The Pauson-Khand reaction as a new entry to the synthesis of bridged bicyclic heterocycles: application to the enantioselective total?synthesis of (-)-alstonerine

Article abstract of DOI:10.1016/j.tet.2008.02.066

The first application of the Pauson-Khand reaction (PKR) to the synthesis of azabridged bicyclic structures is described. Compounds containing azabicyclo[3.3.1]nonane and azabicyclo[3.2.1]octane rings fused to cyclopentenones were efficiently constructed

Full text of DOI:10.1016/j.tet.2008.02.066

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 6884e6900
www.elsevier.com/locate/tet
The PausoneKhand reaction as a new entry to the synthesis
of bridged bicyclic heterocycles: application to the enantioselective
total synthesis of (ꢀ)-alstonerine
*
Kenneth A. Miller, Charles S. Shanahan, Stephen F. Martin
Department of Chemistry and Biochemistry, The University of Texas at Austin, 1 University Station A5300, Austin, TX 78712-0165, United States
Received 23 October 2007; received in revised form 14 February 2008; accepted 21 February 2008
Available online 26 February 2008
Abstract
The first application of the PausoneKhand reaction (PKR) to the synthesis of azabridged bicyclic structures is described. Compounds
containing azabicyclo[3.3.1]nonane and azabicyclo[3.2.1]octane rings fused to cyclopentenones were efficiently constructed via the PKR of
cis-2,6-disubstituted N-acyl piperidine enyne substrates, many of which can be readily prepared from 4-methoxypyridine in a few steps. More-
over, the PKR of cis-2,6-disubstituted piperazine enynes allowed the preparation of diazabicyclo[3.3.1]nonanes fused to cyclopentenones. This
new strategy for the synthesis of azabridged bicyclic frameworks was exploited as a key step in a concise, enantioselective total synthesis of the
macroline alkaloid (ꢀ)-alstonerine.
Ó 2008 Elsevier Ltd. All rights reserved.
O
1. Introduction
H
Me–N
The macroline/sarpagine alkaloids comprise a diverse class
of biologically active natural products characterized by an aza-
bicyclo[3.3.1]nonane annelated to an indole ring.1 A variety of
methods have been devised to access this structural motif, and
these include a sequential PicteteSpengler reaction and Die-
ckmann condensation,2 ring-closing metathesis,3 phosphine-
catalyzed [4þ2] annulation/FriedeleCrafts cyclization,4 and
aza DielseAlder/intramolecular Heck reaction.5 As a represen-
tative member of the macroline family of alkaloids, alstoner-
ine (1) has been the subject of a number of synthetic studies
culminating in two total syntheses and one formal synthesis.4,6
In addition to its challenging structural features, 1 has been
reported to exhibit cytotoxic activity against two human lung
cancer cell lines.7
O
H
N
Me
1
families.8 While developing new transition metal-catalyzed cas-
cade reaction sequences,9 we became interested in examining
possible applications of the PausoneKhand reaction (PKR) to-
ward alkaloid synthesis. The intramolecular version of the PKR
has been applied to the syntheses of a few alkaloid natural prod-
ucts,10 but in each case its use has been limited to the preparation
of bicyclo[3.3.0]octenones and bicyclo[3.3.0]nonenones.11
As is apparent from the retrosynthetic strategy outlined in
Scheme 1, we expected to obtain 1 by reduction, elimination,
and acylation of the lactone 2, which we envisioned would
arise by BaeyereVilliger oxidation and stereoselective reduc-
tion of the enone 3. A key step in the synthesis of 1 would then
be the PKR of the enyne 4, which had been previously
prepared in our group,3 to give 3. We anticipated that the
PKR approach would represent a particularly efficient strategy
for the preparation of 1, because the PKR of 4 would result in
Within the context of an ongoing interest in the synthesis of
complex, biologically active alkaloids, we have been interested
in designing novel and general strategies for the facile prepara-
tion of the representative members of different alkaloid
* Corresponding author. Tel.: þ1 512 471 3915; fax: þ1 512 471 4180.
E-mail address: sfmartin@mail.utexas.edu (S.F. Martin).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.066

K.A. Miller et al. / Tetrahedron 64 (2008) 6884e6900
6885
the formation of three new carbonecarbon bonds and the
assembly of two rings in a single step. Notably, the enone 3
contains all of the carbons present in the core of 1.
yield and diastereoselectivity. Similarly, reaction of 6 with a
vinyl cuprate followed by removal of the silyl group provided
the enyne 8 with excellent diastereoselectivity.
Alternatively, treatment of 4-methoxypyridine (5) with the
zinc reagent derived from 1-trimethylsilyl propargyl bromide
in the presence of CbzeCl gave enone 9 in 77% yield (Scheme
3). Sequential reaction of 9 with a vinyl cuprate followed by
treatment with TBAF gave the enyne 11 with excellent
diastereoselectivity.
Baeyer-Villager
O
H
O
H
O
Acylation
Me–N
CbzN
O
H
H
N
Me
N
Me
R
TMS
1
2
PKR
Cbz
N
Cbz
N
O
MgBr
CuCN, MeLi, (1:1:1)
Br
N
TMS
THF, –78 °C
96% (17:1 dr)
CbzN
NCbz
Zn, HgCl2, THF;
Cbz-Cl, 10% HCl
77%
H
OMe
O
O
N
N
10: R = TMS
11: R = H
TBAF
THF
89%
H
H
9
5
3
4
Scheme 1.
Scheme 3.
2. Results and discussion
With a series of the requisite cis-2,6-disubstituted piperi-
dines 7, 8, and 11 in hand, the PKR of 7 was investigated
utilizing Co2(CO)8 and a number of common promoters,
2.1. Model studies
15
including NMO,13 BuSMe,14 and 4 A molecular sieves.
˚
Inasmuch as the pivotal PKR to form azabridged bicyclic
frameworks lacked precedent, we undertook the synthesis of
a number of cis-2,6-disubstituted piperidine enynes that
differed in the number of carbons separating the alkene and
alkyne moieties from the acylated nitrogen atom. We sought
to use these enynes as substrates for PKRs to assemble azabi-
cyclo[3.3.1]nonanes and azabicyclo[3.2.1]octanes. We rea-
soned that a number of such enynes could be easily prepared
from 4-methoxypyridine (5) via slight modification of chemis-
try we had previously developed that was inspired by the work
of Comins and coworkers.3,12 Accordingly, 4-methoxypyri-
dine (5) was treated with the acetylide ion derived from
TMSeacetylene in the presence of CbzeCl, and following
an acidic workup, the enone 6 was isolated in 95% yield
(Scheme 2). Compound 6 underwent facile conjugate addition
of allyltributylstannane in the presence of TBSeOTf as
a Lewis acid, and treating the intermediate adduct thus ob-
tained in situ with TBAF furnished the enyne 7 in excellent
The conditions that were found to be the most efficient in-
volved reacting 7 with Co2(CO)8 to give an intermediate
cobalt-complex that was then treated with 6 equiv of DMSO
and warmed to 65 ꢁC. Using this protocol, the enone 14 was
isolated in 89% yield as a single diastereomer (Table 1, entry
1). During the course of optimizing this reaction, we discov-
ered that handling and storage of Co2(CO)8 under argon
gave the best results. We briefly examined several catalytic
variants employing either cobalt or rhodium catalysts, but
these conditions failed to provide isolable quantities of the
enone 14,16 and starting enyne 7 was typically recovered.
With the optimized PKR conditions in hand, the enyne 11
was then cyclized to provide 15, again as a single diastereomer
(entry 2). On the other hand, the PKR of enyne 8 gave the
more strained enone 16 as a mixture (3:1) of diastereomers
(entry 3).
Each of the PKR substrates thus far prepared contained
a carbonyl group at C(4) of the piperidine ring, and it was
of interest to determine the effect of having an sp3 carbon
atom at this position. Toward this end, the enyne 7 was treated
with L-Selectride to deliver the alcohol 17, which was
protected as the corresponding TBS-ether 18 (Scheme 4).
We were also interested in enyne substrates lacking func-
tionality at C(4) such as 23. However, preliminary attempts
to deoxygenate either 7 or 17 under a number of standard
conditions to give 23 were unavailing. We therefore developed
a different strategy for preparing 23 that was based upon pre-
vious work in our group.3 In the event, alkylation of the known
sulphone 19 with the acetylide derived from TMSeacetylene
gave the lactam 20, which was N-acylated to provide
21 (Scheme 5). Reduction of the more electrophilic amide
carbonyl group in 21 with DIBALeH gave an intermediate
Cbz
N
SnBu3
TBS-OTf, CH2Cl2
then TBAF
96% (>19:1 dr)
EtMgBr
TMS
Cbz
N
TMS
O
N
THF
7
then Cbz-Cl
10% HCl
95%
MgBr
1)
OMe
O
Cbz
N
CuCN, MeLi (1:1:1)
THF, –78 °C
64% (>19:1 dr)
5
6
2) TBAF, THF
53%
O
8
Scheme 2.

6886
K.A. Miller et al. / Tetrahedron 64 (2008) 6884e6900
Table 1
PausoneKhand reactions of piperidones
TMS
n-BuLi
TMS
H
H
N
O
N
SO2Ph
O
n-BuLi
R
N
n
then Cbz-Cl
THF
THF
71%
n
m
Co2(CO)8 [1.2 eq]
then DMSO [6 eq]
81%
O
NR
O
19
20
THF, 65 °C
m
O
12
Cbz
N
TMS
Cbz
N
R
13
1) DIBAL-H
THF
O
Entry
Substrate
Product
Yield (%)
2) Allyl-TMS
BF3•OEt2
O
21
22: R = TMS
23: R = H
57% (>19:1 dr)
TBAF
THF
86%
H
Cbz
N
N
Scheme 5.
Cbz
1
89
O
7
O
14
and alkylation with allyl bromide provided the known allyl pi-
perazines 26 and 27 (Scheme 6).18 A second directed lithiation
of 26 and 27 followed by formylation of the intermediate carb-
anions with DMF provided a mixture of aldehyde epimers that
underwent equilibration on silica gel to provide solely the cis-
products 28 and 29. Subsequent treatment of aldehydes 28 and
29 with the BestmanneOhira reagent in methanol containing
K2CO3 gave the piperazine enynes 30 and 31.
O
H
Cbz
N
N
Cbz
2
91
O
11
O
15
Boc
N
O
Boc
N
1) s-BuLi, TMEDA,
Et2O, –78 °C
1) s-BuLi, TMEDA,
Cbz
N
Et2O, –78 °C
•
H
2)
3)
then DMF
SiO2, NEt3
CuCN 2LiCl
allyl bromide
N
R
N
R
N
Cbz
2)
3
33 (3:1 dr)
O
8
24: R = Me
25: R = Bn
26: R = Me; 83%
27: R = Bn; 84%
O
16
O
O
P
Boc
N
O
H
Boc
N
OEt
OEt
N,O-acetal that was treated sequentially with allyltrimethylsi-
lane TMS in the presence BF3$Et2O and fluoride ion to furnish
the desired enyne 23.
N2
N
R
N
R
K2CO3, MeOH
28: R = Me; 78%
29: R = Bn; 81%
30: R = Me; 80%
31: R = Bn; 76%
Bicyclic derivatives of piperazine are commonly found in
compounds having useful biological activities, so we were
intrigued by the possibility of preparing cyclopentenone rings
fused to diazabicyclo[3.3.1]nonanes via a PKR. In order to
probe the feasibility of such processes we prepared the piper-
azine derivatives 30 and 31 using chemistry inspired by Beak
and coworkers.17 Accordingly, directed lithiation of the Boc-
protected piperazines 24 and 25 followed by transmetalation
Scheme 6.
We discovered that the substitution at C(4) in 18, 23, 30,
and 31 played a role in the diastereoselectivity of the PKR
(Table 2). For example, the PKR of the silyl ether 18 gave
34 as a single diastereomer (entry 1), whereas 23, which bears
a methylene group at C(4) underwent a PKR to give a mixture
(4:1) of diastereomers favoring 35 as the major product (entry
2). The piperazines 30 and 31 underwent clean PKRs to give
the enones 36 and 37 as single diastereomers (entry 3).
Cbz
N
Cbz
N
L-selectride
4
THF, –78 °C
99%
O
OH
17
7
2.2. Total synthesis of (ꢀ)-alstonerine (1)
Cbz
N
TBS-Cl,
imidazole
As outlined in Scheme 1, our plan for the total synthesis of
(ꢀ)-alstonerine (1) hinged upon the PKR of the enyne 4 to
give the azabridged bicyclic cyclopentenone 3. The precedent
established in the PKRs of the model substrates described in
the previous section strongly suggested that this retrosynthetic
plan was sound. The known enyne 4 was first prepared in four
DMF
81%
OTBS
18
Scheme 4.

