Synthetic studies on reidispongiolide A, an actin-depolymerizing marine macrolide: synthesis of C11-C22 and C23-C35 segments

Article abstract of DOI:10.1016/j.tetlet.2009.06.075

The C11-C22 and C23-C35 segments 2 and 3 of reidispongiolide A (1), an actin-depolymerizing marine macrolide, were synthesized enantioselectively in 12 steps from (R)-glycidyl trityl ether and in 12 steps from chiral ketone 15, respectively.

Full text of DOI:10.1016/j.tetlet.2009.06.075

Tetrahedron Letters 50 (2009) 5012–5014
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Tetrahedron Letters
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Synthetic studies on reidispongiolide A, an actin-depolymerizing marine
macrolide: synthesis of C11–C22 and C23–C35 segments
*
Satoshi Akiyama, Eisuke Toriihara, Kazushi Suzuki, Toshiaki Teruya , Kiyotake Suenaga
Department of Chemistry, Faculty of Science and Technology, 3-14-1 Hiyoshi, Kohoku, Yokohama 223-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The C11–C22 and C23–C35 segments 2 and 3 of reidispongiolide A (1), an actin-depolymerizing marine
macrolide, were synthesized enantioselectively in 12 steps from (R)-glycidyl trityl ether and in 12 steps
from chiral ketone 15, respectively.
Received 26 May 2009
Revised 15 June 2009
Accepted 16 June 2009
Available online 18 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Reidispongiolides and sphinxolides are cytotoxic 26-membered
macrolides that interact with actin.1 Reidispongiolide A (1) is a
member of these macrolides that was isolated in 1994 by D’Auria
et al. from the New Caledonian sponge Reidispongia coerulea
(Fig. 1).2 Actin-depolymerizing macrolides including reidispongio-
lides and sphinxolides are of interest to natural products chemists
and pharmacologists.3 Studies on stereostructure of reidispongio-
lides and sphinxolides were based on detailed NMR analysis and
degradation fragment synthesis,4 and the complete absolute ste-
reostructure of reidispongiolide A was established by synchrotron
X-ray analysis of actin-bound 1.5 Synthetic studies on reidispon-
giolide A have been carried out,4 and the first total synthesis of 1
was achieved by Paterson et al.6 Recently, synthesis of the tail ana-
logs of reidispongiolide A and their effect on actin polymerization
and depolymerization were reported.7 To investigate further struc-
ture-activity relationships and biological activities of reidispongio-
lides, we began to study the synthesis of reidispongiolide A. We
describe here the stereocontrolled synthesis of the C11–C22 and
C23–C35 segments 2 and 3.
The synthesis of C11–C22 segment 2 was carried out using a
Horner–Wadsworth–Emmons reaction between C11–C16 phos-
phonate 4 and C17–C22 aldehyde 5 (Fig. 1). The synthesis of
C23–C35 segment 3 was carried out by connecting C23–C30 vinyl
iodide 6 and C31–C35 aldehyde 7 with Nozaki–Hiyama–Kishi reac-
tion.8 The introduction of chiral centers to 4, 5, 6, and 7 could be
achieved by using the Evans aldol reaction,9 the Paterson aldol
reaction,10 stereoselective reduction of b-hydroxy ketone,11 and
the Roush crotyl boration reaction12 as the key steps.
and Swern oxidation of the resultant hydroxyl group gave
aldehyde 10. Addition of lithiated dimethyl methylphosphonate14
followed by Dess–Martin oxidation provided C11–C16 phospho-
nate 4. The synthesis of C17–C22 aldehyde 5 began with an alkyl-
ation reaction of vinyl magnesium bromide with an (R)-glycidyl
trityl ether (Scheme 1). The hydroxyl group was methylated, and
the olefin was cleaved to afford aldehyde 11. The Evans aldol reac-
tion between 8 and 11 (dr = 97:3), transamidation, and methyla-
tion of a hydroxyl group provided amide 12, which was reduced
with DIBAL to give C17–C22 aldehyde 5. The Horner–Wads-
worth–Emmons reaction between C11–C16 phosphonate 4 and
C17–C22 aldehyde 5 afforded b-hydroxyketone 13 after desilyla-
tion. Stereoselective reduction of 13 with tetramethylammonium
triacetoxyborohydride11 provided an anti-1,3-diol (dr = 15:1),
which was converted into C11–C22 segment 215 in 2 steps. The ste-
reochemistry of the newly formed hydroxyl group at C15 was
determined by the 13C chemical shifts of acetonide methyls (dC
25.3 and 26.4 ppm)16 of derived acetonide 14.
