Total Synthesis of (±)-Crinane from 6,6-Dibromobicyclo[3.1.0]hexane Using a 5- exo- trig Radical Cyclization Reaction to Assemble the C3a-Arylated Perhydroindole Substructure

Article abstract of DOI:10.1021/acs.joc.8b01088

Crinane embodies the tetracyclic framework associated with some of the most common Amaryllidaceae alkaloids. It has now been prepared in 10 steps from 6,6-dibromobicyclo[3.1.0]hexane (2). The initial step involves the thermally induced electrocyclic ring opening of cyclopropane 3 and capture of the resulting π-allyl cation with benzylamine to give an allylic amine that is readily elaborated to the 3°-amine 10. This last compound was engaged in a 5-exo-trig free radical cyclization reaction to give the C3a-arylated perhydroindole 11. Compound 11 was then converted, over two steps, into (±)-crinane, the hydrochloride salt of which has been subjected to single-crystal X-ray analysis.

Full text of DOI:10.1021/acs.joc.8b01088

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Article
Total Synthesis of (±)-Crinane from 6,6-Dibromobicyclo[3.1.0]hexane
Using a 5-Exo-Trig Radical Cyclisation Reaction to
Assemble the C3a-Arylated Perhydroindole Substructure
Ping Lan, Martin G Banwell, and Anthony C Willis
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01088 • Publication Date (Web): 24 May 2018
Downloaded from http://pubs.acs.org on May 24, 2018
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Total Synthesis of (±)-Crinane from 6,6-Dibromobicyclo[3.1.0]hexane Using a 5-Exo-Trig
Radical Cyclisation Reaction to Assemble the C3a-Arylated Perhydroindole Substructure
a
,b,c
b
Ping Lan, Martin G. Banwell,* and Anthony C. Willis
a
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Department of Food Science and Engineering,
Jinan University, Guangzhou, 510632, China
b
Research School of Chemistry, Institute of Advanced Studies,
The Australian National University, Canberra, ACT 2601, Australia
c
College of Pharmacy, Jinan University, Guangzhou, 510632, China
ABSTRACT. (±)ꢀCrinane embodies the tetracyclic framework associated with some of the most
common Amaryllidaceae alkaloids. It has now been prepared in ten steps from 6,6ꢀ
dibromobicyclo[3.1.0]hexane (2). The initial step involves the thermallyꢀinduced electrocyclic
ring opening of cyclopropane 3 and capture of the resulting πꢀallyl cation with benzylamine to
give an allylic amine that is readily elaborated to the 3°ꢀamine 10. This last compound was
engaged in a 5ꢀexoꢀtrig free radical cyclisation reaction to give the C3aꢀarylated perhydroindole
1
1. Compound 11 was then converted, over two steps, into (±)ꢀcrinane, the hydrochloride salt of
which has been subject to singleꢀcrystal Xꢀray analysis.
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Introduction
Natural products possessing the 2,3,4,4aꢀtetrahydroꢀ1H,6Hꢀ5,10bꢀethanophenanthridine
framework 1 (Figure 1) are defined, depending on their absolute configuration, as either
crinine or haemanthamineꢀtype alkaloids. Together they represent a key subclass within the
substantial collection of compounds isolated from the Amaryllidaceae family of herbaceous,
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perennial and bulbous flowering plants.
Figure 1: The 2,3,4,4aꢀtetrahydroꢀ1H,6Hꢀ5,10bꢀethanophenanthridine framework 1 and the
labeling of the associated rings.
A range of significant biological properties has been attributed to such compounds including,
3
for example, antiꢀviral and antiꢀtumor properties. Given this and the oftenꢀlimited availability
of certain of these alkaloids from their natural sources, significant attention has been directed
1
,2,4ꢀ6
toward their synthesis.
Some of these efforts have been focused on the synthesis of
4
,5
compound 1, a.k.a. crinane (which is not itself a natural product). Wildman reported the
4a
first synthesis of (±)ꢀcrinane in 1956, the final step of which involved forming the Dꢀring by
subjecting a C3aꢀarylated perhydroindole (embodying the ACDꢀring system) to a Pictetꢀ
Spengler cyclization reaction. Most, if not all, subsequent syntheses have employed the same
endgame. However, they often vary considerably in the way in which the C3aꢀarylated
perhydroindole and the associated quaternary carbon are constructed. Enantioselective
5
syntheses of crinane have also been reported, particularly in recent years.
