Synthesis studies on the Melodinus alkaloid meloscine

Article abstract of DOI:10.1016/j.tet.2012.12.032

The pentacyclic Melodinus alkaloid (±)-meloscine was synthesized in 19 chemical steps from 2-bromobenzaldehyde through a route featuring an allenyl azide cyclization cascade to deliver the core azabicyclo[3.3.0]octane substructure. Peripheral functionalization of this core included a Tollens-type aldol condensation to set the quaternary center at C(20) and a diastereoselective ring-closing metathesis to forge the tetrahydropyridine ring.

Full text of DOI:10.1016/j.tet.2012.12.032

Tetrahedron 69 (2013) 1434 1445
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Synthesis studies on the Melodinus alkaloid meloscine
*
Ken S. Feldman , Joshua F. Antoline
Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The pentacyclic Melodinus alkaloid (ꢀ) meloscine was synthesized in 19 chemical steps from 2
bromobenzaldehyde through a route featuring an allenyl azide cyclization cascade to deliver the core
azabicyclo[3.3.0]octane substructure. Peripheral functionalization of this core included a Tollens type
aldol condensation to set the quaternary center at C(20) and a diastereoselective ring closing metath
esis to forge the tetrahydropyridine ring.
Received 6 November 2012
Received in revised form 9 December 2012
Accepted 11 December 2012
Available online 19 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Alkaloid
Meloscine
Allenyl azide cycloaddition
1. Introduction
species.1,2 Scandine then can serve as the direct precursor to both
meloscine (1) and epimeloscine (2) via decarboxymethylation.
The Melodinus alkaloids comprise a small class of plant derived
pentacyclic compounds isolated from either Apocynaceae or Kopsia
species.1 Among the 14 members of this family, three related iso
lates all extend from the melodan skeleton, Fig. 1. The complex and
compact framework of scandine (3) has been hypothesized to
emerge from rearrangement of the more common tabersonine
Permissive evidence for this biosynthesis proposal was garnered by
Palmisano et al., who documented a high yield (72%) pinacol type
shift in a system related to 4/3.3a Alternatively, Hugel and Levy
ꢀ
have described a high temperature rearrangement process that
passes through an aziridine intermediate en route to the melodan
skeleton from a tabersonine derivative.3b,5a
The melodan alkaloids have remained an enduring challenge for
chemical synthesis, with reports spanning the last three decades
that describe either approaches to,3,4 or syntheses of,5 one or more
members of this family. The melodan alkaloids’ congested bicyclic
core, featuring four contiguous stereogenic carbon atoms about
a cyclopentane ring, two of which are all carbon quaternary cen
ters, poses a formidable test for stereoselective synthesis. Not sur
prisingly, this challenge has been addressed through widely
differing synthesis strategies, and four total syntheses have been
recorded prior to our work, Scheme 1. The initial success in this area
was reported by Overman et al.,5b who relied on an aza
CopeeMannich sequence (5/6) for the elaboration of the racemic
meloscine core. This work stood as the only total synthesis of
meloscine for almost 20 years, when in 2008 Bach et al. described
a synthesis of natural (þ) meloscine through an enantioselective
[2
p
þ2
p] photocycloaddition of 7 and methyl 2 (trimethylsiloxy)
acrylate to furnish the cyclobutyl containing species 8.5c,d Neither
the Overman work nor the Bach work delivered the core cyclo
pentyl C ring directly; in the former case, a Wolff reaction
mediated ring contraction was utilized to formulate this ring,
whereas in the latter case, a pinacol like ring expansion served the
same strategic function. More recently, Mukai et al. have completed
a synthesis of (ꢀ) meloscine through PausoneKhand cyclization of
Fig. 1. Alkaloids with the melodan skeleton from Apocynaceae Melodinus; a bio-
synthetic hypothesis for the formation of the melodan structure from a tabersonine
precursor.
* Corresponding author. E-mail address: ksf@chem.psu.edu (K.S. Feldman).
0040-4020/$ see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.12.032

K.S. Feldman, J.F. Antoline / Tetrahedron 69 (2013) 1434 1445
1435
Scheme 2. Retrosynthetic analysis of meloscine via allenyl azide cascade cyclization
chemistry.
tetrahydropyridine ring E from the extant C(20) and nitrogen
substituents. At the outset of this work, it was not obvious, which of
these two operations should be executed first, so maintaining
flexibility to pursue both options via appropriate choice of P and P1
was built into the plan. In addition, formation of the C(20) qua
ternary center (16/15) was anticipated to be a difficult trans
formation, given the steric hindrance in the local environment of
the C ring, and so several different options were envisioned. Finally,
the ultimate operation of the synthesis route was anticipated to be
a diastereoselective ring closing metathesis between the N allyl
Scheme 1. Prior art in the total synthesis of meloscine.
fragment and the
b face vinyl appendage of 13. At the initial
planning stages, the expectation for diastereoselectivity in this
transformation was undergirded by nothing more than density
functional calculations on 1 and its C(20) epimer. While this work
was in progress, both the Mukai and the Curran syntheses of
meloscine were published; each utilized this same metathesis
based ring closure, and no evidence for a C(20) epimer was re
ported. A preliminary account of this work has been published;7
this report elaborates on that disclosure and details the detours,
derailments, and dead ends encountered along the way to
meloscine.
the propynoylamide 9 to furnish the tetracyclic core of meloscine
10.5e Soon thereafter, Curran et al. detailed the most efficient con
struction of meloscine to date through a radical mediated [3
atomþ2 atom] addition within divinyl cyclopropane 11 to afford
tetracycle 12.5f Both the Mukai and the Curran approaches do de
liver the central cyclopentanoid C ring directly and with the correct
stereochemistry for meloscine at C(7) and C(21). The Curran cycli
zation chemistry furnishes the product tetracycle with the correct
stereochemistry at C(16) for epimeloscine but not meloscine.
However, the ready epimerization of the epimeloscine skeleton to
meloscine is not problematic per the earlier observations of Ber
nauer et al.1a Thus, Curran’s synthesis delivers not only epi
meloscine but meloscine as well.
2. Results and discussion
A different conceptualization of the meloscine problem can be
envisioned, Scheme 2. Advances in allenyl azide cascade cyclization
chemistry6 has enabled the development of a synthesis strategy for
meloscine that features efficient formation of the C/D ring azabi
cyclo[3.3.0]octane core with complete relative stereochemical
control at C(7) and C(16). In this strategy, allenyl azide 19 plays
a pivotal role; thermolysis of this species is expected to proceed
through a reaction sequence involving first [3þ2] cycloaddition to
deliver an unisolable triazoline 18 whose subsequent fragmenta
tion is driven by release of strain.6d,g Loss of N2 from 18 should
furnish the singlet diyl 17, which is poised for formal electro
cyclization through a conrotatory pathway to provide the C/D ring
bicyclic product 16 as the diastereomer shown.6d,g Two further
operations are required in order to convert 16 into the target
meloscine; (1) union of the aryl ring with a carboxylic acid de
rivative, which would be revealed by deprotecting the OBO func
tion, to deliver lactam ring B, and (2) construction of
Three issues were paramount at the outset of the meloscine
synthesis effort as delineated in Scheme 2: (1) Would the ring
closing metathesis to form the E ring proceed with satisfactory
diastereoselectivity? (remembering that neither the Mukai nor the
Curran precedents were reported yet) (2) What X group at the ortho
position of the aryl ring would be tolerated during the chemistry
used to prepare an advanced intermediate B ring precursor? (3)
Should the E ring or the B ring be closed first? Either option has the
potential to rigidify the resultant molecular skeleton and thereby
influence the facility of the second choice ring closure.
The first issue (metathesis diastereoselectivity) was addressed
with a model system that explicitly tested the metathesis based
closure of the E ring but avoided any issues associated with the
nature of the ‘X’ substituent or its use in lactam ring closure,
Scheme 3. In this model system, the simple unfunctionalized ben
zoyl derivative 208 served as the launch point. Acetylide addition to
20 and acetylation of the resulting alcohol delivered the activated

1436
K.S. Feldman, J.F. Antoline / Tetrahedron 69 (2013) 1434 1445
oxidation of the alcohol within 25 with aqueous formaldehyde and
base furnished the diol 26 in moderate yield and free of byproducts.
The structure and stereochemistry of diol 26 were verified by single
crystal X ray analysis.12
The anticipated problems with a C(20) dialdehyde became real
when the next operationwas attempted; the double oxidation of the
diol within 26 to give the corresponding dialdehyde. Initial failures
with standard oxidation protocols (Swern, PCC, DesseMartin, Par
ikheDoering all resulted in formation of only traces of aldehyde
containing products) led to a rethinking of the problem. TLC evi
dence indicated that in each case, starting diol 26 was readily con
sumed but complex product mixtures, whose mass spectrometric
analysis was consistent with the presence of compounds containing
CH(CHO) and C(CH2OH)(CHO) units, resulted. If product dialdehyde
instability was the issue, then a procedure that minimized the time
that the product was exposed to nucleophilic/basic media might be
advantageous. Toward this end, the rate accelerating effects of
water in DesseMartin oxidations have been noted.13 This modifi
cation was attempted, but the reaction still produced complex
mixtures of aldehyde containing products. Microwave irradiation
of reactions also can provide rate acceleration, and so that experi
mental modification was employed, finally to great consequence.
The dialdehyde derived from diol 26 could be prepared in relatively
clean form and in good yield by a brief microwave assisted water
saturated DesseMartin oxidation protocol, but all attempts to
concentrate, isolate, and characterize this dialdehyde were accom
panied by extensive decomposition. Thus, the dialdehyde was used
as a crude material. Exposure of this sensitive dialdehyde to a large
excess of preformed methylenetriphenylphosphorane proceeded
smoothly to deliver the C(20) divinyl product 27 in overall excellent
yield.
Scheme 3. A meloscine model system to validate the E-ring assembly strategy.
Conversion of the N Boc moiety within 27 into the correspond
ing N allyl derivative proceeded uneventfully, and the tri alkene 28
was in hand to test the final CeC bond forming transformation.
Density functional calculations14 suggested that the desired C(20)
vinyl epimer 29 should be more stable than the C(20) epimeric al
ternative by 12 kcal/mol. Use of the Grubbs II metathesis reagent
should permit the system to reach equilibrium, thus exploiting this
energy difference to achieve the desired diastereoselectivity. In the
event, treatment of triene 28 with a catalytic amount of Grubbs II
catalyst in refluxing methylene chloride sufficed to deliver only the
desired C(20) epimer of tricycle 29, with an intact E ring as per the
ultimate meloscine synthesis goal. Thus, this model system ad
dresses the first strategic concern and sets the stage for exploration
of the other two issues en route to the authentic target meloscine.
The second questions raised above regarding the identity of the
aryl substituent ‘X’ in cyclization substrate 19 was addressed in
a simpler model system (H3CeC^CeLi addition rather than
TBSOCH2C^CeLi addition to ArC(]O)CH2CH2N3) in an earlier
study.6d Attempts to prepare and cyclize allenyl azide substrates
related to 22 with either ortho NO2 or ortho BocHN groups on the
aryl ring did not afford any bicyclic product. These failures left the
ortho bromo alternative as the most attractive option, as detailed
below. This choice of aryl substituent places constraints on the type
of carboxylic acid derivative that can be employed in B ring for
mation, and also on the type of amide forming chemistry planned
for the closure of the B ring (vide infra).
propargyl system 21, which was vinylated using Vermeer’s9 Zn/Pd
based protocol. This allene forming procedure has proven quite
reliable and robust for forming allenyl azide cyclization sub
strates.6d The product allenyl azide exhibited only marginal sta
bility and so it was heated immediately in refluxing toluene to
initiate the cascade cyclization sequence and furnish the meloscine
model system C/D bicyclic core 23 in good yield.
Hydrogenation of the cyclopentenyl alkene within 23 provided
the partially saturated system 24 as an inconsequential mixture of
diastereomers whose ratio varied from run to run. Reduction of the
imine function could not be realized through hydrogenation under
a variety of conditions, presaging one of the more unexpectedly
difficult transformations of the sequence. Many hydride sources
and reaction conditions were examined (i.e., L Selectride,
NaBH3CN/CSA, allyl iodide, then NaBH3CN) before a successful and
reproducible reduction procedure utilizing superhydride at ele
vated temperature was identified. Steric hindrance is plausibly the
culprit, a conclusion consistent with the subsequent failure to at
tach a Boc group to the secondary amine formed from 24 under
standard (Boc2O, DMAP) conditions. Recourse to the more forcing
conditions of Harris,10 which feature a transient O Boc hydroxyl
amine intermediate, did proceed in only modest yield. Desilylation
of the TBS ether in 24 and then oxidation of the resulting primary
alcohol in 25 affords an intermediate aldehyde that serves as input
for one of the key transformations of the synthesis; introduction of
the quaternary all carbon center at C(20). One potential concerning
aspect of the plan to generate a C(20) dialdehyde from 25 extends
The first implementation of these lessons learned began with
the acetate 31a, prepared from the ortho bromoaryl substituted
azide 30,6d Scheme 4. However, this apparently routine beginning
became less than auspicious as this acetate was unreactive in the
Vermeer palladium mediated zincate addition that served so re
liably in all earlier studies. The presence of the OBO group on the
alkene initially was assumed to be responsible for the failure to
react, given that the simple ethylene zincate H2C]CHeZnCl did
work with a similar arylbromide containing substrate6d and with
from the propensity of such systems (or a precursor
a hydrox
ymethyl aldehyde) to suffer facile deformylation or decarbon
ylation. Fortunately, a well precedented workaround presented
itself; use of a Tollens type aldol reaction,11 which generates a dia
lcohol product and thereby avoids all deformylation (decarbon
ylation) triggers. Thus, simply treating the aldehyde derived by

