Synthesis of the tricyclic core of eleutherobin and sarcodictyins and total synthesis of sarcodictyin A

Full text of DOI:10.1021/ja973000g

J. Am. Chem. Soc. 1997, 119, 11353-11354
11353
Synthesis of the Tricyclic Core of Eleutherobin and
Sarcodictyins and Total Synthesis of Sarcodictyin A
K. C. Nicolaou,* J.-Y. Xu, S. Kim, T. Ohshima,
S. Hosokawa, and J. Pfefferkorn
Department of Chemistry and The Skaggs Institute for
Chemical Biology, The Scripps Research Institute
10550 North Torrey Pines Road
La Jolla, California 92037
Figure 1. Structures of eleutherobin (1) and sarcodictyins A (2) and
B (3).
Department of Chemistry and Biochemistry
UniVersity of California San Diego
9500 Gilman DriVe, La Jolla, California 92093
ReceiVed August 26, 1997
Eleutherobin (1, Figure 1)1,2 and sarcodictyins A (2)3,4 and
B (3),3,4 are three marine-derived diterpenoids which share
similar molecular architecture and exciting biological activity.
Eleutherobin (1) was recently isolated by Fenical et al.1,2 from
an Eleutherobia species of soft corals (possibly E. albiflora
Alcynoacea, Alcyoniidea) found in the Indian Ocean near
Bennett’s shoal in Western Australia, while sarcodictyins A (2)
and B (3) were found by Pietra and his group in the Mediter-
ranean stoloniferan coral Sarcodictyon roseum and first reported
in 1987.3 Faulkner5 and Kashman6 have reported the isolation
of similar structures, valdivones5 and eleuthosides.6 Eleuther-
obin (1) and sarcodictyins A (2) and B (3) exhibit potent
antitumor activities1,2,4 against a variety of tumor cells. More-
over, these compounds exert their cytotoxic action via the
paclitaxel-like mechanism7 of inducing tubulin polymerization
and microtubule stabilization. The success enjoyed by paclitaxel
as an anticancer agent8 and the recent excitement generated by
the epothilones9 bode well for the potential of these similarly
behaving molecules in cancer chemotherapy. The novel mo-
lecular structures of eleutherobin and sarcodictyins, coupled with
their natural scarcity and exciting biological actions, prompted
us to undertake their total synthesis. In this communication,
we report the construction of the tricyclic core structure (I,
Figure 2) of these substances and the total synthesis of
sarcodictyin A (2).
Structurally, eleutherobin (1) and sarcodictyins A (2) and B
(3) consist of a synthetically challenging tricyclic skeleton and
a N(6′)-methylurocanic acid side chain linked to the main frame
through an ester bond of the C-8 hydroxyl group. While the
sarcodictyins feature a free OH at C-4 and an ester at C-15,
eleutherobin includes a methoxy group at C-4 and is â-glyco-
sylated at C-15 with D-2-acetylarabinose. A major challenge
of these natural products is the construction of their common
tricyclic core. Figure 2 outlines, retrosynthetically, the present
strategy toward this skeleton. Thus, it was anticipated that I
could be derived by spontaneous ring closure of hydroxy ketone
II, upon the generation of the latter compound from the
Figure 2. Retrosynthetic analysis of the core structure 1.
corresponding 5,6-acetylenic system. The 10-membered ring
of these structures was envisioned to arise from an intra-
molecular acetylide-aldehyde addition causing ring closure at
C4-C5.
