Metal catalysed versus organocatalysed stereoselective synthesis: The concrete case of myrtucommulones

Article abstract of DOI:10.1016/j.tet.2017.10.011

Myrtucommulones belong to a class of pharmacologically active natural compounds which offer various alternatives to the treatment of pain, inflammation and cancer. Their stereoselective synthesis remains therefore a key-challenge towards its use in the pharmaceutical industry. In the present work myrtucommulone A and B were synthesised through metal catalysis with 81 and 72% ee respectively. Thanks to the use of cinchonidine as an organocatalyst, 82 and 84% de were reached for myrtucommulone A and myrtucommulone F respectively. Simultaneously, a new synthetic method emerged and gave access to new range of possibilities for the preparation of myrtucommulone derivatives under mild conditions or through a one-pot reaction.

Full text of DOI:10.1016/j.tet.2017.10.011

Accepted Manuscript
Metal catalysed versus organocatalysed stereoselective synthesis: The concrete case
of myrtucommulones
Maël Charpentier, Johann Jauch
PII:
S0040-4020(17)31026-8
10.1016/j.tet.2017.10.011
TET 29014
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 25 May 2017
Revised Date: 1 October 2017
Accepted Date: 6 October 2017
Please cite this article as: Charpentier Maë, Jauch J, Metal catalysed versus organocatalysed
stereoselective synthesis: The concrete case of myrtucommulones, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.10.011.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Metal catalysed versus organocatalysed stereoselective synthesis: the concrete case of
myrtucommulones.
Maël Charpentiera, Johann Jaucha,
a Organische Chemie II, Universität des Saarlandes, Campus C4.2, 66123 Saarbrücken, Germany
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Myrtucommulones belong to a class of pharmacologically active natural
compounds which offer various alternatives to the treatment of pain, inflammation
and cancer. Their stereoselective synthesis remains therefore a key-challenge
towards its use in the pharmaceutical industry. In the present work myrtucommulone
A and B were synthesised through metal catalysis with 81 and 72 % ee respectively.
Thanks to the use of cinchonidine as an organocatalyst, 82 and 84 % de were reached
for myrtucommulone A and myrtucommulone F respectively. Simultaneously, a new
synthetic method emerged and gave access to new range of possibilities for the
preparation of myrtucommulone derivatives under mild conditions or through a
one-pot reaction.
Available online
Keywords:
Asymmetric synthesis
Natural product
Michael addition
Organocatalysis
Multicomponent reaction
Metal catalysis
2009 Elsevier Ltd. All rights reserved
.
———
Corresponding author. Tel.: +49-(0)681-302-64301; Fax: +49-(0)681-30264151; e-mail: j.jauch@mx.uni-saarland.de

2
ACCEPTED MANUSCRIPT
Tetrahedron
1. Introduction
tautomers are stabilised through hydrogen bonding in “open-
chain” derivatives such as 1 and 7, making the NMR and HPLC
analyses very complicated.10
Extracts from myrtle (Myrtus communis) (leaves, branches
and berries) have been used in the Mediterranean region since the
antiquity for their healing properties. 1 In 1974, Kashman et al. 2
isolated two until then unknown acyl phloroglucinol derivatives
from this evergreen shrub, which they named myrtucommulone
A (MCA) (1) and B (MCB) (2) (Fig. 1). Although MCA (1)
could be also isolated from Callistemon lanceolatus shortly after,
This efficient and direct synthesis led to the identification of
several new myrtucommulone analogues with excellent
pharmaceutical properties.10,12 Despite the attractiveness of this
class of compounds for an industrial implementation (myrtle
extracts are already used in some dermatologic preparations6b),
the hazardous synthetic conditions can be a drawback for the
preparation of myrtucommulones by pharmaceutic companies. In
this regard, we judged useful to develop a one-pot synthesis of
myrtucommulones under mild conditions.
3
the interest in this compound family clearly raised in the last
twenty years when more than thirteen new myrtucommulones
(named MCA to MCM) were discovered either in Myrtle4 or in
Corymbia scabrida from Australia.5
The stereoisomeric composition of MCA (1) isolated from
natural sources has long remained undefined but it has been
recently shown that natural MCA (1) is an 1:1 mixture of the
meso-form and the racemate.13
O
O
O
OHHO
OHHO
O
O
O
OH
O
OH
O
O
OH
In our previous work towards the asymmetric synthesis of
MCA (1), we could achieve the first enantioselective synthesis of
myrtucommulone-like structures with up to 62 % enantiomeric
excess (ee) for MCB (2) and 70 % ee for (R,R)-MCA (1)
(Scheme 2).14 However, no pronounced diastereoselectivity was
observed and both diastereomers 1a and 1b were always
synthesised in almost equal amounts. The reactions were carried
out in presence of several equivalents of an aluminium-lithium-
BINOL (ALB) (9a) complex developed by Shibasaki and easily
prepared by mixing 1,1'-bi-2-naphthol (BINOL) (10) and
LiAlH4.15 These unusual conditions were necessary due to the
presence of the three hydroxyl groups in isobutyryl
phloroglucinol (6) and the very fast background reaction
(uncatalysed, leading to a 1:1 mixture of racemate and meso-
form). The ees may look moderate at first sight but they were
obtained despite the steric hindrance caused by the isopropyl
groups. Usually, any kind of sterically hindered substrate leads to
a poorer yield or ee as found in the literature.16 Through the
synthesis of the intermediate 7 it was also possible to direct the
stereoselectivity to one or the other enantiomer by choosing the
corresponding enantiomer of BINOL (10). In this way, the
myrtucommulone derivative (-)-(R)-7 was synthesised thanks to
the use of (S,S)-ALB ((S,S)-9a) and could be cyclised to
(+)-(R)-MCB ((+)-(R)-2) as shown in Scheme 2. Conversely,
(+)-(S)-7 was obtained through the use of (R,R)-ALB ((R,R)-9a)
and dehydrated to its cyclic derivative (-)-(S)-2. The cyclisation
process is very important as it allows the characterisation and
separation of the enantiomers.17
2
1
Fig. 1. Structures of myrtucommulones A (MCA) (1) and B (MCB) (2).
These compounds exhibit
a very rich pharmaceutical
potential: they show very good anti-bacterial activity,2,4a-b,6
inhibit inflammatory processes,7 and induce apoptosis in cancer
cells.4b,8 Other anti-oxidative4c,9and anti-hyperglycemic4a
properties are also known.
As an answer to the raising interest for this class of
compounds, our group developed in 2010 the first total synthesis
of myrtucommulones A and B as well as some analogues
therof.10 In this short synthesis, the Michael acceptor,
isobutylidene syncarpic acid (3) was prepared through a
Mannich reaction of syncarpic acid (4) and isobutyraldehyde (5)
followed by an elimination (Scheme 1).11 In order to avoid
isomerisation to the dienol iso-3, 3 had to be prepared shortly
before use. Then MCA (1) was synthesised in one step through a
Michael addition of isobutyryl phloroglucinol (6) on the freshly
prepared Michael acceptor 3 in the presence of sodium hydride
(Scheme 1). An important aspect of this synthesis is the
possibility to isolate the intermediate Norsemimyrtucommulone
(NSMC) (7). Hence, MCA (1) can be synthesised in two high
yielding steps allowing the successive formation of the
stereogenic carbon atoms. In order to produce cyclic derivatives
such as MC B (2) or pentacyclic MCA (PMCA) (8), 7 and 1 were
respectively dehydrated in hot toluene in the presence of pTsOH
(Scheme 1). This process is crucial since numerous rotamers and
O
O
O
1) NaH (2.5 eq.)
THF, rt, 10 min
OH
O
HO
OH
O
OHHO
OH
O
O
OH
pTsOH·H2O
2) 3 (1.5 eq.)
THF, rt, 1h,
88 %
toluene, 95°C
1h, 49-82 %
O
O
OH
O
OH
OH
O
4
6
7
2
1)
H
N
H
1) NaH (2,5 eq.)
THF, rt, 10 min
2) 3 (3.0 eq.)
CH2Cl2, rt, 10 min
1) NaH (2,5 eq.)
THF, rt, 10 min
2) 3 (6.0 eq.)
THF, rt, 1h,
95 %
2) 1M HCl/NH4Cl
CH2Cl2, rt, 10 min
THF, rt, 1h, 92 %
O
O
O
OH
O
O
pTsOH·H2O
O
O
OHHO
OHHO
O
O
O
O
toluene, 95°C
1h, 62-95 %
O
O
O
OH
O
O
OH
O
3
iso-3
1
8
Scheme 1. Synthesis of the precursor 3, MCA (1) and its cyclic derivative 8, as well as NSMC (7) and its cyclic derivative MCB (2).

ACCEPTED MANUSCRIPT
O
O
O
1) (S,S)-9a (3.0 eq.)
