Total synthesis of (+)-crotogoudin

Article abstract of DOI:10.1002/anie.201305822

Fellowship of the ring: The first total synthesis of (+)-crotogoudin, a 3,4-seco-atisane diterpenoid natural product, is reported. Asymmetric access to the bicyclo[2.2.2]octane core is achieved through a desymmetrization of a meso-diketone with baker's yeast (LG=leaving group, PG=protecting group). A SmI₂-induced radical cyclopropane-opening/annulation/elimination cascade affords the suitably decorated tetracyclic structure of (+)-crotogoudin. The synthesis led to revision of the reported optical rotation of the natural product and to assignment of its absolute configuration as an ent-atisane (5R,10R). Copyright

Full text of DOI:10.1002/anie.201305822

Angewandte
Chemie
DOI: 10.1002/anie.201305822
Natural Product Synthesis
Total Synthesis of (+)-Crotogoudin**
Simon Breitler and Erick M. Carreira*
In 2010, a joint Madagascan–French research group reported
the isolation of two closely related cytotoxic diterpenes,
crotogoudin (1) and crotobarin (2), from indigenous Croton
plants (Scheme 1).[1] Species of this genus have found wide-
spread ethnomedical use around the globe and have proven to
be a rich source of secondary metabolites, which exhibit
a wide range of biological activity and have long served as
inspiration for synthetic chemists.[2] Both 1 and 2 belong to the
rare 3,4-seco atisane family of diterpenoids and feature
unusual oxidation of the general skeleton at C(9).[3,4] The
congested tetracyclic skeleton of crotogoudin contains four
contiguous stereocenters, within which a tertiary alcohol from
the corresponding seco-acid is flanked by two quaternary
carbons.[5] This challenging motif, in combination with
promising cytotoxic activity, attracted our interest. Herein,
we describe the first total synthesis of (+)-crotogoudin (1)
featuring a novel radical cyclopropane-opening/annulation/
elimination cascade. Of added value, the synthesis permits
assignment of the absolute configuration for this unusual
natural product.
a versatile intermediate to explore annulative cascade reac-
tions because of its ambivalent character as a homoenolate or
homo-Michael acceptor at C(10). In the pivotal step, regio-
selective cyclopropane opening in 4 would initiate a cycliza-
tion sequence engaging the isoprenyl side chain to form the
ꢀ
key C(5) C(10) bond and directly furnish the appropriately
decorated tetracyclic carboskeleton of the seco-atisanes. Late-
stage introduction of the enone at C(16) would complete the
total synthesis.
The synthesis commenced with the one-pot Michael
addition/aldol condensation of ketoester 6[6] with enal 7[7]
followed by Krapcho decarboxylation to furnish cyclohexe-
none 8 in 60% yield over two steps (Scheme 3). Concomitant
Structure-goal strategy-guided retrosynthetic analysis
identified the embedded oxidized bicyclo[2.2.2]octane core
as key (Scheme 2). It can be conveniently accessed from
Scheme 2. Retrosynthetic analysis of crotogoudin.
debenzylation and conjugate reduction under Birch condi-
tions[8] followed by Swern oxidation afforded ketoaldehyde 9,
which underwent acid-catalyzed intramolecular aldol addi-
tion.[9] Racemic hydroxyketone (ꢁ)-5 was obtained as an
inconsequential mixture of diastereomers and subsequently
oxidized with Dess–Martin periodinane[10] to meso-diketone
10 in good yield over four steps (54%) without requiring
purification of the intermediates. This sequence offers
expedient and flexible access to bicyclo[2.2.2]octanones
which are frequently encountered in terpenoid natural
products and serve as precursors for ligands in asymmetric
catalysis.[11,12]
Desymmetrization of meso compounds provides an effi-
cient approach for the preparation of chiral organic molecules
and has long been identified as a prime application of
biocatalysis.[13] In this respect, the reduction of 1,3-dicarbonyl
compounds with bakerꢀs yeast represents a striking example
in terms of selectivity, preparative ease, and cost-effective-
ness.[14] The research groups of Mori and Frejd showed that
the reduction of bicyclo[2.2.2]octadi-2,6-ones proceeds with
excellent enantio- and diastereoinduction, and substituents at
the bridgehead carbon between the ketones were found to
lead to increased selectivity, albeit for only two examples
incorporating up to a two-carbon side chain.[11a,12a,b] Gratify-
ingly, when 10 was treated with a broth of bakerꢀs yeast and
sugar in water, endo-alcohol (ꢀ)-5 was obtained in 77% yield,
as a single diastereomer and enantiomer, as determined by
1H NMR and chiral SFC analysis.[15]
Scheme 1. Crotogoudin and crotobarin and their structural relationship
to the atisane skeleton.
