Convergent Total Syntheses of (?)-Rubriflordilactone B and (?)-pseudo-Rubriflordilactone B

Article abstract of DOI:10.1002/anie.201908917

A highly convergent strategy for the synthesis of the natural product (?)-rubriflordilactone B, and the proposed structure of (?)-pseudo-rubriflordilactone B, is described. Late stage coupling of diynes containing the respective natural product FG rings with a common AB ring aldehyde precedes rhodium-catalyzed [2+2+2] alkyne cyclotrimerization to form the natural product skeleton, with the syntheses completed in just one further operation. This work resolves the uncertainty surrounding the identity of pseudo-rubriflordilactone B and provides a robust platform for further synthetic and biological investigations.

Full text of DOI:10.1002/anie.201908917

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Convergent Total Syntheses of (–)-Rubriflordilactone B and (–)-
pseudo-Rubriflordilactone B
Authors: Mujahid Mohammad, Venkaiah Chintalapudi, Jeffrey Carney,
Steven Mansfield, Polyanna Sanderson, Kirsten Christensen,
and Edward Alexander Anderson
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.201908917
Angew. Chem. 10.1002/ange.201908917
Link to VoR: http://dx.doi.org/10.1002/anie.201908917
http://dx.doi.org/10.1002/ange.201908917

10.1002/anie.201908917
Angewandte Chemie International Edition
COMMUNICATION
Convergent Total Syntheses of (–)-Rubriflordilactone B and (–)-
pseudo-Rubriflordilactone B
Mujahid Mohammad,[a] Venkaiah Chintalapudi,[a] Jeffrey M. Carney,[b] Steven J. Mansfield,[a] Pollyanna
Sanderson,[a] Kirsten E. Christensen[a] and Edward A. Anderson*[a]
Abstract: A highly convergent strategy for the synthesis of the
natural product (–)-rubriflordilactone B, and the proposed structure of
O
O
O
O
[2+2+2]
(–)-pseudo-rubriflordilactone B, is described. Late stage coupling of
diynes containing the respective natural product FG rings with a
common AB ring aldehyde precedes rhodium-catalyzed [2+2+2]
alkyne cyclotrimerization to form the natural product skeleton, with
the syntheses completed in just one further operation. This work
resolves the uncertainty surrounding the identity of pseudo-
rubriflordilactone B, and provides a robust platform for further
synthetic and biological investigations.
H
O
H
O
A
A
D
H
H
D
B
B
C
C
H
H
17
17
E
O
G
E
O
G
O
O
F
F
16
16
H
H
O
O
H
H
H
H
Rubriflordilactone B (1)
pseudo-Rubriflordilactone B (2)
O
TMS
A
O
H
3
OH
H
B
O
H
F
O
O
Plants of the genus Schisandra produce an array of
H
O
G
H
H
alkyne addition
nortriterpenoids
characterized
by
densely-functionalized
polycyclic skeletons.[1] Extracts from these plants feature
prominently in traditional Chinese medicine, and many of their
natural products have been found to display antiviral and
anticancer activities. Stimulated by their structures and
properties, syntheses of a number of these molecules have
been achieved.[2] Among the many family members,
rubriflordilactones A and B (isolated by Sun and co-workers from
Schisandra rubriflora)[3] are of interest due to their contrasting
anti-HIV bioactivities and, from a synthetic perspective, the
challenge of efficient assembly of their polysubstituted arene
cores. Syntheses of rubriflordilactone A were described by the Li
group,[4] and by ourselves.[5] However, the subsequent
completion of rubriflordilactone B (1, Figure 1) by Li et al.[6],[7]
revealed a structural ambiguity: the NMR spectroscopic data of
synthetic 1 (the form of the natural product characterized by X-
ray crystallographic analysis) did not match that recorded for
rubriflordilactone B by the Sun group.[3] This finding appeared to
imply the existence of two rubriflordilactone B natural products –
one corresponding to the X-ray structure, and the other to the
NMR spectroscopic data.
