Formal total synthesis of (±)-cortistatin A

Article abstract of DOI:10.1016/j.tet.2010.01.030

A second-generation synthesis of the pentacyclic core of the cortistatins, a family of rearranged steroidal alkaloids that have recently attracted much attention, is reported. The improved sequence provides access to significant quantities of this key compound, which enabled a formal total synthesis of (±)-cortistatin A by conversion to the key Nicolaou/Hirama dienone. It is anticipated that this new, robust route to the pentacyclic core will facilitate the total synthesis of a range of natural products in the cortistatin family, as well as the construction of key structural analogs to probe the promising biological activity of these important compounds.

Full text of DOI:10.1016/j.tet.2010.01.030

Tetrahedron 66 (2010) 4696–4700
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Formal total synthesis of (ꢀ)-cortistatin A
Eric M. Simmons, Alison R. Hardin-Narayan, Xuelei Guo, Richmond Sarpong
*
Department of Chemistry, University of California, Berkeley, CA 94720, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A second-generation synthesis of the pentacyclic core of the cortistatins, a family of rearranged steroidal
alkaloids that have recently attracted much attention, is reported. The improved sequence provides
access to significant quantities of this key compound, which enabled a formal total synthesis of (ꢀ)-
cortistatin A by conversion to the key Nicolaou/Hirama dienone. It is anticipated that this new, robust
route to the pentacyclic core will facilitate the total synthesis of a range of natural products in the
cortistatin family, as well as the construction of key structural analogs to probe the promising biological
activity of these important compounds.
Received 25 November 2009
Received in revised form 6 January 2010
Accepted 7 January 2010
Available online 18 January 2010
Keywords:
Cortistatin A
Formal total synthesis
Cycloisomerization
Oxidative dearomatization
Angiogenesis
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
endothelial cells (HUVECs), which are a standard model for anti-
angiogenic activity.2 Cortistatin A (1), the most potent member of
The cortistatins are a family of rearranged steroidal alkaloids
isolated from the Indonesian marine sponge Corticium simplex by
Kobayashi and co-workers (Fig. 1).1 In addition to possessing an
unprecedented pentacyclic skeleton, these compounds exhibit
potent antiproliferative activity against human umbilical vein
this family, was found to have an IC50 of 1.8 nM against HUVECs. As
a result of their unique structural features and impressive biological
activity, these compounds have generated significant interest
among the synthetic community.3 This interest has led to one semi-
synthesis4 and two total syntheses of (þ)-cortistatin A,5 and one
Figure 1. Selected members of the cortistatin family.
total synthesis of cortistatin J (3).6 Additionally, one formal total
synthesis of (þ)-cortistatin A7 and a number of synthetic ap-
proaches8 have been reported.
* Corresponding author. Tel.: þ1 510 643 6312; fax: þ1 510 642 9675; e-mail
address: rsarpong@berkeley.edu (R. Sarpong).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.030

E.M. Simmons et al. / Tetrahedron 66 (2010) 4696–4700
4697
Scheme 1.
Although the antiangiogenic activity of the cortistatins suggests
the potential for therapeutic applications, a detailed understanding
of the mode of action of these compounds is still lacking. Important
strides have been made as a result of several structure–activity
studies, which indicated the importance of the isoquinoline and
dimethylamino groups for potent activity.6,9 Additionally, a recent
high-throughput kinase binding assay identified cortistatin A as
a high-affinity ligand for the protein kinases CDK8, CDK11, and
ROCK,10 the latter of which is involved in the regulation of cell
proliferation through modulation of Rho GTPases.11 However, the
experimentally observed discrepancy between the kinase binding
affinity and antiproliferative activity of cortistatin A underscores
the need for further work in this area to fully elucidate the details
surrounding the biological activity of the cortistatins.10 Un-
doubtedly, such advances will hinge upon on the ability of synthetic
chemists to supply meaningful quantities of both the naturally
occurring cortistatins and strategic synthetic analogs. As a step
toward this goal, we report herein a formal total synthesis of
(ꢀ)-cortistatin A, which was enabled by an improved synthesis of
the cortistatin pentacyclic core over our previously reported ap-
proach. The development of a scalable route to this key in-
termediate sets the stage for the synthesis of a range of both natural
and unnatural cortistatins.
