Synthesis of the C1-C9 fragment of the potent antitumor agent dictyostatin

Article abstract of DOI:10.1590/S0103-50532012000200022

We describe herein a short and efficient synthesis of the C1-C9 fragment of the potent antitumor agent dictyostatin. Notable features of this approach include a Sharpless asymmetric epoxidation followed by epoxide opening under Myashita's conditions to in

Full text of DOI:10.1590/S0103-50532012000200022

J. Braz. Chem. Soc., Vol. 23, No. 2, 344-348, 2012.
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Short Report
S
Synthesis of the C1-C9 Fragment of the Potent Antitumor Agent Dictyostatin
Luiz C. Dias,* Danilo P. Sant’Ana, Ygor W. Vieira, Caroline C. S. Gonçalves and Dimas J. P. Lima
Instituto de Química, Universidade Estadual de Campinas, CP 6154, 13083-970 Campinas-SP, Brazil
Descrevemos neste trabalho uma síntese curta e eficiente para o fragmento C1-C9 do potente
agente antitumoral dictiostatina. Esta abordagem sintética inclui uma reação de epoxidação
assimétrica de Sharpless seguida da abertura de epóxido nas condições de Myashita para introduzir
os centros estereogênicos em C6 e C7 e uma reação de olefinação tipo Horner-Wadsworth- Emmons
nas condições de Ando para construir a ligação com geometria /Z/do dieno 1,3-/Z/,/E/.
We describe herein a short and efficient synthesis of the C1-C9 fragment of the potent antitumor
agent dictyostatin. Notable features of this approach include a Sharpless asymmetric epoxidation
followed by epoxide opening under Myashita’s conditions to introduce the stereogenic centers at
C6 and C7, and a Horner-Wadsworth-Emmons type reaction underAndo’s conditions to construct
the Z-double bond of the 1,3-(Z,E)-diene system.
Keywords: total synthesis, dictyostatin, Sharpless asymmetric epoxidation, macrolactone
Introduction
toward the total synthesis of dictyostatin, which resulted
in the synthesis of the C11-C23 fragment.7 In this work we
wish to describe a practical synthesis of the C1-C9 fragment
of this potent antitumor agent.
The marine-derived macrolactone dictyostatin (1) was
isolated by Pettit and co-workers1 from the marine sponge
Spongia sp. as well as by Wright and co-workers2 from
Corallistidae sponges. Dictyostatin is a potent antitumor
agent, with microtubule stabilization activity (Figure 1).3,4
Results and Discussion
Our approach began with monoprotection of diol
2 as the p-methoxybenzyl ether (Scheme 1). We have
applied the strategy of creating a ketal group, followed
by opening of this ketal with DIBAL-H in toluene to give
the monoprotected alcohol 3 in 56% overall yield over
two steps.8 Alcohol 3 was converted to the corresponding
aldehyde using the Swern oxidation protocol, and the crude
aldehyde was directly subjected to a Horner-Wadsworth-
Emmons reaction to give (E)-a,b-unsaturated ester 4 in
70% yield (E:Z > 95:5) over two steps (Scheme 1).9
Me
OH
26
HO
Me Me
Me
O
O
11
Me Me
1
9
OH OH
Dictyostatin (1)
Figure 1. Structure of dictyostatin (1).
The ester 4 was reduced to the allylic alcohol 5 upon
treatment with DIBAL-H in CH2Cl2 at -40 ºC in 90%
yield. Overall, alcohol 5 was prepared in 35% yield after
5 steps starting from diol 2. Then, alcohol 5 was submitted
to a Sharpless asymmetric epoxidation using (-)-DIPT
to afford the desired epoxy alcohol 6 in 78% yield and
98% ee. The absolute configuration of epoxy alcohol 6
was confirmed by comparison of to value of the optical
rotation described in the literature (observed: [a]D +25,
c 1.15; CHCl3; literature: [a]D -25.3 c 1.09, CHCl3, for
antipode epoxy alcohol 6).9,10 The enantiomeric excess
The structure of dictyostatin was deduced by Pettit and
co-workers,1 and the stereochemical assignments were
made on the basis of the total syntheses described by the
research groups of Paterson and Curran.5,6
Due to its potent antitumor activity, a number of
research groups have described the total synthesis of
dictyostatin.5,6 Our research group also initiated a project
*e-mail: ldias@iqm.unicamp.br

Vol. 23, No. 2, 2012
Dias et al.