O
TMS
H
TMS
H
A
O
H
X
X
O
H
H
B
F
F
O
O
O
G
O
O
O
O
G
H
H
H
H
H
H
5 (X=H)
7 (X=I)
6 (X=H)
8 (X=I)
4
Scheme 1. Rubriflordilactone B natural products, and our synthetic strategy.
that this proposed structure is indeed the likely identity of this
natural product.
Our strategy towards these targets built from our studies on
rubriflordilactone A, with the central arene D ring being a focal
point for scaffold disconnection.[5a] Specifically, we viewed the
[2+2+2] cyclotrimerization[10] of suitable triynes 3 as offering a
convergent and stereochemically flexible approach to the natural
products. These triynes conveniently derive from the common
AB ring aldehyde 4,[5a] and diynes such as 5 (required for
rubriflordilactone B, 1) and
6
(required for pseudo-
Subsequent computational work by Kaufman and Sarotti[8]
suggested that the difference between the two forms of
rubriflordilactone B lies at C16 and C17 in the EF rings, leading
to the proposal of 2, dubbed pseudo-rubriflordilactone B, as the
most likely candidate to fit the NMR data reported in the isolation
paper. Here we describe our efforts to solve this stereochemical
puzzle – first by establishing a robust synthetic route to
rubriflordilactone B, and second by modification of this route to
access the proposed structure of pseudo-rubriflordilactone B. In
combination with studies from the Li group,[9] we demonstrate
rubriflordilactone B, 2). Mindful of the potential sensitivity of
these fragments under the basic conditions required for their
union with 4, we also contemplated equivalent iodoalkynes 7
and
8 which would enable a milder Nozaki-Hiyama-Kishi
connection.[11]
Diyne 7 was selected as our initial target. A particular
challenge in this fragment is the need to install four contiguous
stereocenters on the tetrahydrofuran ring, three of which we
envisaged could be created using a dianionic Ireland-Claisen
rearrangement of the (Z)-enolate of a suitable ester.[12] Starting
from aldehyde 9, enantioselective [2+2] cycloaddition[13] with
ketene afforded b-lactone 10. Ring-opening of this lactone with
the magnesium alkoxide of enantioenriched alcohol 11 (obtained
by enzymatic resolution)[14] afforded ester 12. Dianionic Ireland-
Claisen rearrangement followed by treatment with TMS
diazomethane gave ester 13, featuring three of the required F
ring stereocenters;[15] this ring was formed by oxidative cleavage
of the alkene, and cyclization to the methyl acetal 14.
Manipulation of the two oxygen-bearing sidechains gave diyne
15, acetoxylation of which afforded acetal 16. Reaction of the
[a]
M. Mohammad, Dr. V. Chintalapudi, S. J. Mansfield, P. Sanderson,
Dr. K. E. Christensen and Prof. E. A. Anderson
Chemistry Research Laboratory, University of Oxford, 12 Mansfield
Road, Oxford, OX1 3TA, U.K.
E-mail: edward.anderson@chem.ox.ac.uk
[b]
Prof. J. M. Carney
Department of Molecular Biology and Chemistry, Christopher
Newport University, 1 Avenue of the Arts, Newport News, VA 23606.
