Synthetic studies toward (+)-cortistatin A

Article abstract of DOI:10.1016/j.tet.2011.10.026

We describe herein the synthesis of a late-stage intermediate en route to cortistatin A. Key transformations included a Snieckus-like cascade sequence culminating in a 6π-electrocyclization, an alkylative dearomatization, and the stereoselective functiona

Full text of DOI:10.1016/j.tet.2011.10.026

Tetrahedron 67 (2011) 10249e10260
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthetic studies toward (þ)-cortistatin A
,
,b,
*
Zhang Wang a, Mingji Dai a, Peter K. Park a b, Samuel J. Danishefsky a
a Department of Chemistry, Columbia University, Havemeyer Hall, 3000 Broadway, New York, 10027 NY, USA
b Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, 10065 NY, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 August 2011
Received in revised form 9 October 2011
Accepted 10 October 2011
Available online 29 October 2011
We describe herein the synthesis of a late-stage intermediate en route to cortistatin A. Key trans-
formations included a Snieckus-like cascade sequence culminating in a 6p-electrocyclization, an alky-
lative dearomatization, and the stereoselective functionalization of the cortistatin A-ring. While the total
synthesis we sought was not accomplished, the work sets the stage for several approaches to the
preparation of novel analogs via diverted total synthesis.
Ó 2011 Published by Elsevier Ltd.
Keywords:
Total synthesis
Angiogenesis inhibitor
Nitroneearyne cycloaddition
6p-Electrocyclization
1. Introduction
typically focal and self-limited in time in regular tissues.7 Patho-
logical angiogenesis, however, is implicated in a variety of diseases,
Our laboratory devotes much of its effort to the discovery and
development of small molecule natural product (SMNP)ede-
rived agents of potential therapeutic value.1 Under our paradigm
of diverted total synthesis (DTS),1 we identify SMNPs with
compelling biological activity and challenging structural fea-
tures. We first undertake the total synthesis of the natural
product itself and subsequently seek to adapt the synthetic route
to allow access to rationally designed analogs for further in-
vestigation and SAR analysis. Through recourse to the strategy
of DTS, we have discovered a range of promising SMNPederived
lead agentsdincluding those based on the epothilone,2 migras-
tatin,3 and panaxytriol4 natural product frameworksdwhich are
under development in preclinical and clinical settings.
In our ongoing pursuit of new lead structure types, we took note
of a recent report by Kobayashi and co-workers,5 on the isolation of
a novel class of steroidal alkaloids, the cortistatins, from the marine
sponge Corticium simplex (Scheme 1). Notably, members of the
cortistatin family appear to exhibit potent in vitro anti-
angiogenesis activity. Angiogenesis, the formation of new blood
vessels in tissues, is an essential biological process, involved in
embryonic development, reproduction, and wound healing.6 The
process of angiogenesis is regulated by a series of stimulators and
inhibitorsdincluding vascular endothelial growth factor (VEGF)
including atherosclerotic plaques, diabetic retinopathy, anddof
particular interest to our laboratorydthe growth and metastasis of
malignant tumors. Selective small molecule angiogenesis in-
hibitors, perhaps of the cortistatin genre, seemed to represent
a promising avenue of research directed toward the treatment of
angiogenesis-dependent diseases. Cortistatin A, in particular, has
been reported to exhibit potent growth-inhibitory activity against
human umbilical vein endothelial cells (HUVECs), with an IC50 of
1.8 nM and selectivity indices of above 3000 compared to normal
human dermal fibroblast (NHDF) and other tumor cell lines.8 Cor-
tistatin A also exhibits inhibitory effects against the migration of
HUVECs, and against VEGF- and bFGF-induced tubular formation at
a concentration of 2 nM, with comprehensive activity against
neovascularization.9 Thus, cortistatin A, which exhibits strong and
selective anti-angiogenesis activity, could potentially serve as an
exciting lead agent in the development of anti-angiogenic thera-
peutics via chemical synthesis.
In contemplating a total synthesis, one soon comes to focus on
the unique 9(10e19)-abeo-androstane-type steroidal core, in-
corporating an oxabicyclo[3.2.1]octene motif, shared by the cor-
tistatins. Among the various members of this class, three different
types of C17 side chains (isoquinoline, 3-methylpyridine, and
methylpiperidine) and various levels of A-ring oxidation are rep-
resented. Following the initial structureeactivity relationship (SAR)
study reported by the Kobayashi group,9 Nicolaou and co-workers
reported the results of a binding assay screening, which indicated
strong binding affinity of cortistatin A toward a series of biologically
essential kinases with extended C-termini, including cyclin-
and angiopoietin
1 (ANGPT1), respectivelydand is therefore
* Corresponding author. E-mail address: s-danishefsky@ski.mskcc.org (S.J.
Danishefsky).
0040-4020/$ e see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tet.2011.10.026

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Z. Wang et al. / Tetrahedron 67 (2011) 10249e10260
Scheme 1. Cortistatin family of natural products and their IC50 values against HUVECs.
dependent kinases (CDK8 and CDK11) and Rho-associated coiled-
coil containing protein kinases (ROCK I and ROCK II).10 Docking
simulations suggest that the isoquinoline moiety of cortistatin A
projects inside the kinase hinge, while the steroidal skeleton blocks
the ATP-binding cleft and the polar A-ring is exposed to solvent.
The extended C-termini of these kinases apparently place an aro-
matic side chain proximal to cortistatin A, thereby encapsulating
the ATP-binding site. Thus, the cytostatic activity of the cortistatins
against HUVECs is proposed to arise from inhibition of HUVEC ki-
nase activity, resulting in diminished HUVEC proliferation and
migration.
Not surprisingly, the potent biological activity and unique
structures of the cortistatins have prompted many laboratories to
undertake their synthesis. To date, total syntheses have been re-
ported from the Baran,11 Nicolaou,8,12a Shair,13 Myers,14 Hirama,15
and Funk groups,16 and formal syntheses have been achieved by
the Sarpong17 and Yang groups.18 Numerous synthetic studies to-
ward the steroidal core of the cortistatins have been published.19 In
the aggregate, these synthetic studies represent a wide range of
strategies, each of which might be adapted to provide access to
different types of analogs for further investigation. Indeed, a variety
of synthetic cortistatin analogs have been prepared and evaluated
in preclinical settings.20
effect that the AeBeC ‘skeleton angle’ and core ring planarity are
important factors in mediating biological activity.20a
In designing our synthetic strategy toward cortistatin A, of
course, we took note of its rearranged steroidal skeleton. Seeking to
capitalize on the wisdom accumulated over years of research in the
field of steroid synthesis,21 we considered both B-ring22 and C-
ring23 disconnection strategies toward cortistatin A. In the case at
hand, disconnection along the B-ring would reduce the challenge to
the syntheses of the A-ring fragment, from an aromatic precursor,
and the more complex CeD ring system. Pattern recognition
analysis suggests that the CeD ring system could be derived from
the optically enriched HajoseParrish ketone.24,25 As shown in
Scheme 3, following some early experimentation,26 a convergent
strategy, which envisioned 1,3-dipolar cycloaddition between an
aryne (2, A-ring) and an
a,b-unsaturated nitrone (3, CeD ring)
presented itself. The resultant benzoisoxazoline, 4, could well be
R
Me
R
Me
H
X
X
H
X
TBSO
Y
[3+2]
Zn
HOAc
+
TBSO
Y
Z
N
R1
N
3
2
OĞ
R1
+
O
4
Z
Preliminary SAR studies on the cortistatins and synthetic ana-
logs have revealed important information with respect to the
structural features required for biological activity. As shown in
Scheme 2, in order to exhibit inhibitory activity, the A-ring must
incorporate at least one eOH or eNMe2 group and stereointegrity
at C17 must be preserved. Moreover, there is some evidence to the
NHR1
X
electro-
TBSO
Y
TBSO
Y
cyclization
Me
R
Me
R
O
R1NH2
O
H
H
H
Z
5
6
Z
X
X
Me
R
TBSO
FĞ
TBAF
alkylative
O
Me
R
ring flatness,
O
A-B-C 'skeleton angle'
might be important
Y
O
Z
H
Y
H
dearomatization
7
8
A-ring:
OH
at least one –OH or
Me
17
HO
N
C
–NMe required
2
OH
O
B
A
D
Me
N
16
HO
H
Me N
2
C
stereochemistry
is essential
17
O
C
, C oxidation
16 17
Me
H
cortistatin A (1)
N
Me
reduces activity
cortistatin A (1)
Scheme 2. Cortistatin: preliminary SAR data.
Scheme 3. [3þ2] Cycloadditionebased synthetic strategy toward cortistatin A.