hydroxyketone 5, itself available in enantiopure form by
desymmetrization of the corresponding meso-diketone. We
envisioned that the ketone in 5 could provide a handle for the
concomitant construction of the d-lactone and chair-cyclo-
hexane ring in 1. To this end, cyclopropane 4 could serve as
[*] S. Breitler, Prof. Dr. E. M. Carreira
Laboratorium fꢀr Organische Chemie, ETH Zꢀrich, HCI H335
Wolfgang-Pauli-Strasse 10, 8093 Zꢀrich (Switzerland)
E-mail: carreira@org.chem.ethz.ch
Homepage: http://www.carreira.ethz.ch
[**] We are grateful to Dr. B. Schweizer, Dr. N. Trapp, and M. Solar for
X-ray crystallographic analysis, to Dr. M.-O. Ebert, R. Arnold, R.
Frankenstein, and P. Zumbrunnen for NMR measurements and
ETH 15-10-2 for financial support. S.B. acknowledges the Stipen-
dienfond Schweizerische Chemische Industrie (SSCI).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201305822.
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ing lactone 15 under basic conditions, setting the stage for the
key cascade transformation.
Initially, approaches were examined in which the trisub-
stituted olefin would serve as a nucleophile (e.g. X = H,
SiMe3) in the opening of the elecrophilic cyclopropane in 15
to deliver tetracyclic product 17 (Scheme 4).[21] However, no
Scheme 3. Reagents and conditions: a) DBU (2 equiv), MeCN, 08C to
808C; b) LiCl (10 equiv), Me2SO/H2O (10:1), 1608C, 60% over two
steps; c) Na, NH3 (l), EtOH, THF, ꢀ788C; d) (COCl)2 (2.5 equiv),
Me2SO (5 equiv), NEt3 (10 equiv), CH2Cl2, ꢀ788C to RT; e) 2m HCl,
acetone, 608C; f) Dess–Martin periodinane (1.1 equiv), NaHCO3
(5 equiv), CH2Cl2, 54% over four steps; g) baker’s yeast, sugar, EtOH,
H2O, 77% (87% brsm); h) 2-isopropenylMgBr (0.5m in THF,
2.2 equiv), LaCl3·2LiCl (0.5m in THF, 1.1 equiv), THF, 08C, 88%;
i) tBuMe2SiOTf (1.1 equiv), 2,6-lutidine (4 equiv), CH2Cl2, ꢀ788C, 98%;
j) 13 (2 equiv), Rh2(esp)2 (0.1 mol%), CH2Cl2, 08C, d.r.=4.4:1, 66%
(70% brsm); k) aq. sat. NaHCO3, MeOH, RT, quantitative.
brsm=based on recovered starting material, DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene, esp=a,a,a’,a’-tetramethyl-1,3-benzenedipropionic
acid.
Scheme 4. Radical cyclopropane-opening/annulation/elimination cas-
cade. Reagents and conditions: a) SeO2 (50 mol%), tBuO2H (5m in
n-C9H17, 2 equiv), CH2Cl2, 08C to RT; then NaBH4 (1.0 equiv), MeOH,
08C, 74% over two steps; b) Me3COCl (1.2 equiv), 4-dimethylamino-
pyridine (5 mol%), pyridine, 08C to RT, 95%. DMPU=1,3-dimethyl-
3,4,5,6-tetrahydro-2(1H)-pyrimidinone, TBS=tert-butyldimethylsilyl.
such reaction was observed despite extensive experimenta-
tion with various Lewis acids (e.g. EtAlCl2, TiCl4, SnCl4). We
then turned our attention towards a reversal of reactivity
wherein the alkene would serve as an acceptor to a reactive,
nucleophilic species at C(10) derived from reductive opening
of the cyclopropane. Samarium(II) iodide[22] is known to
promote the opening of acceptor-substituted cyclopropanes at
room temperature or above. The resulting carbon-centered
radicals have been exploited in simple systems for subsequent
reactions, such as radical annulations or further reduction to
form organosamarium species.[23]
Exposure of 15 to excess SmI2 in refluxing THF afforded
low yields (< 10%) of tetracyclic 17. Interestingly, 17 was
accompanied by equimolar amounts of reduction product
bearing an isopropyl at C(5) with the remaining mass balance
corresponding to polymeric material. This result was hypothe-
sized to arise from a disproportionation reaction of tertiary
radical II (X = H, Scheme 4), formed through cyclopropane-
opening and subsequent radical olefin cyclization (15!I!