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.201908917
Angewandte Chemie International Edition
COMMUNICATION
b)
b) LiAlH4
c) TBSCl
TBSO
a) LDA;
allyl iodide
PMBO
OH
O
PMBO
OH O
11
a) AcCl, TMSQ,
LiClO4
O
MeMgBr / OH
70%
O
21
OEt
OEt
O
d) OsO4, NMO
e) NaIO4/SiO2
f) TPAP, NMO
PMBO
O
62%
PMBO
O
O
PMBO
OH
O
19
94% ee
OPMB
20
10:1 dr
9
10
60%, 82:18 er
12
N
64% over 5 steps
OTMS
OMe
TMSQ =
O
O
N
c) LDA; TMSCHN2 72%
g) LDA; MeI 72%
(MeO)2P
24
TMS
N2
TMS
h) DIBALH;
CSA, MeOH;
TBAF
TBSO
OH
O
i) TEMPO, BAIB;
Ph3PCH=CHI;
NaHMDS; TMSCl
HO
i) TEMPO, BAIB;
24, NaOMe
d) LiAlH4
e) TBSCl
O
OMe
OMe
OMe
O
O
O
89%
j) n-BuLi; TMSCl
k) DDQ; TEMPO,
BAIB; CBr4, PPh3;
LiHMDS; n-BuLi
OMe
OMe
O
f) OsO4, NMO
g) NaIO4/SiO2
h) CSA; TBAF
PMBO
j) DDQ; TEMPO,
BAIB; CBr4, PPh3
k) LiHMDS; n-BuLi
22
O
OH
O
OPMB
>10:1 dr
PMB
OPMB
14
25
23
15
13
34% overall
59% over 5 steps
63% over 5 steps
24:1 dr
l) H2SO4, AcOH, Ac2O
m) I2, morpholine
8c
77%
l) H2SO4, AcOH, Ac2O
m) I2, morpholine
77%
TMS
TMS
OTIPS
TMS
TMS
TMS
TMS
O
O
OTIPS
18
H
H
22
O
O
23
22
O
23
18
H
H
H
O
O
OAc
O
O
O
O
O
O
OAc
H
H
n) Bi(OTf)3
O
O
O
n) Bi(OTf)3
H
65%
dr 1:1:1:1
8a (C22S, C23S)
8b (C22S, C23R)
8c (C22R, C23S)
8d (C22R, C23R)
16 (X = H)
17(X = I)
I
I
I
26
X
I
7a (31%)
I
7b (35%)
Scheme 3. Synthesis of pseudo-rubriflordilactone B diyne fragments. DIBALH
= i-Bu2AlH; TBS = SiMe2t-Bu; TPAP = tetrapropylammonium perruthenate.
Scheme 2. Synthesis of rubriflordilactone B diyne fragments. Ac = acetyl;
BAIB = PhI(OAc)2; CSA = (±)-camphorsulfonic acid; DDQ = 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone; LDA
=
LiN(i-Pr)2; LiHMDS
=
LiN(SiMe3)2;
NaHMDS = NaN(SiMe3)2; NMO = N-methylmorpholine-N-oxide; PMB = 4-
methoxybenzyl; TBAF = n-Bu4NF; TEMPO = 2,2,6,6-tetramethylpiperidin-1-
yl)oxyl; TIPS = Si(i-Pr)3; TMS = SiMe3.
tetrahydrofuran framework, and coupling constant analysis.[15]
8b and 8c (the identity of the latter being confirmed by X-ray
analysis) were isolated as single stereoisomers, but 8a and 8d
proved inseparable.
terminal alkyne in 16 with iodine and morpholine[16] in turn
generated iodoalkyne 17. Finally, the butenolide G ring was
introduced via Lewis acid promoted addition of siloxyfuran 18.
In our previous work,[5a] we had constructed the arene D ring
via
palladium-
and
cobalt-catalyzed
cyclizations
of
bromoendiynes and triynes, respectively. The former proved
high yielding, but required a non-terminal alkyne (which in the
present context would necessitate later stage arene desilylation),
and also temporary protection of the propargylic alcohol. Under
cobalt catalysis, the challenge of 7-membered C-ring formation
called for microwave heating, which limited scalability, and
alternative catalyst systems were therefore considered.
