Divergent Stereocontrolled Synthesis of the Enantiopure Tetracyclic Cores of Asparagamine A and Stemofoline via an Intramolecular 2-Propylidine-1,3-(bis)silane Bicyclization

Article abstract of DOI:10.1021/acs.joc.5b01625

A concise and highly diastereoselective synthesis of the polyfused tetracyclic cores of the Stemona alkaloids asparagamine A and stemofoline that relies on a 2-propylidine-1,3-(bis)silane bicyclization onto a enantiodefined pyrrolidine 2,5-di(cation) equivalent derived from l-malic acid is reported. A crucial feature of this divergent synthetic approach involves the solvolysis of a transient and highly labile tertiary-propargylic hydroxylactam trifluoroacetate in the strongly ionizing medium 5 M LiClO₄/Et₂O. The acyliminium ion generated in this manner undergoes stereospecific interception by the aforementioned (bis)silane nucleophile.

Full text of DOI:10.1021/acs.joc.5b01625

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pubs.acs.org/joc
Divergent Stereocontrolled Synthesis of the Enantiopure Tetracyclic
Cores of Asparagamine A and Stemofoline via an Intramolecular
2‑Propylidine-1,3-(bis)silane Bicyclization
Bryon K. Anderson and Tom Livinghouse*
Department of Chemistry and Biochemistry, Montana State University, Bozeman, Montana 59717, United States
*
S Supporting Information
ABSTRACT: A concise and highly diastereoselective synthesis of the polyfused tetracyclic cores of the Stemona alkaloids
asparagamine A and stemofoline that relies on a 2-propylidine-1,3-(bis)silane bicyclization onto a enantiodefined pyrrolidine
2,5-di(cation) equivalent derived from L-malic acid is reported. A crucial feature of this divergent synthetic approach involves the
solvolysis of a transient and highly labile tertiary-propargylic hydroxylactam trifluoroacetate in the strongly ionizing medium 5 M
LiClO /Et O. The acyliminium ion generated in this manner undergoes stereospecific interception by the aforementioned
4
2
(
bis)silane nucleophile.
INTRODUCTION
available by a sequential 2-propylidene-1,3-bis(silane) bicycliza-
tion onto an enantiodefined pyrrolidine 2,5-di(cation) equivalent
derived from imide 6, which would ultimately emanate from
amine 3 and L-malic acid (2) (Scheme 1).
■
In 1970, Irie and co-workers isolated a unique alkaloid,
stemofoline (1a), from the plant Stemona japonica and acquired1
structure information from X-ray crystallography examination.
The closely related Stemona alkaloid, asparagamine A (1b), was
isolated from the roots of Asparagus racemosus and completely
Scheme 1. Retrosynthetic Strategy
2
characterized in 1994. Biological studies on these closely
related alkaloids have revealed notable insecticidal properties
when administered orally to the larvae of various crop pests,
3a−c
such as the diamondback moth.
Additionally, asparagamine
A was found to possess antitumor and antioxytocin biological
4
activity in vitro. Subsequent to their discovery, 1a and 1b
have been the topic of several synthetic endeavors, with three
5a−c
culminating in completed syntheses
tetracyclic core substructures present in these alkaloids.
We have previously demonstrated the utility of 2-propylidene-
,3-bis(silane)-terminated cyclizations involving iminium cati-
and four leading to
6
a−d
1
ons for the stereocontrolled synthesis of isotropanes, including
7
a simple azatricycle similar to that found in 1a and 1b. In this
paper, we report the application of this protocol to a concise
and divergent assembly of the enantiopure tetracyclic cores
found in both stemofoline (1a) and asparagamine A (1b). We
envisaged that the saturated and unsaturated core elements 16a
and 16b, respectively, could be transformed into more advanced
intermediates via alkylation of the corresponding nonbridgehead
ketone enolates in a manner reminiscent of previous syn-
theses. Intermediates 16a and 16b, in turn, could converge on
the acetylenic lactol 15 by complete or partial reduction,
respectively, with the latter mapping nicely onto the enyne 11 by
way of inversion of the oxygen-bearing stereocenter and oxidative
alkene cleavage. Enyne 11 was expected to be synthetically
RESULTS AND DISCUSSION
The synthetic plan outlined above was implemented in the
following manner. Sequential treatment of anhydride 4, which
is conveniently prepared from L-malic acid (2), with amine 3
followed by AcCl and subsequent acetate cleavage (HCl−EtOH,
Received: July 14, 2015
■
8
5
a,b
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01625
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
generated in situ from AcCl), in an adaptation of the method of
Chamberlin, furnished imide 5a and ultimately 5b [TBSCl,
imidazole (94% over four steps)]. Subsequent exposure of 5b
allylsilane. Efforts to buffer the reaction medium with various
acid scavengers or molecular sieves led to no improvement in
cyclization efficiency or significant suppression of any reaction.
9
to a preformed THF solution of Zn(CH TMS) in the presence
It is also worthy of note that resubjection of 8 to 5 M LiClO −
2
2
4
of PdCl (PPh ) (7 mol %), led to efficient cross-coupling to
Et O did not result in its protodesilylation. In addition,
2
3 2
2
8
13
deliver bis(silane) 6 in 97% isolated yield (Scheme 2). Our
2-[(trimethylsilyl)methyl]-1-(trimethylsilyl)-2-propene proved
inert to this reaction medium, thereby suggesting that the
hydroxylic proton present in the precyclization substrates 7a,b
was the most likely source of the problem. To explicitly avoid
this possibility, it was ultimately found that treatment of 6 with
Scheme 2. Synthesis of Hydroxylactams 7a and 7b
1
-lithiobutyne (1.2 equiv) in 5 M LiClO −Et O (0 °C → rt)
4
2
followed by alkoxide interception with TFAA gave 8 directly and
without competing protodesilylation in 50% yield as a single
diastereomer (Scheme 3).
Scheme 3. Acyliminium Ion−Allylsilane Cyclization
Protocol
original plans entailed the treatment of 6 with 1-lithiobutyne to
give the corresponding hydroxylactams 7a and/or 7b that would
then be subjected to an “acyliminium ion−allylsilane” cycliza-
10a−d
tion protocol.
Accordingly, addition of 6 to 1-lithiobutyne
(
3 equiv) in THF (−78 °C → −30 °C) provided 7a admixed
with 7b (7a/7b = 85:15), which were readily separated by
chromatography, in 85% combined yield. The chemoselectivity
of addition is in accord with the documented propensity of
preferential nucleophilic attack at the “inductively activated”
Conclusive evidence for the relative stereochemistry of
pyrrolizidine 8 was ultimately obtained by the successful
realization of the subsequent iminium ion−allylsilane cycliza-
tion (vide infra). The observed stereochemistry of ring closure
is also in accord with the prior results of Speckamp and
Hiemstra. By virtue of substrate-directed stereocontrol, the
7,11
carbonyl function in related cyclic imides.
treatment of 6 with the corresponding dichloroceriumacetylide
3 equiv, THF, −78 °C → −30 °C) gave 7b as the predominant
Interestingly,
(
2
-(propylidine)-1,3-bis(silane) terminator is directed in an anti
product (90%, NMR). Although we have yet to firmly establish
that the latter is a result of kinetic control, it is noteworthy that
treatment of 7b with n-BuLi (1 equiv, −78 °C → −30 °C) led to
its equilibration to a mixture of both diastereomers (7a:7b =
orientation relative to the sterically demanding TBSO group.
The stereospecificity of the terminating allylsilane can be rationa-
lized by stereoelectronic factors inherent in the intermediate
14
π-complex configurations. Specifically, the relative stability of
3
5:65). In addition, subjection of 7a to dichloroceriumacetylide
the two relevant π-complex configurations can be accessed by
comparing the steric interactions expected in the competing
chair- or boatlike transition states. In this context, the chairlike
conformation would be preferred due to minimization of
eclipsing interactions that would develop in the boatlike
(
1 equiv, THF, −78 °C → 0 °C) followed by quenching with
saturated aqueous NH Cl resulted in no equilibration. The
4
latter result is consistent with the enhanced rigidity expected for
a Ce−O bond compared to coordination by simple alkali cation.
Cyclization Studies. Attempts to effect the desilylative
cyclization of the hydroxylactams 7a and 7b under a wide
variety of conventional ionizing conditions involving Brønsted
or Lewis acids led, not surprisingly, to extensive protodesily-
lation of the 2-propylidene-1,3-bis(silane) assembly present in
these precursors. In a series of seminal contributions, Grieco
15
alternative (Figure 1).
Elaboration of the Tetracyclic Core. Our attention was
now directed toward the closure of the azatricyclic core
and co-workers have shown that anhydrous 5 M LiClO in
4
Et O (5 M LPDE) is a remarkable medium for accelerating
2
12a−e
organic reactions.
We were therefore encouraged that
simple dissolution of 7a,b in 5 M LiClO −Et O provided 8
4
2
(
(
28% isolated yield) [admixed with the azabicyclic byproduct 9
8%) plus several unidentified products]. The observed
formation of 1-azabicyclo[5.3.0]decane 9 was believed to
arise from an initial monoprotodesilylation event followed by
a classical acyliminium ion cyclization of the resultant pendant
Figure 1. Transition-state analysis.
B
DOI: 10.1021/acs.joc.5b01625
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common to stemofoline and asparagamine A via an iminium
ion−allylsilane cyclization. Apropos of this strategy, the seminal
investigations of Stork regarding the utility of α-cyanoamines as
iminium ion equivalents were considered most relevant.
Recent examples that have been reported for the conversion of
the doublet-of-doublets signal produced by the diastereotopic
hydrogen opposite to the inverted alcohol was shifted down-
field in comparison to the corresponding exo isomer, resulting
from the disposition of this diastereotopic hydrogen in the
deshielding zone of the alkyne. Subsequent single-crystal
X-ray analysis confirmed this structural assignment (Figure 2
and Supporting Information).
16
21
lactams to the corresponding α-cyanoamines include prelimi-
1
7
nary reduction using LiAlH(OEt) followed by KCN/AcOH
3
18
or n-BuLi·DIBAL-H followed by TMSCN. In our hands, the
use of the former reducing reagent proved most unsatisfactory,
while n-BuLi·DIBAL-H exhibited some promise. Recently, it
has been shown that a wide variety of tertiary amides can be
partially reduced in near-quantitative yields (89−99%) using
alkoxy variants of the DIBAL−ate complexes. This proved to
be the case in the present instance wherein partial reduction of
with LiAlH(i-Bu) (i-OPr) (LDBIPA) followed by imme-
19
19
8
2
diate treatment with TMSCN provided cyanoamines 10 in 82%
isolated yield. It should be noted that preliminary cyanoamine
generation was a prerequisite for successful closure to 11.
