A flexible synthesis of C33-C39 polyketide region of apratoxin: Synthesis of natural and unnatural analogues

Article abstract of DOI:10.1016/j.crci.2010.09.002

A flexible synthesis sequence toward the synthesis of the polyketide region of apratoxin has been developed. The common step of the synthesis is a crotylation reaction. Stereospecific aldolisation, sulfate ring opening or Jacobsen HKR is also highlighted. This synthetic scheme led to the synthesis of several analogues. These examples raise the possibility of synthesising numerous analogues of this portion of apratoxins. Then, together with our supported strategy to synthesise the oxazoline analogue of apratoxin A, this paper opens the possibility to provide easily oxoapratoxin analogues for future SAR studies of this potent antitumoral compound.

Full text of DOI:10.1016/j.crci.2010.09.002

C. R. Chimie 14 (2011) 437–440
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Preliminary communication/Communication
A flexible synthesis of C33-C39 polyketide region of apratoxin:
Synthesis of natural and unnatural analogues
*
Arnaud Gilles , Jean Martinez, Florine Cavelier
IBMM, UMR-CNRS 5247, universite´ Montpellier 1, 2, place Euge`ne-Bataillon, 34095 Montpellier cedex 5, France
A R T I C L E I N F O
A B S T R A C T
Article history:
A flexible synthesis sequence toward the synthesis of the polyketide region of apratoxin
has been developed. The common step of the synthesis is a crotylation reaction.
Stereospecific aldolisation, sulfate ring opening or Jacobsen HKR is also highlighted. This
synthetic scheme led to the synthesis of several analogues. These examples raise the
possibility of synthesising numerous analogues of this portion of apratoxins. Then,
together with our supported strategy to synthesise the oxazoline analogue of apratoxin A,
this paper opens the possibility to provide easily oxoapratoxin analogues for future SAR
studies of this potent antitumoral compound.
Received 18 May 2010
Accepted after revision 21 September 2010
Available online 2 November 2010
Keywords:
Natural products
Polyketides
Total synthesis
Asymmetric synthesis
Antitumor agents
ß 2010 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
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R E S U M E
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Un schema de synthese flexible a ete developpe en vue de la synthese de la region
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Mots cle´s :
polycetidique de l’apratoxine. L’etape cle commune de ces syntheses est une reaction de
crotylation. Une re´action d’aldolisation ste´re´ospe´cifique, une ouverture d’un cycle sulfate
ainsi qu’une re´action de re´solution cine´tique par hydrolyse ont e´galement e´te´ utilise´es. Ce
Produits naturels
Polyce´tides
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Synthese totale
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schema synthetique a conduit a la synthese de plusieurs analogues. Les differents
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Synthese asymetrique
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exemples decrits ici demontrent la possibilite d’integrer d’autres modifications dans cette
portion des apratoxines. Ainsi, avec notre strate´gie supporte´e de synthe`se de l’analogue
Agents anti-tumoraux
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oxazoline de l’apratoxine A, ce travail peut conduire a une synthese aisee d’analogues de
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l’oxoapratoxine, dans la perspective de futures etudes de relation structure–activite de ce
compose´ aux proprie´te´s anti-tumorales.
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ß 2010 Academie des sciences. Publie par Elsevier Masson SAS. Tous droits reserves.
Apratoxin A and analogues are a recently discovered
class of cyclodepsipeptides from marine origin, which
possess high cytotoxicity (Fig. 1) [1–4]. Due to their potent
antitumoral activity and uncommon mechanism of action,
they have attracted much attention. Thus, total synthesis
of apratoxins became such a competitive challenge for
chemists that several total syntheses have been already
reported [5–11], including solid supported synthesis of the
oxazoline analogue that we have described [12]. Moreover,
recently published biological studies prompted us to put
on view our progress in the synthesis of new analogues
[13–16].
Indeed, towards our efforts to supply an easy and
versatile synthesis of apratoxin analogues, we developed
an efficient synthetic pathway to provide the polyketide
moiety of apratoxin A and some of its analogues using a
common key step. As a proof of efficiency, the polyketide
fragment corresponding to apratoxin A has been synthe-
sised in a gram scale. The four synthesised polyketides are
displayed in Fig. 2.
The polyketide fragments corresponding to apratoxin
A (1) and apratoxin C (2) (Fig. 2) were first synthesised
starting from pivalaldehyde 5 and butyraldehyde 50
respectively, through a List’s aldolisation reaction using
* Corresponding author.
E-mail address: arnaud.gilles@yahoo.fr (A. Gilles).
1631-0748/$ – see front matter ß 2010 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.crci.2010.09.002

