165–170.
2
For previous biomimetic studies on related dimeric natural
products, see: (a) P. D. Brown, A. C. Willis, M. S. Sherburn
and A. L. Lawrence, Org. Lett., 2012, 14, 4537–4539. (b) K.
Zhao, G.-J. Cheng, H. Yang, H. Shang, X. Zhang, Y.-D. Wu and
Y. Tang, Org. Lett., 2012, 14, 4878–4881. (c) P. D. Brown, A.
C. Willis, M. S. Sherburn and A. L. Lawrence, Angew. Chem.,
2013, 125, 13515–13517; Angew. Chem. Int. Ed., 2013, 52
13273–13275; (d) P. D. Brown and A. L. Lawrence Angew.
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Chem., 2016, 128, 8561–8565; Angew. Chem. Int. Ed., 2016,
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Y. Q. Chen, Y. H. Shen, Y. Q. Su, L. Y. Kong, and W. D. Zhang,
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For our earliest biosynthetic proposals, see page 36 of the SI
for ref 2c.
Scheme 5 Total synthesis of incargranine A.
damage to the plant brings gycosidase enzymes into contact
with the glycosides to release the active aglycones.18
10 J. M. Bobbitt, L. H. Amundsen and R. I. Steiner, J. Org. Chem.,
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Conclusions
In just three-linear steps from 4-aminophenethyl alcohol
12 we have selectively formed 2 new C–N bonds, 2 new C–C
bonds, 2 new rings, and 6 new contiguous stereogenic centres,
in 56% overall yield.19 Key to the development of this efficient
synthetic strategy has been the probing and refinement of a
biosynthetic proposal using chemical synthesis. Ultimately, this
has led to new evidence in support of the notion that dia-
millingtonine (10) is an as-yet-undiscovered natural product.16
Practical quantities of these metabolites are now available for
interested parties to study their biological function.
Bruffaerts and I. Marek, Nat. Chem., 2016, 8, 209–219.
12 Attempts to rearrange hemi-aminals 16 and 22 failed.
Heating solutions in MeOH, EtOH or MeCN returned starting
material. Treatment with TFA appeared to give isomerization
from the syn to the anti configuration, with no sign of further
rearrangement. Treatment with LiOH in refluxing MeOH/H2O
resulted in slow decomposition.
13 Treatment of millingtonine with glucosidase enzymes has
been shown to result in a retro-oxa-Mannich/oxa-
Michael/Mannich reaction sequence to give a diastereomer
of incargranine A, see ref 8.
14 A. R. Vaino and W. A. Szarek, Chem. Commun., 1996, 20
2351–2352.
,
4 | J. Name., 2012, 00, 1-3
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15 Professor Zhang very kindly provided pdf files of the
processed NMR spectra for natural incargranine A, see the
Supporting Information for direct comparisons.
16 For recent examples of natural product anticipation from
biomimetic studies, see: (a) D. P. O’Malley, K. Li, M. Maue, A.
L. Zografos and P. S. Baran, J. Am. Chem. Soc., 2007, 129
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J. Am. Chem. Soc., 2009, 131, 5966–5972; (c) M. Gavagnin, E.
Mollo and G. Cimino, Rev. Bras. Farmacogn., 2015, 25, 588–
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R. P. Pemberton,S. C. Wang, D. J. Tantillo and D. Trauner,
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17 P. Champy, Artifacts and Natural Substances Formed
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849–934.
18 A. Mithofer and W. Boland, Annu. Rev. Plant Biol., 2012, 63
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19 N. J. Green and M. S. Sherburn, Aust. J. Chem., 2013, 66
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,
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