Catalytic and enantioselective synthesis of a key intermediate of the MCHr1 antagonist AMG 076

Article abstract of DOI:10.3987/COM-14-S(K)64

A chiral decahydroisoquinoline was constructed using our asymmetric Diels-Alder reaction catalyzed by a chiral Yb (ytterbium) complex as a key step. The decahydroisoquinoline is a synthetic intermediate of the anti-obesity drug candidate AMG 076 (Amgen).

Full text of DOI:10.3987/COM-14-S(K)64

HETEROCYCLES, Vol. 90, No. 2, 2015
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HETEROCYCLES, Vol. 90, No. 2, 2015, pp. 967 - 977. © 2015 The Japan Institute of Heterocyclic Chemistry
Received, 30th June, 2014, Accepted, 30th July, 2014, Published online, 4th August, 2014
DOI: 10.3987/COM-14-S(K)64
CATALYTIC AND ENANTIOSELECTIVE SYNTHESIS OF A KEY
INTERMEDIATE OF THE MCHr1 ANTAGONIST AMG 076
Shinji Harada, Haruka Ishii, Daisuke Shirasaki, and Atsushi Nishida*
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana,
Chuo-ku, Chiba 260-8675, Japan. E-mail: nishida@p.chiba-u.ac.jp
Abstract – A chiral decahydroisoquinoline was constructed using our asymmetric
Diels-Alder reaction catalyzed by a chiral Yb (ytterbium) complex as a key step.
The decahydroisoquinoline is a synthetic intermediate of the anti-obesity drug
candidate AMG 076 (Amgen).
INTRODUCTION
Biologically active compounds have various types of polycyclic skeletons. The construction of such
skeletons in a chiral form with the least amount of waste is still a major challenge for synthetic organic
chemists and medicinal chemists.
Scheme 1. Our Ytterbium-Catalyzed Asymmetric Diels-Alder Reaction of Danishefsky Diene
We have developed Yb(OTf)3/chiral bis-amide (or bis-urea) ligand/DBU ternary catalyst.1 This catalyst
can activate various dienophiles which possess an oxazolidinone unit, and promote the asymmetric
Diels-Alder reaction with Danishefsky diene2 to give highly functionalized chiral cyclohexenes and
cyclohexenones (Scheme 1). Only exo adducts are obtained in high yields and ees, and we have
demonstrated conversions of these adducts, including the total synthesis of (–)-Platyphillide.3 We
demonstrate here a new synthetic application of our Diels-Alder adduct by constructing chiral
decahydroisoquinoline, which is a key synthetic intermediate of AMG 076.
AMG 076 is an antagonist of MCHr1 (Melanin-Concentrating Hormone receptor 1), which was
developed by Amgen Inc. as a potent anti-obesity drug.4 MCH regulates food intake and the energy

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balance, and MCHr1 knockout mice have been shown to lose weight due to reduced food intake.5 The
structure of AMG 076 contains a tetracyclic skeleton including two heterocycles and three continuous
chiral stereocenters (Scheme 2). Amgen reported the synthesis of this compound through Fischer-indole
synthesis and reductive amination from key intermediate 2 having a decahydroisoquinoline core.6
However, the synthetic route to 2 involved the generation of regio- and stereoisomers besides optical
resolution, and resulted in low overall yield. Therefore, the regio- and stereoselective synthesis of
optically active 2 in a catalytic manner should make possible the environmentally benign supply of AMG
076. We envisioned that the hydroisoquinoline skeleton of AMG 076 could be synthesized from our
Diels-Alder adduct.
Scheme 2. Structures of AMG 076 and Key Synthetic Intermediate 2 reported by Amgen
RESULTS AND DISCUSSION
Our ytterbium-catalyzed asymmetric Diels-Alder reaction of Danishefsky diene (1) and electron-deficient
olefin 3 afforded substituted cyclohexene 5 as a single isomer in 94% yield and 97% ee using chiral
bis-urea ligand 4. This reaction is tolerant to gram-scale synthesis (Scheme 3).
Scheme 3. Catalytic and Asymmetric Diels-Alder Reaction
Reductive removal of the oxazolidone moiety of 5 gave primary alcohol 6 after acidic treatment to form
cyclohexenone (Scheme 4). Subsequent protection of the alcohol with TES afforded 7 in 78% yield in 2
steps. 1,4-Addition of a vinyl group successfully proceeded to give 8 in 93% yield as a single isomer. At

HETEROCYCLES, Vol. 90, No. 2, 2015
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this stage, all of the stereocenters required for the synthesis of AMG 076 were constructed, and it is
noteworthy that no diastereoisomer was generated during this synthesis. Removal of a silyl protective
group and ketal formation gave 10 in good yields.
