Efficient and straightforward preparation of a building block for (-)-teubrevin G synthesis via chemically diversed oriented synthesis

Article abstract of DOI:10.1016/j.tetlet.2011.10.112

A rapid and efficient methodology to highly functionalised molecular units well suited as scaffolds for diversity-oriented molecular construction in the synthesis of natural products is reported herein. A key macrocyclic intermediate in the synthesis of the neo-clerodane diterpene (-)-teubrevin G was successfully synthesized in a 5-step sequence in a 70% overall yield using a novel intramolecular coupling between an allylborating agent and a 1,5-dialdehyde moiety.

Full text of DOI:10.1016/j.tetlet.2011.10.112

Tetrahedron Letters 52 (2011) 7004–7007
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient and straightforward preparation of a building block for (À)-teubrevin
G synthesis via chemically diversed oriented synthesis
Daniel Garcia Velazquez a,b,c, , Rafael Luque d,1
⇑
a Departamento de Química Orgánica, Universidad de La Laguna, Campus de Anchieta, s/n. 38206 La Laguna, Tenerife, Spain
b Instituto Universitario de Bio-Orgánica Antonio González, Universidad de La Laguna, Astrofísico Francisco Sánchez, 2, 38206 La Laguna, Tenerife, Spain
c Instituto Canario de Investigación del Cáncer, Spain
d Departamento de Química Orgánica, Universidad de Córdoba, Edificio Marie Curie, Ctra Nnal IV, Km 396, E-14014 Córdoba, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A rapid and efficient methodology to highly functionalised molecular units well suited as scaffolds for
diversity-oriented molecular construction in the synthesis of natural products is reported herein. A key
macrocyclic intermediate in the synthesis of the neo-clerodane diterpene (À)-teubrevin G was success-
fully synthesized in a 5-step sequence in a 70% overall yield using a novel intramolecular coupling
between an allylborating agent and a 1,5-dialdehyde moiety.
Received 16 September 2011
Revised 17 October 2011
Accepted 19 October 2011
Available online 25 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Diversed oriented synthesis
Teubrevin G
Intramolecular coupling
The quest for new drugs has fostered the development of novel
and simpler synthetic strategies that can grant access to highly
complex molecules in a controllable fashion. Most of the emerging
strategies are based on the paradigm of molecular complexity for
the discovery of new chemical entities. Diversity oriented synthe-
sis (DOS), natural products, and privileged structures based combi-
natorial libraries,1–6 multicomponent reactions, and the latest
introduced concept of Diverted total synthesis (DTS)7,8 have been
successfully utilized to fulfill the above mentioned paradigms.
There is an active search for new synthetic protocols which can
address the modular and diversity-oriented construction of the
aforementioned molecular complexity, particularly for oligosaccha-
rides, glycoconjugates, diterpenoids, and so on. Clerodane diter-
penes are particularly interesting due to their high structural
diversities,9–14 promising biological activities such as semiochemi-
cals for insect repellents (antifeedants) as well as anti-inflammatory
properties.15–18 Many of these compounds have successfully been
isolated from plants (mostly of the Lamiaceae family), microorgan-
isms and/or marine organisms.14,19,20 Many of these polyfunctiona-
lised (neo)clerodane backboned diterpenes have certain structural
motifs which include oxygenated 5-member rings as well as a char-
acteristic decalin-type system.21 However, there are interesting
exceptions which are intrinsically different and thus possess unique
structures and properties in terms of biological activities. One of
such most relevant molecules is (À)-teubrevin G (Scheme 1).
(À)-Teubrevin G 1 is a neo-clerodane diterpene which was originally
isolated from the aerial part of Teucrium brevifolium (Lamiaceae).22
Interestingly, it does not share the common features of most clero-
dane and neo-clerodane families, but comprises of an interesting
carbon scaffold formed by a furan ring fused to an eight member
macrocycle (specifically functionalized), bearing also a spiro chiral
lactone. Such structural changes and peculiar chemical moieties
as compared to similar diterpenes make this molecule highly inter-
esting from a synthetic point of view (offering some advantages in
terms of innovative synthetic strategies) as well as opening up a
wide range of important studies concerning its unexplored biologi-
cal activities.21
The full synthesis of (À)-teubrevin G was to date exclusively
described some years back by Paquette et al.23–25 However the
O
O
O
AcO
O
O
O
⇑
Corresponding author. Fax: +34 922318571.
