Enzymatic Synthesis of Methylated Terpene Analogues Using the Plasticity of Bacterial Terpene Synthases

Article abstract of DOI:10.1002/chem.201905827

Methylated analogues of isopentenyl diphosphate were synthesised and enzymatically incorporated into methylated terpenes. A detailed stereochemical analysis of the obtained products is presented. The methylated terpene precursors were also used in conjunction with various isotopic labellings to gain insights into the mechanisms of their enzymatic formation.

Full text of DOI:10.1002/chem.201905827

A Journal of
Accepted Article
Title: Enzymatic Synthesis of Methylated Terpene Analogs Using the
Plasticity of Bacterial Terpene Synthases
Authors: Anwei Hou, Lukas Lauterbach, and Jeroen Sidney Dickschat
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COMMUNICATION
Enzymatic Synthesis of Methylated Terpene Analogs Using the
Plasticity of Bacterial Terpene Synthases
[
a]
[a]
[a]
Anwei Hou, Lukas Lauterbach and Jeroen S. Dickschat*
Abstract: Methylated analogs of isopentenyl diphosphate were
synthesised and enzymatically incorporated into methylated terpenes.
A detailed stereochemical analysis of the obtained products is
presented. The methylated terpene precursors were also used in
conjunction with various isotopic labellings to gain insights into the
mechanisms of their enzymatic formation.
the conversion of non-natural substrate analogs with additional
Me groups or heteroatoms.[12] This strategy can give a rapid and
potentially enantioselective access towards methylated or
functionalised terpene analogs, but previous work depended on
the chemical synthesis of the oligoprenyl diphosphate analogs.
Here we report on the stereoselective synthesis of homologated
IPP derivatives, the enzymatic incorporation into methylated GPP
and FPP analogs, and their TS-catalysed conversion into
nonnatural homoterpenes.
During the past decade the genome sequences of many bacteria
and fungi became available, which allowed for the discovery and
characterisation of various terpene synthases (TSs).[1-7]
Canonical TSs catalyse the conversion of isoprenoid
diphosphates with the general formula (C5nH8n+1)OPP including
dimethylallyl (DMAPP, n=1), geranyl (GPP, n=2), farnesyl (FPP,
n=3), geranylgeranyl (GGPP, n=4) and geranylfarnesyl
diphosphate (GFPP, n=5) into terpenes. For the larger precursors
(
n>1) the products are usually (poly)cyclic and contain multiple
stereogenic centres. The TS-catalysed transformations proceed
through substrate ionisation by abstraction of diphosphate or by
protonation, followed by a cationic cascade including cyclisation
reactions, hydride or proton migrations and skeletal
rearrangements. The cascade is terminated by deprotonation to
yield a terpene hydrocarbon (C5n
H8n) or by the addition of water
resulting in a terpene alcohol (C5n
H8n+2O). Deviations from these
general molecular formulae may point to non-canonical TSs that
can catalyse the cyclisation of methylated terpene precursors
(
Scheme 1), exemplified by 2-methylisoborneol (1) that is formed
by a methyltransferase (MT) through S-adenosyl-L-methionine
SAM) dependent methylation to 2-Me-GPP and cyclisation by a
(
[
8]
TS. For sodorifen (3) a MT catalyses a methylation-induced
cyclisation to presodorifen diphosphate (2), followed by a second
TS-dependent
cyclisation.[9]
The
recently
investigated
meroterpenoid longestin incorporates (4R,12R)-4,12-dimethyl-
GGPP (4) that is generated by methylation of isopentenyl
diphosphate (IPP) to (Z)-4-methyl-IPP, followed by a programmed
[
10]
skipped incorporation into the isoprenoid diphosphate chain.
14
Scheme 1. Biosynthesis of the homoterpenes A) 2-methylisoborneol (1), B)
sodorifen (3), C) (4R,12R)-4,12-dimethyl-GGPP (4), D) juvenile hormone II (5).
Based on the uptake of radioactivity from [1- C]propionate into
Manduca sexta juvenile hormone II (5) a biosynthetic hypothesis
by the passage of propionyl-CoA substituting for acetyl-CoA
through the mevalonate pathway was proposed.[11] Besides such
natural enzyme systems for the biosynthesis of homoterpenes,
several canonical TSs exhibit a remarkable plasticity that allows
For the enzymatic synthesis of homoterpenes, (E)-4-methyl-IPP
(
8a) was stereoselectively synthesised from (E)-2-bromobut-2-
ene (6a) by halogen-metal exchange with t-BuLi and addition to
oxirane to yield (E)-3-methylpent-3-en-1-ol (7a) (Scheme 2A).
Conversion into the corresponding tosylate and nucleophilic
substitution with (Bu N) HP O gave 8a. Its stereoisomer (Z)-4-
4 3 2 7
methyl-IPP (8b) was prepared via the same route starting from Z
configured 6b. Subsequently, DMAPP was elongated with 8a and