Scheme 4. Transformations of the Diels-Alder Adduct
Alcohol 10 under Mitsunobu conditions formed nosyl amine 11. NIS-mediated cyclization proceeded
smoothly to give decahydroisoquinoline 12 as a single isomer. We next tried the deiodination of 12 under
reductive conditions. Tributyltin hydride did not work at all with AIBN or ultrasound (entries 1 and 2,
Scheme 5).7 Sodium borohydride in DMSO8 decomposed the substrate (entry 3). Samarium iodide9 did not
remove the iodine, but rather reduced the nitro group on the nosyl unit to give compound 14 (entry 4).
Deiodination occurred with palladium chloride and triethylsilane (entry 5),10 where reduction of the nitro
group was inevitable.
Scheme 5. Construction of an N-Nosyl Piperidine Ring Using NIS, and Trials for the Removal of Iodine

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Since nosyl protection created problems for the deiodination process, we went back to alcohol 10 and
planned to change the protective group. TPAP oxidation of the primary alcohol to an aldehyde, reductive
amination, and sequential iodine-mediated amino-cyclization proceeded smoothly to give bicyclic
compound 18 in 87% yield in 3 steps (Scheme 6). The reductive cleavage of iodine with tributyltin
hydride and AIBN followed by deprotection afforded decahydroisoquinolone 20 in 94% yield. A Boc
group was successfully introduced to nitrogen under pressurized hydrogen in the presence of Pd(OH)2 and
Boc2O, and we achieved the synthesis of 2 in 38% overall yield from olefin 3 in 12 steps. Although this
route is longer than that reported by Amgen (19% overall yield in 7 steps), the overall yield is better
because we avoid the need for optical resolution.
Scheme 6. Synthetic Route to the Key Intermediate 2 of AMG 076
In conclusion, we have demonstrated the synthetic utility of our Diels-Alder reaction of Danishefsky
diene by synthesizing a key intermediate of the MCHr1 antagonist AMG 076. While the overall number
of steps is greater than that in the original synthetic route described by Amgen, the overall yield is better
because our route generates no regio- and diastereoisomers, and we can avoid the need for optical
resolution.
EXPERIMENTAL
General Methods: All reactions involving air- or moisture-sensitive reagents or intermediates were
performed under an inert atmosphere of argon in glassware. Unless otherwise noted, solvents and
reagents were reagent grade and used without further purification. DBU was distilled from CaH2.
Anhydrous THF, CH2Cl2 and toluene were used as received from Kanto, Chemical CO., INC. Analytical
and preparative TLC were carried on E. Merck 0.25 mm silica gel 60 F254 plates. Silica gel column
chromatography was performed using Fuji Silysia Chemical Ltd. Silica gel PSQ 60B. Celite® 545 was
purchased from Aldrich. Optical rotations were measured on a JASCO P-1000 polarimeter at 589 nm.

HETEROCYCLES, Vol. 90, No. 2, 2015
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1
13
Data are reported as follows: []Ltemp., concentration (c g/100 mL), and solvent. H NMR and C NMR
1
13
spectra were taken on 400 MHz, 600 MHz for H, and 100 MHz, 150 MHz for C instruments (JEOL
LNM-GSX 400, JEOL JNM-ECS 400, JEOL JNM-ECP 400, JEOL JNM-ECP 600) in the indicated solvent
1
13
at rt. H NMR spectra was recorded with (CH3)4Si (TMS) as an internal reference  0.00 ppm, and C
NMR spectra was recorded with CDCl3 as an internal reference  77.0 ppm. Coupling constants are
reported in hertz (Hz). Spectral splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br, broad. Infrared (IR) spectra was recorded on JASCO FT/IR-230 spectrometer.
MS spectrometry was recorded using ESI mode. High performance liquid chromatography (HPLC)
analyses were performed on Shimadzu LC-2010C (Shimadzu Ind., Ltd.), with detection at 254 nm, and
on Chiralcel OJ-H, Daicel Chemical Ind., Ltd.
