Stereoselective allylation of α-hydroxy aldimines and its application to the formal synthesis of (?)-β-conhydrine

Article abstract of DOI:10.1016/j.tet.2017.12.024

Stereoselective allylation of N-p-methoxyphenyl (PMP)-substituted α-hydroxy aldimines is described. Several Lewis acids (BF₃·OEt₂, SnCl₄, TiCl₄, ZnCl₂, and MgBr₂·OEt₂) were employed to mediate the allylation reactions. The addition of the allyl group generates a new stereocenter and affords the syn vicinal amino alcohol. Formal synthesis of (?)-β-conhydrine (1) was accomplished via syn-selective allyl addition to N-PMP-substituted α-hydroxy aldimine.

Full text of DOI:10.1016/j.tet.2017.12.024

Accepted Manuscript
Stereoselective allylation of α-hydroxy aldimines and its application to the formal
synthesis of (−)-β-conhydrine
Yong-Taek Lee, Changyoung Jung, In-Soo Myeong, Sang-Hyun Lee, Jin-Seok Kim,
Won-Hun Ham
PII:
S0040-4020(17)31275-9
10.1016/j.tet.2017.12.024
TET 29180
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 17 November 2017
Revised Date: 7 December 2017
Accepted Date: 11 December 2017
Please cite this article as: Lee Y-T, Jung C, Myeong I-S, Lee S-H, Kim J-S, Ham W-H, Stereoselective
allylation of α-hydroxy aldimines and its application to the formal synthesis of (−)-β-conhydrine,
Tetrahedron (2018), doi: 10.1016/j.tet.2017.12.024.
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ACCEPTED MANUSCRIPT
Stereoselective Allylation of α-Hydroxy Aldimines
and its Application to the Formal Synthesis of (‒)-β-Conhydrine
Yong-Taek Lee†, Changyoung Jung†, In-Soo Myeong, Sang-Hyun Lee, Jin-Seok Kim, Won-Hun Ham*
whham@skku.edu
School of Pharmacy, Sungkyunkwan University, Seobu-ro 2066, Suwon-si, Gyeonggi-do 16419, Republic of
Korea
* Corresponding author. E-mail address: whham@skku.edu (W.-H. Ham)
† Both authors contributed equally to this work.
Abstract
Stereoselective allylation of N-p-methoxyphenyl (PMP)-substituted α-hydroxy aldimines is described. Several
Lewis acids (BF3·OEt2, SnCl4, TiCl4, ZnCl2, and MgBr2·OEt2) were employed to mediate the allylation
reactions. The addition of the allyl group generates a new stereocenter and affords the syn vicinal amino alcohol.
Formal synthesis of (‒)-β-conhydrine (1) was accomplished via syn-selective allyl addition to N-PMP-
substituted α-hydroxy aldimine.
SnCl4
AllylSnBu3
NPMP
NHPMP
NH
H
CH2Cl2
OBn
OBn
OH
( )- -Conhydrine
− β
Introduction
β-Amino alcohols or vicinal amino alcohols, the structures of which range from simple to complex, are
crucial structural motifs in natural products and medicinal agents.1 For example, conhydrines, sphingosines, and
docetaxel have β-amino alcohol substructures (Figure 1). Conhydrine was isolated from the seeds and leaves of
Conium maculatum L., which is a poisonous plant, in 1856, and its structure was confirmed in 1933.2
Figure 1. Structures of natural compounds that have β-amino alcohol substructures
The typical synthetic strategies used to access β-amino alcohols are i) addition reactions to α-amino
aldehydes;3 ii) addition reactions to α-hydroxy aldimines;4 iii) reduction of α-amino ketones;5 and iv) reduction
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of α-hydroxy ketimines (Figure 2).6 Recently, we have reported stereoselective nucleophilic addition to α-amino
ꢀ-hydroxy aldehydes to afford various vicinal amino alcohols.7 In the current study, as a part of our ongoing
research, we have focused on addition reactions to α-hydroxy aldimines to afford vicinal amino alcohols.
