Scalable synthesis of cortistatin A and related structures

Article abstract of DOI:10.1021/ja202103e

Full details are provided for an improved synthesis of cortistatin A and related structures as well as the underlying logic and evolution of strategy. The highly functionalized cortistatin A-ring embedded with a key heteroadamantane was synthesized by a simple and scalable five-step sequence. A chemoselective, tandem geminal dihalogenation of an unactivated methyl group, a reductive fragmentation/trapping/elimination of a bromocyclopropane, and a facile chemoselective etherification reaction afforded the cortistatin A core, dubbed "cortistatinone". A selective δ¹⁶-alkene reduction with Raney Ni provided cortistatin A. With this scalable and practical route, copious quantities of cortistatinone, δ¹⁶-cortistatin A (the equipotent direct precursor to cortistatin A), and its related analogues were prepared for further biological studies.

Full text of DOI:10.1021/ja202103e

ARTICLE
pubs.acs.org/JACS
Scalable Synthesis of Cortistatin A and Related Structures
Jun Shi, Georg Manolikakes,† Chien-Hung Yeh,† Carlos A. Guerrero, Ryan A. Shenvi, Hiroki Shigehisa, and
Phil S. Baran*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S Supporting Information
b
ABSTRACT: Full details are provided for an improved syn-
thesis of cortistatin A and related structures as well as the
underlying logic and evolution of strategy. The highly functio-
nalized cortistatin A-ring embedded with a key heteroadaman-
tane was synthesized by a simple and scalable five-step
sequence. A chemoselective, tandem geminal dihalogenation
of an unactivated methyl group, a reductive fragmentation/
trapping/elimination of a bromocyclopropane, and a facile
chemoselective etherification reaction afforded the cortistatin
A core, dubbed “cortistatinone”. A selective Δ16-alkene reduction with Raney Ni provided cortistatin A. With this scalable and
practical route, copious quantities of cortistatinone, Δ16-cortistatin A (the equipotent direct precursor to cortistatin A), and its
related analogues were prepared for further biological studies.
’ INTRODUCTION
chemists at Syntex, led by Carl Djerassi, achieved the semisynthe-
sis of cortisone (2) from diosgenin in a 14-step sequence.13 In the
same year, a highly innovative microbiological fermentation
approach was disclosed by Upjohn to functionalize the C11
position of progesterone (3), which led to the successful
commercialization of cortisone (2).14 Currently, most steroid-
based medicines (Figure 2) are prepared by semisynthesis,
including Deltasone (5, anti-inflammatory agent), Flovent (6,
antiasthmatic and antiallergic agent), Lanoxin (7, cardiovascular
agent), Mifepristone (8, pregnancy termination agent), Testo-
sterone (9, treatment of male hypogonadism), and Mestranol
(10, oral contraceptive).
In 2006 and 2007, the Kobayashi group elucidated structures
of novel steroidal alkaloids, cortistatins AꢀJ (11ꢀ21, Figure 3),
and disclosed their highly selective antiangiogenic activity.15
Angiogenesis, a process that involves the formation of new
capillary blood vessels from pre-existing ones, is fundamental
and vital to growth, development, and wound healing but also to
cancer metastasis.16 Currently, Avastin, Erbitux, Vectibix, and
Herceptin are the major monoclonal antibody drugs for cancer
treatment based on the inhibition of this mechanism.17 There-
fore, the isolation and study of new small-molecule natural
products with highly selective antiangiogenic activity is of great
interest and significance. Interestingly, cortistatin A (11) showed
antiproliferative activity against human umbilical vein endothelial
cells (HUVECs) at a low concentration with an IC50 = 1.8 nM,
while it demonstrated a selectivity index of more than 3000-fold
against HUVECs in comparison with NHDF (normal human
dermal fibroblast), KB3-1 (KB epidermoid carcinoma cells),
Steroids are beyond “privileged” structures, playing a vital role
not only in biology, medicine, and society but also in the origins and
development of organic synthesis.1 In 1815, the first steroid,
cholesterol (1, Figure 1), was isolated from gallstones by Chevreul.2
But the correct chemical structure of cholesterol was not eluci-
dated until 1932. Subsequently, during the 1930s to the 1950s,
the discovery of steroids’ useful biological activities coupled with
the need for cortisone (2) specifically in World War II immensely
stimulated the development of chemical syntheses of steroids in
both academic and industrial settings. In 1939, the first total
synthesis of a steroid, equilene, was accomplished by Bachmann.3
Meanwhile, the Robinson,4 Fieser,5 Woodward,6 Barton,7 and
Jones8 groups investigated numerous synthetic methods aimed at
the synthesis of steroids, and a number of total syntheses of cortisone
(2) were reported. The mechanistic, stereochemical model for steroid
biosynthesis proposed by Stork and Eschenmoser,9 and related
studies on polyene cyclization, ultimately led to Johnson’s
biomimetic steroid syntheses, including his landmark total
synthesis of progesterone (3) in 1971.10 Academic inquiry into
the synthesis of steroids has thus resulted in an immense body of
knowledge in the realms of both fundamental organic chemistry
and medicine.
In parallel to academic endeavors on the synthesis of steroids,
the need for commercialization of certain steroid targets steered
the pharmaceutical industry toward more efficient and practical
approaches to semisynthesis. Starting from diosgenin, an abun-
dant ingredient in wild Mexican yams, Marker achieved the
commercialization of progesterone at Syntex by a six-step
sequence (known as “Marker’s degradation”) in 1940.11 In
1946, Sarett at Merck accomplished the first semisynthesis of
cortisone (2) from bile acid in 36 steps.12 In 1951, a group of
Received: March 7, 2011
Published: May 03, 2011
r
2011 American Chemical Society
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Figure 1. Representative steroids.
