Total Synthesis of Ovafolinins A and B: Unique Polycyclic Benzoxepin Lignans through a Cascade Cyclization

Article abstract of DOI:10.1002/anie.201705575

Ovafolinins A and B, isolated from Lyonia ovalifolia var. elliptica, are lignans that contain a unique bridged structure containing a penta- and tetracyclic benzoxepin and an aryl tetralin. We report the first total synthesis of these natural products in which an acyl-Claisen rearrangement was initially utilized to construct the lignan backbone with correct relative stereochemistry. Judicious use of a bulky protecting group placed reactive moieties in the correct orientation, thereby resulting in a cascade reaction to form the bridged benzoxepin/aryl tetralin from a linear precursor in a single step. Modification of this route allowed the enantioselective synthesis of (+)-ovafolinins A and B, which confirmed the absolute stereochemistry, and comparison of optical rotation suggests that these compounds are found as scalemic mixtures in nature.

Full text of DOI:10.1002/anie.201705575

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: The First Total Synthesis of Ovafolinin A and B: Unique
Polycyclic Benzoxepin Lignans via a Cascade Cyclization
Authors: Samuel James Davidson and David Barker
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201705575
Angew. Chem. 10.1002/ange.201705575
Link to VoR: http://dx.doi.org/10.1002/anie.201705575
http://dx.doi.org/10.1002/ange.201705575

10.1002/anie.201705575
Angewandte Chemie International Edition
COMMUNICATION
The First Total Synthesis of Ovafolinin A and B: Unique Poly-
cyclic Benzoxepin Lignans via a Cascade Cyclization
Samuel J. Davidson and David Barker*[a]
Abstract: Ovafolinins A and B, isolated from Lyonia ovalifolia var.
elliptica, are lignans which contain a unique penta- and tetracyclic
benzoxepin bridged aryl tetralin structure. We report the first total
synthesis of these natural products initially utilizing an acyl-Claisen
rearrangement to construct the lignan backbone with correct relative
stereochemistry. Judicious use of a bulky protecting group placed
reactive moieties in the correct orientation resulting in a cascade
reaction forming the benzoxepin bridged aryl tetralin from a linear
precursor in a single step. Modification of this route allowed an
enantioselective synthesis of (+)-ovafolinin A and B which confirmed
the absolute stereochemistry and comparison of optical rotation
suggests these compounds are found as scalemic mixtures in nature.
Ovafolinins A–C (1–3) isolated from Lyonia ovalifolia var.
Figure 2: Acyl-Claisen approach to the synthesis of lignan subclasses.
elliptica; a deciduous tree found in areas of Taiwan, China and
Japan, are classical lignans that have a unique 7 membered
benzoxepin bridged aryl tetralin structure (Figure 1).[1] Ovafolinin
B (2) has also been isolated from Sinocalamus affinis (Rendle)
McClure (Poaceae)[2] which is found and cultivated in the
southwest of China and much of the plant has been used as a
traditional Chinese medicine.[2,3] We have previously shown[4–6]
Our initial approach involved the reaction of allylic morpholine 4
and acid chloride 5 (see Scheme SI1 and SI2 for synthesis) to
give morpholine amide 6 (Figure 3). However, this resulted in
the formation of acrylate 7 when using AlCl3 or phenol 8 when
using TiCl4·2THF which is likely due to the reactivity of the
that the acyl-Claisen rearrangement,[7,8] which has excellent
formed ketene with the very electron rich aryl group promoting
diastereoselectivity when compared to many other Claisen
rearrangement (Table 1). A screen of various acid chlorides
variants, is a useful transformation to construct the 8–8′ linkage
showed oxygenation at the β–position gave only trace amounts
of amide products however alkyl (9–10), vinyl (11), and aryl (12)
present in classical lignans (Figure 2).[4,5]
groups as well as oxygenated allylic morpholine 4 were well
tolerated in the acyl-Claisen rearrangement (Table 1).