THF, rt, 10 min
HO
OH
O
OHHO
OH
O
O
OH
pTsOH·H2O
OH
OH
2 x
2) 3 (1.5 eq.)
THF, 0°C, 1.5h,
55 %
toluene, 95°C
1h, 49-82 %
OH
O
OH
O
OH
(-)-(R)-7 (62 % ee)
(+)-(R)-2 (62 % ee)
6
(S)-10
1) (R,R)-9a (3.0 eq.)
THF, rt, 1h
LiAlH4
THF, 1h, rt
2) 3 (3.3 eq.)
THF, 0°C →rt, 14h, 77 %
O
O
Li
O
OHHO
OHHO
O
O
OHHO
OHHO
O
O
O
O
O
Al
+
O
OH
(R,R)-1a (70 % ee)
O
O
OH
meso-1b
O
(S,S)-9
Scheme 2. Enantioselective Synthesis of MCA (1) and MCB (2) in presence of the aluminium complex 9a.
In order to improve the stereoselectivity of the reaction we
further investigated the metal catalysed enantioselective synthesis
of MCA (1) and MCB (2). Interestingly, it was not possible to
influence the diastereomeric ratio (dr) through metal catalysis.
Therefore, we turned to organocatalysis to achieve our goal. We
Surprisingly, the reaction between isobutyryl phloroglucinol
(6) and isobutylidene syncarpic acid (3) catalysed through the
aluminium-sodium-BINOL-catalyst (9b) showed no stereo-
selectivity (Tab. 1, entry 2). This underlines the prime
importance of lithium in our reaction.
could develop
a proline catalysed one-pot synthesis of
To learn more about the influence of the central metal,
titanium- (9c)19 and lanthanum-BINOL (9d)20 complexes were
prepared but again, no significant enantioselectivity could be
observed (Tab. 1, entry 3-4). We focused next on the shape of the
ligand and replaced BINOL (10) by the well-known TADDOL in
the complex 9e (Tab. 1, entry 5) or by different brominated
BINOLs like in the reagents 9f, 9g and 9h (Tab. 1, entry 6-8).21
Another so-called linked-BINOL was synthesised as well and
used in 9i and 9j for the formation of NSMC (7) (Tab. 1, entry 9-
10).22 Although the 6-bromo-BINOL-aluminium complex 9h led
to an interesting ee of 61 %, these variations of the ALB (9a)
complex could not improve the 62 % ee reached before.14
myrtucommulones as well as the first diastereoselective synthesis
of MCA (1).
2. Results
2.1. Metal Catalysis
Heterobimetallic complexes are catalysts of choice for many
C-C bond forming reactions such aldol addition, Michael
addition, or Friedel-Crafts reactions.18 Based on our previous
work in which ALB (9a) provided NSMC (7) with 62 % ee (Tab.
1, entry 1) we varied the structure of this bimetallic complex to
form the reagents depicted in the Fig. 2. We first concentrated on
the counterion taking into account the results from Shibasaki that
showed that the exchange of lithium through sodium in the
catalyst 9a had no influence on the enantioselectivity of the
Michael reaction between cyclohexenone and dibenzyl-
malonate.15a
O
O
O
O
1O
M
M2
Li
O
O
Li
O La
O
O
O
Tab. 1. Variation of the metal complex structure.
Li
9i: M1 = Al, M2 = Li
9j: M1 = La, M1 = H
O
O
1) 9 (3.0-3.3 eq)
THF, rt, 1h
HO
OH
O
OHHO
OH
9d
2) 3 (1.5 eq.)
THF, 0°C, 1.5h
R2
R1 R1
R2
OH
O
O
O
OH
H
H
M2
Ph
Ph
Ph
(S)-7
6
O
O
1O
Ph
M
O
O
O
O
O
Entry
Reagent
Formula
Yield (%)
eea
62b
2
Li
Al
1
2
(S,S)-
9
9
9
9
9
9
9
9
a
AlLi(BINOL)2
55
72
79
60
37
72
88
69
62
66
R3
R1 R1
R3
Ph
Ph
Ph
(R,R)-
b
AlNa(BINOL)2
Ti(BINOL)2
Ph
9b: M1 = Al, M2 = Na, R1 = H, R2 = H, R3 = H
9c: M1 = Ti, R1 = H, R2 = H, R3 = H
9f: M1 = Al, M2 = Li, R1 = Br, R2 = H, R3 = H
9g: M1 = Al, M2 = Li, R1 = H, R2 = Br, R3 = Br
9h: M1 = Al, M2 = Li, R1 = H, R2 = Br, R3 = H
H
H
3
(R,R)-
c
1
O
O
4
(S,S,S)-
d
LaLi3(BINOL)3
6
5
(R,R)-
e
AlLi(TADDOL)2
AlLi(3,3’-Br2BINOL)2
AlLi(6,6’-Br2BINOL)2
AlLi(6-BrBINOL)2
AlLi(linked-BINOL)
La(linked-BINOL)
4
9e
6
(R,R)-
f
5
Fig. 2. Structures of the different metal complexes used for the synthesis of
7
(R,R)-
g
41
61
0
NSMC (7).
8
(R,R)-
h
We therefore optimised the reaction conditions for the use of
ALB (9a) and first modified the temperature of the reaction. The
temperature issue is tricky since a higher temperature than 0°C
favours the second addition of the Michael acceptor 3 and the
synthesis of MCA (1), unwanted at this point. This leads to the
formation of a mixture of both NSMC (7) and MCA (1) in poor
9
(S,S)-
9
9
i
10
(S,S)-
j
47b
a) determined after cyclisation to 2 by chiral HPLC analysis on CHIRALCEL OD-H,
iPrOH/n-hexane 20:80, 0.5-0.6 mL/min, 15°C; b) in this case, the R enantiomer was
formed predominantly.

4
ACCEPTED MANUSCRIPT
Tetrahedron
yields.23 On the other hand reaction at lower temperature prevents
the formation of MCA (1) but slows the synthesis of NSMC (7)
without increasing the ee (Tab. 2, entry 1).
Consequently, we applied our newly found reaction conditions
to the formation of MCA (1) to form (R,R)-MCA ((R,R)-1) with
81 % ee (Scheme 3). Despite our efforts, the metal catalysed
synthesis of MCA (1) remained unselective concerning the dr
regardless of the catalyst used.23
In most examples of metal catalysis, the choice of the solvent
is crucial for yield and selectivity. In the case of
myrtucommulones though, the starting materials and products are
very polar which strongly restricts the choice of solvents. Our
efforts with toluene only resulted in a mixture of undissolved
material.23 After the reagent 9a was prepared in THF, we isolated
it and suspended it in CH2Cl2 to perform the Michael addition but
no improvement of yield or stereoselectivity was observed
compared to the reaction in THF (Tab. 2, entry 2). We could
nonetheless find out that a 10:1 (v:v) mixture of CH2Cl2 and THF
(DT101) clearly improved the yield of the reaction (Tab. 2, entry
3).
2.2. Organocatalysis
2.2.1. One-pot synthesis
In recent years, synthetic chemists have shown a growing
interest for the use of organocatalysts due to their cost-
effectiveness and environmental friendliness.25 Proline (11) and
other amino acids belong to the most studied ones and were
shown to catalyse a broad variety of organic reactions including
Mannich and Michael reactions.26 In some cases proline is also
known to catalyse a Knoevenagel condensation and a subsequent
Michael addition on Meldrum’s acid (12).27 A very pertinent
example is the dihydroxycoumarin synthesis published by Nair in
1987 where Meldrum’s acid (12), phloroglucinol and
benzaldehyde are simply heated together in the presence of
proline.28 To our knowledge, however, no such multicomponent
reaction cascade has been described for SA (4) despite its
similarity with Meldrum’s acid.29
Tab. 2. Variation of the reaction conditions for the formation of NSMC (7).
O
O
1) 9a (3.0-3.3 eq.)
Solvent, rt, 1h
HO
OH
O
OHHO
OH
2) 3 (1.5 eq.)
Solvent, T
OH
O
OH
6
In the synthesis from 2010,10 Jauch et al. prepared the Michael
acceptor 3 in two steps, by first stirring the starting materials in
CH2Cl2 and then performing an acidic work up (see Scheme 1).
Through the use of proline (11) (0.5 eq.) in EtOH, isobutylidene
syncarpic acid (3) could be eventually prepared in one step
(Scheme 4). Remarkably, the isomerisation did not happen as
quickly as previously observed, the protic solvent and the acidic
hydrogen of proline probably shift the equilibrium to the side of
3. This allowed longer reaction times and the use of smaller
amounts of the Michael acceptor than in our previous procedure.
