Syntheses of (+)-complanadine A and lycodine derivatives by regioselective [2 + 2 + 2] cycloadditions

Article abstract of DOI:10.1021/jo400695c

The dimeric alkaloid complanadine A has shown promise in regenerative science, promoting neuronal growth by inducing the secretion of growth factors from glial cells. Through the use of tandem, cobalt-mediated [2 + 2 + 2] cycloaddition reactions, two synthetic routes have been developed with different sequences for the formation of the unsymmetric bipyridyl core. The regioselective formation of each of the pyridines was achieved based on the inherent selectivity of the molecules or by reversing the regioselectivity through the addition of Lewis bases. This strategy has been successfully employed to provide laboratory access to complanadine A as well as structurally related compounds possessing the lycodine core.

Full text of DOI:10.1021/jo400695c

Article
pubs.acs.org/joc
Syntheses of (+)-Complanadine A and Lycodine Derivatives by
Regioselective [2 + 2 + 2] Cycloadditions
Changxia Yuan, Chih-Tsung Chang, and Dionicio Siegel*
Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, Texas 78712, United States
S
* Supporting Information
ABSTRACT: The dimeric alkaloid complanadine A has shown promise in regenerative science, promoting neuronal growth by
inducing the secretion of growth factors from glial cells. Through the use of tandem, cobalt-mediated [2 + 2 + 2] cycloaddition
reactions, two synthetic routes have been developed with different sequences for the formation of the unsymmetric bipyridyl
core. The regioselective formation of each of the pyridines was achieved based on the inherent selectivity of the molecules or by
reversing the regioselectivity through the addition of Lewis bases. This strategy has been successfully employed to provide
laboratory access to complanadine A as well as structurally related compounds possessing the lycodine core.
from 1321N1 cells (human glial cells derived from brain
astrocytoma), promoting the differentiation of PC-12 cells.11,12
The enhanced expression of NGF mRNA by 1321N1 cells
treated with complanadine B was determined by semi-
quantitative RT-PCR. In addition to its biological effects
complanadine A possesses a unique structure and represented
the first dimeric alkaloid containing a lycodine-type C16N2
skeleton to be characterized. Structurally related natural
products to be isolated include complanadine C (3) and D
(4) as well (Figure 1).12,13 Synthetic interest in this class of
dimeric natural products has led to three successful laboratory
preparations of complanadine A (1)14−16 as well as two
synthetic routes to complanadine B (2).16,17
INTRODUCTION
■
Growth factors can significantly enhance the survival and
regenerative potential of neurons injured as a result of
trauma1−3 or disease.4−6 These proteins prevent apoptosis,
promote the growth and survival of neurons, and aid in the
controlled development of progenitor cells.2,7 Their effective
use as therapeutics, however, has been problematic due to their
pharmacokinetic shortcomings:8 proteolytic degradation re-
quires continual infusion and their limited ability to cross the
blood−brain barrier has meant delivery by intracranial
injection, with attendant serious risks to the patient’s health.
Gene therapy-based approaches to inducing the production of
neurotrophic factors, using both direct and ex vivo techniques,
have had success in animal models of Parkinson’s disease and in
regenerating axons after spinal cord injury.2 Although
promising, gene therapy has yet to overcome the limitations
of short-lived effects, undesirable immune responses, intra-
cranial delivery, and challenges involving the use of viral
vectors.9
RESULTS/DISCUSSION
■
The synthesis of complanadine A was envisioned through the
application of sequential [2 + 2 + 2] cycloaddition reactions
between a disubstituted butadiyne 7 and two molecules of
alkyne nitrile 6 (Figure 2). Two potential sequences for the
ordered, regioselective formation of the pyridine rings were
possible, both generating complanadine A (Figure 2). Through
this approach the corresponding symmetric bipyridyl isomers 9
and 10 bearing 2,2′ or 3,3′ connectivity, respectively, could
Using small molecules provides an alternative approach to
regenerative medicine.10 Able to mimic neurotrophic factors, or
to induce neurotrophic factor biosynthesis, small molecules
possess a pharmacological advantage. Along these lines it was
discovered that the natural product complanadine A (1) and
complanadine B (2), isolated from the club moss Lycopodium
complanatum, induced the secretion of neurotrophic factors
Received: April 16, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo400695c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 1. Structures of complanadines A−D.
Figure 2. Synthetic disconnections of complanadine A.
potentially be produced as undesirable alternative products
arising from the cycloaddition reactions (Figure 3).
Alkyne−nitrile 6 represented a pivotal intermediate for these
studies and a synthetic route that could generate gram scale
quantities was required. The first generation approach toward
the synthesis of the alkyne−nitrile fragment was initiated by
treatment of (+)-pulegone (11) with lithium hydroxide (1.0
equiv) and H2O2 (1.0 equiv, 30% aqueous solution) providing
pulegone oxide, which was reacted with an excess of the anion
of thiophenol (1.3 equiv) to provide thioether 12 as a
diastereomeric mixture in 97% yield over two steps (Scheme
1).18−20 To a solution of thioether 12 in dimethylformamide at
23 °C solid sodium hydride (1.1 equiv) was added in portions
over 10 min with extensive gas evolution. Alkylation of the
resulting thermodynamic enolate with 1-chloro-3-iodopropane
(1.3 equiv) afforded a mixture of diastereomeric products
(1.2:1) along with significant (∼30%) amounts of byproduct
arising from O-alkylation. Oxidation of the mixture of
diastereomers with m-CPBA (1.1 equiv) at −78 °C generated
four diastereomeric sulfoxides that, following warming to 23
°C, underwent a mild syn-elimination, generating enone 13.19
Figure 3. Undesired symmetric isomers.
Scheme 1. Synthesis of Azide Precursor 15 and Attempted Staudinger/Aza-Wittig Reaction
B
dx.doi.org/10.1021/jo400695c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 2. Synthesis of Alkyne−Nitriles 28−30 from Thioether 12
Scheme 3. Regioselective Cobalt-Mediated [2 + 2 + 2] Cycloaddition of Alkyne−Nitrile 28 and Different Butadiynes
Azide 14 was generated by Finkelstein reaction of enone 13
with sodium azide (2.0 equiv) and sodium iodide (2.0 equiv) in
DMF (caution should be taken in handling large quantities of
azides). Addition of an ether solution of enone 14 to a cooled
(−78 °C) solution of the lithium anion of (trimethylsilyl)-
acetonitrile (1.2 equiv) was followed by transferring the
reaction to a −78 °C solution of ethyl salicylate (2.0
equiv).21−23 After 30 min this solution was transferred to a
solution of acetic acid (5 equiv) in ether at −78 °C and,
following complete addition, warmed to 23 °C. After
purification, the mixture of diastereomers was subjected to
desilylation with cesium fluoride (2.0 equiv) in acetonitrile
providing cyclohexanone 15 in 63% yield over two steps. A
major byproduct of this sequence arose from the Peterson
olefination of cyclohexenone 14 by the lithium anion of
(trimethylsilyl)acetonitrile. Unfortunately, the Staudinger/aza-
Wittig reaction of cyclohexenone 15 failed to generate the
desired imine 16, although the corresponding Cbz protected
amine of reduced cyclohexenone 15 could be isolated from the
reaction providing evidence the Staudinger reaction had
occurred.
A second, successful route provided the desired alkyne−
nitrile on the multigram scale using related chemistry (Scheme
2). Equatorial delivery of ethynylmagnesium chloride into
ketone 18 proceeded with a high degree of diastereoselectivity
(>18:1) furnishing propargyl alcohol 19. The assignment was
C
dx.doi.org/10.1021/jo400695c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
corroborated by analysis of the X-ray crystal structure of the
corresponding diol 24. Acylation of the tertiary alcohol using
magnesium perchlorate (CAUTION!) in neat acetic anhydride
at 23 °C provided the activated propargyl system 20.24 Copper-
mediated amination using propargyl acetate 20 was possible
with primary amines providing the desired secondary amines
21−23 in good yields and high diastereoselectivities (>20:1).25
The success of the reaction was dependent on the careful
removal of oxygen to prevent an otherwise rapid Glaser
dimerization. Removal of the primary acetate and cyclization of
the resulting amino alcohols with PPh3/imidazole/carbon
tetrachloride generated alkyne−nitriles 28−30.26,27 Crystals
(mp 138.2−138.5 °C) of alkyne nitrile 28 proved suitable for
X-ray crystallography helping to further confirm the structural
assignment.
With access to alkyne−nitrile 28 [2 + 2 + 2] cyclization
reactions were investigated using 1,4-bis(trimethylsilyl)-
butadiyne (31) and CpCo(CO)2 with or without illumination
in different solvents heated to reflux (Scheme 3).28−32 The
majority of reactions succeeded in generating 2-alkynyl pyrdine
32 to some extent. After optimization we found that carrying
out the reactions, following freeze−pump−thaw degassing
(three cycles), in THF in a sealed tube heated in a 140 °C oil
bath proved optimal, forming pyridylalkyne 32 in 78% yield
along with 3% of the regioisomeric product pyridylalkyne 33
(loss of the TMS occurred following silica gel chromatography)
(Scheme 3).33 Attempts to achieve a tandem [2 + 2 + 2] + [2 +
2 + 2] cycloaddition sequence, assembling protected
complanadine A in a single operation, only succeeded in
generating pyridylalkyne 32. Modifying the stoichiometry of
alkyne−nitrile 28, butadiyne, reaction temperature, and time
only led to the formation of pyridylalkynes.
Figure 4. Isomeric metallacycles leading to the formation of the major
product 32 and minor product 33-pre for the cobalt-mediated [2 + 2 +
2] cycloaddition.
These disubstituted alkynes allowed the examination of their
propensity to undergo the second [2 + 2 + 2] cycloaddition.
Of the disubstituted alkynes prepared only the silicon bearing
alkynes 64, 65, 67, and 70 proved to be competent partners for
[2 + 2 + 2] cycloadditions with alkyne−nitrile 28. Alkyne 64
proved the most effective in generating the corresponding
bipyridyl compound. However, in all these reactions the
undesired 2,2′-bipyridy linkage was formed exclusively (as seen
in bipyridyls 71 and 72) (Scheme 6). Other cobalt, nickel, and
ruthenium catalysts similarly failed to generate the desired
isomer. We propose the selective formation of the metallacycle
75 is responsible for providing the symmetric compound
(Figure 7). This selectivity is similar to the reaction generating
the lycodine derivative 53 in Figure 5. Verification of the
incorrect bipyridyl linkage was readily accomplished by NMR
following desilyation, providing the dimer 73 which possessed a
The regioselective formation of pyridylalkyne 32 was
anticipated following from the studies of Saa and co-workers
́
where they demonstrated that cobalt catalyzed [2 + 2 + 2]
cycloadditions reaction of diynes with tethered alkyne−nitriles
form 2-alkynyl pyridines in preference to 3-alkynyl pyr-
idines.28,29 In addition to their experimental results computa-
tional studies support the formation of the 2-alkynyl metalla-
cycle 38 in preference to the 3-alkynyl metallacycle 39 (Figure
4).
Other alkynes were successfully employed in the [2 + 2 + 2]
cycloaddition reaction providing access to N-benzylated
lycodine derivatives (Figure 5) as well as the parent natural
product lycodine (60) (Scheme 4), a natural product that has
been previously synthesized.34−36 While most substrates
demonstrated high levels of regioselectivity we found that the
positioning of the alkyne on the pyridine was key as seen in the
case of products 49 and 50 formed in a nonselective reaction
while the reaction of alkyne−nitrile 28 and 2-
(trimethylsilylethynyl)pyridine gave rise to only the 2,2′-
bipyridyl isomer 53. For the silicon-bearing alkynes the
selectivities were determined following desilylation of the
pyridine products.
The inability of pyridylalkyne 32 to undergo a second [2 + 2
+ 2] cycloaddition was thought to be due to the steric
impediment caused by the aryltrimethylsilyl group adjacent to
the alkyne (Figure 6). Removal of both trimethylsilyl groups
with TBAF in THF generated alkyne 63 which was silylated
using LDA and TMSCl to generate silylalkyne 64. In addition, a
series of other pyridylalkynes 65-70 were similarly prepared via
deprotonation of 63 with LDA and reaction of the resulting
acetylide anion with the appropriate electrophile (Scheme 5).
1
simplified H NMR spectrum (Scheme 6). Compound 73 was
debenzylated with palladium on carbon and hydrogen to
generate the constitutional isomer of complanadine A, bipyridyl
74.
As the first [2 + 2 + 2] cycloaddition provided a 25:1 ratio
the minor 3-alkynylpyridine 33 could be isolated, albeit in small
amounts. Under the same conditions used for the formation of
the 2,2′-bipyridyl isomer 71, (Scheme 6) pyridylalkyne 33
cyclized to provide the desired 2,3′-bipyridyl linkage within 77
in 28% yield with ≥20:1 regioselectivity (Scheme 7). Following
desilylation and debenzylation complanadine A (1) was formed
matching the spectroscopic data of the isolated natural product
following addition of d4-methanolic DCl solution.37
As the unoptimized reaction proved highly selective for the
formation 2,3′-bipyridyl core we required a scalable route to
access pyridylalkyne 33. The diynes investigated consistently
provided 2-alkynyl pyridines in the [2 + 2 + 2] cycloaddition
reaction therefore a variety of surrogates for diynes were
investigated.38 The majority of alkynes examined failed to react
with alkyne−nitrile 28 (see the Supporting Information),
however, a subset reacted to provide substituted pyridines. The
D
dx.doi.org/10.1021/jo400695c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 5. Regioselective formation of N-benzylated lycodine derivatives.
Scheme 4. Synthesis of Lycodine (60)
silyl ether−alkyne 79 reacted to provide the desired
regioisomer 81 as the major product (Scheme 8).
This product was converted to the desired pyridylalkyne 33
in four steps (Scheme 8). Cleavage of the TBS ether of pyridine
E
dx.doi.org/10.1021/jo400695c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 6. Unsuccessful [2 + 2 + 2] cycloadditions using pyridylalkyne 32.
Scheme 5. Alkynes Prepared for the Second [2 + 2 + 2] Cycloaddition
Scheme 6. Formation of the Symmetric 2,2′-Bipyridyl Isomer 74 of Complanadine A
81 with TBAF and oxidation of the resulting primary alcohol
82 with Dess−Martin periodinane provided aldehyde 83.39
Using the Ohira−Bestmann reagent (84), the aldehyde 83 was
converted to the corresponding alkyne 85 in 86% yield.40 The
alkyne 85 was silylated to generate pyridyl alkyne 33.
Cycloaddition reactions were examined, and unfortunately,
the best conditions discovered were those initially employed,
providing a maximal yield of 77 in 28% yield.
Following the first-generation synthesis of complanadine A,
through two low-yielding [2 + 2 + 2] cycloaddition reactions a
more efficient sequence was investigated. As the first cyclo-
addition reaction proved successful generating pyridylalkyne 33
in good yield and high regioselectivity, attempts were made to
control the second [2 + 2 + 2] cycloaddition reaction.
Conversion of the benzyl group on nitrogen of alkyne−nitrile
28 to a coordinating functionality was investigated. The
removal of the benzyl group of 28 proved challenging;
however, the p-methoxybenzyl and 2,4-dimethoxylbenzyl
groups could be introduced in a related manner (Scheme 2).
Removal of the methoxy bearing groups from 29 or 30 with
CAN provided the secondary amine 86 allowing a variety of
groups to be installed providing new substrates such as
formamide 87 (Scheme 9). The reactivity of these compounds
in the [2 + 2 + 2] cycloaddition reaction was examined (Figure
8). The conversion to coordinating groups provided the first
evidence the desired product could be formed starting from the
F
dx.doi.org/10.1021/jo400695c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 7. Proposed metallacycles 75 and 76.
Scheme 7. Regioselective Cobalt-Mediated [2 + 2 + 2] Cycloaddition of Pyridylalkyne 33 and Alkyne−Nitrile 28 Providing,
after Deprotection, Complanadine A (1)
Scheme 8. Alternative Synthesis of Pyridylalkyne 33 and Complanadine A in Protected Form 77
Scheme 9. Conversion of Alkyne−Nitriles 29 and 30 to Formamide 87
G
dx.doi.org/10.1021/jo400695c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 8. Effects of nitrogen substitution on the regioselectivity of the [2 + 2 + 2] cycloaddition.
Figure 9. Effect of Lewis basic additives on the regioselectivity of the [2 + 2 + 2] cycloaddition.
pyridylalkyne 61. The two substrates that showed the best
reactivity and selectivity were the formyl and urea derivatives
87 and 91.
nonselective reaction with a 1:1.1 ratio of products in 44%
yield. The use of 1,2-bis(diphenylphosphino)ethane completely
inhibited the reaction while the addition of trifurylphosphine
led to rapid loss of starting material with no evidence for the
formation of either bipydridyl product.
Lastly, a screen of solvents (Figure 10), temperatures, and
concentrations (Figure 11) revealed that the use of dioxane (in
a sealed tube) at 140 °C with the addition of triphenylphos-
phine run at 5 mM prove optimal, providing the desired 2,3′-
bipyridyl as the major product 97 in 42% yield with 14% of the
undesired isomer 98 formed (Scheme 10).
Similar to the goal of adding a coordinating group efforts to
reduce the influence of the pyridyl group on the cyclization was
achieved by the addition of a variety of Lewis-basic additives
and, while some completely suppressed the reaction, it was
found that the addition of NMO, DMAP, triphenylphosphine,
triphenylarsine, and tri(o-tolyl)phosphine improved the selec-
tivity (Figure 9). The use of triphenylphosphine provided the
right balance of reactivity and control, providing a nearly
H
dx.doi.org/10.1021/jo400695c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 10. Solvent effects on the on the regioselectivity and yields of the [2 + 2 + 2] cycloaddition.
Figure 11. Temperature and concentration effects on the regioselectivity and yields of the [2 + 2 + 2] cycloaddition.
Completion of the synthesis was achieved by first removal of
the pyridyl-TMS with TBAF in dioxane heated to reflux to
generate bipyridyl 100. Hydrogenolysis of the benzyl group
with palladium on carbon and hydrogen followed by cleavage of
the formyl group using hydrochloric acid in methanol provided
complanadine A (Scheme 11).
related cycloadditions using disubstituted alkynes. The
controlled formation of the 2,3′-bipyridyl core was achieved
through either modifying the partners in the reaction sequence
or the use of Lewis-basic additives. With access to
complanadine A studies of the compound’s effects upon
neuronal growth are underway.
CONCLUSION
EXPERIMENTAL SECTION
■
■
Two routes to complanadine A have been developed utilizing
cobalt-mediated [2 + 2 + 2] cycloaddition reactions. In
addition, related lycodine derivatives can be accessed through
General Information. In addition to characterization data the
structures of reaction intermediates (int-1 to int-19) can be found in
the Supporting Information.
I
dx.doi.org/10.1021/jo400695c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 10. Optimized [2 + 2 + 2] Cycloaddition Conditions
1H), 2.31 (t, J = 7.6 Hz, 2H), 2.37−2.50 (m, 2H), 3.48 (t, J = 6.4 Hz,
2H), 6.72−6.74 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 21.1, 26.9,
30.6, 31.2, 34.3, 44.5, 46.5, 137.8, 145.5, 199.4; IR (neat) ν 2957, 1675,
1384 cm−1; HRMS calcd for C10H16ClO+ [M + H+] 187.0890, found
187.0890.
Scheme 11. Completion of the Synthesis of Complanadine A
(R)-2-(3-Azidopropyl)-5-methylcyclohex-2-enone (14). To a sol-
ution of enone 13 (231 mg, 1.24 mmol, 1.0 equiv) in DMF (10 mL) at
23 °C solid NaI (403 mg, 2.7 mmol, 2.2 equiv) and NaN3 (159 mg, 2.5
mmol, 2.0 equiv) were added. The reaction flask was immersed into 65
°C oil bath and stirred for 24 h. The reaction was diluted with aqueous
saturated NH4Cl solution (20 mL), and the mixture was extracted with
EtOAc (3 × 10 mL). The combined organic extracts were washed with
brine (10 mL), dried over Na2SO4, filtered, and concentrated. The
crude product was purified by silica gel chromatography (10/1 → 2/1
hexanes/EtOAc) to afford 14 as pale yellow oil (171 mg, 72%). Rf =
0.50 (silica gel, hexanes/EtOAc = 5/1); 1H NMR (400 MHz, CDCl3)
δ 1.05 (d, J = 6.0 Hz, 3H), 1.66−2.00 (m, 2H), 2.01−2.27 (m, 5H),
2.38−2.45 (m, 1H), 2.45−2.51 (m, 1H), 3.25 (t, J = 6.8 Hz, 2H),
6.70−6.73 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 21.2, 26.9, 27.8,
30.6, 34.3, 46.6, 51.0, 138.2, 145.3, 199.5; IR (neat) ν 2956, 2097,
1674 cm−1; HRMS calcd for C10H16N3O+ [M + H+] 194.1293, found
194.1291.
(5R)-2-(3-Chloropropyl)-5-methyl-2-(phenylthio)cyclohexanone
(int-1, Precursor for 13). To a solution of thioether 12 (5.0 g, 22.7
mmol, 1.0 equiv) in DMF (120 mL) at 0 °C was added solid NaH
(1.04 g, 60% oil dispersion, 26.0 mmol, 1.2 equiv) in portions over 5
min with extensive gas evolution. After 60 min, neat 1-chloro-3-
iodopropane (5.10 g, 25.0 mmol, 1.1 equiv) was added dropwise over
10 min, and the cooling bath was removed and the solution was stirred
for 1 h. The reaction mixture was diluted with aqueous saturated
NH4Cl solution (500 mL) and EtOAc (250 mL). The organic phase
was separated, and the aqueous phase was extracted with EtOAc (4 ×
100 mL). The combined organic extracts were washed with brine (100
mL), dried over Na2SO4, filtered, and concentrated. The crude
material was purified by silica gel chromatography (5/1 → 2/1
hexanes/Et2O) to afford int-1 (3.54 g, 53%) as a yellow oil: Rf = 0.45
(silica gel, hexanes/EtOAc = 5/1); 1H NMR (400 MHz, CDCl3, int-1-
major:int-1-minor = 0.77:0.23 mixture of diastereomers) δ 0.96 (d, J
= 6.4 Hz, 3H**), 1.08 (d, J = 6.4 Hz, 3H*), 1.42−1.72 (m, 3H),
1.72−2.02 (m, 4H), 2.04−2.15 (m, 2H), 2.28−2.34 (m, 1H), 3.12 (t, J
= 13.2 Hz, 1H*), 3.30 (dd, J = 5.2 and 14.0 Hz, 1H**), 3.44−3.54 (m,
2H), 7.27−7.50 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 19.6, 21.9,
22.2, 27.0, 27.1, 27.8, 29.6, 31.86, 31.91, 32.2, 33.5, 34.5, 35.7, 45.0,
45.1, 45.8, 59.7, 61.4, 128.86, 128.95, 129.0, 129.3, 129.5, 135.3, 136.0,
136.5, 207.2, 207.9; IR ν 2955, 2927, 1701, 1438 cm−1; HRMS calcd
for C16H21ClOS+ [M+] 296.1002, found 296.1005. H* for minor
isomer; H** for major isomer.
