Unique divergent reactivity of Boc-protected homopropargylic alkoxyalkylamines in the gold(I)-catalyzed domino catalytic reactions: Application to the formal synthesis of (-)-pseudodistomin B

Article abstract of DOI:10.1055/s-0033-1338639

By using t-Boc-protected homopropargylic alkoxyalkylamines as substrates, the reactivity between the carboxylation-promoted and the alkoxylation-promoted domino processes in the gold-catalyzed reaction was systematically compared. Interestingly, the resul

Full text of DOI:10.1055/s-0033-1338639

SPECIAL TOPIC
▌2155
sUpenciailqtoupice Divergent Reactivity of Boc-Protected Homopropargylic Alkoxyal-
kylamines in the Gold(I)-Catalyzed Domino Catalytic Reactions: Application
to the Formal Synthesis of (–)-Pseudodistomin B
Gold Catalysis in Chemoselective Alkaloid Synthesis
Ji Hyung Lee, Wook Jeong, Young Ho Rhee*
Department of Chemistry, Pohang University of Science and Technology, Hyoja-dong san 31, Nam-gu, Pohang, Kyungbook 790-784,
Republic of Korea
Fax +82(54)2793399; E-mail: yhrhee@postech.ac.kr
Received: 18.03.2014; Accepted: 15.04.2014
alkynes.3,4 In this context, we recently reported that the
Abstract: By using t-Boc-protected homopropargylic alkoxyalkyl-
MOM-protected homopropargylic amines can give rise to
amines as substrates, the reactivity between the carboxylation-pro-
piperidin-4-ones via sequential gold(I)-catalyzed cyclo-
moted and the alkoxylation-promoted domino processes in the
gold-catalyzed reaction was systematically compared. Interesting-
isomerization and the subsequent hydration.5 Based upon
ly, the result varies significantly depending upon the structure of the the above discussion, we were intrigued by the homoprop-
alkynes and the nature of the phosphine ligands. The alkoxylation-
induced pathway represents a new synthetic method towards 2,4,5-
trisubstituted piperidines. A formal synthesis of (–)-pseudodistomin
type of substrate (Scheme 1). In this paper, we wish to re-
B based upon this interesting chemoselectivity was accomplished.
argylic amines 1 possessing both t-Boc and alkoxyalkyl
group because both reaction pathways are feasible for this
port our recent results describing the competition between
two pathways. Notably, a significant effect of the phos-
phine ligand and alkyne structure on the selectivity was
Key words: gold catalysis, cyclization, piperidines, ligands, total
synthesis
observed.
At the outset, the competitive pathways using terminal
In recent years, there has been great interest in search of
alkyne 2a as the substrate was investigated. As shown in
Scheme 2, employing electron-poor complex 3a gave a
mixture of two products 4 and 5 in 62% and 13% yield, re-
new gold-catalyzed reactions. The unique chemoselectiv-
ity promoted by alkyne activation led to the development
of numerous novel domino catalytic reactions.1 Typically,
spectively. This result clearly shows that two pathways
the reactions are initiated by the addition of carbon or he-
depicted in Scheme 1 are indeed competing. It also shows
teroatom nucleophiles to gold-bound alkynes. Both the
that the alkoxycyclization-induced pathway is favored
carboxyl group and the alkoxy group have been known to
over the carboxycyclization-induced pathway. When the
promote such reactions. For example, homopropargylic
ligand was switched to more electron-donating 3b, only
amines protected with t-Boc group generates the 2-oxazi-
the piperidine compound 4 was formed in excellent yield
nones.2 On the other hand, many reactions are known to
be induced by the addition of the alkoxy group to
with no apparent formation of 2-oxazinone 5.
O
Ot-Bu
CH2OR3
Boc
N
R1
N
O
R1
R1
N
alkoxycyclization
Au+
carboxycyclization
Au+
O
OR3
R2
R2
OR3
R2
1
CH2OR3
Ot-Bu
t-Bu
t-Bu
CH2OR3
R1
N
O
O
O
O
R1
N
O
R1
N
R1
N
+
O
O
Au
R2
OR3
R2
Au
R2
Au
R2
OR3
Au
Scheme 1 Competitive pathways in the gold-catalyzed domino process of t-Boc-protected homopropargylic alkoxyalkylamines 1
SYNTHESIS 2014, 46, 2155–2160
Advanced online publication: 13.05.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338639; Art ID: ss-2014-c0191-st
© Georg Thieme Verlag Stuttgart · New York

2156
J. H. Lee et al.
SPECIAL TOPIC
Boc
N
Boc
N
H
N
MOM
N
R
R
OMe
R
R
O
catalyst
+
NH2
O
CH2Cl2, 0.05 M, r.t.
OH
OMe
2a: R = n-C8H17
4
5
pseudodistomin A
pseudodistomin B
pseudodistomin F
R =
R =
R =
3a: Au[P(C6F5)3]Cl/AgSbF6
62%
99%
13%
<1%
3b: Au[P(t-Bu)2(o-biphenyl)]Cl/AgSbF6
Scheme 2 Gold-catalyzed reaction of 2a
Figure 1 Structure of pseudodistomins
The reaction of internal alkynes was then investigated.