(4R,5S)-5-Methyl-4-(((triethylsilyl)oxy)methyl)cyclohex-2-enone (7).
To solution of 5 (150 mg, 0.41 mmol) in THF (4 mL) was added MeOH (60 mL, 1.23 mmol) and LiBH4
(2.0 M in THF, 0.62 mL, 1.23 mmol) slowly at 0 °C. The mixture was stirred for 1.5 h at room
temperature. The reaction was quenched by addition of 1N HCl at 0 °C and stirred for additional 20 min
at same temperature. The mixture was extracted with CHCl3, the combined organic layers were washed
with brine, dried over Na2SO4 and concentrated under reduced pressure to give the crude alcohol 6 as
yellow oil which was used to next reaction without further purification.
To a solution of 6 (~0.41 mmol) in pyridine (4 mL) was added TESCl (0.1 mL, 0.62 mmol) at room
temperature. The mixture was stirred for 0.5 h at same temperature. The reaction was quenched by the
addition of sat. NH4Cl aq. and extracted with CH2Cl2. The combined organic layers were washed with
brine and dried over Na2SO4. After concentration under reduced pressure, the resulting residue was
purified by flash column chromatography (SiO2, hexane/AcOEt = 20/1) to give 7 (80 mg, yield 78%, 2
1
steps) as colorless oil; H NMR (CDCl3, 400 MHz)  0.61 (6H, q, J = 7.6 Hz), 0.97 (9H, t, J = 7.6 Hz),
1.08 (3H, d, J = 6.0 Hz), 2.06-2.24 (3H, m), 2.49 (1H, dd, J = 2.8, 15.2 Hz), 3.60 (1H, dd, J = 6.8, 10.0
Hz), 3.86 (1H, dd, J = 4.8, 10.0 Hz). 6.04 (1H, dd, J = 2.4, 10.0 Hz), 6.99 (1H, dd, J = 2.4, 10.0 Hz); 13C
NMR (CDCl3, 100 MHz) 4.28, 6.73, 19.6, 31.1, 45.2, 46.1, 63.1, 129.5, 152.4, 200.0; IR (neat) 1679 cm-1;
25
HRMS(ESI) m/z calcd for C14H26O2SiNa [M+Na]+ 277.1600, found 277.1592 ; []D +123.2 (c 1.01,
CHCl3).
(3S,4R,5S)-3-Methyl-4-(((triethylsilyl)oxy)methyl)-5-vinylcyclohexanone (8).
To a solution of CuI (23 mg, 0.12 mmol) in THF (1.2 mL) was added vinylMgBr (1.0 M in THF, 0.24 mL,
0.24 mmol) at –78 °C. After being stirred for 30 min, a solution of 7 (30.5 mg, 0.12 mmol) in THF (1
mL) was gradually added to the reaction mixture at –78 °C and then stirred for 1 h at the same
temperature. The reaction was quenched by addition of sat. NH4Cl aq. and extracted with AcOEt. The
combined organic layers were washed with brine and dried over Na2SO4. After concentration under

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HETEROCYCLES, Vol. 90, No. 2, 2015
reduced pressure, the resulting residue was purified by flash column chromatography (SiO2,
hexane/AcOEt = 20/1) to give 8 (31.8 mg, yield 93%) as yellow oil. 1H NMR (CDCl3, 400 MHz)  0.56
(6H, q, J = 8.0 Hz), 0.94 (9H, t, J = 8.0 Hz), 1.05 (3H, d, J = 5.6 Hz), 1.07-1.22 (1H, m), 2.07-2.13 (2H,
m), 2.26 (1H, dd, J = 13.2, 14.0 Hz), 2.34-2.39 (2H, m), 2.60-2.68 (1H, m), 3.71 (1H, dd, J = 2.4, 10.0
Hz), 3.77 (1H, dd, J = 2.4, 10.0 Hz), 5.04-5.08 (2H, m), 5.64 (1H, ddd, J = 8.8, 10.0, 18.8 Hz); 13C NMR
(CDCl3, 100 MHz)  4.29, 6.82, 20.2, 32.6, 43.4, 47.5, 49.0, 49.3, 59.6, 115.6, 140.6, 210.7; IR (neat) 1717
cm-1; HRMS(ESI) m/z calcd for C16H30O2SiNa [M+Na]+ 305.1913, found 305.1920 ; []D21 +10.5 (c 1.00,
CHCl3).