We have an ongoing interest in the synthesis of crinaneꢀtype alkaloids and related compounds
and established various means for assembling them, including the use of cyclopropane ringꢀ
6
expansion, intramolecular Alderꢀene cyclisation and Claisenꢀtype rearrangement reactions. In
connection with another study we became interested in establishing the viability of a radical
cyclisation route to Wildman’s C3aꢀarylated perhydroindole. Specifically, we imagined that a
2
ꢀarylated 2ꢀcyclohexenylamine incorporating an Nꢀtethered ethyl radical (Figure 2) might
engage in the required 5ꢀexoꢀtrig process and thereby establish the critical quaternary carbon
center of target 1 as well as the cisꢀconfiguration about the newly formed ringꢀjunction. The
only variant on this approach to crinane framework that we are aware of involved the
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cyclization of trichloroacetamides and thus forming, through an atomꢀtransfer radical
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cyclization (ATRC) process, the corresponding and isomeric lactam. As a result subsequent
reductions were required to remove the carbonyl and chlorines embodied in this product.
Accordingly, we now describe the implementation of the approach shown in Figure 2 that has
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culminated in a total synthesis of (±)ꢀcrinane [(±)ꢀ1].
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Figure 2: Proposed radical cyclisation pathway to a C3aꢀarylated perhydroindole embodying
the ACDꢀring system of crinane (1) (R = H or amine protecting group).
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Results and Discussion
The simple and scalable synthetic sequence leading to a C2ꢀarylated cyclohexꢀ2ꢀenꢀ1ꢀamine is
shown in Scheme 1. Heating
a
neat mixture of readily available 6,6ꢀ
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dibromobicyclo[3.1.0]hexane (2) with a fourꢀfold excess of benzylamine (3) at 120 °C
afforded the desired (previously unreported) allylic amine 4 in 91% yield. This conversion
involved electrocyclic ringꢀopening of the cyclopropane ring and trapping of the resulting πꢀ
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allyl cation. Product 4 was reacted with neat tertꢀbutyl dicarbonate (Boc O) and thus
forming carbamate 5 (96%), spectroscopic analysis of which revealed the presence of
rotamers. SuzukiꢀMiyaura crossꢀcoupling of compound 5 with the commercially available
arylboronic acid 6 using triethylamine as base gave the expected C2ꢀarylated cyclohexꢀ2ꢀenꢀ1ꢀ
amine 7 (90%) and on treatment of this with trifluoroacetic acid (TFA) in dichloromethane the
associated Bocꢀgroup was cleaved and so forming the 2°ꢀamine 8 in 92% yield. The crossꢀ
coupling of amine 4 with acid 6 produced amine 8 directly but only in low yield (<10%) and
thus prompting use of the illustrated reaction sequence.
Scheme 1: Synthesis of 2°ꢀamine 8 from precurors 2 and 3.
The conversion of amine 8 into a substrate suitable for studying the proposed free radical
cyclization reaction is shown in Scheme 2. Thus, compound 8 was exposed to an excess of
ethylene oxide in a pressure tube at 45 °C and thereby affording, through Nꢀalkylation, the
aminoꢀalcohol 9 in 92% yield. In this conversion quaternization at nitrogen is not observed.
This could be explained by the zwiterionic nature of the species formed, which would readily
1
1
fragment to regenerate compound 9. The mesylate derived from alcohol 9 was engaged in a
Finkelstein reaction using sodium iodide in acetone and thus affording the anticipated halide
10 in 92% yield. Compound 10 was a rather unstable material but on exposure to nꢀBu SnH
3
and AIBN in toluene at 90 °C under highꢀdilution conditions the desired reductive radical
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cyclization reaction took place. As a result the C3aꢀarylated perhydroindole 11 was obtained,
after flash chromatographic purification, in 40% yield as a clear, colorless oil. NMR and TLC
analysis of the crude product mixture arising from this cyclization reaction suggested that this
had provided compound 11 as the predominant product and that it was only accompanied by
traces of the reductively deiodinatedꢀform of starting material. We thus attribute the low
yields of the purified product 11 to the difficulties arising from the separation of tinꢀ
containing byꢀproducts that have a propensity to complex or react with amines.
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Scheme 2: The closing stages, incorporating a 5ꢀexoꢀtrig radical cyclization, of a synthesis of
(
±)ꢀcrinane [(±)ꢀ1].
The completion of the synthesis of (±)ꢀcrinane involved the hydrogenolysis of benzylamine 11
with dihydrogen in the presence of Pearlman’s catalyst and using 10:1 v/v methanol/TFA as
4
g
solvent. The spectral data acquired on 2°ꢀamine 12 (75%) matched those reported by Padwa
1
3
(
see Supporting Information ꢀ SI ꢀ for a tabulated comparison of the relevant C NMR
spectroscopic data sets). Reaction of the latter compound with paraformaldehyde in refluxing
formic acid resulted in a PictetꢀSpengler cyclization and the formation of (±)ꢀcrinane [(±)ꢀ1]
that was obtained in 74% yield after chromatographic purification. All the spectroscopic data
4
j
acquired on compound (±)ꢀ1 matched those reported previously by Raghavan (see SI for a
1
3
tabulated comparison of the relevant C NMR spectroscopic data sets). On allowing a
chloroform solution of (±)ꢀcrinane to stand at ambient temperatures crystals formed and an Xꢀ
ray analysis of one of these revealed that this was the hydrochloride salt of (±)ꢀcrinane. Details
1
2
of this analysis are provided in the Experimental Section and the SI.