K.S. Feldman, J.F. Antoline / Tetrahedron 69 (2013) 1434 1445
1437
Apparently, access to the CeO bond of silyl ether 33 by the Pt
surface is competitive with simple alkene hydrogenation, leading to
the mixture of 34 and 35. That observation suggests that discour
aging such access, perhaps by increasing the steric profile of the
silyl ether, may suffice to turn the product distribution toward the
desired hydrogenated species. A test of this simple premise was
executed with the TIPS ether analogue of propargyl alcohol,
Scheme 5. Optimization studies of carbonate formation led to the
discovery that performing the initial alkynyl lithiate addition to 30
in CH2Cl2 rather than in THF resulted in far superior yields of the
intermediate alcoholate, and hence better yields of the derived
carbonate 36. The remainder of the azabicyclo[3.3.0]octane prep
aration proceeded without event, and the key C/D ring synthon 38
was formed in overall good yield from carbonate 36. The structure
and stereochemistry of 38 were confirmed by single crystal X ray
analysis.7 In the critical departure from the failed Scheme 4
chemistry, hydrogenation of 38 at high pressure under Pt cataly
sis produced the alkene hydrogenation product 39 with only trace
amounts of a hydrogenolysis byproduct detected. At this point,
reliance on the chemistry developed with the model system
(Scheme 3) sufficed to push the hydrogenation product 39 through
to the C(20) quaternary diol 41. The conversion of monoalcohol 40
into the diol 41 benefited from some optimization efforts relative to
the model system work. Application of the ‘standard’ ( model
system, 25/26) DesseMartin oxidation conditions to 40 pro
ceeded in 32e78% yield to 41, but application of the newly for
mulated superior conditions to the oxidation of 40 (microwave
assisted, water saturated CH2Cl2 solvent, heating to 65 ꢁC) led to
yield improvement. In addition, initial application of the model
Scheme 4. Synthesis of the meloscine C/D bicyclic core via allenyl azide cascade cy-
clization chemistry first attempt.
31a as well.15 An additional control experiment documented that
the OBO bearing zincate (prepared from the corresponding known
lithiate)16 did react smoothly with the des bromo substrate 21 to
give allene product.15 Thus, neither the OBO group nor the presence
of the aryl bromide per se appears sufficient to shut down the
Vermeer chemistry. However, their combination apparently is
deadly to the prospects of forming 32 from 31a. A suitable com
promise between reactivity and stability was found with the car
bonate 31b,17 which did engage the OBO bearing zincate in
productive allene formation and produced the desired cascade
cyclization substrate 32 in good yield. Unfortunately, this allenyl
azide was not stable to isolation and purification by chromatogra
phy, and so the crude allene formed from the zincate addition was
subjected to immediate thermolysis in toluene to afford the ex
pected azabicyclo[3.3.0]octane core of the meloscine structure, 33,
with the key C(7)/C(16) stereochemical relationship set as antici
pated (vide supra).
Standard palladium mediated hydrogenation of the cyclo
pentenyl alkene of 33 via the same procedure used in the des
bromo model system 23 was not an option, given the facility of
palladium mediated AreBr hydrogenolysis. In addition, the acid
lability of the OBO group might render even trace production of HBr
(from minor hydrogenolysis of the AreBr bond) problematic.
Therefore, an extensive catalyst screening effort was undertaken
with 33 and various Pd, Pt, Ni, and Ir based systems in protic and
non protic solvents, at a range of H2 pressures (15e1100 psi), and
with various basic additives. In the end, the only satisfactory con
ditions identified involved Pt/C with Et3N as additive at 1100 psi of
H2 in benzene. Under these specified conditions, the cyclopentenyl
system 33 was converted to an equal mixture of the desired hy
drogenated product 34 and the overreduced hydrogenolysis prod
uct 35. The Br moiety survived intact, but the OTBS ether did not.
This observation led to a minor rerouting of the meloscine syn
thesis approach in order to remove the silyl ether vulnerability.
Scheme 5. Synthesis of the meloscine C/D bicyclic core via allenyl azide cascade cy-
clization chemistry second attempt introduction of the C(20) quaternary center.

1438
K.S. Feldman, J.F. Antoline / Tetrahedron 69 (2013) 1434 1445
system Tollens aldol conditions (KOH, methanol, aqueous formal
dehyde, room temperature) to the aldehyde derived from 40 was
not successful; complete consumption of the aldehyde with no
product diol formation was observed. However, simply elevating
the reaction temperature to 55 ꢁC and using ethylene glycol and
CH2Cl2 as co solvents overcame whatever problems derailed the
room temperature reaction, and the desired diol 41 was formed in
excellent yield.
At this juncture, a strategic decision was at hand; should B ring
formation (41/43) or should E ring formation (41/42) be pur
sued first? Furthermore, the precise timing of OBO hydrolysis fac
tored into this decision, as the OBO group’s acid sensitivity might
limit some approaches to either target 42 or 43. Following the best
traditions of natural product synthesis, all options were pursued
simultaneously, with the winning approach to be identified only in
retrospect.
Initial scouting experiments designed to probe the ‘E ring first’
strategy with the OBO group intact are shown in Scheme 6. The diol
41 could be oxidized under standard DesseMartin conditions and
the resulting sensitive dialdehyde was immediately methylenated
with a large excess of Wittig reagent to provide the divinyl species
44. Partial hydrolysis of the OBO unit in 44 under mild acid catalysis
appeared by 1H NMR spectroscopic analysis to provide an in
termediate 2 methyl 2 (hydroxymethyl)propane 1,3 diol ester.
Unfortunately, all attempts at aminolysis of this intermediate ester
met with either recovery of the ester or complete decomposition. A
reordering of operations seemed justified after this disappointing
result, and so initial hydrolysis/aminolysis of the OBO unit prior to
diol functionalization was pursued next. Acid mediated hydrolysis
of OBO diol 41 again provided an intermediate ester 44, which
resisted aminolysis under anything less than forcing conditions.
High pressures of ammonia maintained in a Parr bomb apparatus in
methanol solvent at 150 ꢁC provided the first glimpse of success, as
small amounts of the desired amide 47 along with methyl ester 46
were isolated. Resubmission of the methyl ester 46 to aminolysis
conditions led to some conversion to the amide 47, but the yield
remained low even after extended reaction times. These observa
tions undermined one of the assumptions underlying this experi
mental approach; passage through an intermediate methyl ester
was initially presumed to be a favorable (or at least not unfavor
able) event, as aminolysis of methyl esters are typically facile.18
Rather, it appeared that methyl ester 46 was actually a ‘trap’ for
substrate from which formation of the desired primary amide was
difficult at best. The obvious workaround was to remove the
offending methanol from the reaction medium. Substitution of
isopropanol as solvent throughout but otherwise maintaining the
vigorous Parr bomb conditions led to formation of the desired
primary amide 47 in good yield, and free of any ester byproduct.
The acquisition of primary amide 47 provided a new substrate
upon which to revisit the earlier question, ‘E ring first or B ring
first?’ An ‘E ring first’ strategy requires conversion of the diol in 47
into a divinyl derivative, Scheme 7. Oxidation of this diol under the
modified DesseMartin conditions did furnish the unstable dia
ldehyde as a clean compound that, like the related dialdehydes
discussed earlier, resisted chromatographic purification. As in the
earlier studies (Scheme 3, 25/26 and Scheme 5, 40/41), a large
excess of preformed methylenetriphenylphosphorane was added
to this crude dialdehyde. Unfortunately, only dialdehyde de
composition ensued, and no characterizable compounds were iso
lated. Exploration of alternative methylenation procedures (Tebbe’s
reagent, Cp2TiMe2, TMSCH2Li, even a few phosphonates) was no
more successful. The primary amide function appeared to be in
compatible with any methylenation conditions attempted. Thus, the
‘E ring first’ strategy was put to rest.
Scheme 7. Completion of the synthesis of (ꢀ)-meloscine.
The ‘B ring first’ approach commenced with a transition metal
mediated amidation reaction between the primary amide nitrogen
and the aryl bromide within 47. Many variants of this formal aza
Ullmann coupling have been described, but the simplicity and re
liability of a Goldberg type Cu mediated recipe stood out.19 In fact,
exposure of 47 to CuI/1,10 phenanthroline in DMSO under both
heating and microwave irradiation19c delivered the intact lactam
ring in excellent yield. No evidence for any debrominated material
was forthcoming. With the E ring installed, attention turned to the
C(20) diol moiety, whose oxidation/methylenation now had to
transpire with the added constraint of the presence of the sec
ondary amide. Fortunately, this sequence proceeded without any
interference from the amide unit, and the C(20) divinyl containing
product 49 was formed in good yield. The large excess of Wittig
reagent necessary to push the bis methylenation to completion had
in this case a deleterious side effect; it proved impossible to purify
the divinyl compound 49 from byproducts from the excess Wittig
species. Therefore, it was expedient at this point to simply carry the
Scheme 6. Functionalization along the C/D core periphery.