Subsequent exposure of 10 to AgBF (1.1 equiv, THF, 22 °C)
4
induced the desired iminium ion−allylsilane cyclization to
20
furnish azatricycle 11 in excellent (88%) yield (Scheme 4).
Scheme 4. Allylsilane Termination To Form the
Azatricyclodecane Core
Figure 2. X-ray crystal structure of azatricycle 14 (ORTEP ellipsoids
are depicted at the 50% level).
It should be noted that the alternative approach involving a
Mitsunobu inversion was not attempted due to the secondary
neopentyl-like site of prospective nucleophilic attack.
Oxidative cleavage of the pendant methylene substituent
present in 14 was most expeditiously achieved by selective
ozonolysis of the corresponding TFA salt 14·TFA (−78 °C)
followed by reductive workup using Ph P, to afford the
3
hemiketal salt 15·TFA in excellent (84%) yield. Subjection
of 15·TFA to hydrogenation (H , Pd/C, cat.) efficiently
2
provided the tetracyclic stemofoline core element 16a·TFA
in 78% isolated yield. Alternatively, O-silylation of 15·TFA
The construction of the alkyne-bearing azatetracyclic core
element was achieved in the following manner. Stereochemical
inversion at the oxygen-bearing center was readily accom-
plished by sequential hydroxyl deprotection (HF, MeCN),
oxidation (Dess−Martin periodinane), and stereospecific
(
N,O-bis(trimethylsilyl)trifluoroacetamide, BSTFA) followed
by direct reduction (Na/NH ) secured the asparaga-
3
mine A based lactol 16b as the free amine in 55% yield
19
(
Scheme 6). Direct reduction of 15·TFA resulted in inferior
carbonyl reduction (LDBIPA) to furnish the azatricyclic
intermediate 14 in 83% overall yield (Scheme 5).
yields of 16b.
Firm evidence for the desired inversion of hydroxyl
configuration was revealed in the H NMR spectrum wherein
1
Scheme 6. Completion of the Azatricyclic Cores
Scheme 5. Stereochemical Modification Sequence
C
DOI: 10.1021/acs.joc.5b01625
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The Journal of Organic Chemistry
Featured Article
The reaction mixture was then diluted with hexanes (25 mL) and
vigorously stirred for 5 min. The supernatant was decanted and filtered
over Celite to provide a crude off-white solid. The solid precipitate
from the reaction was reworked four times by redissolving in
dichloromethane and diluting with hexanes (4 × 25 mL). The crude
CONCLUSION
■
1
In conclusion, a stereocontrolled intramolecular 2-propylidine-
,3-(bis)silane cyclization cascade has been successfully utilized
in a divergent synthetic route to the enantiopure tetracyclic
core elements of stemofoline (1a) and asparagamine A (1b).
Among the most salient features of the present synthetic
strategy are the ability of the 2-propylidine-1,3-(bis)silane
binary nucleophile to engage an incipient tertiary propargylic
acyliminium ion with excellent stereoselectivity and without
concomitant protodesilylation. A subsequent intramolecular
allylsilane−iminium ion cyclization involving an α-cyanoamine
completed the construction of the skeletal core common to the
aforementioned alkaloids. The chiral 2,5-pyrrolidine dication
equivalent that serves as a template for these transformations is
conveniently prepared from L-malic acid (2).
product was then redissolved in CH Cl (40 mL) and treated with
2 2
25
oxalyl chloride (0.85 mL, 9.8 mmol, 2.0 equiv) at 0 °C with stirring.
After 1 h at 22 °C, the reaction mixture was quenched by slow
addition of saturated NaHCO (40 mL) and diluted with hexanes
3
(
30 mL). The organic phase was dried over MgSO , filtered, and
4
concentrated to provide the title compound as a white solid (1.07 g,
1
6
(
7
1%): mp = 115−117 °C; H NMR (300 MHz, chloroform-d) δ 7.87
dd, J = 5.5, 3.1 Hz, 2H), 7.74 (dd, J = 5.5, 3.1 Hz, 2H), 6.46 (t, J =
.3 Hz, 1H), 3.81 (t, J = 6.9 Hz, 2H), 2.51 (q, J = 6.9 Hz, 2H); C
13
NMR (75 MHz, CDCl ) δ 168.2, 134.5, 134.1, 132.0, 123.4, 91.7, 35.6,
3
32.4; IR (film) 3101, 3027, 2942, 2362, 2337, 1767, 1697, 1396, 1364,
−1
1242, 1132, 1043, 988, 873, 747, 718, cm .
,1-Dibromo-4-amino-1-butene (3). An oven-dried 10 mL round-
1
bottom flask equipped with a magnetic stirring bar, condenser, and
nitrogen inlet was charged with 1,1-dibromo-4-phthalimido-1-butene
(4.119 g, 11.47 mmol, 1.0 equiv) in degassed absolute ethanol
(33 mL). Hydrazine monohydrate (1.21 mL, 24.1 mmol, 2.10 equiv)
was added all at once with stirring at 60 °C and held at that
temperature for 20 h or until deemed complete by GC. The
phthalhydrazide byproduct was triturated (30 mL of ethyl ether) and
filtered. The ethanol-containing filtrate was concentrated by azeotropic
distillation (benzene) to afford the compound as a yellow oil, which
could be used without further purification or distilled from calcium
hydride (63−65 °C, 1.3 mmHg) to provide a colorless liquid (1.83 g,
EXPERIMENTAL SECTION
■
Materials and Methods. Reactions employed oven- or flame-
dried glassware under nitrogen unless otherwise noted. Tetrahydrofur-
an and diethyl ether were distilled from sodium/benzophenone ketyl
under nitrogen. Dichloromethane and triethylamine were distilled
from calcium hydride under nitrogen. Dimethylformamide was
distilled from calcium hydride under reduced pressure. Isopropyl
alcohol was dried by distillation from calcium hydride after preliminary
drying from KOH pellets. ZnCl was fused under vacuum using a
2
Bunsen burner prior to use. TBSCl was purified by distillation, and
1
imidazole was recrystallized from 1:1 heptane−toluene. LiClO and
70%): H NMR (300 MHz, chloroform-d) δ 6.38 (t, J = 7.2 Hz, 1H),
4
1
3
AgBF were dried under reduced pressure (0.001 mmHg, 120 °C,
2.73 (t, J = 6.8 Hz, 2H), 2.17 (q, J = 6.8 Hz, 2H), 1.23 (s, 2H);
NMR (75 MHz, CDCl ) δ 136.4, 90.3, 40.4, 37.3. IR (film) 3438,
3312, 3017, 2861, 2924, 2340, 1563, 1475, 1430, 1383, 1317, 810
C
4
2
4 h) and handled in a drybox. All other materials were used as
3
received from commercial sources. Thin-layer chromatography (TLC)
employed 0.25 mm glass silica gel plates with UV indicator and
visualized with UV light (254 nm), potassium permanganate, or
−
1
+
cm ; HRMS (ESI-TOF) m/z [M + H] calcd for C
H Br N
7 2
4
(M + nH) 227.9018, found 227.9024.
2
,4-dinitrophenylhydrazine staining. Flash chromatographic columns
(3S)-2,5-Dioxotetrahydrofuran-3-yl acetate (4). Compound 4 wa9s
were packed with silica gel 60 as a slurry in the initial elution solvent.
Preparative Procedures. 3-Phthalimidopropionaldehyde. The
compound was prepared following an analogous procedure described
by Leete. An oven-dried 250 mL round-bottom flask equipped with a
magnetic stirring bar, condenser, and nitrogen inlet was charged with
phthalimide (15.9 g, 108 mmol, 1.00 equiv) and acrolein (6.67 mL,
prepared following analogous procedures described by Chamberlin
1
1
and Lee. An oven-dried 200 mL round-bottom flask equipped with a
magnetic stirring bar, condenser, and nitrogen inlet was charged with
L-malic acid 2 (6.70 g, 43.9 mmol) and acetyl chloride (83.84 mL).
The reaction mixture was allowed to stir at reflux for 18 h. Evaporation
of solvent under reduced pressure afforded a clear viscous residue,
which was triturated with toluene and dried by codistillation to provide
the title compound as an off-white sold. The crude anhydride was
recrystallized from benzene to furnish the pure product as a white solid
22
119 mmol, 1.10 equiv) suspended in ethyl acetate (64 mL). The
suspension was allowed to stir for 5 min at 65 °C prior to the addition
of Triton B (40% solution of benzyltrimethylammonium hydroxide in
MeOH, 362 μL, 2.17 mmol, 0.020 equiv). Reaction progress was
monitored by TLC (25% ethyl acetate in hexanes, 2,4-DNP stain).
After 15 min, or until the reaction mixture became heterogeneous,
solvents were removed, and the resulting off-white solid was triturated
20
D
1
(7.74 g, 98%): mp 56−59 °C; [α]
NMR (500 MHz, CDCl ), δ: 5.54 (dd, J = 9.6, 6.4 Hz, 1H), 3.40 (dd,
J = 18.9, 9.6 Hz, 1H), 3.04 (dd, J = 18.9, 6.4 Hz, 1H), 2.21 (s, 3H);
= −23.2 (c 1.6, CHCl ); H
3
3
13
C NMR (126 MHz, CDCl ) δ 169.8, 167.8, 166.4, 67.7, 35.4, 20.4;
3
(
30 mL ethyl ether) and filtered to afford the product as a white solid
IR (film) 3005, 2957, 2362, 2333, 1874, 1797, 1749, 1405, 1375, 1275,
1216, 1077, cm .
−1
(
20.12 g, 91%). The product was used without further purification:
1
H NMR (300 MHz, chloroform-d) δ 9.83 (s, 1H), 7.86 (dd, J = 5.5,
(S)-1-(4,4-Dibromobut-3-en-1-yl)-3-hydroxypyrrolidine-2,5-dione
(5a). An oven-dried 50 mL round-bottom flask equipped with a
magnetic stirring bar and nitrogen inlet was charged with (3S)-2,5-
dioxotetrahydrofuran-3-yl acetate 4 (0.655 g, 4.14 mmol, 1.0 equiv)
dissolved in dichloromethane (16 mL). The reaction mixture was
cooled to 0 °C prior to the dropwise addition of 1,1-dibromo-4-amino-
1-butene 3 (0.949 g, 4.14 mmol, 1.0 equiv). The solution was allowed
to stir at 22 °C for 30 min and then was treated with triethylamine
(61 μL, 0.43 mmol, 0.10 equiv). The reaction mixture was then stirred
for 1 h at 22 °C and concentrated in vacuo to provide (S)-3-acetoxy-4-
((4,4-dibromobut-3-en-1-yl)amino)-4-oxobutanoic acid as a crude
yellow oil (1.60 g, 100%). The product was used without further
purification.
