Enantioselective synthesis of the 5-6-7 carbocyclic core of the gagunin diterpenoids

Article abstract of DOI:10.1021/ol401514s

A catalytic enantioselective double allylic alkylation reaction has been employed in the synthesis of the core of the gagunin diterpenoids. Enantioenriched material was advanced in 11 steps to afford the core of the highly oxygenated target, which include

Full text of DOI:10.1021/ol401514s

ORGANIC
LETTERS
2013
Vol. 15, No. 13
3480–3483
Enantioselective Synthesis of the
5À6À7 Carbocyclic Core of the
Gagunin Diterpenoids
Grant M. Shibuya, John A. Enquist Jr., and Brian M. Stoltz*
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical
Engineering, Division of Chemistry and Chemical Engineering, California Institute of
Technology, 1200 East California Boulevard, MC 101-20, Pasadena, California 91125,
United States
stoltz@caltech.edu
Received May 29, 2013
ABSTRACT
A catalytic enantioselective double allylic alkylation reaction has been employed in the synthesis of the core of the gagunin diterpenoids.
Enantioenriched material was advanced in 11 steps to afford the core of the highly oxygenated target, which includes two all-carbon quaternary
stereocenters.
The gagunin family of diterpenoids (1À7, Figure 1) were
isolated from the sponge Phorbas sp. off the coast of South
Korea by Shin and co-workers.1 A wide range of cytotoxi-
city (LC50 = 0.03À50 μg/mL) was reported for gagunins
AÀG against the human leukemia cell line K562. The
cytotoxicity of the gagunins is modulated by the differen-
tial hydroxylation or esterification level present in a spe-
cific gagunin, as Shin and co-workers found gagunins A (1)
and B (2) to be less activethanotherfamilymembers, likely
due to the presence of a butyrate group at C(11) of these
molecules.1 Additionally, a perhydroxylated derivative of
gagunin A (8) exhibited no cytotoxicity, further suggesting
the importance of substitution patterns. Gagunin E (5)
displayed an LC50 value of 0.03 μg/mL (50 nM), the most
potent cytotoxicity within this family of natural prod-
ucts. In the course of a reisolation of the gagunins from
Phorbas sp., gagunin E was not found despite the reisola-
tion of all other known gagunins and the discovery of 10
new gagunins.1b Given the scarcity of gagunin E in nature
and broad range of biological activity displayed by the
gagunin family, we sought to pursue a general synthetic
route toward the gagunins to allow for additional biologi-
cal profiling and structureÀactivity relationship studies.
Herein we report our progress toward a synthesis of the
carbocyclic core of the gagunin family.
The carbon skeleton of the gagunins resembles the
carbon skeleton of the cyathane family of diterpenoids.2
A general route toward the cyathanes was previously
reported byour laboratoryusing our enantioselective Tsuji
(2) (a) Green, D.; Goldberg, I.; Stein, Z.; Ilan, M.; Kashman, Y. Nat.
Prod. Lett. 1992, 1, 193–199. (b) Peng, J.; Walsh, K.; Weedman, V.;
Bergthold, J. D.; Lynch, J.; Lieu, K. L.; Braude, I. A.; Kelly, M.;
Hamann, M. T. Tetrahedron 2002, 58, 7809–7819. (c) Peng, J.; Avery,
M. A.; Hamann, M. T. Org. Lett. 2003, 5, 4575–4578. (d) Peng, J.;
Kasanah, N.; Stanley, C. E.; Chadwick, J.; Fronczek, F. R.; Hamann,
M. T. J. Nat. Prod. 2006, 69, 727–730. (e) Enquist, J. A., Jr.; Stoltz, B. M.
Nat. Prod. Rep. 2009, 26, 661–680.
(1) (a) Rho, J.-R.; Lee, H.-S.; Sim, C. J.; Shin, J. Tetrahedron 2002,
58, 9585–9591. (b) Jang, K. H.; Jeon, J.; Ryu, S.; Lee, H.-S.; Oh, K.-B.;
Shin, J. J. Nat. Prod. 2008, 71, 1701–1707.
r
10.1021/ol401514s
Published on Web 06/26/2013
2013 American Chemical Society