(R)-2-(3-Chloropropyl)-5-methylcyclohex-2-enone (13). To a
solution of ketone int-1 (3.67 g, 12.4 mmol, 1.0 equiv) in CH2Cl2
(150 mL) at −78 °C was added a solution of purified m-CPBA (2.24 g,
13.0 mmol, 1.1 equiv) in CH2Cl2 (50 mL) over 1 h. The mixture was
warmed to 23 °C over one hour then stirred 10 h where upon the
solution became homogeneous. The reaction was diluted with aqueous
NaHSO3 solution (10% w/w, 50 mL). The mixture was extracted with
EtOAc (3 × 50 mL). The combined organic extracts were washed with
brine (50 mL), dried over Na2SO4, filtered, and concentrated. The
crude product was purified by silica gel chromatography (10/1 → 2/1
hexanes/Et2O) to afford 13 as yellow oil (1.9 g, 82%). Rf = 0.50 (silica
gel, hexanes/EtOAc = 5/1); 1H NMR (400 MHz, CDCl3) δ 1.03 (d, J
= 6.0 Hz, 3H), 1.82−1.89 (m, 2H), 1.99−2.09 (m, 2H), 2.12−2.21 (m,
2-((1S,2R,5R)-2-(3-Azidopropyl)-5-methyl-3-oxocyclohexyl)-
acetonitrile (15). To a solution of the diisopropylamine (95 μL, 0.67
mmol, 2.0 equiv) in Et2O (2 mL) was added n-BuLi solution (0.35
mL, 2.0 M, 0.67 mmol, 2.0 equiv) at −78 °C. After 5 min, neat
trimethylsilylacetonitrile (92 μL, 0.67 mmol, 2.0 equiv) was added.
After 30 min, the solution was transferred via cannula to a second flask
containing enone 14 (65 mg, 0.34 mmol, 1.0 equiv) in Et2O (5 mL)
cooled to −78 °C. After 25 min, the resulting yellow solution was
transferred via cannula to a third flask containing ethyl salicylate (0.15
mL, 1.0 mmol, 3.0 equiv) in Et2O (2 mL) cooled to −78 °C. The
reaction was allowed to slowly warm to 23 °C over 1 h. The lithium
phenoxide was quenched by the addition of acetic acid (60 μL, 1.0
mmol, 3 equiv). The reaction was filtered through a pad of Celite. The
solution was washed with aqueous saturated NaHCO3 solution (10
mL) and brine (5 mL). The organic layer was dried over Na2SO4,
filtered, and concentrated. The crude material was purified by silica gel
chromatography (20/1 → 1/1 hexanes/Et2O) to afford yellow oil (42
mg, 72%) as a mixture of 4 diastereomers that was used in the next
reaction (below). To a solution of the above diastereomers (42 mg,
0.14 mmol, 1.0 equiv) in MeCN (3 mL) solid CsF (5.0 mg, 0.030
mmol, 0.24 equiv) was added. The resulting mixture was stirred at 23
°C for 6 h then diluted with aqueous saturated NH4Cl solution (5 mL)
and extracted with EtOAc (3 × 5 mL). The organic extracts were
washed with brine (10 mL), dried over Na2SO4, filtered and
concentrated. The crude material was purified by silica gel
chromatography (10/1 → 1/1 hexanes/EtOAc) to afford ketone 15
(27.8 mg, 87%) as a light yellow oil: Rf = 0.65 (silica gel, hexanes/
1
EtOAc = 2/1); H NMR (400 MHz, CDCl3) δ 1.08 (d, J = 6.4 Hz,
J
dx.doi.org/10.1021/jo400695c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3H), 1.16−1.25 (m, 1H), 1.40−1.51 (m, 1H), 1.56−1.62 (m, 2H),
1.63−1.84 (m, 2H), 1.96−2.17 (m, 3H), 2.31−2.44 (m, 2H), 2.56−
2.61 (m, 2H), 3.24−3.35 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
16.9, 22.0, 23.7, 27.0, 30.0, 37.3, 38.3, 50.1, 51.3, 52.2, 118.2, 210.0; IR
ν 2954, 2098, 1709 cm−1; HRMS calcd for C12H18N4ONa+ [M + Na+]
257.1378, found 257.1373.
The reaction was diluted with aqueous saturated NH4Cl solution (100
mL) and extracted with EtOAc (2 × 200 mL). The organic extracts
were washed with brine (100 mL), dried over Na2SO4, filtered, and
concentrated. The crude material was purified by silica gel
chromatography (10/1 → 1/1 hexanes/Et2O) to afford ketone 18
(2.80 g, 80%) as yellow oil. The two-step yield is 45%: Rf = 0.45 (silica
gel, hexanes/EtOAc = 2/1); 1H NMR (400 MHz, CDCl3) δ 1.07 (d, J
= 6.0 Hz, 3H), 1.15−1.23 (m, 1H), 1.48−1.84 (m, 4H), 1.95−2.17 (m,
7H), 2.31−2.44 (m, 2H), 2.56−2.63 (m, 2H), 3.99−4.09 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 16.8, 20.9, 22.0, 22.8, 26.5, 30.0, 37.2,
38.1, 50.1, 52.0, 64.0, 118.2, 171.1, 210.1; IR 1735, 1710, 1048 cm−1;
HRMS calcd for C14H21NO3Na+ [M + Na+] 274.14191, found
274.14169.
3-((4R)-4-Methyl-2-oxo-1-(phenylthio)cyclohexyl)propyl Acetate
(int-2, Precursor for 17). To a solution of thioether 12 (30.0 g, 136
mmol, 1.0 equiv) in DMF (1.25 L) at 0 °C solid NaH (5.99 g, 60% oil
dispersion, 150 mmol, 1.1 equiv) was added portionwise over 5 min
with extensive gas evolution. After 60 min, the iodo ester (37.3 g, 163
mmol, 1.2 equiv) was added neat, dropwise over 10 min, then the
cooling bath was removed and the resulting solution was stirred at 23
°C for 1 h. The reaction was diluted with aqueous saturated NH4Cl
solution (2 L) and EtOAc (1 L). The organic phase was collected, and
the aqueous phase was extracted with EtOAc (4 × 500 mL). The
combined organic extracts were washed with brine (500 mL), dried
over Na2SO4, filtered, and concentrated. The crude material was
purified by silica gel chromatography (5/1 → 2/1 hexanes/Et2O) to
afford a diastereomeric mixture of ketones int-2 as a yellow viscous oil
3-((1R,2S,4R,6S)-6-(Cyanomethyl)-2-ethynyl-2-hydroxy-4-
methylcyclohexyl)propyl Acetate (19). To a solution of ketone 18
(11.5 g, 45.8 mmol, 1.0 equiv) in THF (350 mL) at 23 °C was added
dropwise a solution of the ethynylmagnesium chloride (114 mL, 0.60
M in toluene/THF, 69 mmol, 1.5 equiv) over 5 min. After 30 min, the
resulting alkoxide was quenched by the addition of aqueous saturated
NH4Cl solution (100 mL) and the mixture was extracted with EtOAc
(3 × 200 mL). The organic extracts were washed with brine (50 mL),
dried over Na2SO4, filtered, and concentrated. The crude alcohol was
purified by silica gel chromatography (5/1 → 2/1 hexanes/EtOAc) to
afford alcohol 19 (12.3 g, 97%) as a yellow oil. 19: Rf = 0.41 (silica gel,
1
(27.3 g, 63%): Rf = 0.31 (silica gel, hexanes/EtOAc = 5/1); H NMR
(400 MHz, CDCl3, 7/3 mixture of diastereomers) δ 0.88 (t, J = 6.8
Hz, 0.7 H), 0.96 (d, J = 6.8 Hz, 2.1 H), 1.08 (d, J = 6.0 Hz, 0.9 H),
1.22−1.30 (m, 0.3 H), 1.46−1.94 (m, 5 H), 1.96−2.36 (m, 7 H), 3.14
(t, J = 13.2 Hz, 0.3 H), 3.35 (dd, J = 6.0 and 14.4 Hz, 0.7 H), 3.98−
4.04 (m, 2H), 7.26−7.37 (m, 5H); 13C NMR (100 MHz, CDCl3) δ
19.3, 20.7, 22.0, 22.5, 22.7, 27.5, 29.5, 30.2, 30.6, 31.6, 33.0, 34.3, 35.4,
44.7, 45.6, 59.6, 60.8, 61.2, 64.2, 64.3, 128.6, 128.7, 129.1, 129.2, 129.9,
130.1, 135.8, 136.3, 170.8, 206.9, 207.7; IR ν 1739, 1700, 1043 cm−1;
HRMS calcd for C18H24O3SNa+ [M + Na+] 343.13438, found
343.13447.
(R)-3-(4-Methyl-6-oxocyclohex-1-en-1-yl)propyl Acetate (17). The
diastereomeric mixture of ketones int-2 (27.0 g, 84 mmol, 1.0 equiv)
in CH2Cl2 (1.0 L) was cooled to −78 °C, and a solution of purified m-
CPBA (15.3 g, 88 mmol, 1.05 equiv) in CH2Cl2 (600 mL) was added
over 1 h. The cooling bath was removed, and the solution was stirred
for 10 h at 23 °C whereupon the solution became homogeneous. The
reaction was then diluted with aqueous NaHSO3 (10% w/w, 200 mL).
The mixture was extracted with EtOAc (3 × 400 mL). The organic
extracts were washed with brine (200 mL), dried over Na2SO4, filtered,
and concentrated. The crude product was purified by silica gel
chromatography (10/1 → 2/1 hexanes/Et2O) to afford enone 17 as
yellow oil (13.6 g, 77%): Rf = 0.39 (silica gel, hexanes/EtOAc = 5/1);
1H NMR (400 MHz, CDCl3) δ 1.05 (d, J = 6.4 Hz, 3H), 1.58−1.77
1
hexanes/EtOAc = 2/1); H NMR (400 MHz, CDCl3) δ 0.95 (d, J =
6.8 Hz, 3H), 1.18−1.25 (m, 1H), 1.41−1.66 (m, 3H), 1.70−1.79 (m,
2H), 1.83−1.93 (m, 1H), 1.93−2.04 (m, 2H). 2.06 (s, 3H), 2.20−2.26
(m, 1H), 2.45−2.51 (m, 2H), 2.80 (dd, J = 8.8 and 17.6 Hz, 1H), 2.92
(dd, J = 0.4 and 14.8 Hz, 1H), 4.04−4.16 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 16.9, 21.0, 21.4, 21.5, 23.2, 25.9, 32.2, 37.6, 45.5, 49.3,
64.2, 70.9, 72.2, 87.5, 120.4, 171.1; IR ν 3462, 1738, 1457, 1024 cm−1;
HRMS calcd for C16H23NO3Na+ [M + Na+] 300.15756, found
300.15724.
3-((1R,2S,4R,6S)-2-Acetoxy-6-(cyanomethyl)-2-ethynyl-4-
methylcyclohexyl)propyl Acetate (20). To a solution of alcohol 19
(9.0 g, 32 mmol, 1.0 equiv) in acetic anhydride (27.6 mL, 92 mmol,
2.8 equiv) at 23 °C was added solid magnesium perchlorate (0.70 g,
3.1 mmol, 0.1 equiv) in one portion. After 30 min, the mixture was
diluted with aqueous saturated NaHCO3 solution (200 mL), and solid
NaHCO3 was added to adjust the pH to 8. The mixture was extracted
with EtOAc (3 × 100 mL). The organic extracts were washed with
brine (100 mL), dried over Na2SO4, filtered, and concentrated. The
crude acetate was purified by silica gel chromatography (5/1 → 2/1
hexanes/EtOAc) to yield diacetate 20 (10.1 g, 97%) as a yellow oil: Rf
= 0.45 (silica gel, hexanes/EtOAc = 2/1); 1H NMR (400 MHz,
CDCl3) δ 0.94 (d, J = 6.4 Hz, 3H), 1.24−1.33 (m, 2H), 1.44−1.64 (m,
4H), 1.69−1.78 (m, 2H), 2.04 (s, 3H), 2.06 (s, 3H), 2.08−2.14 (m,
2H), 2.31−2.34 (m, 1H), 2.52−2.54 (m, 1H), 2.59 (s, 1H), 2.97 (td, J
= 2.8 and 14.8 Hz, 1H), 4.05−4.16 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 17.0, 21.0, 21.3, 21.6, 22.0, 23.0, 25.9, 32.1, 37.3, 43.1, 46.8,
64.0, 74.5, 77.5, 82.7, 119.8, 168.2, 171.1; IR ν 1737, 1727 cm−1;
HRMS calcd for C18H25NO4Na+ [M + Na+] 342.16813, found
342.16774.
General Procedure for the Cu(OAc)2-Catalyzed Amine
Substitution Reaction. A flask containing neat benzylamine and
the diacetate substrate was evacuated and backfilled with N2 three
times. By syringe THF was added, and the mixture was degassed via
iterative freeze−pump−thaw sequences (three cycles). Solid CuCl was
added in one portion with a back flow of N2. The reaction flask was
placed in an 80 °C oil bath for 30 min, cooled to 23 °C, and diluted
with pentane (100 mL). The mixture was filtered through silica gel
(EtOAc/hexanes = 1/1) and concentrated to provide amine product.
3-((1R,2R,4R,6S)-2-(Benzylamino)-6-(cyanomethyl)-2-ethynyl-4-
methylcyclohexyl)propyl Acetate (21). Following the general
procedure, benzylamine (1.2 mL, 11 mmol, 3.5 equiv), diacetate 20
(1.0 g, 3.1 mmol, 1 equiv), THF (24 mL), and CuCl (105 mg, 1.1
mmol, 0.34 equiv) provided amine 21 (1.05 g, 92%) as yellow oil: Rf =
0.35 (silica gel, hexanes/EtOAc = 2/1); 1H NMR (400 MHz, CDCl3)
δ 1.01(d, J = 6.4 Hz, 3H), 1.10 (t, J = 12.0 Hz, 1H), 1.20−1.27 (m,
1H), 1.43−1.65 (m, 4H), 1.72−1.91 (m, 2H), 2.01 (s, 3H), 2.02−2.06
(m, 2H), 2.04−2.09 (m, 4H), 2.09−2.13 (m, 1H), 2.13−2.19 (m, 1H),
2.25 (t, J = 8.0 Hz, 2H), 2.41 (dt, J = 5.0 and 18.0 Hz, 1H), 2.47−2.52
(m, 1H), 4.04 (t, J = 6.4 Hz, 2H), 6.68−6.70 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 21.0, 21.2, 26.0, 27.3, 30.6, 34.3, 46.6, 64.0, 138.3,
144.9, 171.2, 199.5; IR (neat) ν 1734, 1717 cm−1; HRMS calcd for
C12H18O3Na+ [M + Na+] 233.11536, found 233.11490.
3-((1R,2S,4R)-2-(Cyanomethyl)-4-methyl-6-oxocyclohexyl)propyl
Acetate (18). To a solution of trimethylsilyl acetonitrile (0.28 mL, 2.1
mmol, 1.3 equiv) in Et2O (30 mL) at −78 °C was added a solution of
n-butyllithium (1.8 M Hexanes, 1.1 mL, 2.0 mmol, 1.2 equiv) over 1
min. After being stirred for 40 min at −78 °C, the pale yellow solution
was transferred over 3 min via cannula to a stirred solution of the
enone 17 (350 mg, 1.7 mmol, 1.0 equiv) in Et2O (30 mL) at −78 °C.
After 30 min, the bright yellow solution was added over 3 min via
cannula to a stirred solution of ethyl salicylate (0.97 mL, 6.6 mmol, 4.0
equiv) at −78 °C in Et2O (30 mL). After 5 min, the cooling bath was
removed, the reaction was allowed to warm to 23 °C over 20 min, and
acetic acid (0.10 mL, 1.7 mmol, 1.1 equiv) was added in one portion.
The solution was washed with aqueous saturated sodium bicarbonate
solution (50 mL). The organic extract was washed with brine (50 mL),
dried over Na2SO4, filtered, and concentrated. The crude material was
purified by silica gel chromatography (20/1 → 5/1 hexanes/EtOAc)
to afford a mixture of diastereomers as light yellow oil (300 mg, 56%).
To a solution of the above diastereomers (4.50 g, 13.9 mmol, 1.0
equiv) in MeCN (110 mL) at 23 °C was added solid CsF (0.20 g, 1.3
mmol, 0.10 equiv). The resulting mixture was stirred at 23 °C for 6 h.
K
dx.doi.org/10.1021/jo400695c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(m, 1H), 2.22 (m, 1H), 2.30−2.35 (m, 1H), 2.46 (s, 1H), 2.56 (dd, J =
2.4 and 17.2 Hz, 1H), 3.00 (dd, J = 12.4 and 17.2 Hz, 1H), 3.80 (dd, J
= 12.0 and 49.6 Hz, 2H), 4.04−4.07 (m, 2H), 7.25−7.33 (m, 5H); 13C
NMR (100 MHz, CDCl3) δ 16.5, 20.8, 21.8, 22.7, 23.8, 25.9, 33.0,
37.7, 46.2, 46.4, 47.0, 55.7, 64.0, 74.7, 86.6, 120.0, 127.0, 128.3, 128.4,
140.3, 171.0; IR ν 2953, 1737 cm−1; HRMS calcd for C23H31N2O2+ [M
+ H+] 367.23855, found 367.23794.
mL), and brine (50 mL) provided alcohol 25 (1.50 g, 99%) as a yellow
oil: Rf = 0.30 (silica gel, EtOAc); 1H NMR (400 MHz, CDCl3) δ 1.01
(d, J = 6.4 Hz, 3H), 1.10 (t, J = 12.0 Hz, 1H), 1.20−1.27 (m, 1H),
1.41−1.89 (m, 8H), 2.00−2.06 (m, 1H), 2.19−2.25 (m, 1H), 2.31−
2.38 (m, 1H), 2.46 (s, 1H), 2.59−2.64 (m, 1H), 2.98 (dd, J = 12.0 and
17.2 Hz, 1H), 3.63−3.68 (m, 2H), 3.73 (d, J = 11.6 Hz, 1H), 3.84 (d, J
= 11.6 Hz, 1H), 7.25−7.33 (m, 5H); 13C NMR (100 MHz, CDCl3) δ
16.5, 21.9, 22.6, 23.8, 29.7, 33.1, 37.8, 46.1, 46.5, 47.2, 55.9, 62.4, 74.8,
86.7, 120.3, 127.1, 128.48, 128.52, 140.2; IR ν 3344, 3063, 2924, 2867,
3-((1R,2R,4R,6S)-6-(Cyanomethyl)-2-ethynyl-2-((4-
methoxybenzyl)amino)-4-methylcyclohexyl)propyl Acetate (22).
Following the general procedure, p-methoxylbenzylamine (2.0 mL,
15.3 mmol, 4.1 equiv), acetate 20 (1.20 g, 3.8 mmol, 1.0 equiv), THF
(28 mL), and CuCl (110 mg, 1.08 mmol, 0.29 equiv) provided 22
2+
1454, 733 cm−1; HRMS calcd for C42H56N4O2 [2M2+] 324.22016,
found 324.21988.
2-((1S,2R,3R,5R)-3-Ethynyl-2-(3-hydroxypropyl)-3-((4-
methoxybenzyl)amino)-5-methylcyclohexyl)acetonitrile (26). Fol-
lowing the general procedure, propargylamine 22 (1.20 g, 3.0 mmol,
1.0 equiv), methanol (20 mL), K2CO3 (2.0 g, 14.5 mmol, 4.8 equiv),
saturated aqueous NH4Cl solution (60 mL), EtOAc (3 × 50 mL), and
brine (20 mL) provided 26 (1.05 g, 98%) as a yellow oil: [α]24D −51.8
(1.20 g, 81%) as pale yellow oil: [α]24 −38.2 (c 0.19, CH2Cl2); Rf =
D
0.30 (silica gel, hexanes/EtOAc = 2/1); 1H NMR (400 MHz, CDCl3)
δ 1.01 (d, J = 6.4 Hz, 3H), 1.09 (t, J = 12.4 Hz, 1H), 1.19−1.27 (m,
2H), 1.44−1.64 (m, 3H), 1.72−1.77 (m, 2H), 1.83−1.89 (m, 1H),
2.01−2.06 (m, 4H), 2.17−2.23 (m, 1H), 2.31−2.35 (m, 1H), 2.46 (s,
1H), 2.53−2.58 (m, 1H), 3.0 (dd, J = 9.0 and 16.8 Hz, 1H), 3.66 (d, J
= 11.2 Hz, 1H), 3.78−3.81 (m, 4H), 4.03−4.07 (m, 2H), 6.84−6.88
(m, 2H), 7.23−7.25 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 16.5,
20.9, 21.9, 22.8, 23.8, 26.0, 33.0, 37.7, 46.2, 46.5, 46.5, 55.3, 55.7, 64.1,
74.7, 86.8, 113.9, 120.1, 129.6, 132.4, 158.8, 171.1; IR ν 3287, 1735
1
(c 0.55, CH2Cl2); Rf = 0.21 (silica gel, EtOAc); H NMR (400 MHz,
CDCl3) δ 1.01 (d, J = 6.4 Hz, 3H), 1.09 (t, J = 12.0 Hz, 1H), 1.21-
1.27 (m, 2H), 1.41−1.50 (m, 3H), 1.62−1.75 (m, 3H), 1.81−1.90 (m,
1H), 2.01−2.04 (m, 1H), 2.18−2.22 (m, 1H), 2.31−2.34 (m, 1H),
2.47 (s, 1H), 2.61 (dd, J = 3.6 and 17.2 Hz, 1H), 2.97 (dd, J = 12.0 and
17.2 Hz, 1H), 3.58−3.67 (m, 3H), 3.78−3.81 (m, 4H), 6.84−6.90 (m,
2H), 7.23−7.30 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 16.5, 21.9,
22.6, 23.8, 29.7, 33.0, 37.8, 46.1, 46.4, 46.6, 55.3, 55.8, 62.4, 74.7, 86.8,
113.9, 120.3, 129.6, 132.3, 158.7; IR ν 3406, 1510, 1243, 1033 cm−1;
HRMS calcd for C22H31N2O2+ [M + H+] 355.23855, found 355.23805.
2-((1S,2R,3R,5R)-3-((2,4-Dimethoxybenzyl)amino)-3-ethynyl-2-(3-
hydroxypropyl)-5-methylcyclohexyl)acetonitrile (27). Following the
general procedure, propargylamine 23 (195 mg, 0.46 mmol, 1.0
equiv), methanol (5.0 mL), water (0.10 mL), K2CO3 (300 mg, 2.2
mmol, 4.8 equiv), aqueous saturated NH4Cl solution (40 mL), EtOAc
(3 × 40 mL), and brine (30 mL) provided the corresponding alcohol
+
cm−1; HRMS calcd for C24H33N2O3 [M + H+] 397.24912, found
397.24867.
