Total synthesis of (-)-bicubebin A, B, (+)-bicubebin C and structural reassignment of (-)-cis-cubebin

Article abstract of DOI:10.1021/acs.orglett.7b02644

The first total synthesis of (-)-bicubebin A, and two previously unreported dilignans, (-)-bicubebin B and (+)-bicubebin C has been achieved through the dimerization of (-)-cubebin, confirming the structure and absolute stereochemistry of (-)-bicubebin A. Analysis of the data for (-)-bicubebin B showed it matched that of reported compound (-)-cis-cubebin. The NMR data of the subsequently synthesized proposed structure of cis-cubebin confirmed that its original proposed structure was incorrect.

Full text of DOI:10.1021/acs.orglett.7b02644

Letter
pubs.acs.org/OrgLett
Total Synthesis of (−)-Bicubebin A, B, (+)-Bicubebin C and Structural
Reassignment of (−)-cis-Cubebin
Samuel J. Davidson, A. Norrie Pearce, Brent R. Copp, and David Barker*
School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand
S
* Supporting Information
ABSTRACT: The first total synthesis of (−)-bicubebin A, and two
previously unreported dilignans, (−)-bicubebin B and (+)-bicubebin
C has been achieved through the dimerization of (−)-cubebin,
confirming the structure and absolute stereochemistry of (−)-bicu-
bebin A. Analysis of the data for (−)-bicubebin B showed it matched
that of reported compound (−)-cis-cubebin. The NMR data of the
subsequently synthesized proposed structure of cis-cubebin con-
firmed that its original proposed structure was incorrect.
Due to the unique structure, it was decided to explore an
approach to bicubebin A (4) using the putative biological
precursor (−)-cubebin 5 to confirm the unusual structure and
determine the absolute stereochemistry of 4. The synthesis of
(−)-cubebin 5 began with the coupling of (S)-4-benzyl-
oxazolidin-2-one to carboxylic acid 6, which itself was
synthesized over three steps from piperonal 7 (Scheme 1).
This was done through the use of a stabilized Wittig reaction,
followed by hydrogenation of the resultant α,β-unsaturated
ester and subsequent hydrolysis which gave the desired
carboxylic acid 6 in 88% yield over three steps. Carboxylic
acid 6 was converted to the acid chloride, using oxalyl chloride,
prior to addition to the lithium salt of (S)-4-benzyloxazolidin-2-
one to give the desired oxazolidinone 8 in 57% over two steps.
A stereoselective allylation was then performed using a
sterically hindered base and low temperatures to control facial
selectivity,5,6 which gave (+)-(S,S)-9 in 77% yield with greater
than 99% de (as determined by 1H NMR). The chiral auxiliary
was then removed through use of 1 mol % OsO4 in tert-
butanol−water with NMO as the co-oxidant, resulting in
simultaneous dihydroxylation and cyclization to form lactone
10. Subsequent LiAlH4 reduction of lactone 10 followed by
NaIO4 oxidative cleavage gave lactol 11 in 73% yield over three
steps.
ilignans are an uncommon subset of the lignan family of
Dnatural plant products. They are dimers of lignans and
have been isolated in a variety of forms, including
tetrahydrofuran rings, e.g., cynarinine 1,1 1,4-dioxanes, e.g.,
strebluslignanol F (2),2 Diels−Alder products, e.g., ramonanin
A (3),3 and lactol dimers, e.g., (−)-bicubebin A (4) (Figure 1).4
Bicubebin A (4), isolated from Aristolochia pubescens and
Aristolochia lagesiana alongside its monomeric unit (−)-cubebin
5,4 contains six contiguous chiral centers and is the only
reported lignan dimer containing this structural motif.
Lactol 11 was then oxidized using Fet
́
izon’s reagent7,8
(Ag2CO3/Celite) giving lactone 12 in 97% yield (Scheme 1).