345
1. (COCl)2, DMSO, Et3N,
1. p-anisaldehyde
p-TsOH, toluene, ∆
PMBO
OH
OH OH
CH2Cl2, −78 °C
2. (MeO)2P(O)CH2CO2Me
K2CO3, H2O:Et2O, r.t.
70% (2 steps)
2. DIBAL-H, toluene
−78 °C to 25 °C
56% (2 steps)
3
2
OPMB
O
OPMB
OH
DIBAL-H, CH2Cl2
−40 °C, 90%
(L)-DIPT, t-BuOOH
OMe
Ti(i-PrO)4, CH2Cl2
−78 °C, 78%
4
5
O
CF3
OPMB
O
OPMB
OH
O
O
(R)-MTPACl
Ph OMe
Et3N, DMAP, CH2Cl2
25 °C, 100%
7
6
98% dr
Ph OMe
Cl
CF3
(R)-MTPACl
O
Scheme 1. Preparation of epoxy alcohol 6.
was determined using the Mosher ester method, as shown
in Scheme 1.11
organocuprate could be used to install the desired
methyl group at the 2 position of 2,3-epoxyalkanes.13
Unfortunately, we observed poor regioselectivity, and
mixtures of 1,3-diol (12) and 1,2-diol (13) were obtained
(Scheme 3). In addition, the use of n-BuLi/Me3Al led to
a 20:80 mixture of 12 and 13.
To overcome this problem we decided to use Myashita’s
methodology for nucleophilic substitution of g,d-epoxy
acrylates.14 This strategy seemed promising, because
nucleophilic substitution into (E)-g,d-epoxy acrylate would
In addition, we have prepared allylic alcohol 5 by a
shorter synthetic route (Scheme 2).12 Homoallylic alcohol 8
was converted to the corresponding p-methoxybenzyl ether
9 in 80% yield. A cross metathesis reaction of 9 with cis-2-
buten-1,4-diol (10) in the presence of Hoveyda-Grubbs second
generation catalyst 11 afforded allylic alcohol 5 in 85% yield.
Based on literature precedent it seemed feasible
that the regioselective nucleophilic addition of an
OH
NaH, PMBCl
OPMB
OPMB
OH
OH
HO
10
THF, r.t.
80%
Hoveyda-Grubbs
catalyst 11
9
5
8
Me
N
Me
CH2Cl2, r.t., 85%
Me
N
Me
Cl
Me
Cl
Ru Me
Me
11
O
Me
Scheme 2. Alternative preparation of allylic alcohol 5.

346
Synthesis of the C1-C9 Fragment of the Potent Antitumor Agent Dictyostatin
J. Braz. Chem. Soc.
PMBO
OH OH
PMBO
Me OH
PMBO
PMBO
OH
Me2CuCNLi2, THF
−78 ºC, 24 h
O
1
6
6
Me
OH
1,2-diol (13)
ratio 12:13 = 60:40
1,3-diol (12)
PMBO
OH OH
PMBO
Me OH
OH
n-BuLi, 0 ºC, THF
Me3Al, −30 ºC, THF
ratio 12:13 = 20:80
O
2
Me
OH
1,3-diol (12)
1,2-diol (13)
Scheme 3. Attempts to synthesize the 1,3-diol.
stereospecifically provide the two stereogenic centers at C6
and C7, in an anti relationship. Moreover, the E olefin of
dictyostatin would already be present.