K.A. Miller et al. / Tetrahedron 64 (2008) 6884e6900
6887
Table 2
PausoneKhand reactions of piperidines
bridging nitrogen atom, a stereochemical relationship that is
identical to that found in (ꢀ)-alstonerine (1).
R'
N
With the pentacyclic intermediate 3 readily in hand, the
next stage of the synthesis required the ring expansion and
oxidation of the cyclopentenone ring to give a d-lactone ring
as found in 2. We had originally envisioned that such a trans-
formation might be induced via a BaeyereVilliger reaction.
Perhaps not unexpectedly in retrospect, initial experiments
directed toward conducting a BaeyereVilliger reaction on 3
gave complicated reaction mixtures. Reasoning competing
oxidation of the indole ring in 3 might be a source of difficulty,
we also examined the BaeyereVilliger oxidation of 38 to
ascertain whether we might access the unsaturated lactone
41. While the putative oxidation of the indole ring was thus
thwarted, the BaeyereVilliger reaction of 38 was accompa-
nied by unavoidable double bond oxidation to give the epoxy
lactone 39 (Scheme 8), a side reaction we knew was well
precedented.19 As a final attempt, we treated 38 with basic
hydrogen peroxide, a reagent that has been reported to induce
BaeyereVilliger reactions of strained ketones,20 but this reac-
tion afforded only the epoxide 40.
n
n
m
Co2(CO)8 [1.2 eq]
then DMSO [6 eq]
R
X
NR'
O
THF, 65 °C
X
m
R
32
33
Entry
Substrate
Product
Yield (%)
O
H
Cbz
N
N
Cbz
1
69
OTBS
18
OTBS
34
O
H
Cbz
N
N
Cbz
2
74 (4:1 dr)
23
35
O
O
R¼Me; 85
R¼Bn; 81
O
Boc
N
O
H
Cbz-N
a or b
H
N
N
R
N
3
O
Boc
39
Boc
N
30: R = Me
31: R = Bn
Cbz-N
O
O
R
H
36: R = Me
37: R = Bn
N
Cbz-N
Boc
38
c
H
N
Boc
40
steps from L-tryptophan following a procedure previously
developed in our group.3 The PKR of 4 proceeded smoothly
to give the cyclopentenone 3 in excellent yield as a single dia-
stereomer (Scheme 7). At this juncture, it was necessary to
establish the relative stereochemistry of the newly established
stereocenter on the cyclopentenone ring, but 3 was not crystal-
line. However, protection of the indole nitrogen atom with
a Boc group gave 38, which was a crystalline compound.
The X-ray structure of 38 showed that the hydrogen atom on
the newly formed stereocenter was oriented trans to the
O
O
Cbz-N
H
N
Boc
41
(a) MCPBA, CH2Cl2, 60%. (b) CF3CO3H, Na2HPO4, CH2Cl2, 99%.
(c) H2O2, NaOH, THF/MeOH, 78%
Scheme 8.
Since we were unable to obtain the unsaturated lactone 41
by a BaeyereVilliger reaction of 38, it was necessary to devise
an alternate plan for the synthesis of (ꢀ)-alstonerine (1); this is
outlined in retrosynthetic format in Scheme 9. Namely, we
envisioned that the saturated lactone 42 would arise from
reduction of the aldehyde 43 followed by lactonization. The
aldehyde 43 would in turn be prepared by the oxidative cleav-
age of the silyl enol ether 44, which in turn would be obtained
from either 3 or preferably 38 by stereoselective hydrosilyla-
tion of the enone moiety.
O
Co2(CO)8 [1.2 eq]
N-Cbz
Cbz-N
then DMSO [6 eq]
H
THF, 65 °C
92%
N
H
N
H
3
4
O
Cbz-N
Boc2O, DMAP
H
CH3CN
99%
In order to minimize any interference from the electron rich
indole ring, we initiated our studies with the protected indole 38.
After some experimentation, we discovered that hydrosilylation
of 38 was most efficiently induced by treating 38 with 0.5%
N
Boc
38
Scheme 7.

6888
K.A. Miller et al. / Tetrahedron 64 (2008) 6884e6900
O
osmate ester using H2S furnished a mixture of epimeric a-
H
H
CHO
CO2R
O
hydroxy ketones 48 (Scheme 11). This mixture of a-hydroxy
ketones was treated with Pb(OAc)4 in the presence of
MeOH to give an aldehyde/ester intermediate that was reduced
in situ to deliver the hydroxy ester 49. Lactonization of 49
under acidic conditions then gave the lactone 50, which is
a protected derivative of 2.
Cbz-N
Cbz-N
H
H
N
R
N
R
42
43
OSiR3
O
H
HO
H
OTIPS
H
O
Cbz-N
Cbz-N
H
H
Cbz-N
Cbz-N
H
OsO4, THF
H
N
R
N
R
N
then H2S
74 %
N
Boc
44
3: R = H
38: R = Boc
Boc
45
48
Scheme 9.
OH
CO2Me
Pb(OAc)4
benzene, MeOH
Cbz-N
pTsOH
CH2Cl2
99%
platinum divinyltetramethyl disiloxane complex (Karstedt’s
catalyst) in the presence of 5 equiv of i-Pr3SiH at elevated tem-
perature to give 45 in excellent yield (Scheme 10).21 Less bulky
silanes such as TESeH and TBSeH led to the formation of sig-
nificant amounts of the ketone 46 (20e30%), which could have
arisen via two different pathways. Silane dimerization would
form molecular hydrogen that could then reduce the enone in
the presence of the platinum catalyst to give 46.22
Alternatively, hydrolysis of the less stable TES- and TBS-enol
ethers 44 (R3¼Et3 or t-BuMe2) would also produce 46. The
stereochemistry of the hydrosilylation of 38 was determined
by converting the silyl enol ether 45 into the crystalline amino
alcohol 47 in four steps [(a) TBAF, THF; (b) NaBH4, THF;
then NaBH4
72 %
N
Boc
49
O
H
O
Cbz-N
H
N
Boc
50
Scheme 11.
Although we had developed an efficient route to access the
lactone 50, the use of stoichiometric amounts of osmium and
lead reagents inspired us to pursue an oxidative cleavage strat-
egy that was more environmentally benign. The application
of JohnsoneLemieux conditions to the oxidative cleavage of
silyl enol ethers is rare.23 Consequently, we were gratified to
find that reaction of 45 with a catalytic amount of OsO4
(10%) in the presence of NaIO4 gave the intermediate alde-
hyde/ester 51 that underwent facile lactonization upon sequen-
tial treatment with NaBH4 and acid to give 50 (Scheme 12).
Having thus developed an improved route to the intermedi-
ate lactone 50, it was necessary to convert the d-lactone into
a dihydropyran. Toward this objective, 50 was reduced with
DIBALeH to afford an intermediate lactol that was converted
to the dihydropyran 52 by a one step process involving O-
mesylation and elimination (Scheme 13). Compound 52 was
O
OTIPS
H
Me2 Me2
Si Si
Pt
2
Cbz-N
Cbz-N
H
O
H
i-Pr3SiH, Toluene
80 °C, 93%
N
N
Boc
Boc
45
38
O
H
OH
H
Cbz-N
HN
H
H
N
N
H
Boc
47
46
Scheme 10.
(c) silica gel, 100 ꢁC; (d) H2, Pd/C, EtOAc] in about 50% overall
yield. Inasmuch as the X-ray analysis of 47 confirmed that the
relative stereochemistry of 47 was identical to that found in 1,
we could further advance our efforts toward the synthesis of 1.
Because ozonolysis of 45 under several different conditions
gave complex mixtures, we turned to a two-step procedure to
induce oxidative cleavage of the silyl enol ether moiety in 45.
Rubbottom oxidation of 45 using MCPBA or DMDO under
a number of conditions was found to be problematic. Simi-
larly, oxidation of 45 using various protocols involving
catalytic quantities of OsO4 led to low conversions. However,
treatment of 45 with stoichiometric amounts of OsO4 led to
complete consumption of 45, and reduction of the intermediate
OTIPS
CHO
H
CO2Me
OsO4 (10 mol%)
Cbz-N
Cbz-N
NaIO4
H
THF/H2O (5:1)
N
N
Boc
Boc
45
51
O
H
O
NaBH4, MeOH;
then TsOH
55 %, 2 steps
Cbz-N
H
N
Boc
50
Scheme 12.

K.A. Miller et al. / Tetrahedron 64 (2008) 6884e6900
6889
O
O
H
H
O
O
H
H
O
1)
2)
DIBAL-H
Cbz-N
Cbz-N
Cbz-N
Cbz-N
Cl3CCOCl
toluene, –78 °C
H
H
O
H
H
Cl3C
pyridine, 65 °C
MsCl, Et3N,
THF
N
N
N
N
Boc
Boc
Boc
Boc
55
50
52
52
60%
O
O
H
O
H
H
NaH
Cbz-N
Me-N
Me-N
TMS-I
CH3CN
78 %
Zn, AcOH
75% (2 steps)
LiAlH4
THF, reflux
99%
then MeI
O
H
H
H
DMF
88%
N
N
H
N
Me
Boc
53
54
56
Scheme 13.
O
H
O
H
HN
H
Me-N
then transformed into the N,N0-dimethyl derivative 54 by
reduction of the Cbz group to a methyl group and removal
of the Boc group with LiAlH4 followed by methylation of
the indole nitrogen atom of the 53 thus formed.
MeI, THF
then NaH, MeI
72%
O
O
H
N
H
N
Me
57
1
The final phase of the synthesis of (ꢀ)-alstonerine (1)
required acetylation of the dihydropyran ring of 54. We there-
fore examined a number of FriedeleCrafts reaction conditions
that had previously been employed to acetylate dihydropyran
rings.24 However, treatment of 54 with acetylating agents
such as AcCl and Ac2O in the presence of different Lewis
acids (AlCl3, BF3$OEt2, FeCl3, ZnCl2) led to mixtures of
products (Scheme 14). Competitive acylation at C(5) of the
indole ring system was observed as a predominant side reac-
tion, and only small quantities of 1 were obtained. In previous
work directed toward the syntheses of heteroyohimboid
alkaloids,25 we had discovered that dihydropyrans could be
readily trichloroacetylated using trichloroacetyl chloride under
less forcing conditions and in the absence of Lewis acid
catalysts. If 54 could be converted into 55, reduction of the
trichloroacetyl group would afford 1. However, treatment of
54 with trichloroacetyl chloride at room temperature led to
rapid formation of an intractable mixture of unidentifiable
products.
Scheme 15.
generally useful as a method for the synthesis of C(2)-acylated
glycals, a functional motif found widely in biologically active
natural products.26
Removal of both of the carbamate protecting groups from 56
proceeded cleanly upon treatment with TMSeI to give 57,
which was N,N0-dimethylated 57 by sequential reaction with
MeI to methylate the bridging secondary amine followed by
NaH and MeI to alkylate the indole nitrogen atom, thereby
completing the enantioselective synthesis of (ꢀ)-alstonerine
(1). The spectral data (1H and 13C NMR) for the synthetic 1
thus obtained were consistent with those previously reported,6b
and the optical rotation was comparable to the value reported in
the literature.6a
3. Conclusion
This result did not occasion great surprise as we had previ-
ously found that those reactions of pentacyclic indolic dihy-
dropyrans having free amines and/or unprotected indoles
could be problematic.25 Although several attempts to acetylate
the protected substrate 52 with AcCl in the presence of Lewis
acids were unsuccessful, we discovered that trichloroacetyl-
ation of 52 was readily accomplished to give 55 (Scheme
15). Reduction of the trichloroacetyl group using Zn/HOAc
gave the protected (ꢀ)-alstonerine 56 in good yield over the
two steps. This sequence of reactions should prove to be
In summary, we have developed the first application of the
PausoneKhand reaction to prepare azabridged bicyclic com-
pounds. A number of cis-2,6-disubstituted piperidine and piper-
azine enynes were efficiently prepared, and these enynes
underwent PKR to give cyclopentenone rings fused to aza-
and diazabicyclo[3.n.1]alkanes (n¼2, 3), typically in high
yields and high diastereoselectivities. The utility of this new en-
try to bridged nitrogen heterocycles was highlighted by its ap-
plication to the concise, enantioselective total synthesis of the
macroline indole alkaloid (ꢀ)-alstonerine (1). The total synthe-
sis of 1 required only 15 chemical steps from L-tryptophan and
proceeded in a 4.4% overall yield. Other key steps in the synthe-
sis entailed a conjugate hydrosilylation of the cyclopentenone
and an oxidative cleavage that led to an intermediate d-lactone.
Moreover, a novel, mild two-step protocol to acetylate cyclic
enol ethers such as dihydropyrans to give vinylogous esters,
a common structural subunit in many natural products, was de-
veloped. Further applications of PKR reactions to the syntheses
of other biologically active alkaloid natural products are in
progress and will be reported in due course.
O
H
O
H
acylation
or
trichloroacylation
X
Me-N
Me-N
H
O
H
N
R
N
Me
Me
54
1: R = Me
55: R = CCl3
Scheme 14.