[
[()TD$FIG]
438
A. Gilles et al. / C. R. Chimie 14 (2011) 437–440
OMe
OTES
OTBS
OTES
OTBS
CO2H
34
35
34
35
CO2H
Apratoxin
39
39
37
37
X
H
N
A : X= S; R1= Me; R2= H ; R3= Me
B : X= S; R1= Me; R2= H ; R3= H
C : X= S; R1= H ; R2= H ; R3= Me
D : X= S; R1= H ; R2= tBu ; R3= Me
1
2
*
34
N
*
(Apratoxin A)
(Apratoxin C)
O
OH
35
N
O
O
37
*
O
O
Oxoapratoxin A
39
*
OTES
OTBS
N
R1
R2
OTES
OTBS
R3
N
O
34 CO2H
35
34 CO2H
X= O; R1= Me; R2= H; R3= Me
39
37
39
35
37
4
3
Fig. 1. Apratoxin A and analogues.
Fig. 2. The four synthesised polyketides.
proline as organocatalyst to give the corresponding
hydroxyketones (Scheme 1) [17].
It is noteworthy that the butyraldehyde gave a lower
yield, as already described by List. The diastereoselective
reduction of the hydroxyketone 6 and 60 under Prasad
[()TD$FIG]
reaction conditions furnished the corresponding diols 7
and 70, with
better diastereoselectivity for the
pivalaldehyde (dr = 95:5 for 7, 65:35 for 70), due to
steric hindrance. In both cases, the diastereoisomers
have been separated by silica gel chromatography
a
Et3BOMe, NaBH4
OH OH
OH
O
H-D-Pro-OH
acetone/DMSO (1:4)
MeOH, THF
O
-78°C to RT
R
R
R
:R=tBu : 69% (ee= 95%)
:R=iPr : 45% (ee= 93%)
:R=tBu : 65%
:R=iPr : 45%
:R=tBu
:R=iPr
6
6'
7
7'
5
5'
SOCl2, pyr
0°C to RT
O
S
RuCl3 cat., NaIO4
CCl4/ACN/H2O
(1:1:2)
O
O
OH
S
1) allylmagnesium bromide
THF
O
O
O
O
R
2) H2SO4 20%, Et2O
R
R
(30:75)
:R=tBu : 96%
:R=iPr : 97%
:R=tBu : 90%
:R=iPr : 50%
:R=tBu : 100%
:R=iPr : 100%
8
8'
10
10'
9
9'
Scheme 1.
[()TD$FIG]
R,R'-(salen)CoIII.OAc
H2O (0.55 equiv.)1,2-hexan-diol,
0°C to RT
HO
O
O
*
OH
+
12
13
11
40% (max 50%)
ee=97%
homoallylmagnesium
bromide
CuCN, Et2O
OH
14
42%
Scheme 2.

