Relay Cross Metathesis for the Iterative Construction of Terpenoids and Synthesis of a Diterpene-Benzoate Macrolide of Biogenetic Relevance to the Bromophycolides

Article abstract of DOI:10.1021/acs.orglett.0c00935

We report a relay cross metathesis (ReXM) reaction for the construction of terpenoids in an iterative protocol. The protocol features the cross metathesis of a relay-actuated Δ^6,7-functionalized C₁₀-monoterpenoid alcohol with C₁₀-monoterpenoid citral to form a C₁₅-sesquiterpene. Subsequent functional group manipulation allows for the method to be repeated in an iterative fashion. The method is used for the synthesis of a diterpene-benzoate macrolide of biogenetic relevance to the bromophycolide family of natural products.

Full text of DOI:10.1021/acs.orglett.0c00935

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pubs.acs.org/OrgLett
Letter
Relay Cross Metathesis for the Iterative Construction of Terpenoids
and Synthesis of a Diterpene-Benzoate Macrolide of Biogenetic
Relevance to the Bromophycolides
Karim A. Bahou, D. Christopher Braddock,* Adam G. Meyer, and G. Paul Savage
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ABSTRACT: We report a relay cross metathesis (ReXM) reaction
for the construction of terpenoids in an iterative protocol. The
protocol features the cross metathesis of a relay-actuated Δ6,7-
functionalized C10-monoterpenoid alcohol with C10-monoterpe-
noid citral to form a C15-sesquiterpene. Subsequent functional
group manipulation allows for the method to be repeated in an
iterative fashion. The method is used for the synthesis of a
diterpene-benzoate macrolide of biogenetic relevance to the
bromophycolide family of natural products.
erpenoids, consisting of “head-to-tail” and “head-to-head”
Tarrangements of five-carbon isoprene units, are a diverse
and very large class of linear and (poly)cyclic naturally
occurring biomolecules with more than 40,000 distinct
chemical structures, thereby accounting for approximately
60% of known natural products.1 They mediate vital biological
functions including light harvesting and photo-oxidative
protection, lipid membrane modulation, electron transport,
intercellular signaling as hormones, and interspecies defense
among others.2 Traditional herbal remedies from plants have
utilized the medicinal benefits of terpenoids for centuries,1
with the subsequent development of terpenoid derivatives
(e.g., steroidal medicines) as blockbuster drugs in the 20th
century through to the present day.3 While a comprehensive
account of their biogenesis is beyond the scope of this
document, it is important to note that (poly)cyclic terpenoids
all arise from their linear precursors.4 Nature assembles these
linear precursors by enzyme-mediated sequential addition of
C5 units of isopentenyl pyrophosphate (IPP) to (C5)n-terpenyl
pyrophosphates in the mevalonate pathway (Figure 1a).5
However, despite the long-term recognition that these linear
compounds are essentially C5-repeating isoprene units, a
general and iterative chemical protocol for their synthesis
using naturally occurring, terpenoid building blocksdoes not
exist.6 We recently reported an olefin cross metathesis reaction
between relay-actuated Δ6,7-functionalized monoterpenoid
alcohols with trisubstituted alkenes as partner olefins to form
new trisubstituted alkenes (Figure 1b).7 We now report that
the use of readily available and nonexpensive citral as the
partner olefina monoterpenoid with two electronically
distinguishable alkenesallows for the iterative construction
Figure 1. (a) Terpene biosynthesis via sequential addition of C5 units
of isopentenyl pyrophosphate (IPP). (b) Previously reported cross
metathesis reaction between relay-actuated Δ6,7-functionalized mono-
terpenoid alcohols with trisubstituted alkenes to form new
trisubstituted alkenes. (c) Relay cross metathesis for the iterative
construction of terpenoids.
Received: March 13, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00935
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
of terpenoids in line with the above aims (Figure 1c).8
Furthermore, we report the application of this method for the
synthesis of a diterpene-benzoate macrolide of biogenetic
relevance to the bromophycolide natural product family.
To commence our investigations enantiopure epoxide 2, as a
relay-actuated Δ6,7-functionalized monoterpenoid derivative,
was prepared from diol 17 using the method of Corey et al.