E-mail addresses: dgvelazq@ull.es (D.G. Velazquez), q62alsor@uco.es (R. Luque).
URL: http://www.icic.es (D.G. Velazquez).
1
(-) Teubrevin G
1
Tel.: +34 957212065; fax: +34 957212066.
Scheme 1. Chemical structure of (À) teubrevin G, 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.112

D. G. Velazquez, R. Luque / Tetrahedron Letters 52 (2011) 7004–7007
7005
formation of the key compound in the synthesis of 2,3,4-trisubsti-
tuted furan ring turned to be a really challenging step26 that,
although elegantly tackled, definitely required a more efficient
and shorter way of preparation.26
epoxidation, halogenation,
hydrogenation, etc.
derivatization
by oxidation,
alkylation, etc.
In view of these premises, we sought to devise a more efficient
protocol to synthesize a key building block for the synthesis of the
neo-clerodane diterpene (À)-teubrevin G as well as the biological
evaluation of all intermediate compounds in its synthesis.
The retrosynthetic plan for the synthesis of this chemical
intermediate has been described in Scheme 2. Following a slightly
modified chemistry to that performed by Roush,27 the versatile
intermediate 3 will be initially formed by vinylation-allylation of
dialdehyde 4. In principle, the synthesis will rely on two key steps.
Firstly, the formation of 2,3,4-trisubstituted furan building block
through efficientmulticomponent domino reaction between methyl
propiolate 6 and an aldehyde 7 (triggered by tributylphosphine as
the nucleophile),28 and secondly the double allylboration of a 1,
5-dialdehyde system via a novel intramolecular coupling.
In order to match with our interest in the synthesis of new
molecular entities bearing biological properties, we planned to
tackle the diverted total synthesis (DTS) of (À)-teubrevin G with
the intention to explore related derivatives that can be provided
by the chemically versatile advanced intermediate 3 via conve-
niently selected chemistries (Fig. 1).
OH
HO
O
different
O
aldehydes
O
Chemically Diverse Platform
Figure 1. Reactivity pattern of the scaffold 3.
O
O
OH
O
In light of these considerations, herein we report a novel syn-
thetic approach to achieve the synthesis of the intermediate 3,
which can in principle grant us access to different structural ana-
logs and eventually lead to the total synthesis of 1 (Scheme 3). A
selective manipulation of various functionalities for the diversity
sites Dn can potentially produce compound 3 congeners which
could lead to synthetic molecules with improved pharmacokinetic
properties and/or biological activities.
Initially, the versatile intermediate 3 was the target synthetic
molecule. Its synthesis comprised a series of reactions as shown
in Schemes 4–8.
In the first synthetic step, aldehyde 7 was prepared via conden-
sation of b-ketoester 8 with ethyleneglycol and then selective
reduction with DIBAL-H at À80 °C for 8 min, yielding 92% of the de-
sired product (Scheme 4).29
AcO
O
HO
O
O
O
O
O
2
1
(-) Teubrevin G
D3
D4
OH
D5
HO
D2
O
O
D1
Dn : Diversity site
O
O
3
Compound 5 was subsequently prepared by a multicomponent
domino reaction between methyl propiolate 6 and aldehyde 7
(ratio 3:1) in the presence of catalytic amounts of tri-n-butylphos-
phine in chloroform at À60 °C followed by acid promoted aromati-
zation to afford 2,3,4-trisubstituted furan (53% overall yield) as
depicted in Scheme 5. Diester 5 was then completely reduced by
treatment with LiAlH4 to yield compound 11 and then it was selec-
tively oxidized using MnO2 as the catalyst in an overall yield of 83%
(Scheme 6).30
Scheme 3. Hypothetic retro-synthetic pathway to synthesize (À)-teubrevin G from
intermediate 3 via functionalisation of diversity sites.
O
HO
O
OH
pTsOH
96%
O
CO2Et
CO2Et
8
9
DIBAL-H(hexanes)
-78 ºC 7 min.