Conclusions
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The present study has established that a free radical cyclization reaction of the type shown in
Figure 2 provides a viable means for constructing the ACDꢀring system of the crinane
framework. Accordingly, protocols based on the conversion 2 + 3 → 4 shown in Scheme 1
could find utility in the synthesis of crinine and haemanthamineꢀtype alkaloids. An interesting
challenge in carrying this work forward is finding means by which cyclohexꢀ2ꢀenꢀ1ꢀamines
such as 4 could be obtained in homochiral form from the mesoꢀprecursor 2. This would allow
for the synthesis of natural products in either enantiomeric series.
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Experimental Section
General Experimental Procedures
1
13
Unless otherwise specified, proton ( H) and carbon ( C) NMR spectra were recorded at room
temperature in baseꢀfiltered CDCl on a spectrometer operating at 400 MHz for proton and
3
1
1
00 MHz for carbon nuclei. For H NMR spectra, signals arising from the residual protioꢀ
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forms of the solvent were used as internal standards. H NMR data are recorded as follows:
chemical shift (δ) [multiplicity, coupling constant(s) J (Hz), relative integral] where
multiplicity is defined as: s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet or
combinations of the above. The signal due to residual CHCl
central resonance of the CDCl “triplet” appearing at δ
3
appearing at δ
H
7.26 and the
1
3
C
77.0 were used to reference H and
1
3
C NMR spectra, respectively. Infrared spectra (νmax) were recorded on a FTIR Spectrometer.
Samples were analyzed as thin films on KBr plates. Lowꢀresolution ESI mass spectra were
recorded on a single quadrupole liquid chromatographꢀmass spectrometer, while highꢀ
resolution measurements were conducted on a timeꢀofꢀflight instrument. Lowꢀ and highꢀ
resolution EI mass spectra were recorded on a magneticꢀsector machine. Melting points were
measured on an automated melting point system and are uncorrected. Analytical thin layer
chromatography (TLC) was performed on aluminumꢀbacked 0.2 mm thick silica gel 60 F254
plates. Eluted plates were visualized using a 254 nm UV lamp and/or by treatment with a
suitable dip followed by heating. These dips included phosphomolybdic acid : ceric sulfate :
sulfuric acid (conc.) : water (37.5 g : 7.5 g : 37.5 g : 720 mL) or potassium permanganate :
potassium carbonate : 5% sodium hydroxide aqueous solution : water (3 g : 20 g: 5 mL : 300
mL). Flash chromatographic separations were carried out following protocols defined by Still
1
3
et al. with silica gel 60 (40–63 ꢀm) as the stationary phase and using the ARꢀ or HPLCꢀ
grade solvents indicated. Starting materials, reagents and drying agents as well as other
inorganic salts were generally available from commercial sources and used as supplied.
Tetrahydrofuran (THF), diethyl ether, methanol and dichloromethane were dried using a
solvent purification system that is based upon a technology originally described by Grubbs et
14
al. Where necessary, reactions were performed under a nitrogen atmosphere.
Specific Chemical Transformations
N-Benzyl-2-bromocyclohex-2-en-1-amine (4). A magnetically stirred mixture of cycloproꢀ
pane 2 (5.00 g, 21 mmol) and benzylamine (10.0 mL, 92 mmol) was heated at 120 °C (oil
bath temperature) under an atmosphere of nitrogen for 1 h. The cooled reaction mixture was
diluted with ethyl acetate (50 mL) then NH
the separated aqueous phase extracted with ethyl acetate (2 × 40 mL). The combined organics
washed with brine (1 × 40 mL), dried (Na SO ), filtered, and concentrated under reduced
4
Cl (50 mL of a saturated aqueous solution) and
2
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pressure. The ensuing residue was subjected to flash chromatography (silica, 1:9 v/v ethyl
acetate/hexane elution) and concentration of the relevant fractions (R
f
= 0.3 in 5:1 v/v
1
hexane/ethyl acetate) gave allylic amine 4 (5.10 g, 91%) as a paleꢀyellow oil. H NMR (400
MHz, CDCl
H), 3.76 (d, J = 12.9 Hz, 1H), 3.36 (m, 1H), 2.11–2.04 (complex m, 2H), 1.92–1.75
(complex m, 3H), 1.63–1.57 (complex m, 1H) (signal due to NH group proton not observed);
3
) δ 7.40–7.24 (complex m, 5H), 6.21 (t, J = 4.0 Hz, 1H), 3.86 (d, J = 12.9 Hz,
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C NMR (100 MHz, CDCl
3
) δ 140.3, 132.4, 128.3, 128.2, 126.9, 126.4, 58.1, 50.8, 29.2,
2
9
7.9, 18.3; IR νmax 3332, 3027, 2928, 2860, 2833, 1641, 1494, 1452, 1331, 1107, 1066, 1028,
–
1
+•
+•
86 cm ; MS (EI, 70 eV) m/z 267 and 265 (M , 95 and 100%, respectively); HRMS M
79
calcd for C H BrN 265.0466, found: 265.0461.