The synthesis of C23–C35 segment 3 is shown in Scheme 2. The
Paterson aldol reaction between ketone 1517 and aldehyde 16a
afforded b-hydroxyketone 17a stereoselectively (dr = 95:5). Stere-
oselective reduction of 17a with tetramethylammonium triacet-
oxyborohydride gave an anti-1,3-diol (dr = 93:7)4c, which was
transformed into acetonide 18. Its stereochemistry was deter-
mined as follows: based on the 13C chemical shifts of acetonide
methyls (dC 23.4 and 25.3 ppm),16 the relative stereochemistry be-
tween C25 and C27 was determined to be anti. Proton–proton cou-
pling constants (J24,25 = 11.3 Hz and J25,26 = 3.4 Hz) and NOE
between H-25 and H-26 established the relative stereochemistry
of C24, C25, and C26 to be anti–syn. We tried to differentiate be-
tween the two hydroxyl groups at C25 and C27. The samarium-cat-
alyzed intramolecular Evans-Tishchenko reduction18 of 17b
followed by silylation provided benzoate 19 in good yield. How-
ever, removal of the benzoyl group in 19 under various conditions
(DIBAL, LiAlH4, MeLi, NaOH, etc.) failed. Thus, we stopped trying to
differentiate between the two hydroxyl groups. Removal of the TBS
The synthesis of C11–C22 segment 2 is shown in Scheme 1. The
C11–C16 phosphonate 4 was synthesized from amide 913, which
was prepared from imide 8. Removal of the benzyl group of 9
* Corresponding author. Tel./fax: +81 45 566 1819.
E-mail address: suenaga@chem.keio.ac.jp (K. Suenaga).
Present address: Faculty of Education, University of the Ryukyus, 1 Senbaru,
Nishihara, Okinawa 903-0213, Japan.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.075

S. Akiyama et al. / Tetrahedron Letters 50 (2009) 5012–5014
5013
O
O
OMe
11
MeO
MeO
1
MeO
O
O
OMe
O
OMe
Me
N
35
23
MeO
CHO
22
N
1
N
TBDPS
O OMe OTBDPS
N
11
CHO
TBS
N
Ph
SO2
O
O
O
O
O
O
31
23
35
11
MeO
P(OMe)2
30
N
MeO
MeO
16
3
Me
16
4
17
MeO
OMe OMe
OTr
17
PMBO
O
O
MeO
OMe OTBDPS
31
OHC
OTr
22
23
I
OHC
35
22
2
30
5
6
7
Figure 1. Structure of reidispongiolide A and retrosynthesis of the C11–C22 and C22–C35 segments.
protecting group of 18 followed by oxidation of the resultant alco-
hol with TEMPO and PhI(OAc)2 afforded aldehyde, which was
in the later stage of the synthesis, alcohols 22 were used in
the following reactions without the separation of diastereomers.
Catalytic hydrogenation of a double bond in 22, silylation of a
hydroxyl group at C31, and removal of a PMB group gave a pri-
mary alcohol, the hydroxyl group of which was converted into a
tetrazolyl sulfonyl group in two steps to afford C22–C35 seg-
ment 3.22
Thus, we have synthesized the C11–C22 and C23–C35 segments
2 and 3 of reidispongiolide A (1), an actin-depolymerizing marine
macrolide, and further investigations toward the total synthesis
of reidispongiolide A (1) are in progress.