An oven-dried 5 mL round-bottom flask equipped with a magnetic
stirring bar, condenser, and nitrogen inlet was charged with 3-acetoxy-
4-(4,4-dibromobut-3-enylamino)-4-oxobutanoic acid (0.462 g, 1.19 mmol,
1 equiv) and acetyl chloride (2.10 mL). The reaction mixture was
allowed to stir at reflux for 4 h or until deemed complete by TLC. The
reaction mixture was then concentrated, and the resulting dark brown
3
.1 Hz, 2H), 7.74 (dd, J = 5.5, 3.1 Hz, 2H), 4.05 (t, J = 7.0 Hz, 2H),
2
1
2
.89 (td, J = 7.0, 1.4 Hz, 2H); 13C NMR (126 MHz, CDCl ) δ 199.6,
3
68.2, 134.3, 132.2, 123.6, 42.6, 31.9; IR (film) 2946, 2850, 2739,
−1
332, 1767, 1708, 1612, 1464, 1442, 1398, 1139, 1028, 891, 714, cm .
,1-Dibromo-4-phthalimido-1-butene. The compound was pre-
1
2
3
pared following analogous procedures described by Corey and
24
Kercher. An oven-dried 100 mL round-bottom flask equipped with a
magnetic stirring bar and nitrogen inlet was charged with carbon
tetrabromide (3.264 g, 9.842 mmol, 2 equiv) and zinc dust (0.6430 g,
9
.842 mmol, 2.0 equiv) dissolved in dichloromethane (17 mL) freshly
distilled from calcium hydride. The gray reaction mixture was cooled
to 0 °C prior to the dropwise addition of triphenylphosphine (2.581 g,
9
.842 mmol, 2.0 equiv) in dichloromethane (3 mL) over 30 min. After
the resulting olive-green mixture was stirred for an additional 10 min at
°C, 3-phthalimidopropionaldehyde (1.0 g, 4.9 mmol, 1 equiv)
0
dissolved in dichloromethane (7 mL) was added over 30 min via
syringe. The dark burgundy mixture was stirred for 21.5 h at room
temperature and monitored by TLC (25% ethyl acetate in hexanes).
D
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The Journal of Organic Chemistry
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oil was purified by flash chromatography (30% ethyl acetate in
J = 7.1 Hz, 6H); 13C NMR (126 MHz, CDCl ) δ 176.6, 174.1, 134.4,
3
hexanes, R = 0.40) to provide (S)-1-(4,4-dibromobut-3-en-1-yl)-2,5-
dioxopyrrolidin-3-yl acetate as a light yellow oil. Further purification
was obtained by recrystallization from ethanol to provide a white solid
91.8, 68.0, 39.0, 36.3, 31.5, 25.8, 18.4, −4.5, −5.1; IR (film) 3483,
3028, 2954, 2932, 2884, 2858, 2710, 2359, 2340, 1790, 1712, 1628,
1475, 1435, 1402, 1350, 1254, 1162, 1102, 1036, 944, 836, 781, 692,
f
670 cm ; HRMS (ESI-TOF) m/z [M + H]+ calcd for
−1
(
0.424 g, 96%).
An oven-dried 10 mL round-bottom flask equipped with a magnetic
C H Br NO Si 441.9867, found 441.9845.
14
23
2
3
stirring bar and nitrogen inlet was charged with (S)-1-(4,4-
dibromobut-3-en-1-yl)-2,5-dioxopyrrolidin-3-yl acetate (0.260 g,
Preparation for TMSCH MgCl. A flame-dried 250 mL, three-
2
necked, round-bottomed flask equipped with a magnetic stirring bar,
addition funnel, condenser and nitrogen inlet was charged with
magnesium turnings (3.525 g, 144.5 mmol, 1.10 equiv) and THF
(62 mL), followed by 1,2-dibromoethane (0.200 mL, 2.32 mmol). The
magnesium suspension was stirred for 10 min, and chloromethyl-
trimethylsilane (18.33 mL, 131.3 mmol, 1.0 equiv) was added dropwise
over 2 h during which time exotherms resulted in a gentle reflux of the
reaction mixture. Following addition, the dark gray reaction mixture was
stirred for 4 h at 22 °C and stirring then stopped. The reaction mixture
was allowed to stand overnight. Concentrations were determined by
titration using 2-butanol and 1,10-phenanthroline as an indicator.
Preparation for Zn(CH TMS) . A 250 mL flask was charged with
0.705 mmol, 1.0 equiv) suspended in ethanol (4 mL). The reaction
mixture was cooled to 0 °C prior to the dropwise addition of acetyl
chloride (0.150 mL, 2.15 mmol, 3.05 equiv), generating HCl in situ by
reaction with the ethanol. The transparent-yellow reaction mixture was
allowed to warm to 22 °C with stirring over 22 h or until deemed
complete by TLC. The reaction mixture was then concentrated in
vacuo to provide the title compound as a crude yellow oil. The crude
product was purified by flash column chromatography (50% ethyl
acetate in hexanes, R = 0.34) to provide the title compound as a white
f
solid (0.228 g, 99%).
(
S)-1-(4,4-Dibromobut-3-en-1-yl)-3-hydroxypyrrolidine-2,5-dione
2
2
20
1
(
(
5a): mp = 91−93 °C; [α]
= −46.1 (c 1.6, CHCl ); H NMR
ZnCl and fused (melted) under high vacuum via a Bunsen burner.
D
3
2
300 MHz, chloroform-d) δ 6.38 (t, J = 7.5 Hz, 1H), 4.68 (ddd, J =
The resultant dry ZnCl (6.58 g, 48.3 mmol) was dissolved in freshly
2
8.3, 4.8, 2.9 Hz, 1H), 3.77 (d, J = 3.1 Hz, 1H), 3.63 (t, J = 6.9 Hz, 2H),
distilled THF (48 mL) to form a 1 M stock solution. This solution was
3
(
.10 (dd, J = 18.2, 8.3 Hz, 1H), 2.70 (dd, J = 18.2, 4.8 Hz, 1H), 2.41
stored under N . A separate 25 mL round bottomed flask equipped
2
q, J = 6.9 Hz, 2H); 13C NMR (75 MHz, CDCl ) δ 178.6, 174.2,
3
with a magnetic stirring bar and nitrogen inlet was charged with 1 M
1
2
1
6
34.3, 92.1, 67.1, 37.3, 36.6, 31.4; IR (film) 3431, 3028, 2947, 2850,
359, 2340, 1783, 1701, 1634, 1558, 1541, 1507, 1442, 1439, 1402,
350, 1317, 1261, 1171, 1104, 1058, 1024, 963, 903, 794, 755, 692,
ZnCl (5 mL, 5 mmol, 1 equiv) solution. Over 15 min, at 0 °C,
2
TMSCH MgCl (5.10 mL, 10.0 mmol, 1.96 M, 2.0 equiv) was added.
2
The reaction mixture became thick with a white precipitate, which
required settling before use. The resulting light-gray supernatant was
1 M Zn(CH TMS) .
−1
+
14, 517, 509 cm ; HRMS (ESI-TOF) m/z [M + H] calcd for
C H Br NO 327.9002, found 327.9003.
8
9
2
3
2
2
Intermediates from the Formation of 5a. (S)-3-Acetoxy-4-((4,4-
(S)-3-((tert-Butyldimethylsilyl)oxy)-1-(5-(trimethylsilyl)-4-
((trimethylsilyl)methyl)pent-3-en-1-yl)pyrrolidine-2,5-dione (6). To
an oven-dried 25 mL round-bottomed flask equipped with a magnetic
stirring bar and nitrogen inlet was charged with gem-dibromide 5b
(0.967 g, 2.19 mmol, 1 equiv) dissolved in THF (6.58 mL) freshly
distilled from sodium metal. The solution was then treated with
Zn(CH TMS) (4.38 mL, 4.38 mmol, 1 M in THF, 2.0 equiv) in
20.8
dibromobut-3-en-1-yl)amino)-4-oxobutanoic acid: [α]
= −1.3
D
1
(c 1.6, CHCl ); H NMR (300 MHz, chloroform-d) δ 6.42 (m, 2H),
3
5
2
.48 (t, J = 5.9 Hz, 1H), 3.40 (q, J = 6.2 Hz, 2H), 3.00 (dd, J = 5.9,
.1 Hz, 2H), 2.37 (q, J = 7.0 Hz, 2H), 2.20 (s, 3H); 13C NMR
(
75 MHz, CDCl ) δ 174.2, 170.2, 169.4, 135.2, 91.8, 69.9, 37.8, 36.4,
3
3
2
7
6.1, 33.2, 21.3, 20.9; IR (film) 3331, 3095, 2935, 2852, 2590, 2361,
335, 1739, 1651, 1551, 1429, 1369, 1228, 1103, 1058, 944, 807, 784,
39, 628 cm ; HRMS (ESI-TOF) m/z [M + Na] calcd for
2
2
portions and stirred for 5 min at 0 °C. Afterward, PdCl (PPh ) (0.107 g,
2 3 2
−1
+
0.153 mmol, 7 mol %) was added all at once, and the flask was purged
26
C H Br NO 407.9053, found 407.9057.
with N and allowed to warm to room temperature. The yellow
10
13
2
5
2
(
S)-1-(4,4-Dibromobut-3-en-1-yl)-2,5-dioxopyrrolidin-3-yl ace-
suspension began to disappear once it reached 22 °C. The reaction
22
1
tate: mp 57−59 °C; [α]
= −10.3 (c 1.6, CHCl ); H NMR
was allowed to stir for 11 h 45 min at 22 °C. The light-orange reaction
D
3
(
300 MHz, chloroform-d) δ 6.39 (t, J = 7.5 Hz, 1H), 5.43 (dd, J =
.7, 4.7 Hz, 1H), 3.66 (t, J = 7.0 Hz, 2H), 3.18 (dd, J = 18.4, 8.7 Hz,
mixture was then poured over cold satd NH Cl (25 mL), extracted
4
8
1
3
9
2
1
1
with ethyl ether (3 × 25 mL), and washed with brine (25 mL). The
combined extracts were dried over anhydrous magnesium sulfate
and concentrated in vacuo. Trituration of the residue with pentane
(2 × 10 mL) followed by Celite (1/4 in.) filtration of the supernatant
liquid afforded a crude product as a yellow oil, which was purified by
H), 2.68 (dd, J = 18.4, 4.7 Hz, 1H), 2.43 (q, J = 7.0 Hz, 2H), 2.17 (s,
H); 13C NMR (75 MHz, CDCl ) δ 173.38, 173.12, 169.95, 134.2,
3
2.1, 67.5, 36.7, 35.8, 31.3, 20.7; IR (film) 3487, 3028, 2948, 2947,
850, 2360, 2337, 1790, 1749, 1716, 1714, 1712, 1635, 1558, 1541,
507, 1439, 1437, 1403, 1371, 1353, 1316, 1250, 1226, 1165, 1106,
040, 976, 872, 791, 692, 627, 591, 518 cm ; HRMS (ESI-TOF) m/z
M + Na] calcd for C H Br NO 391.8927 and [M + H] 369.9108,
flash column chromatography (SiO , gradient: hexanes then 5% →
2
−1
10% ethyl acetate in hexanes) to provide the title compound as a
+
+
21
1
[
colorless oil (0.228 g, 97%): [α] = −19.1 (c 1.6, CHCl ); H NMR
10
11
2
4
D
3
found 391.8938 and 369.9124, respectively.