[
a]
Dr. Anwei Hou, Lukas Lauterbach, Prof. Dr. Jeroen S. Dickschat
Kekulé-Institute of Organic Chemistry and Biochemistry
University of Bonn
Gerhard-Domagk-Strasse 1
5
3121 Bonn, Germany
8b using the FPP synthase (FPPS) from Streptomyces coelicolor
A3(2),[13] followed by dephosphorylation with calf intestinal
Email: dickschat@uni-bonn.de
Supporting information for this article is given via a link at the end of
the document.
phosphatase (CIP). GC/MS analysis of the products suggested
that with both substrates 8a and 8b mainly only one extension
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step to 4-methyl-GPP (9) was catalysed, while only very small
13941 (TmS)[16] were selected, because these enzymes showed
amounts of double extension products were observed (Figure S1). a particularly effective conversion of their native substrates. While
A preparative scale incubation of DMAPP and 8a (100 mg each)
with FPPS followed by treatment with CIP allowed to isolate the
main product that was identified by NMR spectroscopy (Table S1,
Figures S2 – S8) as 4-methylgeraniol (11). GC analysis using a
chiral stationary phase revealed that the products 11 from 8a and
CpLS naturally accepts only GPP, but no FPP or GGPP, TmS
shows most efficient conversion of FPP and also accepts GPP,
but no GGPP. The main product obtained from GPP with purified
CpLS (Figure S19) was identified by GC/MS as linalool (13),
besides minor amounts of geraniol and a few trace compounds
(Figure S20). Compound 13 was obtained as a mixture of (R)- and
(S)-linalool (81:19, 60% ee, Scheme 3A), as determined by chiral
GC in comparison to authentic (R)-13 (Figure S21). TmS
converted GPP into a mixture of geraniol, (R)- and (S)-13 (66:34,
33% ee), -myrcene and a few minor compounds (Figures S20
and S21). CpLS and TmS were used in this study to obtain the
poorly described 4-methyllinalools[17] and to solve the difficult
problem of their configurations.
8b were enantiomers and were obtained in high enantiomeric
purity (Figure S9). The elongation of GPP with 8a and 8b using
FPPS also resulted in the two enantiomers of 4-methyl-FPP (10)
with high enantiomeric purity, as demonstrated by
dephosphorylation with CIP followed by GC/MS and
enantioselective GC analysis (Figures S10 and S11).
A
preparative scale reaction with 8a and product isolation for
structure elucidation by NMR (Table S2, Figures S12 – S18)
confirmed the structure of 4-methylfarnesol (12). Its optical
2
0
rotation []
D
2 2
= –6.0 (CH Cl , c 0.25) allowed to assign the
absolute configuration of (S)-4-methylfarnesol (12a) for the
product from 8a by comparison to literature data for the same
enantiomer ([]
D
= –10.7, hexane),[ and consequently (R)-12b
14]
was obtained from 8b. Based on the same sign for the optical
2
0
rotation []
D
2 2
= –5.5 (CH Cl , c 0.2) of 11a formed from 8a, and
on the same GC elution order on a chiral stationary phase,
analogous absolute configurations were assigned for (S)-11a and
(
R)-11b. These findings are in agreement with the classical
experiments regarding FPP biosynthesis that demonstrated Si
face attack at C4 of IPP (because of a change in priority orders
this corresponds to the 4Re face of 8a and the 4Si face of 8b).[15]
Scheme 3. Enzyme reactions with CpLS and TmS. Conversion of A) GPP into
13, B) enzymatically prepared 9a and 9b into diastereomeric mixtures of 14,
and C) cyclisation of 14 with Grubbs II (G-II) catalyst.
The incubation of DMAPP and 8a with FPPS and CpLS gave the
two stereoisomers (3S,4S)-14a and (3R,4S)-14a’ (dr 35:65),
while the same reaction with 8b yielded (3R,4R)-14b and (3S,4R)-
14b’ (dr 12:88) (Scheme 3B). Their configurations at C4 were
inferred from the stereostructures of 9a and 9b, but it could not be
assigned at this stage which stereoisomer is major and which one
is minor, because for the acyclic compounds it was not possible
to determine the relative configuration at C3 by NOESY. For full
structure elucidation the racemic mixture of all four stereoisomers
of 14 was synthesised (Scheme S1) and separated by chiral GC
Scheme 2. Preparation of both enantiomers of 4-methyl-GPP (9ab) and 4-
methyl-FPP (10ab). A) Chemical synthesis of (E)- and (Z)-4-methyl-IPP (8ab).
B) Enzymatic coupling of DMAPP and GPP with 8ab by FPPS.
In subsequent experiments bacterial terpene synthases were
investigated for their potential to convert the methylated GPP and
FPP analogs into methylated terpenes. For this purpose, a newly
identified linalool synthase from Chryseobacterium polytrichastri
DSM 26899 (CpLS, accession number WP_073293738) and the
known T-muurolol synthase from Roseiflexus castenholzii DSM