Figure 2. Commercial steroid-based medicines prepared by semisynthesis.
K562 (human chronic myelogenous leukemia cells), and Neuro2A
(murine neuroblastoma cells), indicating that cortistatin A
selectively inhibits angiogenesis but has no apparent cytotoxicity
toward cancer cells. As such, cortistatin A could be a promising
agent not only in cancer biology but also in other angiogenesis-
dependent ailments such as macular degeneration, rheumatoid
arthritis, etc. However, to date, in vivo studies of cortistatin A have
not been published due to its low availability. The significant
potential of its antiangiogenic activity and high selectivity
suggested that it would involve a unique mechanism of action.18
Structurally, all of the cortistatins possess an unusual 9(10,19)-
abeo-androstane skeleton with an oxabicyclo[3.2.1]octene core.
The combination of their exciting bioactivity and scarce avail-
ability from Nature makes the cortistatins worthy candidates for
synthesis. Indeed, these marine sponge (Corticium simplex)-
derived molecules are so rare and valuable that the isolation
chemists have reported efforts toward their total synthesis.19 Not
surprisingly, the past 3 years have witnessed dozens of
publications on the chemistry of the cortistatins.19ꢀ24 Four
elegant total syntheses of cortistatin A have emerged from the
NicolaouꢀChen,20 Shair,21 Myers,22 and Hirama23p laboratories,
and many approaches have been reported.23 Our own efforts
were inspired by the rich history of steroid semisynthesis and a
desire to procure gram quantities of the cortistatins for biological
evaluations.24 Thus, a route was devised beginning from the
abundant terrestrially derived steroid prednisone (4, available for
$1.2/gram). This full account describes our studies toward an
improved synthesis of cortistatin A and related structures as well
as the underlying logic and evolution of strategy.
’ RESULTS AND DISCUSSION
Retrosynthetic Analysis. Given the tremendous success of
steroid semisyntheses to prepare large quantities of biologically
valuable compounds, we decided to explore this higher-level
substructure search strategy to identify candidate steroid starting
materials. In concert with this global search, an initial retro-
synthetic excision of the isoquinoline allowed a bidirectional
search for methods of heterocycle installation to the D-ring, and
for steroid scaffolds that lacked the C17 side chain. Further
considerations for the starting material derived from “ideality”
criteria,25 particularly for an overall isohypsic (redox-neutral)
conversion from commercial steroid to target.26 Since there are
few affordable steroids that bear the appropriate methine oxida-
tion state at C19, a strategic sacrifice was made to introduce this
oxidized carbon from the very common C19 methyl. A look-
ahead search for appropriate A-ring precursors proved more
straightforward, since the cortistatin A-ring is in the same
oxidation state as a cyclohexadienone, which is a common motif
in commercial steroids. Similarly, the C-ring allylic ether motif
corresponded in oxidation state to a C-ring cyclohexanone, a
substructure that has been made available in commercial steroids
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Figure 3. Cortistatin family members and their biological activities.
Scheme 1. A General Retrosynthetic Strategy To Target the Cortistatin A (11) Core: Cortistatinone (22)
by microbial oxidation. When these structures are amalgamated
into an imaginary steroid, the result bears striking resemblance to
predisone, with the exception of the pregnane side chain.
Fortunately, there are several methods for oxidative cleavage of
this side chain to the corresponding cyclopentanone, which
serves as a useful handle for appending the isoquinoline.
Further considerations that bolstered the proposal to begin
from an abundant terrestrial steroid include (1) the unique
strategic opportunities that could arise from rendering a semi-
synthesis amenable to the construction of analogues with deep-
seated modification; (2) the occasion to develop new chemical
methods and tactics to achieve such ends; and (3) the economies
of using prednisone, which possesses ca. 70% of the carbon atoms
and the corresponding enantiopure chirality of the cortistatins.
As discussed above, a crucial target structure became the
cortistatin A ketonic core that we termed (þ)-cortistatinone
(22, Scheme 1). This key structure was anticipated to allow for
straightforward elaboration to the natural product, as well as
divergence to other family members and unnatural analogues. As
part of this plan, numerous exciting challenges had to be
addressed, including control of all four A-ring stereocenters,
oxidation of the unfunctionalized C19 and C8 centers, expansion
of the B-ring, and chemo-/stereoselective installation of the
isoquinoline side chain.
A-Ring Functionalization. Our initial efforts for A-ring
functionalization are depicted in Scheme 2. Starting from pred-
nisone (4), side-chain cleavage and subsequent ketalization led
to the known steroid core 25 in 92% overall yield after
recrystallization.27 Nucleophilic epoxidation of enone 25 gener-
ated epoxide 26 in 82% yield (>30 g) under the mediation of
t-BuOOH, a protocol that is operationally superior on a large
scale to a reported dimethyldioxirane procedure.28 For our first
forays, a straightforward hydride reduction/activation/displace-
ment sequence was pursued to install the C3 amino group. In the
event, ketone reduction provided R-hydroxyl derivative 27 as a
major diastereomer, which upon activation with p-TsCl led to
allylic chloride 29 in 75% yield over two steps. Treatment of 29
with NaN3 delivered the corresponding allylic azide 30, which
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Scheme 2. Initial Efforts To Install the C3 Amino Group on the A-Ringa
a Reagents and conditions: (a) BH3 THF (1.05 equiv), THF, 0 °C, 1.2 h; NaIO4 (5.0 equiv), H2O, acetone, 0 °C f 23 °C, 3 h; (b) p-TsOH (0.07
3
equiv), ethylene glycol (25 equiv), toluene, reflux, 1 h, 92% over two steps; (c) t-BuOOH (2 equiv), DBU (1.8 equiv), THF, 23 °C, 72 h, 82%; (d)
L-selectride (1.5 equiv), THF, ꢀ78 °C, 30 min, 95%; (e) p-TsCl (3.0 equiv), i-Pr2EtN (5.0 equiv), DMAP (1.0 equiv), 23 °C, CH2Cl2, 16 h, 79%; (f)
NaN3 (5.0 equiv), DMF, 23 °C, 14 h, 94%; (g) PPh3 (10 equiv), THF, H2O, 23 °C, 5 h; EtOCHO, reflux, 2 h, 42%. THF = tetrahydrofuran, p-TsOH =
p-toluenesulfonic acid, DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, L-selectride = lithium tri(s-butyl)borohydride, p-TsCl = p-toluenesulfonyl chloride,
DMAP = 4-dimethylaminopyridine, DMF = N,N0-dimethylaminoformamide.