S)-3-((tert-Butyldimethylsilyl)oxy)-1-(4,4-dibromobut-3-en-1-yl)-
(300 MHz, chloroform-d) δ 4.72 (t, J = 7.1 Hz, 1H), 4.55 (dd, J =
8.2, 4.5 Hz, 1H), 3.47 (t, J = 7.5 Hz, 2H), 2.98 (dd, J = 17.9,
(
pyrrolidine-2,5-dione (5b). An oven-dried 50 mL round-bottom flask
equipped with a magnetic stirring bar and nitrogen inlet was charged
with pyrrolidinedione 5a (1.00 g, 3.06 mmol, 1.0 equiv), TBS-Cl
8
1
.2 Hz, 1H), 2.58 (dd, J = 17.9, 4.5 Hz, 1H), 2.21 (q, J = 7.5 Hz, 2H),
.47 (s, 2H), 1.40 (s, 2H), 0.92 (s, 9H), 0.18 (d, J = 3.6 Hz, 6H), 0.02
13
(
1
s, 9H), −0.01 (s, 9H); C NMR (75 MHz, CDCl ) δ 176.8, 174.3,
3
(
2
0.533 g, 3.67 mmol, 1.20 equiv), and imidazole (0.520 g, 7.65 mmol,
.5 equiv) in dry DMF (2 mL) at room temperature. The yellowish
reaction mixture was allowed to stir at 25 °C for 36 h or until deemed
complete by TLC (1:1 ethyl acetate in hexanes, R = 0.91 (5b), 0.34
5a)). The reaction mixture was then diluted and extracted with 1:1
ether−pentane (3 × 15 mL) and the organic layer washed with NH Cl
2 × 15 mL), brine (15 mL) and dried over anhydrous sodium sulfate.
The solvents were then removed under reduced pressure to provide
the crude product as a yellow oil. The crude product was purified by
flash column chromatography (10% ethyl acetate in hexanes, R =
.35) to furnish the title compound 5b as a white solid (1.35 g, 100%):
mp 27−29 °C; [α]
chloroform-d) δ 6.37 (t, J = 7.4 Hz, 1H), 4.58 (dd, J = 8.2, 4.5 Hz,
H), 3.61 (t, J = 6.9 Hz, 2H), 3.01 (dd, J = 18.0, 8.2 Hz, 1H), 2.60 (dd,
J = 18.0, 4.5 Hz, 1H), 2.40 (q, J = 6.9 Hz, 2H), 0.92 (s, 9H), 0.18 (d,
38.4, 114.3, 68.0, 38.96, 38.92, 29.7, 27.0, 25.8, 23.9, 18.4, −0.6, −1.0,
4.5, −5.1; IR (film) 3481, 2954, 2928, 2359, 1788, 1715, 1469, 1400,
−
−1
1
362, 1252, 1152, 1092, 837, 780, 624 cm ; HRMS (ESI-TOF) m/z
+
f
[M + H] calcd for C H NO Si 456.2780, found 456.2789.
22 45 3 3
(
Preparation of Lithiobutyne. To a flame-dried 100 mL Schlenk
flask equipped with a magnetic stirring bar and nitrogen inlet was
charged with THF (15 mL) and 1-butyne (3.25 g, 60.0 mmol,
4
(
1
−
.2 equiv) at −10 °C (salt−ice bath). The solution was then cooled to
78 °C and treated dropwise with nBuLi (23.8 mL, 50.0 mmol,
f
1.0 equiv, 2.13 M in hexanes). After stirring for 30 min at −78 °C, the
solution was allowed to slowly warm to 0 °C. The solvent was then
removed to provide lithiobutyne as a white solid.
0
19.7
1
= −29.3 (c 1.6, CHCl ); H NMR (500 MHz,
D
3
(
S)-4-((tert-Butyldimethylsilyl)oxy)-5-(but-1-yn-1-yl)-5-hydroxy-1-
1
(5-(trimethylsilyl)-4-((trimethylsilyl)methyl)pent-3-en-1-yl)-
pyrrolidin-2-one (7). Method 1. An oven-dried 10 mL round-bottom
E
DOI: 10.1021/acs.joc.5b01625
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
flask equipped with a magnetic stirring bar and nitrogen inlet was
charged with lithiobutyne (47.4 mg, 0.789 mmol, 1.20 equiv) dissolved
in LPDE (5 M, 3.3 mL) at 0 °C. The cooled solution was then treated
dropwise with a solution of imide 6 (0.300 g, 0.658 mmol, 1.0 equiv in
compound as an orange oil. The crude product was purified by flash
column chromatography (SiO , gradient: hexanes then 5% → 10% →
2
15% ethyl acetate in hexanes) to furnish the title compound as a light
yellow oil (695.3 mg, 50%).
1
.50 mL anhydrous ethyl ether) over a period of 2 min. Following
Method 2. An oven-dried 5 mL round-bottom flask equipped with a
magnetic stirring bar and nitrogen inlet was charged with
hydroxylactam 7 (0.033 g, 0.063 mmol, 1.0 equiv) in 5 M LPDE
(0.314 mL, 0.20 M in substrate) at 0 °C. The reaction mixture was
allowed to slowly warm to 22 °C and was stirred at that temperature
for 15 h or until deemed complete by GC analysis. The reaction
complete addition, the reaction mixture was allowed to warm to room
temperature and was stirred for 15 min or until deemed complete by
TLC (15% ethyl acetate in hexanes). The reaction mixture was then
diluted (2 mL Et O), poured over cold 5% NH OH (10 mL),
2
4
extracted with Et O (3 × 10 mL), and dried over magnesium sulfate.
2
Following the removal of solvents, the crude product was provided
as a white solid (314 mg, 94%) that could be purified, and the
diastereomers were separated by column chromatography (SiO2,
gradient: hexanes then 5% → 10% ethyl acetate in hexanes) to provide
both as white solids (7a:7b = 26:74, 270 mg, 81%).
Method 2. An oven-dried 25 mL round-bottom flask equipped with
a magnetic stirring bar and nitrogen inlet was charged with
lithiobutyne (0.153 g, 2.56 mmol, 3.00 equiv) in tetrahydrofuran
mixture was then diluted with cold 5% NH OH (5 mL) and extracted
4
with ether (3 × 10 mL), and the organic layer washed with brine
(15 mL). The combined extracts were dried over anhydrous
magnesium sulfate and concentrated in vacuo to furnish a crude
mixture of inseparable bicyclic lactams 8 and 9 as yellow oils (28% 8;
8% 9). The mixture may be partially purified by flash column
chromatography (SiO , gradient: hexanes then 5% → 10% → 15%
2
ethyl acetate in hexanes) or separated by reversed-phase HPLC to
provide a yellow oil (7.62 mg, 28%).
(
5.3 mL). The reaction mixture was cooled to −78 °C prior to the
dropwise addition of cyclic imide 6 (0.389 g, 0.855 mmol, 1.0 equiv in
.60 mL THF) over 20 min. The red-pink reaction mixture was then
allowed to warm to −20 °C and was stirred at that temperature for
6 h. The reaction mixture was then quenched by slow addition of 1 M
Et NHOAc in THF (5 mL) and extracted with water (10 mL), ether
Note: HPLC purifications resulted in diminished yields (∼10%)
Reversed-phase HPLC purification was performed with a Waters
2487 Dual λ Absorbance detector, 600 controller and pump, and a
Phenomenex Synergi 4 μ Polar RP 80A HPLC column (250 ×
21.2 mm) using Waters Empower 3 software. A gradient of A 0.1%
TFA, H O) and B (0.1% TFA, 19:1 CH CN, H O) was used.
1
1
3
(
3 × 10 mL), and the organic layer was washed with brine (10 mL).
2
3
2
21.2
1
The combined extracts were dried over anhydrous magnesium sulfate
and concentrated in vacuo to provide the desired product as a yellow
oil. The crude product was purified by flash column chromatography
8: [α]
= +29.9 (c 0.65, CHCl ); H NMR (300 MHz,
D 3
chloroform-d) δ 4.69 (s, 1H), 4.55 (s, 1H), 4.12 (dd, J = 10.1, 7.2 Hz,
1H), 3.76 (ddd, J = 11.6, 7.5, 4.1 Hz, 1H), 3.04 (dt, J = 11.6, 7.5 Hz,
1H), 2.85 (t, J = 7.1 Hz, 1H), 2.71 (dd, J = 15.0, 10.1 Hz, 1H), 2.47
(dd, J = 15.0, 7.2 Hz, 1H), 2.24 (q, J = 7.4 Hz, 2H), 2.12 (dq, J = 11.6,
7.0 Hz, 1H), 1.83 (m, 2H), 1.61 (d, J = 13.3 Hz, 1H), 1.14 (t, J =
7.4 Hz, 3H), 0.90 (s, 9H), 0.03 (s, 15H); 13C NMR (75 MHz,
chloroform-d) δ 171.6, 145.3, 108.6, 88.3, 79.2, 71.2, 70.9, 54.8, 42.9,
41.3, 31.2, 29.4, 25.8, 18.1, 14.2, 12.7, −1.2, −3.5, −4.8; IR (film)
3251, 3084, 2953, 2929, 2892, 2857, 2359, 2335, 2236, 1708, 1629,
(
SiO , gradient: hexanes then 5% → 10% ethyl acetate in hexanes) to
2
furnish the title compound as a light orange oil (7a:7b = 85:15,
+
0
.368 g, 85%): HRMS (ESI-TOF) m/z [M + H] Calcd for
C H NO Si 510.3250; Found 510.3245.
