Total Synthesis of Terpenoids Employing a benzannulation of Carvone Strategy: Synthesis of (-)-Crotogoudin

Article abstract of DOI:10.1021/jacs.7b06823

Carvone is a sustainable and readily available starting material for organic synthesis. Herein, we present the syntheses of various natural product scaffolds that rely on a novel benzannulation involving the α-methyl group (C-10) of carvone to afford a versatile tetralin. The utility of our synthetic approach is highlighted by its application to a short synthesis of the ent-3,4-seco-atisane diterpenoid (-)-crotogoudin. The 13-step enantiospecific synthesis features a regioselective double oxidative dearomatization, a Diels-Alder cycloaddition with ethylene gas (to construct the bicyclo[2.2.2]octane framework), and a final acid-mediated lactonization. The versatility of this benzannulation strategy is demonstrated by its utility in the preparation of the carbon skeleton of ent-3,4-seco-abietane diterpenoids using an intramolecular oxidative dearomatization.

Full text of DOI:10.1021/jacs.7b06823

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Communication
Total Synthesis of Terpenoids Employing a ‘Benzannulation
of Car-vone’ Strategy: Synthesis of (–)-Crotogoudin
Peter Finkbeiner, Kenichi Murai, Michael Röpke, and Richmond Sarpong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b06823 • Publication Date (Web): 01 Aug 2017
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Total Synthesis of Terpenoids Employing a ‘Benzannulation of Car-
vone’ Strategy: Synthesis of (–)-Crotogoudin
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Peter Finkbeiner,‡ Kenichi Murai,∆‡ Michael Röpke, Richmond Sarpong*
Department of Chemistry, University of California, Berkeley, California 94720, United States.
∆Graduate School of Pharmaceutical Sciences, Osaka University,1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan
Supporting Information Placeholder
C10a (Figure 1, Panel A) could be accessed from (S)-carvone
ABSTRACT: Carvone is a sustainable and readily available
whereas 3,4-seco-abietanes including seco-hinokiol11 or
starting material for organic synthesis. Herein, we present the
syntheses of various natural product scaffolds that rely on a novel
benzannulation involving the α-methyl group (C-10) of carvone
callicarpic acid A12 (Figure 1, Panel B) could arise from (R)-
carvone.
to afford a versatile tetralin. The utility of our synthetic approach
is highlighted by its application to a short synthesis of the ent-3,4-
seco-atisane diterpenoid (−)-crotogoudin. The 13-step enantiospe-
cific synthesis features a regioselective double oxidative dearoma-
tization, a Diels–Alder cycloaddition with ethylene gas (to con-
struct the bicyclo[2.2.2]octane framework), and a final acid-
mediated lactonization. The versatility of this benzannulation
strategy is demonstrated by its utility in the preparation of the
carbon skeleton of ent-3,4-seco-abietane diterpenoids using an
intramolecular oxidative dearomatization.
A key aspiration in pursuing total syntheses of complex mole-
cules in the modern era is to maximize sustainable practices.1
Designing highly efficient synthetic strategies, as well as powerful
methods to implement them, are paramount to realizing this ob-
jective.2 In addition to considerations of strategies and methods,
the choice of readily available and sustainable starting materials
contributes substantially to achieving the goals of a modern syn-
thesis. In this context, the pool of chiral compounds including
amino acids,3 sugars,4 and terpenes5 (the ‘chiral pool’)6 has served
admirably as starting materials for many practical and inspiration-
al total syntheses over the last century. With regard to the total
synthesis of terpenoid natural products,7 carvone has been a fre-
quently employed starting material due to its ready availability in
both enantiomeric forms, as well as the potential for the orthogo-
nal derivatization of its functional groups.8
Despite the wealth of reactivity that has been established for the
α-methyl (C-10), isopropenyl, and enone (i.e., double bond and
carbonyl) groups of carvone (Figure 1), we recognized that direct
carbon-carbon bond formation involving the α-methyl group has
been underexplored. Direct C–C bond formation to this methyl
substituent holds significant potential in the context of natural
product synthesis. Specifically, we envisioned that if benzannula-
tion of the carvone six-membered ring could be achieved by en-
gaging the C-10-methyl and enone carbonyl groups, the stage
could be set to access myriad natural product classes. In particu-
lar, numerous natural product scaffolds could arise from benzan-
nulation following sequential diastereoselective functionalization
α to the enone carbonyl group (i.e., at C-6) of carvone.9 For ex-
ample, 3,4-seco-atisane natural products10 such as agallochaol
Figure 1. Benzannulation of carvone: a unified approach toward
terpenoids.
