Catalytic Asymmetric Total Syntheses of Naturally Occurring Amarylidaceae Alkaloids, (-)-Crinine, (-)- epi-Crinine, (-)-Oxocrinine, (+)- epi-Elwesine, (+)-Vittatine, and (+)- epi-Vittatine

Article abstract of DOI:10.1021/acs.orglett.8b01703

An expeditious approach to catalytic enantioselective total syntheses of crinine-type Amaryllidaceae alkaloids has been accomplished via a Pd-catalyzed enantioselective decarboxylative allylation of allylenol carbonates as a key step (up to 96% ee). Using this strategy, collective total syntheses of Amaryllidaceae alkaloids such as (-)-epi-elwesine (1b), (-)-crinine (1c), (-)-epi-crinine (1e), (-)-oxocrinine (1f), and (-)-buphanisine (1d) have been accomplished. Gratifyingly, naturally occurring Amaryllidaceae alkaloids such as (+)-vittatine (1g), (+)-epi-vittatine (1h), and (+)-epi-elwesine (1i) [enantiomers of (-)-1c, (-)-1e, and (-)-1b, respectively] have also been achieved by switching the antipode of ligand used in the catalytic enantioselective step.

Full text of DOI:10.1021/acs.orglett.8b01703

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalytic Asymmetric Total Syntheses of Naturally Occurring
Amarylidaceae Alkaloids, (−)-Crinine, (−)-epi-Crinine, (−)-Oxocrinine,
(+)-epi-Elwesine, (+)-Vittatine, and (+)-epi-Vittatine*
Mrinal K. Das, Nivesh Kumar, and Alakesh Bisai*
Department of Chemistry, IISER Bhopal, Bhopal Bypass Road, Bhauri, Bhopal - 462 066, Madhya Pradesh, India
S
* Supporting Information
ABSTRACT: An expeditious approach to catalytic enantioselective total syntheses of crinine-type Amaryllidaceae alkaloids has
been accomplished via a Pd-catalyzed enantioselective decarboxylative allylation of allylenol carbonates as a key step (up to 96%
ee). Using this strategy, collective total syntheses of Amaryllidaceae alkaloids such as (−)-epi-elwesine (1b), (−)-crinine (1c),
(−)-epi-crinine (1e), (−)-oxocrinine (1f), and (−)-buphanisine (1d) have been accomplished. Gratifyingly, naturally occurring
Amaryllidaceae alkaloids such as (+)-vittatine (1g), (+)-epi-vittatine (1h), and (+)-epi-elwesine (1i) [enantiomers of (−)-1c,
(−)-1e, and (−)-1b, respectively] have also been achieved by switching the antipode of ligand used in the catalytic
enantioselective step.
wing to their significant bioactivities such as antitumor,
antiviral, and antiacetylcholinesterase activities and
center as present in crinine (1c) and related alkaloids.6
However, most of the literature reported strategies involve
racemic products6 except few asymmetric variants.7−9
In this regard, the most fascinating way to devise concise
strategies for the total syntheses of either enantiomer of these
polycyclic natural products would be via catalytic enantiose-
lective processes. Among them, the known catalytic method for
the enantioselective construction of a polycyclic framework
possessing all-carbon quaternary centers involves a key Pd(0)-
catalyzed decarboxylative allylation reaction to install such
structures.10−12
O
fascinating structural diversity, Amaryllidaceae alkaloids (1a−
j, Figure 1) have been long-standing synthetic targets.1,2
Toward this end, Trost et al. (2002)13a have reported an
elegant Pd(0)-catalyzed asymmetric decarboxylative allylic
alkylation of allyl enol carbonates (3a in 90.5% ee using L8;
Scheme 1) and, subsequently, allylation of 2-phenylcyclohex-
anone 4 (3a in 88% ee using L6, 2009). However, when it
comes to the utilization of electron-rich aromatics, Kim et al.13c
have reported that only 66% ee was obtained for 3b sharing
3,4-diOMePh as an aryl group using 5.5 mol % of L8 (Scheme
1), clearly indicating that utilization of such processes with a
substrate sharing electron-donating aromatic rings is indeed a
considerable challenge that is worth testing. Herein, based on
Trost’s elegant report,13a,b we envisioned an enantioselective
strategy, which takes advantage of an efficient Pd(0)-catalyzed
decarboxylative allylation reaction via a DYKAT to set an all-
carbon quaternary stereogenic center14,15 required for the
Amaryllidaceae alkaloids.
Figure 1. Selected Amaryllidaceae alkaloids 1a−i.