Scheme 3. Simplified Route to Epoxy Alkenyl Formamide 31a
a Reagents and conditions: (a) NH4OAc (15 equiv), NaBH3CN (1.2 equiv), MeOH, THF, 23 °C, 18 h; then HCO2Et (74 equiv), Et3N (11 equiv),
reflux, 12 h, 73%; (b) Ti(Oi-Pr)4 (2.0 equiv), NH3 (4.0 equiv), CH2Cl2, 6 h, 23 °C; NaBH4 (1.0 equiv), 1 h, 23 °C; HCO2H (1.1 equiv), CDMT
(1.2 equiv), DMAP (0.3 equiv), NMM (1.1 equiv), CH2Cl2, 0 °C f 23 °C, 6 h, 95%. CDMT = 2-chloro-4,6-dimethoxy-1,3,5-triazine, NMM =
N-methylmorpholine.
Scheme 4. First Approach To Open Epoxide 31a
a Reagents and conditions: (a) TFA, 60 °C, 14 h, 93%; (b) n-Bu4NOAc (5 equiv), Co(acac)2 (0.2 equiv), PhH, 90 °C, 24 h, 48%, 76% brsm. TFA =
trifluoroacetic acid, acac = acetylacetonate.
was subjected to a Staudinger reduction with PPh3, followed by
formylation of the resulting amine, to afford epoxy alkenyl
formamide 31 in 39% overall yield.
Capitalizing on the observation that hydride attacks the β-face
of ketone 26, a more concise route to epoxy alkenyl formamide
31 was formulated (Scheme 3). Thus, reductive amination of the
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Scheme 5. Second Approach To Open Epoxide 31a
a Reagents and conditions: (a) Et3N (10 equiv), HOAc (10 equiv), 130 °C, 16 h; 34, 64%; 35, 32%; (b) DMAP (0.1 equiv), toluene, reflux, 24 h; 34,
64%; 35, 31%.
Scheme 6. Attempts at Installing the Requisite R-Disposed C5-Tertiary Alcohola
a Reagents and conditions: (a) PhSH (1.5 equiv), K2CO3 (2 equiv), acetone, 65 °C, 15 h, 96%; (b) m-CPBA (1.1 equiv), CH2Cl2, 0 °C, 1 h, 94%; (c)
m-CPBA (1.4 equiv), CH2Cl2, 0 °C, 1 h; (d) DMP (1.1 equiv), CH2Cl2, 23 °C, 2 h, 90% over two steps; (e) Co(acac)2 (0.2 equiv), PhSiH3 (4 equiv),
THF, O2 (1 atm), 12 h, 23 °C, 75%. m-CPBA = m-chloroperoxybenzoic acid, DMP = DessꢀMartin periodinane.
C3 ketone moiety of 26 with NH4OAc and NaBH3CN furnished
the corresponding allylic amine, which was directly formylated,
to give formamide 31 in 73% overall yield. After extensive
optimization, formamide 31 was obtained in 95% overall yield
by using Ti(Oi-Pr)4, NH3, and NaBH4 for reductive amination
followed by formylation.
With a scalable (>25 g) route to the epoxy alkenyl formamide
31 secured, attention was turned to the C1,C2 trans-vicinal diol
formation via epoxide opening. Acid (TFA)-mediated opening of
the 1,2-epoxide was initially attempted, resulting in cyclization to
the proximal C11 ketone and then dehydration to form di-
hydrofuran 32 in 93% yield (Scheme 4). Solvolysis of 32 to the
desired trans-diol 33 met with failure. Ultimately, it was found
that the epoxide opening could be accomplished with complete
positional selectivity using n-Bu4NOAc as a soluble and highly
nucleophilic source of acetate anion in the presence of catalytic
Co(acac)2 as a Lewis acid additive.
While the above-mentioned epoxide-opening reaction pro-
vided a decent quantity (hundreds of milligrams) of material for
our early-stage studies, the moderate yield for this transformation
deterred us from the preparation of alcohol 34 on a gram scale. A
number of conditions were subsequently investigated, and alter-
native epoxide-opening conditions were established (Scheme 5).
By treatment of epoxide 31 with triethylamine and acetic acid,
both C2 acetate 34 and C1 acetate 35 were obtained in a 2:1 ratio
(34, 64%; 35, 32%). The undesired C1 regioisomer 35 can be
recycled using DMAP in refluxing toluene to deliver the same
equilibrium mixture (34, 64%; 35, 31%; 34:35 = 2:1).
In parallel to the epoxide-opening studies, installation of the
requisite C5 hydroxyl was investigated on several different
intermediates (Scheme 6). For instance, displacement of allylic
chloride 29 with PhSH under basic media followed by m-CPBA
oxidation delivered sulfoxide 36 in 90% overall yield. It was
expected that sulfoxide 36 would undergo a MislowꢀEvans
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Figure 4. Rationale for the stereoselectivity of the C5 hydration.