(
Figure S22). This stereoisomeric mixture was then converted into
the corresponding stereosiomers of 15 using the Grubbs II
catalyst, followed by isolation of (1R*,5S*)-15ab and (1S*,5S*)-
15a’b’ by column chromatography (Scheme 3C), for which the
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Scheme 4. Enzymatic conversions with TmS. A) Cyclisation mechanism from
FPP to 16, B) products obtained from 10a and 10b with TmS. Carbon
numberings for 18 – 22 as for 16, the additional Me group is numbered C16.
relative configurations were solved by NMR spectroscopy (Tables
S3 and S4, Figures S23 – S36). The stereoisomeric mixture of 14
was separated by chiral HPLC, giving access to two pure
stereoisomers of 14 that were identical to the minor enzyme
product from 8a with 4S and the major enzyme product from 8b
with 4R configuration, while the remaining two stereoisomers
coeluted (Figure S37). NMR spectroscopy of the pure
stereoisomers confirmed that they were diastereoisomers (Tables
S5 and S6, Figures S38 – S51). The Grubbs II cyclisation of (4S)-
TmS converts FPP into T-muurolol (16) through a cascade with
isomerisation to NPP, followed by cyclisation to A, a 1,3-hydride
shift to B, cyclisation to C and attack of water (Scheme 4A). The
installation of the stereocentre at C7 in A is explained by FPP
isomerisation through syn-allylic transposition to (R)-NPP and
14 yielded a product with the same retention time as one of the
N
anti-S 2’ attack with 1Re,10Re cyclisation, with a defined
enantiomers of (1R*,5S*)-15ab on a chiral GC phase (Figure S52),
establishing the full structure of (1R,5S)-15 for this material and,
conclusively, of (3S,4S)-14 for its precursor, the minor enzyme
product from 8a. Thus, the major product is (3R,4S)-14. Similarly,
stereochemical course for the enantiotopic C1 hydrogens of FPP.
As a consequence, the 1-pro-S hydrogen of FPP selectively
migrates into the iPr group of B, as demonstrated experimentally
by enantioselective deuteration of FPP.[
18]
(
4R)-14 was converted into a product with the same retention time
as one of the enantiomers of (1S*,5S*)-15a’b’, thus identified as
1R,5R)-15. In conclusion, its precursor (3S,4R)-14 is the major
GPP in conjunction with 8a or 8b was efficiently converted by
FPPS and TmS, however, the observed product selectivity of
TmS was much lower than with FPP and in both cases complex
mixtures of sesquiterpenes were formed (Figure S53). From
substrate 8a, (S)-4-methyl-(E)--farnesene (17), (3S)-3-methyl-T-
muurolol (18) and its epimer (3S)-3-methyl-10-epi-T-muurolol (19),
formed by attack of water from the opposite face at C10 of a cation
C analog, were isolated (Scheme 4B), while the conversion of 8b
yielded (3R,4R,7R)-3-methyl-4-hydroxygermacra-1(10),5-diene
(
and (3R,4R)-14 is the minor enzyme product from 8b.
With 9b a high diastereoselectivity is observed for CpLS, even
higher than its enantioselectivity with GPP, with attack of water at
C3 preferentially from the substrates’ Re faces at C3 in both cases,
while the selectivity with 9a is poor with attack of water mainly
from the Si face. With TmS 9a was converted into (3R,4S)-14a’
and (3S,4S)-14a, while from 9b the products (3R,4R)-14b and
(
20), (3R)-3-methyl-1,6-diepi-T-muurolol (21) and (1S,3R,10S)-3-
(
3S,4R)-14b’ were obtained (Figure S22). For this enzyme the
methylzonarene (22) (NMR data: Tables S7 – S12 and Figures
S54 – S95). For all these molecules the configurations at C3 were
deduced from the structure of their precursor 10a or 10b, while
the relative orientation of the additional stereocentres in
compounds 18 – 22 was determined by NOESY spectroscopy,
ultimately allowing for full structure elucidation of all six
compounds (for 19 vide infra).
attack of water at C3 of 9a and 9b proceeds with good to high
diastereoselectivity mainly at the Si face, while for GPP Re face
attack is preferred. These data suggest that the conformations of
9a and 9b in the active sites of CpLS and TmS in comparison to
GPP are strongly influenced by the additional 4-Me group.
During the biosynthesis of 18 – 22 a similar 1,3-hydride shift as
from cation A to B can be assumed. To investigate this hydride
2
2
migration, (1,1- H
(
2 2
)-8a and (1,1- H )-8b were synthesised
1
3
[19]
Scheme S2A) and enzymatically converted with (7- C)GPP
by FPPS and TmS. 13C-NMR analysis of the obtained products
established the proposed hydride migrations by slightly upfield
shifted triplets for C11, indicating a direct 13C- H bond (Figures
S96 and S97). The hydride migrations were further supported by
GC-EIMS analysis in which the iPr groups of 18 – 22 are lost by
2