6890
K.A. Miller et al. / Tetrahedron 64 (2008) 6884e6900
4. Experimental
4.1. General
1188, 845 cmꢀ1
[C18H22NO3Si (MþH) requires 328.1369], 328 (base), 312, 284.
;
mass spectrum (CI) m/z 328.1373
4.3. 2-Allyl-6-ethynyl-4-oxopiperidine-1-carboxylic acid
benzyl ester (7)
Solvents and reagents were reagent grade and used without
purification unless otherwise noted. Dichloromethane (CH2Cl2)
and triethylamine (Et3N) were distilled from calcium hydride
and stored under nitrogen. After opening, Co2(CO)8 was handled
and stored under argon. Tetrahydrofuran (THF) and diethyl ether
(Et2O) were passed through a column of neutral alumina and
stored under argon. Methanol (MeOH) and dimethylformamide
(DMF) were passed though a column of molecular sieves and
stored under argon. Toluene was passed through a column of
Q5 reactant and stored under argon. All reactions were per-
formed in flame-dried glassware under nitrogen or argon. 1H nu-
clear magnetic resonance (NMR) spectra were obtained at 500 or
400 MHz. Chemical shifts are reported in parts per million (ppm,
d) and referenced to the solvent. Coupling constants are reported
in hertz (Hz). Spectral splitting patterns are designated as: s, sin-
glet; d, doublet; t, triplet; m, multiplet; p, pentuplet; app, appar-
ent; comp, complex; br, broad; and br s, broad singlet. Infrared
(IR) spectra were obtained using a PerkineElmer FTIR 1600
spectrophotometer on sodium chloride plates and reported as
wavenumbers (cmꢀ1). Low-resolution chemical ionization
mass spectra were obtained on a Finnigan TSQ-70 instrument,
and high-resolution measurements were obtained on a VG Ana-
lytical ZAB2-E instrument. Analytical thin layer chromatogra-
phy was preformed using Merck 250 micron 60F-254 silica
plates. The plates werevisualized with UV light, p-anisaldehyde,
and potassium permanganate. Flash column chromatography
was performed according to Still’s method using ICN Silitech
32-63 D 60A silica gel.27
TBSeOTf (924 mg, 3.50 mmol) was added to a solution of 6
(950 mg, 2.91 mmol) and allyltributylstannane (1.15 g,
3.50 mmol) in CH2Cl2 (15 mL) at ꢀ78 ꢁC, and the solution
was stirred for 15 min. TBAF (2.90 g, 9.00 mmol) was added,
and the cooling bath was removed. After 30 min, NH4Cl
(15 mL) was added. The mixture was extracted with CH2Cl2
(3ꢂ20 mL), and the combined organic layers were dried
(Na2SO4) and concentrated under reduced pressure. The resi-
due was purified by flash chromatography eluting with hex-
anes/EtOAc (3:1) to give 830 mg (96%) of 7 as a colorless
1
oil. H NMR (300 MHz, CDCl3) d 7.40e7.20 (comp, 5H),
5.80e5.40 (comp, 2H), 5.20e5.00 (comp, 4H), 4.52 (br s,
1H), 2.80e2.40 (comp, 6H), 2.41 (d, J¼2.7 Hz, 1H); 13C
NMR (75 MHz, CDCl3) d 205.4, 154.8, 135.9, 133.9, 128.5,
128.2, 128.0, 118.3, 82.5, 67.9, 53.2, 45.1, 42.9, 42.7, 39.5;
IR (neat) 3285, 3067, 3033, 2977, 1693, 1642, 1404, 1322,
1112, 1028, 920, 698 cmꢀ1; mass spectrum (CI) m/z
298.1439 [C19H20NO3 (MþH) requires 298.1443].
4.4. 2-Ethynyl-4-oxo-6-vinyl-piperidine-1-carboxylic acid
benzyl ester (8)
MeLi (0.94 mL, 1.6 M in Et2O, 1.5 mmol) was added to
a suspension of CuCN (134 mg, 1.5 mmol) in THF (4 mL) at
ꢀ78 ꢁC. The mixture was cooled to 0 ꢁC, stirred for 1 min,
and then recooled to ꢀ78 ꢁC. A solution of vinyl magnesium
bromide (1.5 mL, 1 M in THF, 1.5 mmol) was added dropwise.
The reaction mixture was stirred for 20 min, whereupon a solu-
tion of 6 (327 mg, 1 mmol) in THF (2 mL) was added dropwise.
The resulting mixture was stirred for 1 h at ꢀ78 ꢁC, at which
point the reaction mixture was poured into a vigorously stirred
mixture (9:1) of satd NH4Cl/NH4OH. The mixture was stirred
for 30 min until all the solids have dissolved, and the solution
was extracted with Et2O (3ꢂ20 mL). The combined organic
layers were washed with H2O (30 mL), brine (30 mL), dried
(Na2SO4), and concentrated under reduced pressure. The resi-
due was purified by flash chromatography eluting with hex-
4.2. 4-Oxo-2-trimethylsilanylethynyl-3,4-dihydro-2H-
pyridine-1-carboxylic acid benzyl ester (6)
EtMgBr (2.35 mL, 2 M in THF, 4.7 mmol) was added to
a solution of TMSeacetylene (508 mg, 5.17 mmol) in THF
(4 mL) at ꢀ78 ꢁC, and the cooling bath was removed while
stirring was continued for 30 min. The solution was added to
a solution of 4-methoxypyridine (430 mg, 3.90 mmol) in
THF (4 mL) at ꢀ78 ꢁC, and the reaction mixture was stirred
for 5 min. Upon warming to ꢀ20 ꢁC, CbzeCl (1.00 g,
5.90 mmol) was added. The reaction mixture was stirred for
an additional 20 min, whereupon 10% HCl (6 mL) was added.
The cooling bath was removed, and stirring was continued for
10 min. Et2O (6 mL) was added, and the aqueous layer was
extracted with Et2O (3ꢂ10 mL). The combined organic layers
were dried (Na2SO4) and concentrated under reduced pressure.
The residue was purified by flash chromatography eluting with
hexanes/EtOAc (3:1) to give 678 mg (96%) of 6 as a colorless
1
anes/EtOAc (3:1) to give 227 mg (64%) of a colorless oil. H
NMR (400 MHz, CDCl3) d 7.36e7.30 (comp, 5H), 6.07 (ddd,
J¼16.8, 10.4, 6.4 Hz, 1H), 5.49 (br s, 1H), 5.22e5.10 (comp,
4H), 4.88 (br s, 1H), 2.97 (dd, J¼15.6, 7.2 Hz, 1H), 2.69e
2.58 (comp, 3H), 0.12 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 205.4, 154.7, 137.6, 136.0, 128.5, 128.2, 128.0, 116.3,
107.7, 104.0, 90.7, 67.9, 54.7, 45.3, 43.2, ꢀ0.49; IR (neat)
2959, 1704, 1403, 1309, 1250, 1224, 1054, 844 cmꢀ1; mass
spectrum (CI) m/z 356 (MþH) (base), 340, 312, 257, 168.
TBAF (400 mg, 1.12 mmol) was added in one portion to a solu-
tion of the above oil (200 mg, 0.56 mmol) in THF (5 mL). The
reaction mixture was stirred for 30 min and concentrated under
reduced pressure. The residue was purified by flash chromatog-
raphy eluting with hexanes/EtOAc (3:1) to give 83 mg (53%) of
1
oil. H NMR (400 MHz, CDCl3) d 7.72 (d, J¼7.2 Hz, 1H),
7.39e7.32 (comp, 5H), 5.41e5.22 (comp, 4H), 2.79 (dd,
J¼16.4, 6.8 Hz, 1H), 2.58 (d, J¼16.4 Hz, 1H), 0.09 (s, 9H);
13C NMR (100 MHz, CDCl3) d 191.1, 134.8, 128.8, 128.7,
128.6, 128.1, 107.7, 100.3, 89.5, 69.1, 45.6, 41.2, 38.1, ꢀ0.39;
IR (neat) 2960, 1732, 1677, 1609, 1329, 1307, 1252, 1213,

K.A. Miller et al. / Tetrahedron 64 (2008) 6884e6900
6891
8 as a pale yellow oil. 1H NMR (500 MHz, DMSO-d6, 100 ꢁC)
d 7.40e7.30 (comp, 5H), 6.07 (ddd, J¼17.0, 10.5, 6.0 Hz, 1H),
5.42 (dt, J¼7.5, 2.5 Hz, 1H), 5.18 (d, J¼17.0 Hz, 1H), 5.17 (s,
2H), 5.10 (d, J¼9.0 Hz, 1H), 5.00 (dd, J¼13.0, 6.0 Hz, 1H),
3.22 (s, 1H), 2.87 (dd, J¼16.0, 7.0 Hz, 1H), 2.80 (dd, J¼16.0,
7.0 Hz, 1H), 2.65 (dd, J¼16.0, 5.5 Hz, 1H), 2.46 (d,
J¼2.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 205.0, 154.8,
137.3, 135.8, 128.5, 128.2, 128.0, 116.7, 82.4, 73.8, 68.0,
54.8, 44.9, 43.2, 42.5; IR (neat) 3285, 2957, 1698, 1403,
1310, 1264, 1310, 1264, 1226, 1113, 1027, 698 cmꢀ1; mass
spectrum (CI) m/z 284.1291 [C17H18NO3 (MþH) requires
284.1287], 284 (base), 266, 240.
d 7.40e7.29 (comp, 5H), 6.02 (ddd, J¼15.5, 10.5, 5.0 Hz,
1H), 5.19e5.10 (comp, 5H), 4.60 (dt, J¼7.0, 6.0 Hz, 1H),
2.79 (dd, J¼16.0, 7.5 Hz, 1H), 2.71 (dd, J¼16.0, 7.5 Hz, 1H),
2.63e2.47 (comp, 5H), 0.12 (s, 9H); 13C NMR (125 MHz,
DMSO-d6, 100 ꢁC) d 205.2, 154.5, 139.0, 136.1, 127.8,
127.2, 126.9, 115.0, 103.4, 86.8, 66.4, 52.6, 51.0, 41.8, 41.7,
25.9, ꢀ0.7; IR (neat) 3089, 3034, 2959, 2900, 1698, 1607,
1403, 1326, 1250, 843 cmꢀ1; mass spectrum (CI) m/z
370.1848 [C21H28NO3Si (MþH) requires 370.1838].
4.7. 4-Oxo-2-prop-2-ynyl-6-vinylpiperidine-1-carboxylic acid
benzyl ester (11)
4.5. 4-Oxo-2-(3-trimethylsilanyl-prop-2-ynyl)-3,4-dihydro-
2H-pyridine-1-carboxylic acid benzyl ester (9)
TBAF$H2O (300 mg, 0.900 mmol) was added in one portion
to a stirred solution of 10 (300 mg, 0.813 mmol) in THF (5 mL).
The reaction mixture was stirred for 5 min and NH4Cl (5 mL)
was added. The mixture was extracted with Et2O (3ꢂ5 mL),
and the combined organic layers were dried (Na2SO4) and con-
centrated under reduced pressure. The residue was purified by
flash chromatography eluting with hexanes/EtOAc (3:1) to
give 166 mg (69%) of 11 as a colorless oil. 1H NMR
(500 MHz, DMSO-d6, 100 ꢁC) d 7.40e7.29 (comp, 5H), 5.99
(ddd, J¼16.0, 10.5, 4.5 Hz, 1H), 5.19e5.12 (comp, 5H), 4.61
(dt, J¼6.5, 5.0 Hz, 1H), 2.80 (dd, J¼16.0, 7.0 Hz, 1H), 2.74
(dd, J¼16.0, 7.0 Hz, 1H), 2.69 (dt, J¼3.0, 1.0 Hz, 1H), 2.59
(ddd, J¼19.2, 3.0, 1.5 Hz, 1H), 2.53e2.46 (comp, 3H); 13C
NMR (125 MHz, DMSO-d6, 100 ꢁC) d 205.2, 154.5, 138.8,
136.1, 127.8, 127.2, 127.0, 115.2, 80.3, 72.4, 66.4, 52.7, 51.2,
41.7, 41.6, 24.7; IR (neat) 3307, 3035, 2959, 1694, 1407,
1320, 1271, 1114, 1057 cmꢀ1; mass spectrum (CI) m/z
298.1443 [C18H20NO3 (MþH) requires 298.1443].
3-Trimethylsilylpropargyl bromide (2.74 g, 14.4 mmol) was
added to a mixture of 4-methoxypyridine (752 mg, 7.2 mmol),
Zn dust (1.87 g, 28.8 mmol), and HgCl2 (30 mg, 0.1 mmol) in
THF (50 mL), and the reaction mixture was heated to reflux
for 3 h. Upon cooling to room temperature, CbzeCl (2.45 g,
14.4 mmol) was added dropwise, and the reaction mixture
was stirred for 10 min. The mixture was filtered through
a plug of Celite (1 cm) to remove excess Zn dust by washing
with EtOAc (30 mL). The filtrate was washed with 1 N HCl
(2ꢂ50 mL), brine (50 mL), dried (Na2SO4), and concentrated
under reduced pressure. The residue was purified by flash chro-
matography eluting with hexanes/EtOAc (9:1e3:1) to give
1.90 g (77%) of 9 as a yellow oil. 1H NMR (400 MHz,
CDCl3) d 7.68 (br s, 1H), 7.34e7.15 (comp, 5H), 5.25 (br s,
1H), 5.20 (s, 2H), 4.66 (br s, 1H), 2.69 (d, J¼6.0 Hz, 2H),
2.50 (d, J¼7.6 Hz, 2H), 0.09 (s, 9H); 13C NMR (100 MHz,
CDCl3) d 191.7, 141.0, 134.6, 128.5, 128.1, 127.1, 126.6,
100.9, 88.2, 68.9, 64.7, 51.6, 38.4, 21.9, ꢀ0.4; IR (neat)
2959, 2900, 1731, 1672, 1604, 1328, 1296, 1198, 1107, 1016,
847, 760, 698 cmꢀ1; mass spectrum (CI) m/z 342.1528
[C19H24NO3Si (MþH) requires 342.1525], 342 (base), 326.
4.8. Representative procedure for PKR of cis-2,6-
disubstituted piperidines
4.8.1. 4,10-Dioxo-12-azatricyclo[6.3.1.02,6]dodec-2-ene-
12-carboxylic acid benzyl ester (14)
Co2(CO)8 (45 mg, 0.130 mmol) was added to 7 (35 mg,
0.118 mmol) in THF (1 mL) under an Ar atmosphere. The reac-
tion mixture was stirred for 1 h and complete conversion to the
alkyneeCo(CO)6 complex observed by TLC. DMSO (55 mg,
0.708 mmol) was added, and the reaction mixture was heated
to 50 ꢁC for 14 h. Et2O (3 mL) was added and the reaction mix-
ture was filtered through Celite by washing with acetone
(5 mL). The combined filtrate and washings were concentrated
under reduced pressure to give a dark oil that was purified by
flash chromatography eluting with hexanes/EtOAc (1:1) to
give 34 mg (89%) of 14 as a white solid. 1H NMR (500 MHz,
DMSO-d6, 100 ꢁC) d 7.60e7.20 (comp, 5H), 5.98 (s, 1H),
5.57 (d, J¼7.0 Hz, 1H), 5.17 (s, 2H), 4.80 (s, 1H), 2.96 (dd,
J¼16.5, 7.0 Hz, 2H), 2.84 (dd, J¼11.0, 7.5 Hz, 2H), 2.54e
2.44 (m, 1H), 2.35 (d, J¼16.5 Hz, 1H), 2.19 (ddd, J¼13.5,
6.5, 2.0 Hz, 1H), 1.92 (dd, J¼18.5, 3.0 Hz, 1H), 1.60 (dt,
J¼13.5, 1.0 Hz, 1H); 13C NMR (125 MHz, DMSO-d6,
100 ꢁC) d 205.8, 205.5, 175.5, 153.1, 136.1, 127.9, 127.4,
127.0, 126.5, 66.5, 50.2, 48.0, 44.0, 43.7, 41.1, 38.4, 32.8; IR
(neat) 3582, 3408, 3063, 2957, 2919, 1694, 1633, 1416, 1096,
4.6. 4-Oxo-2-(3-trimethylsilanylprop-2-ynyl)-6-
vinylpiperidine-1-carboxylic acid benzyl ester (10)
A solution of MeLi (2.88 mmol, 1.8 mL, 1.6 M in hexanes)
was slowly added to a suspension of flame-dried CuCN
(256 mg, 2.88 mmol) at ꢀ78 ꢁC. The reaction mixture was
warmed to 0 ꢁC for 1 min and then recooled to ꢀ78 ꢁC. Vinyl
magnesium bromide (2.88 mmol, 2.88 mL, 1 M in THF) was
added dropwise over 5 min, and the reaction mixture was stirred
for 10 min. A solution of 9 (655 mg, 1.92 mmol) in THF (2 mL)
was added, and the mixture, which turned a deep orange/red
color was stirred at ꢀ78 ꢁC for 1.5 h. The reaction mixture
was poured into a solution of NH4Cl/NH4OH (9:1, 10 mL),
and stirred until all the salts dissolved. The aqueous solution
was extracted with Et2O (3ꢂ10 mL), and the combined organic
layers were dried (Na2SO4) and concentrated under reduced
pressure. The residue was purified by flash chromatography
eluting with hexanes/EtOAc (3:1) to give 678 mg (96%) of 10
1
as a colorless oil. H NMR (500 MHz, DMSO-d6, 100 ꢁC)