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In this Communication, we report our initial investigations into
constitutional isomer 7b in a 1:1 ratio. A Cope rearrangement21 of
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developing this potentially unifying strategy, which has afforded
the frameworks of several terpenoid secondary metabolites via
short diastereoselective sequences. The virtues of this approach
are borne out in a short, enantiospecific total synthesis of the ent-
3,4-seco-atisane diterpenoid (–)-crotogoudin (1)13 in 13 steps
from (S)-carvone.
8 prior to ketene formation and electrocyclization likely explains
the genesis of 7b through conformer 8’. Full conversion of start-
ing material 5 was achieved by heating the reaction mixture to
180 °C for 5 days, resulting in a combined yield of 59% of 6b and
7b (1:1.4 ratio).
In order to obviate the competing Cope rearrangement and with
an eye toward application of the benzannulated bicycle to the
synthesis of the diterpenoids illustrated in Figure 1, the allyl group
of ester 4 was converted to an n-propyl hydroxy group (Scheme
2). This was achieved by chemoselective hydroboration of the
allyl group in the presence of the isopropenyl group using Wil-
kinson’s catalyst (1 mol % loading) and catecholborane followed
by oxidation of the resulting alkylborane.22,23 Saponification of
the intermediate hydroxyester gave acid 10 in 83% yield over 2
steps. Benzannulated bispropionate bicycle 11 was formed in 82%
yield upon heating 10 in propionic anhydride to 180 °C for 5
days.
We commenced our studies with the preparation of benzo-fused
bicycle 6 (Scheme 1A), bearing allyl and methyl groups at C-6
(carvone numbering). The methyl group is resident in many of the
natural products that could arise from this benzannulated interme-
diate, whereas the choice of the allyl substituent was dictated by
its facile introduction as well as its versatility for subsequent deri-
vatizations. Following a well-established sequence, known car-
vone derivative 2 was easily prepared through a sequential meth-
ylation/allylation protocol.9c Conjugate reduction using L-
Selectride® followed by oxidative work-up affords the corre-
sponding ketone,14 which is converted to vinyl triflate 3 upon
deprotonation and treatment of the resulting enolate with Comins’
reagent.15,16 Heck reaction of 3 with ethyl acrylate as the cross-
coupling partner yields an ethyl enoate (4), which upon saponifi-
cation provides acid 5, the substrate for benzannulation.
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Scheme 2. Completion of the synthesis of crotogoudin via a
double-oxidative dearomatization strategy.
Scheme 1. Synthesis of hexadienoic acid 5 and initial ex-
ploration of the proposed benzannulation.
We anticipated that benzannulation would be achieved by con-
version of carboxylic acid 5 to the corresponding ketene17 (9,
Scheme 1B) by ε-deprotonation in mixed anhydride intermediate
8.18 In turn, 6π electrocyclization of 9, aromatization, and acyla-
tion of the resulting phenol would yield 6, consistent with the
precedent of Murali and Rao.19 Several conditions (A–C), as out-
lined in Scheme 1A, were explored to effect the benzannulation.
