Rapid synthesis of the core scaffold of crinane and haemanthamine through a multi-component approach

Article abstract of DOI:10.1016/j.tetlet.2021.153201

A rapid synthesis of the core structures of crinane and haemanthamine has been developed, enabled by a multicomponent approach. This work constitutes a formal synthesis of crinane and sets the stage for access to both families of natural products and key

Full text of DOI:10.1016/j.tetlet.2021.153201

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Rapid synthesis of the core scaffold of crinane and haemanthamine
through a multi-component approach
⇑
Nicholas P. Massaro, Joshua G. Pierce
Department of Chemistry and Comparative Medicine Institute, NC State University, Raleigh, NC 27695, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A rapid synthesis of the core structures of crinane and haemanthamine has been developed, enabled by a
multicomponent approach. This work constitutes a formal synthesis of crinane and sets the stage for
access to both families of natural products and key analogues. A key highlight of the approach is the mod-
ularity of the core synthesis, overcoming existing challenges for these scaffolds and providing a path to
explore site-selective oxidation to expand the scope of molecules accessible from common intermediates.
Ó 2021 Elsevier Ltd. All rights reserved.
Received 3 April 2021
Revised 17 May 2021
Accepted 20 May 2021
Available online xxxx
Keywords:
Amaryllidaceae alkaloids
Heterocycles
Multicomponent
Natural products
Total synthesis
Introduction
cycloaddition [8,9] and Martin and Campbell utilizing a conjugate
addition (Fig. 1b) [10]. Stemming from these pioneering efforts,
The Amaryllidaceae plant family has a legacy of antitumor
properties from very early use as an herbal treatment for uterine
tumors to current isolation and exploration of the alkaloids
responsible for their potency towards a variety of ailments [1].
Amaryllidaceae alkaloids represent a diverse class of molecules
that often contain significant structural variation frequently due
to highly divergent biosynthetic paths from early common inter-
mediates [2]. Examples of this divergence have led to five major
alkaloid structural types, two of which are the crinine alkaloids
represented by crinane (1) and haemanthamine (2a) and the tazet-
tine alkaloids represented by pretazettine (3) and tazettine (4)
various other groups employed similar strategies to access the
hydroindole core, although there remains a lack of mild and mod-
ular approaches to access the core scaffold of these natural prod-
ucts [11–18].
In our research program we have been interested in both the
crinine and tazettine classes of amaryllidaceae alkaloids due to
their challenging synthetic scaffolds as well as their bioactivity.
Furthermore, the co-crystallization of haemanthamine with the
p53 binding site provides an opportunity for rational Structure
Activity Relationship (SAR) design [19]. With this new information,
there is a need to access the crinane scaffold in a modular approach
to facilitate analogue generation [20]. When considering the
biosynthetic origins of these natural products, their proposed bio-
genetic pathway suggests a common precursor for a number of
highly complex molecules such as tazettine, augustamine, pli-
camine, gracilamine, mesembrine, and galasine which all originate
from a N,6-seco-crinane. Furthermore, this biosynthetic intermedi-
ate is proposed to spawn from crinane itself [4]. Three common
approaches to this intermediate have been established; however,
there are currently no multicomponent approaches to the crinane
alkaloids that focus on modularity and the ability to conduct pin-
point modifications for SAR studies. With regard to crinane alka-
loids, a common theme is the construction of a hydroindole core
that is then subjected to Pictet-Spengler conditions yielding the
bridged natural product core. Due to the well precedented litera-
ture for this strategy, we envisioned the same Pictet-Spengler
(
Fig. 1a) [3,4]. One key intermediate of this pathway is 4-O-methyl-
norbelladine originating from the precursors -tyrosine and
-phenylalanine [2]. Tang and co-workers, inspired by the
L
L
biosynthetic pathway, accessed crinane through a transition metal
catalyzed dearomative cyclization [5]. Although biomimetic, this
route provided no access to higher oxidation levels within the
pyrrolidine core necessary to access many oxygenated members
of this class. A more prominent focus for the synthesis of these
molecules has been towards the hydroindole core present within
numerous crinane alkaloids (Fig. 1a). Three representative exam-
ples established early on for accessing this core were by Stevens
utilizing a Robinson annulation [6,7], Tsuda utilizing a 4 + 2
⇑
Corresponding author.
E-mail address: jgpierce@ncsu.edu (J.G. Pierce).
https://doi.org/10.1016/j.tetlet.2021.153201
040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
0
Please cite this article as: N.P. Massaro and J.G. Pierce, Rapid synthesis of the core scaffold of crinane and haemanthamine through a multi-component
approach, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2021.153201

