An Unexpected Transannular [4+2] Cycloaddition during the Total Synthesis of (+)-Norcembrene 5

Article abstract of DOI:10.1002/anie.201912613

We report a concise and versatile total synthesis of the diterpenoid (+)-norcembrene 5 from simple building blocks. Ring-closing metathesis and an auxiliary-directed 1,4-addition are the key steps of our synthetic route. During the synthesis, an unprecede

Full text of DOI:10.1002/anie.201912613

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: An Unexpected Transannular [4+2] Cycloaddition during the Total
Synthesis of (+)-Norcembrene 5
Authors: Michael Breunig, Po Yuan, and Tanja Gaich
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.201912613
Angew. Chem. 10.1002/ange.201912613
Link to VoR: http://dx.doi.org/10.1002/anie.201912613
http://dx.doi.org/10.1002/ange.201912613

10.1002/anie.201912613
Angewandte Chemie International Edition
COMMUNICATION
An Unexpected Transannular [4+2] Cycloaddition during the
Total Synthesis of (+)-Norcembrene 5
Michael Breunig‡, Po Yuan‡, and Tanja Gaich*
Dedicated to Prof. Dr. Johann Mulzer on the occasion of his 75th
birthday
Abstract: We report a concise and versatile total synthesis of the
diterpenoid (+)-norcembrene 5 from simple building blocks. A ring-
closing metathesis as well as an auxiliary-directed 1,4-addition
represent the key steps of our synthetic route. During the synthesis,
an unprecedented, highly oxidized pentacyclic structure motif was
established from
cycloaddition.
a furanocembranoid via transannular [4+2]
Norcembrenolides represent a large and diverse family of
norditerpene natural products. The main source for isolation of
norcembrenolides are gorgonian soft corals found in the Western
Atlantic Ocean.[1] Most of these natural products were isolated
from soft corals of the genus Sinularia (family: Alcyoniidae).
Representative norcembrenolides 1–8 exhibit a variety of different
functional group patterns embedded in a macrocyclic ring, which
is present in all congeners (Figure 1).[2] Several of these
compounds showed biological and pharmacological activities
such as cytotoxicity or antiviral properties. Gyrosanin A[2d] (2) was
tested positive on cytotoxicity against P-388 cancer cell lines
Figure 1. Representative norcembrenolide natural products.
Despite their unique molecular structure featuring
a 14-
membered cembrane ring, a bridging dihydrofuranone, and a
lactone or ester motif, only a few accomplished (semi-)syntheses
of norcembrenolides have been reported so far.[2b, 3]
(mouse
lymphocytic
leukemia).
Sinuleptolide[2c]
(3),
norcembrenolide/5-episinuleptolide[2c] (4), scabrolide E[2e] (5),
leptocladolide A[2f] (6) and 7E-leptocladolide A[2f] (7) showed
strong to moderate cytotoxic activity both against KB (human oral
epidermoid carcinoma) and Hepa59T/VGH (human liver
carcinoma) cancer cell lines. Sinuleptolide (3) furthermore
Norcembrene 5 (1) was first isolated in 1985 by the groups of W.
Fenical and J. Clardy.[2a] Its absolute configuration was not
determined so far, and both enantiomeric structures of
norcembrene 5 were reported in later isolations of this compound
in literature, all referring to the original publication.[2c, 4] Therefore,
its absolute configuration remained ambiguous.
exhibited
antiviral
activity
against
HCMV
(human
cytomegalovirus) cells.[2d]
Herewith, we report the total synthesis of norcembrene 5 as well
as the elucidation of its absolute configuration. Comparison of the
optical rotation of our synthesized material with literature revealed
opposite signs (synthetic +51.4 vs. –77 for the isolated material),
thus establishing the natural product as (–)-norcembrene 5.[2a] In
a retrosynthetic fashion, (+)-norcembrene 5 (1) is assembled from
furanocembranoid
9
(Scheme 1). In
a
biomimetic[3a]
oxidation/transannular cyclization cascade the furan moiety is
cleaved to the 3-furanone motif present in the natural product. In
addition, methanolysis of the butenolide completes the
transformations that convert 9 into 1. The macrocycle of 9 is
constructed via ring-closing metathesis (RCM) from triene 10,
which is accessible from aldehyde 11 and selenolactone 12 by
aldol reaction. The stereocenter of 11 is introduced via an
auxiliary-directed 1,4-addition on compound 13, available from 2-
allylfuran (14) by cross metathesis.
‡
‡
[*]
M. Breunig , P. Yuan , Prof. T. Gaich
Department of Chemistry
University of Konstanz
Universitätsstrasse 10, 78464 Konstanz, Germany
E-mail: tanja.gaich@uni-konstanz.de
[‡]
These authors contributed equally to this work.