Scheme 1. Enantioselective Tsuji Allylic Alkylation Applied to
the Synthesis of Cyanthiwigins F (13), B (14), and G (15)
Scheme 2. Retrosynthesis of Gagunin E (5)
Figure 1. Gagunins AÀG (1À7) and perhydroxylated gagunin A
(8) and their reported biological activities.
allylation methodology.3 Bis-β-ketoester 9, comprised of a
mixture of racemic and meso diastereomers, was treated
with a catalytic amount of Pd2(pmdba)3 and the ligand
(S)-t-Bu-PHOX (10)4 to forge two all-carbon quaternary
stereocentersin a single operation, affording diketone11in
99% ee as a 4.4:1 mixture of (R,R) to meso-diastereomers
(Scheme 1). Diketone11was converted toenol triflate12, a
common intermediate used in the syntheses of cyanthiwi-
gins F (13),5 B (14),5b and G (15).5b
Our retrosynthetic analysis of gagunin E (5) is shown
in Scheme 2. We planned to employ a similar overall
strategy in our approach to the gagunins, as was used in
the cyanthiwigins. Retrosynthetically, we envisionsed a
late-stage installation of the five-membered ring, preceded
by establishing the seven-membered ring through a ring-
closing methathesis (RCM) reaction. Such an approach
would again allow for the early and essentially simulta-
neous introduction of both quaternary stereocenters.
In the forward direction, enol triflate 12 was subjected to
conditions reported by Mulzer and co-workers to effect an
intermolecular Heck reaction at the hindered neopentyl
enol triflate.6 The addition of silyl ketene acetal 17,7
Pd(PPh3)4, and LiOAc afforded methyl ester 18 in 77% yield
(3) (a) Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126,
15044–15045. (b) Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz,
B. M. Angew. Chem., Int. Ed. 2005, 44, 6924–6927. (c) Behenna, D. C.;
Mohr, J. T.; Sherden, N. H.; Marinescu, S. C.; Harned, A. M.; Tani, K.;
ꢀ
Seto, M.; Ma, S.; Novak, Z.; Krout, M. R.; McFadden, R. M.; Roizen,
J. L.; Enquist, J. A., Jr.; White, D. E.; Levine, S. R.; Petrova, K. V.;
Iwashita, A.; Virgil, S. C.; Stoltz, B. M. Chem.;Eur. J. 2011, 17, 14199–
14223.
(4) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336–345.
(5) (a) Enquist, J. A., Jr.; Stoltz, B. M. Nature 2008, 453, 1228–1231.
(b) Enquist, J. A., Jr.; Virgil, S. C.; Stoltz, B. M. Chem.;Eur. J. 2011, 17,
9957–9969.
(6) Magauer, T.; Mulzer, J.; Tiefenbacher, K. Org. Lett. 2009, 11,
5306–5309.
(7) Oisaki, K.; Suto, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2003, 125, 5644–5645.
Org. Lett., Vol. 15, No. 13, 2013
3481

(Scheme 3).8 Next, ketone 18 was converted to the corre-
sponding ketal (19) in 47% yield by treatment with
ethylene glycol and catalytic p-toluenesulfonic acid in
benzene at reflux. Methyl ester 19 was then exposed to
N,O-dimethylhydroxylamine hydrochloride and isopro-
pylmagnesium chloride to afford Weinreb amide 20 in
93% yield. The addition of vinylmagnesium bromide to
amide 20 at À20 °C furnished enone 21 in 74% yield.
final ring.5 Ketone 25 was next diazotized using Danheiser’s
diazo transfer conditions11 to afford 26 in 47% yield over
two steps.
Scheme 4. Synthesis of Diazoketone 26
Scheme 3. Synthesis of Enone 21
Enone 21 was treated with HoveydaÀGrubbs genera-
tion 2 catalyst 229 in benzene at 40 °C to afford RCM
adduct 23 in 85% yield (Scheme 4). The enone of 23 was
next functionalized to the corresponding enol carbonate
(24) in 93% yield after treatment with LHMDS followed
by the addition of methyl chloroformate. A selective Wacker
oxidation was performed on the terminal allyl group of
tetraene 24, giving methyl ketone 25 in 61% yield.10
Further purification by HPLC allowed 25 to be isolated
as a single diastereomer. Previously, the separation of such
diastereomers was accomplished only after closure of the
With diazoketone 26 in hand, we proceeded to form
the final carbocycle of 5. Treatment of 26 with catalytic
Rh2(OAc)4 afforded cyclopropane product 27 in 71%
yield (Scheme 5).12,13 The structure of 27 was confirmed
by single crystal X-ray analysis (Figure 2).14 Finally, enol
carbonate cleavage and cyclopropane opening was accom-
plished by exposing ketone 27 to K2CO3 in methanol at
0 °C, giving the desired ring-opening product 28 and an
unexpected rearranged product (29) in a 1:1.8 ratio as
determinedbycrude1H NMR analysis. The structureof 29
was again unambiguously confirmed by single crystal
X-ray diffraction following chromatographic purification
(8) Our initial investigations centered on a direct RCM approach
to a cycloheptadiene via pentaene ii, available by cross-coupling of i with
enol triflate 12. Unfortunately, RCM of ii produced a mixture of iii and
iv when employing a range of ruthenium catalysts. Therefore, the
approach outlined above was pursued.
(11) Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z.
J. Org. Chem. 1990, 55, 1959–1964.
ꢀ
ꢀ
ꢀ
(12) (a) Fernandez-Mateos, A.; Perez Alonso, J. J.; Rubio Gonzalez,
R. Tetrahedron 1999, 55, 847–860. (b) Srikrishna, A.; Jagadreswar
Reddy, T. J. Chem. Soc., Perkin Trans. 1 2001, 2040–2046.
(13) Concurrent to the preparation of diazo ketone 26, we pre-
pared diazodiketone v using a similar approach. Treatment of v with
Rh2(OAc)4 did not yield a cyclopropanation, but instead a CÀO
insertion product tentatively assigned as vi was isolated in 38% yield.
(9) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2000, 122, 8168–8179. (b) Gessler, S.; Randl, S.;
Blechert, S. Tetrahedron Lett. 2000, 41, 9973–9976.
(10) Using a Parr shaker was necessary to obtain product in good
yield.
(14) Two conformations of the ketal of 27 were observed in the X-ray
structure. Only one has been shown here.
3482
Org. Lett., Vol. 15, No. 13, 2013