(−)-Crinine (1c) is a representative alkaloid of the
Amaryllidaceae family, which was isolated from the bulbs of
Crinum species from South Africa in 1995 (Figure 1), and
displays significant biological activity.1,3 Interestingly, another
alkaloid of this family, (+)-vittatine (1g), bearing opposite
configuration to that of (−)-crinine (1c) also has been
isolated.4 Structurally, they share a 5,10b-ethanophenathridine
skeleton with vicinal quaternary and tertiary carbon stereo-
centers and a fused pyrrolidine ring, which poses a
considerable synthetic challenge (Figure 1).5
This came as a driving force for the development of many
elegant synthetic approaches for the construction of the 5,10b-
ethanophenathridine skeleton bearing an all-carbon quaternary
Received: May 30, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01703
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Scheme 1. Literature Reports on Catalytic Enantioselective
Allylation
Table 1. Optimization of Enantioselective DcA Reaction
Our retrosynthetic strategy to synthesize the core structure
of 1b−f is shown in Scheme 2. We envisioned that cis-3a-
s.
ligand
temp
time
(h)
yield
(%)
c
no.
(mol %)
solvent
(°C)
ee (%)
1
2
3
4
5
6
7
8
5.5 (L1)
5.5 (L2)
5.5 (L3)
5.5 (L4)
5.5 (L4)
5.5 (L5)
5.5 (L6)
5.5 (L7)
5.5 (L8)
5.5 (L8)
7.5 (L8)
7.5 (L8)
7.5 (L8)
7.5 (L8)
7.5 (L8)
7.5 (L8)
7.5 (L8)
7.5 (L8)
7.5 (L8)
7.5 (L8)
7.5 (L8)
7.5 (L8)
Et2O
Et2O
Et2O
Et2O
PhMe
Et2O
Et2O
Et2O
Et2O
PhMe
PhMe
Et2O
PhMe
PhMe
PhMe
MTBE
C6H6
xylene
THF
25
25
25
25
25
25
25
25
25
25
25
0
0
−10
−20
−10
−10
−10
−10
−10
−10
−10
20
22
22
19
17
30
28
28
25
24
24
28
29
32
35
30
33
40
24
40
30
28
64
55
69
75
78
90
89
81
84
93
93
85
95
97
79
91
81
61
66
50
22
40
28 (S)
29 (S)
24 (S)
30 (S)
27 (S)
66 (S)
74 (S)
52 (S)
82 (R)
82 (R)
85 (R)
86 (R)
90 (R)
92 (R)
90 (R)
90 (R)
85 (R)
79 (R)
73 (R)
53 (R)
20 (R)
49 (R)
Scheme 2. Retrosynthetic Analysis of 1 and Our Hypothesis
9
10
11
12
13
14
15
16
17
18
19
20
21
22
aryloctahydroindole scaffold 5 of Amaryllidaceae alkaloids 1b−f
could be obtained from cyclohexanone 8 via the intermediate
enone 7, which in turn could be accessed from an efficient
Pd(0)-catalyzed decarboxylative allylation reaction of enolcar-
bonates 9 via enolate 1014 (Scheme 2).
At the outset, we selected allylenolcarbonate 9a (1 equiv) as
the substrate for initial studies (Table 1). We have utilized a
number of enantioenriched phosphine-oxazoline ligands L1−
L416 and C2-symmetric phosphine-carboxamide Trost ligands
L5−L817 (Table 1). Initially, we found that 2.5 mol %
Pd2(dba)3 and 7.5 mol % PHOX-ligands such as i-PrPHOX
(L1), i-BuPHOX (L2), s-BuPHOX (L3), and t-BuPHOX (L4)
afforded product 5a in the range 24−30% ee at room
temperature under additive-free conditions (entries 1−5).
The use of 5.5 mol % ligands L5−L8 afforded 8a with 66% ee,
74% ee, 52% ee, and −82% ee, respectively, at room
temperature (entries 6−9).
With L8 as the ligand of choice, we further carried out
optimization with different solvents and temperatures. It was
found that 7.5 mol % L8 provided 85% ee of 8a (entry 11).
Among various solvents screened, it was found that toluene is
superior over other solvents (entries 12−21). Following
exhaustive optimization (entries 11−21), it was found that
2.5 mol % Pd2(dba)3 in combination with 7.5 mol % of L8 in
toluene at −10 °C afforded 8a in 97% yield with 92%
enantioselectivity (entry 14, standard conditions). Therefore,
based on our optimization, we selected 2.5 mol % Pd2(dba)3 in
combination with 7.5 mol % of L8 in toluene at −10 °C for
DCE
DME
CHCl3
a
Reactions were carried out with 0.20 mmol of 9a in the presence of
2.5 mol % Pd2(dba)3 in combination with L1−L8 in 3 mL of solvents
in a screw capped vial. Isolated yields. Enantioselectivities were
determined by using chiral HPLC columns.
b
c
further substrate scope study. As shown in Scheme 3, our
optimized conditions could be extended to a variety of
enolcarbonates of type 9 with functionalization on the
aromatic scaffolds. As a result, a wide range of cyclohexanones
bearing all-carbon-quaternary centers at the C2-position are
obtained in good to excellent enantioselectivities with high
yields (8a−l; Scheme 3).
