A convergent stereocontrolled total synthesis of (-)-terpestacin

Article abstract of DOI:10.1039/c2ob25940k

A stereocontrolled total synthesis of (-)-terpestacin has been achieved starting from (R)-(-)-carvone as a chiral pool and (E,E)-farnesol via a highly convergent approach. Thus, (R)-(-)-carvone was transformed into the cyclopentanone segment through a series of high yielding operations with the proper setup of all the stereochemical centers while (E,E)-farnesol was converted into the other requisite building block via a series of high yielding reactions. The cyclopentanone intermediate was both selectively enolized and alkylated at room temperature to yield the desired coupling product, which provided the natural product upon further transformations.

Full text of DOI:10.1039/c2ob25940k

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ARTICLE TYPE
A Convergent Stereocontrolled Total Synthesis of (−)-Terpestacin
Yehua Jin and Fayang G. Qiu*
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
DOI: 10.1039/b000000x
5
A stereocontrolled total synthesis of (−)-terpestacin has been achieved starting from (R)-(−)-carvone as a
chiral pool and (E,E)-farnesol via a highly convergent approach. Thus, (R)-(−)-carvone was transformed
into the cyclopentanone segment through a series of high yielding operations with the proper setup of all
the stereochemical centers while (E,E)-farnesol was converted into the other requisite building block via a
series of high yielding reactions. The cyclopentanone intermediate was both selectively enolized and
10 alkylated at room temperature to yield the desired coupling product, which provide the natural product
upon further transformations.
weak antimicrobial activity,1a suggesting that the activity of
Introduction
terpestacin was selective and thus would potentially be valuable
for the development of anticancer as well as anti-AIDS
therapeutics.
Terpestacin (1a), (Figure 1) a sesterterpene natural product, was
first isolated from Arthrinium1 in 1993 and then from
15 Ulocladium2 in 2001, though the enantiomeric structure was
assigned in the latter case. Soon siccanol from Bipolaris
sorokiniana was reported in 2002 to have the 11-epi-terpestacin
structure.3 Subsequently, Jamison demonstrated that siccanol was
terpestacin through the total synthesis of (−)-terpestacin.4
20 Fusaproliferin (1b), (Figure 1) the C-24 acetate of terpestacin,
was isolated from Fusarium proliferatum in 1993.5 However, the
correct absolute configuration of both (−)-terpestacin and (−)-
fusaproliferin were defined only after Myers’ total syntheses of
both natural products.6
45
Apart from the impressive biological activities, terpestacin
possesses four chiral centers, three E-carbon-carbon double
bonds, two vicinal ketone carbonyl groups and a structural feature
of a five-membered ring fused to a fifteen-membered ring. These
combined structural elements have imposed significant
50 challenges to synthetic chemists. Consequently, terpestacin has
become an important target of total synthesis shortly after its
discovery. So far, four total syntheses of (−)-terpestacin by
Tatsuta (1998),7a Myers (2002),6a Jamison (2003),4a and more
recently by Trost (2007),8 and two for the racemate by Tatsuta
55 (1998)7b and Tius (2007),9a respectively, have been reported,
together with three approaches to the fused ring system
independently described by Takeda (1995),10 Heissler (1999),11
and Tius (2005),9b respectively.