Figure 1: Structures of ovafolinins A–C (1–3)
We now report the use of acyl-Claisen methodology to prepare
the unique lignan scaffolds found in ovafolinin A–C (1–3). It was
envisaged that this could be accomplished through the acyl-
Claisen rearrangement of oxygenated allylic morpholine 4 and
acid chloride 5 to give an oxymethylene disubstituted amide 6.
Stereoselective addition of the appropriately substituted aryl
groups, directed by the defined stereochemistry of amide 6, and
cyclizations therein would allow for a convenient approach to the
synthesis of ovafolinin A–C (1–3) (Figure 3).
[a]
S. J. Davidson, Assoc. Prof. D. Barker*
School of Chemical Sciences
University of Auckland
Figure 3: Initial synthetic approach to ovafolinin A–C (1–3).
23 Symonds St., Auckland, New Zealand
E-mail: d.barker@auckland.ac.nz
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201705575
Angewandte Chemie International Edition
COMMUNICATION
Following synthesis of morpholine amide 14, the amide
functionality was converted to alcohol 16, over three steps, then
coupled to phenol 15 – synthesised from syringaldehyde in four
steps – in a Mitsunobu reaction to give aryl ether 17. The olefin
was then converted to alcohol 18 in 84% over three steps via
alkene oxidation followed by reduction.
Table 1: Acyl-Claisen attempts towards ovafolinin B.
Acid Chloride
Product
Yield
24%a,c
7
8
n.d.b
traceb
traceb
i
Scheme 1: Reagents and conditions: (a) TiCl4·2THF (100 mol%), 4, Pr2NEt,
CH2Cl2, 3 h, 99%; (b) I2, THF/H2O (1:1), 16 h; (c) Zinc dust, AcOH, 80 °C, 19 h,
96% (2 steps); (d) LiAlH4, THF, reflux, 3 h, 97%; (e) K2CO3, iPrBr, DMF, 80 °C,
17 h, 99%; (f) m-CPBA, CH2Cl2, 0 °C, 22 h; (g) KOH, MeOH, 10 min, 57% (2
steps); (h) NBS, CH2Cl2, -78 °C, 1 h, 73% (3 steps); (i) Ph3P, DIAD, 16,
toluene, 18 h, 82%; (j) OsO4 (2.5 mol%), NMO, tBuOH/H2O (1:1), 5 d, 94%; (k)
NaIO4, MeOH/H2O (3:1), 30 min, 92%; (l), NaBH4, MeOH, 2 h, 97%.
95%c
>99%c
91%c
9
10
11
Initial attempts at the synthesis of ovafolinin B from alcohol 18
involved the use of a methoxymethyl protecting group, however
these compounds were unstable and lead to decomposition
products (scheme SI4). The more stable and bulky tert-
butyldiphenylsilyl (TBDPS) group was trialed in order to avoid
decomposition, while simple modelling also suggested that a
TBDPS group at C-9′ should result in the aldehyde being closer
in proximity to the two aromatic rings which we believed should
increase subsequent reactivity (Figure 4).
90%c
12
a) AlCl3 was used in place of TiCl4·2THF
b) Identified by 1H NMR spectroscopy
c) Isolated yields
n.d. - yield not determined
Based on the results of this acyl-Claisen study, a new synthetic
method towards the synthesis of ovafolinin B was investigated
utilizing acid chloride 13 which was synthesized over five high
yielding steps (Scheme SI3) and reacted with allylic morpholine
4 to give morpholine amide 14 as a single diastereoisomer, in
excellent yield, (Scheme 1). An isopropyl protecting group was
used on phenol 15 as opposed to the previous benzyl protecting
group strategy which would need to be selectively removed to
form the reactive aldehyde site.
Figure 4: 3D stick and space filling models of TBDPS derivative structure of
17 showing proximity of aldehyde to the two highly oxygenated aromatic rings:
C = gray, O = red, Si = purple, Br = brown, hydrogen atoms not shown.
Therefore, alcohol 18 was protected as TBDPS ether 19 and
hydrogenation gave an inseparable mixture of brominated and
debrominated alcohol 20. Dess-Martin periodinane oxidation of
This article is protected by copyright. All rights reserved.