(3S,4R,5S)-4-(Hydroxymethyl)-3-methyl-5-vinylcyclohexanone (9).
To a solution of 8 (37.0 mg, 0.13 mmol) in THF (1.23mL) was added TBAF (1.0 M in THF, 0.26 mL,
0.26 mmol) at 0 °C. The mixture was stirred for 0.5 h at same temperature. The reaction was quenched by
addition of water and extracted with AcOEt. The combined organic layers were washed with brine and
dried over Na2SO4. After concentration under reduced pressure, the resulting residue was purified by flash
1
column chromatography (SiO2, hexane/AcOEt = 2/1) to give 9 (20.7 mg, yield 95%) as yellow oil. H
NMR (CDCl3, 400 MHz)  1.11 (3H, d, J = 6.8 Hz), 1.26-1.33 (1H, m), 1.97-2.06 (1H, m), 2.14 (1H, dd,
J = 12.8, 13.6 Hz), 2.29 (1H, dd, J = 12.8, 13.6 Hz), 2.36-2.43 (2H, m), 2.53-2.62 (1H, m), 3.83 (2H, d, J
= 2.8 Hz), 5.08-5.16 (2H, m), 5.7 (1H, ddd, J = 8.8, 10.0, 19.2 Hz); 13C NMR (CDCl3, 100 MHz)  20.2,
32.7, 44.2, 47.2, 48.9, 49.3, 60.5, 116.0, 140.5, 209.8; IR (neat) 3412, 1700 cm-1; HRMS(ESI) m/z calcd
for C10H17O2 [M+H]+ 169.1223, found 169.1230; []D23 –29.1 (c 1.00, CHCl3).
((7S,8R,9S)-7-Methyl-9-vinyl-1,4-dioxaspiro[4.5]decan-8-yl)methanol (10).
To a solution of 9 (22.0 mg, 0.13 mmol) in benzene (5 mL) was added ethylene glycol (70 mL, 1.3 mmol)
and p-TsOH·H2O (2 mg, 0.013 mmol) and the mixture was stirred for 1.5 h under reflux conditions. The
reaction was quenched by addition of sat. NaHCO3 aq. and extracted with AcOEt. The combined organic
layers were washed with brine and dried over Na2SO4. After concentration under reduced pressure, the
resulting residue was purified by flash column chromatography (SiO2, hexane/AcOEt = 3/1) to give 10
(24.5 mg, yield 89%) as yellow oil. 1H NMR (CDCl3, 400 MHz)  0.85-0.92 (1H, m), 1.01 (3H, d, J = 6.4
Hz), 1.34 (1H, dd, J = 12.4, 13.2 Hz), 1.41 (1H, brs), 1.48 (1H, dd, J = 12.4, 13.2 Hz), 1.72-1.86 (3H, m),
2.36-2.45 (1H, m), 3.74 (2H, s), 3.95 (4H, s), 5.04 (1H, dd, J = 1.6, 10.0 Hz), 5.14 (1H, dd, J = 1.6, 16.8
13
Hz), 5.67 (1H, ddd, J = 9.6, 9.6, 19.2 Hz); C NMR (CDCl3, 100 MHz)  19.8, 29.6, 41.3, 42.2, 43.4,
49.3, 61.4, 64.2, 64.4, 108.1, 115.1, 142.2; IR (neat) 3440, 1137 cm-1; HRMS(ESI) m/z calcd for C12H20O3
[M+H]+ 213.1491, found 213.1489; []D25 –19.3 (c 1.00, CHCl3).
(4'
R,4a'R,8'S,8a'R)-4'-Iodo-8'-methyl-2'-((2-nitrophenyl)sulfonyl)octahydro-1'H-spiro[[1,3]dioxolane-
2,6'-isoquinoline] (12).

