Published on Web 07/31/2002

The First Total Synthesis of (()-Ingenol

Jeffrey D. Winkler,* Meagan B. Rouse, Michael F. Greaney,† Sean J. Harrison,‡ and Yoon T. Jeon§

Department of Chemistry, The UniVersity of PennsylVania, Philadelphia, PennsylVania 19104

Received April 19, 2002

The diverse biological activities and the structural complexity ketone, to the formation of 7 in a 14:1 ratio of R:β C-11 methyl
of ingenol have generated intense activity directed toward the total epimers. Three contiguous stereocenters are established in this
synthesis of this highly oxygenated diterpene for almost 20 years.1 reductive alkylation reaction. The cis AB ring fusion results from
The establishment of the highly unusual C-8/C-10 “inside-outside” addition of the crotonate to the sterically less hindered β face of
or trans intrabridgehead stereochemistry of the BC ring system the enolate derived from 6.5 The establishment of the requisite C-10/
presents a particularly daunting challenge.2 We report herein the C-11 relative stereochemistry can be rationalized by examination
first total synthesis of (()-ingenol. Outlined below is the preparation of the diastereomeric chelated transition state structures A and B
of a key tetracyclic intermediate 16 (Scheme 2), containing both in Figure 1. While both A and B experience gauche interactions
the C-11 methyl group and the D-ring cyclopropane, and its between the crotonate and the enolate, conformer B also suffers
elaboration into (()-ingenol, 1 (Scheme 3). from an unfavorable steric interaction between the crotonate
The retrosynthetic strategy that we employed for the total R-proton and the C-4 methine of the enolate leading to the
synthesis of ingenol is outlined in Scheme 1. We anticipated that preferential formation of 7 from conformer A.
ingenol 1 should be available from dioxenone photoaddition-
fragmentation product 2 via the methodology developed in our
laboratory. The requisite photosubstrate 3 would be prepared by
dioxenone formation from bicyclooctane 4, the product of angular
substitution of 5.

Scheme 1

Figure 1. Rationale for the highly diastereoselective Michael reaction.

We were disappointed to find that the extension of this reaction

to the C-3 hydroxyenone 56 led to attenuated yields and diminished
stereoselectivity. We therefore elected to transform 7, albeit devoid
of A ring functionality, into the key tetracyclic intermediate 16.
The absence of oxygen functionality at C-3 in 16 does not
significantly increase the number of steps required for the comple-
tion of the total synthesis of ingenol. Reduction of the ester 7
with LAH, followed by tosylate formation (TsCl, Et3N) and reac-
tion of the derived tosylate with allyl cuprate (CH2dCHCH2MgBr,
CuI), gave on desilylation (HF) the homologated ketone 9.
Elaboration of 9 to the dioxenone chromophore 10 proceeded by
carboxylation with Mander’s reagent,7 ester exchange (p-methoxy-
benzyl alcohol), and dioxenone formation (TFAA, TFA, Ac2O, Me2-
CO).
The first goal in our total synthesis of ingenol was the We reasoned that the incorporation of heteroatom functionality
establishment of the requisite C-10/C-11 relative stereochemistry at C-14 (ingenol numbering) in 10 would facilitate the introduction
as shown in 4 (Scheme 1). We anticipated that the C-11R methyl of the ingenol D-ring cyclopropane via ∆13,14 olefin formation and
stereochemistry could be established via Michael addition of the cyclopropanation. Toward that end, we found that allylic oxidation
enolate derived from dissolving metal reduction of 5 to methyl of 10 (SeO2, TBHP) led to the formation of a 1:1 mixture of
crotonate, based on the models advanced by Heathcock and alcohols 11, epimeric at C-14. While irradiation of 11 led to the
Seebach.3 We first examined this reaction sequence with C-3-deoxy- formation of a unique cyclobutane photoadduct 13 in low (16%)
enone 6 (Scheme 2).4 In the event, the conjugate reduction/Michael yield, we were delighted to find that photocycloaddition of the
reaction led, after silylation (TBSOTf, DIEA) of the intermediate derived allylic chloride 12 [(Cl3C)2CO, Ph3P] proceeded in 60%
yield to give the desired photoadduct 14, accompanied by the C-13
* To whom correspondence should be addressed. E-mail: [email protected]. chloro-isomer (5:2 ratio)!8 Fragmentation of 14 with methanolic
† Current address: Department of Chemistry, University of Edinburgh.
‡ Current address: Millenium Pharmaceuticals, Cambridge, MA. potassium carbonate, followed by LAH reduction of the derived
§ Current address: Bristol-Myers Squibb, Hopewell, NJ. ester, elimination of the chloride with DBU, and silylation of the
9726 9 J. AM. CHEM. SOC. 2002, 124, 9726-9728 10.1021/ja026600a CCC: $22.00 © 2002 American Chemical Society
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Scheme 2