Using the conditions reported by Murali and Rao (Condition A),
only a 13% yield of 6a was isolated from a messy reaction mix-
ture.20 A switch to propionic anhydride as the solvent, which
could be heated to 160 °C, led to a substantial increase in yield to
42% and the isolation of the desired bicycle 6b and, surprisingly,
Following procedures adapted from Kunesch and Kondo,24 the
phenyl propionate in 11 was selectively cleaved using tetra-
methylguanidine. This set the stage for a position selective oxida-
tive dearomatization to afford dienone 12 (along with the corre-
sponding para-quinol ether and isomeric masked ortho-
benzoquinone as side products in 11–13% yield, respectively).25,23
The observed selectivity in this iodine(III)-mediated oxidative
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dearomatization is rather unusual and has, to the best of our
proach has led to a enantiospecific 13-step synthesis of the
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knowledge, only been reported by Mal and co-workers on simpler
substrates.26 Inspired by Fukuyama’s recent synthesis of (−)-
lepenine,27 a diastereoselective [4+2] cycloaddition of cyclohexa-
dienone 12 with ethylene was envisioned. However, in accord-
ance with investigations by Liu and co-workers, compound 12 did
not readily undergo the desired Diels–Alder reaction.28 Cycload-
dition only proceeded under pressure and at elevated temperature
(70 bar, 140 °C, 5 d) to afford tricycle 13 in 90% yield (6:1 d.r.).29
At this stage, Wittig olefination of the ketone group followed by
acid treatment removed both the propionyl group and cleaved the
dimethyl ketal. The resulting primary hydroxyl was oxidized to
the carboxyl group to provide seco-crotogoudin (14) in 75% yield
over 2 steps.30,31 Lactonization of 14 to afford (–)-crotogoudin
was fraught with complicating side reactions.23 Ultimately, condi-
tions were identified that provided crotogoudin (1) in 16% yield
(2.9% total yield over 13 steps), along with rearranged lactone 15
in 14% yield.32 Current efforts are directed at identifying condi-
tions that provide 1 more selectively and in higher yield.33 Croto-
goudin prepared using the strategy outlined here provided spectral
and analytical data consistent with those obtained during its pre-
vious syntheses by Carreira [(+)-crotogoudin, 27 steps,34 1.4%
overall yield]13c and Liu [(±)-crotogoudin, 16 steps,34 3.1% over-
all yield]13b as well as from its isolation by Dumontet and Ra-
soanaivo from croton goudotii.13a
diterpenoid (–)-crotogoudin and provided a platform for the syn-
thesis of other terpenoids. The application of this plan to the syn-
theses of other natural products is the subject of ongoing studies
in our laboratory.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: xxx. Experimental details and
complete analytical data for all new compounds and crystallo-
graphic data for 14 (CIF) and 15 (CIF) are provided.
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AUTHOR INFORMATION
Corresponding Author
E-Mail: *rsarpong@berkeley.edu
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Notably, our synthesis plan affords opportunities to access oth-
er diterpenoid secondary metabolites including the atisane and
abietane frameworks outlined in Figure 1. For example, ester
cleavage of bispropionate bicycle 11 (Scheme 3) and subsequent
intramolecular oxidative dearomatization35 of the intermediate
phenol (not shown) provided dienone 16. Selective reduction of
the less substituted double bond of the cyclohexadienone moiety
of 16 to yield α,β-unsaturated ketone 17 was achieved using a
combination of MAD36 and L-Selectride®.37 A 1,2-addition of an
isopropyl group using Knochel’s method38 readily delivered al-
lylic alcohol 18. The direct treatment of this tertiary alcohol with
a proton source results in elimination to key intermediates (19 and
20) for the synthesis of seco-abietane congeners such as 9-
hydroxycallicarpic acid A and seco-hinokiol, respectively.
This work was supported by the National Institutes of Health
(NIGMS RO1 086374). P.F. is thankful for a postdoctoral schol-
arship from the German Academic Exchange Service (DAAD). K.