effect an aldol condensation to provide enone 9 in 76% yield
(Scheme 1). Two-stage reduction of this -unsaturated enone,
a,b
followed by dehydration of the resultant indanol, gave indene 10 in
67% yield over the three steps. We were gratified to find that sub-
jecting 10 to catalytic PtCl2 at 50 ꢁC promoted enyne cyclo-
isomerization to forge tetracycle 11 in 82% yield, as compared to the
61% yield obtained for cycloisomerization of the PMB analog of 10.8c
Chemoselective reduction of the disubstituted double bond of 11
with diimide, generated in situ from TsNHNH2 and Et3N, was fol-
lowed by cleavage of the benzyl ether moiety with Na/naphthalide
to give phenol 12 in 77% yield over the two steps. Reprotection as
the TES ether and treatment with m-CPBA provided epoxide 13, an
intermediate previously prepared from 6.8c Regioselective opening
of the epoxide moiety accompanied by removal of the TES group
was achieved by treatment of 13 with n-BuLi to provide an in-
termediate allylic alcohol. This species subsequently underwent
oxidative dearomatization13 upon slow addition to a solution of
PhI(OAc)2 at ꢂ78 ꢁC to provide pentacycle 14 in 57% yield over the
two steps. We were pleased to find that this readily scalable se-
quence provided pentacycle 14 in 9.6% overall yield from aldehyde
8 and benzyloxy indanone 7, nearly double the yield of the previous
sequence that employed PMB-protected indanone 6.
With a robust route to pentacycle 14 established, we were
poised to explore conditions for its elaboration to the cortistatin
natural products. In accord with our general synthetic strategy,
compound 14 is imbued with the diene substitution pattern which
directly corresponds to cortistatins K and L (4 and 5) and should
readily serve as a precursor to these natural products. However, as
an intermediate synthetic goal, we chose to target dienone 25,5a,7a
which was previously advanced to (þ)-cortistatin A by Nicolaou
and co-workers.5a This effort would thus constitute a formal total
synthesis of 1. To this end, it was necessary to effect a transposition
of the C1,C19 diene moiety of trienone 14 to reposition this func-
tionality to C10,C9. The direct oxidative conversion of 14–17
(Scheme 2) was attempted with various oxidants such as PdCl2,
DDQ,8h PhI(OAc)2,14 and CAN in the presence of MeOH, but these
endeavors did not prove fruitful. We next attempted to activate the
dienol ether moiety of 14 with a suitable electrophile that could
subsequently be removed to generate the diene. The method of
Venturello and co-workers (NBS or NCS in MeOH)15 gave a mixture
of halogen and methoxy-containing products, none of which could
2. Results and discussion
Our initial synthetic efforts toward the cortistatins led to a syn-
thesis of the cortistatin pentacyclic core (14), which proceeded in 11
steps and 5.3% overall yield from aldehyde 8 and indanone 6
(Scheme 1).8c As a prerequisite to further synthetic studies, we
required access to significant quantities of 14 and sought an im-
proved route to this compound. We had initially chosen to begin
with PMB-protected indanone 6 due to the range of mild conditions
available for cleavage of the PMB ether.12 However, we speculated
that the potential reactivity of this electron-rich moiety toward the
Brønsted and Lewis acids that were employed in several of our
synthetic manipulations (vide infra) might have contributed to the
modest yields of these steps.
To circumvent these obstacles, benzyloxy indanone 7 was
employed in a second-generation synthesis. This sequence com-
menced by treating 7 with KOH in the presence of aldehyde 8 to

4698
E.M. Simmons et al. / Tetrahedron 66 (2010) 4696–4700
Scheme 2.
be readily transformed to diene 17. Similarly disappointing results
were obtained using NIS or 1,3-dibromo-5,5-dimethylhydantoin
(DBDMH). However, treatment of 14 with m-CPBA at 0 ꢁC led to
selective epoxidation of the trisubstituted double bond to yield
epoxide 15, which was subsequently opened with camphor sulfonic
acid (CSA) in MeOH to provide tertiary alcohol 16. After examining
a variety of conditions for the dehydration of 16, we were pleased to
find that activation of the hydroxyl group with trifluoroacetic an-
hydride led to its facile elimination, providing diene 17 in 58% yield
over the three-step sequence.