Z. Wang et al. / Tetrahedron 67 (2011) 10249e10260
10251
tBu
+N
converted to benzopyran intermediate 7 through a sequence in-
volving reductive NeO bond cleavage, followed by 1,4-elimination
OMe
OMe
ŠO
TfO
Br
OTIPS
a
b
+
TIPSO
and 6p
-electrocyclization.27 Finally, alkylative dearomatization of 7
[3+2]
OPMB
N
tBu
17
would deliver intermediate 8 en route to cortistatin A.28
OPMB
15
16
O
OMe
OMe
OMe
2. Results and discussion
TIPSO
TIPSO
O
c,d
e
O
O
O
2.1. Nitroneearyne [3D2] cycloadditionebased route to the
19
18
20
cortistatin core
OPMB
Br
Scheme 5. [3þ2] Cycloaddition: Model studies toward the cortistatin core structure.
Key: (a) n-BuLi, THF, ꢀ78 ꢁC; (b) Zn, HOAc, rt; then 170 ꢁC, toluene, 55% from 15; (c)
Me2BBr, i-Pr2NEt, anisole, CH2Cl2, ꢀ78 ꢁC, 84%; (d) CBr4, PPh3, CH2Cl2, 87%; (e) TBAF,
THF, rt; then 50 ꢁC, 20 min, 52%.
At the outset of our studies, few examples of nitroneearyne
[3þ2] cycloadditions, such as 2þ3/4, had been reported. Model
studies, performed with simple nitrone substrates (11), revealed
that high levels of regioselectivity could be achieved when the
aryne dipolarophiles were equipped with ortho-substituents
(Scheme 4).29 Interestingly, ortho-TMS aryne, 10a, underwent cy-
cloaddition to yield adduct 12a as a single regioisomer. By contrast,
ortho-OMe aryne 10b generated adduct 12b, with completely
inverted regioselectivity. These findings seem to reflect the in-
terplay of competing steric and electronic factors. It was also ob-
served that meta- and para-substituted aryne substrates (cf. 13)
generally underwent cycloaddition to afford mixtures of products
with poor levels of regiocontrol (Scheme 4). Similar regioselectivity
trends have been reported previously.30
elegant precedent of Snieckus,31 with a later adaptation by Alvarez-
Manzaneda,32 we envisioned a cascade sequence commencing
with an aryllithium substrate, 21, and a bicyclic aldehyde of the
type 2215c (Scheme 6). According to our plan, 1,2-addition of 21 to
22 would generate an alkoxide intermediate (23), which would
undergo carbamoyl migration to afford 24. A facile 1,4-elimination
would give rise to quinomethide 25, which was expected to un-
dergo 6p-electrocyclization. Subsequent alkylative dearomatiza-
tion would generate an advanced intermediate of the type 27. At
the outset of our studies, there was uncertainty regarding the ste-
reochemistry at C8 following electrocyclization (see asterisk, 26).
We postulated that the isomer required for cortistatin would be the
thermodynamic product, as it encompasses trans/anti stereo-
connectivity between the angular methyl (C18), the C14 hydrogen,
and the angular two-carbon chain.
TMS
O
tBu
N
R = TMS
41%
+
R
tBu
R
N
TfO
Br
OŠ
12a
nBuLi, THF
11
[3+2]
Š78 ¼C
O
tBu
N
9a, R = TMS
9b, R = OMe
10a, R = TMS
10b, R = OMe
R = OMe
74%
OMe
12b
O
O
tBu
nBuLi, THF
Š78 ¼C
tBu
N
N
Br
OMe
MeO
+
11
TfO
MeO
13
[3+2]
14a
14b
1:1.5 (14a:14b)
Scheme 4. Regioselectivity of nitroneearyne [3þ2] cycloaddition.
Having probed the nature of the nitroneearyne [3þ2] cycload-
dition, we now sought to prepare a more sophisticated model
system, through which we would explore the viability of the pro-
posed alkylative dearomatization sequence. In order to achieve the
requisite sense of regioselectivity in the cycloaddition step, we
elected to install an inductively operating electron-withdrawing
group, eOMe, at the ortho position of the aryne substrate. This
functionality would ultimately become the C1 hydroxyl group of
cortistatin A. In the event, 1,3-dipolar cycloaddition between
nitrone 15 and the aryne generated from 16 afforded benzoisox-
azoline 17. Treatment under mild NeO cleavage conditions fol-
lowed by 1,4-elimination served to generate the intermediate o-
Scheme 6. Snieckus cascade-based route toward cortistatin A.
We first set out to synthesize the A ring precursor fragments. In
order to preserve maximum synthetic flexibility in the later stages
of the synthesis, we prepared both the substrate bearing a MOM
protecting group at the eventual C1 (31a) and the fragment pos-
sessing a C1 methoxy group (31b). As outlined in Scheme 7, the
route commenced with commercially available 28. Bromination,33
followed by selective acylation, afforded carbamate 29. The
remaining free hydroxyl was protected as a TBS group, and
quinomethide, which readily underwent 6p-electrocyclization to
deliver adduct 18, as planned, in high yield. Deprotection and
subsequent bromodehydration afforded 19, which, upon exposure
toTBAF, smoothly underwent alkylative dearomatization to provide
the key model system, 20 (Scheme 5). Given this encouraging
demonstration of ‘reduction to practice’, we hoped to build in to our
scheme a sufficient functionality to enable progression, hopefully
to cortistatin A itself.
OR
CHO
CHO
OH
a,b
TBSO
Br
O
HO
HO
Br
O
f or g
c-e TBSO
Br
O
OH
28
29
30
Et2N
O
Et2N
O
Et2N
O
31a, R = MOM
31b, R = Me
2.2. Snieckus cascadeebased route to the cortistatin core
Scheme 7. Synthesis of aromatic A ring fragments (31a and 31b). Key: (a) Br2, CHCl3;
(b) ClCONEt2, pyridine, DMAP, reflux, 48% over two steps; (c) TBSOTf, lutidine, CH2Cl2,
0
ꢁC/rt, 97%; (d) mCPBA, CH2Cl2; (e) K2CO3, MeOH; (f) MOMCl, i-Pr2NEt, 31a: 58%
An alternative route toward a more highly functionalized ver-
sion of the quinomethide system was also pursued. Based on the
over three steps; (g) TMSCHN2, PhH, MeOH, 31b: 65% over three steps.

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Z. Wang et al. / Tetrahedron 67 (2011) 10249e10260
BaeyereVilliger oxidation with subsequent saponification de-
livered 30. This intermediate was converted to both 31a and 31b
under the conditions shown.
Methods based on electrophilic amination,36 Neber reaction,37 silyl
enol ether aziridination,38 and dimethylamine displacement of a C3
bromide derived from a 3,4-dihydro version of 36b (vide infra)
were all unsuccessful. Finally, following extensive experimentation,
With fragments 31 and 3215c in hand, we were able to reduce the
proposed Snieckus-type cascade sequence to practice (Scheme 8).
Interestingly, isomers bearing the undesired C8 stereochemistry
(epi-33a and epi-33b) were preferentially formed (10:1 dr), pre-
sumably due to unfavorable 1,3-diaxial interactions between C18
an a
-azido ketone fragmentation method39 was found to success-
fully enable emplacement of the C3 amine. As shown, compound
36a was advanced to the C3-bromo intermediate 38a through ex-
posure to L-Selectride, followed by the electrophilic brominating
agent, 37 (Scheme 10). Upon treatment with Bu4NN3 in THF, in-
termediate 38a was susceptible to displacement by azide. Sub-
sequent fragmentation of 39a yielded enamine 40a, as shown. The
stereoselective reduction of 40a was accomplished through treat-
ment with NaBH3(CN) in CH2Cl2. The air-sensitive intermediate 41a
and C6eC7 in the 6p-electrocyclization event. Fortunately, however,
the electrocyclization step (cf. 25/26, Scheme 6) proved to be
reversible, and thermally induced epimerization of isolated epi-33a
and epi-33b afforded isomeric mixtures, of which the thermody-
namic products, 33a and 33b, were predominant (>2:1 dr).
OMOM
O
OMOM
OMOM
TBSO
TBSO
TBSO
Br
a
18
Me
b
18
Me
H
O 8
Me
OTBS
8
*
14
*
14
+
OTBS
OTBS
O
O
TBSO
H
H
TBSO
H
32
31a
OTBS
Et2N
OMe
O
epi-33a undesired
epi-33a:33a = 10:1
desired
33a
epi-33a:33a = 1:2.3
OMe
OMe
O
TBSO
Br
O
TBSO
TBSO
a
18
Me
OTBS
b
18
Me
H
8
+
O 8
*
Me
OTBS
14
*
14
O
OTBS
TBSO
H
TBSO
H
H
OTBS
Et2N
O
31b
32
epi-33b
undesired
desired
33b
epi-33b:33b = 1:2.5
epi-33b:33b = 10:1
Scheme 8. Snieckus-type domino route to cortistatin core. Key: (a) t-BuLi, then 32, ꢀ78/130 ꢁC, 50% (epi-33a), 60% (epi-33b); (b) 192e198 ꢁC.
The diastereomeric product mixtures, which were not readily
separable, were subjected to I2-mediated TBS deprotection
(Scheme 9).34 Chromatographic separation was achieved at this
stage, to afford diastereomerically pure adducts 34a and 34b. The
primary alcohol functionality of 34a was subjected to tosylation
conditions to provide 35a, which, upon exposure to TBAF, un-
derwent the hoped-for alkylative dearomatization to generate
pentacyclic adduct 36a in excellent overall yield. A similar sequence
was employed for the conversion of 34b to adduct 36b (Scheme 9).
was rapidly reduced under Luche conditions,40 to provide in-
termediate 42a. The latter was then protected in the form of either
Boc or Fmoc carbamates. A similar sequence (unoptimized) served
to advance intermediate 36b, bearing the C1 methoxy group, to
compound 43b, as shown.
With the A-ring C2 and C3 stereocenters in place, the task
would now involve deprotection of the C1 MOM (43a) or Me (43b)
protecting group. Unfortunately, all efforts to achieve nucleophilic
deprotection of the methoxy functionality of 43b (and its pre-
OMOM
OMOM
OMOM
Me
TBSO
TBSO
OTBS
a
18
Me
c
O
O
18
Me
O 8
O
*
*
14
14
OTBS
OTBS
O 8
H
RO
H
H
TBSO
H
36a
34a, R = H
35a, R = Ts
b
epi-33a:33a = 1:2.3
OMe
OMe
OMe
Me
TBSO
TBSO
OTBS
a
18
Me
e
18
Me
O 8
8
O
*
*
14
14
OTBS
OTBS
O
H
RO
TBSO
H
36b
34b, R = H
35b, R = Ms
d
epi-33b:33b = 1:2.5
Scheme 9. Alkylative dearomatization. Key: (a) I2, MeOH; chromatographic separation (34a), 54% (34b), 62%; (b) TsCl, pyridine, DMAP, CH2Cl2, 95%; (c) TBAF, 70 ꢁC, 94%; (d) MsCl,
pyridine, CH2Cl2, 90%; (e) TBAF, 130 ꢁC, 95%.
2.3. Functionalization of the A ring en route to cortistatin A
cursor 40b) were unsuccessful. Accordingly, we focused our efforts
on the removal of the MOM protecting group. Extensive experi-
mentation in the context of model systems revealed surprising
complexities associated with this apparently straightforward
proposed transformation. In summary, perhaps due to the desta-
bilizing presence of the conjugated trienyl system, standard acid-
catalyzed methods for the removal of the MOM group were not
productive.
With the cortistatin core framework in place, we now turned our
attention tothe functionalization of the A-ring. Inthenaturalproduct,
the C1, C2, and C3 functionalities (OH, OH, and NMe2, respectively) all
occupy equatorial orientations, thus raising the possibility that they
might be stereoselectively installed through reduction of iminium
and ketone precursors, for instance, with sodium borohydride.35
We first explored methods for the introduction of the C3 amine
functionality. This turned out to be a surprisingly challenging task.
We sought to exploit the reactivity of the triene as a means to
achieve the hoped-for MOM deprotection. We postulated that, if an