Initial studies using the phenyl-substituted and methyl-
substituted internal alkynes showed poor conversion to-
wards the gold-catalyzed cycloisomerization. Unlike
these internal alkynes, ynoate 2b proved to be a highly re-
active substrate (Scheme 3). Quite interestingly, divergent
reactivity was observed, which heavily depended upon the
nature of ligands. When the electron-richer complex 3b
was used at room temperature, piperidine 6 was obtained
in ~90% yield along with small amount of the 2-oxazi-
none 7. Switching to electron-poorer complex 3a com-
pletely changed the course of the reaction.6 In this case,
oxazinone 7 was obtained as the major compound in 53%
yield along with the piperidine 6 in ~8% yield.
of ynoate 10 as described in Scheme 3 would be nicely
suited for the synthesis of the key intermediate enol ether
9 (Scheme 4). The ynoate substrate 10 can be easily syn-
thesized from enantioenriched azide 11, which was previ-
ously prepared by us.5b,11
Boc
N
H
N
Boc
N
R2
R1
R2
ref. 10e
NH2
CO2Me
CO2Me
OH
OR1
OH
8
pseudodistomin B
9
R1
=
gold(I)-catalyzed
cycloisomerization
(CH2)4
R2 = -(CH2)6OBn
n-Bu
Boc
Boc
N
MOM
N
R
N
OMe
cat. 3
CH2Cl2, 0.05 M
R
R
O
Boc
+
R2
N3
R2
N
OR1
O
r.t.
CO2Me
CO2Me
OMe
CO2Me
CO2Me
2b: R = n-C8H17
6
7
11
10
Scheme 4 Retrosynthetic scheme for pseudodistomin B
3b: Au[P(t-Bu)2(o-biphenyl)]Cl/AgSbF6
3a: Au[P(C6F5)3]Cl/AgSbF6
90%
8%
10%
53%
Initially, the reaction of the MOM-acetal 13a was investi-
gated, which was prepared from the azide 11 via the t-Boc
carbamate intermediate 12 (Scheme 5).12 The gold(I)-cat-
alyzed cycloisomerization of 13a using the optimized
condition shown in Scheme 3 gave the desired enol ether
14a in >90% yield with formation of trace amount of the
oxazinone compound analogous to 7. Disappontingly, ex-
tensive efforts towards the cleavage of the methyl ether of
14a under acidic conditions failed to give the desired enol
ester 8. Thus, it was decided to introduce 2-(trimethylsi-
lyl)ethoxymethyl ether (SEM) that can be easily removed
under basic conditions. As shown in Scheme 5, the SEM
ether 13b also proved to be efficient for gold(I)-catalyzed
cycloisomerization. Notably, when the reaction was per-
formed at –15 °C, the cycloisomerized product 14b was
obtained in near quantitative yield with no apparent for-
mation of the oxazinone product. In addition, treatment of
14b with TBAF proceeded smoothly to give the target
compound 8 in 74% yield. The spectral data of this com-
pound were consistent with the literature.10e,g Thus, the
formal synthesis of the pseudodistomin B (cf. also
Scheme 3 Gold-catalyzed reaction of 2b
From a synthetic viewpoint, the alkoxycyclization-
induced pathway may provide a new access to the 2,4,5-
trisubstituted piperidines. In order to illustrate the synthet-
ic utility, a formal synthesis of (–)-pseudodistomin B was
pursued. Pseudodistomin B is a member of pseudodistom-
in alkaloid natural products, which have attracted many
scientists since their first isolation in 1987 (Figure 1).7
Pseudodistomins have interesting 2-alkyl-5-amino-4-hy-
droxypiperidine structure in common. In addition, pseu-
dodistomin A and B showed potent antineoplastic activity
against L1210 and L5178 leukemia cells.8 Furthermore,
they exhibited inhibition effect against calmodulin-acti-
vated brain phosphodiesterase.9 Consequently, there has
been a great effort to synthesize pseudodistomins.10
Based upon the report by Ma and DeBrosse on the trans-
formation of the β-keto ester 8 to pseudodistomin B,10e,g
we reasoned that the gold(I)-catalyzed cycloisomerization
Synthesis 2014, 46, 2155–2160
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Gold Catalysis in Chemoselective Alkaloid Synthesis
2157
to give 130 mg (0.40 mmol, 83%) of 2a as a colorless oil; Rf = 0.53
(hexane–Et2O, 80:20).
IR (neat): 3314, 2928, 2856, 1703 cm–1.
Scheme 4) was completed from the homopropargylic
azide 11.
1H NMR (300 MHz, CDCl3): δ = 4.80–4.62 (m, 2 H), 4.05–3.83 (m,
1 H), 3.32 (s, 3 H), 2.60–2.37 (m, 2 H), 1.96 (s, 1 H), 1.69–1.63 (m,
2 H), 1.48 (s, 9 H), 1.35–1.21 (br, 12 H), 0.87 (t, J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 82.1, 80.6, 80.4, 77.1, 69.8, 56.2,
55.9, 55.5, 32.8, 32.0, 29.9, 29.7, 29.6, 29.4, 28.5, 26.6, 24.5, 23.8,
22.8.