K.S. Feldman, J.F. Antoline / Tetrahedron 69 (2013) 1434 1445
1439
impure 49 through the Boc removal/N allylation sequence and
purify triene product 13. Triene 13 was subjected to the same
Grubbs ring closing metathesis conditions observed to be suc
cessful in the model series (Scheme 3, 28/29) in order to close off
the E ring and deliver (ꢀ) meloscine (1) free of any C(20) epimeric
material.
with CH2Cl2 (3ꢂ75 mL). The combined organics were washed with
water (2ꢂ100 mL), brine (100 mL), and dried over Na2SO4. The
solution was filtered and concentrated in vacuo. The crude mixture
was purified by column chromatography on SiO2 (5% ethyl acetate
in hexanes) to give acetate 21 as a yellow oil (18.4 g, 75%). IR (thin
film) 2099, 1754 cmꢃ1
;
1H NMR (360 MHz, CDCl3)
d
7.53 (d,
8.3 Hz, 2H), 7.38e7.27 (m, 3H), 4.49 (s, 2H), 3.53 (ddd, J 12.4,
10.0, 5.8 Hz, 1H), 3.34 (ddd, J 12.5, 9.9, 5.4 Hz, 1H), 2.46 (ddd,
13.4, 9.6, 5.6 Hz, 1H), 2.21 (ddd, J 13.6, 9.8, 5.6 Hz, 1H), 2.07 (s,
3H), 0.96 (s, 9H), 0.17 (s, 6H); 13C NMR (90 MHz, CDCl3)
167.8,
J
3. Conclusions
J
The Melodinus alkaloid meloscine was prepared by total chem
ical synthesis over 19 steps from ortho bromobenzaldehyde in 2.2%
yield overall. This route compares favorably with the earlier ap
proaches of Overman (26 steps), Bach (25 steps), and Mukai (22
steps), but is less efficient than Curran’s strategy (13 steps). Notable
transformations that emerged from this chemistry include (1)
a completely diastereoselective diradical cyclization at the termi
nus of an allenyl azide cyclization cascade, (2) a Tollens type aldol
to install an all carbon quaternary center in a sterically congested
environment, and, as per the Mukai and Curran work, (3) a dia
stereoselective ring closing metathesis to deliver the final ring of
this pentacyclic target.
d
140.5, 128.4, 128.0, 124.8, 88.0, 81.5, 76.8, 51.6, 47.0, 42.9, 25.6, 21.4,
18.1, 5.3; HRMS (TOF MS ESþ) [MþHþ] calcd for C20H30N3O3Si
388.2056, found 388.2050.
4.3. (6-Azido-4-phenyl-2-vinylhexa-2,3-dienyloxy)-tert-bu-
tyldimethylsilane (22)
To a solution of ZnCl2 (2.81 g, 2.84 mmol) in THF (150 mL) was
added vinyl magnesium bromide (1.0 M in THF, 20.6 mL, 21 mmol).
The solution was stirred at room temperature for 80 min. Solutions
of Pd(PPh3)4 (0.596 g, 0.516 mmol) in THF (25 mL) and acetate 21
(4.00 g, 10.3 mmol) in THF (25 mL) were added sequentially via
cannula. The mixture was stirred for 1 h, then saturated NH4Cl
solution (150 mL) and Et2O (150 mL) were added. The organic layer
was separated and the aqueous layer was extracted with Et2O
(3ꢂ150 mL). The combined organic layers were washed with water
(2ꢂ100 mL) and brine (150 mL), dried over Na2SO4, and concen
trated in vacuo. The crude product was purified by column chro
matography on SiO2 using hexanes as the eluent to give allene 22
(2.44 g, 66%) as a clear oil. IR (thin film) 2097, 1930 cmꢃ1; 1H NMR
4. Experimental
4.1. General experimental
All moisture and oxygen sensitive reactions were carried out in
flame dried glassware under a nitrogen atmosphere unless other
wise stated. Dry solvents such as acetonitrile, dichloromethane,
diethyl ether, tetrahydrofuran, toluene, and triethylamine were
obtained by passing the commercial solvent through activated
alumina columns. Unless otherwise stated, reagents were pur
chased at the highest commercial quality and used without further
purification. Thin layer chromatography was carried out on EMD
0.25 mm silica gel plates with UV visualization or by staining with
potassium permanganate or ceric ammonium molybdate. Purifi
cation of products via flash chromatography was performed with
(300 MHz, CDCl3)
5.32 (d, J 17.7 Hz, 1H), 5.13 (d, J 10.9 Hz, 1H), 4.35 (s, 2H), 3.47 (t,
7.1 Hz, 1H), 2.76 (t, J 7.2 Hz, 1H), 0.86 (s, 9H), 0.03 (d, J 8.0 Hz,
6H); 13C NMR (75 Hz, CDCl3)
206.2, 135.7, 131.9, 128.5, 127.2, 126.1,
d 7.37e7.22 (m, 5H), 6.28 (dd, J 17.7, 10.9 Hz, 1H),
J
d
114.5, 109.9, 105.1, 61.2, 49.8, 29.7, 25.7, 18.2, 5.4; HRMS (TOF MS
ESþ) [M N2þHþ] calcd for C20H30NOSi 328.2097, found 328.2093.
the indicated solvent system using 40e63
m
m silica gel. Melting
4.4. 6-(((tert-Butyldimethylsilyl)oxy)methyl)-3a-phenyl-
2,3,3a,4-tetrahydrocyclopenta[b]pyrrole (23)
points are uncorrected. High resolution mass spectra were ob
tained according to the technique specified and were performed at
the Pennsylvania State University Proteomics and Mass Spectrom
etry Core Facility, University Park, PA. X ray data were obtained at
Pennsylvania State University X ray Crystallography Facility, Uni
versity Park, PA.
Allene 22 (1.73 g, 4.87 mmol) was dissolved in toluene (300 mL,
0.016 M) and sparged with a stream of nitrogen for 30 min. The
solution was heated to 110 ꢁC for 1 h and then concentrated in
vacuo to give a yellow oil. The oil was purified by column chro
matography on SiO2 (2e5% ethyl acetate/hexanes) to give 23
(1.08 g, 68%) as a clear oil. IR (thin film) 2359, 1637 cmꢃ1; 1H NMR
4.2. Acetic acid 1-(2-azido-ethyl)-4-(tert-butyldimethylsila-
nyloxy)-1-phenyl-but-2-ynyl ester (21)
(300 MHz, CDCl3) d 7.29e7.15 (m, 5H), 6.63 (s, 1H), 4.63 (d, J 2.7 Hz,
2H), 4.12 (dd, J 14.9, 7.2 Hz, 1H), 3.79 (ddd, J 18.0, 10.5, 4.8 Hz, 1H),
2.70 (m, 2H), 2.21 (dd, J 11.8, 4.7 Hz, 1H), 2.05 (td, J 11.2, 7.2 Hz,
A solution of tert butyldimethyl 2 propynyloxysilane (13.9 g,
81.6 mmol) in THF (150 mL) was cooled to 78 ꢁC and n butyl
lithium (2.5 M in hexanes, 30.1 mL, 75.4 mmol) was added drop
wise. The reaction mixture was stirred for 1 h at 78 ꢁC, after which
1H), 0.93 (s, 9H), 0.01 (s, 6H); 13C NMR (75 Hz, CDCl3)
d 188.7, 144.4,
144.0, 140.0, 128.2, 126.41, 126.40, 64.4, 64.0, 58.9, 43.3, 41.1, 25.8,
18.3, 5.0; HRMS (TOF MS ESþ) [MþHþ] calcd for C20H30NOSi
328.2097, found 328.2099.
a
solution of 3 azido 1 phenylpropan 1 one (20) (11.0 g,
62.8 mmol) in THF (150 mL) was added via cannula. The mixture
was stirred at 78 ꢁC for 1.5 h, and then treated with saturated
aqueous NH4Cl (150 mL). The organic layer was separated and the
aqueous phase was extracted with diethyl ether (3ꢂ150 mL). The
combined organics were washed with water (2ꢂ200 mL), brine
(150 mL), and then dried over Na2SO4. The solution was concen
trated in vacuo to give a clear yellow oil.
4.5. 6-(((tert-Butyldimethylsilyl)oxy)methyl)-3a-phenyl-
2,3,3a,4,5,6-hexahydrocyclopenta[b]pyrrole (24)
To a solution of 23 (1.00 g, 3.05 mmol) in Et2O (30 mL) was
added 10% palladium on carbon (0.300 g 0.156 mmol, 5 mol %). The
suspension was stirred under 1 atm H2 for 72 h, then filtered
through Celite and concentrated in vacuo to give a yellow oil. This
crude oil was purified by column chromatography on SiO2 (2e5%
ethyl acetate in hexanes) to give imine 24 (0.959 g, 95%, 1:1 mixture
The crude oil was dissolved in CH2Cl2 (300 mL), cooled to 0 ꢁC,
and treated with 4 dimethylaminopyridine (26.1 g, 214 mmol) and
acetic anhydride (10.9 g, 107 mmol). The reaction solution was
allowed to warm to room temperature while stirring for 16 h. The
reaction mixture was then treated with 1 M H3PO4 (100 mL). The
organic layer was separated and the aqueous phase was extracted
of diastereomers) as a clear oil. IR (thin film) 1665 cmꢃ1
(400 MHz, CDCl3) 7.31e7.26 (m, 2H), 7.21e7.16 (m, 3H), 4.13 (m,
1H), 4.00 (dd, J 9.9, 4.3 Hz,1H), 3.90 (m,1H), 3.68 (dd, J 9.8, 7.9 Hz,
;
1H NMR
d