Z. Wang et al. / Tetrahedron 67 (2011) 10249e10260
10253
OMOM
Me
OMOM
OMOM
O
Me
ŠN2
Me
b
a
OTBS
OTBS
O
O
OTBS
O
36a
O
O
O
O
O
Br
Br
Š
+
H
H
N
N
N
H2N
Me
Me
H
Br
40a
39a
38a
O
37
OMOM
OMOM
OMOM
Me
Me
Me
OTBS
OTBS
OTBS
O
HO
HO
d
e or f
c
O
O
O
H
H2N
H
H
H2N
HN
R
41a
42a
43a, R = Boc
44a, R = Fmoc
OMe
OMe
OMe
Me
Me
Me
g,h
i
j,k
OTBS
OTBS
OTBS
O
O
HO
Me2N
36b
O
O
O
H
H
H
43b
Br
Me2N
38b
40b
Scheme 10. A-ring functionalization: installation of C2 and C3 stereocenters. Key: (a) L-Selectride; then 37, 62%, 1.25:1 dr; (b) n-Bu4NN3, THF; (c) HOAc, NaBH3(CN), CH2Cl2; (d)
NaBH4, CeCl3$7H2O, 42% from 38a; (e) Boc2O, NaOH, THF/H2O (43a); (f) FmoceOSu, Na2CO3, THF/H2O (44a); (g) L-Selectride, ꢀ78 ꢁC, 80%; (h) LiHMDS, then 37, ꢀ78 ꢁC, 73%, 1:1 dr;
(i) NaN3, DMF; then NaBH(OAc)3, HOAc, (HCHO)X, 50 ꢁC, 69%; (j) NaBH(OAc)3, HOAc, CH2Cl2; (k) DIBAL-H, ꢀ78 ꢁC, <20% from 40b.
appropriate electrophile were to attack the triene at its C12 termi-
nus, then C1 might be rendered more susceptible to hydrolysis. In
fact, in model systems, mild bromine-induced removal of the MOM
enol ether could, in fact, be achieved (Scheme 11, 45/46).41 In-
(cf. 46). Based on the Hirama precedent, we were optimistic
that we could achieve C12 debromination through recourse to
radical methods.15b,c Surprisingly, however, in a model system,
exposure of compound 50 to radical reduction conditions yiel-
ded an isomeric mixture,42 of which the diene 52 was the major
product (Scheme 13). Moreover, when the reaction mixture was
subjected to prep-TLC in air, 52 was partially converted to 53.
The structural assignment of 53 was supported by 1H NMR and
LR-MS analysis. The facile formation of 53 under these condi-
tions was quite unexpected. We postulate that, considering the
ease with which 52 isomerizes to its trienol form (54) under
acidic conditions, it may well be that 54 is the reactive in-
termediate en route to 53. Similar systems are known to react
with O2 in a similar manner,43,44 and electron paramagnetic
resonance (EPR)/spin trapping studies support a stepwise radi-
cal pathway involving triplet oxygen.45 Small scale attempts to
terestingly, the u-bromodienone adducts were unstable, and under
standard work-up and purification conditions (evaporation of
EtOAc solution, silica gel), these products underwent apparently
rapid HBr elimination to generate trienones of the type 47. Though
unexpected, we postulated that these HBr elimination products
might offer a new avenue for the installation of the C1 and C2
stereocenters. We envisioned a sequence involving reduction of the
C2 ketone, trienoledienone tautomerization, and C1 ketone re-
duction to stereoselectively generate the C1 and C2 trans-diol sys-
tem. We reasoned that protonic solvents might serve to effectively
facilitate proton transfer, and Luche conditions would ensure se-
lective 1,2-reduction.
BrĞBr
Me
Br
Me
O
OMOM
O
O
O
O
Me
Me
OTBS
HO
OTBS
OH
OTBS
HO
HO
a
O
H
H
H
46
45
Br
Me
OH
Me
b
OTBS
O
OTBS
HO
O
O
H
H
47
Scheme 11. Bromine-induced MOM deprotection. Key: (a) Br2, H2O, THF, 0 ꢁC; (b) silica gel or evaporate EtOAc solution.
In the context of our target system, intermediate 43a underwent
prevent peroxidation through freeze-pump-thaw degassing
MOM deprotection followed by rapid HBr elimination to generate
adduct 48, as shown. To our surprise, however, exposure of either
intermediate 48 or its C1 TBS ether derivative to Luche conditions
gave rise to intermediate 49, incorporating an extra hydroxyl on
C12. At that time, the mechanism of this transformation was un-
clear; however, subsequent studies provided a plausible explana-
tion (vide infra).
were unsuccessful.
The mechanistic analysis advanced above might also serve to
explain the unexpected and remarkable C12 formal oxidation ob-
served in the context of the Luche reduction, described above
(Scheme 12, 48/49). According to this reasoning, compound 48
did, perhaps, indeed undergo Luche reduction at the C2 ketone, to
generate intermediate 56 (Scheme 14). Presumably, C12 perox-
idation would be more rapid than enoleketone tautomerization,
and intermediate 57 would be formed. Further reduction would
We now refocused our efforts on derivatizing the C12 bro-
minated system arising from Br2-induced MOM deprotection
OH
OMOM
O
OH
Me
OH
Me
Me
12
OTBS
OTBS
HO
HN
O
a, b
c
OTBS
HO
HN
O
O
H
H
HN
Boc
H
Boc
43a
48
Boc 49
Scheme 12. MOM deprotection and attempted Luche reduction of ring A. Key: (a) Br2, H2O, THF, 0 ꢁC; (b) evaporate in EtOAc; (c) CeCl3$7H2O, NaBH4, MeOH, 0 ꢁC.

10254
Z. Wang et al. / Tetrahedron 67 (2011) 10249e10260
Br
O
O
O
Me
Me
Me
H
OTBS
a
AcO
OTBS
OTBS
AcO
AcO
+
O
O
O
H
H
51 desired
H
52 undesired
50
51:52 = 1:1.6
prep-TLC
air
H
O
OH
O
Me
OTBS
AcO
O
53
¥Proposed mechanism of formation of 53.
¥O ĞO ¥
Me
O
O
OH
OH
O
silica
gel
Me
OTBS
OTBS
AcO
AcO
53
52
O
H
H
54
55
Scheme 13. Radical debromination: model studies. Key: (a) AIBN, n-Bu3SnH, PhH, 80e90 ꢁC.
OH
Me
O
OH
OH
O
OH
Me
Me
12
OTBS
OTBS
HO
HN
HO
HN
OTBS
HO
HN
a
O2
48
O
O
O
H
H
H
Boc 49
Boc
Boc
57
56
Scheme 14. Mechanistic rationale for formation of compound 49. Key: (a) CeCl3$7H2O, NaBH4, MeOH, air, 0 ꢁC.
Br
OMOM
O
OMOM
O
O
Me
Me
Me
Me
OTBS
OTBS
b
c
HO
OTBS
OTBS
Me
a
AcO
AcO
O
H
H
HN
Fmoc
H
H
HN
Fmoc
HN
Fmoc
43b
58
59
OAc
O
OAc
Me
OTBS
AcO
OTBS
AcO
AcO
HN
steps
d,e
O
O
O
Me
H
N
HN
Fmoc
H
Me
62, Shair intermediate
60
Fmoc
61
Scheme 15. Radical debromination and synthesis of compound 61 en route to cortistatin A. Key: (a) Ac2O, pyridine, DMAP, CH2Cl2 (70% from 42); (b) Br2, H2O, THF, 0 ꢁC; (c) AIBN, n-
Bu3SnH, C6D6, 70 ꢁC, w10% from 58; (d) CeCl3$7H2O, NaBH4, MeOH, 0 ꢁC; (e) Ac2O, pyridine, DMAP, CH2Cl2.
deliver the observed adduct, 49. It should be noted that 56 might
exist in its enolate form during the reaction.46 Enolate peroxidation
by O2 has also been suggested to proceed through a chain-reaction-
based radical pathway.47
3. Conclusion
In summary, the synthesis of a late-stage intermediate en route
to cortistatin A has been accomplished. Key transformations in-
clude a Snieckus-like cascade sequence and the development of
methods for the functionalization of the cortistatin A-ring. In this
context, our attempts to manipulate A-ring functionalities led to
surprising findings, which served to deepen our understanding of
the reactivities of the complex cortistatin core system. While even
a formal total synthesis of the natural product was not achieved, the
ability to generate serious amounts of look-alike structures (cf. inter
alia: 38, 40, 42) might well be exploitable to what is now the im-
portant problem of producing an accessible and therapeutically
useful agent based on cortistatin A.
Having realized a two-step sequence for the deprotection of
the C1 MOM functionality in a model setting, we sought to ac-
complish the transformation in the context of the cortistatin core
system. First, the C2 hydroxyl of compound 43b was acylated to
generate 58 (Scheme 15). In the event, exposure to mild bromi-
nation conditions afforded intermediate 59, which subsequently
underwent radical debromination to furnish the target compound
60, albeit in disappointingly low yield (ca. 10% from 58). In this
more complex setting, the debromination reaction was quite
sensitive, and significant levels of decomposition were observed.
Thorough degassing through repeated freeze-pump-thaw was
required. Finally, compound 60 was advanced to 61 through
Luche reduction followed by acylation of the resultant C1 hy-
droxyl. In principle, this compound could be advanced to 62,
a late-stage intermediate in the Shair synthesis, upon Fmoc re-
moval followed by reductive methylation. However, at this stage,
we no longer had adequate levels of material on hand to pursue
even a formal relay total synthesis. What was clear is that this
route, which began on a very promising note, would not lead to
cortistatin A in a useful way.
4. Experimental section
4.1. General methods
Unless mentioned otherwise, all non-aqueous reactions were
carried out in vacuum-flame-dried glassware under a balloon-
pressure of argon; commercially available reagents were used as
received; anhydrous solvents were purchased as the highest grade
from SigmaeAldrich, or passed through a solvent-purification