19
transformed into C23–C30 vinyl iodide
6 using the Takai
procedure.20
A Roush crotylboration reaction between boronate 20 and
3-tert-butyldiphenylsiloxypropanal afforded homoallylic alcohol
2121 (dr 10:1) (Scheme 2). Methylation of a hydroxyl group of
21 followed by oxidative cleavage of the olefin provided C31–
C35 aldehyde 7. The Nozaki–Hiyama–Kishi reaction between 6
and 7 afforded a 2:1 diastereomeric mixture of allylic alcohols
22. Since the hydroxyl group at C31 will be oxidized to ketone
TBS
O
O
TBS
O
ref 12
O
O
O
OBn
a - b
c - d
O
N
MeO
CHO
4
5
MeO
N
3 steps
N
Bn
Me
Me
8
9
10
O
OMe OMe
OMe
k
e - g
h - j
O
OTr
MeO
OTr
OHC
OTr
N
Me
11
12
O
OH
O
OMe OMe
n - p
l - m
MeO
OTr
2
+
5
4
N
Me
13
O
O
O
OMe OMe
MeO
OTr
15
N
Me
14
Scheme 1. Synthesis of C11–C22 segment. Reagents and conditions: (a) H2, 10%Pd-C, EtOAc, rt, quant.; (b) DMSO, (COCl)2, Et3N, CH2Cl2, ꢀ78 °C?0 °C, 86%; (c) tBuLi,
MeP(O)(OMe)2, THF, ꢀ78 °C, 84%; (d) Dess–Martin periodinane, CH2Cl2, rt, 87%; (e) (CH2@CH)MgBr, CuCN, THF, ꢀ78 °C?ꢀ20 °C, 99%; (f) MeI, NaH, THF, rt, 89%; (g) OsO4,
NMO, acetone-H2O, rt; then NaIO4 aq, rt, 90%; (h) 8, Bu2BOTf, Et3N, CH2Cl2, ꢀ78 °C?0 °C, quant.; (i) MeNH(OMe)ꢁHCl, Me3Al, THF–toluene, 0 °C; (j) MeI, NaH, THF, rt, 87% in
two steps; (k) DIBAL, THF–hexane, ꢀ78 °C, 95%; (l) Ba(OH)2, THF–H2O, rt, 95%, (m) HFꢁpyridine, pyridine, THF, 0 °C?rt, quant.; (n) Me4NBH(OAc)3, MeCN–AcOH, ꢀ20 °C, 87%;
(o) MeI, NaH, DMF, rt, quant.; (p) DIBAL, THF–hexane, ꢀ78 °C, 95%.

5014
S. Akiyama et al. / Tetrahedron Letters 50 (2009) 5012–5014
PMBO
O
OR
PMBO
O
OH OR
PMBO
O
O
OTBS
a
b - c
d - f
OHC
6
+
25
27
15
20
16a:
16b:
17a:
R = TBS
R = TBDPS
R = TBS
18
PMBO
17b: R = TBDPS
TES
O
OBz OTBDPS
25
27
O
OH OTBDPS
OTBDPS
B
O
CO2iPr
CO2iPr
g
h - i
19
+
OHC
7
21
PMBO
OH OMe OTBDPS
j
O
O
k - o
31
6
+
7
23
35
3
22
Scheme 2. Synthesis of C23–C35 segment. Reagents and conditions: (a) (cHex)2BCl, Et3N, Et2O, ꢀ78 °C?ꢀ20 °C; (b) Me4NBH(OAc)3, AcOH, MeCN, ꢀ25 °C; (c) (MeO)2CMe2,
PPTS, acetone, rt 87% in three steps; (d) Bu4NF, THF, rt, quant; (e) TEMPO, PhI(OAc)2, CH2Cl2, rt, 90%; (f) CrCl2, CHI3, THF, 0 °C, 82%; (g) MS 4 Å, toluene, ꢀ78 °C, 90%; (h) MeI,
NaH, THF, rt, 88%; (i) OsO4, NMO, acetone–H2O rt, then NaIO4 aq, rt, 93%; (j) CrCl2, NiCl2, DMSO, rt, 79%; (k) H2, 10%Pd-C, EtOH, rt, 96%; (l) TBDPSCl, imidazole, DMAP, DMF,
60 °C; (m) DDQ, CH2Cl2–phosphate buffer (pH 7), rt, 71% in two steps; (n) 5-mercapto-1-phenyltetrazole, Bu3P, DEAD, THF, rt, 86%; (o) H2O2, (NH4)6Mo7O24ꢁ4H2O, EtOH, rt,
53%.