1440
K.S. Feldman, J.F. Antoline / Tetrahedron 69 (2013) 1434 1445
1H), 2.74 (m, 1H), 2.29 (ddd, J 12.3, 6.7, 1.5 Hz, 1H), 2.08e1.95 (m,
4H), 1.74 (dt, J 11.7, 8.4 Hz, 1H), 0.88 (s, 9H), 0.05 (s, 6H); 13C NMR
solution was diluted with brine (15.0 mL) and extracted with
dichloromethane (4ꢂ10.0 mL). The combined organic layers were
dried over Na2SO4, filtered, and concentrated in vacuo to give
a yellow oil. The oil was purified by column chromatography
(10e15e30e35% ethyl acetate/hexanes) to give diol 26 (0.064 g,
(both diastereomers, CDCl3, 90 MHz)
d 190.9, 143.1, 128.5, 126.4,
126.0, 66.1, 64.9, 64.0, 41.5, 38.6, 36.0, 29.2, 25.8, 18.1, 5.5; HRMS
(TOF MS ESþ) [MþH]þ calcd for C20H32NOSi 330.2253, found
330.2250.
51%) as a clear oil. IR (thin film) 3398, 1660 cmꢃ1
;
1H NMR
7.32 (app t, J 7.5 Hz, 2H), 7.23e7.18 (m, 3H),
(300 MHz, CDCl3)
d
4.6. tert-Butyl 6-(hydroxymethyl)-3a-phenylhexahydrocyclo-
penta[b]pyrrole-1(2H)carboxylate (25)
4.27 (s, 1H), 3.90 (s, 1H), 3.68 (app t, J 9.6 Hz, 1H), 3.51e3.31 (m,
4H), 2.21e2.10 (m, 2H), 2.03e1.85 (m, 2H), 1.69e1.64 (m, 2H), 1.49
(s, 9H); 13C NMR (75 MHz, CDCl3)
d 156.3, 147.3, 128.5, 126.3, 125.4,
A solution of super hydride (1.0 M in THF, 9.1 mL, 9.1 mmol) was
added dropwise to a solution of imine 24 (1.00 g, 3.0 mmol) in THF
(30 mL). There was an initial vigorous evolution of gas that subsided
quickly. The mixture was heated at 65 ꢁC for 48 h, then cooled to
0 ꢁC, and the excess hydride was neutralized by the slow addition of
ice. Ethyl acetate (20 mL) and water (30 mL) were added and the
organic layer was drawn off. The aqueous layer was extracted with
ethyl acetate (3ꢂ20 mL) and the combined organic layers were
washed with brine (1ꢂ30 mL) and dried over Na2SO4. The solution
was filtered and concentrated in vacuo to give the secondary amine
as a clear oil.
80.8, 70.7, 66.3, 65.1, 58.7, 52.7, 46.6, 38.5, 34.9, 30.5, 28.4; HRMS
(TOF MS ESþ) [MþH]þ calcd for C20H30NO4 348.2175, found
348.2194.
4.8. tert-Butyl-3a-phenyl-6,6-divinylhexahydrocyclopenta[b]
pyrrole-1(2H)carboxylate (27)
A microwave reaction tube was charged with alcohol 26
(0.055 g, 0.158 mmol) and water saturated dichloromethane
(1.5 mL). DesseMartin periodinane (0.336 g, 0.791 mmol) was
added in a single portion and the tube was flushed with nitrogen
and then sealed with a Teflon cap. The reaction mixture was heated
via microwave irradiation at 65 ꢁC for 30 min and then cooled to
room temperature. A 1:1 solution of saturated aqueous NaHCO3/
saturated aqueous Na2S2O3 (6 mL) was added and the biphasic
mixture was stirred until all of the solids had dissolved and the
mixture was clear. The mixture was poured into a separatory funnel
and the organic layer was drawn off. The aqueous layer was
extracted with dichloromethane (3ꢂ5 mL). The combined organic
layers were dried over Na2SO4 and concentrated in vacuo to give
the desired dialdehyde as a pale yellow oil.
The crude amine was dissolved in CH2Cl2 (30 mL) and triethyl
amine (2.9 mL, 21 mmol), Boc2O (2.3 g, 11 mmol), and hydroxyl
amine hydrochloride (0.42 g, 6 mmol) were added sequentially. The
mixture was stirred for 24 h at room temperature and an additional
1 equiv of Boc2O (0.66 g, 3.0 mmol) was added. The solution was
stirred for an additional 48 h and then concentrated in vacuo to give
a yellow oil. This crude oil was dissolved in hexanes and passed
through a short plug of SiO2 (2% ethyl acetate in hexanes) to remove
the bulk of the contaminants and then concentrated in vacuo to
give a clear oil. The oil was dissolved in THF (30 mL) and Bu4NF
(1.0 M in THF, 10 mL, 10 mmol) was added. The solution was stirred
for 18 h at room temperature then was diluted with water (30 mL)
and ethyl acetate (20 mL) was added. The layers were separated and
the aqueous layer was extracted with ethyl acetate (1ꢂ20 mL) and
CH2Cl2 (2ꢂ20 mL). The combined organics were dried over Na2SO4,
filtered, and concentrated in vacuo to give a yellow oil. The crude
alcohol was purified by column chromatography on SiO2
(5e10e15% ethyl acetate/hexanes) to give alcohol 25 (0.20 g, 20%,
A
suspension of methyltriphenylphosphonium bromide
(0.565 g, 0.1.58 mmol) in THF (0.200 mL) was cooled to 78 ꢁC and
a solution of NaHMDS (1.0 M in THF, 1.50 mL,1.50 mmol) was added
dropwise. The suspension was stirred at 78 ꢁC for 1.5 h. The crude
dialdehyde was dissolved in 0.200 mL of THF and added via cannula
to the ylide suspension, rinsing the flask with an additional
0.150 mL of THF. The reaction mixture was allowed to warm to
room temperature and stirred at that temperature for 72 h. Satu
rated aqueous ammonium chloride (5 mL) and ethyl acetate (5 mL)
were added. The organic layer was drawn off and the aqueous layer
was extracted with ethyl acetate (1ꢂ5.00 mL) and CH2Cl2
(2ꢂ5.00 mL). The combined organics were dried over Na2SO4, fil
tered, and concentrated in vacuo to give a brown oil. The oil was
purified by SiO2 column chromatography (hexanes to 1e5% EtOAc/
hexanes) to give 27 as a clear oil (0.049 g, 91%, 1:2 mixture of
mixture of rotamers) as a yellow oil. IR (thin film) 3432, 1667 cmꢃ1
1H NMR (major rotamer, 300 MHz, CDCl3)
7.34e7.18 (m, 5H), 4.72
;
d
(dd, J 11.3, 2.9 Hz, 1H), 4.63 (d, J 6.1 Hz, 1H), 3.73 (ddd, J 11.6, 7.5,
5.4 Hz, 1H), 3.60 (td, J 11.5, 3.7 Hz, 1H), 3.47 (td, J 10.9, 3.5 Hz, 1H),
3.29 (dt, J 11.5, 7.6 Hz, 1H), 2.49 (m, 1H), 2.21e1.93 (m, 4H), 1.76
(dd, J 12.6, 6.4 Hz, 1H), 1.49 (s, 9H), 1.33 (m, 1H); 13C NMR (75 MHz,
CDCl3)
d 156.5, 148.5, 128.5, 126.1, 125.4, 80.6, 67.8, 62.3, 58.1, 49.7,
47.5, 40.1, 39.8, 28.4, 28.3; HRMS (TOF MS ESþ) [MþH]þ calcd for
rotamers). IR (thin film) 1894 cmꢃ1
major rotamer) 7.34e7.20 (m, 5H), 6.17e5.92 (m, 2H), 5.10e5.00
(m, 4H), 4.35 (s, 1H), 3.65e3.36 (m, 2H), 2.21e1.92 (m, 6H), 1.49 (s,
9H); 13C NMR (75 MHz, CDCl3, both rotamers)
154.3, 148.4, 148.3,
;
1H NMR (300 MHz, CDCl3,
C19H27NO3 318.2069, found 318.2060.
d
4.7. tert-Butyl 6,6-bis(hydroxymethyl)-3a-phenylhexahydroc-
yclopenta[b]pyrrole-1(2H)carboxylate (26)
d
144.3,143.9, 141.3, 128.4, 126.1, 125.7,125.5, 113.2, 112.5,112.4, 112.2,
79.9, 79.2, 75.3, 75.0, 59.1, 58.0, 55.3, 54.7, 46.4, 46.1, 39.0, 38.0, 36.4,
36.0, 33.4, 32.6, 29.7, 28.5; HRMS (TOF MS ESþ) [MþH]þ calcd for
C22H30NO2 340.2277, found 340.2279.
To a solution of alcohol 25 (0.114 g, 0.359 mmol) in CH2Cl2
(15.0 mL) was added DesseMartin periodinane (0.457 g,1.08 mmol)
in one portion. The reaction mixture was stirred at room temper
ature for 45 min. A 1:1 solution (10.0 mL) of saturated aqueous
NaHCO3/saturated aqueous Na2S2O3 was added and the biphasic
mixture was stirred until all of the solids had dissolved and the
mixture was clear. The mixture was poured into a separatory funnel
and the organic layer was drawn off. The aqueous layer was
extracted with dichloromethane (3ꢂ15.0 mL). The combined or
ganic layers were dried over Na2SO4 and concentrated in vacuo to
give a yellow oil. The oil was dissolved in methanol (7 mL), and
aqueous formaldehyde (37% w/w, 1.43 mL, 19.1 mmol) and potas
sium hydroxide (0.371 g, 5.62 mmol) were added sequentially. The
solution was stirred at room temperature for 48 h. The reaction
4.9. 1-Allyl-3a-phenyl-6,6-divinyloctahydrocyclopenta[b]pyr-
role (28)
Carbamate 27 (0.012 g, 0.035 mmol) was dissolved in 10% tri
fluoroacetic acid/CH2Cl2 (1 mL) and stirred for 16 h at room tem
perature. The reaction mixture was concentrated in vacuo to give
a brown oil. This oil was redissolved in CH2Cl2 (5 mL), washed with
saturated sodium bicarbonate (10 mL) and brine (10 mL), dried over
Na2SO4, filtered, and concentrated in vacuo to give the crude amine
as a brown oil. This crude oil was dissolved in THF (0.5 mL). Allyl
bromide (0.040 mL, 0.53 mmol) and lithium hydroxide