Z. Wang et al. / Tetrahedron 67 (2011) 10249e10260
10255
system, or purified as follows: THF was distilled from Na-
benzophenone, CH2Cl2 was distilled from CaH2. Reactions were
monitored by thin-layer chromatography on Merck silica gel 60-F254
coated 0.25 mm plates. Flash column chromatography
was performed using RediSepÒ pre-packed disposable silica gel
columns (normal phase, 230e400 mesh) from Teledyne Isco. Prep-
TLC was performed on Merck silica gel 60-F254 coated 0.50 or
1 mm plates. Yields are reported for isolated, spectroscopically pure
compounds. NMR spectra were obtained on Bruker DRX 300 or
400 MHz, or Bruker DMX 500 MHz spectrometers. CDCl3, dried by
standing over K2CO3, was used for NMR samples and chemical shifts
50 mL dichloromethane was added mCPBA (77% max., 3.79 g) at
0 ꢁC, and the solution was slowly warmed to room temperature and
stirred for 1 day. The reaction was quenched by NH4Cl (satd) so-
lution at 0 ꢁC, and after separation, the aqueous phase was re-
extracted by EtOAc three times, the combined EtOAc solution was
to added hexanes, and then washed with NaHCO3 (satd) and brine
sequentially and dried over MgSO4. The filtrate was evaporated and
the desired crude 2-bromo-6-((tert-butyldimethylsilyl)oxy)-3-
((diethylcarbamoyl)oxy)phenyl formate was directly used in the
next step.
The crude 2-bromo-6-((tert-butyldimethylsilyl)oxy)-3-((dieth-
ylcarbamoyl)oxy)phenyl formate from the last step was dissolved
in 50 mL methanol and K2CO3 (1.50 g) was added at 0 ꢁC. The re-
action mixture was warmed to room temperature and stirred for
0.5 h. The reaction was quenched by NH4Cl (satd) at 0 ꢁC, and the
aqueous phase was extracted with Et2O three times. The organic
phase was evaporated and then re-dissolved in Et2O, and hexanes
were added, then washed with NH4Cl (satd) and brine. After drying
over MgSO4, the filtrate was evaporated and the crude 30 was di-
rectly used in the next step.
were referenced on residual solvent peaks (
d
¼7.26 for 1H NMR and
77.0 for 13C NMR). Abbreviations for 1H NMR: s¼singlet, d¼doublet,
t¼triplet, q¼quartet, m¼multiplet, or br¼broad. IR spectra were
obtained on a PerkineElmer Paragon 1000 FT-IR spectrometer. High
resolution mass spectra were acquired at the Columbia University
Mass Spectral Core facility on a JEOL HX110 spectrometer. Optical
rotations were measured on a JASCO DIP-1000 spectrometer.
4.2. Synthesis of compound 29
The crude 30 was dissolved in 50 mL dichloromethane and
cooled to 0 ꢁC, then diisopropylamine (6.17 mL, 35.2 mmol) was
added, followed by MOMCl (1.34 mL, 17.6 mmol). The reaction
mixture was evaporated 1 h later and the residue was chromato-
graphed (hexanes/EtOAc¼9:1 to 7:1) to give the desired product
31a (1.17 g, 2.53 mmol, 58% yield for three steps).
In another batch, the crude phenol 30 (prepared from 1.11 g 2-
bromo-4-((tert-butyldimethylsilyl)oxy)-3-formylphenyl diethylca-
rbamate) in 10 mL of MeOH and 10 mL of PhH was added TMSCHN2
(1.94 mL, 1.5 equiv) dropwise. The reaction mixture was stirred at
room temperature for 2 h. After removal of the solvents, the residue
was purified by flash chromatography (hexane/EtOAc: 90/10) to
give 0.75 g desired product 31b in 65% yield over three operations.
To a mixture of 2-bromo-3,6-dihydroxybenzaldehyde33 (9.25 g,
42.6 mmol) and DMAP (98.6 mg, 0.81 mmol) in 35 mL pyridine was
added diethyl carbamyl chloride (5.40 mL, 44 mmol) at room
temperature. The reaction mixture was stirred at reflux for 13 h
under argon atmosphere. Then the reaction mixture was poured
into ice water and extracted with ether three times. The combined
organic phases were washed with 1 N HCl, brine and dried with
anhydrous MgSO4, and then filtrated. The residue was purified
by flash chromatography (hexane/EtOAc: 92/8) to give 6.42 g de-
sired product 29 in 48% yield (the synthesis of 2-bromo-3,6-
dihydroxybenzaldehyde from 28 was quantitative).
1H NMR (400 MHz, CDCl3):
d 11.91 (s, 1H), 10.33 (s, 1H), 7.32 (d,
J¼9.2 Hz, 1H), 6.94 (d, J¼9.2 Hz, 1H), 3.50 (q, J¼7.2 Hz, 2H), 3.38 (q,
Compound 31a: 1H NMR (400 MHz, CDCl3):
d
6.87 (d, J¼8.8 Hz,
J¼7.2 Hz, 2H), 1.30 (t, J¼7.2 Hz, 3H), 1.21 (t, J¼7.2 Hz, 3H). 13C NMR
1H), 6.79 (d, J¼8.8 Hz, 1H), 5.16 (s, 2H), 3.63 (s, 3H), 3.48 (q,
J¼7.2 Hz, 2H), 3.38 (q, J¼7.2 Hz, 2H), 1.29 (t, J¼7.2 Hz, 3H), 1.20 (t,
J¼7.2 Hz, 3H), 0.98 (s, 9H), 0.19 (s, 6H). 13C NMR (100 MHz, CDCl3):
(100 MHz, CDCl3): d 196.9,160.6,152.4,141.1,131.9,120.4,117.3,116.8,
41.9, 41.5, 13.7, 12.7. IR (NaCl, cmꢀ1): 2976, 2935, 1725, 1652, 1607,
1580, 1462, 1420, 1380, 1294, 1265, 1240, 1220, 1176, 1152. HR-MS
(FABþ) calcd for C12H15O4N79Br (Mþ1): 316.0184, found 316.0176.
d
153.3, 146.4, 146.3, 143.6, 119.4, 118.7, 113.3, 98.7, 58.2 42.3, 41.9,
25.6, 18.1, 14.2, 13.3, ꢀ4.5. IR (NaCl, cmꢀ1): 2955, 2931, 2857, 1727,
1483, 1469, 1416, 1388, 1241, 1221, 1154. HR-MS (FABþ) calcd for
C19H31O4N79BrSi (Mꢀ1): 460.1155, found 460.1161.
4.3. Synthesis of 2-bromo-4-((tert-butyldimethylsilyl)oxy)-3-
formylphenyl diethylcarbamate
Compound 31b: 1H NMR (400 MHz, CDCl3):
d
6.87 (d, J¼8.8 Hz,
1H), 6.80 (d, J¼8.8 Hz,1H), 3.82 (s, 3H), 3.49 (q, J¼6.8 Hz, 2H), 3.39 (q,
To a solution of 29 (1.37 g, 4.34 mmol) and 2,6-lutidine (1.15 mL,
13.0 mmol) in 20 mL of CH2Cl2 was added TBSOTf (1.19 mL,
5.16 mmol) slowly at 0 ꢁC. The reaction mixture was allowed to
warm to room temperature and stirred overnight. The reaction was
quenched with saturated aqueous NH4Cl at 0 ꢁC and extracted with
ether three times. The combined organic layers were washed with
1 N HCl, saturated aqueous sodium bicarbonate, water, and brine,
sequentially. The combined organic layer was dried over anhydrous
MgSO4, concentrated and then purified by flash chromatography
(hexane/EtOAc: 92/8) to give 1.88 g desired product in 97% yield.
J¼6.8 Hz, 2H),1.30 (t, J¼7.2 Hz, 3H),1.21 (t, J¼6.8 Hz, 3H),1.01 (s, 9H),
0.18 (s, 6H). 13C NMR (100 MHz, CDCl3):
d 153.2, 149.2, 146.9, 143.4,
119.5, 118.6, 112.8, 60.0, 42.2, 41.8, 25.4, 18.0, 14.0, 13.1, ꢀ4.9. HR-MS
(FABþ) calcd for C18H31O4N79BrSi (Mþ1): 432.1206, found 432.1185.
4.5. Synthesis of epi-33a
(Caution: the sealed tube must be thick and strong enough, and
a blast shield is needed) In a flame-dried sealed tube was charged
bromide 31a (37 mg, 0.080 mmol) in 1 mL Et2O, and the mixture
was cooled to ꢀ78 ꢁC. Next, t-BuLi (1.7 M in pentane, 0.160 mmol)
was added dropwise and stirring continued for 10 min. Then al-
dehyde 3215 (32.8 mg, 0.073 mmol) in 2 mL Et2O was added drop-
wise, and the stirring continued for another 10 min. The reaction
mixture was warmed to room temperature and then heated at
130 ꢁC in an oil bath for 4 h before being quenched by brine at room
temperature. The two phases were separated and the aqueous
phase was re-extracted by Et2O twice. The combined organic phase
was dried over MgSO4, and after filtration and evaporation, the
residue was chromatographed by prep-TLC (hexanes/EtOAc¼50:1)
and gave desired product epi-33a (10:1 dr at C8, 31.1 mg, 60% yield).
In a large scale reaction, 11.27 g bromide 31a and 9.98 g alde-
hyde 32 (both divided into two identical batches for the reaction
1H NMR (300 MHz, CDCl3):
d
10.32 (s, 1H), 7.22 (d, J¼9.0 Hz, 1H),
6.81 (d, J¼9.0 Hz, 1H), 3.47 (q, J¼7.2 Hz, 2H), 3.35 (q, J¼7.2 Hz, 2H),
1.27 (t, J¼7.2 Hz, 3H), 1.15 (t, J¼7.2 Hz, 3H), 0.96 (s, 9H), 0.21 (s, 6H).
13C NMR (75 MHz, CDCl3):
d 189.6, 155.7, 153.0, 143.4, 128.6, 126.2,
119.6, 118.0, 42.3, 41.9, 25.5, 18.1, 14.1, 13.1, ꢀ4.5. IR (NaCl, cmꢀ1):
2932, 2859, 1727, 1702, 1591, 1562, 1462, 1420, 1393, 1243, 1221,
1153. HR-MS (FABþ) calcd for C18H27O4N79BrSi (Mꢀ1): 428.0893,
found 428.0899.
4.4. Synthesis of compounds 31a and 31b
To a stirred solution of 2-bromo-4-((tert-butyldimethylsilyl)
oxy)-3-formylphenyl diethylcarbamate (1.89 g, 4.40 mmol) in