α
α
ii) Addition reactions to -hydroxy aldimines
: In this article
i) Addition reactions to -amino aldehydes
: In our previous research
OH
O
H
R1
R2
H
R2
R1
NH
NH2
OH
R2
R1
NH2
O
OH
R2
H
H
R1
R1
R2
NH2
NH
α
iv) Reductions to -hydroxy ketimines
α
iii) Reductions to -amino ketones
Figure 2. Typical strategies for the synthesis of vicinal amino alcohols
Nucleophilic addition to aldimines requires particular conditions because of their lower reactivity than
that of carbonyl compounds.8,9a One of the strategies used to increase the electrophilicity of the azomethine
carbon and thus increase the reactivity of the aldimine is the use of an electron-withdrawing group (EWG) to
protect the imino nitrogen.9a In addition, the coordination of a Lewis acid with the imino nitrogen has an
activating effect, increasing the electrophilicity of the azomethine carbon.8,9b Conversely, protecting the imino
nitrogen using an electron-donating group such as an aryl moiety results in a less reactive aldimine.9b
In case of less reactive aldimines, the electron-donating group can strengthen the coordination between the
Lewis acid and the imino nitrogen.10 Diastereoselective nucleophilic additions to aldimines are stereocontrolled
according to the Felkin-Anh model and chelation1c,11 mediated by Lewis acids.12 Thus, using a Lewis acid can
both increase the reactivity of the aldimine and promote diastereoselective nucleophilic addition to it. To verify
this, we explored Lewis-acid-mediated nucleophilic addition reactions to less reactive aldimines. N-p-
methoxyphenyl (PMP) aldimine was selected as the less reactive aldimine because of its facile deprotection.13a
Although nucleophilic addition to other N-protected α-hydroxy aldimines has been investigated by several
researchers, for example, Fadnavis,14 Das,15 Akiba,16 Saksena,17 Cainelli,18 Evans,19 Yamamoto,4a and
Claremon,4b nucleophilic addition to N-PMP α-hydroxy aldimines remains relatively unexplored, and Lewis-
acid-promoted addition to α-hydroxy aldimines is also relatively novel.
We established the formation method for N-PMP aldimines based on the ketimine formation method
reported by Menche et al.20 The allyl group was selected as a nucleophile because of the versatility afforded by
its possible subsequent transformations, which include ozonolysis, olefin metathesis, hydrogenation, and
dihydroxylation.11e
We herein present a method for stereoselective nucleophilic allyl addition to N-PMP α-hydroxy aldimines
and its application to the formal synthesis of (‒)-β-conhydrine (1).
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Results and Discussion
Allylation of O-protected α-hydroxy aldimines
The enantiomerically pure O-benzyl-protected α-hydroxy aldehyde was prepared by a previously reported
method.14b O-t-Butyldimethylsilyl (TBS)-protected α-hydroxy aldehyde was afforded by a similar method.21
The details of the experimental methods are described in the Experimental Section. The aldehydes are easily
converted to the corresponding N-PMP-protected α-hydroxy aldimines using p-anisidine and Ti(OiPr)4.20
Each aldimine was subjected to allyl addition reactions with different Lewis acids and allyl reagents. The
results of the allylations of the O-protected α-hydroxy aldimines are shown in Table 1.
Table 1. Lewis-acid-mediated nucleophilic allyl addition reactions of O-protected α-hydroxy aldimines
Lewis acid,
NPMP
OR
NHPMP
NHPMP
OR
M
H
CH2Cl2,
temperature
OR
2a R = Bn
2b R = TBS
7a R = Bn
7b R = TBS
7a' R = Bn
7b' R = TBS
Entry
Aldimine
Lewis acid
Allyl reagent
Temp (°C)
Ratio (7a:7a')a
Yield (%)b
1
2
2a
2a
SnCl4
TiCl4
AllylSnBu3
AllylSnBu3
-78
-78
8:1
72%
Trace
Trace
MgBr2ꢁOEt2
BF3ꢁOEt2
3
4
2a
2a
AllylSnBu3
AllylSnBu3
0
2:1
5:1
45%
48%
-78
5
6
2a
2a
2a
2a
2b
2b
N/A
AllylMgBr
AllylMgBr
AllylSiMe3
AllylSnBu3
AllylSnBu3
AllylSnBu3
0
1.3:1
4.5:1
N.R.