K.S. Feldman, J.F. Antoline / Tetrahedron 69 (2013) 1434 1445
1441
monohydrate (0.106 g, 1.41 mmol) were added sequentially. The
resulting solution was heated at 65 ꢁC for 18 h. The reaction mixture
then was cooled to room temperature and diluted with water
(5 mL) and EtOAc (5 mL). The layers were separated, and the
aqueous layer was extracted with EtOAc (3ꢂ5 mL), washed with
water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and
concentrated in vacuo to give a brown oil. This oil was purified by
SiO2 column chromatography to give 28 as a clear oil (0.007 g, 70%).
concentrated in vacuo. The crude reaction mixture was purified by
column chromatography on SiO2 (5% ethyl acetate in hexanes) to
give acetate 31a as a yellow oil (7.82 g, 59%). IR (thin film) 2098,
1754 cmꢃ1; 1H NMR (300 MHz, CDCl3)
d 7.94 (dd, J 7.9, 1.7 Hz, 1H),
7.57 (dd, J 7.9, 1.3 Hz, 1H), 7.32 (td, J 7.6, 1.3 Hz, 1H), 7.14 (td, J 7.6,
1.7 Hz, 1H), 4.48 (s, 2H), 3.59 (ddd, J 12.4, 9.6, 5.9 Hz, 1H), 3.39
(ddd, J 12.4, 9.5, 5.7 Hz, 1H), 2.79 (ddd, J 13.7, 9.5, 5.9 Hz, 1H), 2.38
(ddd, J 13.7, 9.6, 5.6 Hz, 1H), 2.11 (s, 3H), 0.93 (s, 9H), 0.14 (s, 6H);
IR (thin film) 2360 cmꢃ1; 1H NMR (400 MHz, CDCl3)
d
7.34e7.27 (m,
13H NMR (75 MHz, CDCl3)
d 168.1, 138.1, 137.5, 135.5, 130.3, 129.6,
4H), 7.18 (m, 1H), 6.26 (dd, J 17.7, 10.7 Hz, 1H), 5.94 (dddd, J 15.1,
10.1, 7.9, 4.9 Hz,1H), 5.70 (dd, J 17.8,11.0 Hz,1H), 5.21 (d, J 12.8 Hz,
1H), 5.11e5.01 (m, 4H), 4.92 (d, J 13.3 Hz, 1H), 3.55 (dd, J 13.5,
4.9 Hz, 1H), 3.36 (s, 1H), 3.03e2.98 (m, 2H), 2.39 (ddd, J 12.2, 9.0,
5.3 Hz, 1H), 2.18e1.89 (m, 5H), 1.71 (dd, J 12.1, 5.3 Hz, 1H); 13C NMR
127.4, 118.6, 88.5, 81.5, 77.7, 51.7, 47.3, 38.9, 25.7, 21.1, 18.2, 5.2;
HRMS (TOF MS ESþ) [MþH]þ calcd for C20H29N3O3SiBr 466.1162,
found 466.1166.
4.12. 1-Azido-3-(2-bromophenyl)-6-((tert-butyldimethylsilyl)
(75 MHz, CDCl3)
d
150.1, 143.3, 142.8, 136.3, 128.0, 126.3, 125.4,
oxy)hex-4-yn-3-yl methyl carbonate (31b)
116.3, 114.6, 113.2, 80.8, 59.0, 58.9, 55.1, 52.5, 41.6, 38.3, 34.4; HRMS
(TOF MS ESþ) [MþH]þ calcd for C20H26N 280.2065, found 280.2051.
A
solution of tert butyldimethyl(prop 2 yn 1 yloxy)silane
(12.7 g, 62.8 mmol) in THF (100 mL) was cooled to 78 ꢁC and n
butyllithium (2.5 M in hexanes, 23.9 mL, 60 mmol) was added
dropwise. The reaction mixture was stirred for 0.5 h at 78 ꢁC, after
which time a solution of 3 azido 1 (2 bromophenyl)propan 1 one
(7.60 g, 29.9 mmol) in CH2Cl2 (150 mL) was added via cannula. The
mixture was stirred for 1.5 h at 78 ꢁC, and then methyl chlor
oformate (14.1 g, 149 mmol, 11.6 mL) was added dropwise. The
solution was allowed to warm to room temperature while stirring
for 16 h. Water (100 mL) was added and the organic layer was
separated. The aqueous layer was extracted with EtOAc
(3ꢂ150 mL). The combined organics were dried over Na2SO4, fil
tered, and concentrated in vacuo to give a dark yellow oil that was
purified by column chromatography on SiO2 (5% ethyl acetate in
hexanes) to give carbonate 31b as a pale yellow oil (3.59 g, 30%). IR
4.10. 8a-Phenyl-6a-vinyl-1,2,31,4,6a,7,8,8a-octahydrocyclope-
nta[hi]indolizine (29)
To a solution of bicycle 28 (0.007 g, 0.025 mmol) in CH2Cl2
(2 mL) was added tosic acid (0.006 g, 0.03 mmol), followed by
Grubbs second generation metathesis catalyst (0.004 g,
0.005 mmol). The solution was heated to 40 ꢁC for 16 h, then cooled
to room temperature. Saturated aqueous sodium bicarbonate (5 ml)
was added and the resulting biphasic mixture was stirred for 1 h.
The layers were separated, and the aqueous layer was extracted
with CH2Cl2 (3ꢂ5 mL). The combined organics were dried over
Na2SO4, filtered, and concentrated in vacuo to give a brown residue.
This residue was purified by column chromatography on SiO2
(1e5e10e20% EtOAc/hexanes) to give 29 as a clear oil (0.005 g,
(thin film) 2096, 1760 cmꢃ1; 1H NMR (300 MHz, CDCl3)
7.9, 1.7 Hz, 1H), 7.59 (dd, J 7.9, 1.3 Hz, 1H), 7.33 (td, J 7.6, 1.3 Hz,
1H), 7.18 (td, J 7.6, 1.7 Hz, 1H), 4.49 (s, 2H), 4.49 (s, 3H), 3.59 (ddd,
d 7.93 (dd,
79%). 1H NMR (600 MHz, toluene)
7.6 Hz, 2H), 7.05 (t, J 7.6 Hz,1H), 5.71 (dd, J 10.1, 2.2 Hz,1H), 5.61
(dd, J 17.4, 10.6 Hz, 1H), 5.57 (dd, J 10.1, 4.9 Hz, 1H), 4.90 (d,
17.5 Hz, 1H), 4.80 (d, J 4.8 Hz, 1H), 3.52 (s, 1H), 3.32 (d, J 17.0 Hz,
1H), 3.07 (dd, J 17.0, 5.0 Hz, 1H), 2.96 (q, J 7.9 Hz, 1H), 2.72 (td,
8.4, 3.4 Hz, 1H), 2.21e2.14 (m, 2H), 1.86 (dd, J 12.5, 6.0 Hz, 1H),
1.83e1.71 (m, 3H); 13C NMR (150 MHz, toluene)
151.7, 144.7, 137.1,
d
7.44 (d, J 8.0 Hz, 2H), 7.17 (d,
J
J
J
J
12.4, 9.8, 5.7 Hz, 1H), 3.41 (ddd, J 12.4, 9.6, 5.7 Hz, 1H), 2.82 (ddd,
13.7, 9.6, 5.7 Hz, 1H), 2.47 (ddd, J 13.7, 9.7, 5.7 Hz, 1H), 0.93 (s,
J
9H), 0.15 (s, 6H); 13C NMR (75 MHz, CDCl3)
d 152.7, 136.9, 135.6,
J
130.3, 130.0, 127.3, 118.7, 89.0, 81.0, 80.0, 54.8, 51.7, 47.1, 38.9, 25.7,
18.2, 5.3; (TOF MS ESþ) [MþH]þ calcd for C20H29N3O4 482.1111,
found 482.1111.
d
132.2, 126.1, 125.7, 123.1, 111.9, 77.8, 58.3, 53.4, 48.0, 47.2, 45.2, 38.4,
37.3; HRMS (TOF MS ESþ) [MþH]þ calcd for C18H22N 252.1752,
found 252.1766.
4.13. 3a-(2-bromophenyl)-6-(((tert-butyldimethylsilyl)oxy)
methyl)-4-(4-methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl)-
2,3,3a,4-tetrahydrocyclopenta[b]pyrrole (33)
4.11. 1-Azido-3-(2-bromophenyl)-6-((tert-butyldimethylsilyl)
oxy)hex-4-yn-3-yl acetate (31a)
A
solution of 1 [(E) 2 iodoethenyl] 4 methyl 2,6,7 trioxabi
A solution of tert butyldimethyl 2 propynyloxysilane (7.58 g,
44.5 mmol) in THF (175 mL) was cooled to 78 ꢁC and n butyl
lithium (2.5 M in hexanes, 16.4 mL, 41 mmol) was added dropwise.
The reaction mixture was stirred for 1 h at 78 ꢁC and then a so
lution of 3 azido 1 (2 bromophenyl)propan 1 one (30, 6.00 g,
34.2 mmol) in THF (50 mL) was added via cannula. The mixture was
stirred at 78 ꢁC for 1.5 h and then treated with saturated aqueous
NH4Cl (150 mL). The organic layer was separated and the aqueous
was extracted with diethyl ether (3ꢂ150 mL). The combined or
ganic layers were washed with water (2ꢂ200 mL), brine (150 mL),
and dried over Na2SO4. The solution was concentrated in vacuo to
give the crude lithiate addition product a clear yellow oil.
This crude alcohol was dissolved in CH2Cl2 (200 mL), cooled to
0 ꢁC, and treated with 4 dimethylaminopyridine (14.2 g, 116 mmol)
and acetic anhydride (5.50 mL, 58.2 mmol). The solution was stirred
for 16 h, warming to room temperature. The reaction mixture was
then treated with 1 M H3PO4 (100 mL). The organic layer was drawn
off and the aqueous phase was extracted with CH2Cl2 (3ꢂ75 mL).
The combined organics were washed with water (2ꢂ100 mL), brine
(100 mL), and dried over Na2SO4. The solution was filtered and
cyclo[2.2.2]octane16 (1.10 g, 3.90 mmol) in Et2O (20 mL) was
cooled to 78 ꢁC and tert butyllithium (1.7 M in n pentane,
5.30 mL, 9.0 mmol) was added dropwise. The reaction mixture was
stirred for 1 h, at which time a solution of zinc chloride (0.611 g,
4.48 mmol) in THF (10 mL) was added via cannula. The cooling bath
was removed and the solution was allowed to warm to room
temperature and then stirred for 1 h. A solution of Pd(PPh3)4
(0.225 g, 0.195 mmol) in THF (5 mL) and carbonate 31b (0.941 g,
1.95 mmol) in THF (5 mL) were added sequentially via cannula. The
reaction mixture was stirred at room temperature until TLC (10:90
ethyl acetate/hexanes) indicated that the starting material was
consumed. The reaction mixture was poured into a separatory
funnel containing ice and saturated aqueous ammonium chloride
(40 mL). The organic layer was drawn off and the aqueous layer was
extracted with Et2O (3ꢂ20 mL), washed with brine (1ꢂ40 mL), and
dried over Na2SO4. The solution was filtered and concentrated in
vacuo at a bath temperature not exceeding 40 ꢁC to give unstable
allene 32.
The crude allene mixture was dissolved in toluene (750 mL,
0.003 M) and sparged with a stream of nitrogen for 30 min. The