HETEROCYCLES, Vol. 90, No. 2, 2015
973
To a solution of 10 (73.4 mg, 0.35 mmol) in benzene (4 mL) was added PPh3 (184 mg, 0.70 mmol),
NsNH2 (142 mg, 0.70 mmol) and DIAD (1.9 M solution in toluene, 0.37 mL, 0.70 mmol) at room
temperature. After being stirred for 1 h at 60 °C, concentration under reduced pressure, the resulting
residue was roughly purified by flash column chromatography (SiO2, hexane/ EtOAc = 3/1) to give crude
11 as yellow oil. To a solution of crude 11 (~0.35 mmol) in CH2Cl2 (4 mL) was added NIS (157.5 mg,
0.70 mmol) and K2CO3 (96.7 mg, 0.70 mmol) at room temperature. After being stirred for 1 h at the same
temperature, the reaction was diluted with CH2Cl2. The combined organic layers were washed with brine
and dried over Na2SO4. After concentration under reduced pressure, the resulting residue was purified by
flash column chromatography (SiO2, hexane/ EtOAc = 6/1) to give 12 (145.4 mg, yield 80%, 2 steps) as
yellow oil. 1H NMR (CDCl3, 400 MHz)  0.91 (3H, d, J = 6.6 Hz), 1.19-1.26 (2H, m), 1.35 (1H, dd, J =
13.2, 13.2 Hz), 1.59-1.65 (1H, m), 1.73-1.76 (1H, m), 1.96-1.99 (1H, m), 3.08 (1H, dd, J = 11.4, 11.4 Hz),
2.05-2.14 (2H, m), 3.33 (1H, ddd, J = 1.2, 5.4, 10.8 Hz), 3.41 (1H, dd, J = 1.8, 10.8 Hz), 3.63 (1H, dd, J =
13
4.8, 10.8 Hz), 3.94-3.95 (5H, m), 7.68-7.73 (3H, m), 8.08-8.10 (1H, m); C NMR (CDCl3, 100 MHz)
 10.9, 19.8, 31.6, 37.5, 43.0, 48.0, 49.3, 53.3, 63.5, 64.5, 64.5, 108.9, 124.3, 130.7, 131.8, 133.3, 133.7,
148.2; IR (neat) 1542, 1162 cm-1; HRMS(ESI) m/z calcd for C18H24IN2O6SNa [M+Na]+ 523.0400, found
522.0406; []D23 +92.6 (c 1.02, CHCl3).
2-(((4'R,4a'R,8'S,8a'R)-4'-Iodo-8'-methylhexahydro-1'H-spiro[[1,3]dioxolane-2,6'-isoquinolin]-
2'(7'H)-yl)sulfonyl)aniline (14).
To a solution of 12 (33 mg, 0.06 mmol) in THF (0.6 mL) was added MeOH (12 mL, 0.3 mmol), SmI2 (0.1
M solution in THF, 1.8 mL, 0.18 mmol) at room temperature. The mixture was stirred for 5 min at same
temperature. The reaction was quenched by addition of sat. NH4Cl aq. and extracted with EtOAc. The
combined organic layers were washed with brine and dried over Na2SO4. After concentration under
reduced pressure, the resulting residue was purified by flash column chromatography (SiO2, hexane/
EtOAc = 20/1) to give 14 (15 mg, yield 51%) as colorless oil. 1H NMR (CDCl3, 400 MHz)  0.81 (3H, d, J
= 6.4 Hz), 0.87-0.95 (1H, m), 1.11 (1H, dd, J = 12.8, 13.2 Hz), 1.19-1.27 (1H, m), 1.47-1.57 (1H, m), 1.68
(1H, ddd, J = 2.4, 3.6, 13.2 Hz), 1.83-1.93 (1H, m), 2.03 (1H, ddd, J = 2.0, 3.2, 12.4 Hz), 2.87 (1H, dd, J =
11.2, 11.6 Hz), 3.26 (1H, ddd, J = 2.0, 6.0, 10.4 Hz), 3.48 (1H, dd, J = 2.0, 10.4 Hz), 3.67 (1H, dd, J = 6.0,
10.4 Hz), 3.76 (1H, dd, J = 6.4, 11.2 Hz), 3.91-3.95 (4H, m), 5.09 (2H, s), 6.73-6.79 (2H, m), 7.30-7.34 (1H,
m), 7.67 (1H, dd, J = 1.6, 8.0 Hz); 13C NMR (CDCl3, 100 MHz)  11.7, 19.8, 31.5, 38.0, 42.9, 48.0, 49.5,
52.2, 63.0, 64.4, 64.5, 109.0, 117.4, 117.8 , 120.0, 130.1, 134.4, 146.2; IR (neat) 3471, 3370, 1542, 1162
20
cm-1; HRMS(ESI) m/z calcd for C18H26IN2O4S [M+H]+ 493.0658, found 493.0657; []D +63.8 (c 0.75,
CHCl3).