N.R.
6:1
72%
67%
N.R.
N.R.
45%
65%
ZnCl2
SnCl4
SnCl4
SnCl4
TiCl4
0
7
8c
-78
-78
-78
-78
9
10
4:1
MgBr2ꢁOEt2
BF3ꢁOEt2
11
12
2b
2b
AllylSnBu3
AllylSnBu3
0
4:1
4:1
60%
61%
-78
13
14
2b
2b
N/A
AllylMgBr
AllylMgBr
0
0
1.2:1
8:1
85%
62%
ZnCl2
a Ratio determined by the method described below.
bYields refer to three-step yields of mixed isomers.
cTHF was used as the solvent instead of CH2Cl2.
The reactions of O-benzyl α-hydroxy aldimine 2a with the Lewis acids TiCl4, MgBr2·OEt2, and ZnCl2 did
not give satisfactory results (entries 2, 3, and 6). The Grignard reaction in the absence of Lewis acid did not
afford the stereocontrolled product (entry 5). When BF3·OEt2 was used as the Lewis acid, the reaction afforded a
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moderately syn-selective product (entry 4), and the reaction mediated by SnCl4 afforded a syn-selective product
(entry 1). In our previous study, AllylSiMe3 was used as the nucleophile and gave several satisfactory results.7
However, it did not work well in this case (entry 7). When tetrahydrofuran (THF) was used as the solvent, the
reaction did not progress (entry 8), so dichloromethane (CH2Cl2) was adopted as the solvent to allow the Lewis
acids to work sufficiently.
In order to investigate the influence of the α-hydroxy protecting group, reactions with O-TBS α-hydroxy
aldimine 2b were conducted. The Grignard reaction without a Lewis acid was not stereoselective, and reactions
with the Lewis acids SnCl4, TiCl4, MgBr2·OEt2, and BF3·OEt2 did not give satisfactory results (entries 9–12).
The Grignard reaction in the absence of a Lewis acid did not afford the stereocontrolled product (entry 13).
When ZnCl2 was used as the Lewis acid, the reaction afforded a syn-selective product (entry 14). In the case of
7a and 7a', the syn/anti adducts were separated by silica column chromatography and the syn/anti ratios were
determined by NMR. However, in the case of silyl protection, 7b and 7b' were inseparable by TLC. In order to
determine the syn/anti ratios, the TBS group was removed, benzylation was conducted, and the diastereomers
were separated by silica column chromatography. The reaction conditions are decribed in the Experimental
Section. By the formal synthesis of (‒)-β-conhydrine (1) the syn-configuration of the amino alcohol 7a was
confirmed.
The possible transition states for nucleophilic addition are summarized in Figure 3. The preference for the E-
aldimine configuration has been reported,22 which is in accordance with our suggested conformation. The
observed syn-selectivity for allyl addition to O-benzyl α-hydroxy aldimine 2a can be explained by α-chelation
(via a five-membered cyclic transition state) between the hydroxy group and the aldimine nitrogen (transition
state A) (entries 1, 6). The unexpected syn-selectivity reported in entry 4 seems to be due to the steric repulsion
between the Lewis acid and ethyl group in the transition state B and C. Consequently, reaction would proceed
through the more favored transition state C as shown in Figure 3. Similarly, the addition of the allyl reagent to
O-TBS α-hydroxy aldimine 2b proceeded according to the anti-Felkin-Anh model (transition state C) (entries
9−12, and 14).