1442
K.S. Feldman, J.F. Antoline / Tetrahedron 69 (2013) 1434 1445
solution was heated at 110 ꢁC for 1.5 h and then concentrated in
vacuo. The residue was purified by column chromatography on SiO2
(5e10% EtOAc/3% triethylamine/hexanes) to give a yellow solid. The
solid was triturated with hexanes and the crystals were collected by
vacuum filtration to give 33 (0.350 g 34%) as a white solid. Mp
room temperature over 18 h with continual stirring. Water
(100 mL) was added, the organic layer was separated, and the
aqueous layer was extracted with CH2Cl2 (3ꢂ150 mL). The com
bined organics were dried over Na2SO4, filtered, and concentrated
in vacuo to give a dark yellow oil. Purification of this oil by column
chromatography on SiO2 (5% ethyl acetate in hexanes) gave car
bonate 36 as a pale yellow oil (14.0 g, 84%). IR (thin film) 2099,
150e153 ꢁC; IR (thin film) 1638 cmꢃ1 1H NMR (300 MHz, CDCl3)
;
d
7.44 (d, J 7.9 Hz, 1H), 7.38 (br s, 1H), 7.11 (td, J 7.6, 1.0 Hz, 1H),
6.93 (td, J 7.6, 1.6 Hz, 1H), 6.64 (s, 1H), 4.63 (s, 2H), 3.93 (dd, J 14.6,
6.7 Hz, 1H), 3.66e3.48 (m, 7H), 3.33 (br s, 1H), 3.03 (d, J 2 Hz, 1H),
1.93 (m, 1H), 0.90 (s, 9H), 0.64 (s, 3H), 0.08 (s, 6H); 13C NMR
1762 cmꢃ1; 1H NMR (300 MHz, CDCl3)
d 7.94 (dd, J 7.9, 1.7 Hz, 1H),
7.59 (dd, J 7.9, 1.3 Hz, 1H), 7.33 (dt, J 7.6, 1.3 Hz, 1H), 7.18 (td, J 7.6,
1.7 Hz, 1H), 4.57 (s, 2H), 3.73 (s, 3H), 3.60 (m, 1H), 3.41 (m, 1H), 2.82
(m, 1H), 2.47 (m, 1H), 1.21e1.05 (m, 21H); 13C NMR (75 MHz, CDCl3)
(75 MHz, CDCl3) d 188.1, 142.6, 141.3, 138.9, 134.5, 133.5, 127.5, 125.5,
122.9, 108.1, 72.0, 66.1, 63.4, 59.3, 58.9, 42.7, 30.2, 25.8, 18.2, 14.3,
5.5; HRMS (TOF MS ESþ) [MþH]þ calcd for C26H37NO4SiBr
534.1675, found 534.1669.
d 152.7, 137.0, 135.6, 130.4, 130.0, 127.3, 118.8, 89.1, 80.8, 80.0, 54.8,
52.0, 47.2, 38.9, 17.9, 11.9; HRMS (TOF MS ESþ) [MþNH4þ] calcd for
C23H38N4O4SiBr 541.1846, found 541.1866.
4.14. Hydrogenation of cyclopentenylated dihydropyrrole 33
4.16. 3a-(2-bromophenyl)-4-(4-methyl-2,6,7-trioxabicyclo
[2.2.2]octan-1-yl)-6-((triisopropylsilyloxy)methyl)-2,3,3a,4-
tetrahydrocyclopenta[b]pyrrole (38)
A Parr bomb was charged with 33 (0.050 g, 0.094 mmol), ben
zene (5.0 mL), triethylamine (0.014 mL, 0.10 mmol), and 5% plati
num on carbon (0.010 g). The bomb was sealed, purged with
hydrogen gas three times, and then pressurized with hydrogen gas
(1100 psi), and stirred at 40 ꢁC for 18 h. The gas was vented and an
additional 0.010 g of 5% platinum on carbon was added. The bomb
was then resealed, purged with hydrogen gas three times, pres
surized to 1100 psi of hydrogen gas, and stirred at 40 ꢁC for 18 h.
This sequence was repeated until TLC (10:90 ethyl acetate/hexanes)
indicated that the starting material was completely consumed. The
reaction mixture was filtered through Celite, rinsing with EtOAc,
and concentrated in vacuo to give a light yellow oil, which was
purified by column chromatography on SiO2 (5e10% EtOAc/3%
triethylamine/hexanes) to give 34 (0.014 g, 28%) as a clear oil and 35
(0.012 g, 31% 6:1 dr) as a yellow oil.
tert Butyllithium (1.7 M in n pentane, 2.0 mL, 2.0 mmol) was
added dropwise to a solution of 1 [(E) 2 iodoethenyl] 4 methyl
2,6,7 trioxabicyclo[2.2.2]octane16 (0.200 g, 0.709 mmol) in Et2O
(3 mL) at 78 ꢁC. After 1 h of stirring at that temperature, a solution
of zinc chloride (0.106 g, 0.780 mmol) in THF (3 mL) was added via
cannula. The cooling bath was removed and the solution was
allowed to warm to room temperature over 1 h with continual
stirring. Solutions of Pd(PPh3)4 (0.041 g, 0.036 mmol) in THF (1 mL)
and carbonate 36 in THF (1 mL) were added sequentially via can
nula. The reaction mixture was stirred at room temperature until
TLC indicated that the starting material was consumed (10:90
EtOAc/hexanes). The reaction mixture was poured into a mixture of
ice and saturated aqueous ammonium chloride (10 mL). The or
ganic layer was removed and the aqueous layer was extracted with
Et2O (3ꢂ5 mL), washed with brine (1ꢂ10 mL), and the combined
organic phases were dried over Na2SO4. The combined organics
were filtered and concentrated in vacuo at a bath temperature not
exceeding 40 ꢁC to give crude unstable allene 37.
4.14.1. Compound 34. IR (thin film) 1662 cmꢃ1; 1H NMR (300 MHz,
CDCl3) d 7.53 (dd, J 7.9, 1.4 Hz, 1H), 7.32 (dd, J 8.0, 1.5 Hz, 1H), 7.17
(td, J 7.6, 1.4 Hz, 1H), 7.01 (td, J 7.0, 1.7 Hz, 1H), 4.02e3.93 (m, 2H),
3.79e3.71 (m, 6H), 3.68e3.57 (m, 2H), 3.21 (dd, J 12.8, 4.8 Hz, 2H),
2.30e2.14 (m, 3H), 2.04 (td, J 12.2, 7.6 Hz, 1H), 0.90 (s, 9H), 0.74 (s,
The crude allene was dissolved in toluene (75 mL, 0.003 M) and
sparged with a stream of nitrogen for 30 min. This solution was
heated at 110 ꢁC for 1.5 h and then concentrated in vacuo. The
residue was purified by column chromatography on SiO2
(5e10e20% EtOAc/3% triethylamine/hexanes) to give a yellow solid.
The solid was triturated with hexanes and the resulting crystals
were collected by vacuum filtration to give 0.069 g (55%) of 38 as
a white solid. Conducting the above reaction on the following scale:
1 [(E) 2 iodoethenyl] 4 methyl 2,6,7 trioxabicyclo[2.2.2]octane
(3.10 g, 11.0 mmol), tert butyllithium (1.7 M in n pentane, 17.1 mL,
29 mmol), zinc chloride (1.94 g, 14.3 mmol), Pd(PPh3)4 (0.63 g,
0.55 mmol), 36 (3.75 g, 7.15 mmoꢃl)1 gave 38 (0.98 g, 43%). Mp
3H), 0.07 (d, J 3 Hz, 6H); 13C NMR (90 MHz, CDCl3)
d 191.1, 138.5,
134.9, 132.4, 127.9, 125.8, 124.2, 108.7, 72.3, 66.9, 64.8, 64.2, 53.4,
41.8, 31.0, 30.0, 25.9, 25.6, 18.3, 14.6, 5.4, 5.3; (TOF MS ESþ)
[MþH]þ calcd for C26H39NO4SiBr 536.1832, found 536.1815.
4.14.2. Compound 35. IR (thin film) 1665 cmꢃ1; 1H NMR (360 MHz,
CDCl3) d 7.53 (dd, J 7.9, 1.4 Hz, 1H), 7.29 (dd, J 7.9, 1.6 Hz, 1H), 7.16
(td, J 7.6, 1.3 Hz, 1H), 7.01 (td, J 7.6, 1.7 Hz, 1H), 3.96 (dd, J 14.3,
7.5 Hz,1H), 3.80e3.67 (m, 6H), 3.61 (m,1H), 3.25 (dd, J 12.8, 4.9 Hz,
1H), 3.12 (m, 1H), 2.36e2.23 (m, 2H), 2.06 (m, 1H), 1.74 (m, 1H), 1.24
(app s, 3H), 0.71 (s, 3H); 13C NMR (90 MHz, CDCl3)
d 194.9, 138.5,
134.8, 132.3, 127.8, 125.7, 124.6, 108.9, 72.2, 66.6, 63.7, 52.5, 42.3,
35.6, 33.5, 30.0, 18.9, 14.6; (TOF MS ESþMS ESþ) [MþH]þ calcd for
C20H25NO3Br 406.1018, found 406.1010.
159e163 ꢁC; IR (thin film) 1639 cm
;
1H NMR (400 MHz, CDCl3)
d
7.45 (d, J 7.9 Hz, 1H), 7.39 (br s, 1H), 7.12 (t, J 7.4 Hz, 1H), 6.94 (td,
7.5, 1.3, 1H), 6.70 (s, 1H), 4.74 (s, 2H), 3.94 (dd, J 14.6, 6.7 Hz, 1H),
J
3.64e3.51 (m, 7H), 3.32 (br s, 1H), 3.05 (s, 1H), 1.93 (td, J 11.4,
4.15. 1-Azido-3-(2-bromophenyl)-6-(triisopropylsilyloxy)hex-
4-yn-3-yl methyl carbonate (36)
6.8 Hz, 1H), 1.19e1.07 (m, 21H), 0.66 (s, 3H); 13C NMR (100 MHz,
CDCl3)
d 188.8, 143.2, 141.9, 139.5, 135.0, 134.1, 128.0, 126.0, 123.5,
108.7, 72.5, 66.7, 63.9, 60.2, 59.5, 43.5, 30.7, 18.4, 14.9, 12.3; HRMS
(TOF MS ESþ) [MþNH4þ] calcd for C29H43NO4BrSi 576.2145, found
576.2128.
n Butyllithium (2.5 M in hexanes, 18.4 mL, 46 mmol) was added
dropwise to
a solution of triisopropyl(prop 2 ynyloxy)silane
(9.78 g, 46.0 mmol) in CH2Cl2 (150 mL) at 78 ꢁC. The reaction
mixture was stirred for 1.5 h at that temperature, after which time
a solution of 3 azido 1 (2 bromophenyl)propan 1 one (30) (9.00 g,
35.4 mmol) in CH2Cl2 (150 mL) was added via cannula. The mixture
was allowed to warm to room temperature over 18 h with continual
stirring. The mixture was cooled to 0 ꢁC followed by dropwise ad
dition of methyl chloroformate (11.7 g, 123 mmol, 9.58 mL). The
cooling bath was removed and the solution was allowed to warm to
4.17. 3a-(2-Bromophenyl)-4-(4-methyl-2,6,7-trioxabicyclo[2.2.2]
octan-1-yl)-6-(((triisopropylsilyl)oxy)methyl)-2,3,3a,4,5,6-hexa-
hydrocyclopenta[b]pyrrole (39)
A Parr pressure vessel was charged with 38 (0.700 g, 1.21 mmol),
1,4 dioxane (12.0 mL), triethylamine (0.085 mL, 0.61 g, 0.61 mmol),
and 5% platinum on carbon (0.311 g, 0.061 mmol, 5 mol %). The