Scheme 7. Successful Installation of the Requisite R-Disposed C5-Tertiary Alcohola
a Reagents and conditions: (a) Burgess reagent (1.1 equiv), benzene, 20 °C, 30 min, 86%; (b) Cu2O (1.0 equiv), benzene, 80 °C, 1 h, 63%; (c)
Mn(acac)2 (0.2 equiv), PhSiH3 (4 equiv), O2 (1 atm), THF, 50 °C, 6 h, 78%; (d) Co(acac)2 (0.2 equiv), PhSiH3 (4 equiv), O2 (1 atm), THF, 23 °C,
12 h, 85%.
rearrangement29 to furnish allylic alcohol 37. However, 37 was
not observed under a variety of conditions, presumably due to
the pseudoequatorial orientation of the sulfoxide group which
lacks the necessary proximity to C5 for the rearrangement to
occur. An alternative approach for the installation of the C5
hydroxyl group was carried out by treating allylic alcohol 27 with
m-CPBA followed by DessꢀMartin periodinane oxidation to
generate bisepoxy ketone 38 (90% yield over two steps). How-
ever, the C4ꢀC5 epoxide could not be opened to the desired C5
alcohol 39 under a variety of reductive conditions. Finally, Co-
catalyzed Mukaiyama hydration30 of the C4ꢀC5 olefin in 31
delivered the undesired β-oriented tertiary alcohol 40 in 75%
yield. An X-ray crystallographic analysis of 40 confirmed its
stereochemical assignment.
C3 atoms as shown in Figure 4B. To test this hypothesis, the
requisite substrate 48 was synthesized in 54% overall yield by the
following sequence (Scheme 7A): (1) dehydration of formamide
34 to isonitrile 45 by using the Burgess reagent and (2) Cu-
catalyzed cyclization of the C1 hydroxyl onto the isonitrile.32
When imidate 48 was subjected to Mn(acac)2, PhSiH3, and O2,33
the desired C5-oxgenated R-isomer 49 was produced in 78%
yield. Subsequently, it was found that simply reacting 34 with
Co(acac)2, PhSiH3, and O2 produced the desired C5-OH
R-isomer 52, which can be rationalized as arising from the greater
stability of the desired radical configuration 51 over 50 (Scheme 7B).
After extensive experimentation, C5-oxygenated orthoamide
24 was synthesized in one pot from intermediate 34 in 65% yield
via (1) Mukaiyama hydration of the trisubstituted C4ꢀC5 olefin,
(2) condensation of the formamido-diol with trimethyl ortho-
formate, and (3) solvolysis of the C2 acetate (Scheme 8). Thus,
the final optimized route to the fully functionalized cortistatin
A-ring is described in Scheme 8. This simple five-step sequence
provides scalable entry to the highly functionalized A-ring steroid
The origin of this selectivity likely arises from the preference of
the A-ring to adopt a half-chair conformation (41) with the C3
formamide group in an equatorial rather than an axial position
(42, Figure 4A).31 It was reasoned that a complete reversal of
selectivity would arise if a tether was present between the C1 and
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Scheme 8. A Simple Five-Step Stereoselective Process for Converting the Known Steroid Core 25 into the Fully A-Ring-
Functionalized Intermediate 24a
a Reagents and conditions: (a) t-BuOOH (2 equiv), DBU (1.8 equiv), THF, 23 °C, 72 h, 82%; (b) Ti(Oi-Pr)4 (2.0 equiv), NH3 (4.0 equiv), CH2Cl2, 6 h,
23 °C; NaBH4 (1.0 equiv), 1 h, 23 °C; HCO2H (1.1 equiv), CDMT (1.2 equiv), DMAP (0.3 equiv), NMM (1.1 equiv), CH2Cl2, 0 °C f 23 °C, 6 h, 95%;
(c) Et3N (10 equiv), HOAc (10 equiv), 130 °C, 16 h, 64%; (d) Co(acac)2 (0.2 equiv), PhSiH3 (4 equiv), O2 (1 atm), THF, 23 °C, 20 h; HC(OMe)3
(30 equiv), p-TsOH (0.5 equiv), 23 °C, 10 h; then K2CO3 (8 equiv), MeOH, 12 h, 65%.
Scheme 9. Key Considerations and Historical Context for the B-Ring Expansion
intermediate 24. The salient strategic aspect of this work involves
the construction of the key “heteroadamantane” system ex-
pressed in ring A which served three pivotal roles: (1) it
preorganized the system for the ensuing B-ring expansion (vide
infra); (2) it protected three of the four A-ring heteroatoms; and
(3) its subsequent removal would, in principle, not necessitate
additional concession steps25 since the orthoester and formamide
carbons are oxidized forms of the C3 dimethylamino group found
in the cortistatins.
B-Ring Expansion. The hallmark seven-membered B-ring of
the cortistatins (9(10,19)-abeo-androstane, which contains the
6-7-6-5 ring system) presented the exciting challenge of devel-
oping a practical and scalable method for B-ring expansion of a
“normal” steroid (containing the 6-6-6-5 ring system). The
presumed biosynthesis of the cortistatins, initially proposed by
the Kobayashi group,15c was particularly path-pointing to us
(Scheme 9A). Inspired by the known biosynthesis of the Buxus
alkaloids where both the 9β,19-cyclo system (54) and the
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Scheme 10. Synthesis of Cyclopropane 72 and Its B-Ring Expansiona
a Reagents and conditions: (a) PhI(OAc)2 (2 equiv), Br2 (3 equiv), CH2Cl2, light, ꢀ10 °C, 5 min; then TMSCl (5 equiv), imidazole (5 equiv), CH2Cl2,
0 °C, 15 min, 77%; (b) DBU (2 equiv), LiCl (10 equiv), THF, 23 °C, 24 h, 83%; (c) AlH3 (0.5 M in THF, 5 equiv), THF, 23 °C, 1 h; then K2CO3
(4 equiv), MeOH, 23 °C, 12 h, 74%; (d) SmI2 (3.0 equiv), 1:9 DMPU:MeCN, 23 °C, 10 min, 84%; (e) SmI2 (3.0 equiv), 1:9 DMPU:MeCN, 23 °C,
10 min; then PhSeBr (4 equiv), 0 °C, 30 min, 23 °C, 1 h; (f) H2O2 (30% aqueous solution, 135 equiv), NH4Cl (sat. aqueous solution), CHCl3, 23 °C, 30 min,
56% over two steps. DMPU = N,N0-dimethylpropyleneurea, TMSCl = trimethylsilyl chloride.