M
PMP
PMP
M
M
PMP
N
N
N OBn
Et
H
RO
OR
Allyl-
H
Et
H
H
Et
H
Allyl-
Allyl-
H
R = Bn or TBS
R = Bn or TBS
A
B
C
Figure 3. Proposed mechanisms of allylation reactions of O-protected α-hydroxy aldimines
Formal synthesis of (‒)-β-conhydrine (1)
These results allowed the formal synthesis of (‒)-β-conhydrine 1 (Scheme 1). The N-PMP-protected β-
amino alcohol 7a was subjected to PMP deprotection in the presence of ammonium cerium(IV) nitrate. The
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PMP group was removed and the addition of Boc2O to afford the N-Boc-protected β-amino alcohol 8 was
accomplished. Various N-protection groups were tested for the next steps. Unfortunately, the N-PMP-protected
and N-Cbz-protected dienes gave unsatisfactory results. The installation of the allyl group onto nitrogen was
accomplished to afford diene 9. The ring-closing metathesis of 9 with Grubbs’ 2nd generation catalyst produced
compound 10. The spectra and specific rotation of compound 10 were in good agreement with reported data.14b
Compound 10 has previously been transformed into (‒)-β-conhydrine (1), thus completing the formal
synthesis.14b
NHBoc
NHPMP
NBoc
a
b
51%
62%
OBn
OBn
OBn
7a
8
9
NBoc
NH
Ref. 14(b)
c
75%
OBn
10
OH
( )- -Conhydrine 1
− β
Reagents and conditions : (a) (i) CAN, ACN/H2O = 2:1, 0 oC to r.t.; (ii) Boc2O, TEA, CH2Cl2, 0 oC to r.t.;
(b) AllylBr, NaH, TBAI, THF, DMF 0 oC to 50 oC; (c) Grubbs' 2nd generation, CH2Cl2, reflux
Scheme 1. Formal synthesis of (‒)-β-conhydrine (1)
Conclusions
This study describes the Lewis-acid-mediated stereoselective nucleophilic allyl addition to α-hydroxy aldimines
and its application to the formal synthesis of (‒)-β-conhydrine (1). The reaction of O-benzyl α-hydroxy aldimine
mediated by SnCl4 afforded the syn-selective product. The reaction mechanism involves α-chelation between the
hydroxy group and the imino nitrogen. The resulting N-PMP-protected β-amino alcohol was used for the formal
synthesis of (‒)-β-conhydrine (1). Further study and the development of other applications of this methodology
are underway, and the results will be reported in due course.
Experimental Section
General Experimental Methods
Optical rotations were measured with a polarimeter in the solvent specified. 1H and 13C NMR spectroscopic data
were recorded with an FT-NMR spectrometer at 101, 175, 400, or 500 MHz. Chemical shift values are reported
in ppm relative to TMS or CDCl3 as an internal standard, and coupling constants are reported in Hz. The IR
spectra were measured with an FT-IR spectrometer. The mass spectroscopic data were obtained with a high-
resolution mass spectrometer using a magnetic sector-electric sector double focusing analyzer. Flash
chromatography was performed using mixtures of ethyl acetate and hexane as the eluents. Unless otherwise
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stated, all non-aqueous reactions were performed under an argon atmosphere with commercial grade reagents
and solvents. THF was distilled from sodium and benzophenone (indicator). CH2Cl2 was distilled from calcium
hydride.
General procedure for the allylation reactions
Scheme 2. Preparation of O-benzyl α-hydroxy aldimine
To a solution of O-benzyl α-hydroxy aldehyde (143 mg, 0.75 mmol) in anhydrous CH2Cl2 (7.5 mL) Ti(OiPr)4
(330 mL, 1.12 mmol) was added at room temperature. This solution was stirred for 5 min, and p-anisidine (110
mg, 0.9 mmol) diluted with CH2Cl2 was added dropwise. The reaction mixture was stirred at ambient
temperature for 2 h. The mixture was filtered through a pad of Celite and concentrated in vacuo. The resulting
aldimine 2a was used immediately without further purification (Scheme 2).