M. is grateful to the Osaka University Research Abroad Program
and the Osaka University Pharmaceutical Sciences Alumni Asso-
ciation (Yakuyukai) for a 1-year leave to undertake these studies
at UC Berkeley. We also thank Dr. Antonio DiPasquale (UC
Berkeley) and Nicholas S. Settineri (UC Berkeley) for solving the
crystal structures of compounds 14 and 15 (X-ray facilities are
supported by NIH Shared Instrument Grant S10-RR027172). The
authors thank the Catalysis Facility of Lawrence Berkeley Na-
tional Laboratory, which is supported by the Director, Office of
Science, of the US Department of Energy under contract no. DE-
AC02-05CH11231 for generous access to their mass spectrometry
instrument. The Bruker AVB-400, DRX-500, AV-500, AV-600
NMR spectrometers are partially funded by NSF Grants (CHE-
0130862, CHE 82-08992 and CHE 9633007) and by NIH Grants
(1S10RR016634-01, RR 02424A-01 and SRR023679A).
Scheme 3. Synthesis of secondary metabolite congeners via
an intramolecular oxidative dearomatization pathway.
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ruled out.
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(28) In Liu’s synthesis of (±)-crotogoudin [ref 13b] i and ii were tested
in reactions with ethylene (7 MPa) in CH2Cl2 at 70 °C for 48 h. Both
substrates showed no conversion to the desired bicyclo[2.2.2]octane under
these conditions. In our hands, comparable results were obtained for com-
pound 12 under identical reaction conditions.
(29) An attempted Mukaiyama hydration of cycloadduct 13 under the
conditions described by Liu and co-workers (see ref. 13b) resulted in
highly complex reaction mixtures.
(30) Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64, 293.
(31) The absolute stereoconfiguration of compound 14 was
unambiguously determined by single crystal x-ray analysis and the
assignment of the stereocenters in cycloadduct 12 were inferred from this
structure.
(32) Compound 15 may arise from an initial isomerization of the iso-
propenyl double bond to the corresponding tetrasubstituted alkene. Proto-
nation of the endocyclic double bond in the bicyclo[2.2.2]octane and a
subsequent 1,2-methyl migration will then yield an allylic cation which
may be engaged by the carboxyl group to form the γ-lactone.
(33) An iodolactonization using 14 only engaged the isopropenyl group
to form 7-membered lactone iii in 67% yield. See the Supporting
Information for details.
(34) The overall step count and yield are calculated on the basis of the
longest linear sequence starting from the chosen commercially available
starting material. The yields are derived from the corresponding
supporting information and recovered starting material adjustments are not
taken into account.
(35) (a) Tamura, Y.; Yakura, T.; Haruta, J.; Kita, Y. J. Org. Chem.
1987, 52, 3927; (b) Bauer, R. A.; Wenderski, T. A.; Tan, D. S. Nat. Chem.
Biol. 2013, 9, 21; (c) For a review see: Pouységu, L.; Deffieux, D.;
Quideau, S. Tetrahedron 2010, 66, 2235.
(36) MAD
= Methylaluminium bis(2,6-di-tert-butyl-4-alkylphen-
oxide): Maruoka, K.; Nonoshita, K.; Yamamoto, H. Tetrahedron Lett.
1987, 28, 5723.
(37) Doty, B. J.; Morrow, G. W. Tetrahedron Lett. 1990, 31, 6125.
(38) Krasovskiy, A.; Kopp, F.; Knochel, P. Angew. Chem. Int. Ed.
2006, 45, 497.
(19) Murali, D.; Krishna Rao, G. S. Synthesis 1987, 1987, 254.
(20) An extensive investigation of various reaction conditions was
performed and analyzed by qualitative TLC analysis. The addition of acids
(2-nitrobenzoic acid, camphorsulfonic acid, pyridinium p-toluene-
sulfonate), bases (collidine, K2CO3, diisopropylethylamine) or co-solvents
to compound
5 in acetic anhydride did not lead to a significant
improvement in the reaction outcome. Attempts to form dienylketene 9
from mixed anhydrides with either TFAA or tosyl chloride were also not
successful.
(21) Cope, A. C.; Hardy, E. M. J. Am. Chem. Soc. 1940, 62, 441.
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