Scheme 1 summarizes the construction of the required
cyclization precursor 15. Thus, 4 was obtained from (+)-
carvone by a modification of Trost’s method10 and converted
to ester 5 via a Claisen rearrangement [(EtO)3CCH3, EtCOOH,
170 °C, 74% yield]. DIBAL reduction (-78 °C) of 5 resulted
in the formation of 6 in 97% yield, whereas condensation of
the latter with the appropriate ketophosphonate anion gave ester
7 in 100% yield. Reduction of 7 with DIBAL (-78 f 0 °C)
afforded 8 in 91%. Sharpless asymmetric epoxidation11 of 8
gave the expected hydroxy epoxide (87%), which was mesylated
(MsCl-Et3N) and converted to alcohol 9 by the action of sodium
naphthalenide12 (90% for two steps). Alcohol 9 was then
transformed to its PMB ether 10 by exposure to PMBOC(dNH)-
CCl3-PPTS13 (89% based on ca. 50% conversion) and, thence,
to ketone 11 by oxymercuration (Hg(OAc)2; then Li2PdCl4-
CuCl2)14 in 65% yield. The chelation-controlled addition15 of
HCtCMgBr to 11 proceeded in CH2Cl2-THF (3:1) at -78 f
25 °C to afford, after desilylation (TBAF, 72% for two steps),
acetylenic diol 12 (ca. 7:1 ds). The stereochemistry of this
intermediate and its precursors was proven by an X-ray
crystallographic analysis (see Supporting Information) of lactone
A (Scheme 1), which was obtained by oxidation of 12 with
excess of Dess-Martin reagent.16 Careful oxidation of 12,
however, produced the desired aldehyde, which underwent
Knoevenagel condensation with ethyl cyanoacetate17 in the
presence of â-alanine, furnishing, after silylation with TMSOTf-
iPr2NEt, the (E)-cyanoester 13 exclusively (71% for three steps).
The stereochemical outcome of this reaction was attributed to
steric reasons and was confirmed by the successful ring closure
to a 10-membered ring (Vide infra). Finally, DIBAL reduction
of 13 (74%), followed by protection of the resulting hydroxy
alehyde (14) as a silyl ether (TIPSOTf), gave aldehyde 15 as a
single isomer and in 91% yield.
(1) Fenical, W.-H.; Hensen, P. R.; Lindel, T. U.S. Patent No. 5,473,057,
Dec. 5, 1995.
(2) (a) Lindel, T.; Jensen, P. R.; Fenical, W.; Long, B. H.; Casazza, A.
M.; Carboni, J.; Fairchild, C. R. J. Am. Chem. Soc. 1997, 119, 8744. (b)
Long, B. H.; Casazza, A. M.; Carboni, J.; Fairchild, C. R.; Lindel, T.; Jensen,
P. R.; Fenical, W. Cancer Res. Submitted for publication.
(3) (a) D’Ambrosio, M.; Guerriero, A.; Pietra, F. HelV. Chim. Acta 1987,
70, 2019. (b) D’Ambrosio, M.; Guerriero, A.; Pietra, R. HelV. Chim. Acta
1988, 71, 964.
(10) Trost, B. M.; Tasker, A. S.; Ruther, G.; Brands, A. J. Am. Chem.
Soc. 1991, 113, 670.
(11) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
(b) Hanson, R. H.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922.
(12) Yasuda, A.; Yamamoto, H.; Nozaki, H. Tetrahedron Lett. 1976,
2621.
(13) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron Lett.
1988, 29, 4139.
(14) Rodeheaver, G. T.; Hunt, D. F. Chem. Comm. 1971, 818.
(15) Still, W. C.; McDonald, J. H., III. Tetrahedron Lett. 1980, 21, 1031.
(16) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(17) Anderson, N. H.; Golec, F. A., Jr. Tetrahedron Lett. 1977, 3783.
(4) Ciomei, M.; Albanese, C.; Pastori, W.; Grandi, M.; Pietra, F.;
D-Ambrosio, M.; Guerriero, A.; Battistini, C. Abstract 30, Proc. Amer. Ass.
Canc. Res. 1997, 38, 5.
(5) Lin, Y.; Bewley, C. A.; Faulkner, D. J. Tetrahedron 1993, 49, 7977.
(6) Ketzinel, S.; Rudi, A.; Schleyer, M.; Benayahu, Y.; Kashman, Y. J.
Nat. Prod. 1996, 59, 873.