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Z. Wang et al. / Tetrahedron 67 (2011) 10249e10260
and then combined during work-up) gave 8.14 g (51% yield) of the
desired product epi-33a, and only 20 min was needed for heating at
130 ꢁC.
ꢀ4.8. ½a 2D1
ꢂ
þ31.43 (c 0.81, CH2Cl2). IR (NaCl, cmꢀ1): 3417, 2954,
2929, 2886, 2857, 1471, 1361, 1295, 1250, 1159, 1116, 1046, 998. HR-
MS (FABþ) calcd for C33H54O6Si2 (Mþ): 602.3459, found 602.3461.
Compound 34a: 1H NMR (400 MHz, CDCl3):
d
6.60 (d, J¼8.8 Hz,
4.6. Synthesis of 34a and epi-34a
1H), 6.55 (s, 1H), 6.46 (d, J¼8.4 Hz, 1H), 6.02 (d, J¼9.6 Hz, 1H), 5.93
(d, J¼9.2 Hz, 1H), 5.14 (d, J¼6.0 Hz, 1H), 5.07 (d, J¼6.0 Hz, 1H),
3.82e3.65 (m, 3H), 3.52 (s, 3H), 2.30 (dd, J¼13.6, 6.4 Hz, 1H),
2.27e2.18 (m, 1H), 2.11e1.91 (m, 3H), 1.90e1.78 (m, 1H), 1.73 (s, br,
1H), 1.57e1.47 (m, 1H), 1.06 (s, 3H), 0.98 (s, 9H), 0.91 (s, 9H), 0.17 (s,
3H), 0.16 (s, 3H), 0.05 (s, 3H), 0.03 (s, 3H). 13C NMR (100 MHz,
(Caution: the sealed tube must be thick and strong enough, and
a blast shield is needed) In a sealed tube was charged epi-33a
(446 mg, 0.623 mmol) in 10 mL THF, and the vessel was placed in
a 192 ꢁC oil bath and heated for 11 h. The sealed tube was cooled to
room temperature and 10 mL MeOH and I2 (14.7 mg, 0.058 mmol)
were added. 3 h later, the reaction was quenched by 10% Na2S2O3
solution until the color faded. The mixture was evaporated and
then partitioned by Et2O and brine and separated. The aqueous
phase was re-extracted by Et2O twice and the combined organic
phase was dried over MgSO4, and the filtrate was evaporated and
chromatographed, providing 34a (204.4 mg, 0.339 mmol, 54%
yield) and epi-34a (81.4 mg, 0.135 mmol, 22% yield).
CDCl3):
d 147.2, 144.0, 141.9, 137.2, 136.3, 125.4, 120.4, 118.5, 115.0,
111.2, 98.8, 79.3, 78.0, 59.4, 57.6, 50.7, 47.1, 37.5, 30.6, 25.8, 25.7, 20.6,
18.1, 18.0, 14.0, ꢀ4.5, ꢀ4.9. ½a D20
þ4.75 (c 2.04, CH2Cl2). IR (NaCl,
ꢂ
cmꢀ1): 3413, 2955, 2929, 2892, 2857, 1472, 1386, 1296, 1252, 1159,
1120. HR-MS (FABþ) calcd for C33H54O6Si2 (Mþ): 602.3459, found
602.3476.
4.8. Synthesis of epi-33b
4.7. Synthesis of epi-33a from epi-34a
(Caution: the sealed tube must be thick and strong enough, and
a blast shield is needed) To a solution of bromide 31b (72 mg,
0.166 mmol) in Et2O (3 mL) was added t-BuLi (0.215 mL,
0.366 mmol, 1.7 M in pentane) at ꢀ78 ꢁC. The reaction mixture was
epi-34a (20.4 mg, 0.034 mmol) was dissolved in 1 mL
dichloromethane, and imidazole (31.8 mg, 0.467 mmol) and TBSCl
(43.9 mg, 0.291 mmol) were added sequentially. The reaction
mixture was stirred overnight before being quenched by NH4Cl
(satd). Et2O and brine were added, and the separated aqueous
phase was re-extracted with Et2O twice. The combined organic
phase was dried over MgSO4 and filtered, and the filtrate was
evaporated and prep-TLC (hexanes/EtOAc¼10:1) gave the desired
product epi-33a (22.0 mg, 0.031 mmol, 91% yield). This product can
be used for the thermal C8 epimerization reaction.
stirred for 30 min, then
a solution of aldehyde 32 (68 mg,
0.151 mmol) in Et2O (3 mL) was added slowly. After 30 min at
ꢀ78 ꢁC, the reaction was warmed to room temperature for 1 h, then
heated at 130 ꢁC for 5 h. After cooling to 0 ꢁC, it was quenched with
aqueous saturated NH4Cl. The mixture was extracted with ether
three times and the combined organic layers were washed with
water and brine, dried over anhydrous MgSO4 and concentrated.
The residue was purified by flash chromatography (hexane/EtOAc:
98/2 to 97/3) to give 52 mg of 33b in 50% yield (10:1 dr).
epi-33a: 1H NMR (400 MHz, CDCl3):
d
6.62 (d, J¼8.8 Hz, 1H), 6.55
(s, 1H), 6.51 (d, J¼8.8 Hz, 1H), 6.25 (d, J¼9.6 Hz, 1H), 6.17 (d,
J¼9.2 Hz, 1H), 5.16 (d, J¼6.0 Hz, 1H), 5.10 (d, J¼6.0 Hz, 1H), 3.83 (t,
J¼8.4 Hz, 1H), 3.53 (s, 3H), 3.65e3.50 (m, 2H), 2.15e1.91 (m, 4H),
1.86e1.78 (m, 1H), 1.75e1.67 (m, 1H), 1.61e1.51 (m, 1H), 1.00 (s, 9H),
0.903 (s, 9H), 0.896 (s, 3H), 0.83 (s, 9H), 0.18 (s, 3H), 0.17 (s, 3H), 0.07
(s, 3H), 0.05 (s, 3H), ꢀ0.05 (s, 3H), ꢀ0.07 (s, 3H). 13C NMR (100 MHz,
1H NMR (400 MHz, CDCl3):
d
6.61 (d, J¼8.4 Hz, 1H), 6.49 (d,
J¼9.2 Hz, 1H), 6.47 (s, 1H), 6.24 (d, J¼9.2 Hz, 1H), 6.17 (d, J¼9.2 Hz,
1H), 3.83 (t, J¼8.4 Hz,1H), 3.80 (s, 3H), 3.53e3.62 (m, 2H),1.92e2.12
(m, 4H), 1.78e1.85 (m, 1H), 1.67e1.71 (m, 1H), 1.54e1.59 (m, 1H),
1.01 (s, 9H), 0.90 (s, 9H), 0.89 (s, 3H), 0.82 (s, 9H), 0.17 (s, 3H), 0.16 (s,
3H), 0.07 (s, 3H), 0.05 (s, 3H), ꢀ0.06 (s, 3H), ꢀ0.08 (s, 3H). 13C NMR
CDCl3):
d
147.0, 144.1, 141.5, 139.1, 134.7, 126.7, 120.2, 119.5, 114.4,
(100 MHz, CDCl3): d 147.0, 146.9, 142.1, 139.1, 134.9, 126.7, 120.5,
111.9, 98.8, 76.8, 76.8, 59.1, 57.6, 47.8, 46.3, 39.5, 30.7, 25.8, 25.8,19.2,
118.9, 113.9, 111.7, one overlaps with CDCl3, 76.9, 60.8, 59.2, 48.0,
46.4, 39.8, 30.7, 25.84, 25.76, 19.3, 18.2, 18.1, 12.8, ꢀ4.3, ꢀ4.58,
ꢀ4.63, ꢀ4.8, ꢀ5.37, ꢀ5.43. HR-MS (FABþ) calcd for C38H66O5Si3:
686.4218, found 686.4204.
18.2, 18.0, 12.8, ꢀ4.4, ꢀ4.4, ꢀ4.5, ꢀ4.8. ½a D20
þ41.44 (c 0.93, CH2Cl2).
ꢂ
IR (NaCl, cmꢀ1): 2955, 2929, 2893, 2857,1570,1471,1387,1251,1176,
1162, 1094, 1000. HR-MS (FABþ) calcd for C39H68O6Si3 (Mþ):
716.4324, found 716.4312.
Compound 33a: 1H NMR (400 MHz, CDCl3):
d
6.60 (d, J¼8.4 Hz,
4.9. Synthesis of 34b and epi-34b
1H), 6.53 (s, 1H), 6.46 (d, J¼8.8 Hz, 1H), 6.01 (d, J¼9.6 Hz, 1H), 5.92
(d, J¼9.6 Hz, 1H), 5.13 (d, J¼6.0 Hz, 1H), 5.10 (d, J¼6.0 Hz, 1H),
3.82e3.63 (m, 3H), 3.52 (s, 3H), 2.25 (dd, J¼13.2, 6.4 Hz, 1H),
2.21e1.87 (m, 4H), 1.85e1.72 (m, 1H), 1.55e1.45 (m, 1H), 1.07 (s, 3H),
0.98 (s, 9H), 0.91 (s, 9H), 0.80 (s, 9H), 0.16 (s, 3H), 0.15 (s, 3H), 0.05 (s,
3H), 0.03 (s, 3H), ꢀ0.08 (s, 3H), ꢀ0.10 (s, 3H). 13C NMR (100 MHz,
(Caution: the sealed tube must be thick and strong enough, and
a blast shield is needed). The solution of epi-33b (420 mg,
0.611 mmol) in 20 mL THF in a sealed tube was heated at 198 ꢁC for
36 h. After the reaction mixture was cooled to room temperature,
20 mL of MeOH and 7.8 mg of I2 (0.05 equiv, 0.031 mmol) were
added. After 8 h at room temperature, the reaction was quenched
with saturated aqueous NaHCO3 and 20% aqueous Na2S2O3. The
mixture was extracted twice with ether. The combined organic
layer was washed with saturated aqueous NaHCO3, 20% aqueous
Na2S2O3, water and brine, dried over MgSO4. Concentration and
flash column chromatography (hexane/EtOAc: 96/4) gave 34b
(215 mg) in 62% yield as well as epi-34b (87 mg) in 25% yield.
CDCl3):
d 147.4, 144.0, 141.7, 137.0, 136.5, 125.4, 120.3, 118.6, 115.0,
111.4, 98.9, 78.8, 78.0, 59.4, 57.7, 50.6, 47.1, 38.4, 30.6, 25.9, 25.8,
25.8, 20.9, 18.3, 18.2, 18.1, 14.0, ꢀ4.4, ꢀ4.5, ꢀ4.5, ꢀ4.9, ꢀ5.3, ꢀ5.3.
½
a 1D9
ꢂ
ꢀ1.19 (c 2.20, CH2Cl2). IR (NaCl, cmꢀ1): 2953, 2928, 2887, 2857,
1571, 1471, 1384, 1295, 1252, 1161, 1121, 1088. HR-MS (FABþ) calcd
for C39H68O6Si3 (Mþ): 716.4324, found 716.4319.
epi-34a: 1H NMR (400 MHz, CDCl3):
d
6.63 (d, J¼8.8 Hz,1H), 6.58
(s, 1H), 6.51 (d, J¼8.8 Hz, 1H), 6.24 (d, J¼9.6 Hz, 1H), 6.19 (d,
J¼9.2 Hz, 1H), 5.16 (d, J¼6.0 Hz, 1H), 5.09 (d, J¼6.0 Hz, 1H), 3.86 (t,
J¼8.4 Hz, 1H), 3.75e3.66 (m, 1H), 3.64e3.57 (m, 1H), 3.53 (s, 3H),
2.21e2.01 (m, 3H), 1.91 (dd, J¼12.4, 7.2 Hz, 1H), 1.78e1.53 (m, 4H),
1.00 (s, 9H), 0.91 (s, 3H), 0.90 (s, 9H), 0.19 (s, 3H), 0.18 (s, 3H), 0.08 (s,
Compound 34b: 1H NMR (400 MHz, CDCl3):
d
6.60 (d, J¼8.4 Hz,
1H), 6.46 (s, 1H), 6.45 (d, J¼8.8 Hz, 1H), 6.02 (d, J¼10.0 Hz, 1H), 5.94
(d, J¼9.2 Hz, 1H), 3.76 (s, 3H), 3.71e3.81 (m, 3H), 2.10e2.33 (m, 2H),
1.78e2.09 (m, 4H), 1.48e1.56 (m, 1H), 1.07 (s, 3H), 1.01 (s, 9H), 0.92
(s, 9H), 0.18 (s, 3H), 0.16 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H). 13C NMR
3H), 0.06 (s, 3H). 13C NMR (100 MHz, CDCl3):
d
146.5, 144.1, 141.8,
(100 MHz, CDCl3): d 147.1, 146.8, 142.6, 137.1, 136.5, 125.3, 120.6,
139.4, 134.6, 126.4, 120.4, 119.4, 114.6, 111.8, 98.8, 77.1, 76.7, 59.3,
57.6, 48.3, 46.6, 39.6, 30.7, 25.8, 25.7, 19.6, 18.1, 18.0, 12.8, ꢀ4.3, ꢀ4.4,
117.8, 114.5, 111.1, 79.3, 78.0, 60.8, 59.4, 50.7, 47.1, 37.5, 30.6, 25.8,
25.7, 20.7, 18.2, 18.0, 14.0, ꢀ4.5, ꢀ4.6, ꢀ4.7, ꢀ4.9. HR-MS (FABþ)