Rhodium-catalyzed [2+2+2] alkyne cyclotrimerization also has a
rich history in synthetic contexts,[22] and subsequent to our work
on rubriflordilactone A, was reported to promote efficient
cyclization to a truncated rubriflordilactone B fragment.[7a]
To model the cyclization and synthesis endgame, diynes 16
and 17 were first added to hept-6-ynal (Scheme 4). This union
proved far more efficient under Nozaki-Hiyama-Kishi conditions
(with 17, 73%) than via the alkynyllithium (16, 35%), presumably
reflecting the base-sensitivity of the acetoxy acetal. To our
delight, subjection of the desilylated triyne derived from 27 to
rhodium-catalyzed cyclotrimerization using Wilkinson's catalyst
(10 mol%) gave CDEF rings 28 in 73% yield. Dehydration of the
benzylic alcohol was achieved on treatment with Martin
sulfurane[23] (29), and finally bismuth(III)-promoted addition of
furan 18 gave the CDEFG model 30 in 27% yield, along with its
separable C23 epimer.
As observed by Peng and co-workers, bismuth(III) triflate proved
17]
highly efficient in this process,[7c,
affording the butenolide
diastereomers 7a and 7b in good yields. As expected on steric
grounds, these adducts were formed with good control over the
new F ring stereocenter, but as a mixture of stereoisomers on
the G ring.[15] The identity and absolute configuration of 7b (and
therefore by inference 7a, required for rubriflordilactone B) was
confirmed by X-ray crystallographic analysis.[18]
Synthesis of the diyne diastereomer required for pseudo-
rubriflordilactone B necessitated a change of strategy, as the
configuration of this F ring was now not readily suited to a
Claisen rearrangement approach. This route instead began with
enantioenriched b-hydroxy ester 19, prepared by Noyori
hydrogenation[19] of the corresponding known b-ketoester.[20]
Allylation of the enolate derived from 19 afforded 20 with high
selectivity (10:1 dr) which,[21] after further transformations
according to the previous route, led to lactone 21. With two
substituents positioned on the b-face of this ring, methylation of
the lactone enolate gave trisubstituted lactone 22 as a single
stereoisomer, featuring three of the F-ring stereocenters
required for the predicted natural product. After conversion of
this lactone to acetal 23, completion of diyne 8 entailed an
equivalent sequence of steps as employed for its diastereomer 7.
In this case however, the final butenolide addition proceeded
without stereocontrol, delivering the four diastereomeric FG
diynes 8a-d in an approximately equimolar ratio. In the event,
the formation of all four isomers greatly aided assignment of
stereochemistry at the new F and G ring stereocenters via a
combination of 1H NMR nOe enhancements around the
Encouraged by these results, an equivalent sequence was
pursued using the AB ring aldehyde 4. Rhodium-catalyzed
cyclotrimerization of adduct 31 again proceeded efficiently to
give the corresponding hexacycle; due to co-elution with residual
catalyst, this was carried directly to the next step after a short
silica gel filtration. However, attempted dehydration of the
This article is protected by copyright. All rights reserved.

10.1002/anie.201908917
Angewandte Chemie International Edition
COMMUNICATION
a) 16, n-BuLi; hept-6-ynal, 35%
b) 17, hept-6-ynal, CrCl2, 73%
c) TBAF
d) RhCl(PPh3)3
or
H
H
H
e) Ph2S(OCPh(CF3)2)2
f) 18, Bi(OTf)3
TMS
H
O
23
O
73%
over
2 steps
27%
83%
OAc
OAc
TMS
O
O
O
HO
OAc
OH
O
H
H
H
H
OTIPS
O
27
28
29
30
18
I
O
OAc
O
O
O
O
O
O
i) RhCl(PPh3)3
j) o-NO2C6H4SeCN,
PBu3; H2O2
16 (X = H)
17(X = I)
O
H
O
H
O
H
O
g) 17, 4,
CrCl2
H
O
k) 18, Bi(OTf)3
O
H
H
H
H
40% over
2 steps
56%
h) TBAF
O
23
O
H
H
H
H
OAc
OAc
70% over 2 steps
O
O
O
HO
OAc
O
H
H
H
H
Ph
F3C
O
CF3
1: Rubriflordilactone B
epi-1: C23-epi-Rubriflordilactone B
31
32
33
Scheme 4. Late-stage introduction of the butenolide G ring towards rubriflordilactone B.