6892
K.A. Miller et al. / Tetrahedron 64 (2008) 6884e6900
913; mass spectrum (CI) m/z 326.1381 [C19H20NO4 (MþH) re-
mass spectrum (CI) m/z 300.1602 [C18H22NO3 (MþH) re-
quires 326.1392].
quires 300.1600], 300 (base), 258, 256, 238, 214.
4.8.2. 4,10-Dioxo-12-azatricyclo[6.3.1.02,6]dodec-5-ene-
12-carboxylic acid benzyl ester (15)
4.10. 2-Allyl-4-(tert-butyldimethylsilanyloxy)-6-ethynyl-
piperidine-1-carboxylic acid benzyl ester (18)
The PKR of 11 was performed on a scale of 0.17 mmol ac-
cording to the representative procedure, and the crude product
was purified by flash chromatography eluting with EtOAc to
give 15 in a 91% yield as a colorless oil. 1H NMR
(500 MHz, DMSO-d6, 100 ꢁC) d 7.42e7.31 (comp, 5H),
5.93 (s, 1H), 5.21 (s, 2H), 4.94 (dt, J¼8.0, 1.5 Hz, 1H), 4.85
(t, J¼6.5 Hz, 1H), 3.15 (dt, J¼6.5, 1.5 Hz, 1H), 2.83 (d,
J¼14.0 Hz, 1H), 2.74 (dd, J¼15.0, 6.0 Hz, 1H), 2.68 (dd,
J¼16.5, 6.5 Hz, 1H), 2.54 (dd, J¼17.0, 7.0 Hz, 1H), 2.41
(dd, J¼19.0, 7.0 Hz, 1H), 2.28 (t, J¼15.0 Hz, 1H), 2.10 (dd,
J¼19.5, 2.5 Hz, 1H); 13C NMR (125 MHz, DMSO-d6,
100 ꢁC) d 205.0, 204.3, 173.5, 153.3, 136.1, 131.7, 127.9,
127.3, 127.0, 66.5, 50.7, 47.4, 44.8, 43.6, 38.7, 36.7, 34.8;
IR (neat) 3035, 2963, 2902, 1706, 1626, 1416, 1335, 1264,
1220, 1100, 1028 cmꢀ1; mass spectrum (CI) m/z 326.1392
[C19H20NO4 (MþH) requires 326.1392].
Compound 17 (250 mg, 0.84 mmol) was dissolved in DMF
(5 mL) and imidazole (170 mg, 2.5 mmol) and TBSeCl
(151 mg, 1 mmol) were added sequentially. The reaction mix-
ture was stirred at room temperature for 12 h and NH4Cl
(5 mL) was added. The mixture was extracted with CH2Cl2
(3ꢂ10 mL), and the combined organic layers were washed
with H2O (5 mL), brine (5 mL), dried (Na2SO4), and concen-
trated under reduced pressure. The residue was purified by
flash chromatography eluting with hexanes/EtOAc (9:1) to
give 268 mg (81%) of 18 as a colorless oil. 1H NMR
(400 MHz, CDCl3) d 7.37e7.29 (comp, 5H), 5.77 (ddd,
J¼17.2, 10.0, 7.2 Hz, 1H), 5.15 (s, 2H), 5.07 (d, J¼17.2 Hz,
1H), 4.97 (d, J¼10.0 Hz, 1H), 4.26e4.20 (m, 1H), 4.08 (app
p, J¼4.0 Hz, 1H), 3.73 (dt, J¼6.8, 4.4 Hz, 1H), 2.92e2.77
(m, 2H), 2.20 (d, J¼2.4 Hz, 1H), 2.02e1.67 (comp, 4H),
0.90 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 155.5, 136.6, 136.5, 128.4, 127.9,
127.8, 116.8, 85.4, 70.6, 67.3, 64.2, 50.7, 39.1, 38.6, 36.6,
33.6, 25.8, 18.1, ꢀ4.9, ꢀ5.0; IR (neat) 3307, 2953, 2856,
1694, 1640, 1407, 1335, 1312, 1255, 1093, 774 cmꢀ1; mass
spectrum (CI) m/z 414.2466 [C24H36NO3Si (MþH) requires
414.2464], 414 (base), 398, 372, 356, 238.
4.8.3. 4,9-Dioxo-11-azatricyclo[5.3.1.02,6]undec-2-ene-11-
carboxylic acid benzyl ester (16)
The PKR of 8 was performed on a scale of 0.17 mmol ac-
cording to the representative procedure, and the crude product
was purified by flash chromatography eluting with hexanes/
EtOAc (3:1e1:1) to give 14 mg (33%) of 16 as a colorless
1
oil as a mixture (3:1) of diastereomers. H NMR (500 MHz,
DMSO-d6, 100 ꢁC) d 7.42e7.31 (comp, 5H), 6.09 (s, 1H),
5.38 (br s, 1H), 5.20 (s, 2H), 5.24e5.23 (m, 1H), 4.62 (t,
J¼6.0 Hz, 1H), 3.49e3.45 (m, 1H), 2.91 (dd, J¼17.0,
6.0 Hz, 1H), 2.84e2.79 (comp, 1H), 2.60 (dd, J¼18.0, 6.0 Hz,
1H), 2.38 (d, J¼18.0 Hz, 1H), 2.17 (dd, J¼18.0, 3.0 Hz,
1H); mass spectrum (CI) m/z 312.1234 [C18H18NO4 (MþH)
requires 312.1236], 312 (base), 268.
4.11. 6-Trimethylsilanylethynylpiperidin-2-one (20)
A solution of TMSeacetylene (3.23 g, 33 mmol) in THF
(25 mL) was cooled to ꢀ78 ꢁC and n-BuLi (13.2 mL, 2.5 M in
hexanes, 33 mmol) was added dropwise. The reaction mixture
was warmed to 0 ꢁC and stirred for 10 min. The solution was
added to a solution of 19 (2.6 g, 10.9 mmol) in THF (25 mL)
at ꢀ78 ꢁC, and the reaction mixture was stirred for 30 min at
ꢀ78 ꢁC and 30 min at room temperature. The reaction was
quenched with NaHCO3 (30 mL) and the mixture was extracted
with EtOAc (3ꢂ25 mL). The combined organic layers were
dried (Na2SO4) and concentrated under reduced pressure. The
residue was purified by flash chromatography eluting with
EtOAc to give 1.52 g (71%) of 20 as a white solid: mp¼126e
4.9. 2-Allyl-6-ethynyl-4-hydroxypiperidine-1-carboxylic
acid benzyl ester (17)
A solution of 7 (750 mg, 2.52 mmol) in THF (20 mL) was
cooled to ꢀ78 ꢁC and a solution of L-Selectride (3.0 mL, 1 M
in THF) was added dropwise. The reaction mixture was stirred
at ꢀ78 ꢁC whereupon satd NH4Cl (10 mL) was added. The
mixture was extracted with Et2O (3ꢂ10 mL) and the com-
bined organic layers were dried (Na2SO4) and concentrated
under reduced pressure. The residue was purified by flash
chromatography eluting with hexanes/EtOAc (3:1e1:1) to
give 524 mg (70%) of 17 as a colorless oil. 1H NMR
(400 MHz, CDCl3) d 7.36e7.29 (comp, 5H), 5.76 (ddt,
J¼16.8, 10.0, 7.2 Hz, 1H), 5.28e4.96 (comp, 5H), 4.29e
4.22 (m, 1H), 2.83 (t, J¼7.2 Hz, 2H), 2.63 (d, J¼2.4 Hz,
1H), 2.21e1.98 (comp, 3H), 1.73 (ddd, J¼3.2, 7.2, 14.0 Hz,
1H); 13C NMR (125 MHz, CDCl3) (rotamers) d 155.4,
136.4, 135.9, 128.5, 128.0, 127.9, 117.4, 85.5, 71.8, 67.5,
64.6, 50.3, 39.5, 38.2, 36.4, 32.6, 29.7; IR (neat) 3447,
1
127 ꢁC. H NMR (400 MHz, CDCl3) d 5.74 (s, 1H), 4.26e
4.23 (m, 1H), 2.37e2.33 (comp, 2H), 2.04e1.95 (comp, 2H),
1.86e1.70 (comp, 2H), 0.14 (s, 9H); 13C NMR (100 MHz,
CDCl3) d 171.2, 104.4, 88.1, 44.9, 31.1, 28.8, 18.8, ꢀ0.3; IR
(neat) 3190, 3077, 2956, 1687, 1649, 1405, 1309, 1252, 841,
756 cmꢀ1; mass spectrum (CI) m/z 196.1160 [C10H18NOSi
(MþH) requires 196.1158], 196 (base), 180.
4.12. 2-Oxo-6-trimethylsilanylethynylpiperidine-1-carb-
oxylic acid benzyl ester (21)
A solution of 20 (750 mg, 3.85 mmol) in THF (15 mL) was
cooled to ꢀ78 ꢁC and a solution of n-BuLi (1.86 mL, 2.27 M
in hexanes, 4.23 mmol) was added dropwise over 5 min. The
3297, 2953, 1684, 1409, 1324, 1087, 1063, 990, 914 cmꢀ1
;

K.A. Miller et al. / Tetrahedron 64 (2008) 6884e6900
6893
reaction mixture was stirred for 30 min whereupon CbzeCl
4.14. 2-Allyl-4-methyl-piperazine-1-carboxylic acid tert-
butyl ester (26)
(1.30 g, 7.70 mmol) was added. The cooling bath was re-
moved, and the reaction mixture was stirred for 15 min. The
reaction was quenched with satd NH4Cl (15 mL) and extracted
with EtOAc (3ꢂ15 mL). The combined organic layers were
dried (Na2SO4) and concentrated under reduced pressure.
The residue was purified by flash chromatography eluting
with hexanes/EtOAc (9:1e3:1) to give 1.02 g (81%) of 21 as
Compound 24 (1 g, 4.99 mmol), s-BuLi (20 mL of a 0.6 M
solution in n-hexane, 11.98 mmol), TMEDA (1.39 g,
11.98 mmol), CuCN (1.07 g, 11.98 mmol), LiCl (1.02 g,
23.97 mmol), and allyl bromide (1.45 g, 11.98 mmol) in Et2O
(150 mL) were reacted as reported in literature.18 Purification
via flash chromatography eluting with CH2Cl2/MeOH (20:1)
yielded 26 (0.997 g, 83%) as a light yellow oil. 1H NMR
(400 MHz, CDCl3) (rotamers) d 5.65e5.77 (m, 1H), 5.03 (d,
J¼16.8 Hz, 1H), 4.96 (d, J¼10.0 Hz, 1H), 4.05 (br s, 1H),
3.81 (d, J¼9.6 Hz, 1H), 2.30 (t, J¼12.4 Hz, 1H), 2.65 (t,
J¼10.8 Hz, 2H), 2.34e2.47 (m, 2H), 2.18 (s, 3H), 1.97 (d,
J¼11.2 Hz, 1H), 1.86 (t, J¼12.0 Hz, 2H), 1.40 (s, 9H); 13C
NMR (75 MHz, CDCl3) (rotamers) d 154.7, 135.3, 116.9,
79.4, 77.2, 57.1, 55.0, 50.7, 46.4, 39.1, 34.6, 28.3; IR (neat)
2358, 1698, 1458, 1409, 1365, 1247, 1174, 1106 cmꢀ1; mass
spectrum (CI) m/z 241.1919 [C13H25N2O2 (MþH) requires
241.1916] 213, 199, 185.
1
a white solid: mp¼70e71 ꢁC. H NMR (400 MHz, CDCl3)
d 7.43e7.29 (comp, 5H), 5.32e5.24 (comp, 2H), 5.12e5.10
(m, 1H), 2.75e1.79 (comp, 6H), 0.12 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 170.3, 152.9, 135.1, 128.3, 128.0, 127.7,
103.1, 88.8, 68.4, 48.3, 34.0, 28.5, 17.5, ꢀ0.4; IR (neat)
3065, 2959, 2899, 1778, 1738, 1714, 1498, 1455, 1373,
1250, 1134, 1062, 843 cmꢀ1; mass spectrum (CI) m/z
330.1526 [C18H24NO3Si (MþH) requires 330.1525], 330
(base), 286, 270.
4.13. 2-Allyl-6-ethynylpiperidine-1-carboxylic acid benzyl
ester (23)
A solution of 21 (830 mg, 2.52 mmol) in THF (25 mL) was
cooled to ꢀ78 ꢁC and a solution of DIBALeH (3.03 mL, 1 M
in toluene, 3.03 mmol) was added slowly dropwise over 5 min.
The reaction mixture was stirred at ꢀ78 ꢁC for 30 min and
MeOH (0.5 mL) was added. The reaction mixture was warmed
to room temperature and satd Rochelle’s salt (25 mL) was
added with vigorous stirring. The mixture was extracted
with EtOAc (3ꢂ15 mL) and the combined organic layers
were dried (Na2SO4) and concentrated under reduced pressure.
The pale yellow oil was dissolved in CH2Cl2 (25 mL) and
cooled to ꢀ78 ꢁC whereupon allyl TMS (1.43 g, 12.6 mmol)
and BF3$Et2O (1.77 g, 12.6 mmol) were added sequentially.
The reaction mixture was stirred for 30 min and warmed to
room temperature. NaHCO3 (15 mL) was added and the mix-
ture stirred for 15 min. The solution was extracted with
CH2Cl2 (3ꢂ15 mL) and the combined organic layers were
dried (Na2SO4) and concentrated under reduced pressure to
give a crude oil (506 mg). A portion of the oil (200 mg) was
dissolved in THF (10 mL) and TBAF (220 mg, 0.845 mmol)
was added. The reaction mixture was stirred at room temper-
ature for 30 min and NH4Cl (5 mL) was added. The mixture
was extracted with EtOAc (3ꢂ10 mL), and the combined
organic layers were dried (Na2SO4) and concentrated under re-
duced pressure. The residue was purified by flash chromatog-
raphy eluting with hexanes/EtOAc (9:1) to give 138 mg (52%)
of 23 as a colorless oil. 1H NMR (500 MHz, DMSO-d6,
100 ꢁC) d 7.38e7.29 (comp, 5H), 5.73 (ddd, J¼17.5, 10.0,
7.0 Hz, 1H), 5.12 (s, 2H), 5.05 (d, J¼17.5 Hz, 1H), 5.04e
5.02 (m, 1H), 4.98 (d, J¼10.0 Hz, 1H), 4.23e4.19 (m, 1H),
2.99 (d, J¼2.5 Hz, 1H), 2.56e1.48 (comp, 8H); 13C NMR
(125 MHz, DMSO-d6, 100 ꢁC) d 154.2, 136.3, 135.5, 127.7,
127.2, 126.9, 116.0, 84.5, 72.4, 66.0, 50.6, 40.9, 36.0, 29.8,
26.0, 14.0; IR (neat) 3294, 3248, 2944, 1697, 1406, 1318,
4.15. 2-Allyl-6-formyl-4-methyl-piperazine-1-carboxylic
acid tert-butyl ester (28)
s-BuLi (0.95 mL of a 1.2 M solution in n-hexane,
1.14 mmol) was added to a mixture of 25 (0.210 g,
0.874 mmol) and TMEDA (0.132 g, 1.14 mmol) in Et2O
(20 mL) at ꢀ78 ꢁC and the reaction mixture was stirred for
1 h. DMF (0.96 g, 1.31 mL) was quickly added and reaction
mixture was stirred for an additional 1 h. The reaction was
quenched at ꢀ78 ꢁC with satd NH4Cl, allowed to warm to
room temperature, extracted with Et2O (4ꢂ10 mL), dried
(K2CO3), and concentrated. The crude oil was then dissolved
in hexanes/EtOAc/NEt3 (98:2:1, 20 mL) and SiO2 (1.4 g) was
added. The reaction mixture was allowed to stir until the disap-
pearance of the trans-isomer was observed by TLC (eluting
with CH2Cl2/MeOH, 20:1). The reaction mixture was filtered,
concentrated, and the residue purified via flash chromatography
eluting with CH2Cl2/MeOH (30:1) to give 183 mg (78%) of 28
1
as a light yellow oil. H NMR (400 MHz, CDCl3) (rotamers)
d 9.63 (s, 1H), 5.68e5.79 (m, 1H), 5.98e5.04 (comp, 2H),
4.35 (br s, 1H), 4.00 (br s, 1H), 3.30 (d, J¼11.6 Hz, 1H), 2.65
(d, J¼10.8 Hz, 1H), 2.21e2.28 (m, 2H), 2.18 (s, 3H), 2.01
(dd, J¼6.4, 5.2 Hz, 1H), 1.95 (dd, J¼7.6, 4.0 Hz, 1H), 1.48
(s, 9H); 13C NMR (75 MHz, CDCl3) (rotamers) d 200.4,
154.7, 136.1, 117.1, 79.6, 68.7, 61.2, 54.6, 50.5, 46.5, 39.3,
28.3; IR (neat) 2968, 2790, 1731, 1690, 1455, 1402, 1367,
1331, 1296, 1173, 1049 cmꢀ1; mass spectrum (CI) m/z
269.1867 [C14H25N2O3 (MþH) requires 269.1865], 241, 227,
213, 169, 154.
4.16. 2-Allyl-6-ethynyl-4-methyl-piperazine-1-carboxylic
acid tert-butyl ester (30)
1267, 1098 cmꢀ1
;
mass spectrum (CI) m/z 284.1653
To a mixture of 28 (0.480 g, 1.79 mmol), K2CO3 (0.742 g,
5.37 mmol) in MeOH (20 mL) at 0 ꢁC was added Bestmanne
Ohira reagent (0.688 g, 3.58 mmol). The reaction mixture was
[C18H22NO2 (MþH) requires 284.1651], 284 (base), 242,
198, 176.