(Scheme 1).9 Using our previously identified conditions (10
mixtures, along with a triplet with a characteristic coupling
constant of 9.6 Hz that we attributed to 2,3-dihydrofuran,14
implicating ruthenium hydride-induced isomerization of the
expected 2,5-dihydrofuran byproduct.
Known hydride scavengers 1,4-benzoquinone (pBQ, entry
5) and AcOH (entry 6) were therefore explored as possible
additives for the reaction.15 Pleasingly, the use of AcOH was
beneficial, and C10-monoterpene epoxide 2 now underwent
smooth ReXM with C10-monoterpene citral (3) to provide
C15-sesquiterpene 4 in good yield (entry 6). The effect of
temperature (entries 7 and 8), equivalents of citral (3) (entry
9), and catalyst loading (entry 10) were also explored, with
lower yields obtained. Further addition of CuI16 (entry 11)
was found to be beneficial, as was increasing the catalyst
loading (20 mol %, entry 12). Increasing quantities of added
CuI and AcOH (entries 13−14) resulted in a higher yield,
providing a final optimized yield of 88% for this challenging
transformation. We note that the use of Grubbs II catalyst (5)
is important in this process: the use of the Hoveyda−Grubbs II
catalyst17 (entry 15) under conditions that worked well (cf.
entry 6) for catalyst 5 surprisingly gave only a low yield of
product from a complex product mixture.
Scheme 1. Synthesis of Relay-Modified Δ6,7-Functionalized
Monoterpenoid 2
mol % ruthenium benzylidene precatalyst 5,10 alkene [5 equiv],
50 °C, 1 h),7 attempted relay cross metathesis reaction11
between epoxide 2 and citral (3)12,13 to give C15-
sesquiterpenoid 4 using 5 was unsuccessful (Table 1, entry
1). Further attempts with 10 equiv of 3 (entry 2) or at room
temperature (entry 3) or with 2 mol % catalyst loading (entry
4) also failed. In these attempts, truncated olefin 6 was
observed in the 1H NMR spectra of the crude reaction
We then turned our attention to demonstrating that the
protocol is suitable for iteration (Scheme 2). Accordingly,
Scheme 2. Iterative Reduction-Allylation-ReXM
Table 1. ReXM of Relay-Actuated Δ6,7-Functionalized
a
Monoterpenoid 2 with Citral (3) Using GII Catalyst (5)
b
entry equiv of 3 mol % 5 T (°C)
additive(s) (mol %)
% yield
c
1
2
3
4
5
6
7
8
5
10
5
5
5
5
5
5
10
5
10
10
10
2
10
10
10
10
10
2
10
20
20
20
10
50
50
RT
50
50
50
70
RT
50
50
50
50
50
50
50
0
0
0
0
c
c
c
c
pBQ (20)
AcOH (20)
AcOH (20)
AcOH (20)
AcOH (20)
AcOH (20)
AcOH (20), CuI (15)
AcOH (20)
AcOH (20), CuI (30)
AcOH (40), CuI (30)
AcOH (20)
0
64
19
c
0
9
30
4
10
11
12
13
14
15
5
5
5
5
68
80
84
88
14
aldehyde 4 was reduced18 to alcohol 7 and O-allylated19 to
provide C15-relay metathesis substrate 8. A second ReXM with
citral (3), using the optimized conditions developed above,
now produced C20-diterpene 9,20 which could be readily
reduced to the C20-alcohol 10 as the first step of a further
iteration.
d
5
a
b
Reactions conducted on a 0.25 mmol scale. Isolated yields of
sesquiterpene 4 after chromatography; E/Z ratio determined as ca.
3:1 at the newly formed olefin (Δ6,7) and as ca. 2−3:1 at the α,β-
unsaturated aldehyde by 1H NMR and assigned on the basis of
characteristic 13C NMR shielded methyl resonances for E-isomers
(see the Supporting Information). Purification not attempted due to
complex mixtures of products. Hoveyda−Grubbs II catalyst
employed.