10.1002/anie.201705575
Angewandte Chemie International Edition
COMMUNICATION
20 then resulted in formation of the aldehyde which underwent a
cascade cyclization (Figure SI1) during workup to give protected
ovafolinin B (21) and bromo-21 which were easily separable. We
propose that the mildly acidic conditions following the
periodinane oxidation combined with the proximity of the
aldehyde to both aromatic rings due to the steric effects of the
TBDPS group enabled a cascade cyclization to give the
tetracyclic ovafolinin B skeleton (Scheme 2). Benzylic oxidation
of 21 was attempted using PCC-Celite which has been shown to
oxidize other tetralin lignans.[9] However, in this case the highly
oxygenated aromatic ring was instead oxidized to give a ring
opened diester (scheme SI5). To our knowledge this is the first
example of a chromium-based oxidant leading to the oxidative
ring-opening of an aryl ring and opens up synthetic routes
towards lignans containing similar oxidatively opened rings.[10–13]
absolute stereochemistry of these natural products. Initial
attempts at an enantioselective aza-Claisen rearrangement[4,14]
were unsuccessful (see Scheme SI6). Coupling of the carboxylic
acid, formed from the hydrolysis of racemic amide 14, to chiral
amine (S)-(–)-α-methyl-benzylamine gave an inseparable
mixture of diastereomers confirming that had the chiral aza-
Claisen been successful the diastereomers formed would not
have been separable, which is in contrast to previous aza-
Claisen derived amides.[4,14] Therefore, a new strategy was
designed using an Evan’s chiral auxiliary to which
a
stereoselective allylation would allow for the induction of the
desired stereocenters (Scheme 3).
Synthesis began using acid chloride 13 with acylation of (S)-4-
benzyloxazolidin-2-one giving 23, followed by a stereoselective
allylation,[15,16] giving (+)-(S,S)-24 in 78% yield with >97:3 d.r..
Dihydroxylation of olefin 24 then gave lactone 25, with
concomitant removal of the chiral auxiliary, followed by a
reduction and two oxidative steps gave lactone 26 in 52% yield
over 4 steps.
Scheme 2: Reagents and conditions: (a) TBDPSCl, imidazole, DMF, 0 °C, 4 d,
92%; (b) H2, Pd/C, MeOH, 4 h, 99%; (c) DMP, CH2Cl2, 1 h, Br-61%, H-28%;
(d) HCO2NH4, Pd/C, MeOH, reflux, 5 h, 99%; (e) AlCl3, CH2Cl2, 10 min, 88%;
(f) TBAF, THF, 0 °C, 5 h, (1) 19%, (2) 25%.
Scheme 3: Reagents and conditions: (a) (S)-4-benzyloxazolidin-2-one, nBuLi,
THF, -78 °C, 1 h, 74%; (b) LiHMDS, THF, -78 °C, 4 h, 78%; (c) OsO4 (1 mol%),
t
Debromination of 21 and deprotection gave phenol 22. Removal
of the TBDPS ether in 22 surprisingly gave not only ovafolinin B
(2) but also ovafolinin A (1). It was unanticipated that TBAF
would result in the oxidative-cyclization to give pentacyclic
ovafolinin A (1) alongside ovafolinin B (2) and suggests the
highly electron-rich 2 can undergo aerial oxidation to form 1.
Comparison of NMR data (table SI1) of synthetic 1 and 2 to that
of isolated 1 and 2 confirmed the reported structures of these
polycyclic natural products.[1,2] Ovafolinin B (2) has been isolated
from two different plant sources with similar reported optical
rotations.[1,2] Whilst the initial report proposed only relative
stereochemistry further analysis by Xiong et al.[2] proposed the
absolute stereochemistry through the use of circular dichroism
(CD).