O
1
HO
15
RO
11
23
Results and Discussion
OH
Terpestacin (1a) R=H
Fusaproliferin (1b) R=Ac
60 We are interested in the development of a therapeutic material
based on (−)-terpestacin. From a practical point of view, the
starting materials and the reagents must be either commercially
available or readily accessible and conventional reaction
conditions are desired. Based on such consideration and the
65 previous synthetic accomplishments in this area, our synthetic
strategy was designed to utilize high yielding reactions
throughout the synthesis and to involve least number of
chromatographic separations. Herein we wish to disclose a
convergent stereocontrolled total synthesis of (−)-terpestacin
70 starting from (R)-(−)-carvone and (E,E)-farnesol. The
retrosynthetic analysis of terpestacin is outlined in Scheme 1. The
vicinal diketon functionality in the five-membered ring may be
introduced through oxidation of the ketone carbonyl of the
bicyclic intermediate 2, which may be derived from the
25
Figure. 1 Structures of terpestacin and fusaproliferin
After its isolation, terpestacin was reported to be a potent
inhibitor (ID50 0.46µ
g/mL) of the formation of syncytia,1,2 which
are multinucleated cells that account in part for the pathology of
30 HIV infection, and to be an angiogenesis inhibitor both in bovine
aortic endothelial cells and in chorioallantoic membrane from
chick embryos.1d It was also shown that terpestacin had only
Laboratory of Molecular Engineering, and Laboratory of Natural Product Synthesis,
35 Guangzhou Institutes of Biomedicine and Health, The Chinese Academy of Sciences,
190 Kaiyuan Avenue, Guangzhou 510530, China.
E-mail: qiu_fayang@gibh.ac.cn
† Electronic Supplementary Information (ESI) available: Full
experimental procedures and characterization for all new compounds. See
40 DOI: 10.1039/b000000x/
75 cyclopentanone intermediate
3 and phosphonate 4. While
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intermediate
3
may be derived from (R)-(−)-carvone, the 30 incoming hydroborating agent.
phosphonate may be obtained from (E,E)-farnesol according to a
similar known procedure.7,9a
The hydroxyl group in 7 was protected with MEMCl and the
benzoate was hydrolyzed with sodium hydroxide in methanol.
After an extraction work-up, the newly formed alcohol was
oxidized with TEMPO/BAIB to the aldehyde, which was, after a
35 brief work-up, treated with the methyl ylid to provide the desired
alkene 9 (74% for the combined 4 steps). Hydroboration of the
olefin with the borane-THF complex followed by treatment with
basic hydrogen peroxide afforded the desired alcohol 10 (88%).
Subsequent conversion of 10 into the key intermediate 3 was
40 achieved as a single diastereomer determined on the basis of
1HNMR and 13CNMR data analysis through a sequence of
protection of the hydroxyl group with TBSCl/Et3N, selective
removal of the THP protective group with magnesium bromide in
dry diethyl ether and oxidation of the secondary alcohol with
45 TEMPO/BAIB (88% for the combined 3 steps) (Scheme 4).
Alkylation
O
O
1
HO
HO
15
R1O
11
23
OH
O
2
(-)-terpestacin 1a
HWE olefination
O
OTBS
Br
+
OTBS
MEMO
P(OEt)2
O
3
4
O
THPO
THPO
a
OH
b
c
7
MEMO
MEMO
OTBS
OH
10
9
(R)-Carvone
(E,E)-Farnesol
THPO
HO
O
5
Scheme 1. The retrosynthetic analysis of (−)-terpestacin
d
MEMO
e
OTBS
OTBS
MEMO
MEMO
Intermediate 5 was obtained from (R)-(−)-carvone as a single
diastereomer (dr > 19:1) according to the procedure developed
by Ley et al.12 Hydroboration of 5 with disiamylborane afforded
the undesired 5a in 85% yield, in line with the observations of
10 Yoon et al. on a similar system.13 Hydroboration with BH3•Me2S
produced a mixture of the diol 5b, in which both the carbon-
carbon double bond and the ester functionality were hydroborated
(Scheme 2). Thus, the ester functionality was reduced with LAH
11
12
3
Scheme 4. Synthesis of the intermediate 3. a) i) MEMCl, DIPEA,
CH2Cl2, RT, 92%; ii) 1% NaOH in MeOH, 90%; iii) TEMPO, BAIB,
CH2Cl2, RT, 98%; iv) Ph3PCH3Br, NaHMDS, THF, 0 °C, 91%, (74%
50 over 4 steps); b) BH3•THF, THF, 0oC, then NaOH, H2O2, 0 °C, 88%; c)
TBSCl, Et3N, DMAP, CH2Cl2, RT, 98%; d) MgBr2, Et2O, RT, 94%; e)
TEMPO, BAIB, CH2Cl2, RT, 96%.