primary alcohol (TBSCl), gave 15 as a 7:1 ratio of C-6 R:β epimers elimination of the C-6 hydroxyl to generate the ∆6,7 alkene, thereby
in 35% yield over four steps, accompanied by the chromatographi- completing the functionalization of the B ring of ingenol. Previous
cally separable ∆12,13 double bond isomer of 15. work from our laboratories revealed that the C-6 hydroxyl was
We anticipated that carbene addition to the ∆13,14 alkene in 15 resistant to elimination under standard reaction conditions. We
would occur from the sterically less hindered β-face since the trans have described an efficient procedure for the formation of the
intrabridgehead stereochemistry of the tricyclic ring system projects ∆6,7 alkene via elimination of the cyclic sulfate derived from the
the carbonyl group to the R face of 15. In the event, reaction of 15 C-4, C-6 diol in a closely related system.1e,12 The application of
with dibromocarbene and benzyl-triethylammonium chloride gave that methodology to 28 proved straightforward. Reaction of 28
a quantitative yield of a dibromocyclopropane as a single diaste- with thionyl chloride, followed by oxidation of the derived sulfite
reomer, which on reductive methylation (MeLi, CuSCN, MeI) gave
(RuO4), led to the formation of cyclic sulfate 29 in good yield.
16.9
Exposure of 29 to DBU, followed by treatment of the eliminated
Our next objective toward the completion of the synthesis was
sulfate product with H2SO4, gave the desired ∆6,7 alkene, as a
to employ the C-6R hydroxymethyl substituent in 16 to introduce
mixture of TES ether 30 and diol 31. Treatment of 30 with TBAF
the A ring functionality present in ingenol. Toward that end,
deprotection of silyl ether 16 with TBAF and oxidation of the cleanly afforded the requisite diol 31 without the removal of the
resulting C-20 alcohol 17 with the Dess-Martin periodinane led TBDPS group. Having completed the functionalization of the B
to the formation of the aldehyde 18 as a mixture of C-6 epimers in and C rings, it remained only to introduce the requisite A ring
88% yield from 16 (Scheme 3). Oxidation of 18 to the ∆5,6 functionality (C-2 methyl and ∆1,2 alkene) to complete the synthesis
unsaturated aldehyde 20 was effected by bromination of 18 using of ingenol.
t-BuBr/DMSO,10 followed by regioselective elimination of the Reaction of the C-4β, C-5β diol functionality in 31 with
resulting mixture of epimeric R-bromoaldehydes 19 with LiCl/DMF p-methoxybenzaldehyde dimethyl acetal led to the formation of a
to give 20 in 73% overall yield from 18.11 Functionalization of the single acetal product 32, the stereochemistry of which was
A ring was then achieved from 20 by a three-step sequence: (1) established by NOESY. Hydrolysis of 32 (K2CO3, MeOH) and
formation of the dienol acetate (Ac2O, AcCl) of 20; (2) NBS- reaction of the resulting carbinol 33 with the Dess-Martin reagent
mediated bromination of the derived enol acetate to give the C-4 afforded the C-3 ketone 34. Introduction of the C-2 methyl group
brominated product 21; and (3) elimination of the C-4 bromo and the ∆1,2-alkene was achieved via carboxyallylation of 34
substituent in 21 with LiCl/DMF to introduce the requisite ∆3,4 (LDA, CH2dCH-CH2OCOCN), followed by methylation of the
alkene, affording diene aldehyde 22 in three steps from 20 in 50% derived β-ketoester (K2CO3, MeI) and Pd(OAc)2 oxidation13 of the
overall yield. methylated ketoester to generate the C-2 methylated enone 35.
The introduction of the C-3, C-4, C-5 triad of oxygen function- Luche reduction (NaBH4, CeCl3)14 of 35 provided the C-3β
alities into 22 that are present in ingenol was achieved via two allylic alcohol, via addition of hydride anti to the C-4β, C-5β
successive dihydroxylation reactions, both of which occur from the acetal ring. Deprotection of the acetal with methanolic HCl,
sterically more accessible β face of the tetracyclic ring system. We
followed by desilylation of the C-20 TBDPS ether with nBu4NF,
were delighted to find that dihydroxylation of 23, the diene carbinol
led to the formation of (()-ingenol 1, which was, in all respects,
obtained by reaction of 22 with DIBAL-H, led to the selective
identical to an authentic sample with the exception of optical
formation of the C-5β, C-6β diol 24, which on regioselective
rotation.
silylation (TBDPSCl) of the sole primary hydroxyl in the derived
triol gave 25. The regioselectivity of the osmylation reaction is The total synthesis of ingenol outlined above proceeds in 43 steps
consistent with the selective reaction at the more sterically accessible from enone 6 with an 80% average yield per step. It is notable for
∆5,6 alkene in 23. the use of a highly diastereoselective Michael reaction to fix the
Regioselective silylation of the C-5β secondary hydroxyl group C-11 methyl stereochemistry and the incorporation of the dimeth-
in diol 25 led to the formation of the corresponding C-5β TES ylcyclopropane via diastereoselective carbene addition to the ∆13,14
ether 26. Dihydroxylation of 26 from the β-face of the ∆3,4 alkene olefin. The establishment of the C-8/C-10 trans intrabridgehead
gave the C-3β, C-4β diol 27, which could be selectively benzoylated stereochemistry serves as a testament to the utility of the intramo-
at the sterically more accessible C-3β secondary hydroxyl to give lecular dioxenone photoaddition-fragmentation approach to the
28. Having achieved the stereoselective incorporation of the C-3, synthesis of structurally and stereochemically complex natural
C-4, and C-5 oxygen functionalities, it remained only to effect products.15 The elaboration of 16 into 1, using the C-6 hydroxy-