A solution of SnCl4 (0.9 mL, 1.0 M in CH2Cl2, 0.9 mmol) was added slowly to a solution of 2a in anhydrous
CH2Cl2 (0.9 mL) at -78 °C. This solution was stirred for 5 min, then allyltributylstannane (0.7 mL, 2.25 mmol)
was added dropwise to this reaction mixture at -78 °C. The mixture was stirred at -78 °C for 30 min. The
reaction was quenched with aqueous saturated NaHCO3, diluted with EtOAc, and the organic phase was washed
with saturated brine, dried with MgSO4, then concentrated in vacuo. Purification by silica gel chromatography
(hexane/EtOAc, 70:1) gave products 7a as a yellow oil in 64 % yield and 7a' as a yellow oil in 8% yield,
respectively.
N-((4S,5S)-5-(Benzyloxy)hept-1-en-4-yl)-4-methoxyaniline (7a)
[α]2D5 +31.5 (c 0.5, CHCl3); IR (neat) γmax 3725, 3708, 3624, 2924, 2854, 1716, 1619, 1511, 1456, 1241, 1041,
818, 689 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.90 (t, J = 7.2 Hz, 3H), 1.67 (dsxt, J = 16.3, 7.2 Hz, 2H), 2.35 (t,
J = 7.2 Hz, 2H), 3.38–3.49 (m, 2H), 3.73 (s, 3H), 4.53 (d, J = 11.5 Hz, 1H), 4.67 (d, J = 11.4 Hz, 1H), 4.99–5.06
(m, 2H), 5.78 (ddt, J = 17.5, 9.8, 7.6 Hz, 1H) 6.48–6.54 (m, 2H), 6.72–6.74 (m, 2H), 7.26–7.39 (m, 5H); 13C
NMR (101 MHz, CDCl3) δ 10.6, 23.3, 36.0, 55.2, 55.9, 72.4, 80.9, 114.1, 115.0, 117.0, 127.7, 127.9, 128.4,
136.0, 138.7, 142.2, 151.6; HRMS (EI+) [(M)+] m/z calcd for C21H27NO2 325.2042; found 325.2044.
N-((4R,5S)-5-(Benzyloxy)hept-1-en-4-yl)-4-methoxyaniline (7a')
[α]2D5 +64.6 (c 1.0, CHCl3); IR (neat) γmax 3725, 3706, 3625, 3597, 3387, 3064, 3029, 2932, 2875, 2831,
1
1638, 1618, 1509, 1455, 1409, 1356, 1237, 1208, 1179, 1039, 913, 819, 736, 698 cm−1; H NMR (400 MHz,
CDCl3) δ 0.97 (t, J = 7.5 Hz, 3H), 1.61 (dq, J = 14.3, 7.1 Hz, 1H), 1.72 (dq, J = 14.3, 7.1 Hz, 1H), 2.28–2.46 (m,
2H), 3.42–3.52 (m, 2H), 3.73 (s, 3H), 4.46 (d, J = 11.6 Hz, 1H), 4.60 (d, J = 11.6 Hz, 1H), 4.99–5.12 (m, 2H),
5.87 (ddt, J = 17.1, 10.0, 7.2 Hz, 1H) 6.47–6.53 (m, 2H), 6.72–6.77 (m, 2H), 7.25–7.38 (m, 5H); 13C NMR (101
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MHz, CDCl3) δ 10.2, 23.8, 34.1, 55.8, 56.0, 72.6, 76.8, 77.1 ,77.4, 81.6, 114.9, 115.1, 117.0, 127.6, 127.7, 128.4,
136.1, 138.9, 142.0, 152.0; HRMS (EI+) [(M)+] m/z calcd for C21H27NO2 325.2042; found 325.2044.