described by Myashita and co-workers,14 which provided
ester 15 in 94% yield as the only observed product.15
Subsequently, the protection of ester 15 was
accomplished using TBSCl and imidazole in DMF,
followed by treatment with DIBAL-H in dichloromethane
at -78 ºC to give allylic alchol 16 in 68% yield over two
steps. Oxidation of this alcohol with (bis-acetoxyiodo)
benzene (BAIB) and TEMPO provided the desired aldehyde
in 84% yield (Scheme 4). To prepare the C1-C9 fragment
of dictyostatin, we had to construct the 2Z,4E-diene at
C1-C5.16 To carry out this transformation we prepared the
To synthesize the (E)-g,d-epoxy acrylate 14, the epoxy
alcohol 6 was submitted to the Swern oxidation conditions,
cleanly providing the corresponding aldehyde (Scheme 4).
This aldehyde was used in the next step without purification
to form 14 by a Horner-Wadsworth-Emmons reaction in
81% yield for the two-step sequence (E:Z > 95:5). Next,
the (E)-g,d-epoxy acrylate 14 was treated with Me3Al and
H2O in dichloromethane at -40 ºC, following the protocol
1. (COCl)2, DMSO
PMBO
OH
PMBO
O
O
O
Me3Al, H2O, CH2Cl2
Et3N, CH2Cl2, −78 ºC
OEt
−40 ºC, 94%
2. (EtO)2P(O)CH2CO2Et
NaH, THF, 0 ºC
6
14
81% (2 steps)
BAIB, TEMPO
1. TBSCl, DMF
imidazole
PMBO
OH
O
CH2Cl2, r.t., 84%
PMBO
OTBS
Me
OH
OEt
2. DIBAL-H, CH2Cl2
15
Me
16
−78 ºC, 68% (2 steps)
(PhO)2P(O)CH2CO2Et
PMBO
OTBS
Me
NaH, THF, −78 ºC to 0 ºC
O
PMBO
OTBS
Me
70%
18
CO2Et
17
BAIB, TEMPO
CH2Cl2, r.t.
OH OTBS
O
OTBS
DDQ/pH 7 buffer
H
47%
CH2Cl2, 0ºC, 60%
Me 19
CO2Et
Me 20
CO2Et
Scheme 4. Preparation of aldehyde 20.

Vol. 23, No. 2, 2012
Dias et al.
347
phosphonate ester according a method reported by Ando
and co-workers.16 This phosphonate ester was deprotonated
with NaH and the intermediate aldehyde 17 was added at
-78 ºC. The mixture was stirred for 18 h at 0 ºC to provide
ester 18 in 70% yield (Z:E > 95:5). Oxidative removal of
the PMB ether with DDQ in CH2Cl2/pH 7 buffer (9:1) gave
alcohol 19 in 60% yield. Oxidation of the hydroxyl group
with BAIB and TEMPO provided the desired aldehyde 20
in 47% unoptimized yield (Scheme 4).
Britton, R.; Poullennec, K.; Meyer, A.; Wrigth, A. E.; Pat.
WO2005068451-A2, 2005; Curran, D. P.; Shin,Y.; Fournier, J.;
Mancuso, J.; Day, B. W.; Bruckner, A.; Fukui, Y.; Curran, D.
P.; Day, B.; Pat. EP1765073-A2, 2007; Curran, D. P.; Shin, Y.;
Fournier, J.; Mancuso, J.; Day, B. W.; Bruckner, A.; Fukui, Y.
D.; Curran, D.; Day, B.; Pat. JP2008500370-W, 2008; Curran,
D. P.; Shin,Y.; Fournier J.; Mancuso, J.; Day, B. W.; Bruckner,
A; Fukui, Y.; Curran, D.; Day, B.; Pat. US7321046-B2, 2008.
