Total synthesis of ingenol

Article abstract of DOI:10.1021/ja044123l

A total synthesis of the biologically important diterpene ingenol has been completed. Ring-closing olefin metathesis was used to construct the strained "inside-outside" tetracyclic skeleton, and a series of diastereoselective reactions were employed to complete the synthesis. Another naturally occurring ingenane, 20-deoxyingenol, has also been prepared. Copyright

Full text of DOI:10.1021/ja044123l

Published on Web 11/24/2004
Total Synthesis of Ingenol
Andrew Nickel, Toru Maruyama, Haifeng Tang, Prescott D. Murphy, Blake Greene,
Naeem Yusuff, and John L. Wood*
Sterling Chemistry Laboratory, Department of Chemistry, Yale UniVersity, New HaVen, Connecticut 06520-8107
Received September 27, 2004; E-mail: john.wood@yale.edu
Isolated in 1968, ingenol (1) is the parent compound of several
dozen naturally occurring ingenanes that possess the same carbon
skeleton but varied peripheral functionalities.1 In addition to their
intriguing “inside-outside” bridged BC ring system,2 the ingenanes
display interesting biological profiles that range from tumor-
promoting to anti-leukemic and anti-HIV activities.3 Since the early
1980s, this combination of important biological function and
complex architecture has inspired the efforts of numerous synthetic
Figure 1. Structure of ingenol and Chem3D representation of the “inside-
chemists.4 Previously, we reported an approach toward 1 wherein
outside” bridged BC ring system.
known â-ketoester 25 was advanced to diene 3, which served as a
ring-closing metathesis substrate in a first generation Grubbs
Scheme 1
reaction that delivers the ingenane tetracycle 4 (Scheme 1).4e
Although this work established the feasibility of ring closure via
metathesis chemistry, further experiments indicated that competing
ring-opening reactions were likely responsible for the observed poor
conversion. This, coupled with the underfunctionalized nature of
4, led us to explore a modified substrate (5), which, upon ring
Scheme 2
closure, would furnish a more stable trisubstituted olefinic product
6 possessing the requisite C-20 hydroxymethyl group. In the event,
we were delighted to find that substrate 56 undergoes ring-closing
metathesis with improved yield and catalyst loading with respect
to diene 3 (Scheme 2).7
Having prepared an intermediate possessing all of the requisite
carbon atoms and fully functionalized C and D rings, attention was
turned to completing rings A and B. Accordingly, dioxolane 6 was
Scheme 3 a
converted to diene 7 via a deprotection/reduction/elimination
sequence (Scheme 3). Allylic oxidation of 7 (SeO2/t-BuOOH)8
proved highly selective and furnished only one of several possible
allylic alcohol products (8). Further oxidation of 8 to the exo-enone
was followed by rhodium(III) chloride catalyzed isomerization9 to
the corresponding endocyclic isomer 9, which set the stage for
introducing the C-4 hydroxyl. Treatment of 9 with potassium tert-
butoxide in the presence of molecular oxygen and trimethyl
phosphite efficiently delivered R-hydroxy ketone 10.
At this point, all that remained to complete the ingenol A ring
was stereoselective reduction of the C-3 ketone. Unfortunately,
reduction of both free alcohol 10 and the derived silyl ether 11
resulted in predominant reduction from the convex â face, delivering
the undesired anti products 12 and 13, respectively.10
Encouraged by reports in the ingenol literature of structural
alterations in the B ring translating into marked differences in
reactivity of the A ring,11 we opted to address the problem of
stereoselective reduction at C-3 on more advanced substrates. Thus,
attention turned to completing the B ring. Initial studies explored
the feasibility of a singlet oxygen ene reaction12 which was expected
to stereoselectively furnish the requisite alcohol and ∆6,7 unsatura-
tion (i.e., 10 f 15) in a single step; unfortunately, 10 proved inert
to singlet oxygen.13
a Reagents and conditions: (a) HCl, THF-H2O; (b) NaBH4, EtOH-
THF (77% over two steps); (c) I2, PPh3, imidazole, THF; (d) KOtBu, THF-
DMSO (94% over two steps); (e) SeO2, tBuOOH, CH2Cl2-H2O-HOAc
(49%, 68% brsm); (f) Dess-Martin periodinane, CH2Cl2 (74%); (g) RhCl3,
EtOH-H2O (74%); (h) KOtBu, O2, P(OMe)3, THF-tBuOH (94%); (i)
TMSOTf, NEt3, CH2Cl2 (60%); (j) NaBH4, MeOH (99% for 10 f 12, 90%
for 11 f 13); (k) HCl, THF-H2O (76%).
