Mg(ClO4)2-catalyzed intramolecular allylic amination: Application to the total synthesis of demethoxyfumitremorgin C

Article abstract of DOI:10.1016/j.tet.2012.03.097

A Mg(ClO₄)₂-catalyzed intramolecular amination of allylic alcohols with carbamate or sulfonamide nucleophiles to form substituted piperidine and pyrrolidine derivatives has been developed. This method has been successfully applied to the total synthesis of demethoxyfumitremorgin C.

Full text of DOI:10.1016/j.tet.2012.03.097

Tetrahedron 68 (2012) 4225e4232
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Mg(ClO4)2-catalyzed intramolecular allylic amination: application to the total
synthesis of demethoxyfumitremorgin C
,b,
Danfeng Jiang a, Zhengren Xu a, Yanxing Jia a
*
a State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China
b State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A Mg(ClO4)2-catalyzed intramolecular amination of allylic alcohols with carbamate or sulfonamide
nucleophiles to form substituted piperidine and pyrrolidine derivatives has been developed. This method
has been successfully applied to the total synthesis of demethoxyfumitremorgin C.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 29 November 2011
Received in revised form 14 March 2012
Accepted 22 March 2012
Available online 30 March 2012
Keywords:
Amination
Total synthesis
Natural product
Nitrogen heterocycles
Magnesium
1. Introduction
intramolecular amination of allylic alcohol 1, which gave the de-
sired product 2 in higher yield and similar diastereoselectivity
Naturally occurring nitrogen heterocycles are compounds of
great interest due to their interesting and diverse biological prop-
erties.1 The development of efficient methods for the formation of
CeN bond has been the subject of intensive research, and a variety
of well-documented traditional and modern methods are now
available.2 However, the development of general and efficient
methods for CeN bond formation from simple and easily accessible
starting materials remains an active research field.3 In this context,
direct amination of allylic alcohols with amine nucleophiles to form
the CeN bond has recently emerged as an attractive area of re-
search because this process is atom-economy and eco-friendly as
water is the only byproduct.4,5 In fact, a variety of metal-based
catalyst systems such as palladium,6 gold,7 iron,8 bismuth,9 Mo-
lybdenum,10 and mercury,11 I2,12 as well as Brønsted acids13 in
combination with carbamate or sulfonamide nucleophiles have
been documented. Of these, the Pd(II)-catalyzed methods are most
extensively developed and have been widely used in natural
product synthesis.6
comparing with those using PdCl2(CH3CN)2 (Scheme 1).14 Thus,
Mg(ClO4)2 might be a powerful alternative candidate for traditional
Pd catalyst systems in the intramolecular allylic amination. The
mechanism of Mg(ClO4)2-mediated cyclization is postulated that
the magnesium cation, acting as a mild Lewis acid, coordinates to
the alcohol oxygen and activates the allylic alcohol, thus facilitating
the intramolecular SN20 substitution reaction. Since Mg(ClO4)2 is
also low-toxic, inexpensive, and has not been demonstrated in al-
lylic amination, these intriguing results inspired us to explore the
scope of this reaction. Herein, we demonstrate that Mg(ClO4)2 is
able to catalyze the intramolecular amination of a variety of allylic
alcohols to produce the desired N-containing hetercycles and this
method can be applied to the total synthesis of demethoxyfumi-
tremorgin C.
OH
Boc
N
CO2Me
Mg(ClO4)2
MeCN
CO2Me
NHBoc
During the course of our synthesis of (ꢀ)-trans-clavicipitic acid,
we unexpectedly discovered that Mg(ClO4)2 could catalyze an
reflux, 2h
98%
N
N
Boc
Boc
1
2 (trans : cis = 5 : 1)
* Corresponding author. Tel.: þ86 10 8280 5166; fax: þ86 10 8280 2724; e-mail
Scheme 1. Mg(ClO4)2-mediated intramolecular amination.
address: yxjia@bjmu.edu.cn (Y. Jia).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.097