3-((1R,2R,4R,6S)-6-(Cyanomethyl)-2-((2,4-dimethoxybenzyl)-
amino)-2-ethynyl-4-methylcyclohexyl)propyl Acetate (23). Follow-
ing the general procedure 3,4-dimethoxylbenzylamine (0.22 mL, 1.5
mmol, 2.5 equiv), diacetate 20 (185 mg, 0.58 mmol, 1.0 equiv), THF
(6 mL), CuCl (25 mg, 0.25 mmol, 0.44 equiv) provided amine 23
(190 mg, 77%) as a pale yellow oil: Rf = 0.30 (silica gel, hexanes/
1
EtOAc = 2/1); H NMR (400 MHz, CDCl3) δ 1.01 (d, J = 6.8 Hz,
3H), 1.11 (t, J = 12.4 Hz, 1H), 1.18−1.25 (m, 1H), 1.43−1.67 (m,
3H), 1.68−1.79 (m, 4H), 1.83−1.93 (m, 1H), 2.01−2.07 (m, 4H),
2.22 (dt, J = 2.8 and 12.8 Hz, 1H), 2.30−2.33 (m, 1H), 2.44 (s, 1H),
2.57 (dd, J = 2.8 and 17.2 Hz, 1H), 3.01 (dd, J = 12.0 and 17.2 Hz,
1H), 3.61 (d, J = 12.0 Hz, 1H), 3.79 (s, 3H), 3.81−3.84 (m, 4H),
4.05−4.08 (m, 2H), 6.42−6.47 (m, 2H), 7.14−7.17 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 16.5, 20.9, 21.9, 22.7, 23.8, 25.9, 33.1,
37.8, 42.0, 46.0, 46.2, 55.3, 55.4, 55.5, 64.3, 74.7, 86.7, 98.6, 104.1,
120.2, 120.7, 130.4, 158.5, 160.1, 171.1; IR ν 3279, 2953, 2919, 1735
1
27 (166 mg, 94%) as a yellow oil: Rf = 0.30 (silica gel, EtOAc); H
NMR (400 MHz, CDCl3) δ 1.01 (d, J = 6.8 Hz, 3H),1.10 (t, J = 12.4
Hz, 1H), 1.20−1.24 (m, 1H), 1.39−1.55 (m, 2H), 1.63−1.72 (m, 2H),
1.77−2.04 (m, 5H), 2.23 (dt, J = 2.4 and 12.4 Hz, 1H), 2.30−2.34 (m,
1H), 2.44 (s, 1H), 2.62 (dd, J = 2.8 ad 17.2 Hz, 1H), 2.99 (dd, J = 12.0
and 17.2 Hz, 1H) 3.60−3.67 (m, 3H), 3.79 (s, 3H), 3.81 (s, 3H), 3.84
(d, J = 11.6 Hz, 1H), 6.42−6.45 (m, 2H), 7.15 (dd, J = 2.0 and 6.8 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 16.6, 21.9, 22.6, 23.8, 29.8, 33.2,
37.9, 42.1, 45.9, 46.2, 55.3, 55.4, 55.7, 62.4, 74.7, 86.7, 98.7, 104.1,
120.4, 120.5, 130.5, 158.5, 160.2; IR ν 3285, 2921, 1614 cm−1; HRMS
+
cm−1; HRMS calcd for C25H35N2O4 [M + H+] 427.25968, found
427.25929.
2-((1S,2R,3S,5R)-3-Ethynyl-3-hydroxy-2-(3-hydroxypropyl)-5-
methylcyclohexyl)acetonitrile (24). To a solution of acetate 19 (100
mg, 0.36 mmol, 1.0 equiv) in methanol (5 mL) and water (0.1 mL)
was added solid potassium carbonate (248 mg, 1.80 mmol, 5.0 equiv).
The mixture was stirred for 12 h and then diluted with aqueous
saturated NH4Cl solution (20 mL) and extracted with EtOAc (3 × 10
mL). The organic extracts were washed with brine (20 mL), dried over
Na2SO4, filtered, and concentrated to provide 24 as colorless crystals
+
calcd for C23H33N2O3 [M + H+] 385.24912, found 385.24852.
General Procedure for the Synthesis of Bicyclic Compound.
The alcohol was dissolved in CCl4, and then PPh3 (2.0 equiv) and
imidazole (2.0 equiv) were added sequentially as solids. The reaction
was placed in a heated oil bath for 15 h, the oil bath was removed, and
the solution was diluted with saturated aqueous NH4Cl solution and
extracted with EtOAc. The organic extracts were washed with brine,
dried over Na2SO4, filtered, and concentrated. The crude material was
purified by silica gel chromatography (1/0 → 5/1 hexanes/EtOAc) to
afford the bicyclic alkyne−nitrile.
1
(59.9 mg, 71%, mp 89.0−92.1 °C): Rf = 0.15 (silica gel, EtOAc); H
NMR (400 MHz, CDCl3) δ 0.95 (d, J = 6.4 Hz, 3H), 1.20−1.26 (m,
1H), 1.41−1.48 (m, 1H), 1.51−1.73 (m, 7H), 1.82−1.92 (m, 1H),
2.02−2.08 (m, 2H), 2.22−2.24 (m, 1H), 2.48 (s, 1H), 2.50−2.55 (m,
1H), 2.77 (dd, J = 11.6 and 17.6 Hz, 1H), 3.64−3.75 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 16.9, 21.4, 21.5, 23.1, 29.9, 32.2, 37.8,
45.7, 49.3, 62.8, 71.1, 72.2, 87.6, 120.6; IR ν 3299, 2918, 2248 cm−1;
2-((4aR,5R,7S,8aS)-1-Benzyl-8a-ethynyl-7-methyldecahydroqui-
nolin-5-yl)acetonitrile (28). Following the general procedure, alcohol
25 (750 mg, 2.3 mmol, 1.0 equiv), CCl4 (20 mL), PPh3 (1.21 g, 4.6
mmol, 2.0 equiv), imidazole (315 mg, 4.6 mmol, 2.0 equiv), and
saturated aqueous NH4Cl solution (50 mL), extraction with EtOAc (3
×), and washing with brine (20 mL) afforded alkyne−nitrile 28 (530
+
HRMS calcd for C14H22NO2 [M + H+] 236.1651, found 236.1645.
General Procedure for the Deacetoxylation Reaction by
K2CO3. To a solution of the propargylamine in methanol was added
solid K2CO3 in one portion. The heterogeneous solution was stirred
vigorously for 7 h at 23 °C and then diluted with saturated aqueous
NH4Cl solution and extracted with EtOAc. The organic extracts were
washed with brine, dried over Na2SO4, filtered, and concentrated to
provide alcohol.
2-((1S,2R,3R,5R)-3-Ethynyl-2-(3-hydroxypropyl)-3-((4-
methoxybenzyl)amino)-5-methylcyclohexyl)acetonitrile (25). Fol-
lowing the general procedure, propargylamine 21 (1.70 g, 4.64
mmol, 1.0 equiv), methanol (25 mL), K2CO3 (3.0 g, 21.7 mmol, 4.7
equiv), saturated aqueous NH4Cl solution (50 mL), EtOAc (3 × 50
mg, 75%, mp 138.2−138.5 °C) as a pale yellow crystalline solid: [α]24
D
−152.7 (c 1.0, CH2Cl2); Rf = 0.60 (silica gel, hexenes/EtOAc = 10/1);
1H NMR (400 MHz, CDCl3) δ 0.99 (d, J = 6.4 Hz, 3H), 1.12 (t, J =
12.4 Hz, 1H), 1.25−1.66 (m, 6H), 1.93−2.01 (m, 2H), 2.11−2.15 (m,
1H), 2.26−2.34 (m, 2H), 2.51 (s, 1H), 2.55−2.63 (m, 2H), 2.93 (d, J
= 13.6 Hz, 1H), 3.00 (dd, J = 12.0 and 18.0 Hz, 1H), 4.06 (d, J = 13.6
Hz, 1H), 7.20−7.33 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 17.3,
22.2, 24.3, 25.9, 26.7, 37.2, 38.1, 45.9, 46.4, 48.5, 53.4, 58.6, 76.6, 83.6,
120.6, 126.6, 128.1, 128.5, 140.3; IR ν 1454, 1068, 701 cm−1; HRMS
+
calcd for C21H27N2 [M + H+] 307.21742, found 307.21690.
L
dx.doi.org/10.1021/jo400695c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2-((4aR,5R,7S,8aS)-8a-Ethynyl-1-(4-methoxybenzyl)-7-methylde-
cahydroquinolin-5-yl)acetonitrile (29). Following the general proce-
dure, alcohol 26 (450 mg, 1.3 mmol, 1.0 equiv), CCl4 (15 mL), PPh3
(0.67 g, 2.54 mmol, 2.0 equiv), imidazole (172 mg, 2.5 mmol, 2.0
equiv), aqueous saturated NH4Cl solution (30 mL), EtOAc (3 × 20
mL), and brine (20 mL) afforded 29 (530 mg, 74%) as a pale yellow
hexanes/EtOAc = 10/1); 1H NMR (400 MHz, CDCl3) δ 0.29 (s, 9H),
0.75 (d, J = 6.4 Hz, 3H), 0.83−0.88 (m, 2H), 0.97 (d, J = 6.8 Hz, 1H),
1.14−1.21 (m, 1H), 1.2−1.33 (m, 2H), 1.42−1.61 (m, 2H), 1.72−1.80
(m, 2H), 1.89−1.94 (m, 1H), 2.09−2.12 (m, 1H), 2.4−2.52 (m, 2H),
3.19 (dd, J = 6.8 and 19.6 Hz, 1H), 4.14 (dd, J = 14.0 and 63.6 Hz,
2H), 7.24−7.33 (m, 1H), 7.34−7.50 (m, 2H), 7.48−7.50 (m, 2H),
8.15 (d, J = 2.0 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H); IR ν 2949, 2924,
1451, 1249, 843 cm−1; HRMS calcd for C28H37N2Si+ [M + H]+
429.27260, found 429.27203.
oil: [α]24 −70.2 (c 0.69, CH2Cl2); Rf = 0.55 (silica gel, hexanes/
D
1
EtOAc = 10/1); H NMR (400 MHz, CDCl3) δ 1.00 (d, J = 6.4 Hz,
3H), 1.12 (t, J = 12.0 Hz, 1H), 1.28−1.75 (m, 6H), 1.93−2.00 (m,
2H), 2.11−2.15 (m, 1H), 2.22−2.29 (m, 2H), 2.50 (s, 1H), 2.54−2.63
(m, 2H), 2.86 (d, J = 13.2 Hz, 1H), 3.00 (dd, J = 12.0 and 21.2 Hz,
1H), 3.79 (s, 3H), 3.99 (d, J = 13.2 Hz, 1H), 6.83 (d, J = 8.4 Hz, 2H),
7.22 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 17.1, 22.1,
24.2, 25.7, 26.6, 37.1, 40.0, 45.8, 46.2, 48.1, 52.6, 55.1, 58.5, 76.6, 83.5,
113.4, 120.4, 129.4, 132.1, 158.3; IR ν 1512, 1243, 830 cm−1; HRMS
calcd for C22H29N2O+ [M + H]+ 337.22799, found 337.22731.
2-((4aR,5R,7S,8aS)-1-(2,4-Dimethoxybenzyl)-8a-ethynyl-7-meth-
yldecahydroquinolin-5-yl)acetonitrile (30). Following the general
procedure, alcohol 27 (250 mg, 0.65 mmol, 1.0 equiv), CCl4 (6 mL),
PPh3 (0.34 g, 1.3 mmol, 2.0 equiv), imidazole (89 mg, 1.3 mmol, 2.0
equiv), aqueous saturated NH4Cl solution (20 mL), EtOAc (3 × 15
mL), and brine (20 mL) afforded the bicyclic compound 30 (189 mg,
(4aR,5S,10bR,12R)-1-Benzyl-9-(tert-butyldimethylsilyl)-8-((tert-
butyldimethylsilyl)ethynyl)-12-methyl-2,3,4,4a,5,6-hexahydro-1H-
5,10b-propano-1,7-phenanthroline (34). In a 30 mL pressure tube,
1,4-(bistrimethylsilyl)butdiyne (455 mg, 1.63 mmol, 2.0 equiv) and
nitrile 28 (250 mg, 0.82 mmol, 1 equiv) were dissolved in freshly
degassed THF (17 mL). Neat CpCo(CO)2 (0.2 mL, 1.6 mmol, 2
equiv) was added into the solution, and the tube was sealed. The
resulting solution was heated at 140 °C for 20 h. The mixture was
cooled to 23 °C, and the solvent was evaporated. The crude material
was purified by silica gel chromatography (0/1 to 1/5 EtOAc/
Hexanes) to afford compound 34 (300 mg, 63%) as a dark brown
foam: [α]23.0 +4.9 (c 0.23, CH2Cl2); Rf = 0.65 (silica gel, hexanes/
D
EtOAc = 10/1); 1H NMR (400 MHz, CDCl3) δ 0.20 (s, 6H), 0.43 (s,
3H), 0.45 (s, 3H), 0.55 (d, J = 3.6 Hz, 3H), 0.80−0.99 (m, 20H),
1.12−1.30 (m, 2H), 1.36−1.45 (m, 1H), 1.51−1.75 (m, 2H), 1.86−
1.89 (m, 1H), 2.02−2.09 (m, 1H), 2.35−2.50 (m, 2H), 2.66−2.79 (m,
1H), 3.13−3.21 (m, 1H), 4.02 (d, J = 14.4 Hz, 1H), 4.21 (d, J = 14.4
Hz, 1H), 7.20−7.25 (m, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.48 (d, J = 7.6
Hz, 2H), 8.31 (s, 1H); 13C NMR (100 MHz, CDCl3) δ −4.5, 14.1,
16.9, 18.2, 21.1, 22.4, 26.4, 26.9, 27.1, 34.0, 35.1, 38.5, 43.6, 46.0, 48.3,
50.9, 60.2, 86.7, 92.7, 107.9, 126.4, 127.8, 128.2, 132.2, 136.7, 141.9,
142.5, 144.5, 159.2; IR ν 2926, 2856, 1507, 901 cm−1; HRMS calcd for
79%) as a pale yellow oil: [α]23.0 −36.0 (c 0.50, CH2Cl2); Rf = 0.25
D
1
(silica gel, hexanes/EtOAc = 4/1); H NMR (400 MHz, CDCl3) δ
1.00 (d, J = 6.4 Hz, 3H), 1.11 (t, J = 4.0 Hz, 1H), 1.29−1.37 (m, 1H),
1.41−1.51 (m, 2H), 1.58−1.66 (m, 2H), 1.71−1.76 (m, 1H), 1.93−
2.00 (m, 2H), 2.11−2.15 (m, 1H), 2.23−2.30 (m, 2H), 2.50 (s, 1H),
2.55−2.63 (m, 2H), 2.87 (d, J = 17.0 Hz, 1H), 3.00 (dd, J = 12.0 and
17.2 Hz, 1H), 3.86 (s, 3H), 3.88 (s, 3H), 4.01 (d, J = 13.6 Hz, 1H),
6.77−6.85 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 17.3, 22.2, 24.3,
25.9, 26.7, 37.2, 38.1, 45.8, 46.4, 48.3, 53.0, 55.8, 55.9, 58.6, 76.6, 83.6,
110.8, 111.5, 120.4, 120.5, 132.8, 147.7, 148.8; IR ν 3278, 2921, 1612,
1504 cm−1; HRMS calcd for C23H31N2O2+ [M + H+] 367.2386, found
367.2380.
+
C37H57N2Si2 [M + H+] 585.4060, found 585.4056.
(4aR,5S,10bR,12R)-1-Benzyl-12-methyl-8-((triisopropylsilyl)-
ethynyl)-9-(trimethylsilyl)-2,3,4,4a,5,6-hexahydro-1H-5,10b-propa-
no-1,7-phenanthroline (36): [α]23.0D 1+6.0 (c 0.33, CH2Cl2); Rf = 0.70
(silica gel, hexanes/EtOAc = 10/1); H NMR (400 MHz, CDCl3) δ
0.43 (s, 9H), 0.75 (d, J = 6.0 Hz, 3H), 1.05−1.32 (m, 23H), 1.44−1.48
(m, 2H), 1.50−1.56 (m, 1H), 1.69−1.80 (m, 2H), 1.84−1.90 (m, 1H),
2.06−2.11 (m, 1H), 2.37−2.52 (m, 2H), 2.70 (d, J = 18.8 Hz, 1H),
3.17 (dd, J = 7.2 and 18.4 Hz, 1H), 4.07 (d, J = 14.4 Hz, 1H), 4.21 (d,
J = 14.4 Hz, 1H), 7.22−7.26 (m, 1H), 7.34 (t, J = 7.2 Hz, 1H), 7.47 (d,
J = 7.2 Hz, 1H), 8.24 (s, 1H); 13C NMR (100 MHz, CDCl3) δ −1.1,
11.6, 18.7, 21.3, 22.4, 26.4, 27.0, 34.0, 35.1, 38.9, 43.7, 46.0, 48.1, 51.0,
60.3, 91.8, 108.0, 126.4, 127.8, 128.2, 134.2, 137.0, 140.2, 142.7, 144.4,
159.3; IR ν 2944, 2865, 1493, 735 cm−1; HRMS calcd for
(4aR,5S,10bR,12R)-1-Benzyl-12-methyl-9-(trimethylsilyl)-8-
((trimethylsilyl)ethynyl)-2,3,4,4a,5,6-hexahydro-1H-5,10b-propano-
1,7-phenanthroline (32). To alkyne−nitrile 28 (62 mg, 0.20 mmol,
1.0 equiv) and diyne 31 (50 mg, 0.26 mmol, 1.3 equiv) in degassed
chlorobenzene (3 mL) was added a solution of CoCp(CO)2 (0.049
mL, 0.40 mmol, 2 equiv) in degassed chlorobenzene (2.5 mL) over 90
min. During the addition, the reaction was irradiated with a 600 W
slide projector lamp placed 5 cm from the flask. After 4 h, another
portion of diyne 31 (50 mg, 0.26 mmol, 1.3 equiv) was added in one
portion. Irradiation continued for 4 h. The reaction was loaded on a
column and purified by silica gel chromatography (1/0 → 5/1
hexanes/EtOAc) to afford compound 32 (71 mg, 70%): [α]24D +5.0 (c
0.28, CH2Cl2); Rf = 0.60 (silica gel, hexanes/EtOAc = 10/1); 1H NMR
(400 MHz, CDCl3) δ 0.26 (s, 9H), 0.42 (s, 9H), 0.74 (d, J = 6.0 Hz,
3H), 1.13−1.32 (m, 5H), 1.44−1.46 (m, 2H), 1.53−1.61 (m, 1H),
1.69−1.77 (m, 1H), 1.85−1.90 (m, 1H), 2.07−2.10 (m, 1H), 2.37−
2.44 (m, 1H), 2.48−2.53 (m, 1H), 2.68 (d, J = 18.8 Hz, 1H), 3.17 (dd,
J = 14.8 and 18.8 Hz, 1H), 4.14 (dd, J = 14.4 and 60.0 Hz, 2H), 7.22−
7.26 (m, 1H), 7.32−7.36 (m, 2H), 7.46−7.48 (m, 2H), 8.25 (s, 1H);
13C NMR (100 MHz, CDCl3) δ −1.4, −0.4, 21.3, 22.3, 26.4, 27.0,
+
C37H57N2Si2 [M + H+] 585.40603, found 585.40510.
General Procedure for the Initial Cobalt-Mediated [2 + 2 +
2] Reaction (for Figure 5). In a pressure tube specific arylalkyne and
alkyne−nitrile 28 were dissolved in freshly degassed THF. Neat
CpCo(CO)2 was added to the solution and the tube was sealed. The
resulting solution was placed in a 140 °C oil bath. After 24−36 h the
vessel was removed from the oil bath, cooled to 23 °C, and the
solution was concentrated. The crude material was purified by silica gel
chromatography to afford desired compound.
General Procedure for the Desilylation of the TMS Func-
tional Group on the Pyridyl Rings. (for Figure 5 Character-
ization). To a solution of the TMS pyridyl compound in dioxane at
23 °C was added TBAF solution and the resulting solution was placed
in a heated oil bath. After 8−24 h, the mixture was cooled to 23 °C
and concentrated. The crude material was purified on silica gel
chromatography to afford desired compound.
2-((4aR,5S,10bR,12R)-1-Benzyl-12-methyl-2,3,4,4a,5,6-hexahy-
dro-1H-5,10b-propano-1,7-phenanthrolin-8-yl)thiazole (int-4). Fol-
lowing the general procedure 2-((trimethylsilyl)ethynyl)thiazole int-3
(18 mg, 98 μmol, 3.0 equiv), alkyne−nitrile 28 (10 mg, 33 μmmol, 1.0
equiv), THF (2.0 mL), and neat CpCo(CO)2 (8 μL, 57 μmmol, 1.7
equiv), purified by silica gel chromatography (20/1 → 5/1 hexanes/
EtOAc), afforded 43 (9.9 mg, 62%) as a yellow oil; 43 (9.9 mg, 20
μmol, 1.0 equiv), dioxane (1.0 mL) and TBAF solution (81 μL, 1 M in
THF, 81 μmol, 4.0 equiv), purified on silica gel chromatography (1/0
to 5/1 hexanes/EtOAc), afforded int-4 (5.9 mg, 70%) as a light brown
33.9, 35.2, 38.8, 43.7, 46.1, 48.1, 51.0, 60.3, 95.5, 106.0, 126.4, 127.8,
128.2, 134.9, 137.3, 140.2, 142.6, 144.1, 159.2; IR ν 1248, 842 cm−1;
+
HRMS calcd for C31H45N2Si2
[M + H+] 501.31213, found
501.31193.
THF Conditions. In a pressure tube, 1,4-(bistrimethylsilyl)-
butdiyne 31 (317 mg, 1.6 mmol, 2.0 equiv) and alkyne−nitrile 28
(250 mg, 0.82 mmol, 1.0 equiv) were dissolved in freshly degassed
THF (17 mL). Neat CpCo(CO)2 (100 μL, 0.82 mmol, 1.0 equiv) was
added to the solution, and the tube was sealed. The resulting solution
was placed in a 140 °C oil bath, and after 20 h the vessel was cooled to
23 °C and the solvent was removed. The crude material was purified
by silica gel chromatography (1/0 → 5/1 hexanes/EtOAc) to afford
32 (320 mg, 78%) and 33 (12.3 mg, 3% yield).
(4aR,5S,10bR,12R)-1-Benzyl-12-methyl-9-((trimethylsilyl)ethynyl)-
2,3,4,4a,5,6-hexahydro-1H-5,10b-propano-1,7-phenanthroline
(33). From the above THF conditions: Rf = 0.55 (silica gel, silica gel,
M
dx.doi.org/10.1021/jo400695c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
foam: Rf = 0.31 (silica gel, hexanes/EtOAc = 1/1); H NMR (600
MHz, CDCl3) δ 0.75 (d, J = 6.0 Hz, 3H), 1.13−1.16 (m, 1H), 1.20−
1.34 (m, 4H), 1.47−1.59 (m, 2H), 1.74−1.81 (m, 2H), 1.93 (dt, J =
3.2 and 12.7 Hz, 1H), 2.11−2.14 (m, 1H), 2.44−2.60 (m, 2H), 2.74
(d, J = 18.6 Hz, 1H), 3.23 (dd, J = 3.2 and 18.6 Hz, 1H), 4.07 (d, J =
14.1 Hz, 1H), 4.22 (d, J = 14.1 Hz, 1H), 7.22−7.24 (m, 1H), 7.33−
7.37 (m, 3H), 7.47 (d, J = 7.1 Hz, 2H), 7.88 (d, J = 3.3 Hz, 1H), 7.99
(d, J = 8.1 Hz, 1H), 8.20 (d, J = 8.1 Hz, 1H); 13C NMR (150.8 MHz,
CDCl3) δ 21.1, 22.4, 26.5, 27.1, 34.0, 35.3, 38.5, 43.7, 45.9, 48.1, 50.9,
60.6, 117.6, 120.6, 126.5, 128.0, 128.3, 135.4, 139.8, 142.2, 143.9,
148.5, 158.7, 170.0; IR ν 2923, 1384 cm−1; HRMS calcd for
C26H30N3S+ [M + H+] 416.21550, found 416.21562.