resulting benzylic alcohol using Martin sulfurane surprisingly
yielded the substitution product 33, likely reflecting the increased
steric hindrance towards elimination (or subtle conformational
effects) in this substrate compared to 28. Fortunately,
elimination could be effected using the Grieco protocol,[24] which
gave 32 in 40% yield over the two steps. Bismuth-promoted
reaction of 32 with furan 18 delivered rubriflordilactone B (1), as
a 1:1 inseparable mixture with its C23 epimer epi-1.[15]
Although the natural product had been successfully
accessed, the problem of C23 isomer separation directed us to
install the butenolide ring at an earlier stage, which in any event
would represent a more convergent route (Scheme 5). Separate
treatment of 4 with iodoalkynes 7a and 7b led, after alkyne
desilylation, to adducts 34 and 35 as inconsequential mixtures at
the propargylic alcohol stereocenters. To our delight,
cyclotrimerization of these compounds indeed tolerated the
butenolide ring, giving the full natural product frameworks (65%
and 68% yield respectively). With the more acid-stable
butenolide ring now in place, dehydration could now be effected
using p-TsOH (20 mol%) in warm toluene,[7a] which again
afforded rubriflordilactone B 1, and its C23 diastereomer epi-1.
The former not only matched the spectroscopic data reported by
the Li group, but X-ray crystallographic analysis of 1 enabled
unambiguous confirmation of its structure and absolute
configuration (Flack(x) parameter = -0.09(2)).[18]
necessitated addition of this 1:1 mixture to 4, which fortunately
gave separable homopropargylic alcohols. Desilylation of the
adduct destined for conversion to pseudo-rubriflordilactone B
(36) proved somewhat capricious, and both the subsequent
cyclotrimerization and acid-mediated dehydration required
higher loadings of their respective catalysts, and/or extended
reaction times, compared to rubriflordilactone B. This route
nonetheless delivered 2, the predicted structure of pseudo-
rubriflordilactone B. Diyne 8b was also carried through the
sequence, giving the C23 epimer of pseudo-rubriflordilactone B,
epi-2. Comparison of the NMR spectroscopic data of 2 (and epi-
2) with data from the isolation paper revealed a high level of
consistency for the former diastereomer, thus providing strong
support for the computationally-predicted stereochemistry;[8]
further communications with the Li group supported this
conclusion.[9][25}
In summary, we have synthesized four diastereomers of
rubriflordilactone B, one corresponding to the isolation crystal
structure of the natural product, and another to the
computationally-predicted structure of pseudo-rubriflordilactone
B, which corresponds to the isolation NMR spectroscopic data.
Key to this work was the stereoselective synthesis of the
requisite FG ring diynes, and a highly convergent late-stage
coupling / cyclotrimerization / dehydration strategy. These
results resolve the stereochemical ambiguity surrounding this
intriguing natural product, and offer a strategy suitable for
natural product diversification.
Completion of pseudo-rubriflordilactone B (2) proved more
challenging. As iodoalkynes 8a and 8d were inseparable, this
O
O
O
O
1: Rubriflordilactone B
a) 7a,
CrCl2
b) TBAF
a) 8a/8d,
CrCl2
b) TBAF
H
O
O
O
H
O
O
c) [Rh]
d) p-TsOH
34
36
c) [Rh]
d) p-TsOH
O
H
H
H
H
O
O
H
H
O
55%
63%
57%
43%
O
O
O
O
O
H
H
H
H
H
H
H
H
O
O
O
O
HO
[Rh] = ClRh(PPh)3
HO
H
H
H
H
O
O
O
2: pseudo-Rubriflordilactone B
O
H
O
O
H
H
4
O
O
O
O
O
H
O
c) [Rh]
d) p-TsOH
O
O
H
O
c) [Rh]
d) p-TsOH
O
35
37
H
H
67%
75%
H
H
O
O
H
H
O
a) 7b,
CrCl2
b) TBAF
a) 8b,
CrCl2
b) TBAF
36%
61%
O
O
O
O
O
H
H
H
H
H
H
H
H
O
O
O
O
HO
HO
H
H
H
H
epi-1
epi-2
O
O
Scheme 5. Synthesis of rubriflordilactone B and pseudo-rubriflordilactone B. p-Ts = p-toluenesulfonyl.