Boc
R2
X
R2
N
OR1
i) HCHO, Me3SiCl/ROH
ii) BuLi then ClCO2Me
CO2Me
11 X = N3
13a R1 = Me
i) LiAlH4
HRMS (FAB): m/z (MH+) calcd for C19H36NO3: 326.2695; found:
326.2697.
ii) (Boc)2O
55% (over two steps)
13b R1 = Me3Si(CH2)2
12 X = NHt-Boc
98%
(over two steps)
67% (over two steps)
Methyl 5-[tert-Butoxycarbonyl(methoxymethyl)amino]tridec-
2-ynoate (2b)
3b (5 mol%)
To a stirred solution of 2a (325 mg, 1 mmol) in THF (3.3 mL) was
slowly added a 1.6 M of n-BuLi in hexane (0.7 mL, 1.1 mmol) at –
78 °C. After stirring for 2 h at –78 °C, methyl chloroformate (0.15
mL, 1.5 mmol) was added dropwise at –78 °C. The reaction mixture
was stirred for 3 h at –78 °C, and was quenched with sat. aq NH4Cl
(3 mL). After extraction with EtOAc (3 × 3 mL), the combined or-
ganic layers were dried (Na2SO4) and evaporated under reduced
pressure. The residue was purified by flash column chromatography
on silica gel (eluent: hexane–EtOAc, 95:5) to give 247 mg (0.7
mmol, 70%) of 2b as a colorless oil; Rf = 0.50 (hexane–
Et2O, 80:20).
CH2Cl2, –15 °C
Boc
Boc
R2
N
R2
N
TBAF (for 14b)
CO2Me
CO2Me
74%
OR1
OH
14a R1 = Me 95%
14b R1 = Me3Si(CH2)2 99%
8
8, 11–14 R2 = (CH2)6OBn
Scheme 5 Formal synthesis of (–)-pseudodistomin B
IR (neat): 2928, 2856, 1699, 1415 cm–1.
1H NMR (300 MHz, CDCl3): δ = 4.77 (m, 1 H), 4.62 (d, J = 11.0
Hz, 1 H), 4.07–3.88 (m, 1 H), 3.73 (s, 3 H), 3.31 (s, 3 H), 2.79–2.51
(m, 2 H), 1.77–1.58 (m, 2 H), 1.48 (s, 9 H), 1.33–1.20 (br, 12 H),
0.87 (t, J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 154.8, 80.2, 77.5, 55.9, 51.4, 32.1,
31.7, 29.77, 29.68, 29.56, 29.50, 29.44, 28.65, 28.59, 28.54, 26.3,
22.9, 14.3.
In conclusion, we have studied the gold(I)-catalyzed dom-
ino reaction of t-Boc-protected homopropargylic alkoxy-
alkylamines. Interesting competition between the
carboxylation-induced and alkoxylation-induced pathway
was observed. The alkoxylation-induced pathway was
applied to the synthesis of 2,4,5-trisubstituted piperidine
(–)-pseudodistomin B.
HRMS (FAB): m/z (MNa+) calcd for C21H37NO5 + Na: 406.2569;
found: 406.2567.
Gold-Catalyzed Reaction of 2a
Method A
All solvents were dried and distilled according to the standard meth-
ods before use. Au[P(t-Bu)2(o-biphenyl)]Cl and AgSbF6 were pur-
chased from Aldrich Chemicals and stored in a dry-keeper.
Au[P(C6F5)3]Cl was prepared according to the literature proce-
dures.13 Experiments were performed in flame-dried glassware with
rubber septa under a positive pressure of N2. Reactions were moni-
tored by TLC carried out on 0.25 mm E. Merck silica gel plates
(60F-254) using UV light as a visualizing agent, and acidic p-ani-
saldehyde and heat as developing agent. Flash chromatography was
A
mixture of AgSbF6 (3.4 mg, 0.010 mmol, 5 mol%),
Au[P(C6F5)3]Cl (7.6 mg, 0.010 mmol, 5 mol%), and compound 2a
(64 mg, 0.20 mmol) in CH2Cl2 (4 mL) was reacted for 2 min at r.t.
After the addition of a few drops of Et3N, the solution was concen-
trated under reduced pressure. The residue was directly purified by
flash column chromatography on silica gel (deactivated by Et3N be-
fore use, eluent: hexane–Et2O, 90:10) to give 4 (40 mg, 0.12 mmol,
62%) and 5 (7 mg, 0.026 mmol, 13%), respectively, as colorless liq-
uids.
1
carried out on Merck 60 silica gel (230–400 mesh). H and 13C
NMR spectra were recorded on a Bruker (300 MHz) spectrometer.
