Total synthesis of ingenol

Article abstract of DOI:10.1021/ja029226n

Total synthesis of ingenol, a diterpene isolated from the genus Euphorbia, was accomplished on the basis of the novel key reactions. The highly strained ingenane skeleton was constructed through an intramolecular cyclization reaction of an acetylene dicob

Full text of DOI:10.1021/ja029226n

Published on Web 01/17/2003
Total Synthesis of Ingenol
Keiji Tanino,*,† Kei Onuki,† Kohei Asano,† Masaaki Miyashita,† Tsuyoshi Nakamura,§
Yoshinori Takahashi,§ and Isao Kuwajima*,‡
DiVision of Chemistry, Graduate School of Science, Hokkaido UniVersity, Sapporo 060-0810, Japan,
Department of Chemistry, Tokyo Institute of Technology, Meguro, Tokyo 152-8551, Japan,
and Laboratory for Natural Products Chemistry, Kitasato UniVersity, and CREST,
Japan Science and Technology Corporation (JST), S-105 1-15-1, Kitasato, Sagamihara 228-8555, Japan
Received November 5, 2002 ; E-mail: ktanino@sci.hokudai.ac.jp
Ingenol (1),1 isolated from the genus Euphorbia, has been of
Scheme 1. Construction of the Ingenane Skeleton via Tandem
Cyclization-Rearrangement Strategy
great interest as a synthetic target2 because of its unusual structure
involving an “inside-outside” bridged BC ring coupled with a
broad spectrum of biological activities.3 The difficulties in con-
structing the highly strained ingenane skeleton required special
approaches, and five strategically distinct methods2,4 have been
disclosed to date. The first total synthesis of ingenol has recently
been achieved by Winkler5 on the basis of an intramolecular de
Mayo reaction that had been originally reported by the same
authors6 as the first entry for constructing the trans-bicyclo[4.4.1]-
undecane system.
Scheme 2. New Strategy via Rearrangement of Epoxy Alcohol
In 1997, we reported an efficient method for ingenane synthesis
by employing a “tandem cyclization-rearrangement strategy”7 as
shown in Scheme 1. Although the product 2 was further converted
into compound 3 having the complete CD ring system of ingenol,8
the methoxy group at the C(4) position was not sufficient to serve
as an anchor for installation of the hydroxyl groups and the olefin
moieties of the AB ring.
The present work describes the total synthesis of ingenol on the
basis of a new strategy, namely a rearrangement reaction of an
epoxy alcohol giving rise to the key intermediate 4 which possesses
two oxygen functional groups on both the A and B rings (Scheme
2).
The synthetic route for the key intermediate is depicted in
Scheme 3. An allyl ether derived from commercially available
alcohol 5 was subjected to a Claisen rearrangement reaction
promoted by dichloroacetic acid. The resulting ketone 6 reacted
with NBS in water-DMSO9 to yield bromohydrin derivatives 7
and 8 as an almost 1:1 mixture, which was recrystallized from ethyl
acetate to give pure 8 as crystals. It is noteworthy that ketone 6
can be easily recovered from the mother liquid containing 7 by
treating with zinc dust. Silylation of 8 by using TESCl and
imidazole effected selective protection of the secondary hydroxyl
group via opening of the lactol ring. The aldol reaction of ketone
9 with acetaldehyde followed by dehydration afforded (E)-enone
10 stereoselectively. In the presence of LiBr, enone 10 reacted with
lithium enolate of tert-butyl acetate to afford adduct 11 as a single
isomer. In the stereoselective addition reaction, the conformation
of the R-methoxyketone would be restricted by forming a five-
membered chelate ring, and the nucleophile attacks the carbonyl
group from the opposite side of the side chain (Figure 1, A).
Treatment of hydroxyester 11 with trimethylaluminum followed
by LDA effected an intramolecular alkylation reaction to give trans-
decaline derivative 12 as a single isomer. Since a reaction in the
absence of trimethylaluminum failed to give 12, formation of a
six-membered cyclic aluminum enolate intermediate would be
essential for the stereoselective cyclization reaction (Figure 1, B).