This article is protected by copyright. All rights reserved.

10.1002/anie.201908917
Angewandte Chemie International Edition
COMMUNICATION
[11] K. Takai, T. Kuroda, S. Nakatsukasa, K. Oshima, H. Nozakil,
Tetrahedron Lett. 1985, 26, 5585.
Acknowledgements
[12] a) M. J. Kurth, C.-M. Yu, Tetrahedron Lett. 1984, 25, 5003; b) M. J.
Kurth, R. L. Beard, J. Org. Chem. 1988, 53, 4085; c) M. T. Crimmins, J.
D. Knight, P. S. Williams, Y. Zhang, Org. Lett. 2014, 16, 2458.
[13] a) C. Zhu, X. Shen, S. G. Nelson, J Am Chem Soc 2004, 126, 5352; b)
X. Shen, A. S. Wasmuth, J. Zhao, C. Zhu, S. G. Nelson, J. Am. Chem.
Soc. 2006, 128, 7438.
We thank Prof Ang Li for helpful discussions. V.C. thanks the
Marie Skłodowska-Curie actions for an Individual Fellowship
(GA No. 702385). J.M.C. thanks the CNU Office of the Provost
for financial support. S.J.M. thanks the EPSRC Centre for
Doctoral Training in Synthesis for Biology and Medicine
(EP/L015838/1) for a studentship, supported by AstraZeneca,
Diamond Light Source, Defence Science and Technology
Laboratory, Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer,
Syngenta, Takeda, UCB and Vertex. E.A.A. thanks the EPSRC
for funding (EP/M019195/1, EP/E055273/1). We thank Diamond
Light Source for beamtime on I19-1.
[14] P. J. Kocienski, J. A. Christopher, R. Bell, B. Otto, Synthesis 2005, 75.
[15] See the Supporting Information for details of structural assignment.
[16] J. E. Hein, J. C. Tripp, L. B. Krasnova, K. B. Sharpless, V. V. Fokin,
Angew. Chem. Int. Ed. 2009, 48, 8018.
[17] T. Ollevier, J.-E. Bouchard, V. Desyroy, J. Org. Chem. 2008, 73, 331.
[18] Low temperature single crystal X-ray diffraction data were collected for
1, 7b and 16a with
a (Rigaku) Oxford Diffraction SuperNova A
diffractometer at 150K. Data for 8c were collected using I19-1 at the
Diamond Light Source [D. R. Allan, H. Nowell, S. A. Barnett, M. R.
Warren, A. Wilcox, J. Christensen, L. K. Saunders, A. Peach, M. T.
Hooper, L. Zaja, S. Patel, L. Cahill, R. Marshall, S. Trimnell, A. J. Foster,
T. Bates, S. Lay, M. A. Williams, P. V. Hathaway, G. Winter, M. Gerstel,
R. W. Wooley, Crystals 2017, 7, 336] at 100K. All data were reduced
using CrysAlisPro, solved using SuperFlip [L. Palatinus, G. Chapuis, J.
Appl. Crystallogr. 2007, 40, 786-790] and the structures were refined
using CRYSTALS. [P. W. Betteridge, J. R. Carruthers, R. I. Cooper, K.
Prout, D. J. Watkin, J. Appl. Crystallogr. 2003, 36, 1487; R. I. Cooper, A.
L. Thompson, D. J. Watkin, J. Appl. Crystallogr. 2010, 43, 1100-1107].
The Flack(x) parameter [H. D. Flack, Acta Crystallogr. A 1983, 39, 876-
881; H. D. Flack, G. Bernardinelli, J. Appl. Crystallogr. 2000, 33, 1143-
1148] was refined in all cases; see the Supporting Information (CIF) for
further details. CCDC 1904829–1904832 contains the Supplementary
crystallographic data for this paper.