N.P. Massaro and J.G. Pierce
Tetrahedron Letters xxx (xxxx) xxx
haemanthamine core in a modular fashion to enable analogue gen-
eration and SAR studies. Herein, we report our approach to dihy-
dro-demethoxyhaemanthamine and a formal synthesis of crinane.
Results and discussion
We initially sought to improve our reported approach to the
arylpyruvic acid methyl ester multicomponent fragment. Previ-
ously we had made this fragment from an Erlenmeyer reaction fol-
lowed by prolonged acid hydrolysis to yield pyruvic acid 13
followed by alkylation with methyl iodide. Our revised route
begins from commercially available piperonal (12). We performed
an Erlenmeyer reaction utilizing a modified protocol from Buck
and Ide yielding azlactone 13 under neat heating conditions [21].
This azlactone was then subject to hydrolysis with 6 M HCl(aq).
Our original approach to access these aryl pyruvic acids required
heating at reflux for reaction times greater than 18 h. In our revised
protocol we accomplish the same transformation by subjecting 13
to microwave irradiation for 15 min at 130 °C yielding 14 in an
equivalent yield to our previous approach. Although low yielding,
it is noteworthy that no chromatographic purification is necessary
for the synthesis of 14 from piperonal (12) over two steps
(
Scheme 1). Subsequent methanolysis of 14 provided 15 in good
yield.
With fragment 15 and aldehyde 16 derived from 1,5-pentane
diol available via our previously published protocol [22], we then
utilized these key fragments for the synthesis of pyrrolidinedione
1
8, with a modified procedure utilizing activated 3 Å molecular
sieves and slow addition of commercially available 2,4-dimethoxy-
benzylamine (17) which drastically improved our overall yield of
1
8 compared to that previously reported [22]. With 18 in hand
we employed a 6-exo-tet cyclization yielding 19 in good yield as
Fig. 1. Relevance and synthetic strategies currently employed to access the 3-
hydroxy-hydroindoline core.
a single diastereomer [22]. We were able to accomplish a stereos-
elective reduction of this substrate with an excess of LiAlH at
4
room temperature providing the kinetic product (20) with no
observation of the other diastereomer. We then proceeded to
deprotect the 2,4-dimethoxybenzyl (Dmb) group utilized in our
initial multicomponent reaction. Initially, we explored trifluo-
roacetic acid at room temperature and at reflux, however no
desired product 21 was observed [23]. We then moved to more
forcing conditions utilizing microwave irradiation. To our delight,
we obtained 21 with clean conversion. Upon removal of trifluo-
transformation of the haemanthamine core 2b leading to
3
-hydroxy-cis-hydroindoline 9 (Fig. 2a). This intermediate was
envisioned to be easily accessed from our previously reported
convergent approach to hydroindoline scaffolds enabled through
a functionalized multicomponent product (10) that would allow
for an intramolecular 6-exo-tet cyclization to access (11) (Fig. 2b).
We planned for this to provide the foundation to access the
Fig. 2. a) Retrosynthetic approach; b) current multicomponent 6-exo-tet
cyclization.
Scheme 1. Preparation of pyruvic acid methyl ester 15.
2

N.P. Massaro and J.G. Pierce
Tetrahedron Letters xxx (xxxx) xxx
roacetic acid by evaporation and basification of the trifluoroacetate
salt to obtain 21 as the crude free-base, we directly subjected this
substrate to Pictet-Spengler cyclization conditions with formalin
and 6 M HCl at 50 °C yielding the final haemanthamine core (2b)
in 23% over two steps (Scheme 2).
When considering the diastereoselectivity achieved upon
reduction of 19 with LiAlH , we propose that the axial hydrogens
4
create a steric repulsion causing the hydride source to deliver to
the less sterically hindered peripheral face of the molecule provid-
ing the desired diastereomer (See Fig. 3).
Although a similar stereoselectivity was observed by Tsuda and
co-workers with a related scaffold [8,9], we sought to further con-
firm the hydroxyl stereochemistry through NOE analysis. We ini-
tially confirmed the correct stereochemistry of 20 with the
desired NOE interactions. Interestingly, we observed over a short
3
time in CDCl , the full conversion of 2b to the protonated iminium
Fig. 3. Model showing the less sterically hindered face of 19.
form (2c, Fig. 4b). Fortunately, stereochemical assignment of the
hydroxyl could still be accomplished, which confirmed the desired
stereochemistry of the hydroxyl group was obtained. With the con-
Fig. 4. Key NOE interactions of 20 and 2c confirming the hydroxyl stereochemistry.
D structure of 2b/c generated with Chem3D 20.0.
3
firmed stereochemistry, we have in fact synthesized (±)-dihydro-
demethoxyhaemanthamine (2b). It is noteworthy that precursors
1
5 and 16 are both known compounds in the literature, but also
commercially available upon demand, thus our route to the hae-
manthamine core is completed in five steps. Furthermore, Wild-
man and Fales have shown that 2b can be readily converted to
crinane by a deoxygenation sequence utilizing thionyl chloride fol-
lowed by lithium aluminum hydride [24].
Conclusion
In conclusion, we have presented a rapid approach to the cri-
nane and haemanthamine core and a formal synthesis of crinane
itself. This was accomplished through a highly convergent and
modular multicomponent strategy that diastereoselectively con-
structs the natural product cores, which we plan to draw on for
the synthesis of haemanthamine and pretazettine in due course.
A highlight of the present study is the stereoselective installation
of the quaternary center and hydroxyl group, overcoming many
previous challenges in the synthesis of these natural product
families.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgements
We are grateful to the NIH (R35GM139583) for support of this
work and to NC State University for support of our program. Mass
spectrometry data, NMR data, and X-ray data were obtained at the
NC State Molecular, Education, Technology and Research Innova-
tion Center (METRIC).
Scheme 2. Synthetic route to dihydro-demethoxyhaemanthamine.
3