4. Biological activity: Myles, D. C.; Curr. Opin. Biotechnol. 2003,
14, 6273; Madiraju, C.; Edler, M. C.; Hamel, E.; Raccor, B. S.;
Balachandran, R.; Zhu, G.; Giuliano, K. A.; Vogt, A.; Shin, Y.;
Fournier, J. H.; Fukui,Y.; Brückner, A. M.; Curran, D. P.; Day,
B. W.; Biochemistry 2005, 44, 15053; Madiraju, C.; Raccor, B.
S.; Shin,Y.; Curran, D. P.; Day, B. W.; Clin. Cancer Res. 2005,
11, 9090S; Raccor, B. S.; Vogt, A.; Sikorski, R. P.; Madiraju,
C.; Balachandran, R.; Montgomery, K.; Shin, Y.; Fukui, Y.;
Jung, W.H.; Curran, D. P.; Day, B. W.; Mol. Pharmacol. 2008,
73, 718; Canales, A.; Matesanz, R.; Gardner, N.; Andreu, J.;
Paterson, I.; Díaz, J.; Jiménez-Barbero, J.; Chem. Eur. J. 2008,
14, 7557; Salum, L.; Dias, L. C.;Andricopulo,A.; QSAR Comb.
Sci. 2009, 28, 325; Jogalekar,A. S.; Damodaran, K.; Kriel, F. H.;
Jung, W.;Alcaraz,A.A.; Zhong, S.; Curran, D. P.; Snyder, J. P.;
J. Am. Chem. Soc. 2011, 133, 2427;Vollmer, L. L.; Jiménez, M.;
Camarco, D. P.; Zhu, W.; Daghestani, H. N.; Balachandran, R.;
Reese, C. E.; Lazo, J. S.; Hukriede, N. A.; Curran, D. P.; Day,
B. W.; Vogt, A.; Mol. Cancer Ther. 2011, 10, 994; Paterson,
I.; Naylor, G. J.; Gardner, N. M.; Guzmán, E.; Wright, A. E.;
Chem. Asian J. 2011, 6, 459.
Conclusions
We have described an efficient asymmetric synthesis
of the C1-C9 fragment of dictyostatin. Notable features of
this approach include asymmetric Sharpless epoxidation,
Myashita methodology for regioselective nucleophilic
substitution on a g,d-epoxy acrylate, and a Horner-
Wadsworth-Emmons reaction using Ando’s protocol to
construct the 1,3-diene moiety. The synthesis required 12
steps from homoallylic alcohol 8 in 4.0% overall yield.
Extension of this work toward completion of the synthesis
of dictyostatin is underway, and the results will be described
in due course.
Acknowledgments
We are grateful to FAEP-Unicamp, FAPESP, CNPq, and
INCT-INOFAR (Proc. CNPq 573.564/2008-6) for financial
support and to Prof. Carol H. Collins (IQ-Unicamp) for
helpful suggestions about English grammar and style.
5. Relative stereochemistry: Paterson, I.; Britton, R.; Delgado, O.;
Wright, A. E.; Chem. Commun. 2004, 632.
6. Total synthesis: Paterson, I.; Britton, R.; Delgado, O.; Meyer,
A.; Poullennec, K. G.; Angew. Chem. Int. Ed. 2004, 43, 4629;
Paterson, I.; Britton, R.; Delgado, O.; Meyer, A.; Poullennec,
K. G.; Angew. Chem. 2004, 116, 4729; Shin, Y.; Fournier, J.
H.; Fukui, Y.; Brückner, A. M.; Curran, D. P.; Angew. Chem.
Int. Ed. 2004, 43, 4634; Shin, Y.; Fournier, J. H.; Fukui, Y.;
Brückner,A. M.; Curran, D. P.; Angew. Chem. 2004, 116, 4734;
O’Neil, G. W.; Phillips, A. J.; J. Am. Chem. Soc. 2006, 128,
5340; Ramachandran, P.V.; Srivastava,A.; Hazra, D.; Org. Lett.
2007, 9, 157; Florence, G. J.; Gardner, N. M.; Paterson, I.; Nat.
Prod. Rep. 2008, 25, 342; Paterson, I.; Britton, R.; Delgado,
O.; Gardner, N. M.; Meyer, A.; Naylor, G. J.; Poullennec, K.