6894
K.A. Miller et al. / Tetrahedron 64 (2008) 6884e6900
warmed to room temperature and stirred under argon for 16 h.
The reaction mixture was concentrated, dissolved in EtOAc
(30 mL), washed with brine (1ꢂ10 mL), satd NaHCO3
(2ꢂ10 mL), brine (1ꢂ10 mL). The organic layer was dried
(MgSO4), filtered, concentrated, and the residue was purified
via flash chromatography eluting with CH2Cl2/MeOH (30:1)
to give 379 mg (80%) of 30 as a colorless oil. 1H NMR
(400 MHz, CDCl3) (rotamers) d 5.74e5.85 (m, 1H), 5.14 (d,
J¼17.2, 1H), 5.05 (d, J¼10.4, 1H), 4.85 (br s, 1H), 4.00e
4.04 (m, 1H), 2.93 (dt, J¼11.6, 2.0 Hz, 1H), 2.72e2.82
(comp, 2H), 2.60e2.67 (m, 1H), 2.28 (s, 3H), 2.22 (d,
J¼2.4 Hz, 2H), 2.09 (dd, J¼7.2, 4.0 Hz, 1H), 1.95 (dd,
J¼7.2, 4.0 Hz, 1H), 1.45 (s, 9H); 13C NMR (75 MHz,
CDCl3) (rotamers) d 154.7, 136.4, 117.4, 84.7, 80.6, 70.3,
61.5, 59.5, 56.8, 46.9, 37.0, 28.6; IR (neat) 3295, 2978,
2942, 2802, 1696, 1455, 1390, 1337, 1296, 1249, 1179,
1044 cmꢀ1; mass spectrum (CI) m/z 265.1912 [C15H25N2O2
(MþH) requires 265.1916], 249, 237, 223, 209, 165, 154.
concentrated, and the residue purified via flash chromatography
eluting with CH2Cl2/MeOH (30:1) to give 0.134 g (81%) of 29
1
as a light yellow oil. H NMR (400 MHz, CDCl3) (rotamers)
d 9.61 (s, 1H), 7.31e7.20 (comp, 5H), 5.74e5.59 (m, 1H),
5.03e4.83 (comp, 2H), 4.46e4.32 (comp, 1H), 4.02e3.84
(comp, 1H), 3.55 (t, J¼12.8 Hz, 2H), 3.37 (d, J¼13.2 Hz,
2H), 2.77e2.68 (m, 1H), 2.54e2.42 (m, 1H), 2.35e2.26
(comp, 2H), 2.21 (dd, J¼6.4, 4.4 Hz, 1H), 2.06e1.99 (comp,
2H), 1.48e1.45 (comp, 9H); 13C NMR (75 MHz, CDCl3) (ro-
tamers) d 201.9, 154.7, 137.6, 136.3, 135.4, 135.2, 128.8,
128.7, 128.2, 127.2, 127.0, 117.5, 116.9, 80.6, 79.3, 62.7,
62.4, 54.6, 53.3, 53.1, 28.2; IR (neat) 3072, 2966, 2912,
2801, 2707, 1731, 1690, 1455, 1390, 1367, 1249 cmꢀ1; mass
spectrum (CI) m/z 345.2179 [C20H29N2O3 (MþH) requires
345.2178], 318, 303, 289, 261, 201, 173.
4.19. 2-Allyl-4-benzyl-6-ethynyl-piperazine-1-carboxylic
acid tert-butyl ester (31)
4.17. 2-Allyl-4-benzyl-piperazine-1-carboxylic acid tert-
butyl ester (27)
To a mixture of 29 (0.094 g, 0.273 mmol), K2CO3 (0.113 g,
0.819 mmol) in MeOH (3 mL) at 0 ꢁC was added Bestmanne
Ohira reagent (0.105 g, 0.546 mmol). The reaction mixture
was warmed to room temperature and stirred under argon for
16 h. The reaction mixture was concentrated, dissolved in
EtOAc (10 mL), washed with brine (1ꢂ5 mL), satd NaHCO3
(2ꢂ5 mL), brine (1ꢂ5 mL). The organic layer was dried
(MgSO4), filtered, concentrated, and the residue was purified
via flash chromatography eluting with CH2Cl2/MeOH (30:1)
to give 0.093 g (76%) of 31 as a colorless oil. 1H NMR
(400 MHz, CDCl3) (rotamers) d 7.35e7.23 (comp, 5H),
5.74e5.64 (m, 1H), 5.04e4.94 (comp, 2H), 4.07 (br s, 1H),
3.84 (br s, 1H), 3.54 (d, J¼13.2 Hz, 1H), 3.38 (d, J¼13.2 Hz,
1H), 3.07 (t, J¼12.4 Hz, 1H), 2.77 (d, J¼10.8 Hz, 1H), 2.70
(d, J¼11.6 Hz, 1H), 2.54e2.42 (m, 2H), 2.07e2.00 (comp,
2H), 1.48e1.45 (comp, 9H); 13C NMR (75 MHz, CDCl3) (ro-
tamers) d 138.6, 135.7, 129.1, 128.4, 127.2, 117.2, 79.7, 63.1,
55.0, 53.4, 51.6, 34.9, 29.9, 28.6; IR (neat) 3304, 3074, 2975,
2811, 2773, 1697, 1640, 1454, 1399, 1367, 1336, 1302, 1255,
1175 cmꢀ1; mass spectrum (CI) m/z 341.2226 [C21H29N2O2
(MþH) requires 341.2229], 325, 313, 299, 285, 240.
Compound 25 (0.200 g, 0.724 mmol), s-BuLi (1.2 mL of
1.46 M solution in n-hexane, 1.74 mmol), TMEDA
a
(0.202 g, 1.74 mmol), CuCN (0.156 g, 1.74 mmol), LiCl
(0.148 g, 3.48 mmol), and allyl bromide (0.114 g,
0.941 mmol) in Et2O (24 mL) were reacted as reported in liter-
ature.18 Purification via flash chromatography eluting with
CH2Cl2/MeOH (30:1) yielded 27 (0.229 g, 84%) as a light yel-
1
low oil. H NMR (400 MHz, CDCl3) (rotamers) d 7.35e7.22
(comp, 5H), 5.74e5.64 (m, 1H), 5.04e4.93 (comp, 2H), 4.06
(br s, 1H), 3.85 (d, J¼11.2 Hz, 1H), 3.53 (d, J¼13.2 Hz, 1H),
3.38 (d, J¼13.2 Hz, 1H), 3.07 (td, J¼12.6, 2.8 Hz, 1H), 2.76
(d, J¼10.8 Hz, 1H), 2.70 (d, J¼11.2 Hz, 1H), 2.53e2.41 (m,
2H), 2.07e1.99 (comp, 2H), 1.45 (s, 9H); 13C NMR
(75 MHz, CDCl3) (rotamers) d 154.8, 138.4, 135.5, 128.8,
128.2, 127.0, 117.0, 79.4, 62.8, 54.7, 53.2, 34.6, 28.4; IR
(neat) 3064, 2975, 2807, 1694, 1455, 1410, 1364, 1174 cmꢀ1
;
mass spectrum (CI) m/z 317.2229 [C19H29N2O2 (MþH) re-
quires 317.2229], 289, 275, 261, 243, 217, 173.
4.18. 2-Allyl-4-benzyl-6-formyl-piperazine-1-carboxylic
acid tert-butyl ester (29)
4.20. 10-(tert-Butyldimethylsilanyloxy)-4-oxo-12-azatri-
cyclo[6.3.1.02,6]dodec-2-ene-12-carboxylic acid benzyl
ester (34)
s-BuLi (0.4 mL of a 1.46 M solution in n-hexane,
0.584 mmol) was added to a mixture of 27 (0.123 g,
0.389 mmol) and TMEDA (0.068 g, 0.584 mmol) in Et2O
(13 mL) at ꢀ78 ꢁC and the reaction mixture was stirred for
1 h. DMF (0.043 g, 0.05 mL) was quickly added and reaction
mixture was stirred for an additional 1 h. The reaction was
quenched at ꢀ78 ꢁC with satd NH4Cl, allowed to warm to
room temperature, extracted with Et2O (4ꢂ10 mL), dried
(K2CO3), and concentrated. The crude oil was then dissolved
in hexanes/EtOAc/NEt3 (98:2:1, 13 mL) and SiO2 (1.0 g) was
added. The reaction mixture was allowed to stir until the disap-
pearance of the trans-isomer was observed by TLC (eluting
with CH2Cl2/MeOH, 20:1). The reaction mixture was filtered,
The PKR of 27 was performed on a scale of 0.29 mmol ac-
cording to the representative procedure, and the crude product
was purified by flash chromatography eluting with hexanes/
EtOAc (9:1e3:1) to give 39 in a 69% yield as a colorless
1
oil. H NMR (500 MHz, DMSO-d6, 100 ꢁC) d 7.37e7.28
(comp, 5H), 5.87 (d, J¼2.0 Hz, 1H), 5.17 (d, J¼7.5 Hz, 1H),
5.10 (s, 2H), 4.47e4.44 (m, 1H), 4.30e4.24 (m, 1H), 4.09e
4.05 (m, 1H), 2.40 (dd, J¼18.0, 6.5 Hz, 1H), 2.28 (comp,
2H), 2.00 (ddd, J¼13.0, 7.0, 2.0 Hz, 1H), 1.94 (dd, 18.0,
3.0 Hz, 1H), 1.71e1.64 (comp, 2H), 1.53 (dt, J¼12.5,
5.0 Hz, 1H), 0.85 (s, 9H), 0.07 (s, 3H), 0.03 (s, 3H); 13C
NMR (125 MHz, DMSO-d6, 100 ꢁC) d 205.9, 179.0, 153.2,