N.P. Massaro and J.G. Pierce
Tetrahedron Letters xxx (xxxx) xxx
(
(
+)-Vittatine, (+)- epi -vittatine, and (+)-buphanisine, Chem – Asian J. 8 (9)
2013) 1966–1971, https://doi.org/10.1002/asia.201300595.
Appendix A. Supplementary data
[
[
13] P. Lan, M.G. Banwell, A.C. Willis, Total synthesis of (±)-Crinane from 6,6-
dibromobicyclo[3.1.0]hexane using a 5- exo - trig radical cyclization reaction
to assemble the C3a-arylated perhydroindole substructure, J. Org. Chem. 83
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153201.
(
15) (2018) 8493–8498, https://doi.org/10.1021/acs.joc.8b01088.
14] M. Bohno, K. Sugie, H. Imase, Y.B. Yusof, T. Oishi, N. Chida, Total synthesis of
amaryllidaceae alkaloids, (+)-vittatine and (+)-haemanthamine, starting from
d-glucose, Tetrahedron 63 (30) (2007) 6977–6989, https://doi.org/10.1016/j.
tet.2007.05.041.
References
[
[
[
1] A. Kornienko, A. Evidente, Chemistry, biology, and medicinal potential of
narciclasine and its congeners, Chem. Rev. 108 (6) (2008) 1982–2014, https://
doi.org/10.1021/cr078198u.
2] S. Ka, M. Koirala, N. Mérindol, I. Desgagné-Penix, Biosynthesis and biological
activities of newly discovered amaryllidaceae alkaloids, Molecules 25 (2020)
[15] M. Bohno, H. Imase, N. Chida, A new entry to amaryllidaceae alkaloids from
carbohydrates : total synthesis of (+)-vittatine, Chem. Commun. (2004) 1086–
1087, https://doi.org/10.1039/b402762k.
[16] P. Lan, M.G. Banwell, A.C. Willis, Application of electrocyclic ring-opening and
desymmetrizing nucleophilic trappings of meso -6,6-dibromobicyclo[3.1.0]
hexanes to Total syntheses of crinine and haemanthamine alkaloids, J Org
Chem. 84 (6) (2019) 3431–3466, https://doi.org/10.1021/acs.joc.9b00018.
[17] F.-M. Zhang, Y.-Q. Tu, J.-D. Liu, X.-H. Fan, L. Shi, X.-D. Hu, S.-H. Wang, Y.-Q.
Zhang, A general approach to crinine-type Amaryllidaceae alkaloids: total
syntheses of (±)-haemanthidine, (±)-pretazettine, (±)-tazettine, and (±)-
crinamine, Tetrahedron 62 (40) (2006) 9446–9455, https://doi.org/10.1016/j.
tet.2006.07.027.
4
901, https://doi.org/10.3390/molecules25214901.
3] Y. Tian, C. Zhang, M. Guo, Comparative analysis of amaryllidaceae alkaloids
from three lycoris species, Molecules 20 (2015) 21854–21869, https://doi.org/
1
0.3390/molecules201219806.
4] Z. Jin, G. Yao, Amaryllidaceae and sceletium alkaloids, Nat. Prod. Rep. 36 (10)
2019) 1462–1488, https://doi.org/10.1039/C8NP00055G.
[
[
(
5] K. Du, H.e. Yang, P. Guo, L. Feng, G. Xu, Q. Zhou, L.W. Chung, W. Tang, Efficient
syntheses of (À)-crinine and (À)-aspidospermidine, and the formal synthesis
of (À)-minfiensine by enantioselective intramolecular dearomative
[18] M.K. Das, S. De, S. Shubhashish, A. Bisai, Concise total syntheses of (±)-
mesembrane and (±)-crinane, Org. Biomol. Chem. 13 (12) (2015) 3585–3588,
https://doi.org/10.1039/C5OB00183H.
cyclization, Chem. Sci.
C7SC01859B.