2-(((4a'R,8'S,8a'R)-8'-Methylhexahydro-1'H-spiro[[1,3]dioxolane-2,6'-isoquinolin]-2'(7'H)-yl)-
sulfonyl)aniline (15).

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To a solution of 12 (14 mg, 0.027 mmol) in Et3SiH (0.3 mL) was added PdCl2 (0.5 mg, 0.003 mmol) at
room temperature. The resulting mixture was stirred for 1 h at same temperature. Filtration of the reaction
mixture through a Celite pad afforded a residue, which was purified by flash column chromatography
(SiO2, hexane/ EtOAc = 3/1) to give 15 (6 mg, yield 61%) as yellow oil. 1H NMR (CDCl3, 400 MHz) 
0.82 (3H, d, J = 6.8 Hz), 1.10-1.32 (4H, m), 1.35 (2H, d, J = 6.0 Hz), 1.43-1.52 (1H, m), 1.69 (1H, ddd,
J = 2.0, 3.2, 12.0 Hz), 1.81 (1H, ddd, J = 2.0, 3.6, 13.2 Hz), 2.88 (1H, dd, J = 11.2, 11.2 Hz), 3.34-3.41
(1H, m), 3.81 (1H, dd, J = 6.8, 11.2 Hz), 3.90-3.92 (5H, m), 5.04 (2H, s), 6.71-6.77 (2H, m), 7.26-7.31
(1H, m), 7.65 (1H, dd, J = 1.6, 8.0 Hz); 13C NMR (CDCl3, 100 MHz)  19.8, 20.1, 31.9, 37.1, 43.0, 49.1,
49.7, 52.1, 61.1, 64.4, 109.3, 117.2, 117.6, 120.6, 130.0, 134.0, 146.1; IR (neat) 3350, 1152 cm-1;
20
HRMS(ESI) m/z calcd for C18H26N2O4SNa [M+Na]+ 389.1511, found 389.1510; []D +27.8 (c 0.30,
CHCl3).
(7S,8R,9S)-7-Methyl-9-vinyl-1,4-dioxaspiro[4.5]decane-8-carbaldehyde (16).
To a solution of 10 (114 mg, 0.54 mmol), NMO (127 mg, 1.08 mmol) and MS4Å (250 mg) in CH2Cl2 (5.4
mL) was added TPAP (19 mg, 0.054 mmol) at 0 °C. The resulting mixture was stirred for 0.5 h at room
temperature. Filtration of the reaction mixture through a pad of Celite afforded a residue, which was
purified by flash column chromatography (SiO2, hexane/AcOEt = 3/1) to give 16 as yellow oil. 1H NMR
(CDCl3, 400 MHz)  0.92 (3H, d, J = 6.4 Hz), 1.30 (1H, dd, J = 12.8, 13.2 Hz), 1.44 (1H, dd, J = 12.8, 13.2
Hz), 1.74-1.86 (3H, m), 2.03-2.11 (1H, m), 2.63-2.72 (1H, m), 3.98 (4H, m), 4.99-5.06 (2H, m), 5.59 (1H,
ddd, J = 8.4, 10.4, 18.8 Hz), 9.43 (1H, d, J = 5.2 Hz); 13C NMR (CDCl3, 100 MHz)  19.8, 29.4, 39.5, 40.1,
60.8, 64.3, 64.5, 107.7, 115.8, 139.3, 204.7; IR (neat) 1722, 1078 cm-1; HRMS(ESI) m/z calcd for
C12H18O3Na [M+Na]+ 233.1154, found 233.1156; []D24 –12.0 (c 1.00, CHCl3).
N-Benzyl-1-((7S,8R,9S)-7-methyl-9-vinyl-1,4-dioxaspiro[4.5]decan-8-yl)methanamine (17).