128.2, 129.0, 135.7, 141.6, 142.1, 142.7, 151.0, 155.8, 158.5; IR ν 3393,
2918, 1384 cm−1; HRMS calcd for C30H39N2OSi+ [M + H+]
471.28262, found 471.28291.
(4aR,5S,10bR,12R)-1-Benzyl-12-methyl-8-(pyridin-2-yl)-
2,3,4,4a,5,6-hexahydro-1H-5,10b-propano-1,7-phenanthroline (int-
10). Following the general procedure 2-((trimethylsilyl)ethynyl)-
pyridine int-9 (17.2 mg, 98 μmol, 3.0 equiv), alkyne−nitrile 28 (10
mg, 33 μmol, 1.0 equiv), THF (1.5 mL), and neat CpCo(CO)2 (8 μL,
57 μmol, 1.7 equiv), purified by silica gel chromatography (20/1 → 2/
1 hexanes/EtOAc), afforded 47 (8.2 mg, 52%) as a yellow oil; 47 (8.2
mg, 17 μmol, 1 equiv), dioxane (1.0 mL), and TBAF solution (49 μL,
1 M in THF, 49 μmol, 3.0 equiv), purified by silica gel
chromatography (20/1 to 1/1 hexanes/EtOAc) to afford int-10 (6.1
mg, 88%) as a light brown foam: Rf = 0.35 (silica gel, hexanes/EtOAc
(4aR,5S,10bR,12R)-1-Benzyl-12-methyl-8-(thiophene-3-yl)-
2,3,4,4a,5,6-hexahydro-1H-5,10b-propano-1,7-phenanthroline (int-
6). Following the general procedure, trimethyl(thiophene-3-
ylethynyl)silane int-5 (17 mg, 98 μmol, 3.0 equiv), alkyne−nitrile
28 (10 mg, 33 μmol, 1.0 equiv), THF (2.0 mL), and CpCo(CO)2 (8
μL, 57 μmol, 1.7 equiv), purified by silica gel chromatography (20/1
→ 5/1 hexanes/EtOAc), afforded 44 (7.2 mg, 45%) as pale yellow oil;
44 (6.9 mg, 14 μmol, 1.0 equiv), dioxane (1.0 mL), and TBAF
solution (43 μL, 1 M in THF, 43 μmol, 3.0 equiv), purified by silica gel
chromatography (1/0 to 10/1 hexanes/EtOAc), afforded int-6 (5.1
mg, 87%) as a light brown foam: Rf = 0.35 (silica gel, hexanes/EtOAc
1
= 1/1); H NMR (400 MHz, CDCl3) δ 0.68 (d, J = 6.0 Hz, 3H),
0.78−0.83 (m, 1H), 1.08−1.54 (m, 6H), 1.71−1.75 (m, 2H), 1.89 (d, J
= 3.6 and 8.8 Hz, 1H), 2.07−2.09 (m, 1H), 2.45−2.47 (m, 2H), 2.72
(d, J = 18.8 Hz, 1H), 3.21 (dd, J = 7.2 and 18.8 Hz, 1H), 4.05 (d, J =
14.0 Hz, 1H), 4.18 (d, J = 14.0 Hz, 1H), 7.16−7.22 (m, 2H), 7.30 (t, J
= 8.0 Hz, 2H), 7.43 (d, J = 7.6 Hz, 2H), 7.72 (dt, J = 1.6 and 7.6 Hz,
1H), 8.09 (d, J = 7.6 Hz, 1H), 8.15 (d, J = 7.6 Hz, 1H), 8.27 (dt, J =
1.2 and 7.6 Hz, 1H), 8.60−8.63 (m, 1H); 13C NMR (125.7 MHz,
CDCl3) δ 21.3, 22.4, 26.5, 27.2, 34.2, 35.6, 38.8, 43.8, 45.9 48.2, 51.1,
60.5, 119.1, 121.0, 123.2, 126.5, 128.0, 128.8, 135.3, 136.7, 138.6,
142.4, 149.2, 153.4, 156.8, 158.1; IR ν 2919, 1384 cm−1; HRMS calcd
1
= 5/1); H NMR (600 MHz, CDCl3) δ 0.74 (d, J = 5.9 Hz, 3H),
0.82−0.88 (m, 1H), 1.12−1.16 (m, 1H), 1.23−1.29 (m, 2H), 1.30−
1.38 (m, 1H), 1.44−1.57 (m, 2H), 1.72−1.78 (m, 2H), 1.90 (dt, J =
3.2 and 12.7 Hz, 1H), 2.09−2.11 (m, 1H), 2.48−2.50 (m, 2H), 2.72
(d, J = 18.6 Hz, 1H), 3.20 (dd, J = 7.0 and 18.6 Hz, 1H), 4.06 (d, J =
14.2 Hz, 1H), 4.22 (d, J = 14.2 Hz, 1H), 7.07 (dd, J = 3.4 and 5.0 Hz,
1H), 7.22 (d, J = 7.3 Hz, 1H), 7.31−7.35 (m, 3H), 7.46 (d, J = 7.3 Hz,
2H), 7.49 (d, J = 8.2 Hz, 1H), 7.54 (dd, J = 1.1 and 3.4 Hz, 1H), 8.09
(d, J = 8.2 Hz, 1H); 13C NMR (150.8 MHz, CDCl3) δ 21.1, 22.4, 26.5,
27.1, 34.1, 35.4, 38.6, 43.8, 45.9, 48.2, 50.9, 60.4, 117.0, 124.0, 126.5,
126.7, 127.9, 128.0, 128.2, 135.1, 136.8, 142.4, 145.4, 149.7, 158.5; IR
ν 2919, 1384 cm−1; HRMS calcd for C27H31N2S+ [M + H+] 415.2208,
found 415.2208.
(4aR,5S,10bR,12R)-1-Benzyl-12-methyl-8-(thiophene-2-yl)-9-(tri-
methylsilyl)-2,3,4,4a,5,6-hexahydro-1H-5,10b-propano-1,7-phenan-
throline (45). Following the general procedure, trimethyl(thiophene-
2-ylethynyl)silane int-7 (16.1 mg, 89 μmol, 3.0 equiv), alkyne−nitrile
28 (9.1 mg, 30 μmol, 1.0 equiv), THF (2.0 mL), and neat
CpCo(CO)2 (8 μL, 57 μmmol, 1.8 equiv), purified by silica gel
chromatography (20/1 → 5/1 hexanes/EtOAc), afforded 45 (8.9 mg,
51%) as a pale yellow oil: Rf = 0.65 (silica gel, hexanes/EtOAc = 5/1);
1H NMR (400 MHz, CDCl3) δ 0.11 (s, 9H), 0.78 (d, J = 5.6 Hz, 3H),
1.18−1.40 (m, 5H), 1.45−1.58 (m, 3H), 1.76−1.81 (m, 2H), 1.91 (dt,
J = 3.6 and 13.2 Hz, 1H), 2.10−2.12 (m, 1H), 2.53 (d, J = 6.8 Hz, 1H),
2.71 (d, J = 19.2 Hz, 1H), 3.19 (dd, J = 6.8 and 19.2 Hz, 1H), 4.14 (d,
J = 14.4 Hz, 1H), 4.25 (d, J = 14.4 Hz, 1H), 7.23−7.26 (m, 2H), 7.30−
7.34 (m, 4H), 7.50 (d, J = 7.8 Hz, 2H), 8.34 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 0.22, 21.6, 22.5, 26.4, 27.1, 34.1, 35.3, 39.3, 43.8, 45.9,
48.1, 51.2, 60.2, 124.1, 125.0, 126.4, 127.8, 128.2, 129.1, 130.7, 135.3,
141.5, 142.7, 144.7, 157.5, 158.2; IR ν 2923, 1428 cm−1; HRMS calcd
for C30H39N2SSi+ [M + H+] 487.25977, found 487.25969.
(4aR,5S,10bR,12R)-1-Benzyl-8-(furan-2-yl)-12-methyl-9-(trime-
thylsilyl)-2,3,4,4a,5,6-hexahydro-1H-5,10b-propano-1,7-phenan-
throline (46). Following the general procedure (furan-2-ylethynyl)-
trimethylsilane int-8 (16.2 mg, 99 μmol, 3.0 equiv), alkyne−nitrile 28
(10.1 mg, 33 μmol, 1.0 equiv), THF (2.0 mL), and neat CpCo(CO)2
(8 μL, 57 μmmol, 1.7 equiv), purified by silica gel chromatography
(20/1 → 5/1 hexanes/EtOAc), afforded compound 46 (7.9 mg, 51%)
as a yellow oil: Rf = 0.60 (silica gel, Hexanes/EtOAc = 2/1); 1H NMR
(500 MHz, CDCl3) δ 0.30 (s, 9H), 0.76 (d, J = 6.0 Hz, 3H), 1.17−
1.37 (m, 4H), 1.44−1.80 (m, 4H), 1.86−1.92 (m, 1H), 2.11−2.13 (m,
1H), 2.47−2.55 (m, 2H), 2.71 (d, J = 9.5 Hz, 1H), 3.19 (dd, J = 7.3
and 18.8 Hz, 1H), 4.13 (d, J = 14.4 Hz, 1H), 4.24 (d, J = 14.4 Hz, 1H),
6.53 (dd, J = 1.7 and 3.2 Hz, 1H), 6.92 (d, J = 3.2 Hz, 1H), 7.24 (d, J =
7.3 Hz, 1H), 7.35 (t, J = 7.3 Hz, 2H), 7.50 (d, J = 7.3 Hz, 3H), 8.38 (s,
1H); 13C NMR (125.6 MHz, CDCl3) δ 0.38, 21.6, 22.4, 26.4, 27.1,
34.1, 35.3, 39.3, 43.8, 46.0, 48.1, 51.1, 60.3, 109.0, 112.1, 126.4, 127.8,
+
for C28H32N3 [M + H+] 410.25907, found 410.25875.
(4aR,5S,10bR,12R)-1-Benzyl-12-methyl-8-(quinolin-3-yl)-
2,3,4,4a,5,6-hexahydro-1H-5,10b-propano-1,7-phenanthroline (int-
12). Following the general procedure, 3-((trimethylsilyl)ethynyl)-
quinolinetube int-11 (21.6 mg, 96 μmol, 3.0 equiv), alkyne−nitrile 28
(9.8 mg, 33 μmol, 1.0 equiv), THF (2.0 mL), and neat CpCo(CO)2 (8
μL, 57 μmol, 1.7 equiv), purified by silica gel chromatography (20/1
→ 2/1 EtOAc/hexanes), afforded 48 (4.9 mg, 28%) as a yellow oil; 48
(4.9 mg, 9.2 μmol, 1.0 equiv), dioxane (1.0 mL) and TBAF solution (1
M in THF, 37 μL, 37 μmol, 4.0 equiv), purified by silica gel
chromatography (20/1 to 1/1 hexanes/EtOAc), afforded int-12 (4.0
mg, 94%) as a light brown foam: Rf = 0.43 (silica gel, hexanes/EtOAc
1
= 1/1); H NMR (500 MHz, CDCl3) δ 0.79 (d, J = 5.9 Hz, 3H),
0.83−0.90 (m, 1H), 1.18−1.44 (m, 4H), 1.52−1.59 (m, 2H), 1.78−
1.88 (m, 2H), 1.98 (dt, J = 3.7 and 16.1 Hz, 1H), 2.17−2.20 (m, 1H),
2.54−2.57 (m, 2H), 2.84 (d, J = 18.5 Hz, 1H), 3.33 (dd, J = 7.1 and
18.5 Hz, 1H), 4.11 (d, J = 14.2 Hz, 1H), 4.28 (d, J = 14.2 Hz, 1H),
7.24−7.27 (m, 1H), 7.36−7.47 (m, 2H), 7.50 (d, J = 10.0 Hz, 2H),
7.58−7.59 (m, 1H), 7.71−7.76 (m, 2H), 7.93−7.95 (m, 1H), 8.14 (d, J
= 8.5 Hz, 1H), 8.27 (d, J = 8.5 Hz, 1H), 8.78 (d, J = 2.1 Hz, 1H), 9.55
(d, J = 2.1 Hz, 1H); 13C NMR (150.8 MHz, CDCl3) δ 21.1, 22.4, 26.6,
27.2, 34.1, 35.6, 38.6, 43.8, 45.9, 48.2, 51.0, 60.5, 118.9, 126.5, 126.8,
128.0, 128.3, 128.5, 129.0, 129.6, 129.7, 132.4, 133.6, 135.5, 137.8,
142.3, 148.0, 149.6, 151.8, 159.3; IR ν 2917, 1384 cm−1; HRMS calcd
+
for C32H34N3 [M + H+] 460.27472, found 460.27503.
(4aR,5S,10bR,12R)-1-Benzyl-12-methyl-9-phenyl-8-(pyridin-3-yl)-
2,3,4,4a,5,6-hexahydro-1H-5,10b-propano-1,7-phenanthroline
(49). Following the general procedure 3-(phenylethynyl)pyridine int-
13 (23 mg, 0.13 mmol, 2.6 equiv), alkyne−nitrile 28 (15 mg, 49 μmol,
1.0 equiv), THF (2.5 mL), and neat CpCo(CO)2 (10 μL, 82 μmol, 1.7
equiv), purified by silica gel chromatography (20/1 → 1/1 hexanes/
EtOAc), afforded 49 (6.9 mg, 26%) and 50 (3.0 mg, 16%): Rf = 0.31
1
(silica gel, hexanes/EtOAc = 2/1); H NMR (400 MHz, CDCl3) δ
0.81 (d, J = 5.6 Hz, 3H), 0.86−0.95 (m, 1H), 1.21−1.60 (m, 6H),
1.81−1.83 (m, 3 H), 1.96−2.00 (m, 2H), 2.17−2.18 (m, 1H), 2.54−
2.65 (m, 2H), 2.79 (d, J = 18.8 Hz, 1H), 3.30 (dd, J = 7.6 and 18.8 Hz,
1H), 4.12 (d, J = 14.4 Hz, 1H), 4.22 (d, J = 14.4 Hz, 1H), 7.15−7.34
(m, 7H), 7.45 (d, J = 7.6 Hz, 2H), 7.69 (dt, J = 2.0 and 7.6 Hz, 1H),
8.16 (s, 1H), 8.47 (dd, J = 2.0 and 4.8 Hz, 1H), 8.60 (d, J = 2.0 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 21.5, 22.4, 26.5, 27.1, 34.0, 35.3,
38.9, 43.7, 45.9, 48.1, 51.1, 60.4, 122.7, 126.5, 127.2, 128.0, 128.2,
128.3, 128.5, 129.7, 134.4, 136.2, 136.8, 137.2, 137.6, 139.8, 142.2,
+
148.3, 150.9, 158.0; IR ν 2919, 1384 cm−1; HRMS calcd for C34H36N3
[M + H+] 486.29037, found 486.29099.
N
dx.doi.org/10.1021/jo400695c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(4aR,5S,10bR,12R)-1-Benzyl-12-methyl-8-phenyl-9-(pyridin-3-yl)-
2,3,4,4a,5,6-hexahydro-1H-5,10b-propano-1,7-phenanthroline
(50). Following the above procedure: Rf = 0.69 (silica gel, hexanes/
28 (10 mg, 33 μmol, 1.0 equiv), THF (1.5 mL), and neat CpCo(CO)2
(8 μL, 57 μmol, 1.9 equiv), purified by silica gel chromatography (20/
1 → 5/1 hexanes/EtOAc), afforded 56 (8.9 mg, 51%); 56 (8.9 mg, 17
μmol, 1.0 equiv), dioxane (1 mL), and TBAF solution (80 μL, 1 M in
THF, 0.080 mmol, 4.8 equiv), purified by silica gel chromatography
(1/0 to 20/1 hexanes/EtOAc), afforded int-18 (7.2 mg, 94%) as a
1
EtOAc = 2/1); H NMR (400 MHz, CDCl3) δ 0.82 (d, J = 6.0 Hz,
3H), 1.21−1.46 (m, 5H), 1.46−1.62 (m, 2H), 1.81−1.84 (m, 2H),
1.97−2.01 (m, 1H), 2.18−2.19 (m, 1H), 2.59−2.66 (m, 2H), 2.83 (d, J
= 18.8 Hz, 1H), 3.32 (dd, J = 7.2 and 18.8 Hz, 1H), 7.13 (d, J = 14.4
Hz, 1H), 4.24 (d, J = 14.4 Hz, 1H), 7.16−7.27 (m, 6H), 7.32−7.35
(m, 4H), 7.42−7.46 (m, 2H), 8.13 (d, J = 2.0 Hz, 1H), 8.50−8.54 (m,
2H); 13C NMR (125 MHz, CDCl3) δ 21.3, 22.4, 26.5, 27.1, 34.1, 35.3,
38.7, 43.7, 45.9, 48.2, 51.1, 60.4, 122.9, 126.5, 127.8, 128.0, 128.1,
128.3, 130.0, 130.2, 136.4, 136.5, 137.0, 137.0, 139.7, 142.1, 148.0,
1
light brown foam: Rf = 0.45 (silica gel, hexanes/EtOAc = 2/1); H
NMR (400 MHz, CDCl3) δ 0.78 (d, J = 5.8 Hz, 3H), 0.86−0.90 (m,
1H), 1.18−1.46 (m, 4H), 1.50−1.63 (m, 3H), 1.79−1.83 (m, 1H),
1.96 (dt, J = 3.6 and 9.5 Hz, 1H), 2.16−2.18 (m, 1H), 2.55−2.59 (m,
2H), 2.82 (d, J = 18.3 Hz, 1H), 3.33 (dd, J = 3.6 and 18.3 Hz, 1H),
4.13 (d, J = 14.1 Hz, 1H), 4.27 (d, J = 14.1 Hz, 1H), 7.25−7.27 (m,
2H), 7.37 (t, J = 7.8 Hz, 2H), 7.47−7.52 (m, 3H), 7.73 (d, J = 8.2 Hz,
1H), 7.85−7.96 (m, 3H), 8.16 (dd, J = 1.8 and 8.2 Hz, 1H), 8.21 (d, J
= 8.2 Hz, 1H), 8.49 (s, 1H); 13C NMR (125.7 MHz, CDCl3) δ 21.2,
22.4, 26.6, 27.2, 34.2, 35.7, 38.8, 43.9, 45.9, 48.2, 51.0, 60.4, 118.8,
124.8, 126.0, 126.1, 126.2, 126.5, 127.6 128.0, 128.2, 128.3, 128.7,
133.4, 133.6, 135.2, 136.9, 137.1, 142.5, 154.3, 158.7; IR ν 2920, 1384
+
150.2, 154.4, 158.4; IR ν 2913, 1384 cm−1; HRMS calcd for C34H36N3
[M + H+] 486.29037, found 486.29092.
(4aR,5S,10bR,12R)-1-Benzyl-12-methyl-8-phenyl-9-(trimethylsil-
yl)-2,3,4,4a,5,6-hexahydro-1H-5,10b-propano-1,7-phenanthroline
(51). Following the general procedure, trimethyl(phenylethynyl)silane
int-14 (8.4 mg, 48 μmol, 4.1 equiv), alkyne−nitrile 28 (3.6 mg, 12
μmmol, 1.0 equiv), THF (1 mL), and neat CpCo(CO)2 (3 μL, 24
μmmol, 2.0 equiv), purified by silica gel chromatography (20/1 → 10/
1 hexanes/EtOAc), afforded 51 (2.3 mg, 51%) as a brown foam: Rf =
0.65 (silica gel, hexanes/EtOAc = 5/1); 1H NMR (400 MHz, CDCl3)
δ 0.06 (s, 9H), 0.79 (d, J = 5.6 Hz, 3H), 1.19−1.41 (m, 4H), 1.45−
1.54 (m, 2H), 1.75−1.79 (m, 2H), 1.90−1.93 (m, 1H), 2.11−2.12 (m,
1H), 1.75−1.78 (m, 1H), 2.54−2.56 (m, 2H), 2.72 (d, J = 18.8 Hz,
1H), 4.12 (d, J = 14.4 Hz, 1H), 4.15 (d, J = 14.4 Hz, 1H), 4.26 (d, J =
14.4 Hz, 1H), 7.25−7.45 (m, 8H), 7.51 (d, J = 8.0 Hz, 2H), 8.34 (s,
1H); 13C NMR (125 MHz, CDCl3) δ 0.2, 21.7, 22.5, 26.4, 27.1, 34.2,
35.4, 39.4, 43.8, 46.0, 48.2, 51.2, 60.2, 126.4, 127.7, 127.8, 127.9, 128.2,
129.1, 130.2, 135.0, 141.6, 142.8, 143.9, 158.0, 162.3; IR ν 2918, 1384,
837 cm−1; HRMS calcd for C32H41N2Si+ [M + H+] 481.3039, found
481.3033.
+
cm−1; HRMS calcd for C33H35N2 [M + H+] 459.27948, found
459.27940.
(4aR,5S,10bR,12R)-1-Benzyl-12-methyl-9-(trimethylsilyl)-
2,3,4,4a,5,6-hexahydro-1H-5,10b-propano-1,7-phenanthroline
(58). In a pressure tube, 28 (18 mg, 59 μmol, 1.0 equiv) and alkyne 57
(33 mg, 0.19 mmol, 3.3 equiv) were dissolved in freshly degassed
chlorobenzene (0.5 mL). A solution of CpCo(CO)2 (10 μL, 82 μmol,
1.4 equiv) in chlorobenzene (0.5 mL) was added by syringe pump (0.5
mL/h). The reaction was heated to reflux with a projector light for 2 h.
The mixture was cooled to 23 °C, and the solvent was removed. The
crude material was purified by silica gel chromatography (1/0 → 5/1
hexanes/EtOAc) to afford compound 58 (6.1 mg, 26%) as a dark
brown oil: [α]23.0 +20.0 (c 0.35, CH2Cl2); Rf = 0.32 (silica gel,
D
hexanes/EtOAc = 4/1); 1H NMR (400 MHz, CDCl3) δ 0.32 (s, 9H),
0.76 (d, J = 6.0 Hz, 3H), 1.15−1.34 (m, 4H), 1.41−1.58 (m, 3H),
1.74−1.78 (m, 2H), 1.90 (dt, J = 3.2 and 12.4 Hz, 1H), 2.09−2.12 (m,
1H), 2.41−2.53 (m, 2H), 2.67 (d, J = 18.8 Hz, 1H), 3.19 (dd, J = 7.2
and 18.8 Hz, 1H), 4.12 (d, J = 14.4 Hz, 1H), 4.22 (d, J = 14.4 Hz, 1H),
7.23−7.26 (m, 1H), 7.36 (t, J = 7.6 Hz, 2H), 7.48 (d, J = 7.6 Hz, 2H),
8.26 (d, J = 2.0 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 0.0, 22.6, 23.6, 27.5, 28.2, 35.1, 36.4, 40.2, 44.9, 47.0,
49.3, 52.3, 61.3, 127.6, 128.9, 129.3, 133.2, 138.3, 140.7, 143.8, 151.9,
160.0; IR ν 2919, 1360, 837 cm−1; HRMS calcd for C26H37N2Si+ [M +
H+] 405.2726, found 405.2719.