8 (9) (2017) 6247–6256, https://doi.org/10.1039/
[
6] R.V. Stevens, L.E. DuPree, General methods of alkaloid synthesis. A new
approach to the synthesis of the 5,10b-ethanophenanthridine Amaryllidaceae
alkaloids. The total synthesis of (±)-3- epi -elwesine, J. Chem. Soc. D Chem.
Commun. 0 (23) (1970) 1585–1586, https://doi.org/10.1039/C29700001585.
7] R.V. Stevens, L.E. DuPree, P.L. Loewenstein, General methods of alkaloid
synthesis. Synthesis of the 5,10b-ethanophenanthridine Amaryllidaceae
alkaloids. Stereoselective total synthesis of dl-elwesine (dihydrocrinine), J.
Org. Chem. 37 (7) (1972) 977–982, https://doi.org/10.1021/jo00972a012.
8] Y. Tsuda, K. Isobe, Stereoselective total synthesis of the alkaloid
haemanthamine, J. Chem. Soc. D Chem. Commun. (1971) 1555–1556, https://
doi.org/10.1039/c29710001555.
[19] S. Pellegrino, M. Meyer, C. Zorbas, S.A. Bouchta, K. Saraf, S.C. Pelly, G. Yusupova,
A. Evidente, V. Mathieu, A. Kornienko, D.L.J. Lafontaine, M. Yusupov, The
amaryllidaceae alkaloid haemanthamine binds the eukaryotic ribosome to
repress cancer cell growth, Structure 26 (3) (2018) 416–425.e4, https://doi.
org/10.1016/j.str.2018.01.009.
[
[20] A.W. Sun, S. Lackner, B.M. Stoltz, Modularity: adding new dimensions to total
synthesis, Trends Chem.
trechm.2019.05.008.
1 (7) (2019) 630–643, https://doi.org/10.1016/j.
[
[
[21] J.S. Buck, W.S. Ide, Azlactone of a-benzoylamino-b-(3,4-dimethoxyphenyl)-
acrylic acid, Org. Synth. 13 (1933) 8. https://doi.org/10.15227/orgsyn.013.
0008.
[22] N.P. Massaro, J.G. Pierce, Stereoselective, multicomponent approach to
quaternary substituted hydroindole scaffolds, Org. Lett. 22 (13) (2020)
9] Y. Tsuda, K. Isobe, A. Ukai, Synthesis and cycloaddition of 3-phenyl-
D
2 -
pyrroline-4,5-dione, a new dienophile, J Chem Soc D. 0 (23) (1971) 1554–1555,
https://doi.org/10.1039/C29710001554.
5079–5084,
https://doi.org/10.1021/acs.orglett.0c0165010.1021/acs.
[
[
10] S.F. Martin, C.L. Campbell, Total syntheses of (.+-.)-crinine and (.+-.)-
buphanisine, J. Org. Chem. 53 (14) (1988) 3184–3190, https://doi.org/
orglett.0c01650.s001.
[23] N.V. Shymanska, J.G. Pierce, Stereoselective synthesis of quaternary
pyrrolidine-2,3-diones and b-Amino acids, Org Lett. 19 (11) (2017) 2961–
2964, https://doi.org/10.1021/acs.orglett.7b01185.
[24] H.M. Fales, W.C. Wildman, Haemultine and the alkaloids of haemanthus
multiflorus martyn 1, J. Org. Chem. 26 (5) (1961) 1617–1621, https://doi.org/
10.1021/jo01064a076.
1
0.1021/jo00249a011.
11] S. Raghavan, A. Ravi, Synthesis of crinane utilizing an allylic sulfoxide for the
construction of a hydroindole ring via vinylogous C-N bond formation, Org.
Biomol. Chem. 14 (43) (2016) 10222–10229, https://doi.org/10.1039/
C6OB01966H.
[
12] M.-X. Wei, C.-T. Wang, J.-Y. Du, H.u. Qu, P.-R. Yin, X.u. Bao, X.-Y. Ma, X.-H. Zhao,
G.-B. Zhang, C.-A. Fan, Enantioselective synthesis of amaryllidaceae alkaloids
4