1H NMR spectra were referenced to CDCl3 (7.26 ppm). Chemical
shifts of the 13C NMR spectra were measured relative to CDCl3
(77.23 ppm). IR spectra were recorded on a Shimadzu IR-470 spec-
trometer. Specific rotation data were measured on JASCO P-1020
Polarimeter. HPLC was performed on Spectra SYSTEM series in-
struments using 4.6 × 25 cm Daicel Chiralcel OD-H column. Mass
spectral data were obtained from the Korea Basic Science Institute
(Daegu) on a Jeol JMS 700 high-resolution mass spectrometer.
Method B
A mixture of AgSbF6 (3.4 mg, 0.010 mmol, 5 mol%), Au[P(t-
butyl)2(o-biphenyl)]Cl (5.3 mg, 0.010 mmol, 5 mol%), and com-
pound 2a (64 mg, 0.20 mmol) in CH2Cl2 (4 mL) was reacted for 2
min at r.t. After the column chromatography, compound 4 (63 mg,
0.198 mmol, 99%) was obtained as a colorless liquid.
tert-Butyl 4-Methoxy-6-octyl-5,6-dihydropyridine-1(2H)-car-
boxylate (4)
tert-Butyl Dodec-1-yn-4-yl(methoxymethyl)carbamate (2a)
To a stirred solution of paraformaldehyde (22 mg, 0.7 mmol) in an-
hydrous CH2Cl2 (1.2 mL) was added tert-butyl dodec-1-yn-4-ylcar-
bamate (134 mg, 0.48 mmol)5a and Me3SiCl (0.2 mL, 1.4 mmol) at
0 °C. After stirring at 0 °C for 3 h, MeOH (0.5 mL) and Et3N (0.06
mL) were slowly added. After completion of the reaction, sat. aq
NaHCO3 (5 mL) was added to the mixture. The organic layer was
separated, and the aqueous layer was extracted with CH2Cl2 (3 × 10
mL). The organic layers were combined, dried (Na2SO4), and evap-
orated under reduced pressure. The residue was purified by flash
column chromatography on silica gel (eluent: hexane–EtOAc, 95:5)
Rf = 0.53 (hexane–Et2O, 80:20).
IR (neat): 2956, 2928, 2856, 1698 cm–1.
1H NMR (300 MHz, CDCl3): δ = 4.51–4.48 (br, 1 H), 4.42–4.25 (br,
2 H), 3.52 (s, 3 H), 3.50–3.44 (m, 1 H), 2.51 (ddq, J = 13.3, 5.9, 2.9
Hz, 1 H), 1.84 (d, J = 16.4 Hz, 1 H), 1.65–1.55 (m, 2 H), 1.46 (s, 9
H), 1.31–1.25 (br, 12 H), 0.87 (t, J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 155.2, 152.3, 89.8, 79.6, 54.4, 32.1,
31.9, 29.8, 29.7, 29.5, 28.7, 28.6, 26.6, 22.9, 14.3.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2155–2160

2158
J. H. Lee et al.
SPECIAL TOPIC
tert-Butyl (R)-10-(Benzyloxy)dec-1-yn-4-ylcarbamate (12)
HRMS (FAB): m/z (MNa+) calcd for C19H35NO3 + Na: 348.2515;
To a stirred solution of LiAlH4 (161 mg, 4.3 mmol) in Et2O (25 ml)
was slowly added (R)-[(7-azidodec-9-ynyloxy)methyl]benzene
(11;5b 802 mg, 2.8 mmol) in Et2O (3 mL) at 0 °C. The reaction mix-
ture was stirred for 2 h at 0 °C and quenched with H2O (1 mL). The
resulting solution was dried (Na2SO4), filtered through a pad of
Celite, and concentrated under reduced pressure. The resulting
amine was used in the next step without further purification by dis-
solving it in H2O (28 mL) and treating with di-tert-butyl dicarbon-
ate (990 mg, 4.5 mmol) at 0 °C. The reaction mixture was slowly
warmed to r.t. and stirred overnight. After completion of the reac-
tion, EtOAc (50 mL) was added. The organic layer was separated,
and the aqueous layer was extracted with EtOAc (3 × 20 mL). The
combined organic layers were dried (Na2SO4) and concentrated un-
der reduced pressure. The residue was purified by flash column
chromatography on silica gel (eluent: hexane–Et2O, 95:5) to give
12 (1.0 g, 98% yield over two steps) as a yellow oil; Rf = 0.53 (hex-
ane–Et2O, 80:20); [α]D20 +37.7 (c = 1.1, CHCl3).
found: 348.2514.
3-(Methoxymethyl)-6-methylene-4-octyl-1,3-oxazinan-2-one (5)
Rf = 0.23 (hexane–Et2O, 80:20).
IR (neat): 2927, 2855, 1729, 1665 cm–1.