Silylation of the secondary hydroxyl group followed by elongation
of the side chain led to a propargyl alcohol which was converted
into dicobalt acetylene complex 15 in good yield. Under the
influence of methylaluminum bis(2,6-dimethyl-4-nitrophenoxide),
cobalt complex 15 underwent a cyclization reaction to afford allyl
alcohol 16 containing the C(11) R-methyl group. The dicobalt
acetylene complex moiety of 16 was used for stereoselective
construction of the D ring through Birch reduction, dibromocyclo-
propanation, and methylation. Transformation of the tetracyclic
carbon framework into an ingenane skeleton was achieved via
stereoselective epoxidation of allyl alcohol 17 followed by treatment
with trimethylaluminum.10
The key intermediate 19 having a complete ABCD ring system
of ingenol in hand, the stage was set for stereoselective function-
alization of the AB ring moiety (Scheme 4). The condensation
reaction of ketone 20 with tert-butoxy-bis(dimethylamino)methane11
followed by reduction with DIBAL12 afforded enone 21 in an
excellent yield. The C(1)-C(2) double bond was introduced by
dehydration of a secondary alcohol which was obtained through
† Hokkaido University.
§ Tokyo Institute of Technology.
‡ Kitasato University.
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J. AM. CHEM. SOC. 2003, 125, 1498-1500
10.1021/ja029226n CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Construction of the Ingenane Skeleton via
Scheme 4. Stereoselective Introduction of the Oxygen
Rearrangement Strategya
Functionalitiesa
a Reagents and conditions: (a) DMSO, (COCl)2, Et3N, CH2Cl2 (93%);.
(b) tBuO(Me2N)2CH, DMF, 100 °C; (c) DIBAL, CH2Cl2, MeI, THF (98%
in 2 steps); (d) NaBH4, EtOH (95%); (e) DIBAL, CH2Cl2; (f) (CF3SO2)2O,
2,6-lutidine, DBU, CH2Cl2 (83% in 2 steps); (g) TBAF, THF (100%); (h)
PDC, CH2Cl2 (97%); (i) 1,3,4,6,7,8-hexahydro-1-methyl-2H-pyrimido[1,2-
a]pyrimidine, DMF, 120 °C (86%); (j) NaBH4, CeCl3, MeOH-H2O; (k)
TESCl, imidazole, DMF (99% in 2 steps); (l) OsO4, pyridine, ether, then
NaHSO3, H2O (59%); (m) 1,1′-carbonyldiimidazole, toluene (27: 76%,
28: 18%); (n) 4-(dimethyl-amino)pyridine, toluene, 100 °C; (27: 72%,
28: 27%) (o) p-MeOC6H4CH(OMe)2, CSA, DMF (93%); (p) SOCl2,
pyridine; (q) AcOH-H2O (96% in 2 steps); (r) Me2S, NCS, toluene (75%).
a Reagents and conditions: (a) NaH, BrCH2CHdCH2, benzene; (b)
CHCl2CO2H, DMF, reflux (79% in 2 steps); (c) NBS, H2O, DMSO (8:
32% after recrystallization); (d) Zn dust, NH4Cl, ether, H2O (52% of 6 was
recovered); (e) TESCl, imidazole, DMF, rt (99%); (f) LHMDS, ZnBr2,
CH3CHO, THF (71%); (g) (CF3CO)2O, pyridine, DBU, benzene (95%);
t
(h) BuOAc, LDA, LiBr, ether (91%); (i) Me3Al, LDA, THF, then HCl
(66%); (j) TIPSCl, DMAP, DMF (quant); (k) LiAlH4, THF (84%); (l)
SO3‚pyridine, DMSO, Et3N (97%); (m) (EtO)2P(dO)CCl3, BuLi, THF
(85%); (n) BuLi, THF, then (CH2O)n (91%); (o) Ac2O, Et3N, DMAP,
CH2Cl2 (99%); (p) Co2(CO)8, CH2Cl2 (95%); (q) methylaluminum bis(2,6-
dimethyl-4-nitrophenoxide CH2Cl2; (r) Li, liq. NH3 (67% in 2 steps); (s)
CHBr3, NaOH, BnEt3NCl, CH2Cl2, H2O (71%); (t) Me3CuLi2, ether, then
MeI (95%); (u) TBHP, Ti(OiPr)4, MS 4A, CH2Cl2; (v) Me3Al, CH2Cl2 (76%
in 2 steps).