(7) Schiff, P. B.; Fant, J.; Horwitz, S. B. Nature 1979, 277, 665.
(8) Nicolaou, K. C.; Dai, W.-M.; Guy, R. K. Angew. Chem., Int. Ed.
Engl. 1994, 33, 15.
(9) (a) Ho¨fle, G.; Bedorf, N.; Steinmetz, H.; Schomburg, D.; Gerth, K.;
Reichenbach, H. Angew. Chem., Int. Ed. Engl. 1996, 35, 1567.
S0002-7863(97)03000-X CCC: $14.00 © 1997 American Chemical Society

11354 J. Am. Chem. Soc., Vol. 119, No. 46, 1997
Communications to the Editor
Scheme 2. Synthesis of Sarcodictyin A (2)a
Scheme 1. Synthesis of Acetylene-Aldehyde Compound 15a
a a. 2.0 equiv of LiHMDS, THF, 25 °C, 10 min; b. 2.5 equiv of
Dess-Martin periodinane, 20 equiv of NaHCO3, CH2Cl2, 0 f 25 °C,
4.5 h, 85% for two steps; c. 1.0 equiv of PPTS, MeOH, 25 °C, 30 min,
94%; d. 0.3 equiv of Lindlar’s catalyst, H2, PhMe, 25 °C, 20 min, 75%;
e. 2.0 equiv of DDQ, CH2Cl2:H2O, 25 °C, 0.5 h, 80%; f. 1.0 equiv of
PPTS, MeOH, 25 °C, 1 h, 80%; g. 0.5 equiv of Lindlar’s catalyst, H2,
PhMe, 25 °C, 20 min; h. 5.0 equiv of CSA, MeOH, 25 °C, 8 h, 76%;
i. 5.0 equiv of Na-liquid NH3, -78 °C; then 20 in THF-EtOH, 5 min,
95%; ca. 2:1 mixture of 21 and 5,6-dihydro-21; j. 5.0 equiv of 22, 20
equiv of Et3N, 2.0 equiv of 4-DMAP, CH2Cl2, 25 °C, 48 h, 83%; k.
4.0 equiv of TBAF, THF, 25 °C, 2 h, 100%; l. 2.5 equiv of Dess-
Martin periodinane, 10 equiv of NaHCO3, CH2Cl2, 25 °C, 0.5 h; m.
6.0 equiv of NaClO2, 3.0 equiv of NaH2PO4, 50 equiv of 2-methyl-2-
butene, THF, t-BuOH, H2O; n. CH2N2, Et2O, 88% for three steps; o.
2.0 equiv of CSA, CHCl3:H2O (10:1), 25 °C, 6 h, 80%.
a a. 40 equiv of (EtO)3CCH3, 0.1 equiv of EtCOOH, 170 °C, 72 h,
74%; b. 1.0 equiv of DIBAL, CH2Cl2, -78 °C, 0.5 h, 97%; c. 1.5
equiv of (EtO)2P(O)CH2CO2Et, 2.0 equiv of NaH, THF, 0 f 25 °C,
100%; d. 4.0 equiv of DIBAL, CH2Cl2, -78 f 0 °C, 2 h, 91%; e. 0.1
equiv of Ti(Oi-Pr)4, 0.12 equiv of diethyl L-tartrate, 1.5 equiv of
t-BuOOH, CH2Cl2, -20 °C, 8 h, 87%; f. 5.0 equiv of MsCl, 6.0 equiv
of Et3N, CH2Cl2, -78 °C, 1 h; g. 5.0 equiv of sodium naphthalenide,
furnishing, after purification, 23 in 60% overall yield from 20.