(R)-7
Entry
Reagent
(R,R)-
Solvent
THF
T (°C)
-20°C
0°C
time (h)
14h
yield (%)
eea
1
2
3
4
5
9
a
65
62
88
81
81
62b
(S,S)-
(S,S)-
(S,S)-
9a
CH2Cl2
DT101c
DT101c
DT101c
1.5h
63
9
9
a
0°C
1.5h
62
ad
0°C
1.5h
50
72b
(R,R)-
9
a
0°C
1.5h
a) determined after cyclisation to 2 by chiral HPLC analysis on CHIRALCEL OD-H,
iPrOH/n-hexane 20:80, 0.5-0.6 mL/min, 15°C; b) in this case, the S enantiomer was
formed predominantly; c) 2.45 eq. of BINOL (10) were used in the preparation of the
reagent; c) DT101 = mixture of dichloromethane and THF 10:1 (v/v); d) prepared with
LiAlH4 from a freshly opened bottle of a LiAlH4-solution in THF.
When isobutyryl phloroglucinol (6) was added to the mixture
directly after the formation of the acceptor 3, it reacted
immediately to give the intermediate 7 and, after several hours,
MCA (1) was obtained (Method A). Higher amounts of proline
(11) led to higher yield and shorter reaction times (Tab. 3, entry
1-2). By mixing isobutyryl phloroglucinol (6), isobutyraldehyde
(5), syncarpic acid (4), and proline (11) in one single vial, we
could achieve the first one-pot synthesis of MCA (1) (Method B,
Tab. 3, entry 3-4) in 24h with 66 % yield. The slight loss of yield
here is due to the competing reactions of syncarpic acid (4) and
isobutyryl phloroglucinol (6) with the aldehyde 5. Indeed, both
nucleophiles can add on the electrophile 5 but only the
intermediate 3 leads to the formation of the desired products.
We then tested the reagent used by Feringa et al.24 for their
Michael addition of α-nitroesters to α,β-unsaturated ketones, in
which 2.45 eq. of BINOL (10) are added in regard to the amount
of LiAlH4. Unlike the literature, we observed a decrease of
enantioselectivity (50 % ee) with the “enhanced” ALB-catalyst
(Tab. 2, entry 3). Eventually the highest ee of 72 % was reached
when 2 eq. of BINOL (10) were used and LiAlH4 was taken from
a fresh bottle of a 1.0 M solution in THF (Tab. 2, entry 5).
The fact that many metal catalysts are inefficient in the case of
NSMC (7) and that the choice of temperature and solvents is very
restricted, highlights the difficulty that has to be faced when
fundamental methods are applied to a practical example such as
the myrtucommulones. Nevertheless, we could synthesise the
intermediate 7 (and hence MCB (2)) with 72 % ee which is, in
comparison with the literature,16 rather good considering such a
Tab. 3. Investigation of the Methods A and B to synthesise MCA (1).
Reagent
(eq.)
Time
(h)
Yield
(%)
67
Entry
Method
Solvent
sterically hindered case.
O
A
A
B
B
B
B
B
1
2
3
4
5
6
7
11 (0.5)
11 (1.0)
11 (0.5)
11 (1.0)
Phe
MeOH
EtOH
MeOH
EtOH
EtOH
EtOH
EtOH
48
O
OHHO
OHHO
O
72
31
48
66
66
12
0
24
1) (R,R)-9a (3.3 eq.)
O
OH
O
O
DT101, rt, 1h
24
(R,R)-1a (81% ee)
(R,R)-7
Glu
> 48
> 48
2) 3 (2.0 eq.)
DT101, 0°C, 44h
45 %
O
His
0
O
OHHO
OHHO
O
We also demonstrated the unique role of proline (11) in
Method B by choosing other amino acids as catalysts.
Phenylalanine (Phe), histidine (His) and glutamic acid (Glu) were
used but none of them could replace proline (11) to catalyse our
O
OH
meso-1b
Scheme 3. Enantioselective Synthesis of (R,R)-MCA ((R,R)-1)

one-pot reaction (Tab. 3, entry 4-6). For the selectivity of proline-
ACCEPTED MANUSCRIPT
catalysed reaction, see tab. 5, entry 1.
Method A:
O
O
N
OH
H
O
O
OH
O
O
O
OHHO
OH
6
11
H
MeOH
65°C, 30 min
or
O
O
OH
O
3
7
4
5
rt, overnight
OH
Method B:
O
O
O
O
iso-3
HO
OH
OH
O
O
OHHO
OHHO
O
O
11
solvent, rt
+
+
H
OH
O
O
OH
O
6
8
5
1
Scheme 4. Methods A and B for the organocatalysed synthesis of MCA (1).
We only isolated small amounts of product (12 % yield) in the
reaction with Phe.30 This highlights the importance of the
secondary amine character of proline (11). As described in the
literature the formation of the Michael acceptor 3 probably
proceeds over an iminium/enamine intermediate.26
ease of implementation of Method A/B could be interesting for
an industrial application.12c
Tab. 4 Synthesis of various derivatives through the one-pot Method B.
R1
O
HO
OH
R1
OHHO
O
Finally,
we
synthesised
the
naturally
occuring
11
OHHO
R2
myrtucommulone F (MCF) (13) as well as the 1,3-dimedone
derivatives 14 and 15, which showed good cytotoxic activites
against cancer cells, with good yields (Tab. 4 entry 1-3).12c
Unfortunately, when isovaleraldehyde was used, no expected
product but only traces of related derivatives could be isolated
(Tab. 4, entry 4-5). In case of entry 4, the isolated product 16 has
a molecular weight of 678.8 g/mol which corresponds to one
partially cyclised derivative (Fig. 3). As for entry 5, only 17 was
isolated, exhibiting the mass of a product where the Michael
addition took place only once (474.6 g/mol, Fig. 3). When
Meldrum’s acid (12) was used as a 1,3-diketone, a clear main
spot was detected on tlc only after 16h, but mass spectra revealed
that the main product derives from the degradation of the
diketone (Tab. 4, entry 6). The isolated compound 18 is probably
the result of the condensation of the meldrum acid 12 and the
aldehyde 5 on which acetone (coming from the degradation of
12) was added (Fig. 3).
R3
R3
OH
MeOH, rt
O
O
R2
OH
O
H
R2
O
O
O
O
O
O
O
R3
:
O
O
O
O
4
19
12
1,3-dicarbonyl
Time
Product
(yield)
13 (60)
14 (95)
Entry
R1
R2
compound
(h)
48
24
16
40
40
16
Pent
iPr
1
2
3
4
5
6
iPr
iPr
iPr
iBu
iBu
iPr
4
19
19
4
4
12
Pent
iPr
15 (79)
16 (10)
(14)
Pent
iPr
0
O
O
OH HO
O
O
O
O
O
2.2.2. Diastereoselctive synthesis of myrtucommulones under
mild conditions.
O
O
OH
O
In our proline-catalysed one-pot synthesis, only low
stereoselectivity could be detected and the results are not given
here. Since the choice of the catalyst is limited for the reasons
explained earlier, we chose to prepare the Michael acceptor in a
separate step and add it to the Michael donor like in the synthesis
from 2010. That way, no problem concerning the formation of
the acceptor can occur and we could observe the direct effect of
the catalyst on the synthesis. This method will be then called
Method C.
O
16 (678.9 g/mol)
18 (256.3 g/mol)
O
O
OH HO
OH
O
OH
We studied the effect of various chiral amines on the
formation of myrtucommulones (Tab. 5). As seen before with
Method B, proline (11) did not have much influence on the
stereoselectivity of the reaction (Tab. 5, entry 1, dr 44:56, 1a:1b).
Other naturally occurring organocatalysts such as brucine (20)
(tertiary chiral amine) or (-)-ephedrine (21) (secondary chiral
17 (474.6 g/mol)
Structure of the isolated compounds 16 17 18.
Fig. 3
.
,
,
In conclusion, this direct method can be used safely with
syncarpic acid (4), dimedone 19 and some phloroglucinols.
Given the pharmacological potential of myrtucommulones, the

6
ACCEPTED MANUSCRIPT
Tetrahedron
amine) did not improve the effect either (Fig. 4) (Tab. 5, entry 2-
3).
(-)-Eph. (21
CN (22a
)
3
4
5
6
7
8
9c
96
72
69
96
72
72
67
80
77
60
46
67
60
93
0
2
)
36
45
82
44
39
11
13
22
28
14
23
28
N
H
Q (22b
)
OH
O
O
H
CD (22c
)
H
H
N
CPN (22e
Bz-CPN (22f
Bn-CD (22g
)
O
HN
)
21
O
R
N
R
N
)
20
N
OH
a) determined through HPLC on Reprosil 100 Chiral-NR, ACN: Buffer (35:65), Buffer:
30mM NH4OAc, pH9 DEA, 1.0 mL/min, 24°C; b) performed in CH2Cl2; c) performed
in toluene with 2 eq. of a 1M KOH solution in water.
N
OH
Given the good results obtained with cinchonidine (22c), we
investigated its potential for the enantioselective synthesis of
NSMC (7) which only bears one stereocenter (Tab. 6, entry 1-2).