2
6
7
51
3
3
1
8.9
= −15.5 (c 0.062, CHCl ); 1H NMR (300 MHz,
a: [α]
D
3
chloroform-d) δ 4.79 (t, J = 7.2 Hz, 1H), 4.34 (t, J = 5.9 Hz, 1H), 3.96
(
s, 1H), 3.39 (m, 1H), 3.24 (m, 1H), 2.63 (dd, J = 16.6, 6.9 Hz, 1H),
−1
2
3
.44−2.16 (m, 5H), 1.51 (s, 2H), 1.40 (s, 2H), 1.15 (t, J = 7.5 Hz,
1470, 1409, 1389, 1361, 1320, 1248, 1145, 918, 836, 777 cm ; HRMS
+
H), 0.93 (s, 9H), 0.16 (d, J = 7.1 Hz, 6H), 0.01 (d, J = 9.6 Hz, 18H);
(ESI-TOF) m/z [M + H] calcd for C H NO Si 420.2749, found
23
41
2
2
1
3
C NMR (75 MHz, CDCl ) δ 170.9, 136.7, 115.6, 88.2, 84.6, 77.5,
420.2756.
3
1
7
7.0, 76.6, 73.4, 40.7, 38.3, 29.5, 28.4, 25.7, 23.8, 18.1, 13.4, 12.3, −0.7,
9: H NMR (300 MHz, chloroform-d) δ 4.92 (s, 1H), 4.86 (s, 1H),
4.42 (t, J = 6.9 Hz, 1H), 3.97 (dt, J = 14.0, 5.2 Hz, 1H), 3.05 (dd, J =
14.0, 6.8 Hz, 1H), 2.72−2.55 (m, 2H), 2.47−2.29 (m, 3H), 2.20 (q,
−
1.1, −4.7, −4.9; IR (film) 3479, 3334, 2951, 2932, 2894, 2856, 2240,
1
7
712, 1404, 1362, 1316, 1248, 1146, 1081, 982, 952, 925, 837, 784,
−1
00, 624 cm .
J = 7.4 Hz, 3H), 1.92−1.67 (m, 2H), 1.12 (t, J = 7.4 Hz, 3H), 0.91 (s,
7
b: [α]1
8.4
D
= +14.1 (c 0.152, CHCl ); 1H NMR (300 MHz,
9H), 0.12 (d, J = 7.6 Hz, 6H); C NMR (75 MHz, CDCl ) δ 171.4,
13
3
3
chloroform-d) δ 4.83 (t, J = 7.0 Hz, 1H), 4.15 (d, J = 5.6 Hz, 1H), 3.55
dt, J = 14.3, 7.7 Hz, 1H), 3.25 (dt, J = 14.3, 7.7 Hz, 1H), 2.96 (s, 1H),
144.8, 115.8, 88.8, 79.3, 75.0, 64.9, 43.2, 39.8, 39.3, 34.9, 25.9, 18.3,
14.1, 12.5, −4.6, −4.6; IR (film) 3381, 3072, 2954, 2932, 2852, 2358,
2339, 1700, 1445, 1404, 1252, 1142, 1005, 929, 890, 833, 780, 666
(
2
7
6
1
2
3
1
.76 (dd, J = 16.5, 5.6 Hz, 1H), 2.28 (m, 5H), 1.47 (dd, J = 22.4,
−
1
+
.4 Hz, 4H), 1.18 (t, J = 7.5 Hz, 3H), 0.90 (s, 9H), 0.12 (d, J = 4.4 Hz,
cm ; HRMS (ESI-TOF) m/z [M + H] calcd for C H NO Si
2
0
33
2
H), 0.02 (d, J = 5.0 Hz, 18H); 13C NMR (75 MHz, CDCl ) δ 172.8,
3
348.2353, found 348.2338.
38.4, 116.2, 91.5, 89.9, 77.6, 77.2, 76.8, 75.6, 74.9, 40.7, 39.2, 29.8,
8.7, 25.9, 24.3, 18.4, 13.6, 12.7, −0.4, −0.9, −4.5, −4.6; IR (film)
140, 3057, 2954, 2927, 2894, 2852, 2246, 1655, 1453, 1389, 1362,
Preparation of Lithium Diisobutylisopropoxyaluminum
Hydride (LDBIPA). The desired reducing agent lithium diisobutyli-
sopropoxyaluminum hydride (LDBIPA) was obtained as a colorless
solution from DIBAL (1 M in toluene) by the general preparation
−1
317, 1245, 1139, 1078, 995, 930, 844, 783, 695, 628 cm .
1S,7R,7aS)-7a-(But-1-yn-1-yl)-1-((tert-butyldimethylsilyl)oxy)-7-
1
9
(
procedure outlined by An. Concentrations were determined by
(3-(trimethylsilyl)prop-1-en-2-yl)hexahydro-3H-pyrrolizin-3-one (8).
reaction with excess p-methoxybenzaldehyde and analysis of an aliquot
1
28
Method 1. An oven-dried 50 mL round-bottom flask equipped with a
by No-D H NMR.
1S,7R,7aS)-7a-(But-1-yn-1-yl)-1-((tert-butyldimethylsilyl)oxy)-7-
magnetic stirring bar and nitrogen inlet was charged with lithiobutyne
(
(
0.237 g, 3.94 mmol, 1.20 equiv) dissolved in LPDE (5 M, 16.45 mL)
(3-(trimethylsilyl)prop-1-en-2-yl)hexahydro-1H-pyrrolizine-3-car-
bonitrile (10). An oven-dried 5 mL round-bottom flask equipped with
a magnetic stirring bar and nitrogen inlet was charged with lactam 8
(0.405 g, 0.965 mmol, 1.0 equiv) dissolved in THF (1.98 mL). The
solution was then cooled to 0 °C and treated dropwise with LDBIPA
(2.49 mL, 1.45 mmol, 0.580 M, 1.50 equiv) over several minutes. The
reaction mixture was allowed to slowly warm to 22 °C and stir for 24 h
or until deemed complete by TLC (15% EtOAc in hexanes). Upon
completion of the partial reduction, the reaction mixture was treated
dropwise with freshly distilled TMSCN (0.340 mL, 2.70 mmol,
2.80 equiv) and allowed to stir at 22 °C for 7 h or until deemed
complete by TLC. The reaction mixture was then quenched by slow
addition of water (5 mL), filtered over Celite, and extracted from ethyl
ether (3 × 10 mL). The combined extracts were dried over anhydrous
at 0 °C. The cooled solution was then treated dropwise with a solution
of imide 6 (1.50 g, 3.29 mmol, 1.0 equiv in 7.50 mL anhydrous ethyl
ether) over a period of 2 min. Following complete addition, the
reaction mixture was allowed to warm to room temperature and was
stirred for 15 min or until deemed complete by TLC (15% ethyl
acetate in hexanes). The reaction mixture was then cooled to 0 °C and
27
treated with TFAA (0.56 mL, 3.9 mmol, 1.2 equiv). After being
stirred for 12−15 min at room temperature (or until deemed complete
by TLC; 15% EtOAc in hexanes) the reaction was quenched by
inverse addition over cold 5% NH OH (20 mL) and extracted with
4
ether (3 × 20 mL), and the organic layer was washed with brine
(
30 mL). The combined extracts were dried over anhydrous
magnesium sulfate and concentrated in vacuo to furnish the title
F
DOI: 10.1021/acs.joc.5b01625
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
sodium sulfate and concentrated in vacuo to provide desired product
as an orange oil. The crude product was purified by flash column
1H), 3.41 (d, J = 4.0 Hz, 1H), 3.26 (ddd, J = 13.1, 10.6, 4.2 Hz, 1H),
3.07 (ddd, J = 13.1, 8.6, 5.5 Hz, 1H), 2.77 (d, J = 6.1 Hz, 1H), 2.44 (s,
1H), 2.35 (s, 1H), 2.33−2.20 (m, 3H), 2.03 (ddd, J = 6.1, 4.0, 1.3 Hz,
chromatography (SiO , gradient, hexanes then 5% → 10% ethyl
2
1
3
acetate in hexanes) to furnish the title compound 10 as a
2H), 1.73−1.61 (m, 2H), 1.15 (t, J = 7.5 Hz, 3H); C NMR
diastereomeric mixture of light-yellow oils (75:25, 0.339 g, 82%):
(75 MHz, CDCl ) δ 146.9, 108.5, 90.4, 76.9, 75.95, 71.1, 62.3, 54.4,
3
+
HRMS (ESI-TOF) m/z [M + H] calcd for C H N OSi 430.2836,
46.8, 41.8, 34.2, 31.8, 14.2, 12.7; IR (film) 3161, 3076, 2965, 2925,
24
42
2
2
found 430.2827
2850, 2359, 2340, 2245, 1646, 1442, 1376, 1317, 1251, 1098, 981, 906,
884, 814, 722, 670 cm ; HRMS (ESI-TOF) m/z [M + H] calcd for
Major diastereomer: [α]19 = −7.0 (c 0.29, CHCl ); H NMR
1
−1
+
D
3
(
300 MHz, chloroform-d) δ 4.78 (s, 1H), 4.69 (s, 1H), 4.46 (d, J =
C H NO 218.1539, found 218.1547.
14
19
5
2
1
1
1
1
3
3
1
9
.8 Hz, 1H), 4.05 (dd, J = 9.3, 5.5 Hz, 1H), 3.23−3.12 (app m, 2H),
.91 (dd, J = 12.8, 6.0 Hz, 1H), 2.39−2.19 (m, 4H), 2.15 (d, J =
3.4 Hz, 1H), 2.09−1.91 (m, 1H), 1.80−1.70 (m, 1H), 1.61 (d, J =
3.4 Hz, 1H), 1.13 (t, J = 7.5 Hz, 3H), 0.90 (s, 9H), 0.07 (d, J =
(1R,5S,7aS)-7a-(But-1-yn-1-yl)-9-methylenehexahydro-7H-1,5-
ethanopyrrolizin-7-one (13). A 10 mL round-bottomed flask
equipped with a magnetic stirring bar and nitrogen inlet was charged
with tricycle 12 (73.20 mg, 0.3368 mmol, 1.0 equiv) in dichloro-
methane (2.9 mL). To the stirred solution was added Dess−Martin
.0 Hz, 6H), 0.04 (s, 9H); 13C NMR (75 MHz, CDCl ) δ 143.9,
3
18.5, 108.6, 88.9, 80.9, 77.6, 77.2, 76.8, 73.0, 72.6, 55.4, 50.7, 50.1,
9.1, 29.0, 28.6, 25.9, 18.1, 13.9, 12.8, −1.2, −3.6, −4.7; IR (film)
084, 2958, 2932, 2894, 2860, 2361, 2342, 2240, 2224, 1792, 1704,
628, 1472, 1418, 1365, 1320, 1248, 1149, 1088, 1058, 1035, 1005,
periodinane (15 wt % in CH
dropwise at room temperature. The reaction progress was monitored
TLC analysis (silica gel, 9:1 CH Cl −MeOH). The reaction mixture
was then quenched with the addition of sodium hydroxide (1 M,
4 mL) and extracted with CH Cl (3 × 5 mL). The combined extracts
2 2
Cl , 1.20 mL, 0.573 mmol, 1.70 equiv)
2
2
−1
44, 917, 860, 837, 776, 704, 635 cm .