1
3
16
tert-Butyl Benzyl(2-bromocyclohex-2-en-1-yl)carbamate (5). A mixture of compound 4
5.00 g, 19 mmol) and tertꢀbutyl dicarbonate (4.74 g, 23 mmol) was stirred at 22 °C for 4 h
before being subjected to flash chromatography (silica, 1:9 v/v ethyl acetate/hexane elution).
(
Concentration of the appropriate fractions (R
f
= 0.4 in 5:1 v/v hexane/ethyl acetate) afforded
1
compound 5 (6.60 g, 96%) as a white, crystalline solid: mp = 78–80 °C. H NMR (400 MHz,
CDCl ) δ 7.31–7.21 (complex m, 5H), 6.33 (m, 1H), 5.00 (broad s, 1H), 4.59 (d, J = 16.5 Hz,
3
1
H), 4.00 (broadened d, J = 16.5 Hz, 1H), 2.02–2.01 (complex m, 4H), 1.64 (complex m, 2H),
13
1
.51 (s, 3H), 1.33 (s, 6H); C NMR (100 MHz, CDCl
3
) δ 146.7, 140.1, 134.3, 128.3, 128.1,
126.4, 126.2, 124.5, 85.1, 57.4, 47.6, 29.9, 28.2, 27.4, 21.0 (signal broadening and splitting
evident due to the presence of carbamate rotamers); IR νmax 3031, 2974, 2933, 1690, 1495,
–
1
1
452, 1402, 1365, 1320, 1276, 1252, 1167, 1118, 987 cm ; MS (ESI, +ve) m/z 390 and 388
+
+
79
[
(M+Na) , 98 and 100%, respectively]; HRMS (M+Na) , calcd for C18
88.0888, found: 388.0881.
H
24 BrNO
2
Na
3
tert-Butyl (2-(Benzo[d][1,3]dioxol-5-yl)cyclohex-2-en-1-yl)(benzyl)carbamate (7). A magꢀ
netically stirred solution of carbamate 5 (6.50 g, 17.8 mmol), commercially available
benzo[d][1,3]dioxolꢀ5ꢀylꢀboronic acid (6) (5.16 g, 35.6 mmol), PdCl
2 2 2
dppf•CH Cl (900 mg,
1
.25 mmol) and triethylamine (18 mL) in THF/water (60 mL of a 9:1 v/v mixture) was purged
with nitrogen for 0.25 h then heated under reflux for 2 h. The reaction mixture was then
cooled, poured into water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The
combined organic layers were washed with brine (1 × 50 mL) before being dried (Na SO ),
2
4
filtered and concentrated under reduced pressure. The resulting lightꢀyellow oil was subjected
to flash chromatography (silica, 1:9 v/v ethyl acetate/hexane elution) to afford, after
concentration of the relevant fractions (R
f
= 0.3 in 5:1 v/v hexane/ethyl acetate), coupling
1
product 7 (6.50 g, 90%) as a colorless foam. H NMR (400 MHz, CDCl ) δ 7.23–7.19
3
(
complex m, 2H), 7.16–7.12 (complex m, 2H), 7.05 (m, 1H), 6.88–6.85 (complex m, 2H),
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6.74 (m, 1H), 6.09 (broad s, 1H), 5.91 (m, 2H), 5.50 (broad s, 1H), 3.99 (d, J = 16.5 Hz, 1H),
3
9
1
.85 (d, J = 16.5 Hz, 1H), 2.12–2.08 (complex m, 4H), 1.68–1.66 (complex m, 2H), 1.22 (s,
1
3
H); C NMR (100 MHz, CDCl ) δ 156.0, 147.3, 146.3, 140.3, 138.7, 134.7, 130.0, 127.7,
3
25.9, 119.3, 107.7, 106.8, 100.6, 79.2, 52.8, 46.9, 29.2, 28.3, 27.9, 25.5, 20.9 (signal
broadening and splitting evident due to the presence of carbamate rotamers); IR νmax 3028,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
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2
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4
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6
7
8
9
0
2975, 2933, 1690, 1605, 1504, 1488, 1444, 1404, 1365, 1278, 1245, 1225, 1167, 1118, 1040,
–
1
+•
1
002, 966, 938, 905 cm ; MS (EI, 70 eV) m/z 407 (M , 20%), 351 (20), 200 (100%); HRMS
+
•
M calcd for C25
4
H29NO 407.2097, found 407.2095.