Because the ketal moiety seemed to be playing a role in each of
these undesired outcomes, it was cleaved with 1% HCl to give
a-hydroxy ketone 20. Unfortunately, dehydration of this compound
was also unsuccessful under a variety of conditions (Amberlyst 15,19
TsOH,20 POCl3 or TsCl/pyr, TFAA/Et3N, Martin’s sulfurane).
Attempted Barton deoxygenation or Chugaev elimination of the
corresponding thiocarbonate of 20 also led to decomposition. In an
alternative approach, ketone 18 was converted to enol triflate 21 by
sequential treatment with LDA and PhNTf2 in THF at ꢂ78 ꢁC.
However, attempts to reduce the triflate moiety of this species led
to mixtures of products along with significant decomposition. The
corresponding dienone (22) also fared poorly under reduction
conditions.
With diene 17 in hand, we next examined conditions for se-
lective hydrogenation of the enone double bond. Although Crab-
tree’s catalyst proved to be chemoselective toward reduction of the
enone double bond of 17, we were disappointed to observe a sig-
nificant amount of decomposition products in the crude product
mixture. We attribute this fact to the lability of the ketal moiety of
17, which under the Lewis acidic reaction conditions may ionize
and lead to decomposition of both the product and the starting
material. A survey of heterogeneous catalysts revealed Pt/C, PtO2,
and Rh/Al2O3 to be unsuitable for this transformation, leading to
mixtures of over-reduced products and decomposition. However,
using Rh/C in THF,16 we were able to obtain a 72% yield of ketone 18
(Scheme 3). A slight improvement in yield was realized by
employing Wilkinson’s catalyst in benzene, which provided a 75%
yield of 18. Further reduction of ketone 18 with LiEt3BH then de-
livered alcohol 19 in 56% yield.
Because of our inability to cleanly dehydrate alcohols 19 or 20,
or to reduce triflates 21 or 22, we returned to enone 17. We were
pleased to find that Luche reduction of 17 led to a single allylic
alcohol diastereomer. It should be noted that although the relative
configuration of this species has not been determined, it is ulti-
mately inconsequential. The intermediate alcohol was treated with
(Boc)2O and DMAP to provide Boc carbonate 23 in 69% yield over
the two steps (Scheme 4). After some experimentation, we were
pleased to find that treatment of 23 with Pd(dppf)Cl2 and ammo-
nium formate and heating to 60 ꢁC provided dienol ether 24. Al-
though the exact mechanistic details have not been fully elucidated
at this stage, we propose that this transformation proceeds via an
initial oxidative addition of an in situ generated Pd(0) species to the
allylic carbonate moiety of 23 to generate a Pd(II)–allyl complex.21
Dehydration of 19 was attempted with Martin’s sulfurane17 and
the Burgess reagent18 without success. Although the corresponding
thiocarbonate of alcohol 19 could be readily formed, attempted
Chugaev elimination led instead to loss of 1 equiv of MeOH.
Subsequent
b
-alkoxide elimination22 yields 24 and a free Pd(II)
complex, which undergoes reduction by formate to regenerate the
active catalyst. Compound 24 readily underwent selective
Scheme 3.

E.M. Simmons et al. / Tetrahedron 66 (2010) 4696–4700
4699
Scheme 4.
hydrogenation of the disubstituted double bond on treatment with
Wilkinson’s catalyst to deliver an intermediate enol ether, which
upon hydrolysis gave dienone 25 in 77% yield over the three-step
sequence. Spectral data for 25 were in full accord with that pre-
viously reported,5a,7a thus completing the formal total synthesis of
(ꢀ)-cortistatin A (1).
the Mass Spectral Facility at the University of California, Berkeley,
on a VG Prospec Micromass spectrometer (for EI) or a ThermoFisher
Scientific LTQ Orbitrap XL (for ESI).