(4aR,5S,10bR,12R)-1-Benzyl-12-methyl-8,9-diphenyl-2,3,4,4a,5,6-
hexahydro-1H-5,10b-propano-1,7-phenanthroline (52). Following
the general procedure 1,2-diphenylethyne int-15 (25 mg, 0.14 mmol,
3.0 equiv), alkyne−nitrile 28 (14.5 mg, 47 μmol, 1.0 equiv), THF (2.2
mL), and neat CpCo(CO)2 (10 μL, 82 μmol, 1.7 equiv), purified by
silica gel chromatography (20/1 → 10/1 hexanes/EtOAc), afforded 52
(9.9 mg, 43%) as a pale yellow foam: Rf = 0.45 (silica gel, hexanes/
1
EtOAc = 5/1); H NMR (400 MHz, CDCl3) δ 0.81 (d, J = 6.0 Hz,
1H), 1.21−1.25 (m, 1H), 1.33−1.64 (m, 6H), 1.79−1.83 (m, 2H),
1.97 (dt, J = 3.2 and 12.4 Hz, 1H), 2.15−2.17 (m, 1H), 2.53−2.68 (m,
2H), 2.80 (d, J = 18.4 Hz, 1H), 3.30 (dd, J = 7.2 and 18.4 Hz, 1H),
4.16 (d, J = 14.4 Hz, 1H), 4.22 (d, J = 14.4 Hz, 1H), 7.21−7.38 (m,
13H), 7.46 (d, J = 7.2 Hz, 2H), 8.12 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ 21.6, 22.5, 26.5, 27.1, 34.1, 35.3, 39.1, 43.8, 45.9, 48.1, 51.2,
60.3, 126.4, 126.7, 127.4, 127.8, 127.8, 127.9, 128.2, 129.7, 130.0,
133.8, 136.6, 136.6, 140.4, 140.7, 142.4, 154.0, 157.4; IR ν 2922, 1384
(4aR,5S,10bR,12R)-1-Benzyl-12-methyl-2,3,4,4a,5,6-hexahydro-
1H-5,10b-propano-1,7-phenanthroline (59). To a solution of 58 (25
mg, 62 μmol, 1.0 equiv) in THF (2 mL) at 23 °C was added TBAF
solution (0.19 mL, 1 M in THF, 0.19 mmol, 3.0 equiv), and the flask
was immersed in a heated oil bath. After 12 h, the mixture was cooled
to 23 °C, diluted with saturated NH4Cl solution (5 mL), and extracted
with EtOAc (3 × 5 mL). The organic extracts were washed with brine
(5 mL), dried over Na2SO4, filtered, and concentrated. The crude
material was purified by silica gel chromatography (5/1 → 2/1
+
cm−1; HRMS calcd for C35H37N2 [M + H+] 485.2957, found
485.2959.
(4aR,5S,10bR,12R)-1-Benzyl-12-methyl-9-phenyl-8-(pyridin-2-yl)-
2,3,4,4a,5,6-hexahydro-1H-5,10b-propano-1,7-phenanthroline
(53). Following the general procedure, 2-(phenylethynyl)pyridine int-
16 (23 mg, 0.13 mmol, 2.6 equiv), alkyne−nitrile 28 (15 mg, 49 μmol,
1.0 equiv), THF (2.5 mL), and neat CpCo(CO)2 (10 μL, 82 μmol, 1.7
equiv), purified by silica gel chromatography (20/1 → 1/1 hexanes/
EtOAc), afforded 53 (6.9 mg, 26%) as a pale foam: Rf = 0.21 (silica
gel, hexanes/EtOAc = 1/1); 1H NMR (400 MHz, CDCl3) δ 0.79 (d, J
= 5.8 Hz, 3H), 1.22−1.60 (m, 6H), 1.73−1.79 (m, 3H), 1.95−1.99 (m,
1H), 2.16−2.17 (m, 1H), 2.53−2.67 (m, 2H), 2.85 (d, J = 15.6 Hz,
1H), 3.26−3.35 (m, 1H), 4.23 (s, 2H), 7.00 (d, J = 7.6 Hz, 1H), 7.15−
7.38 (m, 9H), 7.44−7.49 (m, 3H), 8.34 (s, 1H), 8.70 (d, J = 4.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 21.9, 22.4, 26.4, 27.1, 34.1, 39.6,
43.8, 46.0, 47.9, 51.3, 60.4, 77.2, 121.6, 125.3, 126.4, 127.9, 128.0,
128.0, 128.1, 128.2, 129.9, 132.5, 135.5, 136.8, 142.4, 149.7, 152.8,
159.8; IR ν 3423, 1918, 1384 cm−1; HRMS calcd for C34H36N3+ [M +
H+] 486.29037, found 486.29031.
hexanes/EtOAc) to afford 59 (20 mg, 97%): [α]23.0 +49.2 (c 0.63,
D
CH2Cl2); Rf = 0.23 (silica gel, hexanes/EtOAc = 4/1); 1H NMR (400
MHz, CDCl3) δ 0.75 (d, J = 6.0 Hz, 3H), 1.13−1.36 (m, 5H), 1.44−
1.50 (m, 1H), 1.55−1.59 (m, 1H), 1.73−1.81 (m, 2H), 1.92 (dt, J =
7.2 and 12.8 Hz, 1H), 2.10−2.13 (m, 1H), 2.43−2.52 (m, 2H), 2.68
(d, J = 18.8 Hz, 1H), 3.21 (dd, J = 7.2 and 18.8 Hz, 1H), 4.07 (d, J =
14.0 Hz, 1H), 4.23 (d, J = 14.0 Hz, 1H), 7.14 (dd, J = 4.8 and 8.0 Hz,
1H), 7.24 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.2 Hz, 2H), 7.47 (d, J = 7.2
Hz, 2H), 8.12 (dd, J = 1.2 and 8.0 Hz, 1H), 8.38 (dd, J = 1.2 and 8.0
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.1, 22.4, 26.5, 27.1, 34.0,
35.4, 38.5, 43.8, 45.5, 48.2, 50.9, 60.3, 121.6, 126.5, 128.0, 128.2, 134.4,
138.2, 142.4, 146.8, 158.6; IR ν 2919, 1359, 735 cm−1; HRMS calcd
+
for C23H29N2 [M + H+] 333.2331, found 333.2327.
Lycodine (60). Under balloon pressure of H2, pyridine 59 (4.2 mg,
0.044 mmol, 1.0 equiv) was dissolved in THF (1.5 mL), and Pd/C (1
mg, 10 wt %, 7%) was added at 23 °C. After 10 h, the same amount of
Pd/C was added. After another 10 h, the reaction was diluted with
EtOAc (10 mL), filtered, and concentrated to afford lycodine (60)
(4aR,5S,10bR,12R)-1-Benzyl-12-methyl-8-(naphthalen-2-yl)-
2,3,4,4a,5,6-hexahydro-1H-5,10b-propano-1,7-phenanthroline (int-
18). Following the general procedure, trimethyl(naphthalen-2-
ylethynyl)silane int-17 (22 mg, 0.10 mmol, 3.0 equiv), alkyne−nitrile
(2.9 mg, 95%) as white crystals: mp 95.3−96.3 °C; [α]23.0 −69.2 (c
D
O
dx.doi.org/10.1021/jo400695c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
0.13, MeOH); Rf = 0.22 (silica gel, CHCl3/MeOH = 100/7); 1H
NMR (400 MHz, CDCl3) δ 0.81 (d, J = 6.4 Hz, 3H), 1.10−1.21 (m,
2H), 1.32 (m, 2H), 1.36−1.43 (m, 1H), 1.49 (ddd, J = 2.0, 3.6, and
12.0 Hz, 1H), 1.56−1.61 (m, 2H), 1.66 (dt, J = 3.6 and 12.8 Hz, 1H),
1.73 (dt, J = 3.6 and 12.8 Hz, 1H), 1.78−1.84 (m, 1H), 2.11−2.15 (m,
1H), 2.45 (dt, J = 3.6 and 12.8 Hz, 1H), 2.68 (d, J = 18.8 Hz, 1H),
2.75−2.80 (m, 1H), 3.15 (dd, J = 7.2 Hz, 1H), 7.29 (dd, J = 4.8 and
8.0 Hz, 1H), 7.89 (dd, J = 1.6 and 8.0 Hz, 1H), 8.31 (dd, J = 1.6 and
4.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 22.3, 27.0, 27.1, 27.4,
34.7, 35.7, 42.0, 44.5, 44.7, 51.5, 58.0, 123.3, 135.3, 137.3, 147.6, 159.6;
2.09−2.11 (m, 1H), 2.37−2.53 (m, 2H), 2.70 (d, J = 18.8 Hz, 1H),
3.19 (dd, J = 7.2 and 18.8 Hz, 1H), 4.02 (d, J = 19.2 Hz, 1H), 4.20 (d,
J = 19.2 Hz, 1H), 7.22−7.25 (m, 1H), 7.32−7.40 (m, 2H), 7.44−7.47
(m, 2H), 8.08 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
−4.68, 16.7, 20.9, 22.3, 26.2, 26.5, 27.1, 33.9, 35.3, 38.2, 43.7, 45.7,
48.1, 50.8, 60.4, 92.0, 105.0, 125.8, 126.5, 128.0, 128.2, 134.4, 138.4,
140.0, 142.2, 159.1; IR ν 2925, 1449, 1384 cm−1; HRMS calcd for
C31H43N2Si+ [M + H+] 471.3196, found 471.3191.
(4aR,5S,10bR,12R)-1-Benzyl-8-ethynyl-12-methyl-9-(trimethylsil-
yl)-2,3,4,4a,5,6-hexahydro-1H-5,10b-propano-1,7-phenanthroline
(66). To a solution of 32 (50 mg, 0.10 mmol, 1.0 equiv) in THF (5
mL) at 23 °C was added TBAF solution (0.15 mL, 1.0 M in THF, 0.15
mmol, 1.5 equiv). After 10 min, the mixture was diluted with aqueous
saturated NH4Cl solution (10 mL) and extracted with EtOAc (3 × 10
mL). The combined organic extracts were washed with brine (10 mL),
dried over Na2SO4, filtered, and concentrated. The crude material was
purified by silica gel chromatography (1/0 → 10/1 hexanes/EtOAc)
to afford compound 66 (39 mg, 91%) as a light yellow foam: Rf = 0.55
+
IR ν 3438, 1635 cm−1; HRMS calcd for C16H23N2 [M + H+]
243.1861, found 243.1856.
(4aR,5S,10bR,12R)-1-Benzyl-8-ethynyl-12-methyl-2,3,4,4a,5,6-
hexahydro-1H-5,10b-propano-1,7-phenanthroline (63). To a sol-
ution of 32 (700 mg, 1.3 mmol, 1.0 equiv) in THF (15 mL) at 23 °C
was added TBAF solution (6.0 mL, 1 M in THF, 6.0 mmol, 4.5 equiv),
and the flask was immersed in a heated oil bath. After 13 h, the mixture
was cooled to 23 °C, diluted with saturated NH4Cl solution (20 mL),
and extracted with EtOAc (3 × 30 mL). The organic extracts were
washed with brine (10 mL), dried over Na2SO4, filtered, and
concentrated. The crude material was purified by silica gel
chromatography (1/0 to 5/1 hexanes/EtOAc) to afford 63 (431 mg,
85%) as a light brown foam: [α]24D +19.1 (c 0.29, CH2Cl2); Rf = 0.43
1
(silica gel, hexanes/EtOAc = 5/1); H NMR (400 MHz, CDCl3) δ
0.42 (s, 9H), 0.75 (d, J = 6.4 Hz, 3H), 0.83−0.92 (m, 1H), 1.11−1.32
(m, 4H), 1.46 (s, 1H), 1.52−1.58 (m, 1H), 1.70−1.77 (m, 2H), 1.89
(dt, J = 3.6 and 12.8 Hz, 1H), 2.08−2.12 (m, 1H), 2.37−2.54 (m, 2H),
2.69 (d, J = 18.8 Hz, 1H), 3.14−3.20 (m, 2H), 4.07 (d, J = 14.4 Hz,
1H), 4.22 (d, J = 14.4 Hz, 1H), 7.24 (t, J = 7.2 Hz, 1H), 7.33−7.36 (m,
2H), 7.46−7.48 (m, 2H), 8.27 (s, 1H); 13C NMR (100 MHz, CDCl3)
δ −1.34, 21.3, 22.4, 26.3, 27.0, 33.9, 35.2, 38.8, 43.7, 46.0, 48.1, 51.0,
60.3, 78.1, 84.8, 126.5, 127.8, 128.2, 134.8, 137.6, 140.3, 142.5, 143.3,
159.3; IR ν 2921, 1247, 841 cm−1; HRMS calcd for C28H37N2Si+ [M +
H+] 429.2726, found 429.2722.
1
(silica gel, hexanes/EtOAc = 5/1); H NMR (400 MHz, CDCl3) δ
0.75 (d, J = 6.0 Hz, 3H), 1.11−1.32 (m, 4H), 1.47−1.58 (m, 3H),
1.74−1.80 (m, 2H), 1.91−1.94 (m, 1H), 2.05−2.12 (m, 1H), 2.37−
2.53 (m, 2H), 2.70 (d, J = 18.8 Hz, 1H), 3.10 (s, 1H), 3.22 (dd, J = 7.2
and 18.8 Hz, 1H), 4.04 (d, J = 14.0 Hz, 1H), 4.21 (d, J = 14.0 Hz, 1H),
7.25−7.47 (m, 6H), 8.11 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 20.8, 22.4, 26.4, 27.1, 33.9, 35.3, 38.2, 43.7, 45.8, 48.1, 50.8,
60.4, 76.1, 83.2, 125.4, 126.5, 128.0, 128.2, 134.6, 138.9, 139.0, 142.1,
(4aR,5S,10bR,12R)-1-Benzyl-12-methyl-8-((triisopropylsilyl)-
ethynyl)-2,3,4,4a,5,6-hexahydro-1H-5,10b-propano-1,7-phenan-
throline (67). To a solution of 63 (14.5 mg, 41 μmol, 1.0 equiv) in
THF (1 mL) at −78 °C were added LiHMDS solution (61 μL, 1.0 M
in THF/toluene, 61 μmol, 1.5 equiv) and neat TIPSOTf (12 μL, 45
μmol, 1.1 equiv). After 1 h, the reaction was diluted with saturated
NH4Cl solution (10 mL) and extracted with EtOAc (3 × 5 mL). The
combined organic extracts were washed with brine (5 mL), dried over
Na2SO4, filtered, and concentrated. The crude material was purified by
silica gel chromatography (1/0 → 10/1 hexanes/EtOAc) to afford 65
+
159.3; IR ν 1559, 1451, 734 cm−1; HRMS calcd for C25H29N2 [M +
H]+ 357.23307, found 357.23225.
(4aR,5S,10bR,12R)-1-Benzyl-12-methyl-8-((trimethylsilyl)ethynyl)-
2,3,4,4a,5,6-hexahydro-1H-5,10b-propano-1,7-phenanthroline
(64). To a solution of 63 (600 mg, 1.7 mmol, 1.0 equiv) in THF (15
mL) at 0 °C was added a solution of LiHMDS (2.0 mL, 1.0 M in THF,
2.0 mmol, 1.2 equiv) dropwise over 2 min. After 10 min, neat TMSCl
(0.30 mL, 2.4 mmol, 1.4 equiv) was added. The resulting solution was
stirred for 1 h, diluted with aqueous saturated NH4Cl solution (20
mL), and extracted with EtOAc (3 × 30 mL). The organic extracts
were washed with brine (30 mL), dried over Na2SO4, filtered, and
concentrated. The crude material was purified by silica gel
chromatography (1/0 → 5/1 hexanes/EtOAc) to afford alkyne 64
(650 mg, 90%) as a light brown foam: [α]24D +73.9 (c 1.9, CH2Cl2); Rf
= 0.65 (silica gel, hexanes/EtOAc = 5/1); 1H NMR (400 MHz,
CDCl3) δ 0.26 (s, 9H), 0.73 (d, J = 6.4 Hz, 3H), 1.11−1.32 (m, 4H),
1.43−1.61 (m, 3H), 1.72−1.82 (m, 2H), 1.91 (dt, J = 3.6 and 12.4 Hz,
1H), 2.09−2.11 (m, 1H), 2.36−2.53 (m, 2H), 2.70 (d, J =18.8 Hz,
1H), 3.18 (dd, J = 7.2 and 18.8 Hz, 1H), 4.3 (d, J = 14.0 Hz, 1H), 4.21
(d, J = 14.0 Hz, 1H), 7.23−7.46 (m, 6H), 8.07 (d, J = 1.4 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ −0.2, 20.8, 22.3, 26.4, 27.1, 33.9, 35.4,
38.2, 43.7, 45.7, 48.1, 50.8, 60.4, 93.5, 104.2, 125.5, 126.5, 128.0, 128.2,
134.5, 138.5, 139.9, 142.2, 159.2; IR ν 1434, 1249, 843 cm−1; HRMS
calcd for C28H37N2Si+ [M + H]+ 429.27260, found 429.27143.
(4aR,5S,10bR,12R)-1-Benzyl-8-((tert-butyldimethylsilyl)ethynyl)-
12-methyl-2,3,4,4a,5,6-hexahydro-1H-5,10b-propano-1,7-phenan-
throline (65). To a solution of 63 (9.0 mg, 25 μmol, 1.0 equiv) in
THF (1.0 mL) at 0 °C was added LiHMDS solution (80 μL, 1.0 M in
THF/toluene, 0.080 mmol, 3.2 equiv) followed by solid TBSCl (6.6
mg, 44 μmol, 1.7 equiv). After 3 h, the reaction was diluted with
saturated NH4Cl solution (10 mL) and extracted with EtOAc (3 × 5
mL). The combined organic extracts were washed with brine (5 mL),
dried over Na2SO4, filtered, and concentrated. The crude material was
purified by silica gel chromatography (1/0 → 10/1 hexanes/EtOAc)
(4.2 mg, 20%) as a clear oil and 67 (4.9 mg, 33%): [α]23.0 +37.5 (c
D
0.40, CH2Cl2); Rf = 0.72 (silica gel, hexanes/EtOAc = 10/1); 1H NMR
(400 MHz, CDCl3) δ 0.74 (d, J = 6.0 Hz, 3H), 0.92 (t, J = 7.2 Hz,
1H), 1.15 (s, 17H), 1.18−1.33 (m, 7H), 1.43−1.49 (m, 1H), 1.52−
1.61 (m, 2H), 1.72−1.79 (m, 2H), 1.91 (dt, J = 3.6 and 12.4 Hz, 1H),
2.09−2.12 (m, 1H), 2.39−2.53 (m, 2H), 2.71 (d, J = 18.8 Hz, 1H),
2.19 (dd, J = 7.2 and 18.8 Hz, 1H), 4.04 (d, J = 15.0 Hz, 1H), 4.22 (d,
J = 15.0 Hz, 1H), 7.24 (t, J = 6.8 Hz, 1H), 7.33−7.37 (m, 3H), 7.45 (d,
J = 6.8 Hz, 2H), 8.09 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 11.3, 18.7, 20.9, 22.3, 26.5, 27.1, 34.0, 35.3, 38.2, 43.7, 45.8,
48.1, 50.8, 60.4, 90.4, 106.6, 126.3, 126.5, 128.0, 128.2, 134.4, 138.3,
140.3, 142.2, 159.0; IR ν 2918, 1384 cm−1; HRMS calcd for
C34H49N2Si+ [M + H+] 513.36595, found 513.36587.
Ethyl 3-((4aR,5S,10bR,12R)-1-Benzyl-12-methyl-2,3,4,4a,5,6-hex-
ahydro-1H-5,10b-propano-1,7-phenanthrolin-8-yl)propiolate (68).
To a solution of 63 (10 mg, 28 μmol, 1.0 equiv) in THF (1 mL) at
0 °C was added LiHMDS solution (0.15 mL, 1.0 M in THF/toluene,
150 μmol, 5.4 equiv) and neat ethyl chloroformate (20 μL, 0.26 mmol,
9.2 equiv). After 2 h, the reaction was diluted with saturated NH4Cl
solution (10 mL) and extracted with EtOAc (3 × 5 mL). The
combined organic extracts were washed with brine (5 mL), dried over
Na2SO4, filtered, and concentrated. The crude material was purified by
silica gel chromatography (1/0 → 2/1 hexanes/EtOAc) to afford 68
(8.8 mg, 76%) as a clear oil: [α]23.0D +12.0 (c 0.25, CH2Cl2); Rf = 0.68
1
(silica gel, hexanes/EtOAc = 5/1); H NMR (400 MHz, CDCl3) δ
0.76 (d, J = 6.0 Hz, 3H), 0.88−0.94 (m, 1H), 1.14−1.36 (m, 5H),
1.40−1.52 (m, 2H), 1.55−1.61 (m, 1H), 1.74−1.80 (m, 2H), 1.92−
1.96 (m, 1H), 2.11−2.14 (m, 1H), 2.36−2.42 (m, 1H), 2.51−2.55 (m,
1H), 2.72 (m, d, J = 18.8 Hz, 1H), 3.20 (dd, J = 6.8 and 18.8 Hz, 1H),
4.03 (d, J = 14.0 Hz, 1H), 4.23 (d, J = 14.0 Hz, 1H), 4.12 (dd, J = 14.0
and 80.0 Hz, 2H), 4.29 (q, J = 7.2 Hz, 2H), 7.23−7.27 (m, 1H), 7.35
to afford 65 (10.1 mg, 85%) as clear oil: [α]23.0 +43.3 (c 0.30,
D
CH2Cl2); Rf = 0.75 (silica gel, hexanes/EtOAc = 10/1); 1H NMR (400
MHz, CDCl3) δ 0.20 (s, 6H), 0.74 (d, J = 3.0 Hz, 3H), 1.01 (s, 9H),
1.11−1.32 (m, 4H), 1.43−1.49 (m, 1H), 1.54−1.59 (m, 2H), 1.64
(brs, 1H), 1.72−1.80 (m, 2H), 1.91 (dt, J = 3.6 and 12.8 Hz, 1H),
P
dx.doi.org/10.1021/jo400695c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(t, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 8.18 (d, J = 8.0 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 14.0, 20.8, 22.3, 26.5, 27.1, 33.8, 35.3,
38.1, 43.6, 45.9, 48.2, 50.8, 60.6, 62.2, 78.5, 84.7, 126.6, 126.7, 128.0,
128.3, 134.8, 137.2, 140.7, 142.0, 153.7, 160.1; IR ν 2923, 1710, 1219
1H), 2.37−2.40 (m, 2H), 2.43−2.59 (m, 4H), 2.70 (d, J = 18.8 Hz,
1H), 3.18 (dd, J = 7.2 and 15.6 Hz, 1H), 3.72 (t, J = 4.8 Hz, 4H), 4.03
(d, J = 15.6 Hz, 1H), 4.21 (d, J = 15.6 Hz, 1H), 7.25 (t, J = 7.6 Hz,
1H), 7.30 (d, J = 8.0 Hz, 1H), 7.35 (t, J = 7.6 Hz, 2H), 7.45 (d, J = 7.6
Hz, 2H), 8.08 (d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ
−1.9, 13.6, 20.80, 20.83, 22.3, 26.5, 27.1, 33.9, 35.3, 38.2, 43.7, 45.8,
48.1, 50.8, 53.7, 60.5, 62.1, 66.9, 92.5, 104.9, 125.6, 126.5, 128.0, 128.2,
134.5, 138.6, 139.8, 142.1, 159.2; IR ν 2925, 1450 cm−1; HRMS calcd
for C34H48N3OSi+ [M + H+] 542.35666, found 542.35636.