Piperonyl bromide (prepared from piperonal in two steps9) was
then added to the lithium enolate of lactone 12 to yield
(−)-hinokinin 13 in 81% yield. Reduction of (−)-hinokinin 13
with di-isobutyl aluminum hydride gave (−)-cubebin 5 in 56%
yield as a 1.5:1 ratio of diastereomers at the anomeric carbon,
Received: August 25, 2017
Figure 1. Structures of dilignans 1−4.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02644
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Organic Letters
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Scheme 1. Synthesis of (−)-Cubebin
Scheme 2. Dimerization of (−)-Cubebin
The spectroscopic data of synthetic 4 was then compared
4
1
C-9. With the synthesis of (−)-cubebin 5 completed,
dimerization to form bicubebin A (4) was then attempted.
Thermal dimerization was first attempted. However, heating at
125 °C resulted in no reaction and heating at temperatures over
250 °C resulted in dehydration to form the dihydrofuran 14
(Scheme 2). Next, anhydrous CuSO4 with catalytic H2SO4 in
acetone was evaluated, as Cubero et al. had shown these
conditions were able to dimerize simple lactols.10
Using stoichiometric amounts of CuSO4 resulted in
cyclization forming isocubebinic ether11 15 in quantitative
yield. Fortunately, reducing the CuSO4 to substoichiometric
amounts resulted in dimerization of cubebin with three
bicubebins being isolated; the unsymmetrical dimer (−)-bicu-
bebin A (4), and two previously unreported symmetrical
bicubebins which were named (−)-bicubebin B (16) and
(+)-bicubebin C (17) (Scheme 2).
with literature values. It was found that the H and 13C NMR
spectra of 4 were almost identical (see Table 1 for selected
NMR peaks and Supporting Information (SI) data for full
details) and the mass spectrum of this compound confirmed
that it was a dimer (M + Na+: 717). As the sign of the optical
rotation for synthetic 4 (−14.5, c 0.19, CHCl3) was the same to
that of the isolated compound 4 (−54.8, c 0.36, CHCl3),4 this
therefore confirms the absolute stereochemistry of (−)-bicu-
bebin A (4) as (8R,9S,8′R,8″R,9″R,8‴R)-4 (see Figure 1 for
atom numbering).
Upon further inspection of the experimental data for
1
synthetic (−)-bicubebin B (16), it was discovered that H
and 13C NMR data (Table S1) and optical rotation values
matched that of previously reported (−)-cis-cubebin 18, which
was isolated alongside 4. De Pascoli et al. reported that 18 was
isolated as a single lactol anomer which was unusually unable to
B
DOI: 10.1021/acs.orglett.7b02644
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Table 1. Selected 1H and 13C NMR Comparison of Synthetic
(CDCl3, 400 MHz) and Isolated (−)-Bicubebin A (4)
(CDCl3, 500 MHz)
Scheme 3. Synthesis of cis-Cubebin
1H NMR (δ ppm)
13C NMR (δ ppm)
a
a
synthetic
reported4
synthetic
38.5
reported4
7
2.34 dd (13.8, 8.1)
2.46−2.51 m
2.32 dd (13.5, 8.0)
2.47 dd (13.5, 7.5)
2.51 d (8.0)
38.5
7′
7″
2.52 d (7.7)
39.4
33.9
39.4
33.9
2.43 dd (13.8, 6.0)
2.46−2.51 m
2.36 dd (13.3, 9.1)
2.61 dd (13.3, 4.9)
4.77 d (1.6)
2.43 dd (13.5, 6.5)
2.49 dd (13.5, 8.5)
2.36 dd (13.5, 9.5)
2.60 dd (13.5, 5.0)
4.76 d (2.0)
7‴
39.4
39.4
9
108.6
72.4
108.6
72.4
9′
3.63 dd (8.4, 7.7)
3.93 dd (8.4, 7.8)
4.81 d (4.6)
3.62 dd (8.5, 7.5)
3.92 t (8.5)
9″
9‴
4.81 d (5.0)
104.2
72.5
104.2
72.4
3.52 dd (8.3, 6.9)
4.01 t (8.3)
3.51 dd (8.5, 7.0)
4.00 t (8.5)
a
Chemical shifts are reported relative to the solvent peak of
chloroform (δ 7.2 for H and δ 77.16 for 13C) for comparison to
1
literature4 values.
be oxidized to the lactone cis-hinokinin.4 This led us to the
belief that the natural product given the structure cis-cubebin
was in fact a symmetrical dimer and not the lactol reported.