On the other hand, (E,E)-farnesol was transformed into the
desired phosphonate 4 through 8 reactions following a modified
55 procedure initially developed by Tatsuda7 and modified by Tius9a
in 42% overall yield.
OTHP
OTHP
OTHP
b
a
HO
HO
O
O
OH
Me
O
O
With both key intermediates in hand, we started to assemble
the entire molecule. A highly selective deprotonation method was
in need. However, the selectivity for the formation of a variety of
60 thermodynamic silyl enol ethers was found to be poor, while the
use of LHMDS or the Yamamoto method,15 which utilized the
precoordination of the starting ketone with an aluminum complex
before treatment with LDA, was unsuccessful in this case, either.
Upon treatment with NaHMDS at −20 °C, intermediate 3 was
65 deprotonated to give 3a, the less highly substituted enolate, as a
major product. The latter was treated with allyl bromide to afford
the corresponding alkylation product in 95% yield. After these
unsuccessful efforts, potassium t-butoxide, sodium hydride, and a
magnesium reagent16 that is reported to be effective for this
70 purpose were all tested, but none provided satisfactory selectivity.
Fortunately, slow addition of NaHMDS (0.95 equiv) during 1h at
room temperature to the ketone moiety 3 and then stirring the
mixture for an additional hour before the addition of phosphonate
4 provides a 3:1 ratio of regioisomers 13a/13b in 93% combined
75 yield, though the separation of the two isomers was difficult. The
enolate equilibration was in favor of the formation of the more
highly substituted enolate. This room temperature enolate
alkylation result is of practical importance since the conventional
methods of enolate alkylation is usually done at low temperatures.
80 The mixture of 13a and 13b was then treated with TBAF to
5b
5a
5
15 Scheme 2. Hydroboration of intermediate 5. a) Disiamylborane, THF, 0
°C, then NaOH, H2O2, 0 °C; b) BH3•DMS, THF, 0 °C, then NaOH, H2O2,
0 °C.
to the alcohol. After protecting the hydroxyl group with benzoyl
chloride to form benzoate 6, compound 7 and 8 were obtained
20 when BH3•Me2S was used (Scheme 3). Compound 8 was
dehydrated to recover the starting material (70%) according to a
similar procedure.14 Thus, the yield of the desired product 7 was
c
OTHP
OTHP
OTHP
OBz
OTHP
OH
OH
a
b
+
OBz
O
7
OBz
8
O
6
5
minor
(undesired)
major
(desired)
dr = 1.5 : 1
Scheme 3. Synthesis of intermediate 7. a) i) LAH, THF, RT; ii) BzCl,
25 Et3N, CH2Cl2, RT, 92% over two steps; b) BH3•DMS, THF, 0 °C, then
NaBO3(H2O)4, 7/8 = 53/35, 88%; c) MsCl, Et3N, LiBr/Li2CO3 , 70%.
promoted to 69% based on the recovered starting material. We
believed that the ester functionality may have mainly displayed
steric hindrance instead of coordination to the boron atom of the
2
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remove the TBS protective groups and the hydroxyl groups were 30 intermediate. Thus, treatment of intermediate 14 with PPTS in
oxidized with IBX to the corresponding carbonyl functionalities.
Following a brief work-up, the product mixture was treated with
refluxing t-BuOH and then with TBSCl in DCM at room
temperature afforded compound 15 in 70% overall yield.
Chemoselective reduction of the C11 carbonyl group afforded the
spectroscopically pure product 16 in 50% yield (75% BORSM)
35 after treatment with (R)-Me-CBS-Borane in THF at −50°C
accompanied by the recovery of some starting materials (Scheme
7).