K.A. Miller et al. / Tetrahedron 64 (2008) 6884e6900
6895
136.3, 127.8, 127.2, 126.8, 125.6, 66.0, 62.2, 48.0, 45.4, 41.8,
37.1, 35.3, 35.0, 32.6, 25.0, 16.9, ꢀ5.6, ꢀ5.7; IR (neat) 2928,
2855, 1713, 1623, 1416, 1322, 1278, 1088, 839 cmꢀ1; mass
spectrum (CI) m/z 442.2411 [C25H36NO4Si (MþH) requires
442.2414], 442 (base), 308.
(75 MHz, CDCl3) (rotamers) d 208.5, 179.6, 179.0, 153.7,
137.5, 128.7, 128.5, 127.3, 126.4, 80.5, 62.9, 56.7, 55.4,
51.8, 47.6, 43.9, 39.2, 38.7, 28.3; IR (neat) 2967, 2920,
2803, 2768, 1692, 1621, 1451, 1315, 1287, 1246,
1175 cmꢀ1; mass spectrum (CI) m/z 369.2175 [C22H29N2O3
(MþH) requires 369.2178], 341, 313.
4.21. 4-Oxo-12-azatricyclo[6.3.1.02,6]dodec-2-ene-12-
carboxylic acid benzyl ester (35)
4.24. 1-(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexa-
hydro-7-benzyloxycarbonyl-6,13-imino-cyclooct[1,2-b]indole
(3)
The PKR of 32 was performed on a scale of 0.35 mmol ac-
cording to the representative procedure, and the crude product
was purified by flash chromatography eluting with hexanes/
EtOAc (1:1) to give 40 in a 74% yield as a colorless oil as a mix-
Co2(CO)8 (1.77 g, 5.12 mmol) was added to a solution of 4
(1.88 g, 5.08 mmol) in THF (50 mL). The reaction mixture
was stirred for 1 h and complete Coealkyne complex forma-
tion was observed by TLC. DMSO (2.20 g, 27.92 mmol)
was added and stirred at 60 ꢁC for 8 h. The reaction mixture
was cooled to room temperature and Et2O (30 mL) was added.
The purple Co-precipitate was removed via filtration through
silica washing with Et2O (30 mL) and the solution was con-
centrated under reduced pressure. The residue was purified
by flash chromatography eluting with hexanes/EtOAc (3:1e
1
ture (4:1) of diastereomers. H NMR (500 MHz, DMSO-d6,
100 ꢁC) d 7.37e7.28 (comp, 5H), 5.89 (br s, 1H), 5.11 (s, 2H),
4.36 (t, J¼4.4 Hz, 1H), 3.57e3.51 (m, 1H), 2.53 (dd, J¼18.0,
6.0 Hz, 1H), 2.50e2.48 (m, 1H), 2.15 (dd, J¼13.5, 7.5 Hz,
1H), 2.08e1.52 (comp, 7H); 13C NMR (125 MHz, DMSO-d6,
100 ꢁC) d 205.7, 178.1, 153.2, 136.4, 127.8, 127.2, 126.8,
125.8, 65.9, 49.5, 46.6, 43.2, 37.2, 35.5, 27.6, 18.4, 14.1; IR
(neat) 2939, 1694, 1621, 1419, 1321, 1085 cmꢀ1; mass spec-
trum (ESI) m/z 312.1601 [C19H22NO3 (MþH) requires
312.1600], 334 (base), 312.
1
1:1) to give 1.86 g (92%) of 3 as a colorless oil. H NMR
(500 MHz, CDCl3) d 10.73 (s, 1H), 7.39 (d, J¼7.9 Hz, 1H),
7.35e7.29 (comp, 6H), 7.07 (dt, 7.2, 1.3 Hz, 1H), 6.98 (dt,
J¼7.9, 1.0 Hz, 1H), 6.05 (br s, 1H), 5.64 (d, J¼6.8 Hz, 1H),
5.50 (br s, 1H), 5.21e5.09 (comp, 2H), 3.33 (dd, J¼16.4,
6.9 Hz, 1H), 2.75 (d, J¼16.4 Hz, 1H), 2.79e2.68 (comp,
1H), 2.34 (dd, J¼18.3, 6.4 Hz, 1H), 2.26 (dq, J¼6.2,
2.4 Hz, 1H), 1.99 (dd, 18.3, 3.0 Hz, 1H), 1.76 (dt, J¼12.6,
3.8 Hz, 1H); 13C NMR (125 MHz) d 205.8, 177.4, 153.4,
136.1, 135.6, 132.3, 127.8, 127.3, 127.0, 126.5, 125.8, 120.6,
118.2, 117.2, 110.8, 105.5, 66.3, 49.3, 47.6, 40.2, 37.1, 34.4,
25.0; IR (neat) 3464, 3052, 2985, 1702, 1623 cmꢀ1; mass
spectrum (CI) m/z 399.1710 [C25H23N2O3 (MþH) requires
399.1709].
4.22. 10-Methyl-4-oxo-10,12-diazatricyclo[6.3.1.02,6]-
dodec-2-ene-12-carboxylic acid tert-butyl ester (36)
The PKR of 30 was performed on a scale of 0.56 mmol ac-
cording to the representative procedure, and the crude product
was purified by flash chromatography eluting with hexanes/
1
EtOAc (2:1) to give 36 in a 85% yield as a colorless oil. H
NMR (500 MHz, DMSO-d6, 100 ꢁC) d 5.86 (d, J¼2.1 Hz,
1H), 4.92 (s, 1H), 4.14 (s, 1H), 3.99e4.05 (m, 1H), 2.92 (d,
J¼11.2 Hz, 1H), 2.87 (d, J¼11.6 Hz, 1H), 2.48 (dd, J¼18.2,
6.5 Hz, 1H), 2.32 (dd, J¼11.5, 3.3 Hz, 1H), 2.26 (dd, J¼1.8,
1.7 Hz, 1H), 2.24 (dd, J¼1.8, 1.7 Hz, 1H), 2.19 (s, 3H), 2.17
(m, 1H), 1.79 (dd, J¼18.2, 3.3 Hz, 1H), 1.87 (m, 1H), 1.40 (s,
9H); 13C NMR (125 MHz, DMSO-d6, 100 ꢁC) d 206.1, 178.6,
152.5, 127.6, 125.4, 79.0, 57.9, 56.4, 57.9, 56.4, 44.6, 42.6,
38.0, 37.6, 27.5; IR (neat) 2973, 2920, 2791, 1696, 1623,
1458, 1407, 1322, 1173, 1046 cmꢀ1; mass spectrum (CI) m/z
293.1866 [C16H25N2O3 (MþH) requires 293.1865], 237.
4.25. 1-(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexa-
hydro-7-benzyloxycarbonyl-14-tert-butoxycarbonyl-6,13-
imino-cyclooct[1,2-b]indole (38)
(Boc)2O (327 mg, 1.22 mmol) was added to a solution of
3 (350 mg, 0.88 mmol) and DMAP (134 mg, 0.88 mmol) in
CH3CN/CH2Cl2 (20 mL, 3:1), and the reaction mixture was
stirred at room temperature for 1 h. Et2O (20 mL) was added
and the reaction mixture was washed with 0.2 M citric acid
(2ꢂ10 mL), satd NaHCO3 (10 mL), and brine (10 mL). The
organic layer was dried (Na2SO4) and concentrated under re-
duced pressure. The residue was purified by flash chromatog-
raphy eluting with hexanes/EtOAc (3:1) to give 430 mg (99%)
of 42 as a white foam. 1H NMR (500 MHz) d 8.12 (d,
J¼8.2 Hz, 1H), 7.48 (d, J¼7.8 Hz, 1H), 7.34e7.28 (comp,
6H), 7.24 (t, J¼6.7 Hz, 1H), 6.08 (br s, 1H), 6.06 (br s, 1H),
5.66 (d, J¼7.2 Hz, 1H), 5.15 (s, 2H), 3.31 (dd, J¼17.1,
7.1 Hz, 1H), 2.79e2.76 (comp, 2H), 2.41e2.35 (comp, 1H),
2.38 (dd, J¼18.4, 6.5 Hz, 1H), 2.01 (dd, J¼18.5, 3.0 Hz,
1H), 1.76 (dt, J¼12.7, 4.1 Hz, 1H), 1.62 (s, 9H); 13C NMR
(125 MHz) d 205.9, 176.8, 153.3, 148.8, 136.0, 135.1, 132.3,
4.23. 10-Benzyl-4-oxo-10,12-diazatricyclo[6.3.1.02,6]-
dodec-2-ene-12-carboxylic acid tert-butyl ester (37)
The PKR of 31 was performed on a scale of 0.100 mmol
according to the representative procedure, and the crude
product was purified by flash chromatography eluting with
hexanes/EtOAc (3:1) to give 37 in a 81% yield as a colorless
oil. 1H NMR (400 MHz, CDCl3) (rotamers) d 7.35e7.24
(comp, 5H), 5.93e5.86 (comp, 1H), 5.07e4.90 (comp, 1H),
4.29 (s, 1H), 4.23 (br s, 1H), 3.51 (d, J¼12.8 Hz, 1H), 3.46
(d, J¼13.2 Hz, 1H), 2.95e2.89 (comp, 2H), 2.67 (dd,
J¼12.0, 6.4 Hz, 1H), 2.50 (dd, J¼8.4, 3.2 Hz, 1H), 2.41 (d,
J¼11.2 Hz, 1H), 2.18e2.12 (m, 1H), 1.90 (dt, J¼18.4,
2.4 Hz, 1H), 1.75e1.59 (comp, 2H), 1.43 (s, 9H); 13C NMR

6896
K.A. Miller et al. / Tetrahedron 64 (2008) 6884e6900
127.8, 127.5, 127.4, 127.1, 126.5, 123.9, 122.4, 117.8, 114.9,
114.1, 84.1, 66.5, 54.1, 48.1, 40.3, 36.2, 33.9, 27.2, 24.6; IR
(neat) 3400, 2977, 2929, 1771, 1713, 1626 cmꢀ1; mass spec-
trum (CI) m/z 499.2211 [C30H31N2O5 (MþH) requires
498.2233].
(neat) 2977, 2928, 1750, 1730, 1703, 1455, 1417, 1360, 1326,
1156, 1012, 755 cmꢀ1; mass spectrum (CI) m/z 515.2175
[C30H31N2O6 (MþH) requires 515.2182].
4.28. 1-(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexa-
hydro-7-benzyloxycarbonyl-14-tert-butoxycarbonyl-6,13-
imino-9-triisopropylsiloxycyclopent-8-ene-cyclooct[1,2-
b]indole (45)
4.26. 1-(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexa-
hydro-7-benzyloxycarbonyl-14-tert-butoxycarbonyl-6,13-
imino-7,11-[2,7-dioxabicyclo[4.1.0]heptan-3-one]-
cyclooct[1,2-b]indole (39)
Solid 38 (1.0 g, 2.0 mmol) was added to a solution of
platinum(0)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex
(0.50 mL, 0.1 Minxylenes, 0.05 mmol, 2.5 mol %)andi-Pr3SiH
(5 mL,24 mmol)intoluene(5 mL), andthereactionmixturewas
heated to 60 ꢁC for 18 h. The reaction mixture was concentrated
under reduced pressure, and the residue was purified by flash
chromatography (neutral alumina) eluting with hexanes/EtOAc
Trifluoroacetic anhydride (15 mg, 0.07 mmol) was added
to a mixture of 38 (10 mg, 0.02 mmol), urea$H2O2 (19 mg,
0.20 mmol), and Na2HPO4 (26 mg, 0.18 mmol) in CH2Cl2
(1 mL) at 0 ꢁC, and the reaction mixture was stirred for 3 h.
The reaction mixture was filtered through a plug of Celite
(1 cm), and concentrated under reduced pressure. The residue
was purified by flash chromatography eluting with hexanes/
EtOAc (3:1e1:1) to give 10 mg (94%) of 39 as a colorless oil.
1H NMR (500 MHz, DMSO-d6, 100 ꢁC) d 7.80 (d, J¼8.0 Hz,
1H), 7.76 (d, J¼7.5 Hz, 1H), 7.40 (t, J¼8.0 Hz, 1H), 7.37e
7.26 (comp, 5H), 7.23 (t, J¼7.5 Hz, 1H), 5.88 (br s, 1H), 5.32
(d, J¼8.0 Hz, 1H), 5.09 (s, 2H), 4.37 (br s, 1H), 3.70 (br s,
1H), 2.78e2.74 (m, 1H), 2.62 (dd, J¼18.0, 6.5 Hz, 1H), 2.32
(d, J¼14.0 Hz, 1H), 2.09 (dd, J¼13.5, 8.0 Hz, 1H), 1.97 (dd,
J¼18.0, 3.5 Hz, 1H), 1.70e1.69 (m, 1H), 1.57 (s, 9H); 13C
NMR (125 MHz) d 205.8, 177.4, 151.9, 148.1, 139.4, 136.2,
128.4, 127.7, 127.1, 126.8, 126.7, 125.7, 124.1, 123.1, 123.3,
121.1, 113.8, 109.2, 83.4, 65.9, 60.6, 54.5, 42.3, 33.3, 27.3,
23.1; IR (neat) 2955, 1791, 1764, 1710, 1632, 1421, 1307,
1252, 1150, 739 cmꢀ1; mass spectrum (CI) m/z 531 (MþH),
463, 319, 243 (base).
1
(1:0e9:1) to give 1.32 g (93%) of 45 as a white foam. H
NMR (300 MHz, CDCl3) (rotamers) d 8.29e8.25 (m, 1H),
7.42e7.26 (comp, 8H), 6.03 (s, 0.5H), 5.93 (s, 0.5H), 5.22 (s,
1H), 5.17 (s, 1H), 4.91 (d, J¼6.6 Hz, 0.5H), 4.83 (d, J¼6.6 Hz,
1H), 4.72 (s, 0.5H), 4.61 (s, 0.5H), 3.27e3.12 (m, 1H), 2.78e
2.54 (comp, 3H), 2.08e1.80 (comp, 4H), 1.76 (s, 4.5H), 1.61
(s, 4.5H), 1.29e1.13 (comp, 21H); 13C NMR (75 MHz,
CDCl3) (rotamers) d 155.7, 155.4, 154.8, 154.7, 149.7, 136.7,
136.5, 135.9, 133.5, 133.2, 128.7, 128.6, 128.3, 128.2, 127.8,
127.7, 127.4, 124.0, 123.9, 122.6, 122.5, 117.7, 117.6, 115.6,
115.3, 114.7, 104.2, 103.8, 83.8, 83.6, 67.1, 66.8, 48.0, 47.8,
47.6, 47.4, 47.3, 47.1, 40.7, 40.6, 31.3, 30.9, 29.9, 28.0, 27.9,
27.6, 27.0, 17.7, 12.3; IR (neat) 2943, 2865, 1731, 1698, 1634,
1455, 1424, 1366, 1325, 1145, 882 cmꢀ1; mass spectrum (CI)
m/z 657 (MþH) (base), 601, 556, 405.
4.29. 1-(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexa-
hydro-7-benzyloxycarbonyl-14-tert-butoxycarbonyl-6,13-
imino-9-oxycyclopentane-cyclooct[1,2-b]indole (46)
4.27. 1-(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexa-
hydro-7-benzyloxycarbonyl-14-tert-butoxycarbonyl-6,13-
imino-7,8-epoxycyclopentane-cyclooct[1,2-b]indole (40)
TBAF$3H2O (158 mg, 0.5 mmol) was added to a solution of
45 (153 mg, 0.25 mmol) in CH2Cl2 (10 mL) and the reaction
mixture was stirred at room temperature for 3 h. Satd NH4Cl
(10 mL) was added and the layers were separated. The aqueous
layer was extracted with CH2Cl2 (2ꢂ10 mL) and the combined
organic layers were dried (Na2SO4) and concentrated under re-
duced pressure. The residue was purified by flash chromatogra-
phy eluting with hexanes/EtOAc (3:1e1:1) to give 100 mg
A solution of NaOH (10 mL, 100 mg NaOH/1 mL H2O,
0.024 mmol) and a solution of H2O2 (15 mL, 30% in H2O,
0.1 mmol) were sequentially added to a solution of 38 (10 mg,
0.02 mmol) in THF/MeOH (0.4 mL, 1:1) at ꢀ20 ꢁC. The reac-
tion mixture was stirred for 30 min, and the cooling bath was re-
moved. A solution of NaOH (10 mL, 100 mg NaOH/1 mL H2O,
0.024 mmol) was added, and the reaction mixturewas stirred for
an additional 1 h. The solution was filtered through a plug of
Na2CO3/silica (1 cm/1 cm) and concentrated under reduced
pressure. The residue was purified by flash chromatography
eluting with hexanes/EtOAc (9:1e3:1) to give 7.8 mg (78%)
of 40 as a colorless oil. 1H NMR (500 MHz, DMSO-d6,
100 ꢁC) d 8.12 (d, J¼8.0 Hz, 1H), 7.54 (d, J¼5.5 Hz, 1H),
7.35e7.25 (comp, 7H), 5.98 (br s, 1H), 5.14 (s, 2H), 4.51 (d,
J¼6.5 Hz, 1H), 3.64 (s, 1H), 3.16 (dd, J¼17.0, 7.0 Hz, 1H),
2.92 (d, J¼17.0 Hz, 1H), 2.44e2.32 (comp, 3H), 1.82e1.73
(comp, 2H), 1.62 (s, 9H); 13C NMR (125 MHz, DMSO-d6,
100 ꢁC) d 207.1, 153.4, 148.7, 135.9, 135.2, 132.1, 127.8,
127.5, 127.2, 127.0, 124.0, 122.4, 117.8, 114.8, 114.2, 84.1,
69.6, 66.6, 61.3, 47.7, 47.3, 37.6, 35.1, 29.0, 27.2, 22.8; IR
1
(66%) of 46 as a colorless oil. H NMR (500 MHz, DMSO-
d6, 100 ꢁC) d 8.10 (d, J¼8.0 Hz, 1H), 7.48 (d, J¼7.5 Hz, 1H),
7.32e7.27 (comp, 6H), 7.24 (t, J¼7.5 Hz, 1H), 5.94 (s, 1H),
5.12 (s, 2H), 4.64 (d, J¼6.5 Hz, 1H), 3.14 (dd, J¼16.5,
7.0 Hz, 1H), 2.74 (d, J¼17.0 Hz, 1H), 2.50e2.48 (m, 1H),
2.28 (dd, J¼18.5, 8.0 Hz, 2H), 2.14e2.08 (comp, 2H), 1.90
(d, J¼18.0 Hz, 2H), 1.61 (s, 9H), 1.54 (td, J¼13.5, 4.5 Hz,
1H); 13C NMR (100 MHz, C6D6) d 215.3, 154.2, 148.8,
136.2, 135.1, 132.4, 127.8, 127.2, 127.0, 126.8, 123.7, 122.2,
117.6, 114.8, 110.7, 83.9, 66.2, 46.9, 44.6, 40.2, 38.4, 29.1,
28.3, 27.9, 27.2, 23.1; IR (neat) 2953, 1731, 1701, 1455,
1423, 1368, 1326, 1147, 1016, 747 cmꢀ1; mass spectrum (CI)
m/z 501 (MþH), 400 (base).