4.2. Ketal 17
To a suspension of pentacycle 14 (87.9 mg, 0.20 mmol) and
NaHCO3 (83.5 mg, 0.99 mmol) in CH2Cl2 (5.0 mL) at 0 ꢁC was added
m-CPBA (w75%, 114 mg, 0.50 mmol). The resulting mixture was
stirred at 0 ꢁC for 10 h and then poured onto half-saturated aq
Na2SO3 (15 mL) and extracted with Et2O (3ꢃ15 mL). The combined
organic layers were washed (2ꢃ15 mL saturated aq NaHCO3, 15 mL
brine), dried (MgSO4), and then concentrated to give 90.4 mg of
crude epoxide 15 as a white powder, which was used without
further purification. Rf 0.20 (4:1 hexanes/EtOAc). To a solution of
crude epoxide 15 (90.4 mg) in CH2Cl2 (2.5 mL) and MeOH (2.5 mL)
3. Conclusions
In summary, we have developed a second-generation synthesis
of the pentacyclic core of the cortistatins (14), which proceeds in
nearly double the yield of our first-generation effort. With access to
significant quantities of this intermediate, the formal total syn-
thesis of (ꢀ)-cortistatin A (1) was completed in eight subsequent
steps. Current efforts are directed at utilizing 14 to complete the
total syntheses of cortistatins A, K, and L and to prepare unnatural
analogs for further biological studies.
at 0 ꢁC was added camphor sulfonic acid (1.0 mg, 4
mmol). The
resulting mixture was stirred at 0 ꢁC for 3 h and then poured onto
half-saturated aq NaHCO3 (15 mL) and extracted with Et2O
(3ꢃ15 mL). The combined organic layers were washed (15 mL
brine), dried (MgSO4), and then concentrated to give 92.7 mg of
crude alcohol 16 as a white powder, which was used without fur-
ther purification. Rf 0.30 (4:1 hexanes/EtOAc). A solution of crude
alcohol 16 (92.7 mg) and DMAP (4.7 mg, 0.04 mmol) in 1,2-di-
chloroethane (3.0 mL) and Et3N (1.5 mL) was treated with tri-
fluroacetic anhydride (0.13 mL, 0.94 mmol). After being stirred for
1 h at rt, the resulting mixture was heated to 60 ꢁC for 4 h. After
cooling to rt, the reaction mixture was poured onto half-saturated
aq NaHCO3 (15 mL) and extracted with Et2O (3ꢃ15 mL). The com-
bined organic layers were washed (15 mL brine), dried (MgSO4),
and then concentrated. Flash chromatography (9:1 hexanes/
EtOAcþ1% Et3N) gave 54.0 mg (0.11 mmol, 58% over three steps) of
ketal 17 as a pale yellow oil. Rf 0.57 (4:1 hexanes/EtOAc); 1H NMR
4. Experimental
4.1. General
Unless otherwise stated, reactions were performed in flame-
dried glassware fitted with rubber septa and were stirred with
Teflon-coated magnetic stirring bars. Liquid reagents and solvents
were transferred via syringe using standard Schlenk techniques.
Tetrahydrofuran (THF) was distilled over sodium/benzophenone
ketyl. Dichloromethane (CH2Cl2) and benzene were distilled over
calcium hydride. All other solvents and reagents were used as re-
ceived unless otherwise noted. Half-saturated aq solutions refer to
a freshly prepared 1:1 v/v mixture of the corresponding saturated
aq solution and deionized water. Reaction temperatures above
23 ꢁC refer to oil bath or heating block temperatures, which were
controlled by an OptiCHEM temperature modulator. Thin layer
chromatography was performed using SiliCycle silica gel 60 F-254
precoated plates (0.25 mm) and visualized by UV irradiation and
anisaldehyde stain. SiliCycle Silia-P silica gel (particle size 40–
(600 MHz, CDCl3)
d
6.65 (d, J¼10.3 Hz, 1H), 6.39 (s, 1H), 6.10 (d,
J¼10.3 Hz, 1H), 5.58 (dd, J¼5.2, 2.6 Hz, 1H), 3.76 (t, J¼8.6 Hz, 1H),
3.54 (s, 3H), 3.19 (s, 3H), 2.38–2.27 (m, 2H), 2.19–2.12 (m, 2H), 2.04–
1.95 (m, 2H), 1.90 (td, J¼10.6, 8.1 Hz, 1H), 1.83 (ddd, J¼16.9, 11.3,
5.4 Hz, 1H), 1.76–1.64 (m, 2H), 1.58–1.50 (m, 1H), 0.88 (s, 9H), 0.77
(s, 3H), 0.028 (s, 3H), 0.025 (s, 3H); 13C NMR (125 MHz, CDCl3)
63 m
m) was used for flash chromatography. 1H and 13C NMR spectra
were recorded on Bruker DRX-500 and AV-600 MHz spectrometers
with 13C operating frequencies of 125 and 150 MHz, respectively.