oxide proceeded smoothly; however, attempts to convert the derived
epoxide (14) to the desired allylic alcohol 15 with a variety of either
Lewis acids or strong bases were unfruitful (Scheme 4).14
Suspecting that the free tertiary alcohol in 14 was interfering
with epoxide opening and aware of the possibility that the desired
R,â-hydroxy ketone (15) might be prone to undergo a retro-aldol
Forced to explore alternatives, we turned to a stepwise, epoxi-
dation ring-opening approach. Toward this end, it was found that
epoxidation of alkene 10 with VO(acac)2 and tert-butyl hydroper-
9
16300
J. AM. CHEM. SOC. 2004, 126, 16300-16301
10.1021/ja044123l CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4
In conclusion, a ring-closing metathesis approach has been
effectively employed in an efficient total synthesis that delivers
the biologically important diterpene ingenol in 32 overall steps from
2.5
Acknowledgment. This report is dedicated to Prof. Amos B.
Smith, III on the occasion of his 60th birthday. Financial support
was provided by Bristol-Myers Squibb, Yamanouchi, Merck,
Amgen, and Pfizer. A.N. thanks Bristol-Myers Squibb for a graduate
student fellowship. T.M. thanks Ono Pharmaceutical Co. Ltd. In
addition, we acknowledge V. B. Birman for helpful suggestions
and C. D. Incarvito for X-ray crystallographic analysis.
Scheme 5 a
Supporting Information Available: Experimental and character-
ization details (PDF, CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) Initial isolation and characterization: (a) Hecker, E. Cancer Res. 1968,
28, 2338-2349. (b) Zechmeister, K.; Brandl, F.; Hoppe, W.; Hecker, E.;
Opferkuch, H. J.; Adolf, W. Tetrahedron Lett. 1970, 11, 4075-4078.
(2) For a review on in/out isomerism, see: Alder, R. W.; East, S. P. Chem.
ReV. 1996, 96, 2097-2111.
(3) See Blanco-Molina, M.; Tron, G. C.; Macho, A.; Lucena, C.; Calzado,
M. A.; Mun˜oz, E.; Appendino, G. Chem. Biol. 2001, 8, 767-778 and
references therein.
(4) There have been two previous total syntheses: (a) Winkler, J. D.; Rouse,
M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc.
2002, 124, 9726-9728. (b) Tanino, K.; Onuki, K.; Asano, K.; Miyashita,
M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003,
125, 1498-1500. For a formal total synthesis, see: (c) Watanabe, K.;
Suzuki, Y.; Aoki, K.; Sakakura, A.; Suenaga, K.; Kigoshi, H. J. Org.
Chem. 2004, 69, 7802-7808. For successful construction of the ingenane
“inside-outside” skeleton, see: (d) Funk, R. L.; Olmstead, T. A.; Parvez,
M.; Stallman, J. B. J. Am. Chem. Soc. 1993, 58, 5873-5875. (e) Tang,
H.; Yusuff, N.; Wood, J. L. Org. Lett. 2001, 3, 1563-1566. (f) Rigby, J.
H.; Bazin, B.; Meyer, J. H.; Mohammadi, F. Org. Lett. 2002, 4, 799-
801.
a Reagents and conditions: (a) TMSOTf, NEt3, CH2Cl2 (72%); (b)
NaBH4, MeOH; (c) 2,2-dimethoxypropane, PPTS, CH2Cl2 (86% over two
steps); (d) DDQ, CH2Cl2-H2O (90%); (e) MsCl, NEt3, CH2Cl2 (96%); (f)
PhSH, Li2CO3, DMF (76%); (g) (NH4)6Mo7O24, H2O2, EtOH-H2O (97%);
(h) DBU, benzene (47%, 88% based on recovered 22); (i) DBU, benzene
(47%, 94% based on recovered 22); (j) Na(Hg), Na2HPO4, MeOH (76%);
(k) HCl, THF-H2O (92%); (l) SeO2/SiO2, THF (40%, 85% brsm).
reaction under strongly acidic or basic conditions, we considered
numerous protection scenarios, eventually recognizing reduction
of the C-3 ketone and protection of the derived diol as an efficient
possibility. In stark contrast to previous reductions (i.e., 11 f 13,
Scheme 3), we were delighted to find that conversion of the tertiary
alcohol in 14 to its TMS ether, followed by reduction and protection,
stereoselectively delivered acetonide 17. Although this result clearly
demonstrates how subtle changes in the ingenane skeleton can
influence reactivity, the underlying forces controlling the stereo-
chemical outcome of the C-3 reduction remain undelineated.