1H NMR (300 MHz, CDCl3): δ = 5.08 (d, J = 10.5 Hz, 1 H), 4.76 (s,
1 H), 4.63 (d, J = 10.5 Hz, 1 H), 4.28 (s, 1 H), 3.57–3.49 (m, 1 H),
3.37 (s, 3 H), 2.63 (dd, J = 14.5, 4.9 Hz, 1 H), 2.56 (dd, J = 14.5, 2.5
Hz, 1 H), 1.68–1.57 (m, 2 H), 1.57–1.46 (m, 12 H), 0.90 (t, J = 6.5
Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 151.4, 94.5, 79.0, 56.5, 52.1, 32.6,
32.0, 30.4, 29.6, 29.6, 29.4, 26.0, 22.9, 14.3.
HRMS (FAB): m/z (MNa+) calcd for C15H27NO3 + Na: 292.1889;
found: 292.1887.
Gold-Catalyzed Reaction of 2b
Method A
IR (neat): 3310, 2933, 2858, 1713, 1503 cm–1.
A
mixture of AgSbF6 (3.4 mg, 0.010 mmol,
5
mol%),
1H NMR (300 MHz, CDCl3): δ = 7.34–7.28 (m, 5 H), 4.59 (d,
J = 8.1 Hz, 1 H), 4.50 (s, 2 H), 3.75–3.66 (m, 1 H), 3.46 (t, J = 6.6
Hz, 2 H), 2.40 (qdd, J = 17.1, 4.7, 2.4 Hz, 2 H), 1.98 (t, J = 2.6 Hz,
1 H), 1.65–1.56 (m, 5 H), 1.44 (s, 9 H), 1.36–1.32 (m, 6 H).
13C NMR (75 MHz, CDCl3): δ = 155.6, 138.9, 128.6, 127.8, 127.7,
80.7, 79.5, 73.1, 70.8, 70.6, 48.8, 33.9, 29.9, 29.4, 28.6, 26.3, 26.2,
24.8.
Au[P(C6F5)3]Cl (7.6 mg, 0.010 mmol, 5 mol%), and compound 2b
(78 mg, 0.20 mmol) in CH2Cl2 (4 mL) was reacted for 2 min at r.t.
The residue was purified by flash column chromatography on silica
gel (deactivated by Et3N before use, eluent: hexane–Et2O, 50:50) to
give 6 (6.1 mg, 0.016 mmol, 8%) and 7 (35 mg, 0.106 mmol, 53%)
as colorless oils.
Method B
HRMS (FAB): m/z (MNa+) calcd for C22H33NO3 + Na: 382.2358;
A mixture of AgSbF6 (3.4 mg, 0.010 mmol, 5 mol%), Au[P(t-bu-
tyl)2(o-biphenyl)]Cl (5.3 mg, 0.010 mmol, 5 mol%), and compound
2b (78 mg, 0.20 mmol) in CH2Cl2 (4 mL) was reacted for 2 min at
r.t. The residue was purified by flash column chromatography on
silica gel (deactivated by Et3N before use, eluent: hexane–
Et2O, 50:50) to give 6 (69 mg, 0.18 mmol, 90%) and 7 (6.5 mg, 0.02
mmol, 10%) as colorless oils.
found: 382.2355.
Methyl (R)-11-(Benzyloxy)-5-(tert-butoxycarbonyl{[2-(trimeth-
ylsilyl)ethoxy]methyl}amino)undec-2-ynoate (13b)
To a stirred solution of paraformaldehyde (75 mg, 1.7 mmol) in an-
hydrous CH2Cl2 (2.2 mL) was added compound 12 (403 mg, 1.1
mmol) and Me3SiCl (0.4 mL, 3.3 mmol) at –15 °C. After stirring at
–15 °C for 10 h, 2-(trimethylsilyl)ethanol (0.64 mL, 4.4 mmol) and
Et3N (0.44 mL, 3.3 mmol) were slowly added. After completion of
the reaction, sat. aq NaHCO3 (5 mL) was added to the mixture. The
organic layer was separated and the aqueous layer was extracted
with CH2Cl2 (3 × 5 mL). The combined organic layers were dried
(Na2SO4) and evaporated under reduced pressure. The residue was
purified by flash column chromatography on silica gel (eluent: hex-
ane–EtOAc, 95:5) to give 420 mg (0.86 mmol, 78%) of (R)-tert-
1-tert-Butyl 3-Methyl 4-methoxy-6-octyl-5,6-dihydropyridine-
1,3(2H)-dicarboxylate (6)
Rf = 0.22 (hexane–Et2O, 80:20).
IR (neat): 2928, 2856, 1723, 1699 cm–1.
1H NMR (300 MHz, CDCl3): δ = 4.62–4.40 (br, 2 H), 3.73 (s, 3 H),
3.71 (s, 3 H), 3.56 (d, J = 17.3 Hz, 1 H), 2.62 (ddt, J = 17.3, 6.2, 3.1
Hz, 1 H), 2.21 (d, J = 17.3 Hz, 1 H), 1.62–1.50 (m, 2 H), 1.46 (s, 9
H), 1.29–1.21 (br, 12 H), 0.86 (t, J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 165.7, 161.6, 154.8, 103.0, 80.2,
55.9, 51.4, 48.0, 38.7, 32.1, 31.7, 31.7, 29.8, 29.6, 29.4, 28.6, 26.3,
22.9, 14.3.
butyl
10-(benzyloxy)dec-1-yn-4-yl{[2-(trimethylsilyl)ethoxy]-
methyl}carbamate as
a colorless oil; Rf = 0.66 (hexane–
Et2O, 80:20); [α]D20 +4.6 (c = 0.9, CHCl3).