To a solution of crude 16 (~0.54 mmol) in MeOH (5 mL) was added benzylamine (0.18 mL, 1.62 mmol) at
room temperature. After being stirred for 1 h at the same temperature, NaBH4 (61 mg, 1.62 mmol) was
added and then stirred for 1 h. The reaction was quenched by addition of sat. NH4Cl aq. and extracted with
AcOEt. The combined organic layers were washed with brine and dried over Na2SO4. After concentration
under reduced pressure, the resulting residue was purified by flash column chromatography (SiO2,
hexane/AcOEt = 1/1) to give 17 as yellow oil. 1H NMR (CDCl3, 400 MHz)  0.85-0.90 (1H, m), 0.92 (3H,
d, J = 6.4 Hz), 1.30 (1H, dd, J = 12.8, 12.8 Hz), 1.44 (1H, dd, J = 12.8, 12.8 Hz), 1.70-1.87 (3H, m),
2.32-2.41 (1H, m), 2.67 (2H, d, J = 3.2 Hz), 3.73 (2H, d, J = 4.8 Hz), 3.94 (4H, s), 4.95 (1H, dd, J = 2.0, 10.0
Hz), 5.05 (1H, dd, J = 2.0, 17.6 Hz), 5.62 (1H, ddd, J = 10.0, 10.0, 19.2 Hz); 13C NMR (CDCl3, 100 MHz)
 19.9, 30.9, 41.4, 42.9, 43.6, 47.7, 47.9, 54.4, 64.1, 64.3, 108.3, 114.5, 126.7, 128.1, 128.1, 128.1, 128.3,
140.8, 142.1; IR (neat) 3026, 1141 cm-1; HRMS(ESI) m/z calcd for C19H27NO2 [M+H]+ 302.2120, found
302.2121; []D22 –3.46 (c 1.02, CHCl3).

HETEROCYCLES, Vol. 90, No. 2, 2015
975
(4'
R,4a'
R
,8'
S
,8a'
R)-2'-Benzyl-4'-iodo-8'-methyloctahydro-1'H-spiro[[1,3]dioxolane-2,6'-isoquinoline]
(18).
To a solution of crude 17 (~0.54 mmol) in CH2Cl2 (5 mL) was added NIS (243 mg, 1.08 mmol) and K2CO3
(149 mg, 1.08 mmol) at room temperature. After being stirred for 2 h at the same temperature, the reaction
was diluted with CH2Cl2. The resulting solution was washed with brine and dried over Na2SO4. After
concentration under reduced pressure, the resulting residue was purified by flash column chromatography
(SiO2, hexane/ AcOEt = 6/1) to give 18 (200 mg, yield 87%, 3 steps) as yellow oil. 1H NMR (CDCl3, 400
MHz)  0.86 (3H, d, J = 6.4 Hz), 1.12-1.25 (2H, m), 1.34 (1H, dd, J = 12.4, 12.8 Hz), 1.47-1.63 (2H, m),
1.70 (1H, dt, J = 2.8, 13.2 Hz), 1.83 (1H, dd, J = 10.8, 11.2 Hz), 2.24 (1H, dt, J = 2.8, 12.8 Hz), 2.53 (1H, dd,
J = 11.2, 11.2 Hz), 3.14 (1H, dd, J = 2.8, 10.8 Hz), 3.31 (1H, dd, J = 4.0, 11.2 Hz), 3.48 (1H, d, J = 12.8 Hz),
3.59 (1H, d, J = 12.8 Hz); 13C NMR (CDCl3, 100 MHz)  18.6, 32.9, 36.8, 42.4, 44.2, 47.5, 48.1, 56.9, 62.0,
64.2, 64.3, 64.3, 108.3, 127.2, 128.3, 128.9, 137.7; IR (neat) 1345, 1119 cm-1; HRMS(ESI) m/z calcd for
C19H26O2NI [M+H]+ 428.1087, found 428.1085; []D23 –23.2 (c 1.01, CHCl3).
(4a'R,8'S,8a'R)-2'-Benzyl-8'-methyloctahydro-1'H-spiro[[1,3]dioxolane-2,6'-isoquinoline] (19).
To a solution of 18 (89 mg, 0.21 mmol) in benzene (2 mL) was added AIBN (7 mg, 0.042 mmol) and
nBu3SnH (1.0 M in cyclohexane, 0.42 mL, 0.42 mmol), then the mixture was stirred for 1 h under reflux
conditions. After concentration under reduced pressure, the resulting residue was purified by flash column
chromatography (KF/silica gel, AcOEt) to give 19 as colorless oil. 1H NMR (CDCl3, 400 MHz)  0.85 (3H,
d, J = 6.4 Hz), 0.92-1.00 (1H, m), 1.25-1.33 (5H, m), 1.50-1.54 (1H, m), 1.67-1.74 (2H, m), 1.90 (1H, dd, J
= 11.2, 14.0 Hz), 2.85 (1H, d, J = 11.6 Hz), 3.08 (1H, dd, J = 2.4, 11.2 Hz), 3.43 (1H, d, J = 13.2 Hz), 3.59
(1H, d, J = 13.2 Hz); 13C NMR (CDCl3, 100 MHz)  18.9, 32.6, 32.9, 38.3, 41.4, 43.7, 46.6, 53.5, 57.6, 63.5,
64.1, 64.3, 108.8, 126.8, 128.1, 129.1, 138.4; IR (neat) 1359, 1101 cm-1; HRMS(ESI) m/z calcd for
C19H28NO2 [M+H]+ 302.2120, found 302.2120; []D22 +7.13 (c 1.05, CHCl3).