2-(Benzo[d][1,3]dioxol-5-yl)-N-benzylcyclohex-2-en-1-amine (8). A magnetically stirred
solution of compound 7 (6.50 g, 16 mmol) in anhydrous dichloromethane (100 mL)
maintained at 22 °C under an atmosphere of nitrogen was treated with trifluoroacetic acid (15
mL). The resulting solution stirred for 1.25 h then treated with sodium hydroxide (4 M
aqueous solution) so as to attain pH 14. The separated aqueous phase was extracted with
2 4
dichloromethane (3 × 75 mL) and the combined organic phases then dried (Na SO ), filtered
and concentrated under reduced pressure. The residue thus obtained was subjected to flash
chromatography (silica, 1:3 v/v ethyl acetate/hexane elution) to afford, after concentration of
the appropriate fractions (R
f
= 0.4 in 3:1 v/v hexane/ethyl acetate) amine 8 (4.50 g, 92%) as a
) δ 7.31–7.21 (complex m, 5H), 6.90–6.81
1
clear, colorless oil; H NMR (400 MHz, CDCl
3
(complex m, 1H), 6.78–6.71 (complex m, 2H), 5.97 (t, J = 4.0 Hz, 1H), 5.94 (s, 2H), 3.84 (d,
J = 13.2 Hz, 1H), 3.68 (d, J = 13.2 Hz, 1H), 3.63 (m, 1H), 2.23–2.13 (complex m, 2H), 2.03–
1.96 (complex m, 1H), 1.84–1.72 (complex m, 1H), 1.73–1.60 (complex m, 2H), 1.45 (broad
1
3
s, 1H); C NMR (100 MHz, CDCl
3
) δ 147.6, 146.4, 140.4, 139.1, 135.4, 128.2, 128.1, 127.5,
126.7, 119.3, 108.0, 106.8, 100.8, 52.1, 51.3, 27.3, 26.1, 17.6; IR νmax 3026, 2932, 2829,
–
1
1752, 1604, 1502, 1488, 1439, 1244, 1218, 1102, 1039, 936 cm ; MS (EI, 70 eV) m/z 307
+
•
+•
(
2
M , 10%), 279 (31), 200 (100), 91 (52); HRMS M calcd for C20H21NO 307.1572, found
307.1573.
2-((2-(Benzo[d][1,3]dioxol-5-yl)cyclohex-2-en-1-yl)(benzyl)amino)ethan-1-ol (9). A soluꢀ
tion of amine 8 (4.00 g, 13 mmol) in methanol (20 mL) was distributed equally between two
sealable pressure tubes and these then cooled to 0 °C before ethylene oxide (5 mL, 100 mmol)
was added to each tube. The tubes were sealed and the contents of each heated at 45 °C for 8 h
before being reꢀcooled to 0 °C, unsealed and then allowed to warm to 22 °C over 18 h. The
residue in each tube was transferred, with the aid of ethyl acetate, to a roundꢀbottomed flask
and resulting solution concentrated under reduced pressure. The residue thus obtained was
subjected to flash chromatography (silica, 1:3 v/v ethyl acetate/hexane elution) to afford, after
f
concentration of the relevant fractions (R = 0.4 in 3:1 v/v hexane/ethyl acetate), aminoꢀ
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alcohol 9 (4.20 g, 92%) as a clear, colorless oil. H NMR (400 MHz, CDCl
3
) δ 7.29–7.24
(
complex m, 3H), 7.02–7.00 (complex m, 2H), 6.74 (d, J = 8.0 Hz, 1H), 6.61–6.57 (complex
m, 2H), 6.05 (m, 1H), 5.95 (dd, J = 7.4 and 1.5 Hz, 2H), 3.83 (broad s, 1H), 3.75 (d, J = 13.0
Hz, 1H), 3.51 (m, 1H), 3.40 (d, J = 13.0 Hz, 1H), 3.23 (m, 1H), 2.71 (m, 1H), 2.58 (m, 1H),
13
2
.20–2.15 (complex m, 2H), 2.00–1.75 (complex m, 4H), 1.66ꢀ1.60 (complex m, 1H);
C
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NMR (100 MHz, CDCl ) δ 147.3, 146.2, 139.7, 139.2, 135.6, 130.4, 129.2, 128.1, 127.1,
3
1
2
3
3
20.0, 107.7, 107.5, 100.8, 58.3, 54.8, 53.5, 50.8, 25.9, 21.6, 21.0; IR νmax 3467, 3026, 2932,
–
1
833, 1604, 1503, 1487, 1438, 1370, 1244, 1222, 1123, 1042, 935 cm ; MS (EI, 70 eV) m/z
+•
+•
51 (M , 7%), 320 (100), 201 (73), 120 (70), 91 (56); HRMS M calcd for C22
51.1834, found 351.1820.