2
2
Minor diastereomer: [α]2
1.4
= +10.9 (c 0.162, CHCl ); H NMR
1
were washed with brine (5 mL), dried over anhydrous magnesium
sulfate, and concentrated in vacuo to provide the desired product as a
yellow oil. Washing of the viscous oil with pentane (3 × 2 mL)
followed by concentration of the triturate furnished the title
D
3
(
300 MHz, chloroform-d) δ 4.63 (d, J = 5.8 Hz, 2H), 3.81 (t, J =
7
2
2
0
1
1
2
1
.4 Hz, 1H), 3.51 (t, J = 8.2 Hz, 1H), 3.22 (dt, J = 12.4, 9.3 Hz, 1H),
.94−2.73 (m, 2H), 2.32−2.13 (m, 5H), 1.67 (dp, J = 10.1, 4.9 Hz,
H), 1.55 (d, J = 13.3 Hz, 1H), 1.11 (t, J = 7.5 Hz, 3H), 0.88 (s, 9H),
compound (68.5 mg, 95%) as a light-yellow viscous oil. The product
13
20
.14 − −0.15 (m, 15H); C NMR (75 MHz, CDCl ) δ 144.4, 119.1,
was used without further purification: [α]
D
= +227.1 (c 0.29,
3
1
08.1, 88.9, 80.7, 72.7, 55.9, 52.9, 38.7, 28.4, 27.6, 25.8, 18.1, 13.9,
2.9, −1.2, −3.6, −4.7; IR (film) 3084, 2954, 2928, 2890, 2860, 2361,
339, 2240, 1784, 1700, 1628, 1476, 1418, 1358, 1324, 1244, 1152,
CHCl ); H NMR (300 MHz, chloroform-d) δ 4.71 (s, 1H), 4.65 (s,
3
1H), 3.60 (dd, J = 6.9, 4.5 Hz, 1H), 3.39 (ddd, J = 13.4, 10.8, 4.1 Hz,
1H), 3.20 (ddd, J = 13.4, 8.3, 5.6 Hz, 1H), 3.01 (d, J = 6.0 Hz, 1H),
2.68 (ddd, J = 17.5, 6.9, 1.7 Hz, 1H), 2.55 (ddd, J = 14.4, 4.5, 2.2 Hz,
1H), 2.37−2.04 (m, 4H), 1.92−1.75 (m, 2H), 1.10 (t, J = 7.5 Hz, 3H);
−1
103, 1084, 1009, 948, 902, 856, 837, 780, 704, 666, 643 cm .
1R,5S,7S,7aS)-7a-(But-1-yn-1-yl)-7-((tert-butyldimethylsilyl)oxy)-
-methylenehexahydro-1H-1,5-ethanopyrrolizine (11). An oven-
(
13
9
C NMR (75 MHz, CDCl ) δ 210.5, 143.8, 110.8, 88.4, 74.8, 57.0,
3
dried 5 mL round-bottom flask equipped with a magnetic stirring
56.1, 49.0, 43.8, 33.5, 31.6, 13.9, 12.7; IR (film) 3072, 2974, 2939,
2878, 2848, 2361, 2339, 2244, 1761, 1647, 1469, 1442, 1396, 1332,
1275, 1221, 1183, 1168, 1149, 1126, 1092, 1073, 1016, 997, 932, 909,
bar and nitrogen inlet was charged with AgBF (in a drybox, 30.12 mg,
4
0
0
.1547 mmol, 1.10 equiv) followed by cyanoamine 10 (60.6 mg,
.141 mmol, 1 equiv) dissolved in THF (1.81 mL). The reaction
−1
+
860, 799, 765, 723, 598, 545 cm ; HRMS (ESI-TOF) m/z [M + H]
mixture was then protected from light and allowed to stir at 22 °C for
calcd for C H NO 216.1383, found 216.1386.
14
17
22 h or until deemed complete by GC/TLC. The reaction mixture was
(1R,5S,7R,7aS)-7a-(But-1-yn-1-yl)-9-methylenehexahydro-1H-
1,5-ethanopyrrolizin-7-ol (14). A 10 mL round-bottomed flask
equipped with a magnetic stirring bar and nitrogen inlet was charged
with tricycle 13 (68.5 mg, 0.318 mmol, 1.0 equiv) dissolved in THF
(3.2 mL). Then the mixture was cooled to 0 °C prior to the dropwise
addition of LDBIPA (0.582 M, 0.820 mL, 0.477 mmol, 1.50 equiv),
and the reaction progress was monitored by TLC (9:1 CH Cl −
then quenched by the addition of 5% NH OH (2.5 mL) and extracted
4
from ethyl ether (4 × 5 mL). The combined extracts were dried over
anhydrous magnesium sulfate and concentrated in vacuo to provide
the desired product 11 as a brown oil. The brown oil may then be
purified by trituration with pentane (5 mL) followed by passing over a
plug of alumina (neutral, activity II, elute with 100% EtOAc) to
provide the title compound as a dark orange oil (41.1 mg, 88%):
2
2
MeOH). Upon completion (24 h), the reaction was then quenched by
slow addition of water (4 mL) and extracted with ethyl ether (3 ×
5 mL). The combined extracts were filtered over a Celite plug, dried
over anhydrous magnesium sulfate, and concentrated in vacuo to
provide desired product as a yellow oil (67.5 mg, 98%). The crude
product may then be recrystallized by dissolving in pentane and
cooling to −30 °C to induce crystallization to provide the desired
20.7
1
[α]
= +110.2 (c 0.33, CHCl ); H NMR (300 MHz, chloroform-
D
3
d) δ 4.65 (s, 1H), 4.59 (s, 1H), 4.26 (dd, J = 7.6, 4.8 Hz, 1H), 3.47−
3
1
1
3
.18 (m, 2H), 3.01 (ddd, J = 13.3, 8.6, 5.4 Hz, 1H), 2.69 (d, J = 6.2 Hz,
H), 2.38−2.11 (m, 4H), 2.04 (dddd, J = 13.0, 6.7, 4.8, 2.1 Hz, 1H),
.91 (dd, J = 13.0, 7.6 Hz, 1H), 1.69−1.53 (m, 2H), 1.11 (t, J = 7.5 Hz,
13
H), 0.90 (s, 9H), 0.08 (d, J = 4.3 Hz, 6H); C NMR (75 MHz,
2
1.7
CDCl ) δ 148.2, 107.7, 87.5, 78.4, 75.3, 72.7, 62.0, 55.0, 46.9, 43.4,
azatricycle as a white solid (63.5 mg, 92%): mp 74−75 °C; [α]
=
3
D
1
3
2
1
4.2, 31.7, 26.1, 18.5, 14.2, 12.9, −4.5, −4.7; IR (film) 3396, 2951,
+136.2 (c 0.149, CHCl ); H NMR (300 MHz, chloroform-d)
3
932, 2856, 2361, 2342, 1712, 1651, 1469, 1362, 1316, 1252, 1122,
δ 4.91 (s, 1H), 4.77 (s, 1H), 4.58 (ddd, J = 12.8, 10.7, 2.8 Hz, 1H),
3.36 (dd, J = 6.9, 4.6 Hz, 1H), 3.26 (ddd, J = 13.1, 10.5, 4.1 Hz, 1H),
3.03 (ddd, J = 13.1, 8.5, 5.5 Hz, 1H), 2.95 (d, J = 6.1 Hz, 1H), 2.85 (d,
J = 12.8 Hz, 1H), 2.69 (dddd, J = 14.0, 10.7, 6.9, 1.8 Hz, 1H), 2.50
(ddd, J = 14.9, 4.6, 2.3 Hz, 1H), 2.40−2.25 (m, 1H), 2.19 (q, J = 7
.5 Hz, 2H), 1.85 (d, J = 14.9 Hz, 1H), 1.62 (ddd, J = 12.7, 8.5, 4.1 Hz,
−1
103, 1005, 936, 841, 776, 666 cm ; HRMS (ESI-TOF) m/z
+
[
M + H] calcd for C H NOSi 332.2404, found 332.2407.
20 33
(1R,5S,7S,7aS)-7a-(But-1-yn-1-yl)-9-methylenehexahydro-1H-1,5-
ethanopyrrolizin-7-ol (12). A PTFE plastic flask equipped with
a magnetic stirring bar was charged with tricycle 11 (0.1173 g,
1
3
0.3537 mmol, 1.0 equiv) dissolved in acetonitrile (11.8 mL). The
1H), 1.28 (dd, J = 14.0, 2.8 Hz, 1H), 1.11 (t, J = 7.5 Hz, 3H); C
solution was then treated with aqueous HF (48%, 0.62 mL) and
NMR (75 MHz, CDCl ) δ 150.2, 108.9, 85.6, 80.1, 78.2, 72.9, 60.8,
3
allowed to stir for 24 h at 22 °C or until deemed complete by TLC
52.1, 47.6, 40.3, 34.8, 32.9, 14.1, 12.7; IR (film) 3538, 3316, 3072,
2961, 2925, 2854, 2736, 2529, 2470, 2359, 2340, 2241, 1761, 1735,
1650, 1450, 1317, 1257, 1162, 1106, 1077, 1017, 888, 799, 729,
(
5% MeOH in DCM + 1% NH OH). The reaction mixture was then
4
quenched by the addition of 1 M KOH (18 mL) and extracted from
ethyl ether (3 × 20 mL). The combined extracts were dried over
anhydrous sodium sulfate and concentrated in vacuo to provide the
desired product as a yellow solid. The crude product was purified by
bulb-to-bulb distillation (1 mmHg, 140−160 °C) to furnish the title
compound 12 as a white solid (73.2 mg, 95%): mp 174−176 °C
−1
+
570 cm ; HRMS (ESI-TOF) m/z [M + H] calcd for C H NO
1
4
20
218.1539, found 218.1529.