N-((4S,5S)-5-(tert-Butyldimethylsilyloxy)hept-1-en-4-yl)-4-methoxyaniline (7b)
[α]2D5 +23.3 (c 0.5, CHCl3); IR (neat) γmax 3728, 3693, 3635, 3624, 3595, 3142, 2924, 2853, 1689, 1619, 1511,
1
1463, 1377, 1242, 1079, 836 cm−1; H NMR (500 MHz, CDCl3) δ 0.05–0.15 (m, 6H), 0.82 (t, J = 7.5 Hz, 3H),
0.91–0.97 (m, 9H), 1.45 (dq, J = 14.0, 7.1 Hz, 1H), 1.63 (dq, J = 14.3, 7.1 Hz, 1H), 2.22–2.36 (m, 2H), 3.26–
3.39 (m, 1H), 3.69–3.73 (m, 1H), 3.75 (s, 3H), 4.99–5.17 (m, 2H), 5.82 (ddt, J = 17.1, 10.0, 7.2 Hz, 1H) 6.48–
6.59 (m, 2H), 6.70–6.82 (m, 2H); 13C NMR (175 MHz, CDCl3) δ –4.2, –3.8, 10.6, 18.4, 26.2, 27.0, 36.1, 56.1,
56.2, 74.6, 114.4, 115.3, 116.8, 136.5; HRMS (EI+) [(M)+] m/z calcd for C20H35NO2Si 349.2437; found
349.2435. The determination of stereochemistry was carried out as follows (Scheme 3).
NHPMP
NHPMP
a
63% for
two steps
OTBS
OBn
7b, 7b'
7a, 7a'
Reagents and conditions : (a) (i) TBAF, THF, 0 oC; (ii) BnBr, NaH, THF,
0 oC to r.t.
Scheme 3. Conversion of protection group to determine syn/anti ratio
Preparation of O-TBS α-hydroxy aldimine (2b)
Scheme 4. Preparation of O-TBS α-hydroxy aldimine
tert-Butyl((S)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)propoxy)dimethylsilane (4)
To a solution of compound 3 (129 mg, 0.8 mmol) in dimethylformamide (DMF) (1.8 mL), tert-
butyldimethylchlorosilane (607 mg, 4 mmol) and imidazole (220 mg, 3.2 mmol) were added at room
temperature and stirred for 2 h. The reaction was quenched with distilled water, diluted with EtOAc, and the
organic phase was washed with saturated brine, dried with MgSO4, and concentrated in vacuo. Purification by
silica gel chromatography (hexane/EtOAc, 20:1) gave product 4 (173 mg, 75%) as a colorless oil. [α]2D5 +28.7 (c
0.2, CHCl3); IR (neat) γmax 3726, 3705, 3624, 3600, 3324, 3012, 2925, 2854, 1686, 1609, 1591, 1572, 1493,
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1
1473, 1455, 1366, 1293, 1237, 1166, 1089, 886, 761, 669 cm−1; H NMR (500 MHz, CDCl3) δ 0.06–0.08 (m,
6H), 0.88–0.91 (m, 12H), 1.33 (s, 3H), 1.39 (s, 3H), 1.53–1.57 (m, 2H), 3.70 (td, J = 5.5, 5.0 Hz, 1H), 3.79–3.85
(m, 1H), 3.97–4.01 (m, 2H); 13C NMR (101 MHz, CDCl3) δ –4.4, –4.2, 8.5, 18.0, 25.5, 25.8, 26.7, 27.0, 66.6,
73.3, 108.8; HRMS (FAB+) [(M+H)+] m/z calcd for C14H31O3Si 275.2042; found 275.2039.