H25NO
3
2-(Benzo[d][1,3]dioxol-5-yl)-N-benzyl-N-(2-iodoethyl)cyclohex-2-en-1-amine (10). Step i:
A magnetically stirred solution of aminoꢀalcohol 9 (3.90 g, 11 mmol) in anhydrous THF (30
mL) maintained at 22 °C under an atmosphere of nitrogen was treated with triethylamine (2
mL, 14 mmol) then methanesulfonyl chloride (1.50 mL, 14.0 mmol). The resulting solution
stirred for 2 h before being filtered through a pad of diatomaceous earth that was washed with
Et O (50 mL). The combined filtrates were concentrated under reduced pressure to give a
2
lightꢀyellow oil.
Step ii: A magnetically stirred solution of the oil obtained from step i in acetone (40 mL)
maintained at 22 °C under an atmosphere of nitrogen was treated with sodium iodide (8.00 g,
5
3.3 mmol). The ensuing mixture was stirred for 3 h then filtered through a pad of
diatomaceous earth that was washed with ethyl acetate (2 × 60 mL). The combined filtrates
were concentrated under reduced pressure and the residue thus obtained dissolved in ethyl
acetate (100 mL) and the solution soꢀformed washed with Na
2 2 3
S O (50 mL of a 5 % w/v
aqueous solution) before being dried (Na SO ), filtered and concentrated under reduced
2
4
f
pressure to afford the title iodide 10 (4.70 g, 92%) as a paleꢀyellow oil, R = 0.7 (in 5:1 v/v
1
hexane/ethyl acetate). H NMR (400 MHz, CDCl
3
) δ 7.26–7.20 (complex m, 3H), 7.03–7.01
(
complex m, 2H), 6.74 (d, J = 8.0 Hz, 1H), 6.70–6.67 (complex m, 2H), 6.01 (m, 1H), 5.98 (s,
2
H), 3.80 (m, 1H), 3.67 (d, J = 13.5 Hz, 1H), 3.52 (d, J = 13.5 Hz, 1H), 2.88–2.73 (complex
m, 3H), 2.37 (m, 1H), 2.17–2.13 (complex m, 2H), 1.98 (m, 1H), 1.82–1.68 (complex m, 2H),
1
3
1
1
2
4
.59 (m, 1H); C NMR (100 MHz, CDCl
3
) δ 147.0, 146.1, 140.1, 139.8, 136.2, 130.1, 128.8,
28.0, 127.0, 120.3, 107.9, 107.5, 100.7, 57.0, 55.0, 53.9, 25.9, 23.1, 21.0, 5.6; IR νmax 3025,
–
1
931, 2833, 1604, 1502, 1487, 1436, 1244, 1222, 1196, 1039, 936 cm ; MS (EI, 70 eV) m/z
+•
+•
61 (M , 5%), 433 (13), 320 (40), 300 (42), 200 (100), 91(56); HRMS M calcd for
461.0852, found 461.0840.
22 2
C H24INO
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This rather lightꢀsensitive and otherwise unstable material was used immediately in the next
step of the reaction sequence.