Scheme 5. Completion of the Tricyclic Core of 5 via
Cyclopropanation and Ring Opening
Figure 2. Single-crystal X-ray structures of 27 and 29.
of 28 and 29.15 Ultimately, desired dienone 28 was isolated
in 31% yield, and cyclopropane 29, in 27% yield; the
change in ratio between the crude analysis and isolated
yields suggest cyclopropane 29 may be unstable to chro-
matography conditions. Cyclopropane 29 is presumably
formed from desired product 28 by a retro-norcaradiene
rearrangement after formation of an enolate following
deprotonation at C(6).16
In summary, an expediant route toward the tricyclic
core of the gagunins has been established, giving 16 of 20
carbons present in the core of these diterpenoids and
the full tricyclic skeleton. The seven-membered ring was
synthesized via an intermolecular Heck reaction at a
hindered neopentyl carbon followed by a ruthenium-
catalyzed RCM reaction of an enone and an allyl group.
The five-membered ring was prepared from an allyl group
via a Wacker oxidation and ring-forming cyclopropana-
tion from a diazoketone. Efforts to optimize this sequence
and carry 28 and 29 forward to the gagunins and their
analogs are ongoing.
Acknowledgment. The authors wish to thank NIH-
NIGMS(R01GM080269-01), Amgen, Abbott, Boehringer
Ingelheim, and Caltech for financial support. Mr. Austin
Moehle (Caltech) is thanked for the preparation of early
compounds. Dr. David Vander Velde (Caltech) is grate-
fully acknowledged for assistance with the characteriza-
tion of compounds by NMR spectroscopy. Mr. Lawrence
Henling (Caltech) is gratefully acknowledged for X-ray
crystallographic structural determination and Dr. Alexander
Goldberg (Caltech) is acknowledged for assisting in the
preparation of crystallographic images for publication.
Ms. Kelly Kim (Caltech) is acknowledged for assistance
with the IR data of a late-stage compound. Materia, Inc.
and Dr. Keith Keitz (Caltech) are thankedfor the generous
donation of ruthenium catalysts. The Bruker KAPPA
APEXII X-ray diffractometer was purchased via an NSF
CRIF:MU award to the California Institute of Technol-
ogy, CHE-0639094. We also wish to acknowledge helpful
discussions with Christina White (UIUC), Huw Davies
(Emory), and other members of the CCI Center for Selective
CÀH Functionalization supported by NSF (CHE-1205646).
(15) For similar structures containing cyclopropane rings, please see:
(a) Nani, R. R.; Reisman, S. E. J. Am. Chem. Soc. 2013, 135, 7304–7311. (b)
Levin, S.; Nani, R. R.; Reisman, S. E. J. Am. Chem. Soc. 2011, 133, 774–776.
(c) Tseng, C.-C.; Ding, H.; Li, A.; Guan, Y.; Chen, D. Y.-K. Org. Lett. 2011,
13, 4410–4413. (d) Ng, W.; Wege, D. Tetrahedron Lett. 1996, 37, 6797–6798.
(e) Ruppert, J. F.; White, J. D. J. Am. Chem. Soc. 1981, 103, 1808–1813.
(16) Alternatively, enol carbonate cleavage of 27 without cyclopro-
pane fragmentation would give an enone that could be deprotonated at
the C(6) position and allow for the formation of 29 directly from 27 after
cyclopropane opening.
Supporting Information Available. Experimental de-
tails and NMR spectra of all intermediates. These
materials are available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 13, 2013
3483