d
193.1, 147.9, 139.2, 134.6, 128.8, 126.6, 125.7, 97.5, 83.9, 81.5, 78.1,
52.5, 50.0, 46.2, 43.4, 39.7, 39.5, 30.7, 30.4, 25.8,19.3,18.0,13.4, ꢂ4.4,
ꢂ4.8; IR (film) nmax 2955, 2857, 1709, 1471, 1463, 1387, 1361, 1250,
1177, 1145, 1111, 1046, 991, 837, 776, 738, 666 cmꢂ1; HRMS (EIþ)
calcd for [C27H40O5Si]þ: m/z 472.2645, found 472.2656.
Chemical shifts (
residual solvent signal (
d) are reported in parts per million relative to the
d
¼7.26 for 1H NMR and
d
¼77.0 for 13C
NMR). Data for 1H NMR spectra are reported as follows: chemical
shift (multiplicity, coupling constants, number of hydrogens). Ab-
breviations are as follows: s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), br (broad). IR spectra were recorded on
a Nicolet MAGNA-IR 850 spectrometer and are reported in fre-
quency of absorption (cmꢂ1). Only selected IR absorbencies are
reported. High resolution mass spectral data were obtained from
4.3. Boc carbonate 23
A solution of ketal 17 (10.8 mg, 23
mmol) in MeOH (0.70 mL) and
CH2Cl2 (0.30 mL) at 0 ꢁC was treated with CeCl3$7H2O (34.1 mg,

4700
E.M. Simmons et al. / Tetrahedron 66 (2010) 4696–4700
92
mmol). After 15 min, a solution of NaBH4 (0.9 mg, 24
mmol) in
0.033 (s, 3H), 0.031 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 198.6,
MeOH (0.20 mL) was added. The resulting solution was stirred at
0 ꢁC for 40 min and then diluted with EtOAc (15 mL). The organic
layer was washed (5 mL saturated aq NaHCO3, 5 mL brine), dried
140.8, 139.8, 132.3, 132.0, 82.5, 81.5, 81.0, 46.2, 43.3, 40.4, 40.1, 39.4,
33.4, 30.7, 30.4, 25.8, 19.5, 19.1, 18.0, 13.7, ꢂ4.4, ꢂ4.8; IR (film) nmax
2925, 2853, 1674, 1625, 1581, 1462, 1249, 1196, 1102, 1022, 841, 777,
665 cmꢂ1; HRMS (ESIþ) calcd for [C25H39O3Si]þ (MþH)þ: m/z
415.2668, found 415.2680.
(MgSO4), and then concentrated to give 9.2 mg (19 mmol, 85%) of
the crude allylic alcohol as a white powder, which was used
without further purification. Rf 0.36 (4:1 hexanes/EtOAc); 1H NMR
(600 MHz, CDCl3)
d
6.46 (s, 1H), 5.71 (dd, J¼10.2, 1.8 Hz, 1H), 5.58
Acknowledgements
(dd, J¼10.2, 1.8 Hz, 1H), 5.51 (dd, J¼5.0, 2.5 Hz, 1H), 4.37 (d,
J¼11.2 Hz, 1H), 3.75 (t, J¼8.5 Hz, 1H), 3.51 (s, 3H), 3.14 (s, 3H), 2.81
(d, J¼11.2 Hz, 1H), 2.27–2.20 (m, 1H), 2.16–2.09 (m, 2H), 2.08–2.02
(m, 1H), 2.02–1.94 (m, 2H), 1.78–1.62 (m, 4H), 1.57–1.49 (m, 1H),
0.88 (s, 9H), 0.76 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR
We are grateful to UC Berkeley, Eli Lilly, GlaxoSmithKline and
AstraZeneca for unrestricted financial support of this research. We
would also like to thank Johnson Matthey for a generous gift of
PtCl2. E.M.S. thanks the ACS Division of Medicinal Chemistry and Eli
Lilly for a predoctoral fellowship (2007–2008). R.S. is a 2009 fellow
of the Alfred P. Sloan Foundation.