The results revealed almost no influence of the catalyst 22c on
the ee of the intermediate 7. On the other hand, the experiments
run in the less polar CH2Cl2 or in the even less polar toluene
provided interesting ee of 41 and 49 % respectively for the
complete molecule 1a (Tab. 6, entry 3-4). This actually shows
that cinchonidine (22c) can catalyse enantioselectively the
Michael addition but to a limited extent. It is possible that the
first Michael addition leading to 7 takes place too rapidly so that
22c doesn’t “have time” to be involved. We changed the amount
of catalyst as well and obtained 65 % de in favour of the meso-
form 1b with 0.25 eq. of cinchonidine (22c) (Tab. 6, entry 5-7).
When we used overstoichiometric amounts of catalyst 22c, no
stereoselectivity was observed. This confirmed that the best
diastereoselectivity (82 %) could be reached with 0.5 eq. of 22c.
Finally the synthesis of MCA (1) was performed at 0°C to
possibly avoid any uncatalysed background reaction but this led
to very long reaction times and poor selectivities (Tab. 6, entry 8-
9). Using the same reaction condition, the above mentioned MCF
(13) was synthesised with a dr of 8:92, also in favour of the
meso-form.
22a: R = H : cinchonine (CN)
22d:R = OMe : quinidine (QD)
22c: R = H : cinchonidine (CD)
22b: R = OMe : quinine (Q)
OH
N
OH
N
Br
N
O
N
N
OH
OH
N
O
22f
22g
22e
Fig. 4
. Structure of various catalysts used for the organocatalysed synthesis of
MCA (
1
)
The use of the well-known Cinchona alkaloids25 (22) on the
other hand represented a real breakthrough concerning our work
with organocatalysts. Cinchonine (22a) and quinine (22b)
increased the diastereomeric excess (de) up to 45 % in favour of
the meso-form of MCA (1b) (Tab. 5, entry 4-5). Unlike generally
observed,30 the use of cinchonidine (22c), the pseudo-enantiomer
of cinchonine (22a), did not inverted the ratio in favour of 1a but
led to a dramatic increase in diastereoselectivity to a dr of 9:91
(1a:1b) (Tab. 5, entry 6). That way, we managed to obtain only
one of the stereoisomers of MCA (1) predominantly. Based on
this result, cupreine (22e) and benzoyl-cupreine (22f) were
synthesised from quinine (22b) but 19e and 19f generated onyl
moderate de (Tab. 5, entry 7-8). Interestingly and unfortunately,
only meso-1b could be synthesised preferentially no matter what
catalyst was used.
Tab. 6. Variation of the reaction conditions of the cinchonidine (22c)
catalysed formation of MCA (
1
) and NSMC (7) (Method C).
O
O
O
OHHO
OHHO
O
HO
OH
Cinchona alkaloids (22) are also used as phase transfer
catalysts because of their easily quaternisable tertiary amine.26b,32
We therefore synthesised some phase transfer catalysts but only
observed modest selectivities. N-benzylcinchonidinium bromide
(22g) provided the most interesting results with an ee of 28 %
(Tab. 5, entry 9).33
OH
O
OH
O
22c (y eq.)
Solvent, T
6
1a + 1b
or
O
O
O
O
OHHO
OH
Tab. 5
.
Use of different catalysts for the synthesis of MCA (
1
) (Method
C).
O
O
OH
3 (x eq.)
O
O
7
Method C
HO
OH
O
OHHO
OHHO
OHHO
OHHO
O
Prod.
(yield)
Entry
x
y
Solvent
T
time
eea
dea
OH
O
OH
1a
O
MeOH
toluene
CH2Cl2
toluene
MeOH
MeOH
MeOH
MeOH
toluene
1
2
3
4
5
6
7
8
9
1.4 0.50
1.4 0.50
4.4 0.50
4.4 0.50
4.4 0.50
4.4 0.33
4.4 0.25
4.4 0.50
4.4 0.50
0°C
0°C
rt
10 d
96 h
27 h
72 h
96 h
96 h
94 h
10 d
96 h
7
7
1
1
1
1
1
1
1
(48)
(56)
(94)
(86)
(46)
(69)
(40)
(44)
(64)
2
-
-
Catalyst (0.5 eq.)
MeOH, rt
6
13
41
49
28
16
14
2
2
O
rt
8
O
O
O
O
82
38
65
2
rt
rt
O
O
OH
meso-1b
O
rt
3
0°C
0°C
40
5
a) determined through HPLC on Reprosil 100 Chiral-NR, ACN: Buffer (35:65),
Buffer: 30mM NH4OAc, pH9 DEA, 1.0 mL/min
Entry
1
2b
Catalyst
Proline (11
Brucine (20
Time (h)
72
Yield (%)
eea
1
dea
12
13
)
72
49
)
114
0

3. Conclusion
along with a RP18 guardcolumn. A ChiralCel OD-H HPLC
ACCEPTED MANUSCRIPT
column (250x4.6 mm, 5 ꢀm) was purchased from VWR
international, Darmstadt, Germany. The Reprosil 100 Chiral-NR
(250x4.6 mm, DR. Maisch, GmbH) column was used for chiral
chromatography on RP and normal phase (NP). Preparative
HPLC was performed with a SYKAM HPLC instrument
(SYKAM, Fürstenfeldbruck, Germany, gradient pump S1122,
DAD S3210, and Rheodyne valve 5330). RP18ec Nucleodur
columns (250x21 mm, 5 ꢀm as stationary phase) from Macherey
& Nagel, Düren, Germany were used as preparative HPLC
columns along with Grom Saphir 110C18 (30x20 mm, 5 ꢀm)
guard columns.
We could synthesise MCA (1) with 81 % ee with the
bimetallic complex ALB (9a), which is a good result for such a
sterically
hindered
Michael
addition.
However,
diastereoselectivity remained very low with metal catalysts. Most
interestingly, we could perform an organocatalysed synthesis of
MCA (1) (82 % de) through the use of cinchonidine (22c). In
some cases, some interesting enantioselectivities were reached,
but not as good as the one obtained through metal catalysis.
Additionally, we also developed an efficient, eco-friendly and
cheap multicomponent reaction (Method B) to form
myrtucommulones and analogues, making them easily accessible.
This could be an interesting method for the synthesis of such and
related compounds, e.g. in pharmaceutical industry.
4.2. General procedures
These results are a good example for the limits of metal
catalysis and organocatalysis but also of their complementarity.
When interested in enantiomerically enriched MCA metal
catalysis is the best answer. When the focus is on meso-MCA,
the organocatalysis is the method of choice. The
myrtucommulone case shows as well the problems that can be
encountered when known methodologies are applied to a tricky
Michael addition with bulky acceptors. Our future research will
focus on the search for a more universal catalyst with higher
selectivity to overcome this kind of problem.
4.2.1. Gp 1: Preparation of isobutylidene syncarpic acid (3) in
CH2Cl2 (classic method)10
Syncarpic acid (4) (3 mmol) was suspended in DCM (10 mL)
and piperidine (6 mmol) and isobutyraldehyde (5) (4.5 mmol)
were added. After stirring for 10 min at room temperature, a
solution of 1M HCl saturated with ammonium chloride
(ca. 10 ml), was added and the biphasic mixture was vigorously
stirred for 15 min. The layers were separated and the aqueous
phase was extracted once with DCM. The organic layers were
combined, filtrated through a 5 cm thick pad of silica gel
(petroleum ether/acetone, 2/1 (v/v)) and the eluent was removed
by evaporation under reduced pressure. Isobutylidene syncarpic
acid (3) was obtained with 95-99 % yield as a clear yellow oil
and was used without further purification.
Acknowledgement
We are grateful to the University of Saarland, the Deutsche
Forschungsgemeinschaft (Ja 616/5-1) and a GradUS-scholarship
(M.C.) of the Saarland University for the generous support of this
project.
4.2.2. Gp 2: Preparation of myrtucommulone derivatives using
metal catalysts.
4. Experimental
4.1. General
Isobutyryl phloroglucinol (6) (1 eq.) was dissolved in the
solvent (2 mL/mmol) under N2 and slowly added to the freshly
prepared solution of the metal complex (9) (0.15-0.25 M
solution) by syringe. The resulting suspension was stirred at
room temperature for an additional hour. Then the alkylidene 1,3-
diketone (0.60-0.75 M solution), freshly prepared according to
the general procedures Gp 1 was added dropwise at the desired
temperature (usually 0°C). Stirring was continued for several
hours (monitored by TLC, petroleum ether/acetone, 1/1 (v/v))
and then the reaction mixture was quenched with 1M HCl
(aqueous solution saturated with NH4Cl). The mixture was
extracted with diethyl ether (3 x 50 mL), and the combined
organic extracts were dried with MgSO4. Filtration and
evaporation of the solvent gave the crude product, which was
purified by flash chromatography (acetone/petroleum ether) to
give the desired myrtucommulone derivative.