NMO, BuOH/THF/H2O (1:1:1), 44 h, 86%; (d) LiAlH4, THF, 3 h; (e) NaIO4,
MeOH/H2O (3:1), 1 h; (f) Fétizon’s reagent, toluene, reflux, 5 h, 61% (3 steps);
(g) BOMCl, LDA, THF, -78 °C, 18 h, 47%; (h) LiAlH4, THF, 0 °C, 9 h, 94%; (i)
TBDPSCl, imidazole, CH2Cl2, 19 h; (j) Ph3P, DIAD, 4-isopropoxy-3,5-
dimethoxyphenol, 0 °C, 17 h; (k) H2, Pd/C, MeOH, 16 h, 20% (3 steps); (l),
DMP, CH2Cl2, 1 h, 87%; (m) AlCl3, CH2Cl2, 0 °C, 20 min, 79%; (n) TBAF, THF,
0 °C, 2 h, (1) 17%, (2) 17%.
The desired benzyloxymethyl group was then introduced to
lactone 26 through stereoselective alkylation to give lactone 27
which followed by reduction gave diol 28 in 44% yield over two
steps with a >95:5 d.r.. Mono-TBDPS protection of diol 28 gave
a
1:1 inseparable mixture of regioisomers. However, a
subsequent Mitsunobu reaction with 4-isopropoxy-3,5-
dimethoxyphenol and hydrogenolysis of the benzyl protecting
group gave (+)-debromo-20 in 20% yield over three steps, easily
separable from the regioisomer. With (+)-20 in hand, oxidation
Following the successful racemic synthesis of 1 and 2 an
enantioselective synthesis was then attempted to determine the
This article is protected by copyright. All rights reserved.

10.1002/anie.201705575
Angewandte Chemie International Edition
COMMUNICATION
[1]
[2]
[3]
K. Kashima, K. Sano, Y. S. Yun, H. Ina, A. Kunugi, H. Inoue, Chem.
Pharm. Bull. (Tokyo) 2010, 58, 191–194.
L. Xiong, C. Zhu, Y. Li, Y. Tian, S. Lin, S. Yuan, J. Hu, Q. Hou, N. Chen,
Y. Yang, et al., J. Nat. Prod. 2011, 74, 1188–1200.
L. Xiong, M. Zhu, C. Zhu, S. Lin, Y. Yang, J. Shi, J. Nat. Prod. 2012, 75,
1160–1166.
C. E. Rye, D. Barker, J. Org. Chem. 2011, 76, 6636–6648.
S. J. Davidson, D. Barker, Tetrahedron Lett. 2015, 56, 4549–4553.
C. Rye, D. Barker, Synlett 2009, 2009, 3315–3319.
T. Yoon, V. Dong, D. MacMillan, J. Am. Chem. Soc. 1999, 121, 9726–
9727.
T. P. Yoon, D. W. MacMillan, J. Am. Chem. Soc. 2001, 123, 2911–2912.
Y. Peng, Z.-B. Luo, J.-J. Zhang, L. Luo, Y.-W. Wang, Org. Biomol.
Chem. 2013, 11, 7574–7586.
with Dess-Martin periodinane facilitated the cascade cyclization
to give tetracyclic 21 in 87% yield. Subsequent deprotections
gave (+)-ovafolinin A (1) and (+)-ovafolinin B (2) over two steps
both with >99:1 d.r.. The sign of the optical rotation of synthetic-
1 was found to be opposite to that of natural-1, with the
magnitude being approximately three times greater: synthetic-1
+154.8 (c 0.16, MeOH), natural-1 –37.3 (c 0.36, MeOH).[1]
Synthetic-2 has the same sign of rotation as natural-2 but again
the magnitude of rotation was three times greater: synthetic-2
+150.0 (c 0.26, MeOH), natural-2 +52.0 (c 0.26, MeOH)[1] and
+43.3 (c 0.12, MeOH).[2]
[4]
[5]
[6]
[7]
[8]
[9]
[10] S.-Y. Li, M.-D. Wu, C.-W. Wang, Y.-H. Kuo, R.-L. Huang, K.-H. Lee,
Chem. Pharm. Bull. (Tokyo) 2000, 48, 1992–1993.
[11] Y.-H. Kuo, H.-C. Huang, LiYang Kuo, C.-F. Chen, J. Org. Chem. 1999,
64, 7023–7027.