With the ability to synthesize enantiopure, Δ14,15 regiose-
lectively functionalized geranylgeraniol 10, we now targeted
diterpene-benzoate macrolide 19 (P = Et), pertinent as a
putative biogenetic precursor of the bioactive bromophycolide
halogenated natural product family (Scheme 3).21 Accordingly,
c
d
B
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Letter
Scheme 3. Synthesis of Diterpene-Benzoate Macrolide 19 (P = Et) Pertinent to the Bromophycolide Family of Natural
a
Products (cf. Structure of Bromophycolide A, Boxed, Bottom Left)
a
MNBA = 2-methyl-6-nitrobenzoic anhydride; DMAP = 4-dimethylaminopyridine.
aryl iodide 13 was produced in a two-step sequence from
ethylparaben 11. Alcohol 10 was converted to its bromide 15
and coupled to aryl iodide 13 to give diterpene-benzoate 16.
Alternatively, taking advantage of our previous observation7
that prenylbenzene was unreactive to the ReXM conditions,
geranyl benzoate 14 was combined in excess (5 equiv) with
relay sesquiterpenoid 8 to also provide diterpene-benzoate 16
in good yield. Subsequent ester hydrolysis gave acid 17 and
regioselective epoxide ring-opening with bromide gave
bromohydrin 18, which was readily separated away from its
minor bromohydrin regioisomer 18a. With the scene now set
for macrocyclization, we anticipated that the inseparable E/Z
alkene isomers that had built up in the ReXM iteration
sequence22 would become chromatographically distinguishable
upon conversion to conformationally constrained rings. Much
to our delight, Shiina macrolactonization23 of seco acid 18
proceeded with high conversion of substrate (91%) and
provided (E,E,E)-macrocycle 19 (P = Et) as the major
macrocyclic component (29%) which was readily separable
from the other more polar Z-olefin containing macrocycles.24
In conclusion, we have demonstrated the use of a relay cross
metathesis reaction between a relay-actuated Δ6,7-function-
alized monoterpenoid and citral as readily available, inex-
pensive and naturally occurring building blocks. This method-
ology allows the unprecedented construction of terpenoids in a
C5n to C5(n+1) fashion (from a monoterpene, to a sesquiterpene,
to a diterpene) via an iterative ReXM-reduction-relay
installation sequence. Although the iterative protocol neces-
sarily gives rise to geometrical mixtures of products because of
the current limitations of olefin metathesis catalysts for the
formation of geometrically pure trisubstituted olefins, we have
used the method to construct an enantiomerically and
geometrically pure diterpene-benzoate macrolide of relevance
to bioactive substances from marine organisms. The method
reported should allow for the synthesis of myriad bespoke
terpenes.25,26
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00935.
General experimental section; experimental details and
1
characterizing data for compounds; comparison of H
and 13C NMR shifts of E,E,E-19 (P = Et) vs E,E,E-19 (P
= MOM); copies of 1H and 13C spectra for all
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
D. Christopher Braddock − Department of Chemistry,
Molecular Sciences Research Hub, Imperial College London,
London W12 0BZ, United Kingdom; orcid.org/0000-0002-
4161-7256; Email: c.braddock@imperial.ac.uk
Authors
Karim A. Bahou − Department of Chemistry, Molecular Sciences
Research Hub, Imperial College London, London W12 0BZ,
United Kingdom; orcid.org/0000-0002-8302-5283
Adam G. Meyer − CSIRO Manufacturing, Jerry Price
Laboratory, Clayton, Victoria 3168, Australia
G. Paul Savage − CSIRO Manufacturing, Jerry Price
Laboratory, Clayton, Victoria 3168, Australia; orcid.org/
0000-0001-7805-8630
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00935
C
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Org. Lett. XXXX, XXX, XXX−XXX

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Letter
(15) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H.
Prevention of Undesirable Isomerization during Olefin Metathesis. J.
Am. Chem. Soc. 2005, 127, 17160−17161.
Notes
The authors declare no competing financial interest.
(16) Voigtritter, K.; Ghorai, S.; Lipshutz, B. H. Rate Enhanced
Olefin Cross Metathesis Reactions: The Copper Iodide Effect. J. Org.
Chem. 2011, 76, 4697−4702.
ACKNOWLEDGMENTS
■
We thank CSIRO and Imperial College London for a
studentship (to K.A.B.) and the EPSRC (Grant No. EP/
P030742/1 to D.C.B.) for financial support.
(17) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
Efficient and Recyclable Monomeric and Dendritic Ru-Based
Metathesis Catalysts. J. Am. Chem. Soc. 2000, 122, 8168−8179.