Keywords: cyclotrimerization • natural products • structure
elucidation • schinorterpenoids • total synthesis
[1]
[2]
a) Y.-M. Shi, W.-L. Xiao, J.-X. Pu, H.-D. Sun, Nat. Prod. Rep. 2015, 32,
367; b) For reviews, see: Y.-G. Xia, B.-Y. Yang, H.-X. Kuang,
Phytochem. Rev. 2015, 14, 155.
a) H. Wang, X. Zhang, P. Tang, Chem. Sci. 2017, 8, 7246; b) D.-D. Liu,
T.-W. Sun, K.-Y. Wang, Y. Lu, S.-L. Zhang, Y.-H. Li, Y.-L. Jiang, J.-H.
Chen, Z. Yang, J. Am. Chem. Soc. 2017, 139, 5732; c) Y.-X. Han, Y.-L.
Jiang, Y. Li, H.-X. Yu, B.-Q. Tong, Z. Niu, S.-J. Zhou, S. Liu, Y. Lan, J.-
H. Chen, Z. Yang, Nat Commun 2017, 8; d) L. Wang, H. Wang, Y. Li, P.
Tang, Angew. Chem. Int. Ed. 2015, 54, 5732; e) L. You, X.-T. Liang, L.-
M. Xu, Y.-F. Wang, J.-J. Zhang, Q. Su, Y.-H. Li, B. Zhang, S.-L. Yang,
J.-H. Chen, Z. Yang, J. Am. Chem. Soc. 2015, 137, 10120; f) Q. Xiao,
W. W. Ren, Z. X. Chen, T. W. Sun, Y. Li, Q. D. Ye, J. X. Gong, F. K.
Meng, L. You, Y. F. Liu, M. Z. Zhao, L. M. Xu, Z. H. Shan, Y. Shi, Y. F.
Tang, J. H. Chen, Z. Yang, Angew. Chem. Int. Ed. 2011, 50, 7373; g)
For reviews on Schisandraceae natural products, see: X. Li, P. H.-Y.
Cheong, R. G. Carter, Angew. Chem. Int. Ed. 2017, 56, 1704; h) B. Ma,
Y. Zhao, C. He, H. Ding, Angew. Chem. Int. Ed. 2018, 57, 15567; i) Z.
Yang, Acc. Chem. Res. 2019, 52, 480.
[19] R. Noyori, T. Ohkuma, M. Kitamura, H. Takaya, N. Sayo, H.
Kumobayashi, S. Akutagawa, J. Am. Chem. Soc. 1987, 109, 5856.
[20] C. Herb, M. E. Maier, J. Org. Chem. 2003, 68, 8129.
[21] M. Nakatsuka, J. A. Ragan, T. Sammakia, D. B. Smith, D. E. Uehling, S.
L. Schreiber, J. Am. Chem. Soc. 1990, 112, 5583.
[22] a) S. Nishigaki, Y. Shibata, K. Tanaka, J. Org. Chem. 2017, 82, 11117;
b) K. Tanaka, Y. Kimura, K. Murayama, Bull. Chem. Soc. Jpn. 2014, 88,
375; c) C. Alayrac, D. Schollmeyer, B. Witulski, Chem. Commun. 2009,
1464; d) M. R. Tracey, J. Oppenheimer, R. P. Hsung, J. Org. Chem.
2006, 71, 8629; e) E. A. Anderson, E. J. Alexanian, E. J. Sorensen,
Angew. Chem. Int. Ed. 2004, 43, 1998; f) H. Kinoshita, H. Shinokubo, K.