10. (a) Paterson, I.; Tiller, R. D. Tetrahedron Lett. 1991, 32, 1749; (b) Paterson, I.;
Acknowledgments
Lister, M. A.; Ryan, G. R. Tetrahedron Lett. 1992, 33, 4233.
11. Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988, 110, 3560.
12. Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.; Halterman, R. L. J. Am.
Chem. Soc. 1990, 112, 6339.
13. Rauhala, V.; Nättinen, K.; Rissanen, K.; Koskinen, A. M. P. Eur. J. Org. Chem. 2005,
This work was supported in part by Keio Gijuku Academic
Development Funds, the Naito Foundation, and the Asahi Glass
Foundation. We are grateful to Daiso Co., Ltd for the donation of
chiral glycidyl trityl ether. We thank Kaneka Corporation for their
gift of chiral methyl 3-hydroxy-2-methylpropionate.
4119.
14. When n-BuLi was used as
a
base, the yield was ca. 60% and was not
reproducible.
15. Compound 2: a colorless oil; ½a D20
ꢂ
ꢀ3.8 (c 0.01, CHCl3);IR (CHCl3) 2818, 1724,
1448, 1090 (br), 974 cmꢀ1 1H NMR (400 MHz, CDCl3) d 9.79 (s, 1H), 7.50–7.45
;
(m, 6H), 7.32–7.20 (m, 9H), 5.66 (dd, J = 15.6, 6.8 Hz, 1H), 5.25 (dd, J = 15.6,
7.8 Hz, 1H), 3.85 (dt, J = 6.8, 3.4 Hz, 1H), 3.67 (m, 1H), 3.40 (s, 3H), 3.42 (m, 1H),
3.37 (s, 3H), 3.27 (dd, J = 10.2, 3.4 Hz, 1H), 3.23 (s, 3H), 3.12 (s, 3H), 3.03 (dd,
J = 10.2, 4.4 Hz, 1H), 2.95 (m, 1H), 2.54 (m, 1H), 2.45 (m, 1H), 1.76–1.44 (m, 4H),
1.05 (d, J = 7.3 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) d
204.4, 144.1, 136.0, 130.0, 128.7, 127.7, 126.9, 86.4, 81.6, 78.9, 78.2, 77.4, 58.3,
57.6, 56.9, 55.9, 50.0, 39.0, 38.2, 32.8, 15.3, 8.0; MS (ESI) m/z 589 (M+H)+, 611
(M+Na)+.
References and Notes
1. (a) Guella, G.; Mancini, I.; Chiasera, G.; Pietra, F. Helv. Chim. Acta 1989, 72, 237;
(b) D’Auria, M. V.; Gomez-Ploma, L.; Minale, L.; Zampella, A.; Verbist, J.-F.;
Roussakis, C.; Debitus, C. Tetrahedron 1993, 49, 8657; (c) Carbonelli, S.;
Zampella, A.; Randazzo, A.; Debitus, C.; Gomez-Ploma, L. Tetrahedron 1999,
55, 14665; (d) Zhang, X.; Minale, L.; Zampella, A.; Smith, C. D. Cancer Res. 1997,
57, 3751.
2. D’Auria, M. V.; Gomez-Ploma, L.; Minale, L.; Zampella, A.; Verbist, J.-F.;
Roussakis, C.; Debitus, C.; Patissou, J. Tetrahedron 1994, 50, 4829.
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Klenchin, V. A.; Rayment, I. Cell. Mol. Life Sci. 2006, 63, 2119.