II). We speculated that offering the radical at C(4) a suitable
leaving group (X) would enable a favorable termination
pathway, leading to increased product formation.
With a route to enantiopure 5 established, nucleophilic
addition of 2-isopropenyl magnesium bromide to the hin-
dered ketone was investigated. Intriguingly, although initial
tests with the corresponding TBS-protected hydroxyketone
failed to give any product,[16] the use of free alcohol 5 with two
equivalents of nucleophile afforded the tertiary alcohol with
complete exo-diastereoselectivity,[17] albeit at low conversion
owing to competing enolization of the starting ketone. This
problem was circumvented by the use of soluble lanthanide
salts (LaCl3·2LiCl in THF),[18] yielding the monoprotected
diol 12 in excellent yield after selective TBS-protection of the
secondary alcohol (86% over two steps).
At this stage, the synthetic plan called for selective
cyclopropanation of the newly introduced olefin. We were
drawn to the use of phenyliodonium malonates such as 13 as
a consequence of their reported selectivity for 1,1-disubsti-
tuted over trisubstituted olefins. Moreover, their use in Rh-
catalyzed cyclopropanations enables the alkene to be the
limiting reagent without the need for slow addition of the
carbene precursor.[19] After preliminary experiments, we were
pleased to observe that [Rh2(esp)2][20] catalyzed the reaction
efficiently to afford cyclopropane 14 as a separable 4.4:1
mixture of diastereomers in good yield (66%). The major
diastereomer was subsequently converted to the correspond-
Inanata and co-workers showed that allylic acetates can
afford terminal olefins in the cyclization of ketyl or aryl
radicals.[24] This was proposed to occur by a second single-
electron reduction of the resulting carbon-centered radical
and subsequent anionic b-elimination. More recently, Nico-
laou and co-workers made use of an allylic carbonate as
a leaving group in the application of a ketyl radical cyclization
in their synthesis of vannusal B.[25]
2
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A variety of allylic acetates and carbonates were prepared
by stereoselective allylic oxidation and functionalization of
the resulting (E)-allylic alcohol (Scheme 4). We were
delighted to observe that both acetates and carbonates
participate in the key cyclopropane-opening/annulation/elim-
ination cascade in dramatically improved yield. Sterically
demanding allylic leaving groups were found to offer higher
diastereomeric ratios at C(5), and optimization of the reaction
conditions (THF/DMPU 9:1, 08C to RT) led to the isolation
of tetracyclic product 17 in 80% yield and high diastereose-
lectivity (d.r. = 7.7:1) from pivaloate 16.
1718C), providing further structural conformation.[28] Com-
parison of the optical rotation revealed matching signs for
both synthetic and natural material, although a significant
20
deviation in magnitude was noted (synthetic: ½aꢃD ¼ + 29.6
20
(c = 0.4, CHCl3); reported: ½aꢃD ¼ + 7 (c = 0.4, CHCl3)).
Intriguingly, the absolute configuration determined for
(+)-1 that follows from the synthesis is noteworthy when
compared to that implicated by the original publication. To
the best of our knowledge it would represent the first example
of an atisane-type natural product that is not in the ent-
configurational series (compare structures in Scheme 6).[29]
Having successfully constructed the tetracyclic core of
crotogoudin, decarboxylation, alcohol deprotection, and
oxidation to arrive at ketolactone 19 proceeded uneventfully
in high yield (Scheme 5). The a-methenylation of ketone 19
Scheme 6. Skeletons of naturally occurring tetracyclic diterpenoids and
(+)-crotogoudin illustrating the absolute configuration.
Although their absolute configuration has not always been
rigorously established, the vast majority of tetracyclic diter-
penoids, such as atisanes, trachylobanes, or kauranes, belong
to the ent-series. These findings prompted us to examine
possible explanations for the anomaly. Discussions with the
team responsible for the isolation and structural character-
ization culminated in re-measurement of the optical rota-
tions.[1] Accordingly, the values for natural crotogoudin (1)
Scheme 5. Completion and crystal structure of (+)-crotogoudin (1);
Thermal ellipsoids are set at 50% probability. Reagents and condi-
tions: a) LiCl (10 equiv), Me2SO/H2O (9:1), 1308C; then 5m HCl,
MeOH, 08C, 96% over two steps; b) Dess–Martin periodinane
(1.2 equiv), CH2Cl2, 08C to RT, 93%; c) iPr3SiOTf (1.3 equiv), NEt3
20
and crotobarin (2) should be revised to (1): ½aꢃD ¼ꢀ25.2 (c =
20
0.4, CHCl3) and (2): ½aꢃD ¼ꢀ23.8 (c = 0.4, CHCl3) respec-
tively.[30] Therefore, natural (ꢀ)-crotogoudin (ent-1) is
assigned the absolute configuration (5R,10R) and belongs to
the expected ent-atisane family.