Scheme 5
chromatography. Although the desired compound 28 was the minor
product, 27 was found to undergo isomerization to give a ca. 3:1
mixture of 27 and 28 simply by heating with 4-(dimethylamino)-
pyridine. Removal of the triethylsilyl group and protection of the
C(5) and C(6) hydroxyl groups as a cyclic acetal was achieved in
one pot, and the resulting tert-alcohol was subjected to a dehydration
reaction to afford olefin 29 as a single regioisomer. Since attempts
for distinction between the C(5) and C(6) hydroxyl groups via
regioselective cleavage of the cyclic acetal moiety were fruitless,
29 was hydrolyzed to the corresponding C(5)-C(6) diol. Fortu-
nately, the diol was selectively converted into R-ketol 30 by
adopting the Corey-Kim protocol13 through oxidation of the less
hindered C(6) hydroxyl group.
Construction of the allylic alcohol moiety by using the C(6) keto
group remained as the final step in the total synthesis. We initially
chose epoxide 31, which was prepared from ketol 30 by successive
treatment with diiodomethane, methyllithium,14 and acetic anhy-
dride, as a precursor of an allylic alcohol (Scheme 5). However,
the conventional methods using an aluminum amide,15 aluminum
isopropoxide,16 or TMSOTf-DBU17 failed to effect the desired
Figure 1. Suggested intermediates of the stereoselective C-C bond-forming
reactions.
successive treatment of enone 21 with sodium borohydride and
DIBAL. Next, silyl ether 22 was converted into the corresponding
ketone with a view to introducing the C(4)-C(5) double bond by
a â-elimination reaction. Under the influence of a guanidine base,
however, ketone 23 yielded conjugated diene 24 via isomerization
of the C(1)-C(2) double bond. The result led us to examine
construction of the polyol moiety by osmium tetroxide oxidation
of both C(2)-C(3) and C(4)-C(5) double bonds in one stage. Since
the oxidation reaction of enone 24 resulted in cleavage of the B
ring via a retro aldol reaction, the C(6) carbonyl group was masked
by stereoselective reduction and silylation. Treatment of diene 25
with an excess amount of osmium tetroxide followed by sodium
hydrogen sulfite gave polyol 26, containing all of the stereogenic
centers of ingenol, as a single isomer. To accomplish functional-
ization of the A ring, it was then required to protect the C(3), C(4),
and C(5) hydroxyl groups selectively. The reaction of 26 with 1,1′-
carbonyldiimidazole yielded a ca. 4:1 mixture of cyclic carbonates
27 and 28, which can be easily separated by silica gel column
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C O M M U N I C A T I O N S
Scheme 6. Final Stages of the Total Synthesisa
We also acknowledge financial support from The Sumitomo
Foundation, Novartis Foundation (Japan) for the Promotion of
Science, and The Akiyama Foundation. We thank Professor G.
Appendino (Dipartimento di Scienze Chimiche, Alimentari, Far-
maceutiche e Farmacologiche) for providing natural ingenol.
Supporting Information Available: Experimental details and
spectroscopic data (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
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a Reagents and conditions: (a) TESOTf, 2,6-lutidine, CH2Cl2; (b) TMSCl,
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a mixture of the crude R-siloxyketone and TMSCl effects the
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the basis of novel key reactions, namely an intramolecular cycliza-
tion reaction of acetylene dicobalt complex 15, a rearrangement
reaction of epoxy alcohol 18 for constructing the ingenane skeleton,
and a stereoselective double dihydroxylation reaction of diene 25.
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Acknowledgment. This research was supported in part by the
Ministry of Education, Culture, Sports, Science and Technology.
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