+
cm−1; HRMS calcd for C28H33N2O2 [M + H+] 429.2542, found
429.2543.
4-((4aR,5S,10bR,12R)-1-Benzyl-12-methyl-2,3,4,4a,5,6-hexahy-
dro-1H-5,10b-propano-1,7-phenanthrolin-8-yl)-2-methylbut-3-yn-
2-ol (69). To a solution of 63 (10 mg, 28 μmol, 1.0 equiv) in THF (1
mL) at 0 °C was added LiHMDS solution (0.15 mL, 1.0 M in THF/
toluene, 0.15 mmol, 5.4 equiv), and after 20 min, neat acetone (20 μL,
0.27 mmol, 9.7 equiv) was added. After 10 min, the reaction was
diluted with saturated NH4Cl solution (10 mL) and extracted with
EtOAc (3 × 5 mL). The organic extracts were washed with brine (5
mL), dried over Na2SO4, filtered, and concentrated. The crude
material was purified by silica gel chromatography (1/0 → 2/1
(5R,5′R,6S,6′S,14R,14′R,16R,16′R)-1,1′-Dibenzyl-16,16′-dimethyl-
11-(trimethylsilyl)-1,1′,2,2′,3,3′,4,4′,5,5′,6,6′,7,7′,15,15′,16,16′,-
17,17′-icosahydro-10,10′-bi(5,10bpropano1,7-phenanthroline)
(71). In a pressure tube, 64 (18.5 mg, 43 μmol, 1.0 equiv) and alkyne−
nitrile 28 (20.0 mg, 65 μmol, 1.5 equiv) were dissolved in degassed
THF (4 mL). Neat CpCo(CO)2 (30 μL, 34 μmol, 0.8 equiv) was
added, and the tube was sealed. The resulting solution was placed in an
oil bath heated to 140 °C. After 14 h, the mixture was cooled, and the
reaction was concentrated. The product was purified by silica gel
chromatography (20/1 to 10/1 hexanes/EtOAc) to afford bipyridyl 71
hexanes/EtOAc) to afford 69 (7.9 mg, 68%) as a clear oil: [α]23.0
D
+41.0 (c 0.56, CH2Cl2); Rf = 0.30 (silica gel, hexanes/EtOAc = 2/1);
1H NMR (400 MHz, CDCl3) δ 0.74 (d, J = 6.4 Hz, 3H), 0.94 (t, J =
(13.6 mg, 43%) as a yellow oil: [α]24 +26.3 (c 0.49, CH2Cl2); Rf =
D
7.2 Hz, 2H), 1.12−1.31 (m, 4H), 1.37−1.49 (m, 1H), 1.52−1.66 (m,
6H), 1.72−1.79 (m, 3H), 1.91 (dt, J = 3.6 and 12.8 Hz, 1H), 2.10−
2.11 (m, 1H), 2.21−2.23 (m, 1H), 2.36−2.52 (m, 2H), 2.70 (d, J =
18.8 Hz, 1H), 3.19 (dd, J = 7.2 and 18.8 Hz, 1H), 4.03 (d, J = 14.0 Hz,
1H), 4.11 (d, J = 14.0 Hz, 1H), 7.25−7.30 (m, 1H), 7.35 (t, J = 7.2 Hz,
2H), 7.45 (d, J = 7.2 Hz, 2H), 8.10 (d, J = 8.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 20.8, 22.3, 26.5, 27.0, 31.2, 33.9, 35.3, 38.1, 43.6,
45.7, 48.1, 50.7, 60.4, 65.5, 81.9, 92.8, 125.3, 126.5, 128.0, 128.2, 134.7,
138.4, 139.6, 142.1, 159.1; IR ν 3500, 1459 cm−1; HRMS calcd for
C28H35N2O+ [M + H+] 415.2749, found 415.2749.
0.65 (silica gel, hexanes/EtOAc = 10/1); 1H NMR (400 MHz,
CDCl3) δ 0.20 (s, 9H), 0.74 (d, J = 6.4 Hz, 3H), 0.77 (d, J = 6.4 Hz,
3H), 1.10−1.59 (m, 14H), 1.70−1.83 (m, 4H), 1.90−1.96 (m, 2H),
2.13 (bs, 2H), 2.54 (brs, 4H), 2.73−2.78 (m, 2H), 3.19−3.28 (m, 2H),
4.11−4.27 (m, 4H), 7.23−7.27 (m, 1H), 7.36 (t, J = 7.6 Hz, 4H), 7.51
(t, J = 8.0 Hz, 5H), 7.80 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H),
8.43 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 1.0, 21.4, 21.8, 22.3,
22.4, 26.3, 26.5, 27.1, 27.2, 34.1, 34.2, 35.1, 35.3, 38.8, 39.5, 43.9, 43.9,
45.9, 45.9, 48.1, 48.1, 51.0, 51.2, 60.3, 60.4, 121.0, 126.4, 126.4, 127.8,
128.0, 128.2, 128.2, 130.5, 135.2, 135.9, 137.3, 142.3, 142.5, 142.8,
156.9, 157.0, 158.0, 159.9; IR ν 1453, 1242, 838, 733 cm−1; HRMS
calcd for C49H63N4Si+ [M + H+] 735.48220, found 735.48176.
(5R,5′R,6S,6′S,14R,14′R,16R,16′R)-1,1′-Dibenzyl-11-(tert-butyldi-
methylsilyl)-16,16′-dimethyl-1,1′,2,2′,3,3′,4,4′,5,5′,6,6′,7,7′,-
15,15′,16,16′,17,17′-icosahydro-10,10′-bi(5,10b-propano1,7-phe-
nanthroline) (72). In a pressure tube, alkyne nitrile 65 (15 mg, 32
μmol, 1.0 equiv) and 28 (15 mg, 49 μmol, 1.5 equiv) were dissolved in
degassed THF (2 mL). Neat CpCo(CO)2 (5.0 μL, 41 μmol, 1.3
equiv) was added, and the tube was sealed. The resulting solution was
placed in an oil bath heated to 140 °C. After 10 h the reaction was
cooled and concentrated. The crude was purified by silica gel
chromatography (20/1 → 10/1 hexanes/EtOAc) to afford 72 (7.2 mg,
29%) as a yellow oil: [α]23.0D +26.3 (c 0.38, CH2Cl2); Rf = 0.62 (silica
(4aR,5S,10bR,12R)-1-Benzyl-8-(((3-chloropropyl)dimethylsilyl)-
ethynyl)-12-methyl-2,3,4,4a,5,6-hexahydro-1H-5,10b-propano-1,7-
phenanthroline (int-19). To a solution of 63 (21.0 mg, 41 μmol, 1.0
equiv) in THF (1.5 mL) at −78 °C were added LiHMDS solution (77
μL, 1.0 M in THF/toluene, 77 μmol, 1.3 equiv) and chloro(3-
chloropropyl)dimethylsilane (13 μL, 77 μmol, 1.3 equiv). After 30
min, the reaction was diluted with saturated NH4Cl solution (10 mL)
and extracted with EtOAc (3 × 5 mL). The combined organic extracts
were washed with brine (5 mL), dried over Na2SO4, filtered, and
concentrated. The crude material was purified by silica gel
chromatography (1/0 → 10/1 hexanes/EtOAc) to afford int-19
(19.0 mg, 66%) as a clear oil: [α]23.0 +41.0 (c 0.56, CH2Cl2); Rf =
D
0.30 (silica gel, hexanes/EtOAc = 2/1); 1H NMR (400 MHz, CDCl3)
δ 0.26 (s, 6H), 0.74 (d, J = 6.0 Hz, 3H), 0.82 (dt, J = 4.4 and 8.0 Hz,
2H), 1.11−1.32 (m, 4H), 1.43−1.63(m, 4H), 1.72−1.80 (m, 2H),
1.89−1.97 (m, 3H), 2.09−2.13 (m, 1H), 2.40 (dt, J = 1.2 and 13.2 Hz,
1H), 2.48−2.53 (m, 1H), 3.19 (dd, J = 7.2 and 18.8 Hz, 1H), 3.57 (t, J
= 8.0 Hz, 2H), 4.03 (d, J = 14.4 Hz, 1H), 4.22 (d, J = 14.4 Hz, 1H),
7.24−7.27 (m, 1H), 7.32−7.37 (m, 3H), 7.45 (dd, J = 0.8 and 8.0 Hz,
2H), 8.09 (d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ −1.9,
13.7, 20.8, 22.3, 26.4, 27.0, 27.5, 33.9, 35.4, 38.1, 43.6, 45.7, 47.7, 48.1,
50.7, 60.5, 91.8, 105.2, 125.7, 126.5, 128.0, 128.2, 134.5, 138.7, 139.7,
142.1, 159.2; IR ν 2920, 1558 cm−1; HRMS calcd for C30H40N2SiCl+
[M + H+] 491.2649, found 491.2645.
1
gel, hexanes/EtOAc = 10/1); H NMR (400 MHz, CDCl3) δ −0.11
(s, 3H), −0.10 (s, 3H), 0.76 (d, J = 6.0 Hz, 3H), 0.76 (d, J = 6.0 Hz,
3H), 0.83−1.02 (m, 12H), 1.15−1.19 (m, 2H), 1.26−1.43 (m, 5H),
1.47−1.63 (m, 4H), 1.70−1.84 (m, 3H), 1.90−1.95 (m, 2H), 2.11−
2.14 (m, 2H), 2.51−2.55 (m, 4H), 2.72 (dd, J = 3.6 and 19.2 Hz, 2H),
3.22 (dd, J = 7.2 and 19.2 Hz, 2H), 4..8−4.14 (m, 2H), 4.23−4.29(m,
2H), 7.23−7.27 (m, 2H), 7.33−7.40 (m, 5H), 7.49−7.51 (m, 4H),
8.14 (d, J = 8.0 Hz, 2H), 8.45 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
−4.0, −3.8, 14.1, 17.8, 21.3, 22.3, 22.4, 22.6, 26.38, 26.44, 27.1, 27.4,
34.1, 34.2, 34.7, 35.3, 38.7, 38.8, 43.8, 43.9, 45.6, 46.0, 48.1, 48.3,
50.95, 51.01, 60.2, 60.4, 121.9, 126.4, 126.4, 127.8, 128.0, 128.1, 128.2,
128.2, 134.6, 135.4, 137.1, 142.4, 142.7, 143.1, 157.0, 157.6, 158.1,
161.3; IR ν 2925, 2854, 733 cm−1; HRMS calcd for C52H69N4Si+ [M +
H+] 777.52915, found 777.52834.
4-(3-((((4aR,5S,10bR,12R)-1-Benzyl-12-methyl-2,3,4,4a,5,6-hexa-
hydro-1H-5,10b-propano-1,7-phenanthrolin-8-yl)ethynyl)-
dimethylsilyl)propyl)morpholine (70). Pyridine int-19 (15.0 mg, 31
μmol, 1.0 equiv) was dissolved in acetone (1 mL), and NaI (15 mg,
3.3 mmol, 3.3 equiv), morpholine (13 mL, 0.15 mmol, 5.0 equiv), and
K2CO3 (10 mg, 2.4 mmol, 2.4 equiv) were added. The heterogeneous
reaction was heated to reflux. After 48 h, the reaction was cooled to 23
°C, diluted with saturated NH4Cl solution (5 mL), and extracted with
EtOAc (3 × 5 mL). The combined organic extracts were washed with
brine (5 mL), dried over Na2SO4, filtered, and concentrated. The
crude material was purified by silica gel chromatography (10/1
hexanes/EtOAc → 10/1 CH2Cl2/MeOH) to afford 70 (13.8 mg,
Benzyl-Masked Pseudosymmetric Complanadine A (73). To a
solution of 71 (21 mg, 29 μmol, 1.0 equiv) in dioxane (1.5 mL) at 23
°C was added TBAF solution (0.15 mL, 1.0 M in THF, 75 μmol, 5.2
equiv). The resulting solution was placed in a heated oil bath. After 10
h, the reaction was concentrated and purified by silica gel
chromatography (1/0 → 10/1 hexanes/EtOAc) to afford compound
73 (15.5 mg, 82%) as a light yellow foam: Rf = 0.65 (silica gel,
1
hexanes/EtOAc = 5/1); H NMR (500 MHz, CDCl3) δ 0.74 (d, J =
83%) as a pale yellow oil: [α]23.0 +24.4 (c 0.86, CH2Cl2); Rf = 0.35
6.5 Hz, 6H), 0.86−1.03 (m, 2H), 1.14−1.61 (m, 8H), 1.77−1.80 (m,
4H), 1.94 (dt, J = 4.5 and 11.5 Hz, 2H), 2.14 (brs, 2H), 2.52 (d, J = 9.5
Hz, 4H), 2.80 (d, J = 23.5 Hz, 2H), 3.29 (dd, J = 9.5 and 23.5 Hz, 2H),
4.12 (d, J = 18.0 Hz, 2H), 4.25 (d, J = 18.0 Hz, 2H), 7.23−7.27 (m,
6H), 7.36 (t, J = 9.5 Hz, 4H), 7.50 (d, J = 9.5 Hz, 4H), 8.10 (d, J =
D
1
(silica gel, CH2Cl2/MeOH = 10/1); H NMR (400 MHz, CDCl3) δ
0.24 (s, 6H), 0.67−0.70 (m, 2H), 0.74 (d, J = 6.4 Hz, 3H), 0.83−0.97
(m, 1H), 1.11−1.33 (m, 4H), 1.42−1.49 (m, 2H), 1.51−1.68 (m, 3H),
1.72−1.82 (m, 2H), 1.91 (dt, J = 3.6 and 12.8 Hz, 2H), 2.09−2.11 (m,
Q
dx.doi.org/10.1021/jo400695c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
10.0 Hz, 2H), 8.21 (d, J = 10.0 Hz, 2H). 13C NMR (125 MHz,
CDCl3) δ 22.4, 26.5, 27.2, 29.7, 34.2, 35.6, 38.8, 34.8, 45.8, 48.2, 51.0,
60.5, 119.2, 126.5, 128.0, 128.2, 135.3, 138.0, 142.5, 154.1, 158.2; IR ν
1H), 1.75−1.81 (m, 2H), 1.85−1.89 (m, 2H), 2.18−2.22 (m, 2H),
2.48−2.57 (m, 2H), 2.76−2.85 (m, 4H), 3.20−3.30 (m, 2H), 7.77 (d, J
= 8.0 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 8.48 (s, 1H), 8.93 (s, 1H); 13C
NMR (100 MHz, MeOH): δ 22.4, 27.1, 27.3, 27.7, 34.8, 34.9, 35.7,
36.2, 42.1, 44.7, 44.8, 44.9, 51.6, 51.7, 57.8, 57.9, 120.4, 133.7, 135.0,
135.9, 136.6, 137.6, 146.1, 153.7, 159.9, 160.5; IR ν 2913, 1575, 1436
+
2965, 1601 cm−1; HRMS calcd for C46H55N4 [M + H+] 663.44267,
found 663.44200.
(5R,5′R,6S,6′S,14R,14′R,16R,16′R)-1,1′-Dibenzyl-16,16′-dimethyl-
11-(trimethylsilyl)-1,1′,2,2′,3,3′,4,4′,5,5′,6,6′,7,7′,15,15′,-
16,16′,17,17′-icosahydro-10,11′-bi(5,10bpropano1,7-phenanthro-
line) (77). In a pressure tube, 33 (14 mg, 33 μmol, 1.0 equiv) and
alkyne−nitrile 28 (14 mg, 46 μmol, 1.4 equiv) were dissolved in
degassed THF (2 mL). Neat CpCo(CO)2 (5 μL, 41 μmol, 1.2 equiv)
was added, and the tube was sealed. The resulting solution was placed
in an oil bath heated to 140 °C. After 10 h, the mixture was cooled to
23 °C, and the reaction was concentrated. The crude was purified by
silica gel chromatography (20/1 →10/1 hexanes/EtOAc) to afford
+
cm−1; HRMS calcd for C32H43N4 [M + H+] 483.34877, found
483.34828.
(4aR,5S,10bR,12R)-1-Benzyl-9-(((tert-butyldimethylsilyl)oxy)-
methyl)-12-methyl-2,3,4,4a,5,6-hexahydro-1H-5,10b-propano-1,7-
phenanthroline (81). In a pressure tube alkyne 79 (218 mg, 0.90
mmol, 2.5 equiv) and alkyne−nitrile 28 (110 mg, 0.36 mmol, 1.0
equiv) were dissolved in freshly degassed THF (2.0 mL). Neat
CpCo(CO)2 (60 μL, 0.48 mmol, 1.4 equiv) was added and the tube
was sealed. The resulting solution was placed in an 140 °C oil bath.
After 30 h the reaction was cooled to 23 °C and concentrated. The
crude material was purified by silica gel chromatography (1/0 → 5/1
hexanes/EtOAc) to afford 81 (65 mg, 34%) as a brown oil and
unreacted 28 (14 mg, 11%) was recovered. If the reaction was run at
0.05 M, the ratio is 1/3 (81/80). The undesired product 80 was
bipyridyl 77 (6.8 mg, 28%) as a yellow oil: [α]23.0 +34.2 (c 0.30,
D
1
CH2Cl2); Rf = 0.2 (silica gel, hexanes/EtOAc = 1/1); H NMR (400
MHz, CDCl3) δ 0.10 (s, 9H), 0.79 (d, J = 5.6 Hz, 3H), 0.82 (d, J = 6.0
Hz, 3H), 0.85−0.91 (m, 2H), 1.12−1.43 (m, 7H), 1.49−1.66 (m, 6H),
1.75−1.84 (m, 4H), 1.93−2.00 (m, 2H), 2.12−2.18 (m, 2H), 2.45−
2.63 (m, 3H), 2.76 (dd, J = 3.6 and 18.4 Hz, 2H), 3.23 (dt, J = 7.6 and
19.0 Hz, 2H), 4.04−4.29 (m, 4H), 7.22−7.42 (m, 6H), 7.45 (d, J = 7.6
Hz, 2H), 7.52 (d, J = 7.6 Hz, 2H), 8.18 (d, J = 1.6 Hz, 1H), 8.38 (s,
1H), 8.48 (d, J = 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 0.6,
14.1, 20.7, 21.7, 22.3, 22.6, 24.9, 26.3, 26.6, 27.1, 31.8, 34.0, 34.1, 35.3,
38.3, 39.4, 43.8, 45.4, 45.8, 47.8, 48.0, 50.7, 51.2, 60.2, 60.6, 126.4,
126.5, 127.6, 127.8, 128.1, 128.2, 128.4, 130.8, 134.3, 135.4, 136.9,
137.5, 141.9, 142.0, 142.7, 147.0, 157.9, 158.5, 159.5; IR ν 3390, 2922,
1559, 732 cm−1; HRMS calcd for C49H63N4Si+ [M + H+] 735.4822,
found 735.4820.
subjected to desiylation for characterization: [α]23.0 +28.5 (c 0.23,
D
1
CH2Cl2); Rf = 0.41 (silica gel, hexanes/EtOAc = 5:1); H NMR (400
MHz, CDCl3) δ 0.13 (d, J = 2.0 Hz, 6H), 0.75 (d, J = 6.0 Hz, 3H),
0.95 (s, 9H), 1.11−1.35 (m, 4H), 1.43−1.58 (m, 3H), 1.71−1.80 (m,
2H), 1.93 (dt, J = 3.6 and 12.8 Hz, 1H), 2.09−2.12 (m, 1H), 2.43−
2.52 (m, 2H), 3.19 (dd, J = 7.2 and 18.8 Hz, 1H), 4.14 (d, J = 14.4 Hz,
1H), 4.23 (d, J = 14.4 Hz, 1H), 4.77 (s, 2H), 7.22−7.26 (m, 1H),
7.32−7.36 (m, 2H), 7.47−7.49 (m, 2H), 8.10 (d, J = 2.4 Hz, 1H), 8.31
(d, J = 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ −5.2, −5.1, 18.4,
21.3, 22.4, 25.9, 26.4, 27.1, 34.0, 35.1, 38.7, 43.8, 45.8, 48.1, 51.1, 60.4,
63.0, 126.4, 127.9, 128.2, 132.5, 134.4, 137.7, 142.4, 144.9, 157.3; IR ν
2918, 1653, 1094 cm−1; HRMS calcd for C30H45N2OSi+ [M + H+]
477.33012, found 477.32948.
((4aR,5S,10bR,12R)-1-Benzyl-12-methyl-9-(trimethylsilyl)-
2,3,4,4a,5,6-hexahydro-1H-5,10b-propano-1,7-phenanthrolin-8-yl)-
methanol (int-20). To a solution of 80 (61 mg, 0.13 mmol, 1.0 equiv)
in THF (5 mL) at 23 °C was added TBAF solution (0.15 mL, 1.0 M in
THF, 0.15 mmol, 1.2 equiv). After 30 min, the mixture was diluted
with saturated NH4Cl solution (10 mL) and extracted with EtOAc (3
× 10 mL). The combined organic extracts were washed with brine (5
mL), dried over Na2SO4, filtered, and concentrated. The crude
material was purified by silica gel chromatography (10/1 → 1/1
hexanes/EtOAc) to afford int-20 (12 mg, 22%) as a light brown foam:
[α]23.0D +57.1 (c 0.35, CH2Cl2); Rf = 0.35 (silica gel, hexanes/EtOAc =
2/1); 1H NMR (400 MHz, CDCl3) δ 0.35 (s, 9H), 0.76 (d, J = 6.0 Hz,
3H), 1.14−1.34 (m, 5H), 1.43−1.57 (m, 3H), 1.71−1.80 (m, 2H),
1.89 (dt, J = 3.6 and 12.8 Hz, 1H), 2.10−2.12 (m, 1H), 2.40−2.53 (m,
2H), 2.65 (d, J = 19.2 Hz, 1H), 3.16 (dd, J = 7.2 and 19.2 Hz, 1H),
4.09 (d, J = 14.0 Hz, 1H), 4.22 (d, J = 14.0 Hz, 1H),4.73 (d, J = 1.6
Hz, 2H), 7.24 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.2 Hz, 2H), 7.47 (d, J =
7.2 Hz, 2H), 8.26 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 0.0, 22.0,
23.0, 27.0, 27.6, 34.6, 35.5, 39.6, 44.3, 46.6, 48.6, 51.6, 60.6, 64.1,
127.0, 128.4, 128.8, 136.2, 142.1, 143.2, 157.5, 159.4, 163.5; IR ν 2923,
1068, 839 cm−1; HRMS calcd for C27H39N2OSi+ [M + H+] 435.2832,
found 435.2826.