K.S. Feldman, J.F. Antoline / Tetrahedron 69 (2013) 1434 1445
1443
vessel was sealed, purged with hydrogen gas three times, and then
pressurized with hydrogen gas (1400 psi), and stirred for 18 h at
40 ꢁC. The gas was vented and a further 0.05 equiv of 5% platinum
on carbon was added. The vessel was then resealed, purged with
hydrogen gas three times, pressurized to 1400 psi of hydrogen gas,
and stirred at 40 ꢁC for 18 h. This sequence was repeated until TLC
analysis (10:90 EtOAc/hexanes) indicated that the starting material
was completely consumed. The reaction mixture was filtered
through Celite, which was rinsed with EtOAc, and the combined
organics were concentrated in vacuo to give a light yellow oil. This
oil was purified by column chromatography on SiO2 (5% EtOAc/3%
triethylamine/hexanes) to give imine 39 (0.566 g, 80%) as a clear oil.
65.3, 64.4, 61.4, 47.6, 45.1, 42.3, 34.8, 30.0, 28.3, 28.1, 14.2; HRMS
(TOF MS ESþ) [MþHþ] calcd for C25H35NO6Br 524.1648, found
524.1657.
4.19. tert-Butyl-3a-(2-Bromophenyl)-6,6-bis(hydroxymethyl)-
4-(4-methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl)-hexahydro-
cyclopenta[b]pyrrole-1(2H)carboxylate (41)
A microwave reaction tube was charged with alcohol 40
(0.167 g, 0.318 mmol), water saturated CH2Cl2 (3.20 mL), and 2,6
lutidine (0.184 mL, 0.171 g, 1.59 mmol). DesseMartin periodinane
(0.405 g, 0.955 mmol) was added in a single portion and the tube
was purged with nitrogen and then sealed with a Teflon cap. The
reaction mixture was heated via microwave irradiation at 65 ꢁC for
0.5 h and then cooled to room temperature. A 1:1 solution (3 mL) of
saturated aqueous NaHCO3/saturated aqueous Na2S2O3 was added
and the biphasic mixture was stirred at room temperature until all
of the solids had dissolved and the mixture was clear. The organic
layer was drawn off and the aqueous layer was extracted with
CH2Cl2 (3ꢂ5 mL). The combined organic layers were dried over
Na2SO4 and concentrated in vacuo to give a pale yellow oil.
IR (thin film) 2246, 2215, 1667 cmꢃ1
;
1H NMR (major isomer,
300 MHz, CDCl3) 7.52 (dd, J 7.9, 1.4 Hz, 1H), 7.32 (d, J 8.0, 1.5 Hz,
d
1H), 7.17 (app td, J 7.6, 1.4 Hz, 1H), 7.01 (app td, J 7.6, 1.6 Hz, 1H),
4.07 (dd, J 9.7, 4.3 Hz, 1H), 3.96 (dd, J 14.4, 7.6 Hz, 1H), 3.79e3.60
(m, 8H), 3.21 (app dd, J 12.8, 3.2 Hz, 2H), 2.12e2.35 (m, 3H), 2.05
(m, 1H),1.12e1.04 (m, 21H), 0.73 (s, 3H); 13C (major isomer, 75 MHz,
CDCl3)
d 191.1, 138.5, 134.9, 132.3, 127.8, 125.7, 124.2, 108.7, 72.2,
66.8, 65.0, 64.2, 53.4, 41.9, 41.7, 31.0, 29.9, 18.0, 14.6, 12.0; HRMS
(TOF MS ESþ) [MþHþ] calcd for C29H45NO4BrSi 578.2301, found
578.2298.
This crude aldehyde prepared above was dissolved in ethylene
glycol (3.18 mL) and CH2Cl2 (0.100 mL). Aqueous formaldehyde
(37% w/w, 1.43 mL, 1.56 g, 19.1 mmol) and KOH (0.371 g, 5.62 mmol)
were added sequentially. The reaction solution was heated to 55 ꢁC
and stirred for 48 h at that temperature. After this time period, the
reaction solution was cooled to room temperature, diluted with
brine (15 mL), and extracted with CH2Cl2 (4ꢂ10 mL). The combined
organic layers were dried over Na2SO4, filtered, and concentrated in
vacuo to give a white foam. This foam was purified by column
chromatography (1e5e10% MeOH/CH2Cl2) to give diol 41 (0.149 g,
84%, mixture of rotamers) as a white solid. Mp 208e212 ꢁC; IR (thin
4.18. tert-Butyl-3a-(2-Bromophenyl)-6-(hydroxymethyl)-4-(4-
methyl-2,6,7-trioxabicyclo [2.2.2] octan-1-yl)hexahydrocycl-
openta[b]pyrrole-1(2H)carboxylate (40)
Superhydride (1.0 M in THF, 10 mL, 10 mmol) was added drop
wise to a solution of 39 (0.586 g, 1.01 mmol) in THF (10.1 mL). An
initial vigorous evolution of gas subsided quickly. The mixture was
heated at reflux for 72 h and then cooled to 0 ꢁC, and the excess
hydride reagent was destroyed by the slow addition of ice. Satu
rated ammonium chloride solution (10 mL) was added and the
biphasic solution was stirred for 1 h at room temperature. EtOAc
(10 mL) was added and the organic layer was drawn off. The
aqueous layer was extracted with EtOAc (3ꢂ10 mL) and the com
bined organics were washed with brine (1ꢂ15 mL) and dried over
Na2SO4. The solution was filtered and concentrated in vacuo.
The crude amine prepared above was dissolved in CH2Cl2
(10.0 mL) and triethylamine (0.706 mL, 0.512 g, 5.06 mmol), Boc2O
(0.442 g, 2.03 mmol), and hydroxylamine hydrochloride (0.035 g,
0.506 mmol) were added sequentially. The reaction mixture was
stirred at room temperature for 24 h and an additional portion of
Boc2O (0.111 g, 0.506 mmol) was added. The solution was stirred for
an additional 48 h at room temperature and then concentrated in
vacuo to give a white oil. The crude N Boc product mixture was
dissolved in acetonitrile (10 mL) and extracted with hexanes
(5ꢂ10 mL). The combined hexanes extracts were concentrated in
vacuo to give a clear oil.
film) 3492, 1659 cmꢃ1
;
1H NMR (major rotamer, 300 MHz CDCl3)
d
7.54 (app dd, J 7.8, 1.0 Hz, 1H), 7.21e7.11 (m, 2H), 7.01 (app dt,
J
J
7.3, 2.0 Hz, 1H), 4.9 (s, 1H), 4.55 (d, J 11.2 Hz, 1H), 4.02 (d,
10.8 Hz, 1H), 3.82 (dd, J 11.0, 6.0 Hz, 1H), 3.61 (app t, J 11.1 Hz,
1H), 3.48e3.38 (m, 7H), 3.32 (dd, J 6.7, 3.0 Hz, 1H), 3.23 (app t,
9.9 Hz, 1H), 2.99 (dd, J 13.1, 6.7 Hz, 1H), 2.88 (dt, J 11.2, 7.0 Hz,
J
1H), 2.42 (t, J 6.1 Hz, 1H), 2.14, (dt, J 12.3, 9.5 Hz, 1H), 2.07e1.98
(m, 2H), 1.43 (s, 9H), 0.59 (s, 3H); 13C NMR (major rotamer, 75 MHz,
CDCl3)
d 155.6, 140.6, 134.1, 129.1, 127.2, 126.1, 126.0, 109.3, 80.4,
71.8, 69.6, 68.1, 67.9, 61.7, 49.1, 47.1, 45.0, 34.3, 31.8, 30.1, 28.4, 14.3;
HRMS (TOF MS ESþ) [MþHþ] calcd for C26H37NO7Br 554.1753,
found 554.1773.
4.20. tert-Butyl 3a-(2-bromophenyl)-4-(4-methyl-2,6,7-triox-
abicyclo[2.2.2]octan-1-yl)-6,6-divinylhexahydrocyclopenta[b]
pyrrole-1(2H)carboxylate (44)
The crude N Boc species was dissolved in THF (10 mL) and n
Bu4NF solution (1.0 M in THF, 5.0 mL, 5.0 mmol) was added. The
reaction mixture was stirred at room temperature for 18 h, diluted
with water (20 mL), and EtOAc (15 mL) was added. The layers were
separated and the aqueous layer was extracted with EtOAc
(1ꢂ10 mL) and CH2Cl2 (2ꢂ10 mL). The combined organic phases
were dried over Na2SO4, filtered, and concentrated in vacuo. The
crude alcohol was purified by column chromatography on SiO2
(1e4e10% ethyl acetate/3% triethylamine/hexanes) to give alcohol
40 (0.317 g, 59%) as white crystals. Mp 82e86 ꢁC; IR (thin film) 3441,
A microwave reaction tube was charged with diol 41 (0.030 g,
0.54 mmol), lutidine (0.144 g, 1.35 mmol, 0.156 mL), and water
saturated CH2Cl2 (1.5 mL). DesseMartin periodinane (0.229 g,
0.541 mmol) was added in a single portion and the tube was purged
with nitrogen and then sealed with a Teflon cap. The reaction
mixture was heated via microwave irradiation for 0.5 h at 65 ꢁC and
then cooled to room temperature. A 1:1 solution of saturated
aqueous NaHCO3/ saturated aqueous Na2S2O3 (3 mL) was added
and the biphasic mixture was stirred at room temperature until all
of the solids had dissolved and the mixture was clear. The organic
layer was drawn off and the aqueous layer was extracted with
CH2Cl2 (3ꢂ5 mL). The combined organic layers were dried over
Na2SO4 and concentrated in vacuo to give the crude dialdehyde as
a pale yellow oil.
2244, 1667 cmꢃ1; 1H NMR (400 MHz, CDCl3)
7.23 (d, J 7.7 Hz, 1H), 7.14 (app. t, J 7.5 Hz, 1H), 6.99 (app t,
d 7.51 (d, J 7.8 Hz, 1H),
J
J
J
7.4 Hz, 1H), 5.17 (d, J 9.5, 1H), 3.51e3.37 (m, 9H), 3.30 (d,
7.2 Hz, 1H), 3.21 (t, J 9.5 Hz, 1H), 2.88e2.75 (m, 3H), 2.31 (dd,
8.8, 6.9 Hz, 1H), 1.94 (app. q, J 11.7 Hz, 1H), 1.57 (m, 1H, over
THF (1 mL) was added to a commercially available 1:1 mixture of
methyltriphenylphosphonium bromide/sodium amide (0.264 g,
0.739 mmol). The resulting mixture was stirred for 1 h at room
lapping with H2O), 1.43 (s, 9H), 0.56 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 156.5,141.1,134.1,129.0, 127.1,126.0, 125.8, 109.5, 80.3, 71.8,

1444
K.S. Feldman, J.F. Antoline / Tetrahedron 69 (2013) 1434 1445
temperature, at which time a solution of the dialdehyde prepared
above in THF (1 mL) was added via cannula to the ylide suspension.
The resulting mixture was stirred at room temperature for 16 h. The
solution was poured into EtOAc (5 mL) and saturated aqueous
NH4Cl (5 mL). The organic layer was separated and the aqueous
phase was extracted with EtOAc (3ꢂ5 mL). The combined organic
layers were washed with water (1ꢂ5 mL), brine (1ꢂ5 mL), dried
over Na2SO4, filtered, and concentrated in vacuo to give a brown oil.
This oil was purified by SiO2 column chromatography (1e5% EtOAc/
hexanes) to give 44 as a clear oil (0.017 g, 57%, mixture of rotamers).
purified by preparative TLC on SiO2 (5% MeOH/CH2Cl2, applying the
crude mixture to the TLC plate using no more than 10% MeOH/
CH2Cl2) to give lactam 48 as a yellow solid (0.006 g, 78%, mixture of
rotamers). Mp 218e221 ꢁC; IR (thin film) 3241, 1661 cmꢃ1; 1H NMR
(both rotamers, 500 MHz, CD3OD)
d 7.30 (m, 1H), 7.19 (t, J 6.9 Hz,
1H), 7.10 (t, J 7.5 Hz, 1H), 6.87 (d, J 7.9 Hz, 1H), 4.46 (s, 0.6H, major
rotamer), 4.42 (s, 0.4H, minor rotamer), 3.99 (t, J 9.9 Hz, 1H), 3.59
(d, J 12.8 Hz, 1H), 3.54e3.37 (m, 3H), 2.98 (dd, J 12.0, 6.6 Hz, 1H),
2.30 (dd, J 12.9, 6.6 Hz, 1H), 2.19e1.80 (m, 3H), 1.64 (t, J 12.5 Hz,
1H), 1.51 (s, 6H), 1.28 (s, 3H); 13C NMR (both rotamers, 125 MHz,
IR (thin film) 2358, 1692 cmꢃ1
major rotamer) 7.51 (d, J 7.7 Hz, 1H), 7.15e7.11 (m, 2H), 6.99 (q,
6.3 Hz, 1H), 6.35 Hz (dd, J 17.4, 10.6 Hz, 1H), 5.89 (ddd, J 16.8,
10.9, 6.6 Hz, 1H), 5.18e4.97 (m, 5H), 3.51e3.32 (m, 7H), 3.15 (t,
9.7 Hz, 1H), 2.91e2.79 (m, 2H), 2.47e2.39 (m, 2H), 2.06 (m, 1H),
1.41 (s, 9H), 0.58 (s, 3H); 13C NMR (212 MHz, CDCl3, all rotamers)
154.7, 154.3, 146.7, 143.5, 142.8, 141.1, 141.0, 134.1, 133.9, 132.2,
;
1H NMR (850 MHz, toluene d8,
CD3OD) d 173.6, 173.1, 156.7, 155.9, 136.8, 129.2, 129.0, 128.0, 127.6,
d
125.3, 125.1, 116.9, 116.8, 82.0, 81.9, 76.6, 75.0, 68.0, 67.2, 64.0, 62.0,
60.0, 58.9, 53.4, 52.6; 48.2, 47.9 (overlapping with CD3OD), 40.5,
39.8, 37.2, 36.5, 30.8, 28.8, 28.6; HRMS (TOF MS ESþ) [MþHþ] calcd
for C21H29N2O5 389.2076, found 389.2103.
J
J
d
4.23. 3-Allyl-4,4-divinyl-2,3,3a,4,5,5a-hexahydro-1H-pyrrolo
[30,20:2,3]cyclopenta[1,2-c]quinolin-6(7H)-one (13)
131.5, 129.8, 129.3, 128.5, 127.0, 125.9, 125.8, 112.65, 111.8, 110.6,
109.4, 79.7, 79.0, 74.0, 71.6, 61.6, 60.8, 51.1, 51.0, 47.5, 44.8, 44.4, 34.1,
33.4, 32.8, 32.2, 30.1, 29.7, 28.6, 28.4, 14.3; HRMS (TOF MS ESþ)
[MþH]þ calcd for C28H37NO5Br 546.1855, found 546.1833.
DesseMartin periodinane (0.076 g, 0.18 mmol) was added to
a solution of lactam diol 48 (0.007 g, 0.02 mmol) in water saturated
CH2Cl2 (0.180 mL) in a microwave reactor tube. The tube was
purged with nitrogen, sealed with a Teflon cap, and heated to 65 ꢁC
for 0.5 h under microwave irradiation. The reaction mixture was
cooled to room temperature and 3 mL of a 1:1 mixture of saturated
aqueous sodium bicarbonate/saturated aqueous Na2S2O3 was
added. The biphasic solution was stirred until all of the solids had
dissolved and the mixture was clear. The organic layer was re
moved, and the aqueous layer was extracted with CH2Cl2 (3ꢂ5 mL).
The combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo to give the unstable 1,3 dialdehyde as a pale
yellow oil.
4.21. tert-Butyl-3a-(2-bromophenyl)-4-carbamoyl-6,6-bis(hy-
droxymethyl)- hexahydrocyclopenta[b]pyrrole-1(2H)carbox-
ylate (47)
Orthoester diol 41 (0.119 g, 0.214 mmol) was dissolved in 10% (v/
v) H3PO4/THF (3.00 mL). The solution was stirred at room tem
perature until consumption of the orthoester was indicated by TLC
(10% MeOH/CH2Cl2). This solution of crude ester was transferred to
a Parr pressure vessel and isopropyl alcohol (5 mL) was added. The
vessel was purged with NH3 gas three times, pressurized with NH3
gas at 100 psi, and stirred for 0.5 h while connected to the NH3 tank.
The vessel was sealed and heated at 110 ꢁC for 20 h. The Parr vessel
was cooled to room temperature, the ammonia gas was vented, and
the reaction solution remained unperturbed for 1 h to give a milky
suspension. The suspension was filtered through Celite and the
filtrate was concentrated in vacuo to give a yellow solid. This solid
was purified via column chromatography on SiO2 (1e5e10% MeOH/
CH2Cl2) to give 47 as a white solid, as a 2:1 mixture of rotamers
(0.068 g, 68%). Mp 206 ꢁC (decomp.); IR (solid) 3331, 2151,
A
suspension of methyltriphenylphosphonium bromide
(0.129 g, 0.360 mmol) in THF (0.3 mL) was cooled to 78 ꢁC and
a solution of NaHMDS (1.0 M in THF, 0.34 mL, 0.34 mmol) was
added dropwise. This suspension was stirred at 78 ꢁC for 1.5 h.
The crude 1,3 dialdehyde prepared above was dissolved in 0.15 mL
of THF and added via cannula to the ylide suspension, rinsing the
flask with an additional 0.15 mL of THF. The reaction mixture was
allowed to warm to room temperature and stirred for 72 h at that
temperature. Saturated aqueous ammonium chloride (5 mL) and
EtOAc (5 mL) were added. The organic layer was removed and the
aqueous layer was extracted with EtOAc (1ꢂ5 mL) and CH2Cl2
(2ꢂ5 mL). The combined organics were dried over Na2SO4, filtered,
and concentrated in vacuo to give 49 as a brown oil.
1662 cmꢃ1
8.0 Hz, 1H), 7.25 (m, 1H), 7.14e7.07 (m, 2H), 4.95 (s, 1H, over
lapping with HOD), 4.17 (d, J 8.9 Hz, 1H), 3.95 (m, 1H), 3.71 (d,
10.7 Hz, 1H), 3.61 (d, J 10.7 Hz, 1H), 3.48 (m, 1H), 3.36 (m, 1H),
2.87 (m, 1H), 2.64e2.26 (m, 3H), 1.66 (d, J 14.9 Hz, 1H), 1.48 (s, 9H);
13C NMR (both rotamers, 75 MHz, CD3OD)
179.6, 179.4, 157.1,
; d 7.59 (d,
1H NMR (major rotamer, 300 MHz, CD3OD)
J
J
This crude oil was dissolved in 10% (v/v) TFA/CH2Cl2 (3 mL) and
stirred at room temperature for 4 h. The reaction solution was
concentrated in vacuo and saturated aqueous sodium bicarbonate
(3 mL) and CH2Cl2 (5 mL) were added to the residue. The organic
layer was removed and the aqueous layer was extracted with
CH2Cl2 (3ꢂ5 mL). The combined organic layers were dried over
Na2SO4, filtered, and concentrated in vacuo to give the crude free
amine as a brown oil.
d
156.2, 143.1, 142.9, 136.4, 130.1, 130.0, 129.5, 129.4, 128.3, 128.2,
123.0, 122.9, 82.0, 81.9, 72.0, 71.3, 68.6, 67.9, 67.2, 66.3, 65.3, 63.2,
62.9, 51.4, 50.5, 50.4, 50.3, 46.5, 46.3, 36.4, 34.9, 34.1, 34.1, 28.9,
28.7; HRMS (TOF MS ESþ) [MþHþ] calcd for C21H30N2O5Br
469.1361, found 469.1338.
4.22. tert-Butyl-4,4-bis(hydroxymethyl)-6-oxo-3a,4,5,5a,6,7-
hexahydro-1H-pyrrolo[30,20:2,3]cyclopenta[1,2-c]quinoline-
3(2H)carboxylate (48)
This crude amine was dissolved in MeCN (0.5 mL), and K2CO3
(0.015 g, 0.11 mmol) and allyl bromide (0.010 mL, 0.11 mmol) were
added sequentially. The reaction mixture was stirred at room
temperature for 24 h and then water (3 mL) and CH2Cl2 (3 mL) were
added. The organic layer was drawn off, and the aqueous layer was
extracted with CH2Cl2 (3ꢂ3 mL). The combined organic layers were
dried over Na2SO4, filtered, and concentrated in vacuo to give
a brown residue. The residue was purified on SiO2 (5e15% EtOAc/
hexanes) to give 13 as a colorless oil (0.004 g, 57% from 48). IR (thin
Cs2CO3 (0.650 g, 0.198 mmol), copper(I) iodide (0.004 g,
1.98ꢂ10ꢃ2
mmol),
and
1,10 phenanthroline
(0.007
g,
3.97ꢂ10ꢃ2 mmol) were added to a solution of primary amide 47
(0.008 g, 0.02 mmol) in DMSO (0.200 mL) in a microwave reactor
tube. The tube was purged with N2, sealed with a Teflon cap, and
heated at 110 ꢁC for 0.5 h under microwave irradiation. The reaction
solution was cooled to room temperature and filtered through
Celite, which was rinsed with CH2Cl2. The combined organics were
concentrated in vacuo to give a blue residue. The residue was
film) 1674 cmꢃ1; 1H NMR (300 MHz, CDCl3)
7.2 Hz, 1H), 7.15 (td, J 7.6, 1.4 Hz, 1H), 7.05 (td, J 7.5, 1.3 Hz, 1H),
6.65 (dd, J 7.8, 1.2 Hz, 1H), 6.24 (dd, J 17.7, 10.9 Hz,1H), 5.93 (dddd,
17.4, 10.2, 7.5, 5.1 Hz, 1H), 5.74 (dd, J 17.5, 10.8 Hz, 1H), 5.30e5.09
d 7.79 (br s, 1H), 7.31 (d,
J
J