The same compound was obtained from 16 via a sequence
involving: (i) DDQ deprotection of the PMP group (80%); (ii)
removal of the TMS group with PPTS in MeOH (80%); (iii)
H2-Lindlar’s catalyst; (iv) PPTS-MeOH to give 21 (52% for 2
steps); and (v) esterification with 22 (83%). Desilylation
(TBAF, 100%) of 23, followed by stepwise oxidation and
esterification (CH2N2, 88% for three steps) as indicated in
Scheme 2, gave methoxy sarcodictyin A (27) via intermediates
24-26. Finally, exposure of 27 to CSA in CHCl3:H2O (10:1)
furnished sarcodictyin A (2) in 90% yield. Synthetic sarco-
dictyin (2) exhibited identical properties to those reported3 for
the natural substance (1H and 13C NMR, MS, [R]25D, IR and
UV).
THF,
0 °C, 10 min, 90% for two steps; h. 5.0 equiv of
PMBOC(dNH)CCl3, 1.0 equiv of PPTS, CH2Cl2, 25 °C, 48 h, 89%,
ca. 50% conversion; i. 1.1 equiv of Hg(OAc)2, MeOH, 25 °C, 12 h;
then 1.0 equiv of Li2PdCl4, 3.0 equiv of CuCl2, MeOH, 55 °C, 3 h,
65%; j. 15 equiv of HCtCMgBr, CH2Cl2:THF, -78 f 25 °C, 12 h;
k. 4.0 equiv of TBAF, THF, 25 °C, 1 h, 72% for two steps, ds ratio ca.
7:1; l. 1.5 equiv of Dess-Martin periodinate, 20 equiv of pyr, 20 equiv
of NaHCO3, CH2Cl2, 0 f 25 °C, 4 h; m. 30 equiv of NCCH2COOEt,
4.0 equiv of â-alanine, 95% EtOH, 25 °C, 72 h; n. 5.0 equiv of
TMSOTf, 10 equiv of i-Pr2NEt, CH2Cl2, -78 °C, 10 min, 71% for
three steps; o. 4.0 equiv of DIBAL, CH2Cl2, -78 °C, 2 h, 74%; p. 10
equiv of TIPSOTf, 20 equiv of i-Pr2NEt, CH2Cl2, -78 °C, 1 h, 91%.
The described chemistry renders sarcodictyin A (2) readily
available and paves the way for the construction of other
members of the sarcodictyin family for chemical biology studies.
The ring closure of acetylenic aldehyde 15 was smoothly
realized with LiHMDS in THF (0 f 25 °C), and the resulting
alcohol was oxidized with Dess-Martin periodinate to afford
the 10-membered ring ketone 16 (85% for two steps). Removal
of the TMS group from 16 was achieved with PPTS in MeOH,
leading to compound 17 (94%). Careful semireduction of the
acetylene moiety was performed with H2 and Lindlar’s cat. in
toluene, yielding directly the desired tricyclic compound 19
(75%), presumably via the intermediacy of 18. With PPTS in
MeOH, lactol 19 was converted to 20.
The total synthesis of sarcodictyin A (2) was accomplished
as shown in Scheme 2. Treatment of 20 with Na-liqNH3
furnished the rather labile alcohol 21, together with its 5,6-
dihydro derivative (95%, ca. 2:1 ratio). This mixture was
immediately esterified using mixed anhydride 22 (prepared from
N(6′)-methylurocanic acid ethyl ester18 by hydrolysis and
reaction with t-BuCOCl) in the presence of Et3N and 4-DMAP,
Acknowledgment. We thank Dr. W. Fenical for preprints refs 2a,b.
This work was supported by The Skaggs Institute for Chemical Biology,
the NIH, Novartis, CaPCURE, the Japanese Society for the Promotion
of Science for Young Scientists (fellowship to S.H.), and the Department
of Defense, U.S.A. (fellowship to J.P.).
Supporting Information Available: Physical data and procedures
for selected compounds (34 pages). See any current masthead page
for ordering and Internet access instructions.
JA973000G
(18) Viguerie, N. L.; Sergueeva, N.; Damiot, M.; Mawlawi, H.; Riviere,
M.; Lattes, A. Heterocycles 1994, 37, 1561.