Benzyl-Masked Complanadine A (78). To a solution of 77 (8.1
mg, 11 μmol, 1.0 equiv) in dioxane (1 mL) at 23 °C was added TBAF
solution (1.0 M in THF, 50 μL, 50 μmol, 4.6 equiv), and the reaction
was placed in a heated oil bath. After 10 h, the mixture was cooled to
23 °C, diluted with saturated NH4Cl solution (10 mL), and extracted
with EtOAc (3 × 5 mL). The combined organic extracts were washed
with brine (5 mL), dried over Na2SO4, filtered, and concentrated. The
crude material was purified by silica gel chromatography (5/1 → 1/1
hexanes/EtOAc) to afford 78 (7.3 mg, 97%) as a light yellow oil:
[α]23.0D +36.9 (c 0.73, CH2Cl2); Rf = 0.40 (silica gel, hexanes/EtOAc =
1
1/1); H NMR (400 MHz, CDCl3) δ 0.76 (d, J = 6.0 Hz, 3H), 0.77
(d, J = 6.0 Hz, 3H), 1.17−1.21 (m, 2H), 1.23−1.37 (m, 3H), 1.37−
1.44 (m, 1H), 1.44−1.55 (m, 2H), 1.55−1.69 (m, 4H), 1.73−1.83 (m,
4H), 1.92−1.99 (m, 2H), 2.13−2.19 (m, 2H), 2.53−2.57 (m, 4H),
2.79 (dd, J = 18.8 and 34.4 Hz, 2H), 3.22−3.35 (m, 2H), 4.10−4.32
(m, 4H), 7.24−7.28 (m, 4H), 7.38 (dt, J = 3.6 and 7.2 Hz, 4H), 7.51
(d, J = 7.2 Hz, 2H), 7.56 (d, J = 7.2 Hz, 2H), 7.61 (d, J = 8.0 Hz, 1H),
8.22 (d, J = 8.0 Hz. 1H), 8.74 (d, J = 2.4 Hz, 1H), 8.98 (d, J = 2.4 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 21.1, 21.7, 22.3, 22.4, 26.4, 26.6,
27.2, 34.1, 34.2, 35.3, 35.6, 38.7, 39.3, 43.8, 45.9, 46.0,48.0, 48.2, 50.9,
51.2, 60.4, 60.5, 118.4, 126.4, 126.5, 128.0, 128.2, 132.7, 133.3, 135.3,
137.1, 137.9, 142.4, 142.6, 145.3, 152.5, 158.7, 158.9; IR ν 3446, 2921,
+
1447, 732 cm−1; HRMS calcd for C46H55N4 [M + H+] 663.4427,
found 663.4427.
Complanadine A (1). To protected complanadine (78) (8.0 mg, 12
μmol, 1.0 equiv) in THF (1 mL) was added solid 10% palladium on
carbon (2.0 mg, 15.6 μmol, 0.16 equiv), and the heterogeneous
solution was rapidly stirred under a balloon of H2 (1 atm) at 23 °C.
After 20 h, the solution was filtered through a Celite pad and
concentrated to afford the complanadine A (5.1 mg, 88%) as a pale
yellow oil. Additional purification was achieved as follows: the above
complanadine A (12 mg, 25 μmol, 1.0 equiv) was dissolved in 5% HCl
solution (5 mL) and washed with Et2O (2 × 5 mL), the aqueous layer
was adjusted to a pH of 13 with 10% aqueous NaOH solution, and the
white suspension was extracted with EtOAc (3 × 5 mL). The
combined organic extracts were washed with brine (5 mL), dried over
Na2SO4, filtered, and concentrated to provide complanadine A (1)
((4aR,5S,10bR,12R)-1-Benzyl-12-methyl-2,3,4,4a,5,6-hexahydro-
1H-5,10b-propano-1,7-phenanthrolin-9-yl)methanol (82). To a
solution of 81 (200 mg, 0.42 mmol, 1.0 equiv) in THF (5 mL) at
23 °C was added TBAF solution (0.80 mL, 1.0 M in THF, 0.80 mmol,
1.9 equiv). After 30 min, the reaction was concentrated. The crude
material was purified by silica gel chromatography (5/1 → 0/1
hexanes/EtOAc) to afford 82 (119 mg, 78%) as light brown oil:
1
[α]23.0 +29.0 (c 0.24, CH2Cl2); Rf = 0.32 (silica gel, EtOAc); H
D
NMR (400 MHz, CDCl3) δ 0.75 (d, J = 6.0 Hz, 3H), 0.91−0.99 (m,
1H), 1.12−1.33 (m, 4H), 1.45−1.58 (m, 3H), 1.74−1.80 (m, 2H),
1.92 (dt, J = 4.0 and 13.2 Hz, 1H), 2.08−2.12 (m, 1H), 2.39−2.53 (m,
2H), 2.69 (d, J = 18.8 Hz, 1H), 3.18 (dd, J = 6.8 and 18.8 Hz, 1H),
4.09 (d, J = 14.4, 1H), 4.22 (d, J = 14.4 Hz, 1H), 4.73 (s, 2H), 7.23−
7.26 (m, 1H), 7.39 (t, J = 7.2 Hz, 2H), 7.47 (d, J = 7.2 Hz, 2H), 8.11
(d, J = 2.4 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H); 13C NMR (100 MHz,
1
(5.1 mg, 90%) as a pale yellow oil: [α]24D +14.5 (c 0.30, MeOH); H
NMR (400 MHz, MeOH): δ 0.85 (d, J = 6.4 Hz, 3H), 0.86 (d, J = 6.4
Hz, 3H), 1.21−1.49 (m, 10H), 1.53−1.64 (m, 5H), 1.68−1.72 (m,
R
dx.doi.org/10.1021/jo400695c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
CDCl3) δ 21.1, 22.4, 26.4, 27.0, 33.9, 35.0, 38.5, 43.7, 45.8, 48.1, 51.0,
60.4, 63.1, 126.5, 128.0, 128.2, 133.6, 134.1, 138.1, 142.2, 145.7, 157.9;
IR ν, 2921, 1453, 732 cm−1; HRMS calcd for C24H31N2O+ [M + H+]
363.2436, found 363.2433.
0.25 (silica gel, neutralized by Et3N, EtOAc); H NMR (400 MHz,
CDCl3) δ 0.95 (d, J = 6.4 Hz, 3H), 1.13 (t, J = 12.1 Hz, 1H), 1.24−
1.32 (m, 1H), 1.43−1.66 (m, 4H), 1.70−1.80 (m, 2H), 1.91−2.08 (m,
3H), 2.44 (s, 1H), 2.50−2.56 (m, 1H), 2.81−2.86 (m, 1H), 2.93 (dd, J
= 4.0 and 17.2 Hz, 1H), 3.04−3.11 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 16.9, 21.8, 24.1, 26.1, 26.4, 36.3, 38.4, 42.3, 45.8, 48.6, 54.1,
75.1, 87.5, 120.5; IR ν 3285, 1457, 1124, 637 cm−1; HRMS calcd for
(4aR,5S,10bR,12R)-1-Benzyl-12-methyl-2,3,4,4a,5,6-hexahydro-
1H-5,10b-propano-1,7-phenanthroline-9-carbaldehyde (83). To a
solution of 82 (46 mg, 0.13 mmol, 1.0 equiv) in CH2Cl2 (5 mL) was
added solid Dess−Martin periodiane (215 mg, 0.51 mmol, 4.0 equiv)
at 23 °C. After 30 min, the heterogeneous solution was diluted with
saturated NH4Cl solution (10 mL) and extracted with EtOAc (3 × 10
mL). The combined organic extracts were washed with brine (10 mL),
dried over Na2SO4, filtered, and concentrated. The crude material was
purified by silica gel chromatography (20/1 → 2/1 hexanes/EtOAc)
to afford 83 (44.1 mg, 96%) as a pale yellow oil: [α]23.0D +28.5 (c 0.23,
CH2Cl2); Rf = 0.20 (silica gel, hexanes/EtOAc = 2/1); 1H NMR (400
MHz, CDCl3) δ 0.77 (d, J = 6.0 Hz, 3H), 1.14−1.37 (m, 4H), 1.53−
1.63 (m, 3H), 1.75−1.81 (m, 2H), 1.99 (dt, J = 3.2 and 12.4 Hz, 1H),
2.11−2.18 (m, 1H), 2.35−2.42 (m, 1H), 2.53−2.58 (m, 1H), 2.79 (d, J
= 19.6 Hz, 1H), 3.27 (dd, J = 7.2 and 19.2 Hz, 1H), 4.18 (dd, J = 14.4
and 64.0 Hz, 2H), 7.24−7.28 (m, 1H), 7.37 (t, J = 8.0 Hz, 2H), 7.49
(d, J = 8.0 Hz, 2H), 8.57 (d, J = 2.0 Hz, 1H), 8.47 (d, J = 2.0 Hz, 1H),
10.1 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.0, 22.3, 26.4, 27.1,
33.8, 36.0, 38.2, 43.5, 45.8, 48.1, 51.0, 60.5, 126.7, 128.0, 128.3, 130.3,
134.9, 139.3, 141.8, 149.0, 165.5, 191.3; IR ν 2919, 1698, 1384 cm−1;
HRMS calcd for C24H29N2O+ [M + H+] 361.2280, found 361.2278.
(4aR,5S,10bR,12R)-1-Benzyl-9-ethynyl-12-methyl-2,3,4,4a,5,6-
hexahydro-1H-5,10b-propano-1,7-phenanthroline (85). To a sol-
ution of 83 (50 mg, 0.14 mmol, 1.0 equiv) and K2CO3 (47.9 mg, 0.35
mmol, 2.5 equiv) in methanol (2 mL) was added dimethyl 1-diazo-2-
oxopropylphosphate 84 (66.6 mg, 0.35 mmol, 2.5 equiv) at 23 °C.
After 8 h, the reaction was diluted with saturated aqueous NH4Cl
solution (10 mL) and extracted with EtOAc (3 × 10 mL). The
combined organic extracts were washed with brine (10 mL), dried
over Na2SO4, filtered, and concentrated. The crude material was
purified by silica gel chromatography (20/1 → 5/1 hexanes/EtOAc)
C14H21N2 [M + H+] 217.17014, found 217.16996.
2-((4aR,5R,7S,8aS)-8a-Ethynyl-1-formyl-7-methyldecahydroqui-
nolin-5-yl)acetonitrile (87). To a solution of 86 (260 mg, 1.2 mmol,
1.0 equiv) in THF (7 mL) were added neat AcOCHO (200 μL, 1.9
+
mmol, 1.6 equiv) and Hunig’s base (300 μL, 1.6 mmol, 1.4 equiv) at
̈
23 °C. After 30 min, the solution was diluted with aqueous saturated
NH4Cl solution (10 mL) and extracted with EtOAc (3 × 10 mL). The
combined organic extracts were washed with brine (10 mL), dried
over Na2SO4, filtered, and concentrated to afford 87 (290 mg, 97%,
mp 155.0−155.2 °C) as a pale yellow solid: [α]24 +81.8 (c 1.0,
D
CH2Cl2); Rf = 0.28 (silica gel, hexanes/EtOAc = 1/1); 1H NMR (400
MHz, CDCl3) δ 1.07 (d, J = 6.8 Hz, 3H), 1.32 (dt, J = 5.2 and 13.6 Hz,
1H), 1.42−1.67 (m, 4H), 1.78−1.85 (m, 2H), 1.98−2.19 (m, 3H),
2.34 (d, J = 11.6 Hz, 1H), 2.59−2.64 (m, 2H), 2.87−2.97 (m, 2H),
4.47−4.51 (m, 1H), 8.36 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
16.9, 21.9, 24.4, 25.1, 26.5, 36.5, 37.6, 37.7, 44.0, 46.9, 57.4, 76.6, 83.8,
119.8, 158.7; IR 1659, 1385, 1131, 913 cm−1; HRMS calcd for
C15H21N2O+ [M + H+] 245.16539, found 245.16486.
(4aR,5R,7S,8aS)-Methyl 5-(Cyanomethyl)-8a-ethynyl-7-methyl-
octahydroquinoline-1(2H)-carboxylate (90). To a solution of 86
(50 mg, 0.23 mmol, 1.0 equiv) in CH2Cl2 (3 mL) were added Et3N
(0.097 mL, 0.69 mmol, 3.0 equiv) and methyl chloroformate (36 μL,
0.46 mmol, 2.0 equiv) at 23 °C. After 1 h, the resulted solution was
diluted with saturated NH4Cl solution (10 mL) and extracted with
EtOAc (3 × 10 mL). The organic extracts were washed with brine (10
mL), dried over Na2SO4, filtered, and concentrated. The crude
material was purified by silica gel chromatography (10/1 → 5/1
hexanes/EtOAc) to afford carbamate 90 (55 mg, 87%) as a yellow oil:
[α]23.0D +30.0 (c 0.20, CH2Cl2); Rf = 0.70 (silica gel, hexanes/EtOAc =
to afford 85 (42.3 mg, 86%) as a white foam: [α]23.0 +27.5 (c 0.29,
D
CH2Cl2); Rf = 0.65 (silica gel, hexanes/EtOAc = 5/1); 1H NMR (400
MHz, CDCl3) δ 0.76 (d, J = 6.0 Hz, 3H), 1.14−1.33 (m, 4H), 1.48−
1.50 (m, 1H), 1.56−1.64 (m, 2H), 1.73−1.83 (m, 2H), 1.93 (dt, J =
3.6 and 12.8 Hz, 1H), 2.10−2.13 (m, 1H), 2.40−2.54 (m, 2H), 2.68
(d, J = 19.2 Hz, 1H), 3.16−3.23 (m, 2H), 4.05 (d, J = 14.0 Hz, 1H),
4.23 (d, J = 14.0 Hz, 1H), 7.25−7.27 (m, 1H), 7.36 (t, J = 7.6 Hz, 2H),
7.47 (d, J = 7.6 Hz, 2H), 8.21 (d, J = 2.0 Hz, 1H), 8.50 (d, J = 2.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 20.9, 22.3, 26.4, 27.0, 33.8, 35.4,
38.2, 43.6, 45.7, 48.1, 50.8, 60.3, 79.2, 81.4, 116.7, 126.6, 128.0, 128.3,
137.5, 137.9, 142.0, 149.8, 158.9; IR ν 2921, 1450, 1384 cm−1; HRMS
1
2/1); H NMR (400 MHz, CDCl3) δ 1.00 (d, J = 6.4 Hz, 3H), 1.30
(dt, J = 5.2 and 13.2 Hz, 1H), 1.40 (t, J = 13.2 Hz, 1H), 1.51−1.63 (m,
2H), 1.70−1.80 (m, 3H), 1.91−1.99 (m, 2H), 2.14−2.19 (m, 1H),
2.51 (s, 1H), 2.63 (ddd, J = 0.8, 4.0, and 17.2 Hz, 1H), 2.94 (dd, J =
12.0 and 17.2 Hz, 1H), 3.24−3.31 (m, 2H), 3.64 (s, 3H), 3.91−3.96
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 17.2, 22.0, 24.7, 24.8, 25.9,
37.4, 37.9, 43.8, 45.6, 45.7, 52.3, 58.2, 75.3, 84.6, 120.3, 156.7; IR ν
+
2924, 1713, 1384, 1268 cm−1; HRMS calcd for C16H23N2O2 [M +
H+] 275.1759, found 275.1753.
(4aR,5R,7S,8aS)-5-(Cyanomethyl)-8a-ethynyl-N,N,7-trimethyloc-
tahydroquinoline-1(2H)-carboxamide (91). To a solution of
secondary amine 86 (100 mg, 0.46 mmol, 1.0 equiv) in THF (5
mL) was added solid DMAP (56 mg, 0.46 mmol, 1.0 equiv) following
by Et3N (0.30 mL, 2.3 mmol, 5.0 equiv) and neat dimethylcarbamoyl
chloride (1.0 mL, 10.2 mmol, 22.0 equiv) at 23 °C. After 12 min, the
solution was diluted with saturated NH4Cl solution (10 mL) and
extracted with EtOAc (3 × 10 mL). The combined organic extracts
were washed with brine (10 mL), dried over Na2SO4, filtered, and
concentrated. The crude material was purified by silica gel
chromatography (5/1 → 1/1 hexanes/EtOAc) to afford urea 91 (96
+
calcd for C25H29N2 [M + H+] 357.2331, found 357.2326.
2-((4aR,5R,7S,8aS)-8a-Ethynyl-7-methyldecahydroquinolin-5-yl)-
acetonitrile (86). Amine 29 (600 mg, 1.78 mmol, 1.0 equiv) was
dissolved in acetonitrile/water (6/1, 15 mL). Solid CAN (4.0 g, 7.3
mmol, 4.1 equiv) was added in one portion, and the solution was
placed in a 75 °C oil bath. After 5 h, the mixture was neutralized with
aqueous NaOH solution (1.0 M, 15 mL) and filtered through a Celite
pad. The mixture was extracted with EtOAc (3 × 15 mL), washed with
brine (10 mL), dried over Na2SO4, filtered, and concentrated. The
crude material was purified by silica gel chromatography (the column
was neutralized with 1% Et3N in hexane) (5/1 → 0/1 hexanes/
EtOAc) to afford the secondary amine 86 (260 mg, 67%, mp 153.8−
154.2 °C) as a pale yellow solid. Alternatively, the following procedure
was used: Amine 30 (200 mg, 0.55 mmol, 1.0 equiv) was dissolved in
acetonitrile/water (6/1, 12 mL) at 23 °C. Solid CAN (500 mg, 0.91
mmol, 1.6 equiv) was added in one portion. After 5 min at 23 °C, the
mixture was neutralized with aqueous NaOH solution (1 M, 5 mL)
and filtered through a Celite pad. The mixture was extracted with
EtOAc (3 × 10 mL), and the combined organic extracts were washed
with brine (10 mL), dried over Na2SO4, filtered, and concentrated.
The crude material was purified by silica gel chromatography (column
was neutralized with 1% Et3N in hexane) (5/1 → 0/1 hexanes/
EtOAc) to afford the secondary amine 86 (81 mg, 70%, mp 153.8−
mg, 72%) as yellow oil: [α]23.0 +54.5 (c 0.11, CH2Cl2); Rf = 0.50
(silica gel, hexanes/EtOAc = 1/1); H NMR (400 MHz, CDCl3) δ
D
1
0.78 (t, J = 12.4 Hz, 1H), 0.89 (d, J = 6.4 Hz, 3H), 1.18−1.25 (m, 2H),
1.42−1.73 (m, 5H), 1.86−1.99 (m, 2H), 2.02−2.08 (m, 1H), 2.50 (s,
1H), 2.55 (ddd, J = 0.8, 4.0, and 17.2 Hz, 1H), 2.73 (td, J = 2.4 and
12.0 Hz, 1H), 2.84 (brs, 6H), 2.88−2.96 (m, 1H), 3.12 (td, J = 2.8 and
12.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 17.3, 21.9, 24.1, 25.6,
26.4, 37.2, 38.4, 44.0, 46.5, 47.0, 56.3, 85.1, 120.5, 139.8, 163.3; IR ν
2924, 1652, 1385 cm−1; HRMS calcd for C17H26N3O+ [M + H+]
288.2076, found 288.2068.
2-((4aR,5R,7S,8aS)-1-Acetyl-8a-ethynyl-7-methyldecahydroqui-
nolin-5-yl)acetonitrile (92). To a solution of 86 (200 mg, 0.93 mmol,
1.0 equiv) in CH2Cl2 (10 mL) were added neat acetyl chloride (0.20
mL, 0.28 mmol, 3.0 equiv) and neat triethylamine (0.28 mL, 0.20
154.2 °C) as a pale yellow solid: [α]24 −24.1 (c 0.27, CH2Cl2); Rf =
D
S
dx.doi.org/10.1021/jo400695c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
mmol, 2.0 equiv) at 50 °C. After 2 h, the resulting solution was diluted
with saturated NH4Cl solution (10 mL) and extracted with EtOAc (3
× 15 mL). The combined organic extracts were washed with brine (10
mL), dried over Na2SO4, filtered, and concentrated to amide 92 (178
1H), 2.50−2.54 (m, 2H), 2.72−2.88 (m, 3H), 3.02 (s, 6H), 3.05−3.09
(m, 1H), 3.18−3.27 (m, 2H), 4.12 (d, J = 14.4 Hz, 1H), 4.24 (d, J =
14.4 Hz, 1H), 7.24−7.27 (m, 1H), 7.36 (t, J = 7.2 Hz, 2H), 7.50 (d, J =
7.2 Hz, 2H), 7.78 (d, J = 8.0 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 8.38 (s,
1H); 13C NMR (125 MHz, CDCl3) δ 1.0, 14.7, 21.4, 22.2, 22.3, 25.0,
26.1, 26.5, 26.6, 27.2, 28.5, 31.6, 33.9, 34.1, 35.1, 37.7, 38.8, 41.2, 43.6,
43.9, 45.4, 45.9, 46.4, 48.1, 51.1, 60.4, 61.5, 121.1, 126.5, 128.0, 128.2,
130.7, 134.2, 135.2, 137.4, 142.5, 143.3, 156.9, 157.0, 157.9, 160.2,
164.2; IR ν 2919, 1649, 1384 cm−1; HRMS calcd for C45H62N5OSi+
[M + H+] 716.4724, found 716.4721.
mg, 78%) as a yellow oil: [α]23.0 +22.5 (c 0.80, CH2Cl2); Rf = 0.40
D
1
(silica gel, hexanes/EtOAc = 1/1); H NMR (400 MHz, CDCl3) δ
0.97 (d, J = 6.0 Hz, 3H), 1.24−1.33 (m, 2H), 1.52−1.59 (m, 1H),
1.63−1.71 (m, 1H), 1.76−1.97 (m, 5H), 2.08 (s, 3H), 2.14−2.20 (m,
1H), 2.50 (s, 1H), 2.65 (ddd, J = 1.2, 4.0, and 17.2 Hz, 1H), 2.95 (dd, J
= 11.6 and 17.2 Hz, 1H), 3.34−3.42 (m, 2H), 3.52−3.58 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 17.3, 21.8, 24.3, 24.6, 24.6, 25.6, 37.3,
38.0, 43.9, 44.4, 44.8, 58.1, 75.0, 84.5, 120.2, 172.1; IR ν 3216, 1650,
1390 cm−1; HRMS calcd for C16H23N2O+ [M + H+]259.1810, found
259.1807.