We then proceeded to apply the new method for the
asymmetric total synthesis of (−)-epi-elwesine (1b) (Scheme
4). Toward this end, (−)-8a was converted to enone (−)-7a in
92% yield over 2 steps viz. α-bromination using PTAB (phenyl
trimethylammonium tribromide) followed by elimination
using DBU. Enone (−)-7a upon oxidation with H2O2 in the
presence of NaOH afforded (−)-13 as the sole diastereomer,18
which was reduced regioselectively to afford (−)-6a in 85.6%
B
DOI: 10.1021/acs.orglett.8b01703
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Substrate Scope of DcA of Enolcarbonates 9
Scheme 5. Total Synthesis of Naturally Occurring
(−)-Crinine (1c), (−)-epi-Crinine (1e), (−)-Oxocrinine
(1f), and (−)-Buphanisine (1d)
Scheme 4. Total Synthesis of (−)-epi-Elwesine (1b)
synthesis of (−)-oxocrinine (1f). Since, the total synthesis of
1d is known from (−)-crinine (1c) in one step, our effort
culminated in the formal total synthesis of (−)-buphanisine
(1d).
Furthermore, in our search for total syntheses of naturally
occurring (+)-vittatine (1g) and (+)-epi-vittatine (1h), we
carried out a Pd-catalyzed enantioselective decarboxylative
allylation of 9a in the presence of (R,R)-L8 to afford (+)-8a in
94% yield with 93% ee (Scheme 6). Utilizing the reaction
sequence shown in Schemes 4 and 5, we have completed the
total syntheses of naturally occurring (+)-vittatine (1g) and
(+)-epi-vittatine (1h).
yield over 2 steps. TBS-protection of (−)-6a afforded (−)-14,
followed by oxidative cleavage of the olefin functionality
affording γ-keto-aldehyde (−)-15 in 85% yield over 3 steps. A
reductive amination of (−)-15 with ammonium acetate in the
presence of NaBH3CN afforded cis-3a-aryloctahydroindole
(−)-16, which was subsequently reacted with Eschenmoser’s
salt to afford (−)-17 in 76% yield over 2 steps. Next, the total
synthesis of (−)-epi-elwesine (1b) was achieved by TBS-group
removal (Scheme 4).
Scheme 6. Total Synthesis of Naturally Occurring
(+)-Vittatine (1g), (+)-epi-Vittatine (1h), and (+)-epi-
Elwesine (1i)
Later, we moved ahead for the collective total synthesis of
Amaryllidaceae alkaloids 1a−j shown in Figure 1. Toward this
end, cis-3a-aryloctahydroindole (−)-16 was converted to
ketone (−)-20 in 72% yield over 3 steps viz. N-Boc-protection,
TBS-romoval, and DMP oxidation (Scheme 5). The latter was
transformed to enone (−)-21 in 80% yield via Sagusa−Itoh
oxidation [TMS enol ether was reacted with 10 mol %
Pd(OAc)2 under an O2-atmosphere].19 Enone (−)-21 was
reduced under Luche conditions to afford cis-3a-arylhexa-
hydroindoles (−)-22 and (−)-23 in 95% yield with 3:1 dr in
favor of (−)-22. Gratifyingly, both these diastereomers were
separable via column chromatography. The only thing left at
this stage was to craft the tetracyclic skeleton of Amaryllidaceae
alkaloids following a Pictet−Spenglar cyclization.20 This was
achieved by Boc-removal of allylalcohols (−)-22 and (−)-23
followed by reaction with formalin in the presence of HCl to
complete the total synthesis of (−)-crinine (1c) (79% over 2
steps) and (−)-epi-crinine (1e) (81% over 2 steps). Oxidation
of (−)-crinine (1c) via MnO2-oxidation ensures the total
In summary, a concise strategy for catalytic enantioselective
total syntheses of Amaryllidaceae alkaloids, (−)-elwesine (1b),
(−)-crinine (1c), (−)-vittatine (1e), (−)-oxocrinine (1f), and
(−)-buphanisine (1d), has been accomplished. The key
strategy in this report is a Pd(0)-catalyzed asymmetric
decarboxylative allylation reaction of an allylenolcarbonate to
obtain enantioenriched 2-aryl 2′-allycyclohexanone bearing an
all-carbon quaternary center at the C2-position. Importantly,
both enantiomers of naturally occurring Amaryllidaceae
alkaloids have been achieved by switching the antipode of
the ligand used in the catalytic enantioselective step (93% ee).