(4a'R,8'S,8a'R)-2'-Benzyl-8'-methyloctahydro-1'H-spiro[[1,3]dioxolane-2,6'-isoquinoline] (20).
To a solution of crude 19 (~0.21 mmol) in acetone/H2O (10/1, 10 mL) was added p-TsOH·H2O (72 mg, 0.42
mmol) and the mixture was stirred for 5 h under reflux conditions. The reaction was quenched by addition
of sat. NaHCO3 aq. and extracted with AcOEt. The combined organic layers were washed with brine and
dried over Na2SO4. After concentration under reduced pressure, the resulting residue was purified by flash
1
column chromatography (SiO2, AcOEt) to give 20 (50 mg, yield 94%, 2 steps) as yellow oil. H NMR
(CDCl3, 400 MHz)  0.95 (3H, d, J = 6.4 Hz), 1.25-1.47 (3H, m), 1.53-1.69 (3H, m), 1.93 (1H, dd, J = 2.8,
23.2 Hz), 2.05-2.14 (2H, m), 2.32-2.37 (2H, m), 2.89-2.92 (1H, m), 3.17-3.20 (1H, m), 3.48 (1H, d, J = 13.2
Hz), 3.63 (1H, d, J = 13.2 Hz); 13C NMR (CDCl3, 100 MHz)  19.2, 33.0, 36.4, 41.2, 46.2, 47.9, 49.9, 53.2,
57.3, 63.3, 127.0, 128.2, 129.1, 138.0, 210.4; IR (neat) 1717, 1241 cm-1; HRMS(ESI) m/z calcd for
C17H23NO [M+H]+ 258.1852, found 258.1853; []D21 –13.5 (c 1.01, CHCl3).

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HETEROCYCLES, Vol. 90, No. 2, 2015
(4aR,8S,8aR)-tert-Butyl 8-methyl-6-oxooctahydroisoquinoline-2(1H)-carboxylate (2).
To a solution of 20 (50 mg, 0.19 mmol) in AcOEt (8 mL) was added Boc2O (62 mg, 0.29 mmol) and 20
w/w% Pd(OH)2 (10 mg). The reaction mixture was under the pressure of hydrogen (5 atm) for 1 day at
room temperature. The excess amount of Boc anhydride was destroyed by adding imidazole (excess) and
stirring for 3 h at same temperature, and the palladium catalyst was removed through a pad of Celite. The
resulting residue was extracted with AcOEt and the combined organic layers were washed with 1% HCl and
1
dried over Na2SO4. Concentration under reduced pressure gave 2 (41 mg, yield 81%) as white solid. H
NMR (CDCl3, 400 MHz)  1.05 (3H, d, J = 6.4 Hz), 1.21-1.27 (1H, m), 1.33 (1H, ddd, J = 4.4, 13.0, 13.0
Hz), 1.48 (9H, s), 1.51-1.65 (1H, m), 2.11 (2H, ddd, J = 2.4, 13.0, 13.0 Hz), 2.20-2.33 (1H, m), 2.38 (2H,
dddd, J = 2.4, 4.4, 16.0, 16.0 Hz), 2.69 (1H, br, t, J = 12.4 Hz), 4.16 (1H, br, s), 4.44 (1H, br, s); 13C NMR
(CDCl3, 100 MHz)  19.1, 28.4, 33.0, 36.1, 41.3, 44.2, 46.1, 46.8, 47.8, 49.7, 79.6, 154.7, 209.6; IR (neat)
24
1687, 1137 cm-1; HRMS(ESI) m/z calcd for C15H25NO3Na [M+Na]+ 290.1732, found 290.1728; []D
–31.6 (c 1.05, CHCl3).
ACKNOWLEDGEMENTS
This work was supported by JSPS KAKENHI Grant Numbers 22790007, 25460006 (SH), and 21390002,
25293001 (AN).
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