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.201912613
Angewandte Chemie International Edition
COMMUNICATION
experimentation, we found that the diastereomers 19a and 19b
behaved differently in the Wittig olefination. 19a was successfully
converted to 10a by using KHMDS as a base for ylide formation
in 72% yield. By contrast, for the conversion of diastereomer 19b
LiHMDS gave better yields (64%) than the use of KHMDS (47%).
With compounds 10a and 10b in hand, ring-closing metathesis as
key step of the synthetic route could be performed. Initial studies
for this transformation applying a continuous addition of Grubbs II
catalyst to the starting material in refluxing benzene resulted in
very inconsistent reaction yields varying from 9–53% of product.
After screening a number of different reaction parameters, two
distinct changes eventually gave reasonable access to the
desired macrocycles 20a and 20b. First, 1,4-benzoquinone was
added to the reaction mixture in catalytic amounts. In literature it
Scheme 1. Retrosynthetic analysis of (+)-norcembrene 5 (1).
is reported to prevent isomerization during olefin metathesis[11]
,
but we suppose that it operated as scavenger for decomposition
species formed by the catalyst at high temperatures. Secondly,
the catalyst was added in several portions to the reaction mixture
Our synthesis began with the preparation of enantiopure
aldehyde 11 (Scheme 2). Cross metathesis of 2-allylfuran[5] (14)
with acrylic acid and Hoveyda–Grubbs II catalyst afforded
unsaturated carboxylic acid 15 in high yields.[6] The Evans
auxiliary for the stereoselective 1,4-addition was attached via
amidation of the lithiated oxazolidinone with the in situ formed acid
chloride from 15 furnishing enone 13 in 81% yield.[7]
Diastereoselective installation of the isopropenyl moiety was
performed using freshly recrystallized CuBr∙SMe2 as copper
source.[8] Under optimized conditions, compound 16 was obtained
in quantitative yield as single diastereomer. With this auxiliary-
controlled 1,4-addition we introduced optical activity into the
molecule. Subsequent reductive cleavage of the auxiliary directly
afforded aldehyde 11 in 77% yield.
instead of
a continuous addition. Under these optimized
conditions, furanocembranoids 20a and 20b could be prepared in
58% and 69% yield, respectively.
Scheme 3. Synthesis of furanocembranoids 20a/b via RCM reaction.
For further functionalization, the trisubstituted double bond of the
macrocycle needed to be hydrated stereo- and regioselectively
(Markovnikov). Since direct hydration such as Mukaiyama
hydration failed, a two-step sequence consisting of Upjohn
dihydroxylation[12] followed by deoxygenation of the secondary
alcohol was applied (Scheme 4). Under similar conditions as
established by Theodorakis and co-workers, furanocembranoid
20a was treated with a mixture of OsO4 and NMO to perform site-
selective dihydroxylation of the cyclic C–C double bond.[2b] In
doing so, diol 21a could be afforded as single diastereomer in
46% yield. After preparation of 21a we observed slow but
spontaneous reaction of this compound to another product when
stored in solution. Thorough characterization via 2D-NMR
spectroscopy revealed, that 21a underwent a transannular [4+2]
cycloaddition between the furan and the butenolide moiety. In this
transformation, pentacyclic compound 22 was formed as single
diastereomer representing the exo-Diels–Alder product, which
could be confirmed by NOESY experiments. This unprecedented
Scheme 2. Synthesis of enantiopure aldehyde 11.
In the next sequence, the macrocycle of the furanocembranoid
scaffold was established (Scheme 3). First, aldehyde 11 was
assembled with selenolactone 12 (available in three steps from
(S)-(–)-glycidol)
via
aldol
reaction
and
subsequent
oxidation/elimination under the conditions reported by Mulzer and
co-workers.[9] The two diastereomeric butenolides 17a and 17b
were obtained in a ratio of 3.2:1, were separated and used
independently for further transformations. Acetylation of the
secondary alcohol followed by Vilsmeier–Haack formylation[10] of
the furan ring furnished aldehydes 19a and 19b both in high
yields. Subsequent olefination of the aldehyde functionality
initially caused synthetic drawbacks. After extensive
This article is protected by copyright. All rights reserved.