92%
OH
O
O
CHO
CHO
OHC
HO
7
O
O
O
O
Scheme 4. Synthesis of dialdehyde 7.
O
O
4
3
Subsequently, compound 8 was synthesized according to the
Roush protocol27 (Scheme 7), in which allenylmagnesium bromide
14 was added over an ethylether solution of 15 at À78 °C, yielding
60% of 16 along with magnesium salts. Then, 16 was transferred
in situ with a cannula to a ethylether solution of ethylenglycolbo-
rane 17 at 0 °C, affording compound 18 (95% yield, based on 16).
In our convergent approach, the synthesis of the eight-mem-
bered cycle was performed by a novel intramolecular coupling of
dialdehyde 12 with the boryl-substituted allylboronate 18
CO2Me
CO2Me
6
7
MeO2C
O
O
O
O
O
CHO
5
Scheme 2. Synthetic plan to obtain advance intermediate 3.

7006
D. G. Velazquez, R. Luque / Tetrahedron Letters 52 (2011) 7004–7007
MeO2C
MeO2C
CO2Me
6
O
O
O
O
nBu3P / CHCl3
B
O
O
B
CHO
O
O
B
O
O
O
O
O
O
-60ºC
H
O
O
H
O
B
10
7
O
O
MeO2C
MeO2C
O
pTsOH, toluene
53%
O
O
O
O
O
Intermediate A
O
Transition state
5
Scheme 9. Hypothetic transition state of the coupling reaction of compound (18)
with the 1,5-dialdehyde (12).
Scheme 5. Synthesis of diester 5.
was subjected to standard oxidative workup (NaOH, H2O2) before
product isolation, yielding 48% of the intermediate 3 upon chro-
matographic purification.
MeO2C
MeO2C
HOH2C
HOH2C
LiAlH4 ,Et2O
r.t.
It is important to point out that compound 3 was obtained as a
racemic mixture and its structural elucidation was determined
using a two dimensional spectroscopic experiment (HMBC), which
allowed us to establish proton-carbon correlation (See ESI).
The proposal formation mechanism of compound 3 was based
on the different reactivity of the aldehyde groups. We concluded
that the first coupling originated the adduct b-alkoxyallylboronate
A, which spontaneously folds and reacts with the less reactive
aldehyde group through a chair-type transition state (Scheme 9).
In summary, we have reported a facile access to the highly func-
tionalized fragment 3 of (À)-teubrevin G (1), which was obtained
in 5 steps and 70% overall yield, starting from cheap and commer-
cially available compounds in a relatively simple and straightfor-
ward protocol. To the best of our knowledge, this is the first
example of an intramolecular coupling between an allylboronating
agent and a 1,5-dialdehyde structure for the generation of com-
pound 3. The evaluation of the biological activities of all com-
pounds and the completion of the total synthesis of 1 will be
reported in due course.
O
89%
O
O
O
O
O
5
11
OHC
O
MnO2, DCM
r.t.
OHC
92%
O
O
12
Scheme 6. Synthesis of dialdehyde 12.
O
B
O
15
Mg/ HgCl2
MgBr
Cl
Br
HC
H2C
Et2O
-78 ºC
60%
H
Experimental section
13
14
O
All chemicals were utilized as purchased unless otherwise sta-
ted. Product 5 was synthesized from 7 as described in Scheme 5.