Z. Wang et al. / Tetrahedron 67 (2011) 10249e10260
10257
calcd for C32H52O5Si2: 572.3353, found: compound is not stable
under various mass conditions.
3H). 13C NMR (100 MHz, CDCl3):
d
181.8, 150.5, 147.1, 144.2, 142.4,
140.7, 129.1, 125.5, 115.5, 97.7, 85.2, 77.3, 77.1, 57.5, 47.5, 46.1, 37.7,
30.3, 29.4, 25.8, 19.2, 18.0, 15.0, ꢀ4.4, ꢀ4.9. ½a D20
þ109 (c 2.20,
ꢂ
4.10. Synthesis of 35a
CH2Cl2). IR (NaCl, cmꢀ1): 2954, 2928, 2896, 2855, 1659, 1633, 1583,
1149, 1119, 1018. HR-MS (FABþ) calcd for C27H39O5Si (Mþ1):
471.2567, found 471.2576.
To a stirred solution of 34a (338.4 mg, 0.56 mmol) in 2 mL
dichloromethane
was
added
pyridine
(0.20 mL),
4-
dimethylaminopyridine (10.5 mg), and p-toluenesulfonyl chloride
(300.2 mg, 1.57 mmol). The reaction mixture was stirred overnight
before being quenched by NH4Cl (satd), then Et2O and brine were
added, and the separated aqueous phase was re-extracted with
Et2O twice. The combined organic phase was dried over MgSO4 and
filtered, and the filtrate was evaporated and flash column chro-
matography (hexanes/EtOAc¼1:0 to 9:1) gave the desired product
35a (403.8 mg, 0.533 mmol, 95% yield).
4.13. Synthesis of 36b
To a solution of mesylate 35b (300.8 mg, 0.462 mmol) in 18 mL
THF was added TBAF (1.0 M in THF, 508 mL, 0.508 mmol). The re-
action mixture was stirred for 15 min at room temperature, and
then heated to 130 ꢁC for 1 h (oil bath). After it was cooled to room
temperature, it was quenched with aqueous saturated NH4Cl. The
mixture was extracted with EtOAc three times. The combined or-
ganic layer was washed with water and brine, dried over MgSO4,
filtered, and concentrated. The residue was purified by flash col-
umn chromatography (hexane/EtOAc: 90/10) to give the desired
product 36b (194 mg, 95%).
1H NMR (400 MHz, CDCl3):
d
7.65 (d, J¼8.4 Hz, 2H), 7.27 (d,
J¼8.4 Hz, 2H), 6.56 (d, J¼8.4 Hz, 1H), 6.53 (s, 1H), 6.32 (d, J¼8.8 Hz,
1H), 5.98 (d, J¼9.6 Hz, 1H), 5.90 (d, J¼9.6 Hz, 1H), 5.11 (d, J¼6.0 Hz,
1H), 5.06 (d, J¼6.0 Hz, 1H), 4.20e4.11 (m, 1H), 4.11e4.03 (m, 1H),
3.72 (t, J¼8.0 Hz, 1H), 3.50 (s, 3H), 2.43 (s, 3H), 2.28e2.10 (m, 3H),
2.05e1.94 (m, 1H), 1.91e1.82 (m, 1H), 1.68e1.55 (m, 1H), 1.52e1.41
(m, 1H), 1.00 (s, 9H), 0.94 (s, 3H), 0.91 (s, 9H), 0.19 (s, 3H), 0.17 (s,
1H NMR (400 MHz, CDCl3):
d
6.83 (d, J¼10.0 Hz, 1H), 6.45 (s, 1H),
6.22 (d, J¼9.6 Hz, 1H), 6.19 (d, J¼10.0 Hz, 1H), 6.03 (d, J¼9.6 Hz, 1H),
3.83 (t, J¼8.4 Hz, 1H), 3.78 (s, 3H), 1.94e2.27 (m, 5H), 1.84e1.89 (s,
1H), 1.67e1.74 (m, 2H), 1.52e1.58 (m, 1H), 0.93 (s, 3H), 0.89 (s, 9H),
3H), 0.04 (s, 3H), 0.03 (s, 3H). 13C NMR (100 MHz, CDCl3):
d 146.7,
0.05 (s, 3H), 0.03 (s, 3H). 13C NMR (100 MHz, CDCl3):
d 181.8, 150.2,
144.4, 144.0, 142.1, 137.0, 135.2, 132.9, 129.7, 127.8, 125.2, 120.6,
118.4, 115.5, 111.2, 98.7, 77.8, 77.7, 67.0, 57.6, 50.2, 46.9, 34.1, 30.4,
146.9, 143.7, 143.4, 142.2, 129.2, 125.4, 115.3, 85.1, 77.15, 77.09, 60.6,
47.4, 46.1, 37.6, 30.3, 29.4, 25.7, 19.1, 17.9, 14.9, ꢀ4.5, ꢀ4.9. FT-IR
(NaCl, cmꢀ1): 2955, 2858, 1775, 1731, 1659, 1631, 1582, 1462, 1441,
25.7, 25.7, 21.5, 20.5, 18.1, 18.0, 13.8, ꢀ4.5, ꢀ4.9. ½a D19
þ24.37 (c 2.39,
ꢂ
CH2Cl2). IR (NaCl, cmꢀ1): 2954, 2929, 2887, 2857, 1472, 1386, 1363,
1252, 1178, 1124. HR-MS (FABþ) calcd for C40H60O8Si2S (Mþ):
756.3547, found 756.3535.
1399. ½a 1D9
ꢂ
ꢀ126.47 (c 0.45, CHCl3). HR-MS (FABþ) calcd for
C26H37O4Si: 441.2461; found 441.2471.
4.11. Synthesis of 35b
4.14. Synthesis of 38a
To a solution of 34b (215 mg, 0.376 mmol) and pyridine (304
mL,
To a stirred solution of 36a (51 mg, 0.11 mmol) in 2 mL THF was
added L-Selectride (1.0 M, 0.12 mL) at ꢀ78 ꢁC. 20 min later, 5,5-
dibromo-Meldrum’s acid 37 (39.5 mg, 0.13 mmol) was added in
one portion. 0.5 h later, the reaction was quenched by adding NH4Cl
(satd), then EtOAc and brine were added, and the separated
aqueous phase was re-extracted with EtOAc twice. The combined
organic phase was dried over MgSO4 and filtered, and the filtrate
was evaporated and flash column chromatography (hexanes/
EtOAc¼9:1) gave the desired product 38a (38 mg, 0.069 mmol, 62%
yield). It is recommended that the product be used in the next step
as soon as possible.
3.76 mmol) in 15 mL CH2Cl2 was added MsCl (146 L, 1.88 mmol)
m
slowly at 0 ꢁC. The reaction mixture was allowed to warm to room
temperature and stirred for 24 h before it was quenched with
aqueous saturated NH4Cl. The mixture was extracted with ether
and washed with 1 N HCl, water and brine, dried over MgSO4, fil-
tered, and concentrated. The residue was purified by flash chro-
matography (hexane/EtOAc: 92/8) to give the desired product
(220 mg, 90%).
1H NMR (400 MHz, CDCl3):
d
6.63 (d, J¼8.8 Hz, 1H), 6.50 (s, 1H),
6.48 (d, J¼8.4 Hz, 1H), 6.03 (d, J¼9.6 Hz, 1H), 5.95 (d, J¼9.2 Hz, 1H),
4.35e4.41 (m, 1H), 4.23e4.29 (m, 1H), 3.79 (s, 3H), 3.76 (t, J¼8.4 Hz,
1H), 2.83 (s, 3H), 2.27e2.38 (m, 3H), 1.94e2.06 (m, 2H), 1.69e1.75
(m, 1H), 1.49e1.56 (m, 1H), 1.07 (s, 3H), 1.00 (s, 9H), 0.91 (s, 9H), 0.17
(s, 3H), 0.16 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H). 13C NMR (100 MHz,
Selected characterization of 38a: 1H NMR (400 MHz, CDCl3) key
peaks:
d 6.46 (s, 1H, a-Br-38a), 6.41 (s, 1H, e-Br-38a), 4.80 (dd,
J¼14.0, 5.2 Hz, 1H, e-Br-38a), 4.68 (dd, J¼4.8, 2.0 Hz, 1H, a-Br-38a).
HR-MS (FABþ) calcd for C27H40O759BrSi (Mþ1): 551.1828, found
551.1854.
CDCl3):
d 147.0, 146.7, 142.8, 137.2, 135.5, 125.2, 120.9, 117.7, 115.0,
111.2, 77.9, 77.8, 66.3, 60.9, 50.3, 47.0, 37.2, 34.4, 30.5, 25.8, 25.7,
20.8, 18.2, 18.0, 14.0, ꢀ4.5, ꢀ4.6, ꢀ4.7, ꢀ4.9. FT-IR (NaCl, cmꢀ1):
2955, 2926, 2858, 1475, 1361, 1254. HR-MS (FABþ) calcd for
C33H54O7Si2S: 650.3129, found 650.3131.
4.15. Synthesis of 3,4-dihydro-36b
To a cooled (ꢀ78 ꢁC) solution of 36b (37.1 mg, 84.2
mmol;
4.12. Synthesis of 36a
azeotroped twice with benzene) in THF (4 mL) was added L-
Selectride (1.0 M in THF, 92 mL, 92 mmol) dropwise. The clear, yellow
To a vial with 2 mL THF solution of 35a (46.6 mg, 0.062 mmol)
was added TBAF (1.0 M in THF, 0.065 mL). After stirring for 5 min,
the reaction mixture was heated at 70 ꢁC for 30 min. The vial was
cooled to room temperature and all the volatiles were evaporated.
Flash column chromatography (hexanes/EtOAc¼9:1) gave the de-
sired product 36a (27.3 mg) in 94% yield.
solution was stirred for 22 min at ꢀ78 ꢁC, then quenched by suc-
cessive addition of MeOH (0.10 mL), NaOH (1.0 M in H2O, 0.50 mL),
and H2O2 (30 wt % in H2O, 80 mL). The mixture was allowed to
warm to room temperature with vigorous stirring. The resulting
clear, dull yellow solution was then diluted with EtOAc (12 mL)
and brine (6 mL). The layers were separated, and the aqueous phase
was extracted with EtOAc (3ꢃ6 mL). The combined organic layers
were dried (MgSO4), filtered, and concentrated to give a cloudy
yellow oil. Purification by flash chromatography (10% EtOAc/hex-
anes) afforded the desired trienone product 3,4-dihydro-36b as
1H NMR (400 MHz, CDCl3):
d
6.86 (d, J¼10.0 Hz, 1H), 6.53 (s, 1H),
6.25 (d, J¼9.6 Hz, 1H), 6.22 (d, J¼10.0 Hz, 1H), 6.05 (d, J¼9.6 Hz, 1H),
5.15 (d, J¼6.0 Hz, 1H), 5.10 (d, J¼6.0 Hz, 1H), 3.85 (t, J¼8.4 Hz, 1H),
3.51 (s, 3H), 2.31e1.96 (m, 5H), 1.93e1.86 (m, 1H), 1.80e1.65 (m,
2H), 1.60e1.50 (m, 1H), 0.95 (s, 3H), 0.91 (s, 9H), 0.06 (s, 3H), 0.04 (s,
a clear, yellow oil in 80% yield (30.0 mg, 67.8 mmol).