K.S. Feldman, J.F. Antoline / Tetrahedron 69 (2013) 1434e1445
1445
ꢀ
5. (a) Levy, J.; Hugel, G. J. Org. Chem. 1986, 51, 1594e1595; (b) Overman, L. E.;
Robertson, G. M.; Robichaud, A. J. J. Am. Chem. Soc. 1991, 113, 2598e2610; (c)
Selig, P.; Bach, T. Angew. Chem., Int. Ed. 2008, 47, 5082e5084; (d) Selig, P.;
Herdtweck, E.; Bach, T. Chem.dEur. J 2009, 15, 3509e3525; (e) Hayashi, Y.;
Inagaki, F.; Mukai, C. Org. Lett. 2011, 13, 1778e1780; (f) Zhang, H.; Curran, D. P. J.
Am. Chem. Soc. 2011, 133, 10376e10378.
(m, 4H), 4.94 (dd, J¼10.8, 0.8 Hz, 1H), 4.88 (dd, J¼17.6, 0.8 Hz, 1H),
3.51 (m, 1H), 3.43 (s, 1H), 3.29 (dt, J¼10.1, 5.0 Hz, 1H), 3.04 (dd,
J¼13.7, 7.5, 1H), 2.94 (dd, J¼8.8, 7.0 Hz, 1H), 2.84 (dt, J¼10.0, 8.1 Hz,
1H), 2.41 (dd, J¼12.6, 6.9 Hz, 1H), 2.17 (dd, J¼12.6, 8.9 Hz, 1H),
2.02e1.97 (m, 2H); 13C (150 Hz, CDCl3)
d 171.5, 143.0, 140.6, 135.8,
6. (a) Feldman, K. S.; Iyer, M. R. J. Am. Chem. Soc. 2006, 127, 4590e4591; (b)
Feldman, K. S.; Iyer, M. R.; Hester, D. K., II. Org. Lett. 2006, 8, 3113e3116; (c)
Lopez, C. S.; Faza, O. N.; Feldman, K. S.; Iyer, M. R.; Hester, D. K., II. J. Am.
134.4, 130.0, 127.7, 127.3, 123.7, 116.9, 115.3, 114.4, 113.7, 87.6, 58.6,
56.9, 55.6, 53.4, 50.5, 43.7, 41.4; HRMS (TOF MS ESþ) [MþHþ] calcd
for C21H25N2O 321.1967, found 321.1961.
ꢀ
ꢀ
Chem. Soc. 2007, 129, 7638e7646; (d) Feldman, K. S.; Iyer, M. R.; Lopez, C. S.;
Faza, O. N. J. Org. Chem. 2008, 73, 5090e5099; (e) Feldman, K. S.; Hester, D.
ꢀ
K.; Lopez, C. S.; Faza, O. N. Org. Lett. 2008, 10, 1665e1668; (f) Feldman, K. S.;
ꢀ
Hester, D. K.; Iyer, M. R.; Munson, P. J.; Lopez, C. S.; Faza, O. N. J. Org. Chem.
2009, 74, 4958e4974; (g) Faza, O. N.; Feldman, K. S.; Lopez, C. S. Curr. Org.
4.24. ( )-Meloscine (1)
ꢀ
Chem. 2010, 14, 1646e1657.
7. Feldman, K. S.; Antoline, J. F. Org. Lett. 2012, 14, 934e937.
8. Singh, P. N. D.; Muthukrishnan, S.; Murthy, R. S.; Klima, R. F.; Mandel, S. M.;
Hawk, M.; Yarbrough, N.; Gudmundsdottir, A. D. Tetrahedron Lett. 2003, 44,
9169e9171.
HoveydaeGrubb’s second-generation catalyst (0.00023 g,
0.00036 mmol) in toluene (0.10 mL) was added to a solution of 13
(0.0023 g, 0.0072 mmol) in toluene (2.0 mL). The reaction mixture
was heated for 24 h at 60 ꢁC and then cooled to room temperature
and concentrated in vacuo to give a brown residue. The residue was
purified via column chromatography on SiO2 (hexanes/1e2e4%
MeOH/CH2Cl2) to give 1 as a white solid (0.0014 g, 76%). Mp
ꢀ
9. Ruitenberg, K.; Kleijn, H.; Elsevier, C. J.; Meijer, J.; Vermeer, P. Tetrahedron Lett.
1981, 22, 1451e1452.
10. Harris, R. B.; Wilson, I. B. Tetrahedron Lett. 1983, 24, 231e232.
11. (a) Tollens, B.; Wigand, P. Liebigs Ann. 1891, 265, 316e340; (b) Burr, J. G. J. Am.
Chem. Soc. 1951, 73, 5170e5172; (c) Yu, J.; Wearing, X. Z.; Cook, J. M. J. Org. Chem.
2005, 70, 3963e3979.
12. Cambridge Crystallographic Data Centre deposition number for 26: 893544.
The data can be obtained free from Cambridge Crystallographic Data Centre via
http://www.ccdc.cam.ac.uk/data_request/cif.
13. Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549e7552.
14. Spartan 10 was used with an initial MMFF force field conformational search and
then density functional calculations (B3LYP/6-31G**) on the lowest-energy
conformer.
15. Control experiments to probe the factors behind failure of the Vermeer
chemistry with 31a and OBOeHC]CHeZnCl addition.
205e210 ꢁC (lit.5e 208e209); IR (thin film) 1672 cmꢃ1
;
1H NMR
7.58 (s,1H), 7.39 (d, J¼7.9 Hz,1H), 7.15 (t, J¼7.7 Hz,
(500 MHz, CDCl3)
d
1H), 7.05 (t, J¼7.6 Hz, 1H), 6.65 (d, J¼7.9 Hz, 1H), 6.01 (ddd, J¼10.0,
5.5, 2.2 Hz,1H), 5.72 (dd, J¼9.9, 2.4 Hz,1H), 5.53 (dd, J¼17.4,10.5 Hz,
1H), 4.91 (d, J¼17.3 Hz, 1H), 4.79 (d, J¼10.5 Hz, 1H), 3.51 (s, 1H), 3.30
(dd, J¼16.1, 5.5 Hz,1H), 3.25e3.08 (m, 2H), 2.96 (t, J¼8.8 Hz,1H), 2.88
(td, J¼8.0, 4.5 Hz, 1H), 2.31 (dd, J¼12.7, 8.3 Hz, 1H), 2.22e2.08 (m,
2H), 1.96 (dt, J¼12.8, 7.5 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 171.4,
143.2, 135.0, 132.4, 127.9, 127.7, 127.6, 127.0, 123.9, 115.1, 112.6, 82.5,
56.8, 53.0, 51.0, 48.1, 46.8, 43.4, 42.2; HRMS (TOF MS ESþ) [MþHþ]
calcd for C19H21N2O 293.1654, found 293.1643.
Acknowledgements
We thank the National Institutes of Health, General Medical
Sciences (GM 72572) for support of this work. The X-ray facility is
supported by NSF CHE 0131112.
References and notes
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