All solvents were purchased from Merck, Darmstadt in HPLC
grade. Tetrahydrofuran (THF) was freshly distilled from sodium
benzophenone under N2 and CH2Cl2 (DCM) from calcium
hydride. 1.0 M LiAlH4 in THF, (R)- and (S)-BINOL were
purchased from Aldrich, Steinheim, Germany. Reactions with
metal catalysts were carried out in dried flasks under N2. NMR
1
spectroscopic data [1D: H and 13C NMR, DEPT 135; 2D:H,H-
COSY, heteronuclear single quantum correlation (HSQC),
HMBC, NOESY] were recorded with a Bruker AVANCE II 400
(1H NMR at 400 MHz, 13C NMR at 101 MHz). Chemical shifts
are given in ppm, and coupling constants are in Hz. MestReC
4.9.9.6 was used to process the NMR spectroscopic data. MS
(ESI) were measured with a Shimadzu LC-MS 2020 (Shimadzu
Germany, Duisburg) and analysed with LabSolutions 5.65 from
SHIMADZU. HRMS (ESI) were measured with a LTQ Orbitrap
XL from Thermo Scientific, Dreieich, Germany. TLC was
performed on silica glass plates (Si60-F254 from Merck). Flash
chromatography was carried out by using silica gel with 40–63
ꢀm particle size from Merck. Analytical HPLC was performed
with a SYKAM HPLC instrument (SYKAM, Fürstenfeldbruck,
Germany, gradient pump S3100, mixer S8111, DAD S3210,
Rheodyne valve 5210i, and Jet-Stream II column oven) and the
the data was processed with the Chromstar 6.3 Software from
SCPA GMBH. Analytical HPLC was also performed with a
Beckmann System Gold® HPLC equipment (127 NM Solvent
Module, a 166 NM Detector and a Rheodyne 7125 Injector Valve
and Jet-Stream II column oven). The data was treated with the
Clarity Lite 2.6.4.402 Software from Data Apex. RP18ec
Nucleodur columns (250x4.6 mm, 5 ꢀm) from Macherey &
Nagel, Düren, Germany were used as analytical HPLC columns
4.2.3. Gp 3: Method A for the preparation of myrtucommulones
(preparation of the intermediate 3 in MeOH)
Syncarpic acid (4) (4.0-6.0 eq.) was dissolved in MeOH (1.5
mL/mmol), then proline (11) (0.5 eq.) and isobutyraldehyde (5)
(8.0 eq.) were added. The reaction was stirred for 30-40 min at
60°C (TLC monitoring) and then cooled down. At this point, the
Michael acceptor 3 could be isolated following the work-up as in
Gp 1. Otherwise an acyl phloroglucinol (1.0 eq.) was directly
added and the mixture was stirred at room temperature until
completion of the reaction was observed by TLC. Diethyl ether
(40 mL/mmol of acyl phloroglucinol) and a saturated solution of
ammonium chloride (same volume) were added. The layers were
separated and the aqueous phase was extracted twice with the
same volume of Et2O. The combined organic layers were dried
over magnesium sulfate, filtrated and the solvents were removed

8
ACCEPTED MANUSCRIPT
Tetrahedron
3
under reduced pressure. The crude product was purified on silica
gel column chromatography.
(2 x sept, JH2‘’’,H3’’‘-H4‘‘‘ = 6.9 Hz, 1H, H2’’’), 3.85, 3.82 (2 x d,
3JH1’,H8‘ = 11.0 Hz, 1H, H1’), 3.30, 3.25 (2 x dsept, 3JH8’,H1‘ = 11.0
3
Hz, JH8’,H9‘-H10‘ = 6.3 Hz, 1H, H8’), 1.31-1.25 (m, 6H, H11’,
4.2.4. Gp 4: One-Pot preparation of myrtucommulone
H12’, H13’, H14’), 1.22-1.17 (s, 6 H, (m, 6H, H11’, H12’, H13’,
H14’), 1.14, 1.13 (2 x d, JH3‘’’,H2’’‘ = 6.9 Hz, 3H, H3‘‘‘), 1.09,
1.08 (2 x d, JH4‘’’,H2’’‘ = 6.9 Hz, 3H, H4‘‘‘), 0.83, 0.82 (2 x d,
derivatives (Method B)
The 1,3-diketone (4.0-6.0 eq.), proline (11) (0.5 eq.) and the
acyl phloroglucinol (1.0 eq.) were dissolved in EtOH (8
mL/mmol of acyl phloroglucinol). After the addition of the
aldehyde (8.0 eq.), the mixture was stirred at room temperature
until completion of the reaction was observed by TLC. Diethyl
ether (40 mL/mmol of acyl phloroglucinol) and a saturated
solution of ammonium chloride (same volume) were added. The
layers were separated and the aqueous phase was extracted twice
with the same volume of Et2O. The combined organic layers
were dried over magnesium sulfate, filtrated and the solvents
were removed under reduced pressure. The crude product was
purified on silica gel column chromatography.
3JH9’,H8‘ = 6.3 Hz, 3H, H9’), 0.71, 0.67 (2 x d, JH10’,H8‘ = 6.3 Hz,
3
3H, H10’) ppm.13C-NMR (125 MHz, CO(CD3)2): δ = 218.7
(C5’), 212.1, 211.8 (C1'), 195.0, 192.5 (C7’), 167.39, 166.36
(C4), 166.64, 166.58 (C6), 164.1, 163.5 (C3’, C2), 114.2, 113.7
(C3), 113.3, 113.1 (C2’), 106.8, 106.2
(C1), 98.4, 97.4 (C5), 56.5, 53.54,
53.4, 53.34, 53.26 (C4’, C6’), 43.6,
43.4 (C-1’), 40.25, 40.18 (C2’’’),
27.5, 27.19 (C8’), 27.3, 27.24, 26.9,
26.8, 26.72, 26.65 (C11’, C12’, C13’,
C14’), 23.9, 23.8, 23.76, 23.74, 23.68
(C4’’’, C3’’’), 21.4, 21.2 (C9’), 20.7, 20.3 (C10’) ppm.
4.2.5. Gp 5: Preparation of myrtucommulone derivatives using
different catalysts (Method C)
The acyl phloroglucinol (1.0 eq.) and the catalyst (0.5 eq.,
variable) were dissolved in the solvent (4 mL/mmol acyl
phloroglucinol) and brought to the desired temperature (normally
rt). The alkylidene 1,3-diketone (1.5-6.0 eq.), prepared according
to the general procedures Gp 1 or Gp 3, was dissolved in the
solvent (0.5 mL/mmol alkylidene) and added to the mixture. The
reaction was stirred at room temperature until completion of the
reaction was observed on TLC. After the reaction was hydrolysed
with a saturated solution of ammonium chloride, the crude
product was extracted with diethyl ether (3 x 20 mL). The
product was then dried with magnesium sulfate and the solvent
was evaporated under reduced pressure. The product was purified
by column chromatography on silica gel.
4.3.2. Myrtucommulone B (MCB) (2)
Following the Gp 6 procedure, NSMC (7) (70 mg, 0.16 mmol,
1.0 eq.) and pTsOH (93 mg, 0.49 mmol, 3.0 eq.) were heated at
95°C in toluene (7 mL) for 1h to yield, after purification on
column chromatography (acetone/petroleum ether, 1/9, Rf
=
0.08), 43 mg of MCB (2) (0.10 mmol, 65 % yield). It was
dissolved in a DCM/PE (1/9) mixture and evaporated under
reduced pressure to afford a white foam. HRMS (ESI+) calcd. for
+
1
C24H31O6 [M+H]+: 415.2121, found: 415.2112. H-NMR (400
MHz, CDCl3): δ = 13.40 (s, 1H, C6-OH), 7.98 (brs, 1H, C4-OH),
3
6.36 (s, 0.13H, H5), 6.33 (s, 0.82H, H5), 4.42 (d, JH1’,H8’ = 3.8
3
Hz, 0.84H, H1’), 4.39 (d, JH1’,H8’ = 3.8 Hz, 0.14H, H1’), 3.95-
3.83 (m, 1H, H2’’’), 1.92 (dsept, 3JH8’,H1’ = 3.8 Hz, 3JH8’,H9’-10’= 6.8
Hz, 1H, H8’), 1.62 (s, 3H, 12’), 1.46 (s, 3H, H14’), 1.44 (s,
0.50H, H11’), 1.42 (s, 2.71H, H11’), 1.39 (s, 3H, H13’), 1.26 (d,
4.2.6. Gp 6 Cyclisation of myrtucommulones
The myrtucommulone derivative (1.0 eq.) was suspended in
toluene (1 mL/10 mg) and a few drops of acetone were added to
dissolve it completely. pTsOH·H2O (3.0 eq. for derivatives with
only one condensation site, 6.0-7.0 eq. otherwise) was added and
the mixture was stirred at 95°C (bath temperature) until
completion of the reaction (monitored by TLC, usually 1h). The
solvents were removed under reduced pressure and the residue
was directly transferred on a silica gel chromatography column
for purification.