Despite a fully protected A ring, the epoxide in 17 again proved
unreactive toward ring-opening conditions. In an attempt to bias
the system, the protected C-20 alcohol in 17 was unmasked and
converted to phenyl sulfone 21 via nucleophilic displacement of
the corresponding mesylate (19) with lithium phenylthiolate fol-
lowed by oxidation. Gratifyingly, treatment of epoxy sulfone 21
under mildly basic conditions initially gave vinyl sulfone 22, which
smoothly isomerized under the reaction conditions to desired allylic
sulfone 23 (Scheme 5).15
With allylic sulfone 23 in hand, the major remaining challenge
in the synthesis of ingenol was the conversion of the C-20 sulfonyl
to the corresponding primary alcohol. While attempts to effect this
transformation via displacement or oxidation were unsuccessful,
sodium amalgam reduction of 23 followed by hydrolytic removal
of the acetonide furnished 20-deoxyingenol (24).16 Upon treatment
with silica supported selenium dioxide, 24 was found to undergo
selective oxidation at the least hindered allylic site to furnish 1,17
completing the most concise total synthesis of ingenol reported to
date.
(5) Prepared as a single enantiomer in five steps from commercially available
3-carene: Funk, R. L.; Olmstead, T. A.; Parvez, M. J. Am. Chem. Soc.
1988, 110, 3298-3300.
(6) Prepared in an analagous manner to 3. See Supporting Information.
(7) The conversion of 5 to 6 required the Hoveyda modified second generation
Grubbs catalyst for acceptable yields. See: Garber, S. B.; Kingsbury, J.
S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168-
8179.
(8) Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 5526-
5528.
(9) Disanayaka, B. W.; Weedon, A. C. Synthesis 1983, 952.
(10) In reductions of 10, 11, or C-20 variants with NaBH4 ( CeCl3‚7H2O,
DIBAL, or L-selectride, none of the desired syn diol was detected.
(11) Kim, S.; Winkler, J. D. Chem. Soc. ReV. 1997, 26, 387-399.
(12) For recent reviews, see: (a) Stratakis, M.; Orfanopoulos, M. Tetrahedron
2000, 56, 1595-1615. (b) Clennan, E. L. Tetrahedron 2000, 56, 9151-
9179.
(13) Enone 10 and C-20 variants were recovered unreacted from reactions under
typical conditions for the generation of singlet oxygen: O2, hν, and either
rose bengal, TPP, or methylene blue in suitable solvents.
(14) A similar epoxide-opening approach also proved unsuccessful for the
Kuwajima group. See ref 4b.
(15) Sulfones 22 and 23 were isolated as a 1:1 mixture. For a leading reference
of the isomerizion of R,â-unsaturated sulfones to â,γ-unsaturated sulfones,
see: (a) O’Connor, D. E.; Lyness, W. I. J. Am. Chem. Soc. 1964, 86,
3840-3846. For recent examples of one-pot epoxide-opening/isomeriza-
tion of â,γ-epoxysulfones, see: (b) Trost, B. M.; Acemoglu, M.
Tetrahedron Lett. 1989, 30, 1495-1498. (c) Lee, S. W.; Fuchs, P. L.
Tetrahedron Lett. 1991, 32, 2861-2864. (d) Ohtani, Y.; Shinada, T.;
Ohfune, Y. Synlett 2003, 619-622.
(16) 20-Deoxyingenol (24) is a natural product: (a) Uemura, D.; Ohwaki, H.;
Hirata, Y.; Chen, Y.-P.; Hsu, H.-Y. Tetrahedron Lett. 1974, 15, 2527-
2528. The intermediate 3,4-O-isopropylidene of 24 is a previously reported
natural product derivative: (b) Gotta, H.; Adolf, W.; Opferkuch, H. J.;
Hecker, E. Z. Naturforsch. 1984, 39b, 683-694. This is the first total
synthesis of 24, and its first structural confirmation by X-ray crystal-
lographic analysis.
(17) Chromatographically and spectroscopically identical to an authentic sample
(Sigma).
JA044123L
9
J. AM. CHEM. SOC. VOL. 126, NO. 50, 2004 16301