(1R,5S,7R,7aS)-7a-(But-1-yn-1-yl)-9-methylenehexahydro-1H-
1,5-ethanopyrrolizin-7-ol Ammonium Trifluoroacetate (14·TFA). A
5 mL round-bottomed flask equipped with a magnetic stirring bar
and nitrogen inlet was charged with tricycle 14 (67.5 mg, 0.311 mmol,
0.3
1
(
sublime); [α]2
= +237.7 (c 0.039, CHCl ); H NMR (300 MHz,
D
3
chloroform-d) δ 4.67 (s, 1H), 4.63 (s, 1H), 4.21 (app t, J = 6.1 Hz,
1.0 equiv) dissolved in Et O (6 mL). The solution was treated with
2
G
DOI: 10.1021/acs.joc.5b01625
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
1
3
TFA (26.3 μL, 0.342 mmol, 1.10 equiv) dropwise with stirring at 0 °C.
After being stirred for 1 h at 0 °C, the reaction mixture was
concentrated in vacuo, and the resulting viscous oil was washed with
C NMR (75 MHz, CDCl ) δ 104.0, 86.9, 78.1, 77.6, 62.1, 54.5, 46.9,
3
19
36.4, 32.8, 28.8, 26.9, 23.4, 22.9, 14.0; F NMR (282 MHz, C D6) δ
−75.45; IR (film) 3271, 2961, 2935, 2871, 2768, 2614, 2546, 2360,
2342, 1673, 1466, 1427, 1360, 1197, 1133, 1088, 1023, 982, 838, 796,
6
pentane (3 × 5 mL). The residue was dissolved in Et O and filtered
2
−1
+
through a Celite plug to furnish the crude compound as a light yellow
721 cm ; HRMS (ESI-TOF) m/z [M + H] calcd for C H NO
13 21 2
oil. The crude oil was then purified by column chromatography (SiO2,
224.1645, found 224.1652.
1
1
gradient, 100% EtOAc → 7:1 EtOAc−MeOH; R = 0.37) to provide
(1S,2a R,4R,5S,7aS)-2a -((E)-But-1-en-1-yl)hexahydro-1,4-
methanofuro[2,3,4-gh]pyrrolizin-1(2aH)-ol (16b). A 10 mL double-
necked round bottomed flask equipped with a magnetic stirring
bar and nitrogen inlet was charged with hemiketal trifluoroacetate
salt 15·TFA (12.9 mg, 0.0387 mmol, 1.0 equiv) dissolved in THF (2
mL) at room temperature. To the stirred solution was added N,O-
bis(trimethylsilyl)trifluoroacetamide (10.2 μL, 0.0387 mmol, 1.0 equiv)
all at once, and the resulting solution was allowed to stir until
completion (3 h). Upon completion, solvent and volatile byproducts
were removed under high vacuum to provide the sensitive
intermediate TMS protected hemiketal as a colorless oil which must
be used immediately.
The TMS-protected hemiketal (15.6 mg, 0.0387 mmol, 1.0 equiv)
was then dissolved in THF (1 mL) at room temperature. The stirred
solution was cooled to −78 °C, equipped with a dry ice condenser,
and charged with anhydrous liquid ammonia (3 mL). The cooled
solution was then treated piecewise with sodium metal (8.70 mg,
0.395 mmol, 10.2 equiv) to provide a dark blue reaction mixture. The
reaction mixture turned clear after 35 min and was then quenched by
f
trifluoroacetate salt 14·TFA as a nearly colorless oil (95.5 mg, 93%):
21
1
[
α] = +58.4 (c 0.24, CHCl ); H NMR (300 MHz, chloroform-d) δ
D
3
5
3
.08 (s, 1H), 4.96 (s, 1H), 4.77 (dd, J = 10.7, 2.9 Hz, 1H) 3.86 (s, 1H),
.71−3.57 (app m, 1H), 3.34 (ddd, J = 13.7, 8.7, 6.0 Hz, 1H), 3.16 (d,
J = 6.1 Hz, 1H), 3.04−2.88 (m, 1H), 2.70 (d, J = 15.9 Hz, 1H), 2.64−
2
1
.50 (m, 1H), 2.30−2.09 (m, 3H), 1.79 (ddd, J = 12.9, 8.7, 4.1 Hz,
H), 1.53 (dd, J = 14.3, 2.9 Hz, 1H), 1.13 (t, J = 7.5 Hz, 3H); 13
C
NMR (75 MHz, CDCl ) δ 144.1, 113.2, 90.6, 75.9, 75.2, 73.6, 60.9,
3
19
5
2.1, 46.5, 38.6, 33.5, 30.8, 13.6, 12.7; F NMR (282 MHz, CDCl ) δ
3
−
75.46; IR (film) 3356, 2986, 2958, 2927, 2854, 2770, 2575, 2502,
2
8
359, 2341, 2247, 1770, 1642, 1432, 1195, 1135, 1073, 1038, 961, 905,
−1
+
33, 797, 721 cm ; HRMS (ESI-TOF) m/z [M + H] calcd for
C H NO 218.1539, found 218.1529.
1
4
(
20
1
1
1S,2a S,4R,5S,7aS)-2a -(But-1-yn-1-yl)hexahydro-1,4-
methanofuro[2,3,4-gh]pyrrolizin-1(2aH)-ol Ammonium Trifluoroa-
cetate (15·TFA). A 10 mL double-necked round-bottomed flask
equipped with a magnetic stirring bar and oxygen inlet was charged
with tropane trifluoroacetate salt 14·TFA (28.8 mg, 0.0869 mmol,
1
.0 equiv) in dichloromethane (2.2 mL) at −78 °C (dry ice−acetone
bath). Ozone was bubbled into the solution at an oxygen pressure of
psi, 110 V, and a flow rate of 0.040 cu ft/min for 2 min or until a
cautious addition of saturated NH
evaporated by removal of the condenser and extracted using Et
4
Cl (1 mL), and the ammonia was
O (4 ×
2
8
3 mL). The combined extracts were dried over anhydrous magnesium
sulfate, concentrated in vacuo, and purified by extraction (3 × 5 mL
MeOH/hexanes, product in MeOH) to provide the desired product as
light-blue color persisted. The reaction mixture was then purged of
excess ozone for 5 min using a stream of N and treated with PPh3
2
a colorless oil (4.71 mg, 55%): [α]2
0.6
D
= +2.3 (c 0.131, CHCl
NMR (300 MHz, C D ) δ 5.83 (dt, J = 15.5, 6.5 Hz, 1H), 5.56−5.42
6 6
); H
1
(
25.0 mg, 0.0956 mmol, 1.10 equiv in 0.50 mL CH Cl ). After being
3
2
2
stirred for an additional 2 min, the reaction mixture was allowed to
slowly warm to 22 °C, and solvent was removed to provide the crude
mixture as a light yellow oil. The crude product was purified
by reversed-phase HPLC (gradient, 25% CH CN to 5% CH CN
(m, 1H), 4.26 (s, 1H), 3.09 (s, 1H), 2.94 (ddd, J = 13.1, 9.7, 6.0 Hz,
1H), 2.61 (ddd, J = 13.1, 8.0, 5.2 Hz, 1H), 2.32 (d, J = 5.6 Hz, 1H),
1.95 (dq, J = 7.3, 6.5 Hz, 2H), 1.83−1.44 (m, 6H), 0.91 (t, J = 7.3 Hz,
3
3
13
in H O) to furnish the title compound 15·TFA as a faint-yellow oil
3H); C NMR (75 MHz, C D ) δ 132.5, 129.0, 105.9, 83.3,
6 6
2
(
24.3 mg, 84%).
82.9, 61.5, 58.0, 48.8, 38.3, 35.4, 27.3, 26.0, 14.2; IR (film) 3338, 3027,
2962, 2874, 2749, 2602, 2361, 1742, 1670, 1559, 1472, 1453, 1347,
1328, 1297, 1285, 1259, 1225, 1195, 1134, 1095, 1058, 1023, 978,
Reversed-phase HPLC purification was performed with a Waters
2487 Dual λ Absorbance detector, 600 controller and pump, and a
−1
Phenomenex Synergi 4 μ Polar RP 80A HPLC column (250 ×
944, 902, 876, 807, 722, 735, 700, 659, 586, 567, 541 cm ; HRMS
+
(
2
ESI-TOF) m/z [M + H] calcd for C H NO 222.1489, found
22.1483.
2
1.2 mm) using Waters Empower 3 software. A gradient of A 0.1%
13 20 2
19
TFA, H O) and B (0.1% TFA, 19:1 CH CN, H O) was used: [α] =
+
2
3
2
D
1
19.8 (c 0.238, CHCl ); H NMR (300 MHz, chloroform-d) δ 4.74 (s,
3
1
H), 4.13 (s, 1H), 3.84 (td, J = 12.5, 5.4 Hz, 1H), 3.49 (m, 1H), 2.82
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01625.
■
(
2
d, J = 5.6 Hz, 1H), 2.56−2.34 (m, 2H), 2.27 (q, J = 7.5 Hz, 2H),
13
.23−1.94 (m, 4H), 1.15 (t, J = 7.5 Hz, 3H); C NMR (75 MHz,
*
S
CDCl ) δ 162.5, 162.1, 161.6, 118.7, 114.8, 103.8, 95.4, 81.0, 78.5,
3
19
6
9.9, 61.9, 59.2, 47.5, 36.9, 32.2, 23.8, 13.2, 12.7; F NMR (282 MHz,
CDCl ) δ −75.32; IR (film) 3224, 2981, 2943, 2925, 2882, 2852,
3
1H NMR, 13C NMR, HSQC, and COSY spectra (PDF)
X-ray crystallographic data for compound 14 (PDF)
X-ray crystallographic data for compound 14 (CIF)
2
1
5
2
761, 2602, 2551, 2361, 2339, 2251, 1670, 1480, 1457, 1430, 1358,
282, 1199, 1134, 1077, 1062, 978, 898, 833, 799, 719, 662, 571,
37 cm ; HRMS (ESI-TOF) m/z [M + H] calcd for C H NO
2
−1
+
13
18
20.1332, found 220.1333.
1
1
(
1S,2a R,4R,5S,7aS)-2a -Butylhexahydro-1,4-methanofuro[2,3,4-
gh]pyrrolizin-1(2aH)-ol Ammonium Trifluoroacetate (16a). A
0 mL round-bottomed flask equipped with a magnetic stirring
bar and hydrogen inlet was charged with Pd/C (5 wt %, 27.6 mg,
.0130 mmol, 0.20 equiv) and hemiketal trifluoroacetate salt 15·TFA
21.7 mg, 0.0651 mmol, 1.0 equiv) in ethyl acetate (5.6 mL) at 22 °C.
1
AUTHOR INFORMATION
■
*
Corresponding Author
Tel: 406-994-5408. E-mail: livinghouse@chemistry.montana.edu.