(5R,5′R,6S,6′S,14R,14′R,16R,16′R)-1′-Benzyl-N,N,16,16′-tetra-
methyl-11-(trimethylsilyl)-1′,2,2′,3,3′,4,4′,5,5′,6,6′,7,7′,15′,16,16′,-
17,17′-octadecahydro[10,10′-bi(5,10b-propano1,7-phenanthro-
line)]-1(15H)carboxamide (96). Following the above procedure:
[α]23.0 +27.4 (c 0.73, CH2Cl2); Rf = 0.40 (silica gel, hexanes/
D
2-((4aR,5R,7S,8aS)-8a-Ethynyl-7-methyl-1-picolinoyldecahydro-
quinolin-5-yl)acetonitrile (93). To a solution of 86 (15 mg, 69 μmol,
1.0 equiv) in THF (3 mL) were added pyridine (17 μL, 0.21 mmol,
3.0 equiv) and acid chloride int-21 (19 μL, 0.14 mmol, 2.0 equiv), and
the solution was placed in a 50 °C oil bath. After 3 h, the solution was
diluted with saturated NH4Cl solution (10 mL) and extracted with
EtOAc (3 × 10 mL). The combined organic extracts were washed with
brine (10 mL), dried over Na2SO4, filtered, and concentrated to afford
EtOAc = 5/1); 1H NMR (400 MHz, CDCl3) δ 0.12 (s, 9H), 0.78 (d, J
= 5.6 Hz, 3H), 0.80 (d, J = 5.6 Hz, 3H), 0.83−0.88 (m, 1H), 0.96 (d, J
= 6.4 Hz, 1H), 1.18−1.59 (m, 13H), 1.71−1.79 (m, 2H), 1.92−2.01
(m, 2H), 2.13 (brs, 2H), 2.39−2.43 (m, 1H), 2.53−2.55 (m, 2H), 2.76
(t, J = 18.8 Hz, 2H), 2.92−3.10 (m, 8H), 3.16−3.29 (m, 2H), 4.11 (d,
J = 14.4 Hz, 1H), 4.25 (d, J = 14.4 Hz, 1H), 7.25−7.27 (m, 1H),
7..34−7.38 (m, 3H), 7.50 (d, J = 7.2 Hz, 2H), 8.14−8.17 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 0.26, 14.1, 21.3, 22.3, 22.4, 25.3, 26.0,
26.5, 26.8, 27.2, 31.6, 34.1, 34.2, 34.7, 35.25, 35.30, 38.8, 43.0, 43.6,
43.9, 45.5, 46.0, 46.2, 48.1, 51.1, 60.3, 61.8, 121.1, 126.5, 128.0, 128.2,
133.6, 133.9, 135.1, 136.4, 141.2, 142.6, 156.9, 157.4, 157.6, 163.5,
164.0; IR ν 3446, 2918, 1652, 732 cm−1; HRMS calcd for
C45H62N5OSi+ [M + H+] 716.4724, found 716.4727.
amide 93 (11 mg, 49%) as a yellow oil: [α]23.0 −11.4 (c 0.35,
D
CH2Cl2); Rf = 0.38 (silica gel, hexanes/EtOAc = 1/1); 1H NMR (400
MHz, CDCl3) δ 1.00 (d, J = 6.4 Hz, 3H), 1.35 (dt, J = 5.2 and 13.2 Hz,
1H), 1.41 (t, J = 13.2 Hz, 1H), 1.59−1.63 (m, 1H), 1.70−1.87 (m,
3H), 1.94−2.09 (m, 3H), 2.20−2.24 (m, 1H), 2.59 (s, 1H), 2.69 (ddd,
J = 0.8, 4.0, and 17.2 Hz, 1H), 2.99 (dd, J = 12.0 and 17.2 Hz, 1H),
3.22−3.29 (m, 1H), 3.50 (dt, J = 2.4 and 12.8 Hz, 1H), 3.61−3.66 (m,
1H), 7.34 (ddd, J = 1.2, 4.8, and 8.8 Hz, 1H), 7.69 (dt, J = 1.2 and 7.6
Hz, 1H), 7.79 (dt, J = 2.0 and 7.6 Hz, 1H), 8.59 (dq, J = 1.2, and 5.2
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 17.3, 21.9, 24.6, 24.7, 25.7,
37.5, 38.0, 44.1, 45.2, 46.4, 58.2, 75.7, 84.2, 120.3, 124.1, 124.9, 137.2,
148.6, 155.0, 171.5; IR ν 2926, 1650, 1384 cm−1; HRMS calcd for
C20H24N3O+ [M + H+] 322.1919, found 322.1915.
(5R,5′R,6S,6′S,14R,14′R,16R,16′R)-1-Benzyl-16,16′-dimethyl-10′-
(trimethylsilyl)-1,2,2′,3,3′,4,4′,5,5′,6,6′,7,7′,15,16,16′,17,17′-
octadecahydro[10,11′-bi(5,10b-propano1,7-phenanthroline)]-
1′(15′H)-carbaldehyde (97). In a pressure tube, pyridylalkyne 61
(15.6 mg, 36 μmol, 1.0 equiv), alkyne−nitrile 86 (12.9 mg, 52 μmol,
1.4 equiv), and triphenylphosphine (79 mg, 0.30 mmol, 8.4 equiv)
were dissolved in freshly degassed dioxane (8 mL). Neat CpCo(CO)2
(10 μL, 80 μmol, 2.2 equiv) was added, and the tube was sealed. The
resulting solution was placed in a 140 °C oil bath. After 24 h, the
reaction was cooled to 23 °C and concentrated. The crude material
was purified by silica gel chromatography (20/1 → 2/1 hexanes/
EtOAc) to afford bipyridyls 97 (10.2 mg, 42%) and 98 (3.4 mg, 14%)
2-((4aR,5R,7S,8aS)-8a-Ethynyl-7-methyl-1-(2,2,2-trifluoroacetyl)-
decahydroquinolin-5-yl)acetonitrile (94). To a solution of 86 (50
mg, 0.23 mmol, 1.0 equiv) in CH2Cl2 (3 mL) were added trifloroacetic
anhydride (64 μL, 0.46 mmol, 2.0 equiv) and triethylamine (0.097 mL,
0.69 mmol, 3.0 equiv) at 23 °C. After 30 min, the solution was diluted
with saturated NH4Cl solution (10 mL) and extracted with EtOAc (3
× 10 mL). The combined organic extracts were washed with brine (10
mL), dried over Na2SO4, filtered, and concentrated to afford amide 94
both as yellow oils: [α]24 +26.6° (c 0.50, CH2Cl2); Rf = 0.35 (silica
D
1
gel, hexanes/EtOAc = 2/1); H NMR (400 MHz, CDCl3) δ 0.12 (s,
9H), 0.74 (d, J = 6.0 Hz, 3H), 0.90 (d, J = 6.0 Hz, 3H), 1.15−1.18 (m,
1H), 1.24−1.32 (m, 4H), 1.35−1.69 (m, 10H), 1.74−1.84 (m, 4H),
1.93−1.96 (m, 2H), 2.05 (s, 1H), 2.11−2.15 (m, 1H), 2.21−2.32 (m,
1H), 2.52−2.54 (m, 1H), 2.76 (d, J = 40.0 Hz, 1H), 2.82 (d, J = 40.4
Hz, 1H), 3.20−3.31 (m, 2H), 4.18 (dd, J = 13.6 and 54.8 Hz, 2H),
4.55−4.59 (m, 1H), 7.36 (t, J = 7.2 Hz, 2H), 7.46−7.53 (m, 2H), 7.59
(s, 1H), 7.55−7.70 (m, 1H), 7.80 (d, J = 8.0 Hz, 1H), 8.23 (d, J = 8.0
Hz, 1H), 8.72 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 0.8, 21.2, 22.2,
22.3, 25.4, 25.8, 26.5, 26.7, 27.2, 33.6, 34.0, 35.0, 35.1, 37.2, 38.6, 42.8,
43.8, 44.2, 45.8, 46.5, 48.1, 51.0, 60.4, 61.8, 121.0, 126.5, 128.0, 128.2,
128.5, 131.4, 131.9, 135.3, 137.9, 140.6, 142.3, 156.4, 157.3, 160.5,
161.3; IR ν 1653, 1386, 838 cm−1; HRMS calcd for C43H57N4OSi+ [M
+ H+] 673.43016, found 673.43002.
(23 mg, 32%) as a white foam: [α]23.0 +58.0 (c 0.50, CH2Cl2); Rf =
D
0.55 (silica gel, hexanes/EtOAc = 4/1); 1H NMR (400 MHz, CDCl3)
δ 1.00 (d, J = 6.4 Hz, 3H), 1.28−1.42 (m, 2H), 1.58−1.66 (m, 1H),
1.69−1.77 (m, 1H), 1.81−2.00 (m, 5H), 2.18−2.24 (m, 1H), 2.61 (s,
1H), 2.67 (ddd, J = 1.2, 4.0, and 16.8 Hz, 1H), 2.92 (dd, J = 12.0 and
16.8 Hz, 1H), 3.25 (dt, J = 2.8 and 13.2 Hz, 1H), 3.47−3.54 (m, 1H),
3.65−3.71 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 17.2, 21.8, 24.0,
24.5, 24.7, 37.2, 37.8, 42.80, 42.84, 43.9, 44.4, 60.1, 82.8, 116.4 (t, J =
288.7 Hz), 119.9, 157.0 (t, J = 34.9 Hz); IR ν 3265, 2956, 1689, 1184
+
cm−1; HRMS calcd for C16H20N2OF3 [M + H+]313.1528, found
313.1523.
(5R,5′R,6S,6′S,14R,14′R,16R,16′R)-1-Benzyl-N,N,16,16′-tetra-
methyl-10′-(trimethylsilyl)-1,2,2′,3,3′,4,4′,5,5′,6,6′,7,7′,15,16,-
16′,17,17′-octadecahydro[10,11′-bi(5,10bpropano-1,7-phenan-
throline)]-1′(15′H)carboxamide (95). In a pressure tube, alkyne−
nitrile 91 (11 mg, 38 μmol, 1.4 equiv) and pyridylalkyne 61 (12 mg,
28 μmol, 1.0 equiv) were dissolved in degassed THF (2.5 mL). Neat
CpCo(CO)2 (5 μL, 41 μmol, 1.7 equiv) and triphenylphosphine (44
mg, 0.17 mmol, 6.0 equiv) were added, and the tube was sealed. The
resulting solution was placed in an oil bath heated to 140 °C for 24 h.
The mixture was cooled and the solvent was removed. The product
was purified by silica gel chromatography (20/1 to 2/1 hexanes/
EtOAc) to afford bipyridyl 95 (4.5 mg, 22%) and bipyridyl 96 (4.1 mg,
(5R,5′R,6S,6′S,14R,14′R,16R,16′R)-1′-Benzyl-16,16′-dimethyl-11-
(trimethylsilyl)-1′,2,2′,3,3′,4,4′,5,5′,6,6′,7,7′,15′,16,16′,17,17′-
octadecahydro[10,10′-bi(5,10bpropano-1,7phenanthroline)]-1-
(15H)-carbaldehyde (98). Following the above procedure: [α]24
D
+35.2 (c 0.40, CH2Cl2); Rf = 0.28 (silica gel, hexanes/EtOAc = 2/1);
1H NMR (400 MHz, CDCl3) δ 0.09 (s, 9H), 0.79 (d, J = 6.4 Hz, 3H),
0.89 (d, J = 6.4 Hz, 3H), 1.18−1.65 (m, 11H), 1.71−1.87 (m, 5H),
1.93−1.98 (m, 2H), 2.13−2.16 (m, 1H), 2.22−2.24 (m, 1H), 2.29−
2.42 (m, 2H), 2.51−2.55 (m, 2H), 2.73 (d, J = 18.8 Hz, 1H), 2.87 (d, J
= 18.8 Hz, 1H), 2.96−3.12 (m, 1H), 3.21−3.29 (m, 2H), 4.18 (dd, J =
14.4 and 64.8 Hz, 2H), 4.50−4.54 (m, 1H), 7.19 (d, J = 8.0 Hz, 1H),
7.23−7.27 (m, 1H), 7.34−7.38 (m, 3H), 7.49 (d, J = 7.6 Hz, 2H), 8.18
(d, J = 8.0 Hz, 1H), 8.66 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
−0.1, 0.8, 21.1, 22.2, 22.4, 25.4, 25.8, 26.5, 26.6, 27.2, 33.7, 34.1, 34.9,
35.3, 37.3, 38.5, 42.8, 43.8, 44.2, 45.9, 46.4, 48.2, 50.9, 60.3, 62.0,
121.6, 126.5, 128.0, 128.2, 131.0, 131.4, 135.1, 137.2, 142.1, 142.4,
20%) both yellow oils: [α]23.0 +62.2 (c 0.45, CH2Cl2); Rf = 0.50
D
1
(silica gel, hexanes/EtOAc = 5/1); H NMR (400 MHz, CDCl3) δ
0.14 (s, 9H), 0.74 (d, J = 5.6 Hz, 3H), 0.79 (d, J = 5.6 Hz, 3H), 1.15−
1.61 (m, 11 H), 1.72−2.05 (m, 8 H), 2.12 (brs, 2H), 2.21−2.25 (m,
T
dx.doi.org/10.1021/jo400695c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
155.9, 156.6, 157.9, 160.6, 164.8; IR ν 1657, 1652, 1386, 839, 733
cm−1; HRMS calcd for C43H57N4OSi+ [M + H+] 673.43016, found
673.43030.
Notes
The authors declare no competing financial interest.
(5R,5′R,6S,6′S,14R,14′R,16R,16′R)-1-Benzyl-16,16′-dimethyl-
1,2,2′,3,3′,4,4′,5,5′,6,6′,7,7′,15,16,16′,17,17′-octadecahydro[10,11′-
bi(5,10b-propano1,7-phenanthroline)]-1′(15′H)-carbaldehyde (99).
To a solution of bipyridyl 97 (36 mg, 0.053 mmol, 1.0 equiv) in
dioxane (1 mL) was added TBAF solution (1.0 M in THF, 200 μL,
0.20 mmol, 3.8 equiv), and the mixture was placed in a 101 °C oil
bath. After 10 h, the solution was cooled to 23 °C, diluted with
saturated NH4Cl solution (10 mL), and extracted with EtOAc (3 × 10
mL). The combined organic extracts were washed with brine (5 mL),
dried over Na2SO4, filtered, and concentrated. The crude material was
purified by silica gel chromatography (20/1 → 1/1 hexanes/EtOAc)
to afford amine 99 (32.0 mg, 98%) as a dark yellow oil: [α]24D +35.1 (c
0.40, CH2Cl2); Rf = 0.22 (silica gel, hexanes/EtOAc = 1/1); 1H NMR
(400 MHz, CDCl3) δ 0.69 (d, J = 6.0 Hz, 3H), 0.82 (d, J = 6.4 Hz,
3H), 1.09−1.38 (m, 6H), 1.43−1.80 (m, 12H), 1.88 (td, J = 3.6 and
12.8 Hz, 1H), 1.97−2.09 (m, 2H), 2.17−2.27 (m, 2H), 2.41−2.45 (m,
2H), 2.72 (dd, J = 19.2 and 30.8 Hz, 2H), 3.18−3.27 (m, 2H), 4.11
(dd, J = 14.8 and 68.0 Hz, 2H), 4.48−4.52 (m, 1H), 7.18−7.20 (m,
1H), 7.27−7.31 (m, 2H), 7.41−7.45 (m, 3H), 7.83 (d, J = 2.4 Hz,
1H), 8.15 (d, J = 12.0 Hz, 1H), 8.68 (s, 1H), 8.89 (d, J = 2.4 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 21.0, 22.1, 22.4, 25.4, 25.9, 26.5, 26.7,
ACKNOWLEDGMENTS
■
We are grateful for the financial support of the Welch
Foundation (F-1694), the Texas Institute for Drug and
Diagnostic Development (H-F-0032), and The University of
Texas at Austin. Wealso thank Prof. Richmond Sarpong at the
University of California, Berkeley, and Prof. Carlos Saa at the
́
Universidad de Santiago de Compostela for helpful discussions.
REFERENCES
■
(1) Tobias, C. A.; Shumsky, J. S.; Shibata, M.; Tuszynski, M. H.;
Fischer, I.; Tessler, A.; Murray, M. Exp. Neurol. 2003, 184, 97.
(2) Tuszynski, M. H. Expert Opin. Biol. Ther. 2003, 3, 815.
(3) Gros, T.; Sakamoto, J. S.; Blesch, A.; Havton, L. A.; Tuszynski, M.
H. Biomaterials 2010, 31, 6719.
(4) Kordower, J. H.; Emborg, M. E.; Bloch, J.; Ma, S. Y.; Chu, Y.;
Leventhal, L.; McBride, J.; Chen, E. Y.; Palfi, S.; Roitberg, B. Z.;
Brown, W. D.; Holden, J. E.; Pyzalski, R.; Taylor, M. D.; Carvey, P.;
Ling, Z.; Trono, D.; Hantraye, P.; Deglon, N.; Aebischer, P. Science
2000, 290, 767.
(5) Mattson, M. P. Brain Res. 2000, 886, 47.
27.1, 33.5, 34.0, 34.9, 35.5, 37.5, 38.5, 42.8, 43.7, 44.1, 45.8, 46.3, 48.2,
50.9, 60.4, 61.9, 118.9, 126.5, 128.0, 128.2, 131.5, 133.4, 134.4, 135.4,
137.7, 142.3, 146.7, 151.7, 157.8, 159.3, 160.5; IR ν 1653, 1443, 1385,
733 cm−1; HRMS calcd for C40H49N4O+ [M + H+] 601.39064, found
601.39037.
(6) Tuszynski, M. H. Lancet Neurol. 2002, 1, 51.
(7) Taylor, L.; Jones, L.; Tuszynski, M. H.; Blesch, A. J. Neurosci.
2006, 26, 9713.
(8) Tuszynski, M. H.; Grill, R.; Jones, L. L.; Brant, A.; Blesch, A.;
Low, K.; Lacroix, S.; Lu, P. Exp. Neurol. 2003, 181, 47.
(9) Thomas, C. E.; Ehrhardt, A.; Kay, M. A. Nat. Rev. Genet. 2003, 4,
346.
(10) Wilson, R. M.; Danishefsky, S. J. Acc. Chem. Res. 2006, 39, 539.
(11) Kobayashi, J.; Hirasawa, Y.; Yoshida, N.; Morita, H. Tetrahedron
Lett. 2000, 41, 9069.
(12) Morita, H.; Ishiuchi, K.; Haganuma, A.; Hoshino, T.; Obara, Y.;
Nakahata, N.; Kobayashi, J. Tetrahedron 2005, 61, 1955.
(13) Ishiuchi, K.; Kubota, T.; Mikami, Y.; Obara, Y.; Nakahata, N.;
Kobayashi, J. Bioorg. Med. Chem. 2007, 15, 413.
(14) Yuan, C.; Chang, C. T.; Axelrod, A.; Siegel, D. J. Am. Chem. Soc.
2010, 132, 5924.
(15) Fischer, D. F.; Sarpong, R. J. Am. Chem. Soc. 2010, 132, 5926.
(16) Zhao, L.; Tsukano, C.; Kwon, E.; Takemoto, Y.; Hirama, M.
Angew. Chem., Int. Ed. 2013, 52, 1722.
(17) Newton, J. N.; Fischer, D. F.; Sarpong, R. Angew. Chem., Int. Ed.
2013, 52, 1726.
(18) Reusch, W.; Johnson, C. K. J. Org. Chem. 1963, 28, 2557.
(19) Caine, D.; Procter, K.; Cassell, R. A. J. Org. Chem. 1984, 49,
2647.
(20) Mutti, S.; Daubie, C.; Decalogne, F.; Fournier, R.; Rossi, P.
Tetrahedron Lett. 1996, 37, 3125.
(5R,5′R,6S,6′S,14R,14′R,16R,16′R)-16,16′-dimethyl-1,2,2′,3,3′,-
4,4′,5,5′,6,6′,7,7′,15,16,16′,17,17′-octadecahydro[10,11′-bi(5,10b-
propano1,7-phenanthroline)]-1′(15′H)carbaldehyde (100). To a
solution of amine 99 (35 mg, 0.058 mmol, 1.0 equiv) in methanol
(1 mL) was added solid 5% palladium on carbon (20 mg), and then
the solution was rapidly stirred under H2 (1 atm) at 23 °C. After 8 h,
the solution was filtered through a Celite pad and concentrated to
afford formamide 100 (22.6 mg, 78%) as pale brown oil: [α]24D +25.2
(c 0.40, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 0.81 (d, J = 6.4 Hz,
3H), 0.90 (d, J = 6.4 Hz, 3H), 1.24−1.45 (m, 7H), 1.53−1.57 (m,
1H), 1.62−1.70 (m, 6H), 1.78−1.86 (m, 4H), 2.04−2.09 (m, 2H),
2.24−2.31(m, 3H), 2.66−2.73 (m, 1H), 2.80−2.86 (m, 2H), 3.10−
3.34 (m, 3H), 4.57 (d, J = 5.6 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.93
(s, 1H), 8.28 (bs, 1H), 8.74 (s, 1H), 8.93 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 21.5, 22.1, 24.6, 25.4, 25.9 (two peaks very close),
26.7, 32.9, 33.4, 34.9, 35.0, 37.5, 40.7, 41.4, 42.5, 42.7, 44.1, 44.4, 46.3,
47.4, 60.7, 61.9, 119.3, 131.6, 133.7, 134.7, 146.6, 153.4, 158.6, 158.8,
160.5, 170.0, 188.6; IR ν 3419, 1652, 1575, 1262, 910, 731 cm−1;
HRMS calcd for C33H43N4O+ [M + H+] 511.34369, found 511.34377.
Optical Rotation Data. We have found the optical rotation of
complanadine A changes as the molecule transitions from the free base
form to protonated forms.
Effects of acid addition on rotation:
(21) Krause, N. Angew. Chem., Int. Ed. Engl. 1994, 33, 1764.
(22) Krause, N.; Ebert, S.; Haubrich, A. Liebigs Ann. Chem. 1997,
2409.
(23) Krause, N.; Mackenstedt, M. Tetrahedron Lett. 1998, 39, 9649.
(24) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Marcantoni, E.; Massaccesi,
M.; Rinaldi, S.; Sambri, L. Synlett 2003, 39.
−19.0° complanadine A free base
−9.5° complanadine A free base with 2 equiv of TFA
−4.7° complanadine A free base with 4 equiv of TFA
+2.4° complanadine A free base with 6 equiv of TFA
and +10.5° complanadine A free base with 6 equiv of HCl
(25) Imada, Y.; Yuasa, M.; Nakamura, I.; Murahashi, S. J. Org. Chem.
1994, 59, 2282.
(26) Song, Y. C.; Okamoto, S.; Sato, F. Tetrahedron Lett. 2002, 43,
8635.
(27) Takahashi, M.; Micalizio, G. C. J. Am. Chem. Soc. 2007, 129,
7514.
(28) Varela, J. A.; Castedo, L.; Saa, C. J. Org. Chem. 1997, 62, 4189.
(29) Varela, J. A.; Castedo, L.; Saa, C. J. Am. Chem. Soc. 1998, 120,
12147.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, spectroscopic data, and NMR spectra
for new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(30) Varela, J. A.; Saa, C. Chem. Rev. 2003, 103, 3787.
(31) Saa, C.; Crotts, D. D.; Hsu, G.; Vollhardt, K. P. C. Synlett 1994,
487.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dsiegel@cm.utexas.edu.
(32) Chopade, P. R.; Louie, J. Adv. Synth. Catal. 2006, 348, 2307.
U
dx.doi.org/10.1021/jo400695c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(33) Gray, B. L.; Wang, X.; Brown, W. C.; Kuai, L.; Schreiber, S. L.
Org. Lett. 2008, 10, 2621.
(34) Kleinman, E.; Heathcock, C. H. Tetrahedron Lett. 1979, 4125.
(35) Heathcock, C. H.; Kleinman, E. F.; Binkley, E. S. J. Am. Chem.
Soc. 1982, 104, 1054.
(36) Tsukano, C.; Zhao, L.; Takemoto, Y.; Hirama, M. Eur. J. Org.
Chem. 2010, 4198.
(37) See the Supporting Information.
(38) See the Supporting Information for a list of alkynes.
(39) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(40) Muller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996,
521.
V
dx.doi.org/10.1021/jo400695c | J. Org. Chem. XXXX, XXX, XXX−XXX