Tri-n-butylphosphine (0.44 mL, 1.72 mmol, 0.4 equiv) was added
to a cooled solution (À60 °C) of methyl propiolate (1.13 mL,
12.7 mmol, 3 equiv) and 7 (550 mg, 4.23 mmol) in dry CHCl3
(12 mL). The reaction mixture was stirred for 2 h and then
quenched with HCl 5% (10 mL). After extraction with CH2Cl2
(3 Â 10 mL), the organic layers were dried over anhydrous sodium
sulfate. After the solvent had been removed at reduced pressure,
products were purified by flash column chromatography (silica
gel, n-hexane/EtOAc 90:10) to yield 10 (53%) as a mixture of iso-
mers (Z/E 1:2.9). A mixture of isomers of 10 (200 mg, 0.67 mmol)
and toluene-4-sulfonic acid monohydrate (0.2 equiv) was dis-
solved in toluene (10 mL) and the resulting solution was heated
to 90 °C. The reaction was monitored by TLC until the conversion
was completed. The reaction mixture was loaded directly into a sil-
ica gel column and eluted with n-hexane/EtOAc 80:20 to yield 5
(187.5 mg, 92%) as an oil. IR (KBr, cmÀ1): 3198.8, 2973.6, 2862.6,
1720.8, 1436. 1H NMR (300 MHz, d, CDCl3): 1.49 (s, 3H), 2.69 (s,
2H), 3.51 (s, 2H), 3.64 (s, 3H), 3.79 (s, 3H), 3.96-4.17 (m, 4H),
7.69 (s, 1H). 13C NMR (75 MHz, d, CDCl3): 21 (q), 32 (t), 40 (t), 49
(q), 51 (q), 64 (t), 65 (t), 106 (s), 115 (s), 122 (s), 144 (d), 152 (s),
160 (s), 168 (s). Anal. Calcd for C14H18O7: %C 56.37; %H 6.08. Found:
%C 56.12; %H 6.24.
O
BH 17
O
O
B
B
B
O
O
O
H2C
O
H
Et2O 0 ºC
95%
16
18
Scheme 7. Synthetic pathway to achieve c-borinanyl-allylboronate 18.
O
O
B
OH
B
O
OHC
O
O
OHC
18
HO
-78 ºC
O
O
high dilution
O
(dropwise adition 2h)
48%
O
O
3
12
Scheme 8. Intramolecular coupling of
hyde 12 to afford compound 3.
c-borinanyl-allylboronate 18 with dialde-
(Scheme 8). The double allylboration reaction was performed by
slowly adding 1 equiv of allylboronating agent 18 for 2 h over
1 equiv of 12 in ethylether at À78 °C. The mixture was then
allowed to stir at room temperature for 24 h. The crude product

D. G. Velazquez, R. Luque / Tetrahedron Letters 52 (2011) 7004–7007
7007
Product 11 was synthesized from 5 as described in Scheme 6. A
solution of LiAlH4 (140 mg, 3.70 mmol, 2.2 equiv) in dry THF (5 mL)
was added dropwise to a solution of 5 (500 mg, 1.67 mmol) in THF
(3 mL) at room temperature for 1 h. The mixture was stirred for 4 h
and then washed several times with a solution of ammonium sul-
fate (15 mL) and left under stirring overnight. The final solution
was filtered through celite and extracted with EtOAc. Compound
11 was obtained as a yellowish oil (360 mg, 89% yield). The crude
product was employed in the following reaction without purifica-
tion. IR (KBr, cmÀ1): 3397, 2972, 2870.6, 1723, 1452. 1H NMR
(300 MHz, d, CDCl3): 1.39 (s, 3H), 2.57 (s, 2H), 2.63–2.71
(t, J = 10 Hz, 2H), 3.65 (t, J = 8 Hz, 2H), 4.15–4.22 (m, 4H), 4.89
(s, 2H), 7.69 (s, 1H). 13C NMR (75 MHz, d, CDCl3): 20 (q), 26 (t),
45(t), 56 (t), 61 (t), 63 (t), 65 (t), 108 (s), 118 (s), 121 (s), 137 (d),
149 (s). Anal. Calcd for C12H18O5: %C 59.49; %H 7.49. Found: %C
59.52; %H 7.42.
Product 12 was synthesized from 11 as described in Scheme 6.