cis-3a-(Benzo[d][1,3]dioxol-5-yl)-1-benzyloctahydro-1H-indole (11). A magnetically stirrꢀ
ed solution of iodide 10 (2.00 g, 4.34 mmol) in anhydrous toluene (250 mL) maintained at 90
°
C under an atmosphere of nitrogen was treated with AIBN (290 mg, 1.77 mmol, added in
1
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2
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2
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3
3
3
3
4
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4
4
4
4
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5
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5
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1
2
3
4
5
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7
8
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1
2
3
4
5
6
7
8
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2
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4
5
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7
8
9
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9
0
three equal portions over 2 h) then, dropwise over 2.5 h, with a solution of triꢀnꢀbutyltin
hydride (1.92 mL, 7.2 mmol) in anhydrous toluene (50 mL). The reaction mixture thus
obtained was then cooled, concentrated under reduced pressure and the ensuing residue
dissolved in ethyl acetate (100 mL). The resulting solution was stirred with KF (40 mL of a 1
M aqueous solution) for 0.66 h and the ensuing suspension was filtered through a pad of
diatomaceous earth that was washed with ethyl acetate (100 mL). The combined filtrates were
washed with brine (1 x 100 mL) before being dried (Na
reduced pressure. The residue thus obtained was subjected to flash chromatography (silica, 1:7
v/v ethyl acetate/hexane elution) to afford, after concentration of the appropriate fractions (R
0.5 in 5:1 v/v hexane/ethyl acetate), the title compound 11 (580 mg, 40%) as a clear,
2 4
SO ), filtered and concentrated under
f
=
1
colorless oil. H NMR (400 MHz, CDCl
3
) δ 7.41 (m, 2H), 7.35 (m, 2H), 7.28 (m, 1H), 6.94
(
broadened s, 1H), 6.89 (dd, J = 8.2 and 1.9 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 5.95 (s, 2H),
4.17 (d, J = 13.3 Hz, 1H), 3.20 (d, J = 13.3 Hz, 1H), 3.09 (m, 1H), 2.98 (broad t, J = 2.7 Hz,
1H), 2.30 (m, 1H), 2.07 (m, 1H), 1.92 (m, 2H), 1.85–1.80 (complex m, 3H), 1.69 (m, 1H),
13
1
.55 (m, 1H), 1.42–1.38 (complex m, 1H), 1.31–1.24 (complex m, 1H); C NMR (100 MHz,
CDCl ) δ 147.5, 145.0, 141.4, 140.5, 128.3, 128.1, 126.5, 119.6, 107.7, 107.6, 100.7, 66.0,
3
5
1
7.8, 51.0, 47.6, 40.6, 35.0, 24.1, 23.0, 20.5; IR νmax 3027, 2930, 2855, 2797, 1607, 1506,
–1
+•
487, 1452, 1376, 1342, 1233, 1041, 937 cm ; MS (EI, 70 eV) m/z 335 (M , 100%), 334
+
•
(92), 91 (76); HRMS M calcd for C H NO 335.1885, found 335.1888.
2
2
25
2
cis-3a-(Benzo[d][1,3]dioxol-5-yl)octahydro-1H-indole (12). A magnetically stirred mixture
of benzylamine 11 (160 mg, 0.48 mmol), Pd(OH) (50 mg, 20% w/w on charcoal) and
2
trifluoroacetic acid (1 mL, 13 mmol) in methanol (10 mL) was maintained under a balloon of
hydrogen for 10 h then flushed with nitrogen. The mixture thus obtained was concentrated
under reduced pressure and the residue treated with NaOH (20 mL of a 20% w/v aqueous
solution) and methanol (20 mL) before being filtered and the filtrate concentrated under
reduced pressure. The ensuing residue was partitioned between water (30 mL) and chloroform
(50 mL). The separated aqueous phase was extracted with chloroform (2 x 30 mL) then the
2 4
combined organic phases dried (Na SO ), filtered and concentrated under reduced pressure.
The residue thus obtained was subjected to flash chromatography (silica, 1:10 v/v ammoniaꢀ
saturated methanol/chloroform elution) to afford, after concentration of the appropriate
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fractions (R
f
= 0.7), the title compound 12 (88 mg, 75%) as a clear, colorless oil. H NMR
(
400 MHz, CDCl ) δ 6.86 (d, J = 1.8 Hz, 1H), 6.80 (dd, J = 9.5 and 1.8 Hz, 1H), 6.75 (d, J =
3
9
.5 Hz, 1H), 5.91 (s, 2H), 3.40 (t, J = 4.3 Hz, 1H), 3.15–3.08 (complex m, 1H), 3.01–2.95
(
complex m, 1H), 2.16 (broad s, 1H), 2.02–1.95 (complex m, 1H), 1.91–1.82 (complex m,
H), 1.82–1.72 (complex m, 3H), 1.70 (m, 1H), 1.52–1.42 (complex m, 3H), 1.26–1.20
1
1
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(complex m, 1H); C NMR (100 MHz, CDCl ) δ 147.5, 145.2, 141.0, 119.3, 107.7, 107.5,
3
1
1
00.8, 61.0, 47.9, 43.1, 41.4, 33.9, 26.3, 22.1, 21.1; IR νmax 3325, 2930, 1687, 1610, 1506,
–
1
+•
488, 1432, 1233, 1204, 1128, 1039, 934 cm ; MS (EI, 70 eV) m/z 245 (M , 100%) 244
+
•
(96); HRMS M calcd for C H NO 245.1416, found: 245.1416.