3JH4’’’,H2’’’ = 6.5 Hz, 3H, H4’’’), 1.24 (d, JH3’’’,H2’’’ = 7.0 Hz, 3H,
3
3
3
H3’’’), 0.84 (d, JH8’,H9’ = 6.8 Hz, 3H, H9’), 0.80 (d, JH8’,H10’
=
6.8 Hz, 3H, H10’) ppm.13C-NMR (101 MHz, CDCl3): δ = 211.8
(C5’), 208.9 (C1’’’), 199.3 (C7’), 168.5, 168.3 (C3’), 164.72,
164.69 (C4), 160.02, 159.97 (C6), 153.4, 153.3 (C2), 112.2,
112.1 (C2’), 103.9, 103.8 (C3), 103.63,
103.58 (C1), 100.6 (C5), 56.14, 56.11
(C6’), 47.3 (C4’), 39.6 (C2’’’), 34.8, 34.7
(C8’), 31.41, 31.37 (C1’), 25.1 (C12’),
25.03 (C14’), 24.95, 24.92 (C11’), 24.15,
24.10 (C13’), 20.9 (C3’’’), 18.91, 18.86
(C9’), 18.6, 18.5 (C10’), 17.7 (C4’’’)
ppm.
4.3. Synthesis of various myrtucommulones
4.3.1. Norsemimyrtucommulone (NSMC) (7)
According to Gp 2, isobutyryl phloroglucinol (6) (390 mg, 2.0
mmol, 1.0 eq.) was dissolved in DT101 (8 mL) and added
dropwise to the freshly prepared (R,R)-ALB ((R,R)-9a) (36.4 mL
of a 0.18 M solution in DT101, 6.4 mmol, 3.2 eq.). Isobutylidene
syncarpic acid (3) (654 mg, 2.77 mmol, 1.4 eq.) was dissolved in
DT101 (5.5 mL, 0.68 M solution) and added dropwise to the
mixture at 0°C. After 2h stirring at 0°C, the reaction was
quenched and the product extracted and dried. After purification
by column chromatography on silica gel (acetone/petroleum
ether, 1/2 (400 mL), 1/1 (1000 mL), Rf = 0.15 (A/P, 1/1)), 661
mg of NSMC (7) (1.53 mmol, 81 % yield) were obtained as a
pale yellow powder. HRMS (ESI+) calcd. for C24H32NaO7+
[M+Na]+: 455.2045, found: 455.2030.1H-NMR (500 MHz,
CO(CD3)2): δ = 14.36 (brs, 0.46H, OH), 13.75-13.60 (brs, 1H,
OH), 13.49 (brs, 0.31H, OH), 13.04 (brs, 0.35H, OH), 5.67, 5.66
4.3.3. Myrtucommulone A (MCA)(1)
Metal Catalysed:
According to Gp 2, (-)-(R)-NSMC ((R)-7) (183 mg, 0.42
mmol, 1.0 eq.) was dissolved in DT101 (0.8 mL) and added
dropwise to the freshly prepared (R,R)-ALB ((R,R)-9a) (7.6 mL
of a 0.18 M solution in DT101, 1.38 mmol, 3.3 eq.).
Isobutylidene syncarpic acid (1.1 mL of a 0.73 M solution, 0.80
mmol, 2.0 eq.) was added dropwise to the mixture at 0°C and the
reaction was stirred at this temperature for 10h then at room
temperature for 6h. The reaction was quenched and the product
extracted and dried. After purification by column
chromatography on silica gel (acetone/petroleum ether, 1/2), 216
(2
x
s,
1H,
H5),
4.21,
4.16

H10’, H9’’, H10’’) ppm.13C-NMR (101 MHz, CO(CD3)2): δ =
216.1, 200.1, 181.7, 167.3, 162.8, 145.0, 116.0, 115.4, 112.3,
112.2, 111.9, 106.4, 55.5,
mg of MCA (1) (0.32 mmol, 77 % yield) wereAobCtaiCneEdPasTaEpaDle MANUSCRIPT
[M+H]+: 669.3638, found: 669.3628.
+
yellow powder with 70% ee. HRMS (ESI+) calcd. for C38H53O10
55.4, 51.2, 45.6 (C2’’’),
41.3 (C1’, C1’’), 33.6
Method B:
(C4’’’), 28.3 (C8’, C8’’),
28.1, 26.8 (C3’’’), 26.7,
26.4, 26.3, 26.1, 24.4,
23.6, 23.5, 23.4, 23.3,
According to the general procedure Gp 4, isobutyryl
phloroglucinol (6) (98 mg, 0.50 mmol, 1.0 eq.), proline (11) (57
mg, 0.50 mmol, 1.0 eq.), syncarpic acid (4) (550 mg, 3.02 mmol,
6.0 eq.) and isobutyraldehyde (5) (0.36 mL, 3.94 mmol, 8.0 eq.)
were mixed in ethanol (4 mL) and stirred at room temperature for
24 h. The reaction was worked up and the product was purified
through column chromatography on silica gel (acetone/petroleum
ether, 1/2, Rf = 0.15) to afford 219 mg of MCA (1) (0.33 mmol,
66 % yield) as a pale yellow powder. HRMS (ESI+) calcd. for
C38H53O10+ [M+H]+: 669.3638, found: 669.3666.
23.1, 20.3, 15.3 ppm.
4.3.5. Myrtucommulone derivative 14
According to the general procedure Gp 4, isobutyryl
phloroglucinol (6) (98 mg, 0.50 mmol, 1.0 eq.), proline (11) (57
mg, 0.50 mmol, 1.0 eq.), dimedone (19) (420 mg, 3.00 mmol, 6.0
eq.) and isobutyraldehyde (5) (0.36 mL, 3.94 mmol, 8.0 eq.) were
mixed in ethanol (4 mL) and stirred at room temperature for 24 h.
The reaction was worked up and the product was purified
Method C:
According to the general procedure Gp 5, isobutyryl
phloroglucinol (6) (98 mg, 0.50 mmol, 1.0 eq.), cinchonidine
(22c) (73.6 mg, 0.25 mmol, 0.5 eq.), and isobutylidene syncarpic
acid (3) (520 mg, 2.2 mmol, 4.4 eq.), were mixed in MeOH (5
mL) and stirred at room temperature for 91h. The reaction was
worked-up and the product was purified through column
chromatography on silica gel (acetone/petroleum ether, 1/2) to
afford 151 mg of MCA (1) (0.23 mmol, 46 % yield) as a pale
yellow powder. This sample showed an ee of 28 % and de of 82
through
column
chromatography
on
silica
gel
(Acetone/Petroleum ether, 1/5, Rf = 0.25) to afford 278 mg of the
dimedone derivative 14 (0.48 mmol, 95 % yield) as a yellow
powder LC-MS (ESI-) for C34H47O8 [M-H]-: 583.75.1H-NMR
-
(400 MHz, CO(CD3)2): δ = 13.59-11.32 (m, 0.60H, OH), 10.94-
9.52 (m, 0.21H, OH), 6.57 (s, 0.77H, OH), 5.84 (brs, 0.74H,
3
OH), 4.21 (d, J= 5.5 Hz, 0.08H), 4.17-4.05 (m, 0.63H, H2’’’),
+
%. HRMS (ESI+) calcd. for C38H53O10 [M+H]+: 669.3638,
4.00-3.79 (m, 1.26H, H1’, H1’’), 3.12-2.90 (m, 1.75H, H8’,
found: 669.3649.