MnO2 (144 mg, 1.65 mmol, 20 equiv) was added to a solution of 5
(20 mg, 0.08 mmol) in dry dichloromethane (3 mL). The mixture
was stirred for 48 h at room temperature, then filtered off through
celite and washed with EtOAc. The organic layer was dried over
anhydrous MgSO4 and the solvent was evaporated in a rotary evap-
orator to yield compound 12 (17.6 mg, 92% yield) as an oil, without
further chromatographic purification needed. IR (KBr, cmÀ1):
3380.8, 2932, 2859, 1723.5, 1642, 1450. 1H NMR (300 MHz, d,
CDCl3): 1.42 (s, 3H), 2.59 (s, 2H), 3.46 (s, 2H), 3.64 (d, J = 11 Hz,
2H), 4.15–4.22 (m, 4H), 7.67 (s, 1H), 9.59 (s, 1H), 9.77–9.81 (t,
J = 14 Hz, 1H). 13C NMR (75 MHz, d, CDCl3): 21 (q), 36 (t), 43 (t),
64 (t), 66 (t), 109 (s), 111,(s) 132 (s), 149 (d), 154 (s), 184 (s),
200 (s). Anal. Calcd for C12H14O5: %C 60.50; %H 5.92. Found: %C
60.38; %H 5.98.
Product 18 was synthesized from 16 as described in Scheme 7:
A solution of 16 (ethylenglycolborane, 65.5 mg, 0.91 mmol) in dry
Et2O (5 mL) was added dropwise to a suspension of 17 (100 mg,
0.91 mmol) in dry Et2O (3 mL) at 0 °C under nitrogen atmosphere.
The mixture was stirred until complete dissolution, indicating
reaction completion. The solvent was evaporated in a rotary evap-
orator, yielding 18 (157 mg, 95%) as a transparent oil. The crude
product was used in the next step without further chromato-
graphic purification. IR (KBr, cmÀ1): 3287.8, 2934.5, 2873.8,
1408.6. 1H NMR (300 MHz, d, CDCl3): 1.22–1.27 (d, J = 8.25 Hz,
2H), 4.15 (s, 4H), 4.37 (s, 4H), 5.21–5.26 (d, J = 15.3 Hz, 1H),
6.57–6.62 (dt, J = 7.2 Hz, J = 15.3 Hz, 1H). 13C NMR (75 MHz, d,
CDCl3): 32 (t), 63 (t), 66 (t), 126 (d), 138 (d). Anal. Calcd for
C7H12B2O4: %C 46.25; %H 6.65. Found: %C 46.23; %H 6.77.
Product 3 was synthesized from 12 as described in Scheme 8. A
freshly prepared solution of 18 (13.63 mg, 0.075 mmol) in dry Et2O
(7 mL) was added dropwise (2 h) to a solution of 12 (18 mg,
0.075 mmol) in dry Et2O (0.5 mL) under nitrogen atmosphere at
À78 °C. The mixture was stirred for 2 h at À78 °C and then for
24 h at room temperature. The reaction flask was subsequently
7.60 (s, 1H), 5.67 (m, J=7.92 Hz, 1H), 5.53 (m, J = 16.3, 7.9 Hz, 1H),
4.85 (m, J = 12.2 Hz, 1H), 4.57 (m, 1H), 4.16 (m, 4H), 3.12 (d,
J = 18 Hz, 2H), 2.75 (t, J = 12.5 Hz, 2H), 2.59 (s, 2H), 1.39 (s, 3H).
13C NMR (75 MHz, d, CDCl3): 23 (q), 38 (t), 41 (t), 65 (t), 65.5 (t),
71 (d), 73 (d), 110 (s), 120 (s), 127 (s), 132 (d), 134 (d), 145 (d),
156 (s). Anal. Calcd for C15H20O5: %C 64.27; %H 7.19. Found: %C
64.35; %H 6.98. More details of this compound including 1H and
13C NMR as well as HMDC spectra can be found in the ESI.
Acknowledgments
This research was supported by the Ministerio de Educación y
Ciencia de España (MEC, SAF2006-06720). DGV acknowledges
Gobierno de Canarias for a pre-doctoral fellowship. RL gratefully
acknowledges Ministerio de Ciencia e Innovación for the conces-
sion of a Ramon y Cajal contract (RYC-2009-04199) and funding
in the framework of project CTQ2011-28954-C02-02 as well as
Consejeria de Ciencia e Innovacion, Junta de Andalucia for funding
project P10-FQM-6711.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.10.112.
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(22 L). The reaction was stirred vigorously for 4 h at room tem-
lL) was then
l
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solution of NaHCO3 (2 mL) and another saturated solution of NaCl
(2 mL). The aqueous phase was extracted with DCM and subse-
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