K.A. Miller et al. / Tetrahedron 64 (2008) 6884e6900
6897
4.30. 1-(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexa-
hydro-6,13-imino-9R-hydroxycyclopentane-cyclooct[1,2-
b]indole (47)
4.32. 1-(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexa-
hydro-7-benzyloxycarbonyl-14-tert-butoxycarbonyl-6,13-
imino-7-hydroxymethyl-11-carboxylic acid methyl ester-
cyclooct[1,2-b]indole (49)
NaBH4 (34 mg, 1.0 mmol) was added in one portion to a so-
lution of 46 (200 mg, 0.4 mmol) in THF (10 mL) at room tem-
perature. The reaction mixture was stirred for 1 h and satd
NaHCO3 (5 mL) was added. The reaction mixture was ex-
tracted with EtOAc (3ꢂ5 mL) and the combined organic
layers were dried and concentrated under reduced pressure.
The crude oil was adsorbed on to silica gel (2.0 g) and heated
at 80 ꢁC under vacuum (1 mmHg) for 6 h. The flask was
cooled and the silica was washed with EtOAc (5 mL) to which
10% Pd/C (20 mg) was added under an atmosphere of H2
(1 atm). The reaction mixture was stirred for 3 h and was fil-
tered through Celite (1 cm) and concentrated to give 53 mg
(45%) of 47 as a white solid. Slow evaporation from
CH2Cl2/MeOH (2 mL) gave white needles suitable for X-
Pb(OAc)4 (640 mg, 1.45 mmol) was added to a solution of
48 (375 mg, 0.722 mmol) in MeOH/benzene (10 mL, 1:1) at
0 ꢁC and the reaction mixture was stirred for 15 min at 0 ꢁC.
NaBH4 (430 mg, 10 mmol) was added in six portions over
5 min, and the reaction mixture was stirred at 0 ꢁC for
15 min. NaHCO3 (20 mL) was added and the solution was ex-
tracted with EtOAc (3ꢂ30 mL). The combined organic layers
were washed with brine (20 mL), dried (Na2SO4), and concen-
trated under reduced pressure. The residue was purified by
flash chromatography eluting with hexanes/EtOAc (1:1) to
give 291 mg (72%) of 49 as a colorless oil. 1H NMR
(500 MHz, DMSO-d6, 100 ꢁC) d 8.10 (d, J¼8.0 Hz, 1H),
7.47 (d, J¼7.0 Hz, 1H), 7.31e7.22 (comp, 7H), 5.93 (br s,
1H), 5.08 (s, 2H), 4.91 (d, J¼7.5 Hz, 1H), 3.55 (dd, J¼11.0,
5.0 Hz, 1H), 3.49 (s, 3H), 3.50e3.46 (m, 1H), 3.21 (dd,
J¼17.5, 8.0 Hz, 1H), 2.57 (d, J¼17.5 Hz, 1H), 2.37 (dd,
J¼15.5, 7.0 Hz, 1H), 2.27e2.17 (comp, 2H), 1.88e1.84 (m,
1H), 1.76e1.67 (comp, 2H), 1.60 (s, 9H); 13C NMR
(125 MHz, DMSO-d6, 100 ꢁC) d 171.6, 154.3, 148.8, 136.4,
134.9, 133.7, 127.7, 127.1, 126.6, 123.6, 122.2, 117.6,
114.7, 83.7, 65.9, 57.6, 50.3, 46.3, 45.3, 36.0, 33.6, 29.6,
27.2, 26.2, 25.0, 23.1; IR (neat) 2931, 1729, 1697, 1454,
1367, 1328, 1155, 1116, 912, 747 cmꢀ1; mass spectrum (CI)
m/z 549 (MþH) (base), 493, 449.
1
ray: mp¼200e204. H NMR (400 MHz, CD3OD) d 7.26 (d,
J¼9.5 Hz, 1H), 7.15 (d, J¼9.5 Hz, 1H), 6.91 (td, J¼8.5,
1.5 Hz, 1H), 6.85 (dt, J¼8.5, 1.5 Hz, 1H), 4.17e4.11 (m,
1H), 4.01 (s, 1H), 3.28 (d, J¼7.5 Hz, 1H), 3.21e3.19 (m,
1H), 3.09 (dd, J¼19.5, 8.0 Hz, 1H), 2.46 (d, J¼19.5 Hz, 1H),
2.02e1.43 (comp, 7H), 1.17 (dd, J¼18.0, 3.0 Hz, 1H); 13C
NMR (100 MHz, CD3OD) d 137.6, 135.5, 128.6, 121.7,
119.6, 118.4, 111.8, 108.2, 72.9, 49.7, 45.5, 42.2, 39.4,
35.4, 34.1, 32.3, 30.0; IR (neat) 3394, 2924,1450, 1335,
742 cmꢀ1; mass spectrum (CI) m/z 270 (MþH).
4.31. 1-(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexa-
hydro-7-benzyloxycarbonyl-14-tert-butoxycarbonyl-6,13-
imino-8-hydroxy-9-oxycyclopentane-cyclooct[1,2-b]-
indole (48)
4.33. 1-(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexa-
hydro-7-benzyloxycarbonyl-14-tert-butoxycarbonyl-6,13-
imino-7,11-[tetrahydropyran-2-one]-cyclooct[1,2-b]-
indole (50)
OsO4 (289 mg, 1.18 mmol) was added in one portion to
a solution of 45 (690 mg, 1.12 mmol) in THF (10 mL) at
room temperature. The reaction mixture was stirred at room
temperature for 12 h, and then H2S was bubbled through the
reaction mixture for 15 min. The thick black precipitate was
removed by filtering through Celite (1 cm), washing with
THF (30 mL), and the solvent was removed under reduced
pressure. The residue was purified by flash chromatography
eluting with hexanes/EtOAc (3:1e1:1) to give 480 mg (71%)
of a mixture of epimers 48 as a colorless oil. Major isomer:
1H NMR (500 MHz, DMSO-d6, 100 ꢁC) d 8.10 (d, J¼
8.0 Hz, 1H), 7.48 (d, J¼8.0 Hz, 1H), 7.32e7.22 (comp, 7H),
5.96 (s, 1H), 5.16e5.09 (comp, 2H), 4.86 (d, J¼7.0 Hz, 1H),
3.90 (d, J¼10.5 Hz, 1H), 3.19 (dd, J¼16.5, 7.0 Hz, 1H), 2.69
(d, J¼16.5 Hz, 1H), 2.28 (dd, J¼19.0, 8.0 Hz, 1H), 2.08e
1.98 (comp, 4H), 1.69e1.65 (m, 1H), 1.61 (s, 9H); 13C
NMR (125 MHz, DMSO-d6, 100 ꢁC) d 215.1, 154.3, 148.8,
136.3, 135.1, 132.5, 127.9, 127.8, 127.2, 126.8, 123.7,
122.3, 117.7, 115.1, 114.8, 83.9, 72.9, 66.2, 47.2, 45.1, 40.5,
39.0, 30.7, 27.2, 25.7, 23.2; IR (neat) 3436, 2976, 1729,
1699, 1456, 1424, 1360, 1328, 1153, 754 cmꢀ1; mass spec-
trum (CI) m/z 517 (MþH), 473, 461, 417.
OsO4 (4 mg, 0.015 mmol) was added to a slurry of NaIO4
(130 mg, 4 mmol) and 49 (100 mg, 0.152 mmol) in THF/
H2O (1.5 mL, 5:1). The reaction mixture was stirred at room
temperature for 48 h and H2O (5 mL) was added. The solution
was extracted with CH2Cl2 (3ꢂ3 mL) and the combined or-
ganic layers were concentrated to give a crude black oil.
The oil was dissolved in MeOH (5 mL) and NaBH4 (6 mg,
0.152 mmol) was added. The reaction mixture stirred at
room temperature for 30 min and TsOH$H2O (48 mg,
0.25 mmol) was added and stirred for an additional 4 h. Satd
NaHCO3 (5 mL) was added and the solution was extracted
with CH2Cl2 (3ꢂ3 mL). The combined organic layers were
dried (Na2SO4) and concentrated under reduced pressure.
The residue was purified by flash chromatography eluting
with hexanes/EtOAc (1:1) to give 43 mg (55%) of 50 as
1
a white foam. H NMR (500 MHz, DMSO-d6, 100 ꢁC)
d 8.10 (d, J¼8.0 Hz, 1H), 7.46 (d, J¼8.0 Hz, 1H), 7.31e
7.27 (comp, 6H), 7.24 (t, J¼7.5 Hz, 1H), 5.98 (br s, 1H),
5.11 (s, 2H), 4.51 (d, J¼7.5 Hz, 1H), 4.40 (dd, J¼11.5,
5.5 Hz, 1H), 4.32 (t, J¼11.5 Hz, 1H), 3.18 (dd, J¼17.0,
7.5 Hz, 1H), 2.73 (d, J¼17.0 Hz, 1H), 2.60 (dd, J¼18.0,
7.5 Hz, 1H), 2.37e2.33 (m, 1H), 2.16e2.09 (dd, J¼18.0,