abeo-9(10,19)-diene (55) are naturally occurring, 54 was pro-
posed to be the biogenetic precursor of 55. Based on this
information, the Kobayashi group proposed that the cortistatin
family might be generated from 3,29-diaminosterol (53), a
hypothetical metabolite that bears resemblance to related natural
products (Scheme 9A).34 Starting with this key precursor,
cyclopropane formation via C19-methyl activation followed by
subsequent ring expansion should produce 55. Dehydrogenation
to triene 56 and oxidation would afford the unique THF (5,8-oxide)
ring system in 57 and in all other members of the cortistatin family.
This biosynthetic pathway has parallels in a number of early
synthetic studies. For instance, in Martín and co-workers’ semi-
synthesis of the Buxus alkaloid cycloprotobuxine A (64) from
lanosterol (60, Scheme 9B),35 the C19 methyl group in 61 was
transformed into the alkyl iodide 62 via Barton nitrite photolysis and
trapping with I2. Subsequent ketone formation and cyclopropana-
tion delivered cyclopropane 63 in 60% yield over four steps. In other
reports, B-ring expansions of steroids have also been documented
(Scheme 9C),36 such as in the case of 65 which was smoothly
transformed to abeo-9(10,19)-diene 66 in 82% yield under TFA
mediation.36a Radical conditions (AIBN, Bu3SnH) have also been
used in these types of fragmentations, as illustrated with the
conversion of 67 to 69 via the cyclopropyl radical 68.36b It was
within this context that a synthetic plan for cortistatin B-ring
formation was devised, involving a remote C19 methyl group
functionalization/cyclopropanation/ring expansion sequence.
For the first stage of the planned B-ring expansion, a mild
method was needed for C19 methyl functionalization. Conve-
niently, the rigidity imparted by the “heteroadamantane” A-ring
forced the C2 hydroxyl and the C19 methyl groups into a
pseudo-1,3-diaxial conformation and thus in very close proximity
to one another (distance between C2-oxygen and C19 is 2.894 Å
based on the X-ray crystal structure of 24). Several potential
methods were therefore at our disposal for an alcohol-directed
CꢀH functionalization. The Barton nitrite ester reaction was
attempted first, but unfortunately, this chemistry failed to
produce the desired result from 24. Subsequently, conditions
for the controlled halogenation of C19 were explored. It was
found that modification of Suꢀarez’s conditions37 for remote
methyl oxidation using PhI(OAc)2 and Br2 effected monobro-
mination of C19 (Scheme 10A). The reaction proceeds by in situ
formation of AcOBr that most likely leads to formation of an
OꢀBr bond at the C2 hydroxyl, subsequent OꢀBr bond
homolysis, hydrogen atom abstraction, and recombination with
bromine radical or Br2 at C19. The intermediate hydroxy
bromide was not isolated due to its rapid closure to a tetrahy-
drofuran; instead, immediate protection of the C2 alcohol as a
trimethylsilyl ether and base-induced cylcopropanation afforded
cyclopropane 72 in 64% yield over two steps. It should be noted
that the use of the well-precedented PhI(OAc)2/I2 conditions for
monoiodination resulted in competitive THF formation, likely
due to a much larger coefficient of the σ*CꢀI orbital.38 For the
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Scheme 11. Synthesis of Bromocyclopropane 80a
a Reagents and conditions: (a) PhI(OAc)2 (5 equiv), Br2 (8 equiv), CH2Cl2, light, ꢀ30 °C, 10 h; then TMSCl (5 equiv), imidazole (5 equiv), CH2Cl2,
0 °C, 15 min, 57%; (b) DBU (2 equiv), LiCl (5 equiv), THF, 23 °C, 24 h, 85%.
subsequent B-ring expansion, selected attempts to open cyclo-
propane 72 are shown in Scheme 10B. AlH3-mediated reduction
of the orthoamide moiety provided 73 in 74% yield. Unfortu-
nately, acid-catalyzed fragmentation of cyclopropyl alcohol 73 to
diene 74 was unsuccessful. After extensive experimentation,
cyclopropyl ketone 72 could be efficiently fragmented to give
cycloheptyl ketone 75 upon exposure to SmI2 followed by acidic
workup in 84% yield. Alternatively, quenching the reaction with
PhSeBr and subsequent oxidative elimination furnished conju-
gated enone 77 in 56% yield over two steps. Clearly, the
obtention of cycloheptyl ketones 75 and 77 marked a milestone
in our studies since they were the first intermediates to bear a
seven-membered B-ring. Cycloheptyl ketones 75 and 77 merely
required a loss of four or two hydrogens, respectively, in order to
arrive at the desired cycloheptyl dienone 76. The realization of
this crucial dehydrogenation, however, proved challenging: no
reaction conditions were identified to perform this transforma-
tion chemoselectively on these ketones.