IR (neat): 3312, 2932, 2858, 1699 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.35–7.27 (m, 5 H), 4.85 (m, 1 H),
4.69 (q, J = 9.2 Hz, 1 H), 4.50 (s, 2 H), 3.97 (m, 1 H), 3.58 (dt,
J = 16.4, 7.8 Hz, 2 H), 3.47 (t, J = 6.6 Hz, 2 H), 2.61–2.40 (m, 2 H),
1.96 (s, 1 H), 1.70–1.60 (m, 4 H), 1.49 (s, 9 H), 1.39–1.27 (m, 8 H),
0.93 (t, J = 8.4 Hz, 2 H), 0.03 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 156.1, 155.2, 138.8, 128.5, 127.7,
127.6, 82.2, 80.4, 80.2, 75.1, 73.0, 70.5, 69.8, 69.7, 65.4, 56.0, 55.4,
32.7, 32.1, 29.9, 29.4, 28.5, 26.6, 26.3, 24.5, 23.9, 18.3, –1.2.
HRMS (FAB): m/z (MH+) calcd for C21H38NO5: 384.2750; found:
384.2747.
Methyl (Z)-2-[3-(Methoxymethyl)-4-octyl-2-oxo-1,3-oxazinan-
6-ylidene]ethanoate (7)
Rf = 0.05 (hexane–Et2O, 80:20).
IR (neat): 2927, 2856, 1753, 1738, 1665 cm–1.
1H NMR (300 MHz, CDCl3): δ = 5.08 (dd, J = 6.1, 4.4 Hz, 2 H),
4.66 (d, J = 10.5 Hz, 1 H), 3.77 (s, 3 H), 3.63–3.55 (m, 1 H), 3.39
(s, 3 H), 2.74 (ddd, J = 15.0, 5.4, 0.9 Hz, 1 H), 2.55 (dd, J = 15.0,
2.3 Hz, 1 H), 1.74–1.64 (br, 1 H), 1.59–1.47 (m, 1 H), 1.34–1.24 (br,
12 H), 0.90 (t, J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 164.2, 157.1, 149.3, 100.3, 79.3,
56.7, 51.7, 51.7, 32.7, 32.0, 31.8, 29.9, 29.6, 29.5, 29.4, 26.1, 22.9,
14.3.
HRMS (FAB): m/z (MNa+) calcd for C28H47NO4Si + Na: 512.3172;
found: 512.3169.
To a stirred solution of the above compound (98 mg, 0.2 mmol) in
THF (0.7 mL) was slowly added a 1.6 M solution of n-BuLi in hex-
ane (0.27 mL, 0.44 mmol) at –78 °C. After stirring for 2 h at –78 °C,
methyl chloroformate (46 μL, 0.6 mmol) was added dropwise at
–78 °C. The reaction mixture was stirred for 3 h at –78 °C, and
quenched with sat. aq NH4Cl (10 mL) at that temperature. The solu-
tion was slowly warmed to r.t. The organic layer was separated, and
the aqueous layer was extracted with EtOAc (3 × 20 mL). The com-
bined organic layers were dried (Na2SO4) and evaporated under re-
duced pressure. The residue was purified by flash column
HRMS (FAB): m/z (MNa+) calcd for C17H29NO5 + Na: 350.1943;
found: 350.1946.
Synthesis 2014, 46, 2155–2160
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Gold Catalysis in Chemoselective Alkaloid Synthesis
2159
chromatography on silica gel (eluent: hexane–EtOAc, 95:5) to give
75 mg (0.14 mmol, 70%, 55% yield over two steps) of 13b as a col-
orless oil; Rf = 0.57 (hexane–Et2O, 80:20); [α]D20 –1.5 (c = 3.6, CH-
Cl3).
Acknowledgment
This work was supported by the National Research Foundation fun-
ded by the Korean government (NRF-2013R1A2A2A01068684).
IR (neat): 2932, 2858, 2239, 1717, 1703 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.33–7.25 (m, 5 H), 4.85 (m, 1 H),
4.62 (d, J = 11.1 Hz, 1 H), 4.48 (s, 2 H), 4.02 (m, 1 H), 3.71 (s, 3 H),
3.59 (q, J = 10.3 Hz, 2 H), 3.45 (t, J = 6.5 Hz, 2 H), 2.77–2.54 (m,
2 H), 1.68–1.54 (m, 5 H), 1.48 (s, 9 H), 1.41–1.26 (m, 7 H), 0.91 (t,
J = 8.4 Hz, 2 H), 0.01 (s, 9 H).