2
H8’’), 2.55 (d, J = 15.3 Hz, 1.04H, H6a’, H6a’’), 2.49-2.33 (m,
4.37H, H4’, H4’’, H6’, H6’’), 2.21 (d, 2J = 15.3 Hz, 0.97H, H6b’,
H6b’’), 1.96 (dd, 2J = 13.8 Hz, 4J = 0.8 Hz, 0.89H, H4a’, H4a’’),
1.67 (d, 2J = 13.8 Hz, 0.97H, H4b’, H4b’’) 1.39, 1.27 (2 x s, 6H,
H11’, H11’’), 1.20-1.02 (m, 14.72H, H3’’’, H4’’’, H9’, H12’,
H12’’), 1.00 (s, 3H, H12’, H12’’), 0.94-0.83 (m, 5.09H), 0.80 (d,
3J = 6.5 Hz, 0.76H), 0.74 (d, 3J = 6.5 Hz, 1.25H), 0.71 (d, 3J = 6.5
1H-NMR (400 MHz, CO(CD3)2): δ = 15.80 (brs, 0.38H, OH),
15.41 (brs, 0.51H, OH), 14.54-14.08 (m, 0.33H, OH), 13.93-
13.59 (m, 0.11H, OH), 13.14-12.77 (m, 0.85H, OH), 4.47-4.26
3
(m, 0.58H), 4.22 (d, J =11.3 Hz, 1.08H, H1’, H1’’), 4.16-4.03
(m, 0.96H, H2’’’), 3.81 (dd, 3J =6.0 Hz, J = 2.0 Hz, 0.08H), 3.28-
2.99 (m, 1.78H, H8’, H8’’), 1.47-1.06 (m, 30.0H, H3’’’ H4’’’,
H11’, H12’, H13’, H14’’, H11’’, H12’’, H13’’, H14’’), 0.89-0.64
(m, 12H, H9’, H10’, H9’’, H10’’) ppm.13C-NMR (101 MHz,
CO(CD3)2): δ = 216.1, 212.9, 200.0, 180.6, 180.5, 162.81,
162.78, 157.5, 148.5,
3
3
Hz, 0.73H), 0.65 (d, J = 6.5 Hz, 0.32H), 0.62 (d, J = 6.5 Hz,
0.51H) (H9’, H10’, H9’’, H10’’) ppm.13C-NMR (101 MHz,
CO(CD3)2): δ = 199.2, 162.0, 147.3, 139.3, 137.2, 118.0, 117.9,
117.6, 117.5, 117.4, 111.7, 106.7, 106.4, 98.5, 79.8, 75.9, 56.4,
55.2, 53.7, 45.9, 41.0,
147.4,
119.4,
119.8,
118.8,
119.7,
112.3,
40.9, 40.7, 40.4, 33.0,
32.9, 32.8, 32.7, 32.5,
32.0, 31.5, 28.6, 28.2,
28.14, 28.06, 27.9, 27.6,
25.1, 24.4, 23.7, 23.6,
23.5, 23.3, 23.2, 23.1,
23.0, 22.9, 21.3, 20.8,
20.7, 20.6, 20.2, 19.6 ppm.
101.9, 97.5, 92.4, 91.4,
55.4, 51.2, 41.4, 40.4,
36.4, 28.3, 28.1, 26.9,
26.8, 26.2, 26.0, 23.6,
23.43, 23.38, 23.34, 21.1
ppm.
4.3.4. Myrtucommulone F (13)
According to the general procedure Gp 4, hexanoyl
phloroglucinol (112 mg, 0.50 mmol, 1.0 eq.), proline (11) (57
mg, 0.50 mmol, 1.0 eq.), syncarpic acid (4) (550 mg, 3.02 mmol,
6.0 eq.) and isobutyraldehyde (5) (0.36 mL, 3.94 mmol, 8.0 eq.)
were mixed in ethanol (4 mL) and stirred at room temperature for
48 h. The reaction was worked up and the product was purified
through column chromatography on silica gel (acetone petroleum
ether, 1/2, Rf = 0.19) to afford 202 mg of MCF (13) (0.30 mmol,
60 % yield) as a light yellow powder. LC-MS (ESI-) for
4.3.6. Myrtucommulone derivative 15
According to the general procedure Gp 4, hexanoyl
phloroglucinol (112 mg, 0.50 mmol, 1.0 eq.), proline (11) (57
mg, 0.50 mmol, 1.0 eq.), dimedone (19) (550 mg, 3.02 mmol, 6.0
eq.) and isobutyraldehyde (5) (0.36 mL, 3.94 mmol, 8.0 eq.) were
mixed in ethanol (4 mL) and stirred at room temperature for 16 h.
The reaction was worked up and the product was purified
through column chromatography on silica gel (acetone/petroleum
ether, 1/15, Rf = 0.08) to afford 243 mg of the dimedone
derivative 15 (0.40 mmol, 79 % yield) as a yellow oil. LC-MS
-
C40H55O10 [M-H]-: 696.80.1H-NMR (400 MHz, CO(CD3)2): δ =
15.86 (brs, 0.34H, OH), 15.47 (brs, 0.64H, OH), 14.67-14.15 (m,
0.30H, OH), 14.06-13.80 (m, 0.08H, OH), 13.23-12.75 (m,
-
(ESI-) for C36H51O8 [M-H]-: found: 611.80.1H-NMR (400 MHz,
3
1.09H, OH), 4.51-4.25 (m, 0.41H), 4.21 (d, J = 11.0 Hz, 1.30H,
CO(CD3)2): δ = 13.73-11.40 (m, 0.92H, OH), 11.73-8.92 (m,
0.29H, OH), 6.57 (s, 0.46H, OH), 5.84 (brs, 0.41H, OH), 3.99-
3.79 (m, 1.96H, H1’, H1’’), 3.27-2.88 (m, 6.16H, H8’, H8’’,
H2’’’), 2.55 (d, 2J = 15.0 Hz, 0.95H, H6a’, H6a’’), 2.46-2.28 (m,
7.07H, H4’, H4’’, H6’, H6’’), 2.21 (d, 2J = 15.0 Hz, 0.80H, H6b’,
H1’, H1’’), 4.09-3.90 (m, 0.12H), 3.82-3.77 (m, 0.04H), 3.23-
3.00 (m, 3.77H, H8’, H8’’, H2’’’), 1.70-1.60 (m, 2H, H3’’’),
1.45-1.10 (m, 29H, H4’’’, H5’’’, H11’, H12’, H13’, H14’’,
H11’’, H12’, H13’’, H14’’), 0.94-0.65 (m, 15H, H6’’’, H9’,

10
ACCEPTED MANUSCRIPT
Tetrahedron
H6b’’), 1.96 (dd, 2J = 13.8 Hz, 4J = 0.8 Hz, 1.02H, H4a’, H4a’’),
1.72-1.62 (m, 2.55H, H3’’, H4b’, H4b’’), 1.42-1.32 (m, H11’,
H11’’, H4’’’), 1.27 (s, 1.69, H11’, H11’’), 1.15 (s, 2.12H, H12’,
H12’’) 1.14-1.02 (m, 12.35H, H11’, H11’’, H12’, H12’’, H5’’’),
1.00 (s, 3H, H12’, H12’’), 0.96-0.86 (m, 9.83H), 0.80 (d, 3J = 6.5
Hz, 1.10H), 0.74 (d, 3J =
group as described in A. C. Jain, T. R. Seshadri, Proc. Indian
Natl. Sci. Acad. Part A 1955, 42, 279 – 284.
12. (a) Müller, H. Ph.D. Thesis, Universität des Saarlandes 2012
;
(b) Jauch, J.; Müller, H.; Werz, O.; Wiechmann, K.
EP2695874A1, 2014; (c) Wiechmann, K.; Müller, H.; Huch,
V.; Hartmann, D.; Werz, O.; Jauch, J. Eur. J. Med. Chem.
2015, 101, 133-149; (d) Tan H.; Liu H.; Zhao L.; Yuan Y.; Li
B., Jiang Y.; Gong L.; Qiu S. Eur. J. Med. Chem. 2017, 125,
492-499.
6.5 Hz, 2.11H), 0.69 (d,
3J = 6.5 Hz, 1.11H), 0.65
13. Hans, M.; Charpentier, M.; Huch, V.; Jauch, J; Bruhn, T.;
Bringmann, G; Quandt, D. J. Nat. Prod, 2015, 78, 2381-2389.
3
(d, J = 6.5 Hz, 0.59H),
0.62 (d, 3J = 6.5 Hz,
14. Charpentier, M.; Hans, M.; Jauch, J. Eur. J. Org. Chem. 2013
,
4078-4084.
1.23H) (H9’, H10’,
H9’’, H10’’) ppm.13C-
15. (a) Arai, T.; Sasai, H.; Aoe, K.; Okamura, K.; Date, T.;
Shibasaki, M. Angew. Chem. Int. Ed. Engl. 1996, 35, 104-106;
Xu, Y.; Ohori, K.; Ohshima,; T. Shibasaki, M. Tetrahedron
2002, 58, 2585-2588.
16. (a) Halland N.; Hazell R. G.; Jorgensen, K. A.; J. Org. Chem.
2002, 67, 8331-8338; (b) Halland, N.; Aburel, P. S.; Jorgensen,
K. A. Angew. Chem. Int. Ed. 2003, 42, 661-665; (c) Chen, W.;
Du, W.; Yue, L.; Li, R.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. Org.
Biomol. Chem. 2007, 5, 816-821; (d) Xie, J. W.; Yue, L.; Chen,
NMR-APT (101 MHz,
CO(CD3)2): δ = 197.6, 139.3, 53.8, 45.9, 45.8, 41.0, 40.7, 40.3,
33.4, 33.0, 32.9, 32.8, 32.5, 31.5, 28.5, 28.2, 28.14, 27.9, 27.4,
26.3, 26.2, 25.1, 24.4, 24.3, 23.6, 23.5, 23.3, 23.2, 23.1, 22.9,
15.3 ppm.
W.; Du, W.; Zhu, J.; Deng, J.-G.; Chen, Y.-C. Org. Lett. 2007
,
9, 413-415. Northrup, A. B.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2002, 124, 2458-2460.