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Paloma, L. Eur. J. Org. Chem. 2001, 39; (b) Zampella, A.; Bassarello, C.; Bifulco, G.;
Gomez-Paloma, L.; D’Auria, M. V. Eur. J. Org. Chem. 2002, 785; (c) Paterson, I.;
Ashton, K.; Britton, R.; Kunst, H. Org. Lett. 2003, 5, 1963; (d) Zampella, A.; Sepe,
V.; D’Orsi, R.; Bifulco, G.; Bassarello, C.; D’Auria, M. V. Tetrahedron: Asymmetry
2003, 14, 1787; (e) Zampella, A.; Sepe, V.; D’Orsi, R.; D’Auria, M. V. Lett. Org.
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U.S.A. 2005, 102, 14527.
6. (a) Paterson, I.; Ashton, K.; Britton, R.; Cecere, G.; Chouraqui, G.; Florence, G. J.;
Stafford, J. Angew. Chem., Int. Ed. 2007, 46, 6167; (b) Paterson, I.; Ashton, K.;
Britton, R.; Cecere, G.; Chouraqui, G.; Florence, G. J.; Knust, H.; Stafford, J. Chem.
Asian J. 2008, 3, 367.
7. Perrins, R. D.; Cecere, G.; Paterson, I.; Marriott, G. Chem. Biol. 2008, 15, 287.
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1983, 24, 5281; (b) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc.
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D. A.; Rieger, D. L. Tetrahedron Lett. 1990, 31, 7099; (c) Rychnovsky, S. D.;
Rogers, B.; Yang, G. J. Org. Chem. 1993, 58, 3511.
17. Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. J. Am. Chem. Soc.
2001, 123, 9535.
18. Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, 6447.
19. Mico, D. A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem.
1997, 62, 6974.
20. Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408.
21. Ferrié, L.; Boulard, L.; Pradaux, F.; Bouzbouz, S.; Reymond, S.; Capdevielle, P.;
Cossy, J. J. Org. Chem. 2008, 73, 1864.
22. Compound 3 (a 2:1 diastereomeric mixture at C31): a colorless oil; IR (CHCl3)
1463, 1343, 1224, 1108, 998, 761, 703 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
(signals due to minor diastereomer in brackets) d 7.76–7.56 (m, 13H), 7.45–
7.26 (m, 12H), 4.18–4.02 (m, 1H) 3.85–3.71 (m, 3H), 3.50–3.20 (m, 4H), 3.14 (s,
1H), 3.07 [3.01] (s, 3H), 2.81 [2.96] (m, 1 H), 2.37–2.24 (m, 1H), 1.92–1.75 (m,
2H), 1.75–1.40 (m, 7H), 1.18 [1.21] (s, 3 H), 1.16 [1.20] (s, 3H), 1.06–1.03 (m,
18H), 1.01 [1.05] (d, J = 6.8 Hz, 3H), 0.87 [0.85] (d, J = 6.4 Hz, 3H), 0.65 [0.75] (d,
J = 6.4 Hz, 3H), 0.58 [0.74] (d, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
154.3, 136.1, 136.0, 135.9, 135.8, 135.6, 135.5, 135.5, 133.9, 133.1, 131.4, 120.6,
120.5, 129.6, 129.5, 129.5, 129.4, 129.3, 129.3, 127.6, 127.6, 127.4, 127.3, 127.2,
125.4, 100,6, 100.6, 78.6, 78.2, 73.2, 71.6, 60.4, 60.1, 59.1, 56.6, 56.5, 39.8, 37.4,
36.7, 34.3, 34.2, 33.3, 32.2, 29.1, 29.0, 27.2, 27.1. 27.0, 26.9, 25.4, 25.3, 23.1,
21.0, 19.6, 19.5, 19.2, 19.1, 15.3, 15.3, 15.3, 15.0, 14.2, 12.3, 12.1, 10.6, 9.2; MS
(ESI) m/z 1059 (M+H)+, 1081 (M+Na)+.
9. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127.