(2R,3S)-3-(tert-Butyldimethylsilyloxy)pentane-1,2-diol (5)
Trifluoroacetic acid (50% in aqueous solution, 12 mL, 0.75 mmol) was added dropwise to a solution of
compound 4 (145 mg, 0.5 mmol) in CH2Cl2 (5 mL) at 0 °C and stirred for 7 h. The reaction was quenched with
aqueous saturated NaHCO3, diluted with EtOAc, and the organic phase was washed with saturated brine, dried
with MgSO4, and concentrated in vacuo. Purification by silica gel chromatography (hexane/EtOAc, 6:1) gave
diol 5 (83 mg, 71%) as a colorless oil. [α]2D5 +14.4 (c 1.0, CHCl3); IR (neat) γmax 3727, 3704, 3680, 3629, 3600,
2955, 2926, 2855 cm−1; 1H NMR (500 MHz, CDCl3) δ 0.08–0.12 (m, 6H), 0.90–0.91 (m, 12H), 1.49 (quind, J =
7.2, 1.5 Hz, 1H), 1.61 (quind, J = 7.2, 1.5 Hz, 1H), 3.63 (td, J = 6.4, 3.5 Hz, 1H), 3.68 (dd, J = 11.1, 3.5 Hz, 1H),
3.76 (quin, J = 5.9 Hz, 2H); 13C NMR (175 MHz, CDCl3) δ –4.4, –4.3, 9.7, 18.3, 26.0, 26.7, 63.5, 73.0, 76.3;
HRMS (FAB+) [(M+H)+] m/z calcd for C11H27O3Si 235.1729; found 235.1726.
(S)-2-(tert-Butyldimethylsilyloxy)butanal (6)
To a solution of diol 5 (83 mg, 0.36 mmol) in 60% aq. acetonitrile (1.8 mL) was added NaIO4 (167 mg, 0.72
mmol) in one portion. The mixture was stirred at room temperature for 4 h and then extracted with CH2Cl2. The
combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting
aldehyde 6 was used immediately without further purification.
(S)-N-(2-(tert-Butyldimethylsilyloxy)butylidene)-4-methoxyaniline (2b)
To a solution of the crude aldehyde 6 in anhydrous CH2Cl2 (3.6 mL) Ti(OiPr)4 (0.16 ml, 0.54 mmol) was
added at room temperature. This solution was stirred for 5 min at the same temperature and p-anisidine (53 mg,
0.43 mmol) diluted with CH2Cl2 was added dropwise at the same temperature. The reaction mixture was stirred
at ambient temperature for 2 h. The mixture was filtered through a pad of Celite and concentrated in vacuo. The
resulting aldimine 2b was used immediately without further purification.
Formal synthesis of (‒)-β-conhydrine (1)
tert-Butyl (4S,5S)-5-(benzyloxy)hept-1-en-4-ylcarbamate (8)
Ammonium cerium(IV) nitrate (171 mg, 0.31 mmol) was diluted with distilled water and added dropwise to
a solution of compound 7a (18 mg, 0.078 mmol) in acetonitrile (0.8 mL) at 0 °C. This solution was stirred at
room temperature overnight. The reaction was quenched with aqueous saturated NaHCO3, filtered through a pad
of Celite, and concentrated in vacuo. The resulting free amine was immediately used without further purification.
To a solution of the crude amine in anhydrous CH2Cl2 (0.8 mL), triethylamine (0.03 mL, 0.19 mmol) was added
at 0 °C and di-tert-butyl dicarbonate (0.026 ml, 0.12 mmol) was added dropwise at the same temperature. This
solution was stirred at room temperature overnight. The reaction was then quenched with aqueous saturated
NH4Cl, diluted with EtOAc, and the organic phase was washed with saturated brine, dried with MgSO4, and
concentrated in vacuo. Purification by silica gel chromatography (hexane/EtOAc, 70:1) gave compound 8 (13
mg, 51%) as a red oil. [α]2D5 +42.5 (c 0.2, CHCl3); IR (neat) γmax 3725, 3706, 3624, 3601, 2922, 2852, 1720,
8

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1461, 1377 cm−1; 1H NMR (500 MHz, CDCl3) δ 0.90 (t, J = 7.5 Hz, 3H), 1.56 (s, 9H), 1.65–1.74 (m, 2H), 2.31
(tt, J = 20.2, 7.0 Hz, 2H), 3.34 (tt, J = 20.2, 6.2 Hz, 1H), 3.71–3.82 (m, 1H), 4.36–4.73 (m, 2H), 4.99–5.11 (m,
2H), 5.76 (ddt, J = 17.5, 10.0, 7.5 Hz, 1H) 7.19–7.42 (m, 5H); 13C NMR (101 MHz, CDCl3) δ 10.3, 23.6, 27.7,
28.4, 29.7, 37.5, 51.7, 72.3, 81.0, 83.7, 117.2, 122.1, 127.7, 127.9, 128.4, 135.3, 138.5, 148.4; HRMS (EI+)
[(M)+] m/z calcd for C19H29NO3 319.2147; found 319.2148.