Oshima, J. Am. Chem. Soc. 2003, 125, 7784; g) B. Witulski, T. Stengel,
Angew. Chem. Int. Ed. 1999, 38, 2426; h) F. E. McDonald, H. Y. H. Zhu,
C. R. Holmquist, J. Am. Chem. Soc. 1995, 117, 6605; i) R. Grigg, R.
Scott, P. Stevenson, J. Chem. Soc., Perkin Trans. 1 1988, 1357; j) R.
Grigg, R. Scott, P. Stevenson, Tetrahedron Lett. 1982, 23, 2691.
[23] R. J. Arhart, J. C. Martin, J. Am. Chem. Soc. 1972, 94, 5003.
[24] P. A. Grieco, S. Gilman, M. Nishizawa, J. Org. Chem. 1976, 41, 1485.
[25] Discrepancies were observed at H11, H12, C11, C12 and C15
compared to the natural product isolation NMR spectroscopic data, as
were noted by Sarotti and Kaufman in Reference 8. It is our belief that
these signals were misassigned in the original isolation work due to the
presence of phthalate impurities, and due to highly broadened peaks in
the 13C NMR spectrum. See the Supporting Information for further
discussion.
[3]
W. L. Xiao, L. M. Yang, N. B. Gong, L. Wu, R. R. Wang, J. X. Pu, X. L.
Li, S. X. Huang, Y. T. Zheng, R. T. Li, Y. Lu, Q. T. Zheng, H. D. Sun,
Org. Lett. 2006, 8, 991.
[4]
[5]
J. Li, P. Yang, M. Yao, J. Deng, A. Li, J. Am. Chem. Soc. 2014, 136,
16477.
a) S. S. Goh, G. Chaubet, B. Gockel, M.-C. A. Cordonnier, H. Baars, A.
W. Phillips, E. A. Anderson, Angew. Chem. Int. Ed. 2015, 54, 12618; b)
G. Chaubet, S. Goh, S., M. Mohammad, B. Gockel, M. C. Cordonnier,
A., H. Baars, A. Phillips, W., E. Anderson, A., Chem. Eur. J. 2017, 23,
14080.
[6]
[7]
P. Yang, M. Yao, J. Li, Y. Li, A. Li, Angew. Chem. Int. Ed. 2016, 55,
6964.
a) Y. Wang, Z. Li, L. Lv, Z. Xie, Org. Lett. 2016, 18, 792; b) Y. Wang, Y.
Zhang, Z. Li, Z. Yang, Z. Xie, Org. Chem. Front. 2017, 4, 47; c) Y. Peng,
S.-M. Duan, Y.-W. Wang, Tetrahedron Lett. 2015, 56, 4509; d) S. S.
Goh, H. Baars, B. Gockel, E. A. Anderson, Org. Lett. 2012, 14, 6278; e)
M.-C. A. Cordonnier, S. B. J. Kan, E. A. Anderson, Chem. Commun.
2008, 5818.
[8]
[9]
N. Grimblat, T. S. Kaufman, A. M. Sarotti, Org. Lett. 2016, 18, 6420.
A. Li et al., personal communication.
[10] P. R. Chopade, J. Louie, Adv. Synth. Catal. 2006, 348, 2307.
This article is protected by copyright. All rights reserved.

10.1002/anie.201908917
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
A convergent late-stage fragment
coupling and rhodium-catalyzed
[2+2+2] alkyne cyclotrimerization
strategy provides access to the
natural product (–)-rubriflordilactone
B, and the proposed structure of (–)-
pseudo-rubriflordilactone B. In doing
so, the uncertainty surrounding the
identity of pseudo-rubriflordilactone B
is resolved, and a synthetic platform is
established that offers broad scope for
the exploration of this natural product
family.
Mujahid Mohammad, Venkaiah
Chintalapudi, Jeffrey M. Carney, Steven
J. Mansfield, Pollyanna Sanderson,
Kirsten E. Christensen and Edward A.
Anderson*
Page No. – Page No.
Convergent Total Syntheses of (–)-
Rubriflordilactone B and (–)-pseudo-
Rubriflordilactone B
This article is protected by copyright. All rights reserved.