G.; Tetrahedron 2010, 66, 6534; Dalby, S.; Paterson, I.; Curr.
Opin. Drug. Discov. 2010, 13, 777; Zhu, W.; Jiménez, M.; Jung,
W.; Camarco, D. P.; Balachandran, R.; Vogt, A.; Day, B. W.;
Curran, D. P.; J. Am. Chem. Soc. 2010, 132, 9175.
Supplementary Information
Product characterization as well as copies of NMR
spectra for the prepared compounds are available free of
charge at http://jbcs.sbq.org.br as a PDF file.
References
1. Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Boyd, M. R; Schmidt, J.
M.; J. Chem. Soc., Chem. Commun. 1994, 1111.
2. Isbrucker, R. A.; Cummins, J.; Pomponi, S. A.; Longley, R. E.;
Wright, A. E.; Biochem. Pharmacol. 2003, 66, 75; Wright, A.
E.; Cummins, J. L.; Pomponi, S. A.; Longley, R. E.; Isbrucher,
R.; PCT Int. Appl. WO 0162239, 2001.
3. Pettit, G. R.; Cichacz, Z. A.; US Pat. 5430052, 1995; Curran,
D. P.; Shin,Y.; Fournier, J.; Mancuso, J.; Day, B. W.; Bruckner,
A.; Fukui,Y.; Curran, D.; Day, B.; US Pat. WO2005117588-A2,
2005; Curran, D. P.; Shin, Y.; Fournier, J.; Mancuso, J.;
Day, B. W.; Bruckner, A.; Fukui, Y.; Curran, D.; Day, B.;
Pat. AU2005249480-A1, 2005; Delgado, O.; Paterson, I.;
7. Dias, L. C.; Lima, D. J. P.; Gonçalves, C. C. S.; Andricopulo,
A. D.; Eur. J. Org. Chem. 2009, 1491.
8. Bartels, B.; Hunter, R.; J. Org. Chem. 1993, 58, 6756; Cordero,
F. M.; Pisaneschi, F.; Gensini, M.; Goti, A.; Brandi, A.; Eur. J.
Org. Chem. 2002, 1941.

348
Synthesis of the C1-C9 Fragment of the Potent Antitumor Agent Dictyostatin
J. Braz. Chem. Soc.
9. Oka, T.; Murai, A.; Tetrahedron 1998, 54, 1.
15. Nakamura, R.; Tanino, K.; Miyashita, M.; Org. Lett. 2003, 5,
3579.
10. Hatakeyama, S.; Okano, T.; Maeyama, J.; Esumi, T.; Hiyamizu,
H.; Iwabuchi, Y.; Nakagawa, K.; Ozono, K.; Kawase, A.;
Kubodera, N.; Bioorg. Med. Chem. 2001, 9, 403.
11. Dale, J. A.; Mosher, H. S.; J. Am. Chem. Soc. 1973, 95, 512;
Sullivan, G. R.; Dale, J. A.; Mosher, H. S.; J. Org. Chem. 1973,
38, 2143.
16. Ando, K.; J. Org. Chem. 1997, 62, 1934; Ando, K.; J. Org.
Chem. 1999, 64, 8406;Ando, K.; Oishi, T.; Hirama, M.; Ohno,
H.; Ibuka, T.; J. Org. Chem. 2000, 65, 4745.
Submitted: September 22, 2011
12. Raghavan, S.; Krishnaiah, V.; J. Org. Chem. 2010, 75, 748.
13. Chong, J. M.; Cyr, D. R.; Mar, E. K.; Tetrahedron Lett. 1987,
28, 5009.
Published online: November 29, 2011
FAPESP has sponsored the publication of this article.
14. Miyashita, M.; Hoshino, M.; Yoshikoshi, A.; J. Org. Chem.
1991, 56, 6483; Abe, N.; Hanawa, H.; Maruoka, K.; Sasaki,
M.; Miyashita, M.; Tetrahedron Lett. 1999, 40, 5369.