10258
Z. Wang et al. / Tetrahedron 67 (2011) 10249e10260
1H NMR (400 MHz, CDCl3):
d
6.38 (s, 1H), 6.25 (d, J¼9.4 Hz, 1H),
addition of solid NaCl and extracted with Et2O (3ꢃ14 mL). The
combined organic layers were dried (Na2SO4), filtered, and con-
centrated to give a clear, yellow-orange oil. Purification by flash
chromatography (8% EtOAc/hexanes with 1% Et3N) afforded 40b as
6.04 (d, J¼9.4 Hz, 1H), 3.83 (t, J¼8.2 Hz, 1H), 3.71 (s, 3H), 2.67e2.58
(m, 1H), 2.52 (td, J¼14.3, 4.4 Hz, 1H), 2.43 (td, J¼14.3, 4.8 Hz, 1H),
2.24e2.11 (m, 3H), 2.10e1.99 (m, 3H), 1.96e1.87 (m, 1H), 1.79e1.63
(m, 2H), 1.59e1.48 (m, 1H), 0.93 (s, 3H), 0.90 (s, 9H), 0.06 (s, 3H),
a clear, yellow-orange oil in 69% yield (11.7 mg, 24.2
mmol).
0.04 (s, 3H). 13C NMR (100 MHz, CDCl3):
d
193.2, 152.4, 145.7, 143.2,
1H NMR (400 MHz, CDCl3):
d
6.44 (s, 1H), 6.23 (d, J¼9.3 Hz, 1H),
142.7, 125.4, 115.4, 82.4, 79.2, 77.2, 60.6, 47.4, 46.2, 36.4, 35.1, 33.2,
6.05 (d, J¼9.5 Hz, 1H), 5.79 (s, 1H), 3.84 (dd, J¼8.5, 7.8 Hz, 1H), 3.78
(s, 3H), 2.72 (s, 6H), 2.28 (dd, J¼12.3, 7.4 Hz, 1H), 2.24e1.93 (m, 4H),
1.93e1.66 (m, 3H), 1.63e1.48 (m, 1H), 0.95 (s, 3H), 0.91 (s, 9H), 0.07
31.5, 30.3, 25.8, 19.3, 18.0, 14.6, ꢀ4.4, ꢀ4.9. ½a D19
ꢀ70.28 (c 0.88,
ꢂ
CHCl3). IR (NaCl, cmꢀ1): 2955, 2887, 2857, 1672, 1585, 1464, 1440,
1367, 1121. HR-MS (FABþ) calcd for C26H39O4Si (Mþ1): 443.2613,
found 443.2602.
(s, 3H), 0.05 (s, 3H). 13C NMR (100 MHz, CDCl3):
d 179.6, 150.4, 147.0,
143.8, 142.5, 142.0, 125.5, 122.1, 115.2, 84.6, 77.1, 76.4, 60.6, 47.4,
46.3, 42.0, 38.3, 30.4, 29.4, 25.8, 19.2, 18.0, 15.0, ꢀ4.4, ꢀ4.9. ½a D20
ꢂ
4.16. Synthesis of 3-bromo-3,4-dihydro-36b (38b)
ꢀ148.3 (c 0.515, CH2Cl2). IR (NaCl, cmꢀ1): 2953, 2857, 2360, 2342,
1650, 1588, 1471, 1462, 1439, 1375, 1322, 1283, 1258, 1215, 1157,
1120, 1098, 1051, 1014, 968, 904, 887, 868, 837, 799, 776. HR-MS
(FABþ) calcd for C28H42O4NSi (Mþ1): 484.2883, found 484.2893.
To a cooled (ꢀ78 ꢁC) solution of trienone 3,4-dihydro-36b
(35.8 mg, 80.9 mmol; azeotroped twice with benzene) in THF
(1.5 mL) was added LiHMDS (1.0 M in THF, 89 mL, 89 mmol) quickly
down the side of the flask. The resulting clear, bright yellow solu-
4.18. Synthesis of 3,4-dihydro-40b
tion was stirred at ꢀ78 ꢁC for 20 min. A clear, colorless solution of
37 (1.0 M in THF, 100
mL, 100
mmol; freshly prepared) was then
To a clear, yellow solution of 40b (2.9 mg, 6.0
(0.30 mL) was added sodium triacetoxyborohydride (9.2 mg,
43 mol) and glacial acetic acid (3 L, 52 mol). After 36 h, the re-
mmol) in CH2Cl2
added quickly down the side of the flask. After stirring at ꢀ78 ꢁC for
50 min (TLC indicated some starting material remained; some di-
bromination is also generally observed), the reaction was
quenched with Na2S2O3 (10% in H2O, 10 mL) and allowed to warm
to room temperature with vigorous stirring. The mixture was then
extracted with Et2O (3ꢃ10 mL). The combined organic layers were
dried (MgSO4), filtered, and concentrated to give a yellow solid.
Purification by flash chromatography (5% EtOAc/hexanes) afforded
m
m
m
action was quenched by carefully adding it to another flask con-
taining NaOH (1.0 M in H2O, 3 mL). The aqueous phase was
saturated by the addition of solid NaCl, then the layers were sep-
arated, and the aqueous phase was extracted with EtOAc (3ꢃ3 mL).
The combined organic layers were dried (MgSO4), filtered, and
concentrated to give a clear, golden yellow oil. The amine product
has a tendency to undergo spontaneous oxidation back to the en-
amine (and decompose by other pathways), and thus the crude
amine (3,4-dihydro-40b) was generally carried directly into the
next step without further purification.
38b as a yellow foam in 73% yield (30.7 mg, 58.9
mmol, 1:1 mixture
of diastereomers).
1H NMR (500 MHz, CDCl3, peaks for both diastereomers):
d
6.39
(s, 1H), 6.35 (s, 1H), 6.30 (d, J¼9.3 Hz, 1H), 6.29 (d, J¼9.3 Hz, 1H),
6.04 (d, J¼9.5 Hz,1H), 6.04 (d, J¼9.4 Hz,1H), 4.77 (dd, J¼14.1, 5.0 Hz,
1H), 4.66 (dd, J¼4.7, 2.2 Hz, 1H), 3.84 (t, J¼8.2 Hz, 1H), 3.83 (t,
J¼8.2 Hz, 1H), 3.74 (s, 3H), 3.74 (s, 3H), 2.96 (dd, J¼15.0, 4.8 Hz, 1H),
2.91 (dd, J¼14.0, 12.3 Hz, 1H), 2.66 (dd, J¼12.2, 5.0 Hz, 1H), 2.48 (dd,
J¼15.0, 2.0 Hz, 1H), 2.48e2.36 (m, 2H), 2.22e2.09 (m, 6H),
2.09e1.99 (m, 2H), 1.97e1.89 (m, 2H), 1.74e1.64 (m, 4H), 1.60e1.49
(m, 2H), 0.94 (s, 3H), 0.93 (s, 3H), 0.90 (s, 18H), 0.06 (s, 6H), 0.04 (s,
6H). 13C NMR (75 MHz, CDCl3, peaks for both diastereomers):
4.19. Synthesis of 43b
To a cooled (ꢀ78 ꢁC) solution of the crude aminoketone (3,4-
dihydro-40b, from the previous step) in THF (0.40 mL) was added
DIBAL-H (1.0 M in toluene, 10 mL, 10 mmol). The clear, yellow solu-
tion was stirred at ꢀ78 ꢁC for 30 min, then a second portion of
DIBAL-H (1.0 M in toluene, 10 mL, 10 mmol) was added. After a total
d
186.2, 186.1, 153.2, 153.1, 146.2, 145.8, 143.6, 143.5, 141.7, 141.5,
reaction time of 50 min, the reaction was quenched at ꢀ78 ꢁC by
125.4, 125.3, 115.1, 115.0, 82.6, 81.5, 78.3, 77.6, 77.1, 60.7, 60.2, 48.4,
47.6, 47.5, 46.0, 45.9, 45.2, 44.8, 40.9, 38.2, 36.6, 31.4, 31.2, 30.3, 25.8,
the addition of EtOAc (50 mL). Saturated aqueous Rochelle salt
(2 mL) was then added, and the mixture was stirred vigorously for
ca. 1.5 h while allowing to warm to room temperature, resulting in
a biphasic mixture with a clear, yellow layer on top, and a clear,
colorless layer below. The aqueous phase was extracted with EtOAc
(3ꢃ3 mL), then the combined organic layers were dried (MgSO4),
filtered, and concentrated to give a clear, orange-yellow oil. Puri-
fication by flash chromatography (5e20% MeOH/CH2Cl2) afforded
43b as a minor product in <20% yield from 40b and moderate
purity (ca. 0.5 mg).
19.2, 18.0, 14.6, ꢀ4.4, ꢀ4.9. ½a D21
ꢀ16.6 (c 0.91, CH2Cl2). IR (NaCl,
ꢂ
cmꢀ1): 2954, 2930, 2884, 2856, 1671, 1580, 1471, 1462, 1439, 1367,
1312,1302,1283,1258,1213,1193,1169,1120,1093,1046,1031,1013,
952, 903, 874, 860, 837, 776, 740. HR-MS (FABþ) calcd for
C26H38O749BrSi (Mþ1): 521.1723, found 521.1714.
4.17. Synthesis of 40b
To a clear, pale yellow solution of 38b (18.2 mg, 34.9
azeotroped twice with benzene) in DMF (0.70 mL) was added so-
dium azide (3.4 mg, 52.3 mol). The resulting mixture was stirred
at room temperature for 1 h, then a second portion of sodium azide
(3.4 mg, 52.3 mol) was added. A reddish brown color was ob-
mmol;
Selected characterization of 43b: 1H NMR (500 MHz, CDCl3) key
peaks:
d
6.21 (s, 1H), 5.97 (d, J¼9.4 Hz, 1H), 5.93 (d, J¼9.4 Hz, 1H),
m
4.39 (d, J¼8.5 Hz, 1H), 3.79 (t, J¼8.2 Hz, 1H), 3.74 (s, 3H), 2.82e2.74
(m, 1H), 2.37 (s, 6H). HR-MS (FABþ) calcd for C28H46O4NSi (Mþ1):
488.3196, found 488.3181.
m
served over time. After a total reaction time of 5 h, TLC analysis
indicated consumption of starting material. To this mixture was
added paraformaldehyde (11.0 mg, 0.366 mmol, based on mono-
mer), sodium triacetoxyborohydride (37.1 mg, 0.175 mmol), and
4.20. Synthesis of 42a
To a stirred solution of 38a (111.9 mg, 0.203 mmol) in 5 mL THF
was added tetrabutylammonium azide (103.0 mg, 0.363 mmol) in
one portion, and 50 min later, the solvent was evaporated and the
crude mixture of 40a was covered by argon and directly used in the
next step.
glacial acetic acid (2 mL, 34.9mmol). The cloudy, orange-brown
suspension was then heated in a 50 ꢁC oil bath. Additional por-
tions of paraformaldehyde were added at 2 h (11.0 mg, 0.366 mmol)
and 5 h (5.6 mg, 0.186 mmol). After a total reaction time of 6 h, the
reaction was quenched at room temperature by dropwise addition
NaOH (1.0 M in H2O, 7 mL). The aqueous phase was saturated by the
The crude mixture of 40a was re-dissolved in dichloromethane
and NaBH3(CN) (36 mg) was added, followed by adding HOAc