(
-cleavage, allowing to locate deuterium within this group
Figures S98 and S99). The specific migration of the enantiotopic
C1 hydrogens in FPP in the 1,3-hydride shift from A to B depends
on the configuration at C7 of A, with migration of H for (S)-A and
of H
for (R)-A.[18] Conclusively, if the stereocentre at C7 is
retained in the final product, the fate of H and H can serve as a
S
R
S
R
marker to determine absolute configurations. This strategy was
also applied to the methylated sesquiterpene analogs obtained
13
2
with TmS by synthesis of (R)- and (S)-(1- C,1- H)-8a, and (R)-
1
3
2
and (S)-(1- C,1- H)-8b (Scheme S2B) that were all obtained in
high enantiomeric purity (Figure S100). Their incubation with GPP,
FPPS and TmS showed for 18 – 22 migration of the 1-pro-S
hydrogen of 10a or 10b into the iPr group (Figures S101 and
S102), while the 1-pro-R hydrogen remains bound to C6 of 18 –
2
(
1, which further supports their assigned absolute configurations
Figures S103 and S104). Only for 22 the deuterium label ends
up in a neighbouring position (C1) as indicated by a characteristic
 = –0.07 ppm for the labelled carbon (Figure S105). For 17 a

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COMMUNICATION
specific stereochemical course for the C1 hydrogens was
observed by product analysis through HSQC spectroscopy,
Keywords: terpenoids • substrate analogs • enzyme catalysis •
isotopes • configuration determination
revealing that the 1-pro-R hydrogen ends up in the H1
Z
and the 1-
pro-S hydrogen in the H1 position (Figure S106), which supports
E
[
1]
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its enzymatic formation and reflects the situation in the
intermediate (R)-NPP towards 16 (Scheme 4A). For the
biosynthesis of 22 another 1,2-hydride shift from C6 to C7 of 10b
was assumed. Direct evidence for this step was obtained by
[2]
[3]
M. B. Quin, C. M. Flynn, C. Schmidt-Dannert, Nat. Prod. Rep. 2014, 31,
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1
3
2
[5]
incubation of (3- C,2- H)GPP and 8b with FPPS and TmS,
resulting in an upfield shifted triplet for C10 of 22 as a result of
[
[
[
6]
7]
8]
D. W. Christianson, Chem. Rev. 2017, 117, 11570.
R. J. Peters, Nat. Prod. Rep. 2010, 27, 1521.
1
3
2
C- H spin coupling (Figure S107). The terminal deprotonation to
a) J. S. Dickschat, T. Nawrath, V. Thiel, B. Kunze, R. Müller, S. Schulz,
Angew. Chem. Int. Ed. 2007, 46, 8287; b) M. Komatsu, M. Tsuda, S.
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[20]
this compound was followed by incubation of (2- H)DMAPP,
IPP and 8b with FPPS and TmS. The main product of this reaction
2
was (7- H)-16, but unlabelled 22 was also detected (Figure S108).
[
[
9]
It is well known that the elongation of oligoprenyl diphosphates
with IPP proceeds with inversion of configuration at C1 of the allyl
diphosphate[21] and Si face attack at C4 of IPP.[15] As discussed
11855.
above, the face selectivity regarding the IPP analogs 8a and 8b
10] T. Ozaki, S. S. Shinde, L. Gao, R. Okuizumi, C. Liu, Y. Ogasawara, X.
is the same. To investigate whether also configuration inversion
Lei, T. Dairi, A. Minami, H. Oikawa, Angew. Chem. Int. Ed. 2018, 57,
13
at C1 of the allyl diphosphate occurs, (R)- and (S)-(1- C,1-
2H)GPP[22] and 8a or 8b were incubated with FPPS and TmS.
HSQC analysis of the obtained products revealed selective
6629.
[11] D. A. Schooley, K. J. Judy, B. J. Bergot, M. S. Hall, J. B. Siddall, Proc.
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ChemBioChem 2007, 8, 1826; c) O. Cascón, S. Touchet, D. J. Miller, V.
Gonzalez, J. A. Faraldos, R. K. Allemann, Chem. Commun. 2012, 48,
deuterium incorporation into H2