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000084. Included are spectral data for compounds 2,
4–8, 12, 13b, and 14b. SnuIpgfori
m
p
nirtSatnoIuofrpi
m
tgiornat
13C NMR (75 MHz, CDCl3): δ = 155.8, 154.9, 154.1, 138.8, 128.4,
127.7, 127.5, 87.3, 80.5, 75.2, 74.5, 74.0, 72.9, 70.4, 65.5, 55.1,
54.8, 53.5, 52.5, 32.7, 32.1, 29.8, 29.2, 28.4, 26.4, 26.2, 24.9, 24.2,
18.2, –1.3.
HRMS (FAB): m/z (MNa+) calcd for C30H49NO6Si + Na: 570.3227;
found: 570.3229.
References
(1) For selected recent reviews on gold-catalyzed reactions, see:
(a) Corma, A.; Leyva-Pérez, A.; Sabater, M. J. Chem. Rev.
2011, 111, 1657. (b) Bandini, M. Chem. Soc. Rev. 2011, 40,
1358. (c) Hashmi, A. S. K.; Bührle, M. Aldrichimica Acta
2010, 43, 27. (d) Nevado, C. Chimia 2010, 64, 247.
(e) Belmont, P.; Parker, E. Eur. J. Org. Chem. 2009, 6075.
(f) Fürstner, A. Chem. Soc. Rev. 2009, 38, 3208.
(2) (a) Robles-Machin, R.; Adrio, J.; Carretero, J. C. J. Org.
Chem. 2006, 71, 5023. (b) Lee, E.-S.; Yeom, H.-S.; Hwang,
J.-H.; Shin, S. Eur. J. Org. Chem. 2007, 3503. (c) Istrate, F.
M.; Buzas, A. K.; Jurberg, I. D.; Odabachian, Y.; Gagosz, F.
Org. Lett. 2008, 10, 925.
1-tert-Butyl 3-Methyl (R)-6-[6-(Benzyloxy)hexyl]-4-[2-(trimeth-
ylsilyl)ethoxy]-5,6-dihydropyridine-1,3(2H)-dicarboxylate
(14b)
Following the Method B described above for the gold-catalyzed re-
actions, a mixture of AgSbF6 (2.7 mg, 0.008 mmol, 5 mol%),
Au[P(t-butyl)2(o-biphenyl)]Cl (4.2 mg, 0.008 mmol, 5 mol%), and
compound 13b (89 mg, 0.16 mmol) in CH2Cl2 (3.2 mL) was reacted
for 15 min at –15 °C. The residue was purified by flash column
chromatography on silica gel (deactivated by Et3N before use, elu-
ent: hexane–Et2O, 80:20) to give 88 mg of 14b (0.16 mmol, 99%)
(3) Zi, W.; Toste, F. D. J. Am. Chem. Soc. 2013, 135, 12600; and
references cited therein.
(4) For early examples on platinum- and gold-catalyzed
carboalkoxylation reaction of alkynes, see: (a) Nakamura, I.;
Bajracharya, G. B.; Mizushima, Y.; Yamamoto, Y. Angew.
Chem. Int. Ed. 2002, 41, 4328. (b) Nakamura, I.;
Mizushima, Y.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127,
15022. (c) Fürstner, A.; Davies, P. W. J. Am. Chem. Soc.
2005, 127, 15024. (d) Nakamura, I.; Bajracharya, G. B.; Wu,
H.; Oishi, K.; Mizushima, Y.; Gridnev, I. D.; Yamamoto, Y.
J. Am. Chem. Soc. 2004, 126, 15423.
20
as a colorless oil; Rf = 0.44 (hexane–Et2O, 80:20); [α]D +29.4
(c = 2.3, CHCl3).
IR (neat): 2933, 2858, 1715, 1695 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.35–7.25 (m, 5 H), 4.59–4.39 (m,
4 H), 3.99 (dd, J = 16.6, 6.3 Hz, 2 H), 3.70 (s, 3 H), 3.57 (d, J = 17.5
Hz, 1 H), 3.44 (t, J = 6.5 Hz, 2 H), 2.65–2.57 (m, 1 H), 2.18 (d,
J = 17.0 Hz, 1 H), 1.59 (dt, J = 12.4, 7.3 Hz, 4 H), 1.45 (s, 9 H),
1.33–1.25 (m, 8 H), 1.06 (t, J = 8.5 Hz, 2 H), 0.03 (s, 9 H).
(5) (a) Kim, C.; Bae, H. J.; Lee, J. H.; Jeong, W.; Kim, H.;
Sampath, V.; Rhee, Y. H. J. Am. Chem. Soc. 2009, 131,
14660. (b) Kim, H.; Rhee, Y. H. J. Am. Chem. Soc. 2012,
134, 4011.
13C NMR (75 MHz, CDCl3): δ = 166.2, 160.9, 154.8, 138.9, 128.5,
127.8, 127.6, 103.8, 80.1, 73.0, 70.5, 66.6, 51.3, 31.6, 29.9, 29.4,
28.6, 26.4, 26.3, 18.8, –1.3.
HRMS (FAB): m/z (MNa+) calcd for C30H49NO6Si + Na: 570.3227;
found: 570.3229.