6898
K.A. Miller et al. / Tetrahedron 64 (2008) 6884e6900
2.0 Hz, 1H), 2.12 (m, 1H), 1.95e1.86 (comp, 2H), 1.61 (s,
13
175 ꢁC. 1H NMR (400 MHz, C6D6) d 7.61e7.58 (m, 1H),
7.28e7.24 (comp, 2H), 7.15e7.11 (m, 1H), 6.47 (d,
J¼6.0 Hz, 1H), 6.23 (br s, 1H), 4.48 (dd, J¼11.0, 4.4 Hz,
1H), 4.42 (d, J¼11.0 Hz, 1H), 3.91 (d, J¼9.2 Hz, 1H), 3.29
(s, 1H), 2.98 (dd, J¼16.8, 7.2 Hz, 1H), 2.56 (d, J¼6.4 Hz,
1H), 2.14 (s, 3H), 2.11 (s, 1H), 1.99 (td, J¼12.0, 3.6 Hz,
1H), 1.87e1.79 (comp, 2H), 1.47 (d, J¼12.0 Hz, 1H); 13C
NMR (100 MHz, C6D6) d 144.1, 136.2, 132.0, 128.5, 121.6,
119.7, 118.5, 111.1, 107.2, 105.0, 66.8, 55.5, 54.9, 41.7,
40.8, 35.8, 24.2, 22.8; IR (neat) 3394, 2927, 2360, 1646,
1457, 1244, 1070, 741, 668 cmꢀ1; mass spectrum (CI) m/z
281.1657 [C18H21N2O (MþH) requires 281.1654].
9H); C NMR (125 MHz, DMSO-d6, 100 ꢁC) d 168.9,
153.9, 148.7, 136.2, 135.2, 132.4, 127.8, 127.2, 126.9,
125.9, 122.2, 117.6, 114.9, 110.7, 106.4, 83.9, 67.4, 66.2,
47.4, 46.9, 36.8, 33.6, 30.6, 29.9, 27.2, 23.4; IR (neat) 2976,
1731, 1698, 1455, 1423, 1329, 1141, 912, 733 cmꢀ1; mass
spectrum (CI) m/z 517 (MþH), 545, 517 (base), 417.
4.34. 1-(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexa-
hydro-7-benzyloxycarbonyl-14-tert-butoxycarbonyl-6,13-
imino-7,11-[3,4-dihydro-2H-pyran]-cyclooct[1,2-b]indole
(52)
A solution of 50 (235 mg, 0.455 mmol) in toluene (10 mL)
was cooled to ꢀ78 ꢁC, and a solution of DIBALeH
(0.547 mL, 1 M in toluene, 0.547 mmol) was slowly added
dropwise. The reaction mixture was stirred for 1 h at ꢀ78 ꢁC
and then MeOH (0.5 mL) was added. The reaction mixture
was warmed to room temperature and satd Rochelle’s salt
(20 mL) was added. The solution was extracted with EtOAc
(3ꢂ10 mL) and the combined organic layers were dried
(Na2SO4) and concentrated under reduced pressure. The resi-
due was dissolved in THF (5 mL) and cooled to 0 ꢁC. Et3N
(340 mg, 3.36 mmol) and MsCl (121 mg, 1.05 mmol) were se-
quentially added and the reaction mixture was stirred at 0 ꢁC for
30 min. Satd NH4Cl (5 mL) was added and the solution was ex-
tracted with EtOAc (3ꢂ5 mL). The combined organic layers
were dried (Na2SO4) and concentrated under reduced pressure.
The residue was purified by flash chromatography eluting with
hexanes/EtOAc (9:1) to give 130 mg (61%) of 52 as a colorless
4.36. 1-(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexa-
hydro-7,14-dimethyl-6,13-iminopyrano[30,40:5,6]cyclo-
oct[1,2-b]indole (54)
NaH (12 mg, 0.311 mmol) was added to a solution of 53
(29 mg, 0.104 mmol) in DMF (1 mL) at ꢀ5 ꢁC. The reaction
mixture was stirred for 15 min and MeI (22 mg, 0.150 mmol)
was added. The reaction mixture was stirred for 1.5 h during
which time the temperature had warmed to 5 ꢁC. The reaction
was quenched with H2O/brine (2 mL, 1:1) and extracted with
CH2Cl2 (4ꢂ5 mL). The combined organic layers were washed
with H2O (5 mL), dried (Na2SO4), and concentrated under re-
duced pressure. The solvent was removed under reduced pres-
sure and the residue was purified by flash chromatography
eluting with hexanes/EtOAc (1:1) to give 29 mg (86%) of 54
as a white solid: mp¼192e193 ꢁC. 1H NMR (400 MHz,
C6D6) d 7.66e7.63 (m, 1H), 7.30e7.28 (comp, 2H), 7.10e
7.07 (m, 1H), 6.47 (d, J¼6.0 Hz, 1H), 4.49 (t, J¼5.6 Hz, 1H),
4.43 (d, J¼11.0 Hz, 1H), 3.92 (ddd, J¼11.0, 4.0, 1.6 Hz, 1H),
3.48 (t, J¼3.2 Hz, 1H), 3.04 (dd, J¼16.4, 6.8 Hz, 1H), 2.84 (s,
3H), 2.59 (d, J¼6.8 Hz, 1H), 2.20 (d, J¼16.4 Hz, 1H), 2.15 (s,
3H), 1.99 (dd, J¼12.4, 4.0 Hz, 1H), 1.93e1.83 (m, 2H), 1.48
(dt, J¼12.4, 3.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 136.9, 133.3, 126.5, 120.8, 118.8, 117.9, 109.7, 108.7,
106.3, 104.8, 66.6, 55.2, 53.6, 41.8, 40.5, 37.9, 34.7, 23.7,
22.9; IR (neat) 2925, 2360, 2340, 1644, 1467, 1379, 1070,
895, 738, 668 cmꢀ1; mass spectrum (CI) m/z 293.1659
[C19H21N2O (MꢀH) requires 293.1654].
1
oil. H NMR (500 MHz, DMSO-d6, 100 ꢁC) d 8.10 (d,
J¼8.5 Hz, 1H), 7.45 (d, J¼7.5 Hz, 1H), 7.32e7.27 (comp,
6H), 7.23 (t, J¼7.0 Hz, 1H), 6.30 (d, J¼6.0 Hz, 1H), 5.93 (br
s, 1H), 5.11 (s, 2H), 4.61 (t, J¼5.5 Hz, 1H), 4.55 (d, J¼
7.5 Hz, 1H), 4.00 (dd, J¼11.0, 2.5 Hz, 1H), 3.76 (t,
J¼11.0 Hz, 1H), 3.15 (dd, J¼17.0, 7.5 Hz, 1H), 2.75 (d,
J¼17.0 Hz, 1H), 2.12e1.96 (comp, 3H), 1.79e1.73 (m, 1H),
13
1.61 (s, 9H); C NMR (125 MHz, DMSO-d6, 100 ꢁC)
d 153.8, 148.8, 142.8, 136.2, 135.1, 132.5, 127.7, 127.3,
127.2, 126.9, 123.6, 122.2, 117.6, 114.9, 114.8, 103.6, 83.8,
66.2, 63.7, 47.5, 46.5, 37.9, 32.0, 27.2, 26.0, 23.3; IR (neat)
2976, 1729, 1699, 1455, 1422, 1330, 1142, 747 cmꢀ1; mass
spectrum (CI) m/z 500 (MþH), 401, 387 (base), 267, 229.
4.37. 1-(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexa-
hydro-7-benzyloxycarbonyl-14-tert-butoxycarbonyl-6,13-
imino-7,11-[1-(5,6-dihydro-4H-pyran-3-yl)-ethanone]-
cyclooct[1,2-b]indole (56)
4.35. 1-(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexa-
hydro-7-methyl-6,13-iminopyrano[30,40:5,6]cyclooct[1,2-
b]indole (53)
Trichloroacetyl chloride (0.4 mL, 3.6 mmol) was added to
a solution of 52 (170 mg, 0.34 mmol) in pyridine (2 mL), and
the reaction mixture was heated to 65 ꢁC for 18 h. The reaction
mixture was concentrated under reduced pressure and the resi-
due was dissolved in CH2Cl2 (10 mL). The solution was washed
with NH4Cl (2ꢂ10 mL), filtered through a silica plug (1 cm),
and concentrated to give a crude yellow oil. The oil was dis-
solved in AcOH (2 mL) and added dropwise to a suspension of
Zn dust (200 mg, 3.0 mmol) in AcOH (2 mL). The reaction mix-
turewas stirred for30 min and more Zn dust(200 mg, 3.0 mmol)
LiAlH4 (18 mg, 0.48 mmol) was added in one portion to
a solution of 52 (60 mg, 0.12 mmol) in THF (5 mL). The re-
action mixture was heated to reflux for 1 h and cooled to
room temperature. MeOH was added until bubbling ceased
(3 drops) and the reaction mixture was filtered through Celite
(1 cm) by washing with EtOAc (5 mL). The solvent was re-
moved under reduced pressure and the residue was purified
by flash chromatography eluting with hexanes/EtOAc (1:1e
0:1) to give 29 mg (86%) of 53 as a white solid: mp¼174e

K.A. Miller et al. / Tetrahedron 64 (2008) 6884e6900
6899
was added. The reaction mixture was stirred for an additional
15 min, filtered through Celite (1 cm), and concentrated under
reduced pressure. The residue was purified by flash chromatog-
raphyelutingwithhexanes/EtOAc (3:1)to give138 mg (75%)of
under reduced pressure and the crude residue dissolved in
CH2Cl2 (5 mL) and washed with NaHCO3 (5 mL). The organic
layer was dried (Na2SO4) and concentrated under reduced pres-
sure. The residue was purified by flash chromatography eluting
with hexanes/EtOAc (1:1e0:1) to give 6 mg (72%) of 1 as
a white film. 1H NMR (400 MHz, CDCl3) d 7.51 (s, 1H), 7.45
(d, J¼8.0 Hz, 1H), 7.29 (d, J¼8.0 Hz, 1H), 7.17 (t, J¼7.2 Hz,
1H), 7.07 (t, J¼8.0 Hz, 1H), 4.39 (t, J¼11.2 Hz, 1H), 4.15
(ddd, J¼10.8, 4.0, 1.6 Hz, 1H), 3.86 (t, J¼3.2 Hz, 1H), 3.63
(s, 3H), 3.31 (dd, J¼16.4, 6.8 Hz, 1H), 3.07 (d, J¼6.8 Hz,
1H), 2.60 (app dt, J¼10.0, 4.4 Hz, 1H), 2.48 (d, J¼16.4 Hz,
1H), 2.30 (s, 3H), 2.11 (ddd, J¼11.2, 4.6, 4.0 Hz, 1H), 2.07
(s, 3H), 1.89 (m, 1H), 1.80 (dd, J¼12.0, 3.6 Hz, 1H); 13C
NMR (75 MHz, CDCl3) d 195.5, 157.4, 137.2, 133.2, 126.5,
121.1, 120.8, 118.7, 117.8, 109.0, 105.9, 67.8, 54.7, 53.8,
41.8, 38.5, 32.4, 29.1, 25.0, 22.9, 22.8; IR (neat) 2895, 2359,
1617, 1468, 1320, 1276, 1192, 911, 741 cmꢀ1; mass spectrum
(CI) m/z 337.1914 [C21H25N2O2 (MþH) requires 337.1916];
[a]D25 ꢀ187 (c 0.30, EtOH) {lit.6 [a]2D5 ꢀ195 (EtOH)}.
1
56 as a colorless oil. H NMR (500 MHz, DMSO-d6, 100 ꢁC)
d 8.15 (d, J¼8.0 Hz, 1H), 7.71 (s, 1H), 7.47 (d, J¼8.0 Hz, 1H),
7.33e7.23 (comp, 7H), 5.93 (br s, 1H), 5.12 (s, 2H), 4.62
(d, J¼7.5 Hz, 1H), 4.24 (dd, J¼11.0, 3.0 Hz, 1H), 3.94 (t,
J¼11.5 Hz, 1H), 3.20 (dd, J¼16.5, 7.5 Hz, 1H), 2.77 (d,
J¼17.0 Hz, 1H), 2.63 (dt, J¼11.5, 4.5 Hz, 1H), 2.22e2.18 (m,
1H), 2.06e2.03 (m, 1H), 2.04 (s, 3H), 1.70e1.65 (m, 1H),
13
1.60 (s, 9H); C NMR (125 MHz, DMSO-d6, 100 ꢁC)
d 193.9, 156.8, 153.9, 148.8, 136.2, 135.1, 132.7, 127.7, 127.4,
127.3, 126.9, 123.7, 122.3, 119.3, 117.6, 114.8, 110.7, 83.8,
66.2, 64.7, 47.7, 46.0, 35.9, 29.9, 27.2, 25.7, 24.2, 22.3; IR
(neat) 2913, 1721, 1691, 1612, 1427, 1318, 1090, 740 cmꢀ1
;
mass spectrum (CI) m/z 543 (MþH), 488, 444 (base), 400.
4.38. 1-(4aR,6S,13S,13aR)-1,4a,5,6,7,12,13,13a-Hexa-
hydro-7,14-dimethyl-6,13-imino-7,11-[1-(5,6-dihydro-4H-
pyran-3-yl)-ethanone]-cyclooct[1,2-b]indole (57)
Acknowledgements
Freshly distilled TMSeI (19 mg, 0.093 mmol) was added
to a solution of 56 (12 mg, 0.022 mmol) in CH3CN (1 mL)
at 0 ꢁC. The reaction mixture was stirred for 30 min at 0 ꢁC
and 15 min at room temperature. Methanolic HCl (1 mL,
1 M) was added and the reaction mixture was concentrated un-
der reduced pressure. The residue was dissolved in aqueous
HCl (5 mL, 1 M) and extracted with CH2Cl2 (3ꢂ5 mL). The
aqueous layer was basified with 30% NH4OH dropwise until
pHw12 and then extracted with CH2Cl2 (3ꢂ5 mL). The com-
bined organic layers were dried (Na2SO4) and concentrated
under reduced pressure. The residue was purified by flash
chromatography eluting with EtOAc/MeOH (9:1) to give
6 mg (78%) of 57 as a white film. 1H NMR (400 MHz,
CDCl3) d 7.99 (br s, 1H), 7.53 (s, 1H), 7.44 (d, J¼7.6 Hz,
1H), 7.28 (d, J¼7.6 Hz, 1H), 7.13 (t, J¼6.8 Hz, 1H), 7.07 (t,
J¼7.6 Hz, 1H), 4.43 (t, J¼11.6 Hz, 1H), 4.19 (ddd, J¼11.2,
4.0, 1.6 Hz, 1H), 4.10 (br s, 1H), 3.44 (d, J¼6.8 Hz, 1H),
3.22 (dd, J¼16.0, 6.8 Hz, 1H), 2.74e2.67 (m, 1H), 2.66 (d,
J¼16.4 Hz, 1H), 2.11e2.06 (m, 1H), 2.08 (s, 3H), 1.92e
1.70 (comp, 4H); 13C NMR (75 MHz, CDCl3) d 195.5,
157.5, 135.6, 135.5, 127.2, 121.5, 121.3, 119.3, 117.7,
111.2, 107.9, 67.4, 48.3, 47.7, 37.4, 32.3, 28.8, 25.0, 23.7;
IR (neat) 2921, 1614, 1453, 1321, 1195, 738 cmꢀ1; mass spec-
trum (CI) m/z 309 (MþH) (base).
We thank the National Institutes of Health (GM 25439 and
31077), the Robert A. Welch Foundation, Pfizer, Inc., Merck
Research Laboratories, and Boehringer Ingelheim Pharmaceu-
ticals for their generous support of this research.
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