Since dehydrogenation at C10 and C19 following the B-ring
expansion proved difficult, establishing the desired oxidation
state on C19 prior to B-ring expansion was evaluated. Fortui-
tously, during our studies on the Suꢀarez-type monobromi-
nation37 (Scheme 10A), small quantities of bis-brominated
material were always isolated. It was reasoned that this geminal
dibromide (see 79, Scheme 11) possessed the exact oxidation
state required of the C19 carbon atom for its eventual expression
in 76. After substantial optimization, 79 was obtained in 53%
yield via an iterative, double CꢀH activation process, while
suppressing SN2 attack of the alcohol on the σ*CꢀBr orbital of
monobromide 81. To the best of our knowledge, this is a rare
example of an alcohol-directed, geminal dihalogenation of an
unactivated hydrocarbon.39 The unstable dibromo alcohol 83
was capped with a trimethylsilyl group to prevent an unwanted
intramolecular cyclization. R-Alkylation of the C11 ketone with
the proximal dibromomethyl group proceeded with DBU and
LiCl to generate the exotic bromocyclopropane 80 as a single
diastereomer in 48% yield over two steps, whose configuration
was confirmed by X-ray crystallographic analysis.
expansion as anticipated and unconjugated enone 88 was
obtained, bearing no bromine atom but rather a C10ꢀC19
alkene (Scheme 12A). This product is presumably formed via
radical-induced ring expansion from 85 to 86, extrusion of
bromine radical, and quenching of dienolate 87 with H2O.40
Reduction of the C11 ketone in 88, elimination of resulting
hydroxyl group, and heteroadamantane reduction with AlH3
afforded diene 89 in 23% yield over three steps. Thus, the
oxidation state deliberately embedded into C19-methyl dibro-
mide 79 was translated smoothly into the olefinic C19-methine
of the cortistatin core. In addition, 89 possessed all of the correct
A-ring functionalities with their correct stereochemistry and the
hallmark C10ꢀC19/C9ꢀC11 diene expressed in the natural
product. However, thereafter, all attempts to oxidize the C8
position in order to form the THF ring unfortunately met with
failure. In essence, what we hoped to achieve was an isohypsic
reaction26 (in this case an isomerization) to convert bromo-
cyclopropane 80 into the redox-isomeric dienone 76 in a single
operation. Thus, a set of trapping experiments on the reactive
samarium dienolate 87 was investigated as shown (Scheme 12B).
Trapping dienolate 87 with O2 afforded γ-hydroxy enone 91 in
72% yield, whose structure was identified by X-ray crystallo-
graphic analysis. Dehydration of 91 turned out to be difficult, and
the desired product was not observed. Eventually, it was found
that trapping dienolate 87 with 2,4,4,6-tetrabromocyclohexa-2,5-
dienone (TBCHD) delivered the R-disposed allylic C9-bromide
92 with high diastereoselectivity, which could be converted to the
cross-conjugated dienone 76 on a gram scale under mildly basic
conditions (LiBr, Li2CO3). This two-step process took place in
65% overall yield, and the structure of the coveted dienone 76
was verified by X-ray crystallographic analysis.
THF Ring Closure. Dienone 76 represented a “point of no
return” in our path to the cortistatins with carbons 8, 9, 10, and 19
having the correct oxidation state. All that remained in order to
complete the core synthesis was a THF ring formation and a
chemoselective dismantling of the heteroadamantane-cloaked
A-ring. It was reasoned that the THF ring could be constructed
by attack of the C5 tertiary alcohol onto the C8 position by an
SN10 or SN20 mechanism. Treatment of dienone 76 with AlH3 led
to a notably clean and precise delivery of five hydrides to give an
intermediate dimethylamino triol. Addition of MeOH to the
Now that the desired oxidation state at C19 was obtained,
bromocyclopropane 80 was subjected to the SmI2 reductive
fragmentation conditions. Pleasingly, 80 underwent B-ring
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Scheme 12. Ring-Opening of the Bromocyclopropanea
a Reagents and conditions: (a) SmI2 (2.5 equiv), LiCl (0.4 M in THF), THF, 23 °C, 5 min; (b) NaBH4 (1.05 equiv), MeOH, 23 °C, 5 min; then
SOCl2 (1.5 equiv), pyridine (3 equiv), CH2Cl2, 0 °C f 23 °C, 30 min; (c) AlH3 (0.5 M in THF, 5 equiv), THF, 23 °C, 30 min, 23% over three steps;
(d) SmI2 (2.5 equiv), 1:9 DMPU:THF, 23 °C, 5 min; then O2 (1 atm), 23 °C, 5 min, 72%; (e) SmI2 (2.5 equiv), 1:9 DMPU:THF, 23 °C, 10 min; then
TBCHD (2 equiv), ꢀ78 °C, 1 h; (f) LiBr (20 equiv), Li2CO3 (20 equiv), DMF, 60 °C, 1 h, 65% over two steps. TBCHD = 2,4,4,6-tetrabromocyclohexa-
2,5-dienone.
reaction mixture served to quench any remaining hydride, and
the addition of K2CO3 removed the TMS group on the C2
alcohol to afford tetraol 23 in 85% yield. Acetylation of tetraol 23
furnished triacetate 93 in 93% yield, which allowed us to test the
hypothesis that the bicyclic ether in cortistatin A might be formed
through selective ionization. After screening a number of condi-
which it was found that both Lewis and Brønsted acids (for
example, HCl, entry 5) were able to produce the desired
compound — cortistatinone (22). BiCl3 was identified as the
superior reagent to perform the cyclization and deketalization
simultaneously in 73% yield. This improvement reduced the
operations of the original route by three and enabled the
preparation of multigram quantities of cortistatinone (22).