(6) Varying the counteranions had little effect on the selectivity.
(7) Ishibashi, M.; Ohizumi, Y.; Sasaki, T.; Nakamura, H.;
Hirata, Y.; Kobayashi, J. J. Org. Chem. 1987, 52, 450.
(8) (a) Kiguchi, T.; Yuumoto, Y.; Ninomiya, I.; Naito, T.; Deki,
K. Tetrahedron Lett. 1992, 33, 7389. (b) Ishibashi, M.; Deki,
K.; Kobayashi, J. J. Nat. Prod. 1995, 58, 804. (c) Kobayashi,
J.; Natioh, K.; Doi, Y.; Deki, K.; Ishibashi, M. J. Org. Chem.
1995, 60, 6941. (d) Freyer, A.; Patil, A.; Killmer, L.; Troupe,
N.; Menter, M.; Carte, B.; Faucette, L.; Johnson, R. J. Nat.
Prod. 1997, 60, 986.
1-tert-Butyl 3-Methyl (6R)-(+)-6-(6-Benzyloxyhexyl)-4-hydroxy-
5,6-dihydro-2H-pyridine-1,3-dicarboxylate (8)
To a stirred solution of compound 14b (90 mg, 0.16 mmol) in THF
(2 mL) was slowly added n-Bu4NF (1 M solution in THF, 1.0 mL,
1 mmol) at r.t. The reaction mixture was quenched with H2O (5
mL). After stirring for 0.5 h at r.t., the solution was extracted with
EtOAc (3 × 10 mL). The combined organic layers were dried (Na2-
SO4) and evaporated under reduced pressure. The residue was puri-
fied by flash column chromatography on silica gel (eluent: hexane–
EtOAc, 95:5) to give 55 mg (0.12 mmol, 74%) of 8 as a colorless
oil. The spectral data of this compound were fully consistent with
(9) (a) Kobayashi, J.; Ishibashi, M. Heterocycles 1996, 42, 943.
(b) Ninomiya, I.; Kiguchi, T.; Naito, T. In The Alkaloids;
Vol. 50; Cordell, G. A., Ed.; Elsevier: Amsterdam, 1998,
317–342.
20
the literature;10e Rf = 0.50 (hexane–Et2O, 80:20); [α]D +50.1
(c = 1.33, CHCl3) {Lit.10e [α]D23 +52.9 (c 0.33, CHCl3)].
(10) (a) Naito, T.; Yuumoto, Y.; Ninomiya, I.; Kiguchi, T.
Tetrahedron Lett. 1992, 33, 4033. (b) Knapp, S.; Hale, J.
J. Org. Chem. 1993, 58, 2650. (c) Ishibashi, M.; Kobayashi,
J. Tetrahedron 1996, 52, 4573. (d) Kiguchi, T.; Ikai, M.;
Shirakawa, M.; Fujimoto, K.; Ninomiya, I.; Naito, T. J.
Chem. Soc., Perkin Trans. 1 1998, 893. (e) Ma, D.; Sun, H.
J. Org. Chem. 2000, 65, 6009. (f) Langlois, N. Org. Lett.
2002, 4, 185. (g) Davis, F.; Zhang, J.; Li, Y.; Xu, H.;
DeBrosse, C. J. Org. Chem. 2005, 70, 5413. (h) Haddad, M.;
Larchevęque, M.; Tong, H. Tetrahedron Lett. 2005, 46,
6015. (i) Trost, B. M.; Fandrick, D. R. Org. Lett. 2005, 7,
823.
IR (neat): 1798, 1656, 1548, 1482 cm–1.
1H NMR (300 MHz, CDCl3): δ = 11.96 (s, 1 H), 7.33–7.26 (m, 5 H),
4.53–4.39 (m, 4 H), 3.77 (s, 3 H), 3.53–3.43 (m, 3 H), 2.69–2.60 (m,
1 H), 2.11–2.03 (m, 1 H), 1.64–1.55 (m, 4 H), 1.46 (s, 9 H), 1.34–
1.25 (m, 6 H).
13C NMR (75 MHz, CDCl3): δ = 171.1, 154.9, 138.9, 128.5, 127.8,
127.7, 80.2, 73.1, 70.6, 51.7, 31.8, 29.9, 29.4, 28.6, 26.38, 26.31.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2155–2160

2160
J. H. Lee et al.
SPECIAL TOPIC
(11) The compound was prepared in 98% ee from (S)-2-[6-
(benzyloxy)hexyl]oxirane by using the procedure described
in ref. 5a.
(12) (a) Barnes, D. M.; Barkalow, J.; Plata, D. J. Org. Lett. 2009,
11, 273. (b) Use of basic conditions (for example
NaH/MOMBr) showed poor conversion.
(13) Kang, J.-E.; Kim, H.-B.; Kim, J.-W.; Shin, S. Org. Lett.
2006, 8, 3537.
Synthesis 2014, 46, 2155–2160
© Georg Thieme Verlag Stuttgart · New York