tert-Butyl allyl((4S,5S)-5-(benzyloxy)hept-1-en-4-yl)carbamate (9)
To a solution of compound 8 (25 mg, 0.07 mmol) in DMF (0.35 mL) and THF (0.35 mL), NaH (15 mg, 0.35
mmol) and n-Bu4NI (31 mg, 0.08 mmol) was added at 0 °C. Allyl bromide (0.035 mL, 0.42 mmol) was added
dropwise at the same temperature and stirred at 50 °C overnight. The reaction was quenched with aqueous
saturated NH4Cl, diluted with EtOAc, and the organic phase was washed with saturated brine, dried with
MgSO4, and concentrated in vacuo. Purification by silica gel chromatography (hexane/EtOAc, 30:1) gave diene
9 (16 mg, 62%) as a yellow oil. [α]2D5 +25.1 (c 0.1, CHCl3); IR (neat) γmax 3051, 2990, 2838, 1625, 1435, 1243,
1
1053, 925, 725 cm−1; H NMR (400 MHz, CDCl3) δ 0.95 (t, J = 7.4 Hz, 3H), 1.44 (s, 9H), 1.52–1.70 (m, 2H),
2.20–2.40 (m, 1H), 2.44–2.56 (m, 1H), 3.41–3.56 (m, 1H), 3.74–4.02 (m, 2H), 4.09–4.26 (m, 1H), 4.44–4.63 (m,
2H), 4.99–5.11 (m, 4H), 5.64–5.97 (m, 2H), 7.19–7.42 (m, 5H); 13C NMR (101 MHz, CDCl3) δ 9.8, 23.9, 28.4,
28.5, 29.7, 34.3, 48.5, 57.8, 72.4, 79.3, 82.3, 115.4, 116.8, 127.3, 127.4, 128.3, 135.8, 136.7, 153.0; HRMS (EI+)
[(M)+] m/z calcd for C22H33NO3 359.2460; found 359.2462.
(S)-tert-Butyl 6-((S)-1-(benzyloxy)propyl)-5,6-dihydropyridine-1(2H)-carboxylate (10)
To a solution of diene 9 (16 mg, 0.045 mmol) in anhydrous CH2Cl2 (0.45 mL) Grubbs’ 2nd generation
catalyst (41 mg, 0.05 mmol) was added and the reaction mixture was stirred at room temperature for 12 h. The
reaction mixture was then concentrated in vacuo and the residue was purified by silica gel chromatography
(hexane/EtOAc, 10:1) to give compound 10 (11 mg, 75%) as a colorless oil. [α]2D5 −33.7 (c 0.2, CHCl3); IR (neat)
γmax 2966, 2927, 2855, 1694, 1456, 1411, 1365, 1219, 1173, 1105, 770 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.96
(t, J = 7.4 Hz, 3H), 1.42 (s, 9H), 1.43–1.50 (m, 1H), 1.61–1.75 (m, 1H), 2.00–2.13 (m, 1H), 2.34–2.46 (m, 1H),
3.38–3.53 (m, 2H), 4.06–4.29 (m, 1H), 4.31–4.65 (m, 3H), 5.52–5.77 (m, 2H), 7.22–7.27 (m, 5H); 13C NMR
(101 MHz, CDCl3) δ 11.3, 28.4, 28.5, 29.7, 30.1, 34.3, 42.3, 59.3, 72.3, 78.3, 82.3, 124.3, 126.3, 127.3, 127.4,
128.3, 135.8, 136.7, 153.1; HRMS (EI+) [(M)+] m/z calcd for C20H29NO3 331.2147; found 331.2149.
Acknowledgements
Yonsung Fine Chemicals Corporation is acknowledged with gratitude.
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