of 18, 20 and 22 from (R)- and
13
2
into H2

from (S)-(1- C,1- H)GPP (Figures S109 – S111), in
agreement with configurational inversion. Based on these findings,
an NMR data assignment for the diastereotopic C5 hydrogens of
9702; d) S. Touchet, K. Chamberlain, C. M. Woodcock, D. J. Miller, M. A.
17 was possible (Figure S112). Also the NMR shifts of the C2
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hydrogens of 19 could be assigned (Figure S113), which allowed
for its unambiguous configuration determination, that was without
this information obscured by the identical chemical shifts of H1
and H2
1 with almost identical chemical shifts were distinguished (Figure
S114, 1.75 ppm for H2 and 1.72 ppm for H2 ).

. Through this labelling strategy also the C2 hydrogens of
[
2


[
14] T. Koyama, K. Ogura, S. Seto, J. Am. Chem. Soc. 1977, 99, 1999.
15] J. W. Cornforth, R. H. Cornforth, G. Popjak, L. Yengoyan, J. Biol. Chem.
In summary, we have demonstrated that methylated IPP analogs
can be enzymatically incorporated into methylated terpenes,
giving access to a chemical space that is naturally realised only
in a few known cases. The incorporation sites of the extra Me
groups set a stereochemical anchor in the products that allows to
assign their absolute configurations. In conjunction with labelling
experiments complex and interesting stereochemical problems
and enzyme mechanistic aspects can be solved. We will extend
this work in the future using further IPP analogs and TSs for the
enzymatic synthesis of methylated terpenes.
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Acknowledgements
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This work was funded by the DFG (DI1536/7-1). We thank
Andreas Schneider for HPLC purifications.
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Chemistry - A European Journal
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COMMUNICATION
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The methylated IPP analogs (E)- and
Anwei Hou, Lukas Lauterbach and
(
Z)-4-methyl-IPP were synthesised
Jeroen S. Dickschat*
and incorporated into terpenes by
enzymatic reactions with FPP
synthase and terpene synthases,
yielding methylated mono- and
sesquiterpenes. The cyclisation
mechanisms towards the obtained
nonnatural terpene analogs were
studied using isotopically labelled
natural terpene precursors and their
methylated analogs.
Page No. – Page No.
Enzymatic Synthesis of Methylated
Terpene Analogs Using the Plasticity
of Bacterial Terpene Synthases
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