NaO
NaO
3
a
3
OTBS
OTBS
MEMO
MEMO
room temp
3a
3b
O
O
O
O
a
4
+
MEMO
MEMO
O
TBSO
O
MEMO
14
15
OTBS
TBSO
(EtO)2P
OTBS
P(OEt)2
OTBS
O
13a
major
(desired)
13b
minor
(undesired)
O
O
regioselectivity = 3 : 1
b
OH
TBSO
O
16
b, c, d
Scheme 7. Synthesis of intermediate 16. a) i) PPTS, t-BuOH, reflux; ii)
40 TBSCl, Et3N, DMAP, CH2Cl2, RT, 70% over 2 steps; b) (R)-Me-CBS,
BH3•THF, THF, −50 °C, 50%. (75% BORSM)
MEMO
O
14
The C11-hydroxyl group was silylated with TBSOTf at −78 °C
in essentially quantitative yield and the product was subjected to
the Davis’ oxidation at −78 °C. After a brief work-up, cupric
45 acetate was added to the methanol solution of the crude product
to introduce the desired ketone carbonyl group (79%), which
automatically enolized to arrive at product 18 as a single
5
Scheme 5. Regioselective enolate formation from 3 and the Synthesis of
intermediate 14. a) NaHMDS (0.95 equiv), 2h, then phosphonate 4, 93%;
b) TBAF, THF, RT, 93%; c) IBX, DMSO, RT, 80%; d) DIPEA, LiCl,
CH3CN, RT, C = 0.005M, 65%. (45% over 4 steps).
DIPEA and lithium chloride under high dilution conditions at
1
10 room temperature and only the desired isomer provided the
macrocyclization product 14 as a single isomer with correct
stereochemistry and double bond geometry (Scheme 5).
Obviously, the undesired macrocyclization from the other isomer
was slow compared with the desired one. The net overall yield of
15 the desired product for the combined four-step operations was
45%.
diastereomer determined on the basis of HNMR and 13CNMR
data analysis. Finally, removal of the TBS groups with aqueous
50 HF afforded the desired product in 90% yield (Scheme 8), which
showed identical characteristic patterns in both the NMR spectra
(proton and carbon-13) and the sign and magnitude of the optical
rotation with the natural product reported2 (See supporting
information).
Lewis acid
or
protic acid
O
O
O
(R)-Me-CBS
BH3-THF
a
14
b
16
THF, - 50oC
TBSO
Complex
Mixture
OH
OH
OTBS
MEMO
HO
14a
17
50% (75% BORSM)
Scheme 6. Unsuccessful deprotection of the MEM group from 14a.
O
O
c
Hydroboration of 14 with the boran-THF complex in the
20 presence of CBS led to the isolation of 14a as a single
diastereomer determined on the basis of HNMR and 13CNMR
HO
HO
HO
TBSO
1
OTBS
OH
data analysis. However, the subsequent removal of the MEM
protection was problematic. Compound 14a was unstable under
strongly acidic conditions that can be used to remove the MEM
25 protective group due to the presence of the allylic alcohol at C11,
while the MEM protection can survive the weakly acidic
conditions (Scheme 6).
18
(-)-terpestacin 1a
55
Scheme 8. Completion of the total synthesis of (−)-terpestacin. a)
TBSOTf, 2.6-Lutidine, CH2Cl2, −78°C, 97%; b) i) NaHMDS, N-
o
Sulfonyloxaziridines, THF, −78 C; ii) Cu(OAc)2 in MeOH, RT, 79%; c)
HF, THF, RT, 90%.
60 Conclusions
Obviously, the MEM protective group has to be replaced by a
different protective group before the reduction of the diketone
A total synthesis of (−)-terpestacin starting from a chiral pool was
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achieved in 22 steps (3% overall yield from intermediate 5).
Notes and references
There are several features in this synthetic strategy: 1) Controlled
introduction of the C23 chiral center; 2) The formation of the
more highly substituted enolate of intermediate 3 through enolate
equilibration and the alkylation of the resulting enolate at room
temperature; and 3) The stereoselective CBS-borane reduction at
C11 carbonyl of the diketone intermediate 15. All these effective
elements combined with mild reaction conditions will make this
synthesis practically feasible.
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