Z. Wang et al. / Tetrahedron 67 (2011) 10249e10260
10259
(0.40 mL) dropwise. 5 min later, 138 mg NaBH3(CN) was added in
three portions, and the reaction mixture was stirred for 10 min
before being quenched by adding NaHCO3 (satd) slowly. The two
phases were separated and the aqueous phase was re-extracted by
dichloromethane, and the combined dichloromethane solution was
evaporated and immediately used in the next step. The product 41a
is not very stable to air, and rapid operation is recommended.
To a stirred solution of 41a in 10 mL methanol was added
a methanol solution (10 mL) of CeCl3$7H2O (0.18 g), and stirring
continued for 2 min at 0 ꢁC. NaBH4 (0.20 gþ0.24 gþ0.21 g) was
added in three portions with an interval of 15 min, and the total
reaction lasted for 1 h. Methanol was evaporated and Et2O, brine
and NH3$H2O (28%) were added, and the organic phase was sepa-
rated and the aqueous phase was re-extracted with Et2O twice. The
combined organic phase was dried over Na2SO4, and prep-TLC
(dichloromethane/methanol¼5:1, with a few drops of NH3$H2O)
gave the desired product 42a (41.4 mg, 0.085 mmol, 42% yield
from 38a).
1H), 4.76 (d, J¼6.0 Hz, 1H), 3.80 (t, J¼8.0 Hz, 1H), 3.43 (s, 3H),
2.43e2.34 (m, 1H), 2.09 (s, 3H), 2.26e1.46 (m, 12H), 0.90 (s, 3H),
0.90 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H). 13C NMR (100 MHz, CDCl3):
d
170.6, 145.8, 142.3, 138.4, 130.1, 125.6, 115.0, 97.2, 82.2, 79.1, 77.6,
68.8, 56.9, 47.1, 46.5, 38.6, 33.1, 32.3, 30.6, 26.5, 25.8, 21.2, 19.3, 18.0,
14.4, ꢀ4.4, ꢀ4.9. ½a D17
ꢂ
þ35.1 (c 1.36, CH2Cl2). IR (NaCl, cmꢀ1): 2954,
2926, 2856, 1739, 1636, 1472, 1369, 1246, 1157, 1120, 1102, 1050,
1013, 951, 895, 867, 837, 775. HR-MS (FABþ) calcd for C29H44O6Si
(Mþ): 516.2907, found 516.2934.
4.23. Synthesis of 58
To a stirred solution of 43a (41.4 mg, 0.085 mmol) in 3 mL di-
oxane was added 0.50 mL 10% aqueous Na2CO3, and then a solution
of 125.0 mg FmoceOSu in 2 mL dioxane was added. 2 h later, the
reaction mixture was evaporated and the residue was taken up by
Et2O, brine and NH4Cl (satd), and separated. The aqueous phase was
re-extracted by Et2O twice, and the combined organic phase was
dried over Na2SO4, and then evaporated. The crude mixture of 44a
was directly used in the next step.
The mixture of 44a was dissolved in 20 mL dichloromethane,
and 4-dimethylaminopyridine (48.0 mg) was added, followed by
pyridine (0.40 mL). Acetic anhydride (0.25 mL) was then added
dropwise. 10 min later, all volatiles were evaporated and the resi-
due was purified by flash column chromatography (hexanes/
EtOAc¼4:1) to give the desired product 58 (44.5 mg, 0.059 mmol)
in 70% yield for two steps.
Compound 42a: 1H NMR (400 MHz, CDCl3):
d 6.13 (s, 1H), 6.00
(d, J¼9.2 Hz, 1H), 5.92 (d, J¼9.6 Hz, 1H), 4.98 (d, J¼6.4 Hz, 1H), 4.89
(d, J¼6.4 Hz, 1H), 4.06 (d, J¼8.0 Hz, 1H), 3.79 (t, J¼8.0 Hz, 1H), 3.52
(s, 3H), 3.01 (m, 1H), 2.21e1.45 (m, 11H), 0.90 (s, 12H, C18 methyl
and tert-butyl), 0.05 (s, 3H), 0.03 (s, 3H). 13C NMR (100 MHz, CDCl3):
d
145.2, 144.5, 138.0, 126.1, 125.6, 114.9, 96.6, 82.1, 78.6, 77.5, 73.7,
56.8, 52.6, 47.0, 46.4, 41.4, 39.4, 33.3, 30.6, 25.7, 19.2, 18.0, 14.3, ꢀ4.5,
ꢀ5.0. ½a 1D9
ꢂ
þ2.18 (c 1.51, CH2Cl2). IR (NaCl, cmꢀ1): 3351, 3287, 2954,
2931, 2886, 2858, 1639, 1470, 1386, 1360, 1303, 1254, 1155, 1119,
1009. HR-MS (FABþ) calcd for C27H44O5NSi (Mþ1): 490.2989, found
490.3006.
Compound 58: 1H NMR (500 MHz, CDCl3):
d
7.76 (d, J¼7.5 Hz,
2H), 7.58 (d, J¼7.0 Hz, 2H), 7.40 (t, J¼7.5 Hz, 2H), 7.32 (d, J¼7.5 Hz,
2H), 6.16 (s, 1H), 6.05 (d, J¼9.0 Hz, 1H), 5.94 (d, J¼9.5 Hz, 1H), 5.68
(d, J¼8.5 Hz, 1H), 5.17 (d, J¼7.5 Hz, 1H), 4.86 (d, J¼6.0 Hz, 1H), 4.77
(d, J¼6.0 Hz, 1H), 4.40e4.28 (m, 2H), 4.22 (t, J¼7.5 Hz, 1H),
4.06e4.00 (m, 1H), 3.80 (t, J¼8.0 Hz, 1H), 3.43 (s, 3H), 2.28e1.48 (m,
14H), 0.91 (s, 3H), 0.90 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H). 13C NMR
4.21. Synthesis of 45
To a stirred solution of 36a (27.3 mg, 0.057 mmol) in 1 mL THF
was added 0.063 mL L-Selectride (1.0 M in THF) at ꢀ78 ꢁC. 5 min
later, 0.10 mL H2O was added and the whole reaction mixture was
warmed to 0 ꢁC. Next, 2 mL MeOH was added, followed by
CeCl3$7H2O (36.3 mg) and then NaBH4 (15.3 mg). 5 min later,
aqueous NH4Cl solution (satd) was added, followed by Et2O and
brine. After separation, the aqueous layer was re-extracted by Et2O
twice. The combined organic layer was dried over Na2SO4, and after
evaporation of the solvents, prep-TLC (hexanes/EtOAc¼2:1) gave
the desired product 45 (18.0 mg, 65% yield from 36a).
(125 MHz, CDCl3):
d 171.6, 155.8, 146.3, 143.8, 141.2, 140.0, 139.0,
130.0, 127.7, 127.0, 125.4, 125.1, 119.9, 114.5, 97.5, 82.4, 77.9, 77.5,
71.7, 66.9, 57.0, 51.2, 47.2, 47.1, 46.4, 39.4, 38.5, 33.0, 30.5, 25.8, 21.1,
19.2, 18.0, 14.3, ꢀ4.4, ꢀ4.9. ½a D18
þ65.27 (c 2.95, CH2Cl2). IR (NaCl,
ꢂ
cmꢀ1): 3314, 2955, 2930, 2886, 2857, 1736, 1694, 1641, 1549, 1450,
1375, 1297, 1260, 1233, 1159, 1119, 1016. HR-MS (FABþ) calcd for
C44H55O8NSi (Mþ): 753.3697, found 753.3690.
1H NMR (400 MHz, CDCl3):
d
6.14 (s, 1H), 5.99 (d, J¼9.6 Hz, 1H),
4.24. Synthesis of 61
5.92 (d, J¼9.6 Hz, 1H), 4.95 (d, J¼6.4 Hz, 1H), 4.89 (d, J¼6.4 Hz, 1H),
4.44 (t, J¼8.0 Hz, 1H), 3.79 (t, J¼8.0 Hz, 1H), 3.52 (s, 3H), 3.18 (s, 1H),
2.34e2.26 (m, 1H), 2.22e2.08 (m, 2H), 2.08e1.84 (m, 5H), 1.84e1.76
(m, 1H), 1.74e1.58 (m, 3H), 1.57e1.46 (m, 1H), 0.89 (s, 12H), 0.04 (s,
To a solution of 58 (43.8 mg, 0.058 mmol) in 2 mL THF was
added 0.5 mL water, and the reaction mixture was cooled to 0 ꢁC.
Then 0.10 mL solution of Br2 in THF (made by adding 0.033 mL Br2
into 1.0 mL THF) was added dropwise, and the whole reaction
mixture was stirred for 2 min before quenching by 10% aqueous
solution of Na2S2O3. Et2O and brine were added, and the two layers
were separated. The organic layer was re-extracted by Et2O twice.
The combined organic phase was dried over MgSO4, and after fil-
tration, the solvent was evaporated. The crude mixture 59 (about
49.1 mg) was directly used in the next step. This procedure was
used for other bromine-induced MOM deprotection reactions.
The crude mixture of 59 was evenly divided into three batches.
In each batch, 16.4 mg crude 59 was dissolved in 0.8 mL C6D6 in a J-
Young NMR tube, and then a C6D6 solution of AIBN (2 mg in 0.20 mL
C6D6) was added. The whole mixture was degassed twice (freeze-
pump-thaw) and refilled with Ar. Then 0.030 mL n-Bu3SnH was
added, and the reaction mixture was further degassed four times
before being immersed in a 70 ꢁC oil bath. The reaction was care-
fully monitored by 1H NMR, and 4 h later, the reaction mixture was
cooled and combined. After evaporating all the volatiles, prep-TLC
(hexanes/EtOAc¼3:2) gave 11.5 mg crude product 60, which was
used directly in the next step.
3H), 0.02 (s, 3H). 13C NMR (100 MHz, CDCl3):
d 147.1, 145.5, 138.1,
125.6, 115.0, 97.1, 82.1, 79.5, 77.6, 66.2, 56.8, 47.1, 46.6, 39.0, 33.3,
32.4, 30.6, 28.8, 25.8, 19.3, 18.0, 14.4, ꢀ4.4, ꢀ4.9. ½a D20
ꢀ5.14 (c 2.92,
ꢂ
CH2Cl2). IR (NaCl, cmꢀ1): 3424, 2954, 2886, 2859, 1637, 1462, 1388,
1361, 1256, 1156, 1120, 1100, 1006, 956, 869, 837, 776. HR-MS (FABþ)
calcd for C27H42O5Si (Mþ): 474.2802, found 474.2812.
4.22. Acetylation of 45
Compound 45 (15.7 mg, 0.033 mmol) was dissolved in 1 mL
CH2Cl2. 0.05 mL pyridine and 5.3 mg DMAP were added, followed
by 0.03 mL Ac2O. The reaction was quenched 20 min later by adding
MeOH, and aqueous NaHCO3 (satd) was added 2 min later. The
aqueous mixture was extracted with Et2O three times, and the
combined organic layer was dried over MgSO4. After evaporation of
the solvents, prep-TLC (hexanes/EtOAc¼3:1) gave the desired
product (13.6 mg, 0.026 mmol) in 79% yield.
1H NMR (400 MHz, CDCl3):
5.93 (d, J¼9.6 Hz, 1H), 5.66 (dd, J¼8.8, 7.2 Hz, 1H), 4.87 (d, J¼6.4 Hz,
d
6.20 (s, 1H), 6.01 (d, J¼9.6 Hz, 1H),

10260
Z. Wang et al. / Tetrahedron 67 (2011) 10249e10260
Watanabe, Y.; Tanabe, D.; Setiawan, A.; Arai, M.; Kobayashi, M. Tetrahedron Lett.
Intermediate 60 was dissolved in 1 mL dichloromethane/MeOH
2007, 48, 4485e4488 Unless otherwise stated, all numberings are based on the
numbering system of cortistatin A.
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(1:1) solution, and the reaction mixture was cooled to 0 ꢁC.
CeCl3$7H2O (7.6 mg) was added, and NaBH4 (5.2 mg) was added to
this stirred mixture 2 min later. The reaction was quenched by
NH4Cl (satd) after 5 min, and brine and dichloromethane were
added. The separated aqueous layer was re-extracted with
dichloromethane twice, and the combined organic phase was dried
over MgSO4. After filtration, the solvent was evaporated and prep-
TLC gave 4.4 mg crude reduction product, which was directly used
in the next step.
The Luche reduction product was dissolved in 1 mL dichloro-
methane, and 5.5 mg DMAP and 0.040 mL pyridine were added,
followed by dropwise addition of 0.030 mL Ac2O. MeOH was added
10 min later and after 2 min, all volatiles were evaporated and
prep-TLC (hexanes/EtOAc¼3:2) gave the desired product 61
(2.9 mg, 7% from 58).
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Compound 61: 1H NMR (400 MHz, CDCl3):
d
7.76 (d, J¼7.2 Hz,
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2H), 7.56 (t, J¼6.8 Hz, 2H), 7.40 (t, J¼7.2 Hz, 2H), 7.31 (d, J¼7.6 Hz,
2H), 5.81 (s, 1H), 5.61 (d, J¼9.2 Hz, 1H), 5.44 (m, 1H), 5.17 (d,
J¼8.4 Hz, 1H), 4.92 (t, J¼8.8 Hz, 1H), 4.34 (m, 2H), 4.20 (t, J¼7.2 Hz,
1H), 3.93 (m, 1H), 3.77 (t, J¼8.4 Hz, 1H), 2.15 (s, 3H), 2.02 (s, 3H),
2.36dca. 1.20 (m, 13H), 0.89 (s, 9H), 0.74 (s, 3H), 0.04 (s, 6H). IR
(NaCl, cmꢀ1): 2954, 2928, 2857, 1741, 1540, 1450, 1376, 1278, 1246,
1143, 1106, 1021. HR-MS (FABþ) calcd for C44H56O8NSi (Mþ1):
754.3775, found 754.3773.
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Acknowledgements
This work is generously supported by National Institute of
Health (HL 25848). Z.W. thanks Eli Lilly for a helpful graduate fel-
lowship (2008e2009), M.D. thanks Bristol-Myers Squibb, Guthi-
konda family, and Roche for financial support. P.K.P. thanks Amgen
for financial support (2009–2010) and the American Cancer Society
for a postdoctoral fellowship (PF-11-014-01-CDD; 2011–present).
We thank John Hartung Jr., Feng Peng, and Dr. Ping Wang for helpful
discussions, and Ms. Rebecca Wilson for preparation of this
manuscript.
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Supplementary data
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.10.026.
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