A third bicubebin, (+)-bicubebin C (17) which was also
isolated alongside bicubebin A (4) and B (16), is also a
symmetrical dimer varying only in the stereochemistry at C-9
with comparison to 16. The structure of 17 was confirmed
using mass spectrometry which concluded that this is in fact a
dimer, 2D NMR (Figure S2) and coupling constants to
determine the stereochemistry. An 8−9-H coupling constant of
1.5 Hz for bicubebin B (16) relates to a trans-relationship
between vicinal protons whereas an 8−9-H coupling constant
of 5.0 Hz for bicubebin C (17) is indicative of a cis-
relationship.12,13 Therefore, the absolute stereochemistry for
the symmetrical dimer (−)-bicubebin B is (8R,9S,8′R)-16 and
(+)-bicubebin C is (8R,9R,8′R)-17.
To unequivocally confirm the data attributed to (−)-cis-
cubebin 18 was in fact an alternative bicubebin; (−)-bicubebin
B (16), it was decided to prepare the reported structure of 18.
The synthesis began with an acyl-Claisen rearrangement14−20 of
the acid chloride formed from acid 6 and allylic morpholine 19
giving syn-substituted morpholine amide 20 in 92% yield
(Scheme 3). Iodo-lactonization followed by zinc mediated
reductive cleavage gave a carboxylic acid which underwent
LiAlH4 reduction giving alcohol 21 in 48% yield over three
steps. Alcohol 21 was then protected using benzyl bromide
giving bis-benzyl ether 22 in 90% yield. The olefin of 22 was
then oxidatively converted to aldehyde 23 in 80% yield over
two steps.
To complete the synthesis, aryl lithium 24 was added to
aldehyde 23 to yield the desired secondary alcohol 25 in 89%
yield as a 2:1 mixture of diastereomers at the newly formed
stereocenter (Scheme 3). Hydrogenolysis, in the presence of
catalytic acid, removed both benzyl protecting groups and the
benzylic alcohol giving the meso-diol 26 in 61% yield. Finally,
Dess−Martin periodinane oxidation of 26 gave lactol 18 in
quantitative yield as a 1:0.3 mixture of diastereomers at the
anomeric carbon, C-9. The spectroscopic data for synthetic
lactol 18 was then compared with that reported for cis-cubebin
and was found to be significantly different. Most notably the 1H
signals for synthetic cis-cubebin were shifted downfield and the
methylenedioxy signals had a distinctive pattern of two singlets
compared to the reported four doublets (Table S2). It can
therefore be confirmed that the lactol structure reported as cis-
cubebin is in fact a second dimeric lignin (−)-bicubebin B (16).
In conclusion, the first total synthesis of the unique dimeric
lignan (−)-bicubebin A has been completed alongside the
synthesis of the symmetric dimers (−)-bicubebin B and
(+)-bicubebin C. Comparison of the experimental data for
synthetic bicubebin B as well as the synthesis of the proposed
structure for cis-cubebin has confirmed the corrected structure
of cis-cubebin as bicubebin B.
C
DOI: 10.1021/acs.orglett.7b02644
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Organic Letters
Letter
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02644.
Experimental procedures, NMR spectra for all com-
pounds, data comparison tables for final compounds, and
mass spectra of dilignans (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: d.barker@auckland.ac.nz.
ORCID
Brent R. Copp: 0000-0001-5492-5269
David Barker: 0000-0002-3425-6552
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the University of Auckland for funding this project
and a doctoral scholarship to S.D. We thank Prof. L. M. X.
■
Lopes (Sao Paulo State University) for providing copies of
̃
original spectra of the natural products.
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