C
DOI: 10.1021/acs.orglett.8b01703
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01703.
■
S
Experimental procedures, additional reaction optimiza-
tion, details of stoichiometric reactions, spectroscopic
data for all new compounds (PDF)
Accession Codes
CCDC 1853119 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: alakesh@iiserb.ac.in.
ORCID
(11) (a) Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126,
15044. (b) Reeves, C. M.; Behenna, D. C.; Stoltz, B. M. Org. Lett.
2014, 16, 2314. (c) Liu, Y.; Han, S.-J.; Liu, W.-B.; Stoltz, B. M. Acc.
Chem. Res. 2015, 48, 740. (d) Behenna, D. C.; Mohr, J. T.; Sherden,
N. H.; Marinescu, S. C.; Harned, A. M.; Tani, K.; Seto, M.; Ma, S.;
Alakesh Bisai: 0000-0001-5295-9756
Notes
́
Novak, Z.; Krout, M. R.; McFadden, R. M.; Roizen, J. L.; Enquist, J.
A., Jr; White, D. E.; Levine, S. R.; Petrova, K. V.; Iwashita, A.; Virgil, S.
The authors declare no competing financial interest.
C.; Stoltz, B. M. Chem. - Eur. J. 2011, 17, 14199.
ACKNOWLEDGMENTS
■
(12) For Pd(0)-catalyzed sequential allylations, see: (a) Enquist, J.
A., Jr.; Stoltz, B. M. Nature 2008, 453, 1228. (b) Trost, B. M.; Osipov,
M. Angew. Chem., Int. Ed. 2013, 52, 9176. (c) Ghosh, S.; Bhunia, S.;
Kakde, B. N.; De, S.; Bisai, A. Chem. Commun. 2014, 50, 2434.
(13) (a) Trost, B. M.; Schroeder, G. M.; Kristensen, J. Angew. Chem.,
Int. Ed. 2002, 41, 3492. (b) Trost, B. M.; Xu, J.; Schmidt, T. J. Am.
Chem. Soc. 2009, 131, 18343. (c) Park, J.; Kim, Y. K.; Kim, G. Bull.
Korean Chem. Soc. 2011, 32, 3141.
Financial support from the SERB, DST [EMR/2016/000214],
MoES [09-DS/11/2018-PC-IV], and CSIR [02(0295)/17/
EMR-II], Govt. of India, is gratefully acknowledged. M.K.D.
and N.K. thank the CSIR for senior research fellowships
(SRFs). We sincerely thank Prof. Vinod K. Singh, Director,
IISER Bhopal for excellent research facilities.
(14) For reviews, see: (a) Trost, B. M.; Fandrick, D. R. Aldrichimica
Acta 2007, 40, 59. (b) Steinreiber, J.; Faber, K.; Griengl, H. Chem. -
Eur. J. 2008, 14, 8060 and references cited therein.
(15) (a) Ghosh, S.; Chaudhuri, S.; Bisai, A. Chem. - Eur. J. 2015, 21,
17479. (b) Roy, A.; Das, M. K.; Chaudhuri, S.; Bisai, A. J. Org. Chem.
2018, 83, 403.
(16) PHOX ligands: (a) Helmchen, G.; Pfaltz, A. Acc. Chem. Res.
2000, 33, 336. (b) Krout, M. R.; Mohr, J. T.; Stoltz, B. M. Org. Synth.
2009, 86, 181.
(17) Trost ligands L5−L7: (a) Trost, B. M.; Van Vranken, D. L.
Angew. Chem., Int. Ed. Engl. 1992, 31, 228. (b) Trost, B. M.;
Thaisrivongs, D. A.; Hartwig, J. J. Am. Chem. Soc. 2011, 133, 12439.
(18) The relative stereochemistry of epoxide (−)-13 was proven
unambiguously by X-ray analysis (CCDC No. 1853119) of ( )-13
(synthesized from ( )-7a in 92% yield using a similar procedure as
shown in Scheme 4).
(19) (a) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
(b) Bisai, A.; West, S. P.; Sarpong, R. J. Am. Chem. Soc. 2008, 130,
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Spengler cyclization, see: (a) Kano, T.; Hayashi, Y.; Maruoka, K. J.
Am. Chem. Soc. 2013, 135, 7134. (b) Pupo, G.; Properzi, R.; List, B.
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Angew. Chem., Int. Ed. 2018, 57, 1995.
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