0
(
Reaction progress was monitored by TLC (7:1 EtOAc in MeOH).
Following reaction completion (approximately 3 h), the reaction
mixture was filtered over Celite and concentrated in vacuo to afford
the title compound as a crude oil. The product was then purified by
Notes
The authors declare no competing financial interest.
column chromatography (SiO , gradient, 100% EtOAc to 7:1 EtOAc
ACKNOWLEDGMENTS
2
■
in MeOH) to furnish the pure stemofoline core as the trifluoroacetate
1
9.1
Generous financial support from the National Science
Foundation (CHE-0848848 and CHE-1337908) is gratefully
acknowledged. We are indebted to Professor Orion Berrymen
of the University of Montana for obtaining the X-ray crystal
structure of azatricycle 14.
salt 16a as a colorless oil (17.1 mg, 78%): [α]
= +28.1 (c 0.079,
D
1
CHCl ); H NMR (300 MHz, chloroform-d) δ 4.55 (s, 1H), 4.10 (s,
3
1H), 3.71 (ddd, J = 13.6, 11.1, 5.8 Hz, 1H), 3.44 (m, 1H), 2.65 (d, J =
6.1 Hz, 1H), 2.33−2.05 (m, 5H), 2.03−1.89 (m, 2H), 1.76 (dt, J =
16.4, 6.6 Hz, 1H), 1.40 (dp, J = 16.4, 5.7 Hz, 4H), 0.97−0.87 (m, 3H);
H
DOI: 10.1021/acs.joc.5b01625
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
Tetrahedron 2009, 65, 3222−3231. (n) Fustero, S.; Mateu, N.; Simon
Fuentes, A.; Acena, L. Org. Lett. 2010, 12, 3014−3017. (o) Grzeszczyk,
B.; Szechner, B.; Furman, B.; Chmielewski, M. Tetrahedron 2010, 66,
́
-
REFERENCES
■
̃
(
1) Irie, H.; Masaki, N.; Ohno, K.; Osaki, K.; Taya, T.; Uyeo, S. J.
Chem. Soc. D 1970, 1066.
3
2
(
904−3911. (p) Watkin, S. V.; Camp, N. P.; Brown, R. C. D. Org. Lett.
(
2) Sekine, T.; Fukasawa, N.; Kashiwagi, Y.; Ruangrungsi, N.;
Murakoshi, I. Chem. Pharm. Bull. 1994, 42, 1360−1362.
3) (a) Jiwajinda, S.; Hirai, N.; Watanabe, K.; Santisopasri, V.;
Chuengsamarnyart, N.; Koshimizu, K.; Ohigashi, H. Phytochemistry
001, 56, 693−695. (b) Kaltenegger, E.; Brem, B.; Mereiter, K.;
Kalchhauser, K. H.; Hofer, O.; Vajrodaya, S.; Greger, H. Phytochemistry
003, 63, 803−816. (c) Brem, B.; Seger, C.; Pacher, T.; Hofer, O.;
Vajrodaya, S.; Greger, H. J. J. Agric. Food Chem. 2002, 50, 6383−6388.
4) Sekine, T.; Ikegami, F.; Fukasawa, N.; Kashiwagi, Y.; Aizawa, T.;
Fujii, Y.; Ruangrungsi, N.; Murakoshi, I. J. Chem. Soc., Perkin Trans. 1
995, 391−393.
5) (a) Kende, A. S.; Smalley, T. L., Jr.; Huang, H. J. Am. Chem. Soc.
999, 121, 7431−7432. (b) Huang, P-Q; Huang, S-U.; Gau, L-H.;
Mao, Z-Y.; Wang, A-E. Chem. Commun. 2015, 51, 4576−4578.
c) Bruggemann, M.; McDonald, A. I.; Overman, L. E.; Rosen, M. D.;
Schwink, L.; Scott, J. P. J. Am. Chem. Soc. 2003, 125, 15284−15285.
6) (a) Carra, R. J.; Epperson, M. T.; Gin, D. Y. Tetrahedron 2008,
013, 15, 4596−4599.
16) Stork, G.; Tang, P. C.; Casey, M.; Goodman, B.; Toyota, M. J.
(
Am. Chem. Soc. 2005, 127, 16255−16262.
17) Scott, J. D.; Williams, R. M. J. Am. Chem. Soc. 2002, 124, 2951−
956.
18) Reddy, P. V.; Koos, P.; Veyron, A.; Greene, A. E.; Delair, P.
Synlett 2009, 2009, 1141−1143.
19) Choi, Y. M.; Kim, M. E.; An, D. K. Bull. Korean Chem. Soc. 2009,
0, 2825−2826.
20) (a) Alternative Ag(I) sources such as AgOTf or AgOTFA
(
2
(
2
2
(
3
(
(
1
(
1
proved inferior in the intended capacity. (b) Livinghouse, T.
Tetrahedron 1999, 55, 9947−9978.
(
21) Mallory, F. B.; Baker, M. B. J. Org. Chem. 1984, 49, 1323−1326.
(22) Leete, E.; Louters, L. L.; Rao, H. S. P. Phytochemistry 1986, 25,
(
̈
2
(
3
(
753−2758.
23) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769−
772.
24) Kercher, T. S. Development and Synthetic Application of the
(
6
4, 3629−3641. (b) Burns, T.; Helliwell, M.; Thomas, E. J.
Tetrahedron Lett. 2013, 54, 2120−2123. (c) Shanahan, C. S.; Fang,
Allylbis(silane) Cyclization Terminator. Ph. D. Thesis, Montana State
C.; Paull, D. H.; Martin, S. F. Tetrahedron 2013, 69, 7592−7607.
UniversityBozeman, 1997.
(
d) Ideue, E.; Shimokawa, J.; Fukuyama, T. Org. Lett. 2015,
(25) Byrne, P. A.; Rajendran, K. V.; Muldoon, J.; Gilheany, D. G. Org.
DOI: 10.1021/acs.orglett.5b02373.
7) Kercher, T.; Livinghouse, T. J. Am. Chem. Soc. 1996, 118, 4200−
201.
8) For a related study involving the synthetic utilization of 2-
propylidine-1,3-bis(silane) terminated cyclizations involving C-acylni-
trilium cations, see: Kercher, T.; Livinghouse, T. J. Org. Chem. 1997,
2, 805−812.
9) Chamberlin, A. R.; Chung, J. Y. L. J. Am. Chem. Soc. 1983, 105,
653−3656.
10) (a) Hubert, J. C.; Wijnberg, J. B. P. A.; Speckamp, W. N.
Biomol. Chem. 2012, 10, 3531−3537.
(
4
(
(26) Special care should be taken when conducting this reaction
because introduction of the slightest impurity has been observed to
result in greatly diminished yields. The PdCl (PPh ) source used was
2
3 2
a new and unopened bottle purchased from Aldrich.
27) The TFAA source used was shown to be pristine by 19F NMR
(
6
(
3
(
containing only one signal at −75.03 ppm in CDCl .
3
(28) Hoye, T. R.; Aspaas, A. W.; Eklov, B. M.; Ryba, T. D. Org. Lett.
2
005, 7, 2205−2208.
Tetrahedron 1975, 31, 1437. (b) Hiemstra, H.; Klaver, W. J.;
Speckamp, W. N. J. Org. Chem. 1984, 49, 1149. (c) Hiemstra, H.;
Sno, M. H. A. M.; Vijn, R. J.; Speckamp, W. N. J. Org. Chem. 1985, 50,
4
014−4020. (d) Mooiweer, H. H.; Hiemstra, H.; Fortgens, H. P.;
Specamp, W. N. Tetrahedron Lett. 1987, 28, 3285−3288.
11) Lee, Y. S.; Lee, J. Y.; Kim, D. W.; Park, H. Tetrahedron 1999, 55,
631−4636.
12) (a) Grieco, P. A.; Fobare, W. F. Tetrahedron Lett. 1986, 27,
067−5070. (b) Larsen, S. D.; Grieco, P. A.; Fobare, W. F. J. Am.
(
4
(
5
Chem. Soc. 1986, 108, 3512−3513. (c) Hunt, K. W.; Grieco, P. A. Org.
Lett. 2001, 3, 481−484. (d) Pearson, W. H.; Schkeryantz, J. M. J. Org.
Chem. 1992, 57, 2986−2967. (e) Martin, S. F.; Bur, S. K. Tetrahedron
Lett. 1997, 38, 7641−7644.
(
3
(
1
13) Guyot, B.; Pornet, J.; Miginiac, L. Tetrahedron 1991, 47, 3981−
988.
14) Dewar, M. J. S.; Reynolds, C. H. J. Am. Chem. Soc. 1984, 106,
744−1750.
15) For additional references concerning stereoselective annulations
(
involving iminium cations, see: (a) Evans, D. A.; Thomas, E. W.
Tetrahedron Lett. 1979, 20, 411−414. (b) Hiemstra, H.; Klaver, W. J.;
Speckamp, W. N. J. Org. Chem. 1984, 49, 1149. (c) Larsen, S. D.;
Grieco, P. A.; Fobare, W. F. J. Am. Chem. Soc. 1986, 108, 3512−3513.
(
1
d) Hong, C. Y.; Kado, N.; Overman, L. E. J. Am. Chem. Soc. 1993,
15, 11028−11029. (e) Heerding, D. A.; Hong, C. Y.; Kado, N.; Look,
G. C.; Overman, L. E. J. Org. Chem. 1993, 58, 6947−6948. (f) For a
review on silane chemistry see: Fleming, I.; Barbero, A.; Walter, D.
Chem. Rev. 1997, 97, 2063−2192. (g) Agami, C.; Bihan, D.; Hamon,
L.; Kadouri-Puchot, C.; Lusinchi, M. Eur. J. Org. Chem. 1998, 1998,
2
2
461−2465. (h) Amorde, S. M.; Judd, A. S.; Martin, S. F. Org. Lett.
005, 7, 2031−2033. (i) Jung, J.; Shin, D.; Seo, S.; Kim, S.; Paek, S.;
Jung, J.; Suh, Y. Tetrahedron Lett. 2005, 46, 573−575. (j) Judd, W. R.;
Ban, S.; Aube, J. J. Am. Chem. Soc. 2006, 128, 13736−13741.
(
2
1
k) Remuson, R.; Gelas-Mialhe, Y. Mini-Rev. Org. Chem. 2008, 5, 193−
08. (l) Yang, D.; Micalizio, G. C. J. Am. Chem. Soc. 2009, 131,
7548−17549. (m) Amorde, S. M.; Jewett, I. T.; Martin, S. F.
I
DOI: 10.1021/acs.joc.5b01625
J. Org. Chem. XXXX, XXX, XXX−XXX