The final optimized route from orthoamide 24 to cortistatinone
(22) is shown in Scheme 14. It features a number of gram-scale
transformations: (1) a newly invented alcohol-directed dibromina-
tion; (2) an isohypsic cascade to access the 9(10,19)-abeo-andro-
stane skeleton; (3) an olefin-sparing, heteroadamantane fragmen-
tions, it was found that MgBr2 Et2O and 2,6-di-tert-butylpyr-
3
idine was an effective combination of reagents to perform the
desired cyclization. Subsequent deketalization and saponification
delivered cortistatinone (22) in 82% overall yield. Comparison of
the 1H NMR data with those of cortistatin A (11) was encoura-
ging, as all of the non-aliphatic carbons bore strong resemblance
to the natural product spectra.
0
tation to differentiate the tethered aminodiol; and (4) a mild SN
cyclization to close the THF ring. With this robust pathway
developed, over 2 g of cortistatinone (22) has been prepared to date.
Isoquinoline Installation. In parallel to our efforts to synthe-
size cortistatinone (22), methods were evaluated for the intro-
duction of the C17 isoquinoline moiety at earlier stages in our
The three-step sequence from tetraol 23 to cortistatinone
(22), while easy to perform, was not efficient in terms of step
count and reaction time. Therefore, a direct route from tetraol 23
to cortistatinone (22) was investigated. A variety of acids were
screened to effect this transformation (Scheme 13B), upon
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Scheme 13. THF Ring Closurea
a Reagents and conditions: (a) AlH3 (0.5 M in THF, 6 equiv), THF, 23 °C, 1 h; then K2CO3 (5 equiv), MeOH, 23 °C, 12 h, 85%; (b) Ac2O (20 equiv),
Et3N (40 equiv), DMAP (0.1 equiv), CH2Cl2, 23 °C, 3 h, 93%; (c) MgBr2 Et2O (1.1 equiv), 2,6-(t-Bu)2-pyridine (2.1 equiv), PhH, 80 °C, 1 h;
3
(d) PPTS (5 equiv), butanone:H2O (1:1), 90 °C, 2 h; then K2CO3 (10 equiv), 23 °C, 5 h, 82% over two steps. PPTS = pyridinium p-toluenesulfonate.
b Reagents and conditions: acid (4 equiv), MeCN, 40 °C, 2 h; H2O, 40 °C, 4 h.
Scheme 14. Final Optimized Route to Cortistatinone (22)a
a Reagents and conditions: (a) PhI(OAc)2 (5 equiv), Br2 (8 equiv), CH2Cl2, light, ꢀ30 °C, 10 h; then TMSCl (5 equiv), imidazole (5 equiv), CH2Cl2,
0 °C, 15 min, 57%; (b) DBU (2 equiv), LiCl (5 equiv), THF, 23 °C, 24 h, 85%; (c) SmI2 (2.5 equiv), 1:9 DMPU:THF, 23 °C, 5 min; then TBCHD
(2 equiv), ꢀ78 °C, 1 h; (d) LiBr (20 equiv), Li2CO3 (20 equiv), DMF, 80 °C, 1 h, 65% over two steps; (e) AlH3 (0.5 M in THF, 6 equiv), THF, 23 °C,
1 h; then K2CO3 (5 equiv), MeOH, 23 °C, 12 h, 85%; (f) BiCl3 (5 equiv), MeCN, 40 °C, 2.5 h; H2O, 40 °C, 5 h, 73%.
synthesis (Scheme 15). The fundamental strategic problem with
such an approach is that it prevents the desired late-stage
diversification, and the isoquinoline moiety itself poses incom-
patibilities with key reactions. For example, intermediate 24
could be transformed to isoquinoline-containing steroid 96 in
10% overall yield by a sequence employing ketal cleavage, Barton
vinyl iodide formation (leading to 95),41 Stille coupling42 with
stannane 105, and stereoselective hydrogenation with Pd/C.
Unfortunately, the isoquinoline moiety was incompatible with
halogenation conditions.37 In a similar vein, bromocyclopropaneꢀ
isoquinoline conjugate 99 could be prepared in 16% overall yield,
but bromocyclopropane was not compatible with hydrogenation
conditions. Therefore, the original plan for late-stage isoquinoline
installation remained the most logical, and indeed the only viable
option.
With two free alcohols, one tertiary amine, and a sensitive
diene adjacent to a THF ring, cortistatinone (22) requires
“gentle” chemistry for derivatization. Barton’s vinyl iodide pre-
paration (vide supra) fulfills this requirement, as does the Stille
coupling.43 In the event, this reaction sequence works well to
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Scheme 15. Studies on Isoquinoline Installationa
a Reagents and conditions: (a) PPTS (1 equiv), 1:4 H2O:acetone, 80 °C, 30 min; (b) NH2NH2 (20 equiv), Et3N (40 equiv), EtOH, 50 °C, 2 h; I2
(2 equiv), Et3N (3 equiv), THF, 23 °C, 10 min, 70% over two steps; (c) 105 (1 equiv), Pd(PPh3)4 (0.5 equiv), CuCl (10 equiv), LiCl (10 equiv), DMF,
60 °C, 1 h, 53%; (d) 10% Pd/C (1.5 equiv), H2 (1 atm), 1:1 EtOAc:MeOH, 2 h, 28%; (e) PPTS (1 equiv), 1:4 H2O:acetone, 80 °C, 30 min; (f) NH2NH2
(20 equiv), Et3N (40 equiv), EtOH, 50 °C, 2 h; I2 (2 equiv), Et3N (3 equiv), THF, 23 °C, 10 min; (g) 105 (1 equiv), Pd(PPh3)4 (0.5 equiv), CuCl
(10 equiv), LiCl (10 equiv), DMF, 60 °C, 1 h, 16% over three steps; (h) NH2NH2 (10 equiv), Et3N (10 equiv), EtOH, 50 °C, 6 h; I2 (2 equiv), Et3N
(3 equiv), THF, 23 °C, 5 min; (i) 105 (1 equiv), Pd(PPh3)4 (0.5 equiv), CuCl (10 equiv), LiCl (10 equiv), DMSO, 60 °C, 1 h, 55% over two steps;
(j) Raney Ni (10 wt equiv), i-PrOH, H2O, 50 °C, 1 h, (50%, 50% brsm). DMSO = dimethyl sulfoxide.