5. References
17. It could be proved later by cyclising a sample of MCA (1)
1. Alipour, G.; Dashti, S.; Hosseinzadeh, H. Phytother. Res. PTR
2014, 28, 1125-1136.
2. Kashamn, Y.; Rotstein, A.; Lifshitz, A. Tetrahedron 1974, 30,
991-997.
3. Lounasmaa, M.; Puri, H.-S.; Widén, C.-J. Phytochemistry
1977, 16, 1851-1852.
whose ee and dr were known that cyclisation affects neither
one nor the other.
18. Shibasaki, M.; Sasai H.; Arai, T. Angew. Chem. Int. Ed. Engl.
1997, 36, 1236-1256
19. (a) Yuan, Y., Wang, X; Li, X.: Ding, K. J. Org. Chem. 2004
,
69, 146-149; (b) Blay, G.; Cano, J.; Cardona, L.; Fernandez, I.;
Munoz, E.; Pedro, J. R.; Vila, C. J. Org. Chem. 2012, 77,
10545-10556.
4. (a) Myrtucommulones B-E: Shaheen, F. ; Ahmad, M.; Kahn,
S.; N. Hussain, S. S.; Anjum, S.; Tashkhodajev, B.; Turgunov,
K.; Attar-ur-Rahman Eur. J. Org. Chem. 2006, 2371-2377;
(b) Myrtucommulones J-L: Cottiglia, F.; Casu, L.; Leonti, M.;
Caboni, P.; Floris, C.; Busonera, B.; Farci, P.; Ouhtit, A.;
20. (a) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M.
Angew. Chem. Int. Ed. Engl. 1997, 36, 1871-1873; (b) Sasai,
H.; Arai, T.; Satow, Y.; Houk, K. N.; Shibasaki, M. J. Am.
Chem. Soc. 1995, 117, 6194-6198.
21. (a) Zimmer, R.; Schefzig, L.; Peritz, A.; Dekaris, V.; Reissig,
H.-U. Synthesis 2004, 2004, 1439-1445, (b) Sogah, G. D. Y.;
Cram, D. J. J. Am. Chem. Soc. 1979, 101, 3035-3042, (c)
Hocke, H.; Y. Uozumi, Y. Tetrahedron 2003, 59, 619-630 (d)
Lingenfelter, D. S.; Helgeson, R. C.; Cram, D. J. J. Org. Chem.
1981, 46, 393-406; (e) Pathak, K.; Bhatt, A. P.; Abdi, S. H. R.;
Kureshy, R. I.; Khan, N.-u. H.; Ahmad, I.; Jasra, R. V.
Tetrahedron: Asymmetry 2006, 17, 1506-1513.
Sanna, G. J. Nat. Prod. 2012
,
75, 225-229; (c)
Myrtucommulone M : Iqbal Choudhary, M.; Khan, N.; Ahmad,
M.; Yousuf, S.; Fun, H.-K.; Soomro, S.; Asif, M.; Ahmed
Mesaik, M.; Shaheen, F. Org Lett 2013, 15, 8, 1862-1865.
5. Myrtucommulones F-I: Carroll, R.; Lamb, J.; Moni, R.;
Guymer, G. P.; Foster, P. I.; Quinn, R. J. J. Nat. Prod. 2008
,
71, 1564-1568.
6. (a) Appendino, G.; Bianchi, F.; Minassi, A.; Sterner, O.;
Ballero, M.; Gibbons, S. J. Nat. Prod. 2002, 65, 334-338;
(b) Fiorini-Puybaret, C.; Luc, J.; Pierre Fabre Dermo-
22. Kim, Y. S.; Matsunaga, S.; Das, J.; Sekine, A.; Ohshima, T.;
Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 6506-6507
23. Charpentier, M. Ph.D. Thesis, Universität des Saarlandes,
Cosmétique, FR2992862A1, 2012
.
7. (a) Werz, O.; Koeberle, A. Patent DE102006058450A1,
Germany, 2006; (b) Koeberle, A.; Pollastro, F.; Northoff, H.;
Werz, O. Brit. J. Pharmacol. 2009, 156, 952-961.
Saarbrücken, 2015
.
24. Keller, E.; Veldman, N.; Spek, A. L.; Feringa, B. L.
Tetrahedron: Asymmetry 1997, 8, 3403-3413.
25. Yeboah, E. M. O.; Yeboah, S. O.; Singh, G. S. Tetrahedron
2011, 67, 1725-1762.
26. (a) List, B. Tetrahedron 2002, 58, 5573-5590; (b) Notz, W.;
Tanaka, F.; Barbas, C. F. Acc. Chem. Res. 2004, 37, 580-591;
(c) Jarvo, E. R.; Miller, S. Tetrahedron 2002, 58, 2481-2495.
d) Dalko, P. I.; Moisan, L. Angew. Chem. 2004, 116, 5248 (e)
Al-Momani, L. A. ARKIVOC 2012, vi,101-111.
8. (a) Werz, O.; Tretiakova, I. Patent DE102006021154A1,
Germany, 2006; (b) Tretiakova,I.; Blaesius, D.; Maxia, L.;
Wesselborg, S.; Schulze-Osthoff, K.; Cinatl, J. Jr.; Michaelis,
M.; Werz, O. Apoptosis 2008, 13, 119-131. (c) Izgi, K.;
Iskender, B.; Jauch, J.; Sezen, S.; Cakir, M.; Charpentier, M.;
Canatan, H.; Sakalar, C. J. Biochem. Molec. Toxicol. 2015, 29,
432-439. (d) Iskender, B.; Izgi, K.; Hizar, E.; Jauch, J.;
Arslanhan, A.; Yuksek, E. H.; Canatan, H. Tumor Biology
2016, 37, 8281-8291. (e) Wiechmann, K.; Müller, H,; König,
S.; Wielsch, N.; Svatoš, A.; Jauch, J.; Werz, O. Cell Chemical
Biology 2017, 24, 614–623.
27. (a) Oikawa, Y.; Hirasawa, H.; Yonemitsu, O., Tet. Lett. 1978
,
20, 1759-1762; b) Simon, C.; Constantieux, T.; Rodriguez, J.
Eur. J. Org. Chem. 2004, 4957-4980.
28. Nair, V. Synthetic Commun. 1987, 17, 6, 723-727.
29. During the preparation of this manuscript, Ref. 12d) was
9. Rosa, A.; Melis, M. P.; Deiana, M.; Atzeri, A.; Appendino, G.;
Corona, G.; Incani, A.; Loru, D.; Dessi, M. A. Chem. Phys.
Lipids 2008, 155, 16-23.
published. These authors mentioned
a proline catalysed
10. (a) Müller, H.; Paul, M.; Hartmann, D.; Huch, V.; Blaesius, D.;
Knoevenagel condensation of syncarpic acid and iso-
valeraldehyde. Besides an experimental procedure and
additional details were presented.
Koeberle, A.; Werz, O.; Jauch, J. Angew. Chemie Int. Ed. 2010
49, 11, 2045-2049; (b) Jauch, J. Ger. Offen. 2010, DE
102008044993 A1 20100318
,
30. It was observed on TLC that Glu did not catalyse the formation
of the isobutylidene derivative 3, and His enhanced the
formation of the Michael acceptor 3 but also the reaction
between isobutyryl phloroglucinol (6) and isobutyraldehyde (5)
which consumed the starting material did not lead to any
product.
11. Isobutyryl phloroglucinol (6) was synthesized according to
Reininger, W.; Hartl, A. Process for the preparation of
humulone, Ger. Pat. (1976). DE2519990 (A1)-1976-12-12.
Syncarpic acid (4) was prepared from acetyl phloroglucinol by
methylation according to Riedl, W.; Risse, K. H. Justus Liebigs
Ann. Chem. 1954, 585, 209 – 219 and Murin, B.; Riedl, W.;
31. (a) He, P.; Liu, X.; Shi J.; Lin, L.; Feng, X. Org. Lett. 2011, 13,
5, 936-939, (b) Deng, Y.-Q.; Zhang, Z.-W.; Feng, Y.-H.; Chan,
A. S. C.; Lu, G. Tetrahedron : Asymmetry 2012, 23, 1647-
Risse, K. H.; Scheublein, M. Chem. Ber. 1959
2033 – 2037, followed by hydrolytic cleavage of the acetyl
, 92,

1652. (c) Xie, J.-W.; Yue, L.; Chen, W.; Du, W.; Zhu, J.;
2007, A9, 3C, 4C13E-41P5.TED MANUSCRIPT
Deng, J.-G.; Chen, Y-C. Org. Lett.
32. Diez-Barra, E. ; De la Hoz, A. ; Merino, S. ; Rodriguez, A. ;
Sanchez-Verdu, P. Tetrahedron 1998, 54, 1835-1844.
33. Adam, W.; Rao, P. B.; Degen, H.-G.; Levai, A.; Patonay, T.;
Saha-Möller, C. R. J. Org. Chem. 2002, 67, 259-264.