[12] Y.-H. Kuo, S.-Y. Li, R.-L. Huang, M.-D. Wu, H.-C. Huang, K.-H. Lee, J.
Nat. Prod. 2001, 64, 487–490.
[13] Y.-N. Yang, X.-Y. Huang, Z.-M. Feng, J.-S. Jiang, P.-C. Zhang, J. Agric.
Food Chem. 2015, 63, 7958–7966.
[14] T. Tsunoda, M. Sakai, O. Sasaki, Y. Sako, Y. Hondo, S. Itô, Tetrahedron
Lett. 1992, 33, 1651–1654.
[15] M. So, T. Kotake, K. Matsuura, M. Inui, A. Kamimura, J. Org. Chem.
2012, 77, 4017–4028.
[16] F. Allais, T. J. L. Pla, P.-H. Ducrot, Synthesis 2011, 2011, 1456–1464.
[17] L. I. Pilkington, J. Wagoner, S. J. Polyak, D. Barker, Org. Lett. 2015, 17,
1046–1049.
The absolute stereochemistry of synthetic
1 and 2 is
7R,8R,7′R,8′R and 8R,7′R,8′R respectively. Based on the optical
rotation data we propose that these natural products were
actually isolated as scalemic mixtures with natural-1 being found
predominantly as the 7S,8S,7′S,8′S enantiomer whilst natural-2
is predominantly found with the same absolute stereochemistry
as that synthesized. It is possible that racemic 2 is the first
formed natural product and that the 8S,7′S,8′S enantiomer is
preferentially oxidized to give 1 enriched in the 7S,8S,7′S,8′S
enantiomer, i.e. (–)-1, thus leaving 2 to be enriched in the
opposite enantiomer, (+)-2. The absolute stereochemistry of (+)-
2 was proposed using CD analysis to be 8S,7′S,8′S however this
has been shown to be incorrect, with this synthesis determining
the absolute stereochemistry of natural (+)-2 to be 8R,7′R,8′R.
This is a further example where the use of CD as the sole
determining method for the absolute stereochemistry in complex
lignans has been shown to give incorrect assignments.[17]
In summary the unique polycyclic structures of both ovafolinin A
(1) and B (2) have been confirmed through the use of a high
yielding synthesis resulting in 9% and 11% overall yield from
allylic morpholine 4 over 14 linear steps respectively and utilizes
a
spontaneous cascade cyclization giving the tetracyclic
structure in a single step. Following the confirmation of the
relative stereochemistry of 1 and 2 an enantioselective synthesis
was used to determine the absolute stereochemistry of these
complex natural products. This synthesis was also achieved in
14 steps with an overall yield (0.3% each of 1 and 2) with the
reduced yield being due to the difficulty transforming 28 to (+)-20.
From these findings it is proposed that natural-1 and 2 are
present as scalemic mixtures and may be formed through the
preferential oxidation of one enantiomer in vivo. Furthermore,
the original stereochemical assignment of ovafolinin B (2) using
CD spectra was shown to be incorrect highlighting the use of
synthesis in conclusively determining absolute stereochemistry
in complex natural products.
Acknowledgements
We acknowledge the University of Auckland for funding and a
Doctoral Scholarship (S.D.).
Keywords: lignan • tetralin • benzoxepin • acyl-Claisen •
cascade cyclization
This article is protected by copyright. All rights reserved.

10.1002/anie.201705575
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Samuel J. Davidson and David Barker*
Page No. – Page No.
The First Total Synthesis of
Ovafolinin A and B: Unique Poly-
cyclic Benzoxepin Lignans via a
Cascade Cyclization
Ovafolinins A and B, isolated from Lyonia ovalifolia var. elliptica, contain a unique
penta- and tetracyclic benzoxepin bridged aryl tetralin structure. These natural
products have been synthesized utilizing an acyl-Claisen rearrangement and a
cascade cyclization forming the benzoxepin bridged aryl tetralin and a subsequent
enantioselective synthesis of ovafolinin A and B has assigned the absolute
stereochemistry of these natural products.
This article is protected by copyright. All rights reserved.