Scheme 16. Scalable Synthesis of 7-Substituted Isoquinolinea
a Reagents and conditions: (a) NBS (1.1 equiv), NaOH (30%, 5 equiv), CH2Cl2, 1.5 h, 92%; (b) KNO3 (1.5 equiv), H2SO4, 0 °C f 23 °C, 2 h; 60 °C,
4 h, 72%; (c) MnO2 (7 equiv), toluene, reflux, 2 h, 91%; (d) Pd/C (10%), H2 (1 atm), 3 h; (e) CuBr (1.2 equiv), NaNO2 (1.1 equiv), H2O, HBr, 0 °C f
75 °C, 30 min; 23 °C, 12 h, 63% over two steps; (f) Pd(PPh3)4 (0.1 equiv), hexamethylditin (1.05 equiv), LiCl (6 equiv), toluene, 105 °C, 1 h, 88%.
NBS = N-bromosuccinimide.
deliver Δ16-cortistatin A (101) in 53% isolated yield (on scales
ranging from 1 to 300 mg). The final conversion of 101 to
cortistatin A (11) required numerous screens in order to
identify a suitably chemoselective reducing agent that could
differentiate a styrene-like olefin from an isoquinoline and a
diene and do so in the presence of numerous unprotected
functionalities. Whereas Sm- and Pd-based agents led to over-
reduction (observed by LC-MS, uncharacterized), and Rh-
mediated transfer hydrogenation or diimide methods did not
work in our hands, Raney Ni led to an excellent conversion to
11, thus completing the synthesis. This reaction was never run
beyond a 10 mg scale since it was soon found that 101 is nearly
equipotent to 11 in all biological assays tested. In a separate
report, we have demonstrated the generality of this reaction and
explored its mechanism.18d
In passing, we note that although isoquinoline 104 is commer-
cially available, it is prohibitively expensive (ca. $80/10 mg in
2007 when we started our studies). Furthermore, the existing
method to synthesize 7-bromoisoquinoline by the Pomeranzꢀ
Fritsch reaction44 gives 5-bromoisoquinoine as a byproduct that
is difficult to separate. Therefore, a scalable and practical syn-
thesis of 7-bromoisoquinoline was developed, as shown in
Scheme 16. Starting from tetrahydroisoquinoline (102), imine
formation with NBS/NaOH,45 nitration at the C7 position,46
and dehydrogenation with MnO2 furnished 7-nitroisoquinoline
(103) in 61% yield over three steps. Subsequent reduction of the
nitro group and Sandmeyer reaction afforded the desired 7-bro-
moisoquinoline (104) in 63% yield over two steps. Lastly,
stannylation of 7-bromoisoquinoline (104) delivered 7-tri-
methylstannylisoquinoline (105) in 88% yield.
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’ CONCLUSION
Amgen, Bristol-Myers Squibb, Leo Pharma, and the Skaggs Institute
for Chemical Biology.
This full account describing a scalable synthesis of cortistatin A
and related structures stands as an example of how the judicious
choice of strategy can yield new insights into chemical reactivity,
even in a field as exhaustively studied as steroid synthesis. Several
transformations were developed that were either not feasible or
not possible prior to this work: the easily scalable side-chain
cleavage protocol; the chemoselective, tandem geminal dihalo-
genation of an unactivated methyl group; the reductive frag-
mentation/trapping/elimination of a bromocyclopropane to
simultaneously establish both the Δ10(19)- and Δ8(9)-olefins
and the 7-membered B-ring; the facile chemoselective etherifica-
tion reaction for installation of the oxido bridge; and the
remarkably selective Δ16-alkene reduction with Raney Ni.
Although our primary motive for pursuing a synthesis of the
cortistatins was to uncover new reactivity, develop new strategies,
and educate students, we were keenly aware of the societal need
for a scalable route due to their extraordinary biological activity.
With these factors in mind, a semisynthetic approach was
chosen — one that successfully converted one of the most
abundant terrestrial-based steroids into one of the ocean’s
scarcest steroidal alkaloids ever isolated. The synthesis outlined
in this work is amenable, in an academic setting, to the gram-scale
production of the cortistatins and has also been successfully
outsourced to an industrial setting.47 It is sufficiently short and
flexible for analogue studies, especially those which vary the
aromatic heterocycle at the late stage of the synthesis. Finally, the
copious quantities prepared thus far, particularly of cortistatin A’s
equipotent analogue 101, have been widely distributed to
numerous academic laboratories and pharmaceutical companies.
Indeed, extremely promising biological findings enabled by this
synthesis have already been made and will be described in due
course.
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Corresponding Author
pbaran@scripps.edu
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†These authors contributed equally to this paper
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’ ACKNOWLEDGMENT
We thank Dr. C. Moore and Prof. A. Rheingold for X-ray
crystallographic measurements, Dr. G. Siuzdak for mass spectro-
metric assitance, and Dr. D.-H. Huang and Dr. L. Pasternack for
NMR assistance. We thank Dr. C. C. Li and Mr. T. Urushima for
synthesizing early-stage material. We are grateful to Novartis and
Bristol-Myers Squibb (predoctoral fellowship to J.S.), the German
Academic Exchange Service (DAAD, postdoctoral fellowship to
G.M.), the NSC of Taiwan (NSC98-2917-I-007-122, graduate
fellowship to C.-H.Y.), the Department of Defense (predoctoral
fellowship to R.A.S.), the NIH (predoctoral fellowship to C.A.
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ship to H.S.). Financial support for this work was provided by
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