[()TD$FIG]
A. Gilles et al. / C. R. Chimie 14 (2011) 437–440
439
17a: 97%
17b: 90%
17c: 85%
17d: 95%
O3, DCM, MeOH
-78°C then PPh3
TESCl, Imidazole
DMF
OH R'
TESO
R
R'
TESO
R
R'
O
R
16a: 88%
16b: >99%
16c: 77%
16d: 94%
10 (R=tBu ; R'=Me)
10' (R=iPr ; R'=Me)
14 (R=tBu ; R'=H)
15 (R=H ; R'=H)
1) trans-butene, t-BuOK, BuLi
THF, -40°C
2) H2O2, NaOH
then (+)-(ipc)2BOMe, -78°C
then BF3.Et2O and 17
19a: 98%
TESO
R
R'
OTBS
TBSOTf, 2,6-lutidine
DCM, -25°C
18a: 93% (dr 9:1)
TESO
R
R'
OH
19b: 92%
19c: >99%
19d: >99%
18b: 88% (dr 9:1)
18c: 40% (dr 8:2)
18d: 68% (dr 8:2)
1) O3, DCM, MeOH 2) NaClO2, amylene
-78°C, then PPh3 t-BuOH/H2O, pH 4.5
1: 90% (R=tBu ; R'=Me)
2: 88% (R=iPr ; R'=Me)
3: >99% (R=tBu ; R'=H)
4: 92% (R=H ; R'=H)
TESO
R'
37
OTBS
CO2H
34
35
R
39
Scheme 3.
(yields reported on Scheme 1 are given for the good
diastereoisomer) [18]. The cyclic sulfate was obtained by
cyclic sulfite formation (8 and 80) with thionyl chloride
followed by oxidation with RuCl3 and NaIO4 as cooxidant
(9 and 90) [19]. The sulfate was then subjected to a
regioselective nucleophilic substitution with allylmag-
nesium bromide. When R = iPr (90), the regioselectivity of
the reaction was not complete due to less steric
hindrance, as we observed the formation of its regioi-
somer in a 30% yield (50% yield reported on Scheme 1 is
given for the good regioisomer). The substitution
reaction induced complete inversion of configuration
(SN2) in both cases. Final hydrolysis of the newly formed
sulfate furnished the free alcohol (10 and 100).
For the analogue 3 (Fig. 2), we started from the racemic
epoxide 11. Hydrolytic kinetic resolution furnished the
pure (R) epoxide 13 (ee = 97% obtained from optical
rotation) [20], which was subjected to a regioselective
nucleophilic substitution with homoallyl magnesium
bromide to yield 14 (Scheme 2).
efficient to yield the corresponding homoallylic alcohol
(18) [22].1
(+)-a-methoxydiisopinocampheyl borane was used as
chiralauxiliarytoobtainthedesiredenantioselectivityatthe
C35chiralcenter,andthetrans-butenewasusedasadductto
give the anti-compound with a good diastereoselectivity
(dr = 8:2 to 9:1, determined from the NMR spectrum). We
have been able to isolate the syn diastereoisomers by silica
gel chromatography. It is noteworthy that the compounds
17c and 17d which did not possess a methyl group in the
b
position from the aldehyde have less diastereoselectivity,
probably due to a loss a steric hindrance. The latter was then
protected as TBDMS silyl ether (19), followed by ozonolysis
to give an aldehyde (20), which was oxidized with NaClO2
into its corresponding carboxylic acid to furnish the four
corresponding polyketide moities [23] (Scheme 3).
In summary, we described the syntheses of the
polyketide moiety of apratoxins A and C and two other
polyketide analogues. We stuck here to the stereochemis-
For the less hindered analogue 4 without alkyl group,
we started the synthesis from the commercially available
hex-5-en-1-ol (15).
From this stage, the rest of the synthesis was identical
for all the four analogues and was performed as
follows. The free alcohol was first silylated with TESCl
(16), and the double bond was subjected to oxidative
1
General procedure for the crotylation reaction: To an excess of trans-
butene was added potassium t-butylate (2 equiv.) at ꢀ78 8C. After 10 min
stirring at ꢀ78 8C, n-BuLi (2 equiv., 1.6 M/hexane) was added dropwise.
The temperature was then allowed to raise to ꢀ45 8C and the mixture was
stirred for 30 min. The mixture was then cooled down to ꢀ78 8C and a
solution of diisopinocamphenylborane (2 equiv.) in a minimum of THF
was added dropwise. After stirring for 45 minutes at ꢀ78 8C, BF3.Et2O (2.6
cleavage
with ozone to give the corresponding
equiv.) was quickly added, immediately followed by
a solution of
aldehyde (17).
aldehyde (1 equiv.) in THF. The mixture was stirred at ꢀ78 8C for 5 hours
stirring at room temperature, the mixture was diluted with AcOEt and
brine. The aqueous layer was extracted 3 times with AcOEt, and the
combined organic layers were washed with brine, dried over Na2SO4 and
concentrated under reduced pressure. Silica gel chromatography
(hexane/AcOEt 93:7, Rf: ꢁ0.4) afforded the homoallylic alcohol as a
colorless oil.
Then, our first trial to obtain the two last stereo-
centers was a non-Evans anti-aldolisation type reaction
[21], but various attempts to furnish the aldol adduct
were unsuccessful. Thus, we skipped to
crotylation reaction, which turned out to be very
a Brown’s

440
A. Gilles et al. / C. R. Chimie 14 (2011) 437–440
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choose independently all the four chiral center’s stereo-
chemistry. Thus, we demonstrated the versatility of this
synthesis, since there is also the possibility to introduce
different alkyl groups at the C39 position, giving the
potentiality to synthesise numbers of new polyketide
analogues, and consequently, using our supported strate-
gy, new apratoxin analogues [12]. The synthesis of some of
these apratoxin analogues is already planned for future
work, opening new perspective for future SAR studies.
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Conflict of interest statement
There is no conflict of interest between the coauthors.
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We thank La Ligue Contre le Cancer for financial
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