15 19 2
(
±)-Crinane [(±)-1]. A magnetically stirred solution of amine 12 (70 mg, 0.29 mmol) in
formic acid (10 mL) maintained at 22 °C under a nitrogen atmosphere was treated with
paraformaldehyde (150 mg). The resulting mixture was heated under reflux for 18 h then
cooled and concentrated under reduced pressure. The residue thus obtained was dissolved in
chloroform (20 mL) and resulting solution treated with NaOH (20% w/v aqueous solution) so
as to attain pH 14. The separated aqueous phase was extracted chloroform (2 x 50 mL) and the
combined organic phases were dried (Na SO ) before being filtered then concentrated under
2
4
reduced pressure. The residue so obtained was subjected to flash chromatography (silica, 1:10
v/v ammoniaꢀsaturated methanol/chloroform) to afford, after concentration of the relevant
1
fractions (R
f
= 0.4), compound (±)ꢀ1 (54 mg, 74%) as a clear, colorless oil. H NMR (400
MHz, CDCl ) δ 6.60 (s, 1H), 6.37 (s, 1H), 5.79 (s, 2H), 4.34 (d, J = 16.6 Hz, 1H), 3.75 (d, J =
3
1
6.6 Hz, 1H), 3.40 (m, 1H), 2.88–2.76 (complex m, 2H), 2.25–2.15 (complex m, 2H), 1.82
13
(
m, 1H), 1.73–1.64 (complex m, 3H), 1.56–1.38 (complex m, 2H), 1.17 (m, 2H); C NMR
100 MHz, CDCl ) δ 146.3, 145.6, 140.9, 123.9, 106.0, 103.0, 100.5, 67.2, 61.0, 51.5, 42.7,
(
3
36.9, 28.4, 26.6, 23.7, 21.2; IR νmax 2932, 2854, 1504, 1481, 1242, 1232, 1094, 1041, 1000,
–
1
+•
+•
9
38, 909 cm ; MS (EI, 70 eV) m/z 257 (M , 100%), 228 (70); HRMS M calcd for
16 2
C H19NO
257.1416, found 257.1415.
The hydrochloride salt of (±)ꢀcrinane was obtained by allowing a chloroform solution of the
free base to stand at ambient temperatures in an open vessel until crystals formed. One of
these crystals was subjected to singleꢀcrystal Xꢀray analysis (see below and in the SI for
details).
Crystallographic Study on Compound (±)-1•HCl
Crystal data
2
Compound (±)-1•HCl: C16H19NO •HCl, M = 293.79, T = 200(1) K, triclinic, space group P1,
Z = 2, a = 7.0293(3), b = 9.9371(7), c = 11.3882(8) Å, α = 111.307(3)°, β = 101.280(4)°, γ =
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–3
92.617(4), V = 720.83(8) Å , D
2.0σ(I); R = 0.042, Rw = 0.110, S = 1.00.
Structure Determination
Images were measured on a Nonius Kappa CCD diffractometer (MoKα, graphite
x
= 1.354 g.cm , 3294 unique data (2θmax = 55°), 2597 with I
>
1
5
monochromator, λ = 0.71073 Å) and data extracted using the DENZO package. Structure
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
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6
solution was by direct methods (SIR92). The structure of compound (±)ꢀ1•HCl was refined
1
7
using the CRYSTALS program package. Atomic coordinates, bond lengths and angles, and
displacement parameters have been deposited at the Cambridge Crystallographic Data Centre
(
CCDC Deposition number 1840264). These data can be obtained freeꢀofꢀcharge via
www.ccdc.cam.ac.uk/data_request/cif, by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
ASSOCIATED CONTENT
Supporting Information
Cif and anisotropic displacement ellipsoid plot from the singleꢀcrystal Xꢀray analysis of
1
13
compound (±)ꢀ1•HCl. H and C NMR spectra of compounds 4, 5, 7ꢀ12 and (±)ꢀ1. This
material is available freeꢀofꢀcharge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*
Tel: +61ꢀ2ꢀ6125ꢀ8202. Fax: +61ꢀ2ꢀ6125ꢀ8114. Eꢀmail: Martin.Banwell@anu.edu.au
ORCID
Martin G. Banwell: 0000ꢀ0002ꢀ0582ꢀ475X
Ping Lan: 0000ꢀ0002ꢀ9285ꢀ3259
Author Contributions
The manuscript was written through contributions from all of the authors. All of the authors
have given approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank the Australian Research Council, the Institute of Advanced Studies at the
Australian National University, Jinan University, the Pearl River Scholar Program of
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Guangdong Province and the Famous Foreign Supervisor Program (grant 2018ꢀHWMS001)
of the Ministry of Education, People’s Republic of China for financial support.
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(±)ꢀ3′ꢀMethoxyꢀ4′ꢀOꢀmethyljoubertꢀ
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. For enantioselective syntheses of crinane, see: (a) Grigg, R.; Santhakumar, V.;
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