(150 MHz, CDCl3) d 140.0, 134.9, 133.2, 128.3, 126.2, 124.3, 97.4, 82.6,
81.6, 78.4, 72.0, 52.0, 48.4, 46.3, 43.4, 39.5, 30.7, 30.6, 25.8, 19.3,18.0,
13.5, ꢂ4.4, ꢂ4.8. A solution of the crude allylic alcohol (7.4 mg,
16 mmol), 4-dimethylaminopyridine (0.4 mg, 3.3 mmol), and di-tert-
Supplementary data
butyl dicarbonate (17.1 mg, 78
(0.60 mL) was heated at 40 ꢁC. After 17 h, an additional 17.1 mg
(78 mol) of di-tert-butyl dicarbonate was added and heating was
mmol) in 1,2-dichloroethane
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.01.030.
m
continued for an additional 20 h. After cooling to rt, the reaction
mixture was diluted with EtOAc, filtered through SiO2, and then
concentrated to give 11.7 mg of a yellow oil. Flash chromatography
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d
6.44 (s, 1H), 5.70 (ddd, J¼10.2, 2.1, 0.7 Hz, 1H),
5.66 (dd, J¼10.2, 2.0 Hz, 1H), 5.52 (dd, J¼5.3, 2.5 Hz, 1H), 5.39 (t,
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4H), 1.57–1.50 (m, 1H), 1.47 (s, 9H), 0.88 (s, 9H), 0.76 (s, 3H), 0.03 (s,
3H), 0.02 (s, 3H); 13C NMR (150 MHz, CDCl3)
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4.4. Dienone 25
A solution of Pd(dppf)Cl2$CH2Cl2 (0.6 mg, 0.7
(0.20 mL) was added to a suspension of carbonate 23 (1.8 mg,
3.1 mol) and ammonium formate (ca. 2 mg, 32 mol) in THF
mmol) in DMF
m
m
(0.40 mL). The resulting mixture was stirred at rt for 30 min to give
an orange solution and then heated to 60 ꢁC for 2.5 h. After cooling
to rt, the reaction mixture was diluted with Et2O (12 mL) and
washed (2ꢃ5 mL water, 5 mL brine), dried (MgSO4), and then
concentrated. The crude material was directly purified by passage
through a short plug of SiO2, eluting with 4:1 hexanes/EtOAc, to
give dienol ether 24 as a yellow oil. Rf 0.67 (4:1 hexanes/EtOAc). A
mixture of the above dienol ether and Rh(PPh3)3Cl (ca. 0.2 mg,
9. (a) Shi, J.; Shigehisa, H.; Guerrero, C. A.; Shenvi, R. A.; Li, C.-C.; Baran, P. S.
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48, 8952–8957.
0.2 mmol) in benzene (0.50 mL) was placed in a Parr bomb and set
under 100 psi of H2. After being stirred for 11 h, the reaction mix-
ture was diluted with 2:1 hexanes/EtOAc, filtered through SiO2 and
then concentrated to give the crude enol ether as a light brown oil.
This material was directly dissolved in THF (0.50 mL), cooled to
0 ꢁC, and treated with 1% HCl (three drops). The resulting solution
was stirred for 3.5 h, during which time the cooling bath was
allowed to gradually expire. The reaction mixture was then diluted
with EtOAc, filtered through SiO2, and concentrated. Flash chro-
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5224–5226.
matography (4:1 hexanes/EtOAc) gave 1.0 mg (2.4
three steps) of dienone 25 as a colorless film. Rf 0.28 (4:1 hexanes/
EtOAc); 1H NMR (600 MHz, CDCl3)
mmol, 77% over
19. Righi, G.; Bovicelli, P.; Sperandio, A. Tetrahedron Lett. 1999, 40, 5889–5892.
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d
6.93 (s, 1H), 5.87 (dd, J¼5.2,
2.8 Hz, 1H), 3.77 (t, J¼8.6 Hz, 1H), 2.61–2.53 (m, 1H), 2.38–2.29 (m,
1H), 2.28–2.18 (m, 3H), 2.14 (dd, J¼11.5, 8.2 Hz, 1H), 2.08–1.94 (m,
5H), 1.79–1.66 (m, 5H), 1.61–1.49 (m, 1H), 0.88 (s, 9H), 0.76 (s, 3H),