10.1002/anie.201912613
Angewandte Chemie International Edition
COMMUNICATION
structure motif features a highly oxygenated and congested
compound bearing eight stereocenters (five of them contiguous)
and one quaternary carbon center. This motif is of interest for
further SAR studies in the future. For better characterization, full
conversion of 21a to 22 was achieved by heating the starting
material in refluxing benzene. Despite this unexpected
transannular reaction we were able to convert diol 21a into 9a by
deoxygenation of the secondary alcohol moiety. Treatment of 21a
with Et3SiH and BF3∙OEt2 was fast enough to furnish alcohol 9a in
47% yield[2b], before 21a was able to undergo the undesired
transannular [4+2] cycloaddition. Likewise, 9a was prone to
undergo transannular [4+2] cycloaddition to give pentacycle 23 as
single product featuring identical stereochemical relationships.
be obtained was 24% yield of diol 21b despite screening different
temperatures, solvent systems and concentrations. Other
reagents for dihydroxylation such as AD-mix, K2OsO4/NMO or
RuCl3/NaIO4 showed no reaction at all. Nevertheless, the
synthesis was continued and by treatment of 21b with
Et3SiH/BF3∙OEt2, alcohol 9b was afforded in 36% yield (61%
brsm). To our surprise, neither compound 21b nor compound 9b
showed any tendency for transannular cycloaddition at all (see
Figure 2 for further details). With 9b in hand, oxidation of the furan
moiety followed by 5-exo-trig cyclization of the tertiary alcohol was
triggered upon treatment with Jones reagent to afford
norcembrenolide 24 in high yields.[2b, 16] Finally, a sequence of
deprotonation of the butenolide and elimination of the acetate
group via intermediate 25, followed by methanolysis of the lactone
gave access to (+)-norcembrene 5 (1) in good yields. The
absolute stereochemistry of 1 was established with the help of
single crystal X-ray analysis of furanocembranoid 20b. Since the
absolute configuration at C1 was introduced earlier in the
synthesis via the enantioselective 1,4-addition, all other
stereocenters could be correlated.
Scheme 4. Site-selective hydration of furanocembranoid 20a and [4+2]
cycloaddition products 22/23 with key NOESY correlations.
This transannular [4+2] cycloaddition is of general interest, since
similar transannular cycloadditions on these natural products
have previously been reported and seem to reflect a general
reactivity trend in this natural product family. In his synthesis of
intricarene, D. Trauner relied on
a
transannular [5+2]
oxidopyrylium cycloaddition of similar furanocembranoid
bipinnatin J to obtain the natural product.[13] Another example is
the transannular [2+2] photocycloaddition in an approach to
bielschowskysin accomplished by L. West and S. P. Roche via a
dearomatization of the furan ring with concomitant transannular
[2+2] cycloaddition reaction.[14] These previously reported
transannular cyclizations are considered to act in the actual
biosynthesis of these natural products, thus contributing largely to
the architectural diversity in the molecular scaffolds present in
furanocemranoid diterpenes. Therefore, it is highly likely that in
future isolation efforts novel natural product congeners with a
molecular architecture of 22 and 23 will be discovered from
Sinularia type soft corals, thus comprising an additional case of
“natural product anticipation”.[15]
Scheme 5. Preparation of (+)-norcembrene 5 (1) from furanocembranoid 20b.
Since there was no obvious reason that could explain the different
reactivity of compounds 21a/9a (transannular [4+2] cycloaddition)
and their diastereomeric compounds 21b/9b (no transannular
reaction), we performed DFT calculations for further clarification
(Figure 2, for experimental details and calculated structures see
Supporting Information). Therefore, we decided to calculate the
Gibbs free energies of diol 21a and its reaction product 22 via
transition state 21a‡. On the other hand, the free energies of diol
21b and its (not observed) reaction product 22b via transition
state 21b‡ were calculated. In doing so, the first interesting result
was the clearly higher free energy and therefore higher reactivity
of 21a in comparison to 21b (ΔG = 11.9 kcal/mol) in the ground
state. As second result we observed the lower free energy of
transition state 21a‡ compared to possible transition state 21b‡
The two-step sequence for hydration of the C–C double bond was
also applied to diastereomeric furanocembranoid 20b (Scheme
5), since direct Mukaiyama hydration proved to be unsuccessful
as previously described for Scheme 4. However, applying the
same reaction conditions for dihydroxylation (OsO4/NMO) as for
20a only gave unsatisfactory yields. The best results that could
This article is protected by copyright. All rights reserved.