J. AM. CHEM. SOC. 9 VOL. 124, NO. 33, 2002 9727

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Scheme 3

methyl group as the sole handle for oxidation of seven contiguous J. Org. Lett. 2002, 4, 799. (b) Tang, H.; Yusuff, N.; Wood, J. Org. Lett.
2001, 3, 1563. (c) Kigoshi, H.; Suzuki, Y.; Aoki, K.; Uemura, D.
carbon centers, leads to the completion of the total synthesis of Tetrahedron Lett. 2000, 41, 3927. (d) Tanino, K.; Nakamura, T.; Matsui,
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Acknowledgment. This work is dedicated to the memory of Am. Chem. Soc. 1999, 121, 296. (f) Nakamura, T.; Matsui, T.; Tanino,
K.; Kuwajima, I. J. Org. Chem. 1997, 62, 3032.
Professor Josef Fried, in gratitude for his enthusiasm and encour- (2) For the first synthesis of the tricyclic core of the ingenane ring system
agement during the early stages of this work. This work is presented with trans-intrabridgehead stereochemistry, see: Winkler, J.; Henegar,
K.; Willard, P. J. Am. Chem. Soc. 1987, 109, 2850.
in part by J.D.W. at the Pfizer Lecture in Organic Synthesis at the (3) (a) Oare, D.; Heathcock, C. Top. Stereochem. 1989, 19, 227. (b) Seebach,
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(5) All new compounds were characterized by full spectroscopic (NMR, IR,
of Pennsylvania), Dr. Sharon Callahan, Dr. Sarah Traeger, and high resolution MS) data. Yields refer to spectroscopically and chromato-
Dr. Xiaohua Huang (Bristol-Myers Squibb) in obtaining NMR graphically homogeneous (>95%) materials.
(6) We thank Professor Philip E. Eaton (University of Chicago) for providing
spectral characterization is gratefully acknowledged. We would like an unpublished procedure for the conversion of 6 to 5.
to thank the National Institutes of Health (CA40250 and 45686), (7) Crabtree, S.; Chu, W.; Mander, L. Synlett 1990, 3, 169.
Boehringer-Ingelheim, Bristol-Myers Squibb, Dupont Pharmaceu- (8) The details of the pathways of the photocycloaddition of the allylic alcohol
and allylic chloride photosubstrates 11 and 12 will be reported sepa-
ticals, Glaxo SmithKline, GPC Biotech, Merck, Pfizer, and Wyeth- rately: Winkler, J.; Harrison, S.; Greaney, M., manuscript in preparation.
Ayerst for generous financial support of this project. M.F.G. is the (9) The introduction of the dimethylcyclopropane ring by dibromocarbene
addition and reductive methylation in a closely related system has also
recipient of the GlaxoWellcome Fellowship for Postdoctoral been reported by Kuwajima and co-workers (ref 1f).
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(11) For similar selectivity in a closely related system, see ref 1e.
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9728 J. AM. CHEM. SOC. 9 VOL. 124, NO. 33, 2002