(18) Zeynizadeh, B.; Shirini, F. Mild and Efficient Reduction of α,β,-
Unsaturated Carbonyl Compounds, α-Diketones and Acyloins with
Sodium Borohydride/Dowex1-x8 System. Bull. Korean Chem. Soc.
2003, 24, 295−298.
(19) Rao, H. S.; Senthilkumar, S. P. A Convenient Procedure for the
Synthesis of Allyl and Benzyl Ethers from Alcohols and Phenols. Proc.
- Indian Acad. Sci., Chem. Sci. 2001, 113, 191−196.
(20) After the second iteration, it was no longer possible to
determine the three E:Z ratios at Δ2,3, Δ6,7, and Δ10,11 in compound 9
by NMR methods.
(21) The synthesis of macrocycle 19, as a MOM-protected phenol,
has previously been reported: (a) Lin, H.; Pochapsky, S. S.; Krauss, I.
J. A Short Asymmetric Route to the Bromophycolide A and D
Skeleton. Org. Lett. 2011, 13, 1222−1225. For the original isolation
of bromophycolides A−C, see: (b) Kubanek, J.; Prusak, A. C.; Snell,
T. W.; Giese, R. A.; Hardcastle, K. I.; Fairchild, C. R.; Aalbersberg,
W.; Raventos-Suarez, C.; Hay, M. E. Antineoplastic Diterpene-
Benzoate Macrolides from the Fijian Red Alga Callophycus serratus.
Org. Lett. 2005, 7, 5261−5264. For isolations of other members of
the family, see: (c) Kubanek, J.; Prusak, A. C.; Snell, T. W.; Giese, R.
A.; Fairchild, C. R.; Aalbersberg, W.; Hay, M. E. Bromophycolides C-I
from the Fijian Red Alga Callophycus serratus. J. Nat. Prod. 2006, 69,
731−735. (d) Lane, A. L.; Stout, E. P.; Lin, A.-S.; Prudhomme, J.; Le
Roch, K.; Fairchild, C. R.; Franzblau, S. G.; Hay, M. E.; Aalbersberg,
W.; Kubanek, J. Antimalarial Bromophycolides J-Q from the Fijian
Red Alga Callophycus serratus. J. Org. Chem. 2009, 74, 2736−2742.
(e) Lin, A.-S.; Stout, E. P.; Prudhomme, J.; Le Roch, K.; Fairchild, C.
R.; Franzblau, S. G.; Aalbersberg, W.; Hay, M. E.; Kubanek, J.
Bioactive Bromophycolides R-U from the Fijian Red Alga
Callophycus serratus. J. Nat. Prod. 2010, 73, 275−278.
(22) On the basis of an approximate 3:1 E:Z alkene ratio for each of
the two ReXM iterations and an approximate 2:1 E:Z alkene ratio for
olefin derived from the α,β,-unsaturated portion of citral (3), we
estimate (E,E,E)-16 to be the major component of the mixture at
37%.
(23) Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. An
Effective Use of Benzoic Anhydride and Its Derivatives for the
Synthesis of Carboxylic Esters and Lactones: A Powerful and
Convenient Mixed Anhydride Method Promoted by Basic Catalysts.
J. Org. Chem. 2004, 69, 1822−1830.
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15.9, and 15.0 ppm (for E-olefins) and the absence of 13C NMR
resonances between 22 and 24 ppm (for Z-olefins). See, e.g., for E-
and Z-8-(3,3-dimethyloxiran-2-yl)-6-methyloct-5-en-2-one:
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experiments previously conducted with nerol vs geraniol derived O-
allyl epoxides7 are consistent with this expectation.
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(14) However, despite the characteristic J value, the chemical shift of
4.12 ppm does not match the literature chemical shift of 4.30 ppm
(CDCl3). A referee suggested that this might instead be due to R2C
CHCH2CH2OCH[Ru] (from ring-opening of 2,3-dihydrofuran).
1
(25) H NMR, 13C NMR, IR, and MS data are available via a data
repository as Bahou, K. A.; Braddock, D. C. Imperial College HPC
Data Repository, 2019. DOI: 10.14469/hpc/6103 (accessed 2020-01-
29).
(26) The first version of this article was deposited to the ChemRxiv
preprint server on June 13, 2019. DOI: 10.26434/chem-
rxiv.8267837.v1.
D
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