10.1002/anie.201912613
Angewandte Chemie International Edition
COMMUNICATION
(ΔG = 4.47 kcal/mol). Both results further imply activation
energies of 22.8 kcal/mol for the transition of 21a to 21a‡ (black
dash) and 39.2 kcal/mol for the transition of 21b to 21b‡ (red
dash). In conclusion, the activation barrier for diol 21b is almost
twice the amount as for 21a. For this reason, it is very plausible
that transannular Diels–Alder reaction of 21a takes place,
whereas compound 21b fails to undergo the transannular
reaction. Since compounds 9a, 9b, and 23 have the same
molecular scaffolds and only differ in substitution pattern from
21a, 21b, and 22, analogous behavior can be presumed.
structure refinement. We are very grateful to Jan Herberger from
the University of Konstanz for help with DFT calculations. We
acknowledge support by the state of Baden-Württemberg through
bwHPC and the German Research Foundation (DFG) through
grant no. INST 40/467-1 FUGG (JUSTUS cluster).
Keywords: furanocembranoid • norcembrenolide • ring-closing
metathesis • total synthesis • transannular [4+2] cycloaddition
[1]
[2]
A. D. Rodríguez, Tetrahedron 1995, 51, 4571–4618.
a) A. Sato, W. Fenical, Z. Qi-tai, J. Clardy, Tetrahedron 1985, 41, 4303–
4308; b) A. Saitman, P. Rulliere, S. D. E. Sullivan, E. A. Theodorakis,
Org. Lett. 2011, 13, 5854–5857; c) J.-H. Sheu, A. F. Ahmed, R.-T. Shiue,
C.-F. Dai, Y.-H. Kuo, J. Nat. Prod. 2002, 65, 1904–1908; d) S.-Y. Cheng,
C.-T. Chuang, Z.-H. Wen, S.-K. Wang, S.-F. Chiou, C.-H. Hsu, C.-F. Dai,
C.-Y. Duh, Bioorg. Med. Chem. 2010, 18, 3379–3386; e) A. F. Ahmed,
J.-H. Su, Y.-H. Kuo, J.-H. Sheu, J. Nat. Prod. 2004, 67, 2079–2082; f) A.
F. Ahmed, R.-T. Shiue, G.-H. Wang, C.-F. Dai, Y.-H. Kuo, J.-H. Sheu,
Tetrahedron 2003, 59, 7337–7344; g) B. Bowden, J. Coll, S. Mitchell, J.
Mulder, G. Stokie, Aust. J. Chem. 1978, 31, 2049–2056; h) N. Shoji, A.
Umeyama, S. Arihara, J. Nat. Prod. 1993, 56, 1651–1653.
[3]
[4]
a) Y. Li, G. Pattenden, Tetrahedron 2011, 67, 10045–10052; b) M. S.
Kwon, S. H. Sim, Y. K. Chung, E. Lee, Tetrahedron 2011, 67, 10179–
10185.
a) B. R. Chitturi, V. B. Tatipamula, C. B. Dokuburra, U. K. Mangamuri, V.
R. Tuniki, S. V. Kalivendi, R. A. Bunce, V. Yenamandra, Tetrahedron
2016, 72, 1933–1940; b) N. P. Thao, B. T. T. Luyen, S. H. Lee, H. D.
Jang, P. V. Kiem, C. V. Minh, Y. H. Kim, Med. Chem. Res. 2015, 24,
3551–3560; c) K.-E. Lillsunde, C. Festa, H. Adel, S. De Marino, V.
Lombardi, S. Tilvi, D. A. Nawrot, A. Zampella, L. D'Souza, M. V. D'Auria,
P. Tammela, Mar. Drugs 2014, 12, 4045–4068; d) N. P. Thao, N. H. Nam,
N. X. Cuong, B. T. T. Luyen, B. H. Tai, J. E. Kim, S. B. Song, P. V. Kiem,
C. V. Minh, Y. H. Kim, Arch. Pharmacal Res. 2014, 37, 706–712; e) N.
P. Thao, N. H. Nam, N. X. Cuong, T. H. Quang, P. T. Tung, L. D. Dat, D.
Chae, S. Kim, Y.-S. Koh, P. V. Kiem, C. V. Minh, Y. H. Kim, Bioorg. Med.
Chem. Lett. 2013, 23, 228–231; f) M. Qin, X. Li, B. Wang, Chin. J. Chem.
2012, 30, 1278–1282; g) Y.-J. Tseng, A. F. Ahmed, C.-H. Hsu, J.-H. Su,
C.-F. Dai, J.-H. Sheu, J. Chin. Chem. Soc. 2007, 54, 1041–1044.
M. Lautens, S. Kumanovic, J. Am. Chem. Soc. 1995, 117, 1954–1964.
T.-L. Choi, A. K. Chatterjee, R. H. Grubbs, Angew. Chem. Int. Ed. 2001,
40, 1277–1279.
Figure 2. Comparison of Gibbs free energies of compounds 21a/b and 22/22b
via 21a/b‡ concerning transannular [4+2] cycloaddition based on DFT
calculations.