=
(4.3 equiv), MeCN, 08C to RT; then LiN(SiMe3)2 (2.0 equiv), CH2
NMe2+Iꢀ (4.0 equiv), THF, ꢀ788C to ꢀ508C; then MeI (10 equiv),
Et2O/CH2Cl2 (3:1), RT; then basic Al2O3, CH2Cl2, RT, 54% over four
steps.
In conclusion, we have reported a total synthesis of ent-
crotogoudin (1). The synthesis relies on a key radical cyclo-
propane-opening/annulation/elimination cascade to diaste-
reoselectively access the tetracyclic carbon skeleton. Addi-
tional salient features of the route include versatile and
efficient access to 1-substituted bicyclo[2.2.2]octa-2,6-diones
for desymmetrization by bakerꢀs yeast reduction and the
application of a selective rhodium-catalyzed cyclopropana-
tion of phenyliodonium malonates in a complex setting.
Additional efforts to gain insight into the bioactivity of 1 and
to expand the strategy to crotobarin (2) along with other
related natural products are the subject of current research in
our laboratories and will be reported in due course.
required protection of the lactone, as the latter was found to
undergo preferential reaction with electrophiles compared to
the ketone. We consequently devised a procedure involving
transient masking of the lactone in 19 as the corresponding
silyl ketene acetal. This enabled subsequent generation of the
ketone enolate and its participation in chemoselective
=
reaction at C(16) with Eschenmoserꢀs salt (CH2
NMe2 Iꢀ).[26] In the experiment, after formation of the
+
triisopropylsilyl ketene acetal (TIPSOTf, NEt3), the ketone
=
was deprotonated (LiHMDS) and quenched with CH2
+
NMe2 Iꢀ. Careful control of the reaction temperature (ꢂ
Received: July 5, 2013
Published online: && &&, &&&&
ꢀ508C) was necessary to minimize formation of byprod-
ucts.[27] Hofmann elimination (MeI, then basic Al2O3) then
afforded (+)-crotogoudin (1) as a white, crystalline solid in
54% yield over four steps.
Keywords: cyclopropanation · natural products ·
.
radical cascade · samarium iodide · total synthesis
1D/2D NMR data for synthetic 1 was in full agreement
with that reported for the natural product.[1] Additionally,
recrystallization of the synthetic material (hexane/CH2Cl2)
afforded crystals suitable for X-ray diffractometry (mp 170–
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[28] CCDC 943670 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif. Additionally, the absolute stereo-
chemistry was unambiguously determined by X-ray diffractom-
etry (CCDC 946770) of the Mosherꢀs ester derived from alcohol
18 (Scheme 5); see the Supporting Information for details.
[29] a) C. Demetzos, K. S. Dimas in Studies in Natural Products
Chemistry, Vol. 25 (Ed.: Atta-ur-Rahman), Elsevier, New York,
2001, pp. 235 – 292; b) J. M. Finefield, D. H. Sherman, M. Kreit-
man, R. M. Williams, Angew. Chem. 2012, 124, 4886 – 4920;
Angew. Chem. Int. Ed. 2012, 51, 4802 – 4836.
[19] S. R. Goudreau, D. Marcoux, A. B. Charette, J. Org. Chem. 2009,
74, 470 – 473.
4
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Natural Product Synthesis
S. Breitler,
E. M. Carreira*
&&&& — &&&&
Total Synthesis of (+)-Crotogoudin
Fellowship of the ring: The first total
synthesis of (+)-crotogoudin, a 3,4-seco-
atisane diterpenoid natural product, is
reported. Asymmetric access to the
bicyclo[2.2.2]octane core is achieved
through a desymmetrization of a meso-
diketone with baker’s yeast. A SmI2-
induced radical cyclopropane-opening/
annulation/elimination cascade affords
the suitably decorated tetracyclic struc-
ture of (+)-crotogoudin. The synthesis
led to revision of the reported optical
rotation of the natural product and to
assignment of its absolute configuration
as an ent-atisane (5R,10R).
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!