[5]
[6]
In conclusion, we have established the absolute configuration of
[7]
[8]
B. M. Trost, Z. T. Ball, J. Am. Chem. Soc. 2004, 126, 13942–13944.
J. Ouyang, R. Yan, X. Mi, R. Hong, Angew. Chem. Int. Ed. 2015, 54,
10940–10943.
(–)-1 and accomplished
a concise synthetic route to its
enantiomer (+)-norcembrene 5 (1) in 13 isolated steps from 2-
allylfuran (14). An optimized ring-closing metathesis reaction was
applied as a key step to assemble the 14-membered carbocyclic
scaffold. Our route is very versatile and can be adopted for the
synthesis of further furanocembranoids and norcembrenolides. In
addition, we demonstrated the formation of the unprecedented
and highly congested pentacyclic structure motifs 22 and 23 via
transannular [4+2] cycloaddition. The frequent occurrence of
transannular cycloaddition reactions in furanocembranoid (bio)-
synthesis ([5+2] and [2+2]) strongly suggests that the molecular
scaffold obtained from our transannular [4+2] cycloaddition is yet
another case of natural product anticipation.
[9]
H. Weinstabl, T. Gaich, J. Mulzer, Org. Lett. 2012, 14, 2834–2837.
[10] T. Feng, H. Wang, H. Su, H. Lu, L. Yu, X. Zhang, H. Sun, Q. You, Bioorg.
Med. Chem. 2013, 21, 5339–5354.
[11] S. H. Hong, D. P. Sanders, C. W. Lee, R. H. Grubbs, J. Am. Chem. Soc.
2005, 127, 17160–17161.
[12] V. VanRheenen, R. C. Kelly, D. Y. Cha, Tetrahedron Lett. 1976, 17,
1973–1976.
[13] P. A. Roethle, P. T. Hernandez, D. Trauner, Org. Lett. 2006, 8, 5901–
5904.
[14] a) K. C. Nicolaou, C. R. H. Hale, C. Ebner, C. Nilewski, C. F. Ahles, D.
Rhoades, Angew. Chem. Int. Ed. 2012, 51, 4726–4730; b) P. Scesa, M.
Wangpaichitr, N. Savaraj, L. West, S. P. Roche, Angew. Chem. Int. Ed.
2018, 57, 1316–1321.
[15] a) D. P. O’Malley, K. Li, M. Maue, A. L. Zografos, P. S. Baran, J. Am.
Chem. Soc. 2007, 129, 4762–4775; b) P. Sharma, B. Lygo, W. Lewis J.
E. Moses, J. Am. Chem. Soc. 2009, 131, 5966–5972; c) M. Gavagnin, E.
Mollo, G. Cimino, Rev. Bras. Farmacogn. 2015, 25, 588–591; d) A. L.
Lawrence, R. M. Adlington, J. E. Baldwin, V. Lee, J. A. Kershaw A. L.
Thompson, Org. Lett. 2010, 12, 1676–1679; e) V. Sofiyev, J.-P. Lumb,
M. Volgraf, D. Trauner, Chem. Eur. J. 2012, 18, 4999–5005; f) S. Strych,
G. Journot, R. P. Pemberton, S. C. Wang, D. J. Tantillo, D. Trauner,
Angew. Chem. Int. Ed. 2015, 54, 5079–5083; Angew. Chem., 2015, 127,
5168–5172; g) P. Ellerbrock, N. Armanino, M. K. Ilg, R. Webster, D.
Trauner, Nat. Chem. 2015, 7, 879–882.
Acknowledgements
We thank the China Scholarship Council for a CSC-scholarship
for P. Yuan. We thank the NMR department of the University of
Konstanz (A. Friemel and U. Haunz) for extensive analyses, and
Dr. Inigo Göttker and Dr. Thomas Huhn for X-ray analysis and
[16] S. J. Hayes, D. W. Knight, A. W. T. Smith, M. J. O’Halloran, Tetrahedron
Lett. 2010, 51, 720–723.
This article is protected by copyright. All rights reserved.

10.1002/anie.201912613
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Michael Breunig‡, Po Yuan‡, and Tanja
Gaich*
Page No. – Page No.
An Unexpected Transannular [4+2]
Cycloaddition during the Total
Synthesis of (+)-Norcembrene 5
Different reactivities of diastereomeric compounds (at C13) were observed. The α-isomer underwent clean and spontaneous Diels–
Alder reaction at room temperature, whereas the β-isomer did not undergo any Diels–Alder reaction, but was oxidized to the
corresponding furanone, and was further transformed to norcembrene 5.
This article is protected by copyright. All rights reserved.