4226
D. Jiang et al. / Tetrahedron 68 (2012) 4225e4232
2. Results and discussions
OH
OH
NHBoc
OH
I
O
O
O
O
2.1. Preparation of allylic alcohol substrates
Pd(OAc)2, Ag2CO3
toluene, 80 °C
NHBoc
NHR
5a
3a
To explore the scope of this reaction, a variety of allylic alcohols
3aej (see Table 1) were prepared. The synthesis of 3aeh is illus-
trated in Scheme 2. Heck reaction of 5aec with different allylic
alcohols in air under ligand-free conditions provided the desired
product 3a, 3b, 3f, and 3e.14 Heck reaction of 5a and 5b with allyl
acetate under above-mentioned conditions provided the corre-
sponding product 3d and 3h, respectively. Basic hydrolysis of ace-
tate 3d and 3h gave allylic alcohols 3c and 3g, respectively.
OH
I
O
O
O
Pd(OAc)2, Ag2CO3
toluene, 80 °C
O
NHR
3b, R = Boc
3f, R = Ts
5a, R = Boc
5b, R = Ts
OAc
O
OR1
NHR
Pd(OAc)2, Ag2CO3
toluene, 80 °C
O
3d, R = Boc, R1 = Ac
3c, R = Boc, R1 = H
3h, R = Ts, R1 = Ac
3g, R = Ts, R1 = H
Table 1
LiOH, EtOH/H2O (3:1)
LiOH, EtOH/H2O (3:1)
Substrate scope of Mg(ClO4)2-catalyzed intramolecular amination of allylic alcohols
Entry
Substrate
Product
Yield (%)[a]
OH
O
O
OH
1
98%
O
O
OH
I
NHBoc
NBoc
NHBoc
NHBoc
Pd(OAc)2, Ag2CO3
toluene, 80 °C, 80%
N
H
O
3a
4a
N
O
H
OH
5c
3e
O
O
2
94%
O
O
Scheme 2. Preparation of allylic alcohols 3aeh.
NBoc
NBoc
NHBoc
The synthesis of allylic alcohols 3i and 3j was shown in Scheme 3.
The known aldehyde 7 was prepared from -glutamic acid accor-
ding to Martín’s procedure.15 Wittig olefination of
with
2-oxopropyltriphenylphosphonium chloride (8) in THF/H2O at reflux
furnished the (E)- -unsaturated ketone 9. Luche reduction of ke-
3b
4b
L
7
O
O
OR
O
O
a,b
NHBoc
tone 9 afforded the desired allylic alcohol 3i as a pair of diastereomers
3[b]
4
3c: R = H
4c
4c
26%
50%
3d: R = Ac
O
O
O
O
O
Cl (8)
PPh3
OH
ref. 15
HO
OH
H
OMe
Na2CO3, THF/H2O
reflux, 20 h, 68%
5[c]
41%
NBoc
NH2
N(Ts)Boc
7
NHBoc
O
L
-glutamic acid (6)
N
H
N
H
O
CeCl3•7H2O
O
O
OH
O
3e
4e
NaBH4, CH3OH
OMe
N(Ts)Boc
OMe
N(Ts)Boc
OH
92%
O
3i
6
90%
9
O
NTs
NTs
O
NHTs
O
1. TsCl, Et3N, 97%
2. TESCl, Et3N, 84%
3f
4f
HO
NH2
TESO
NHTs
10
11
O
O
OR
O
O
NHTs
1. DMAP, Boc2O, 96%
2. Swern oxidation, 98%
Na2CO3, THF/H2O
N(Boc)Ts
OH
Ο
3g: R = H
4g
4g
7
8
73%
76%
8, reflux, 72%
12
3h: R = Ac
OH
O
CeCl3•7H2O
CO2Me
9
82%
NaBH4, CH3OH
CO2Me
Boc
Boc
N
N
N
Ts
N(Ts)Boc
Ts
Ts
86%
13
3i
4i (cis : trans = 1:1.3)
3j
Scheme 3. Preparation of allylic alcohols 3i and 3j.
OH
10[b]
Boc
95%
N
N
Ts
Ts
in a ratio of 1:1.3, which could not be separated by either careful
chromatography or HPLC. The allylic alcohol 3j was prepared from 5-
aminopentan-1-ol 10 following a similar scheme as described for 3i.
3j
4j
[a] Concentration 0.1 M in CH3CN, 0.10 equiv of Mg(ClO4)2, 1.0 equiv of 3, 80 oC. All
the yields are isolated yields.[b] Mg(ClO4)2 (1 equiv).[c] The reaction time was 7 d.

D. Jiang et al. / Tetrahedron 68 (2012) 4225e4232
4227
2.2. Amination of allylic alcohols
key step to construct the tetrahydro-
b
-carboline. Now we managed
to apply the Mg(ClO4)2-catalyzed intramolecular allylic amination
reaction to construct the tetrahydro- -carboline, and then finished
the total synthesis of demethoxyfumitremorgin C (Scheme 5).
The reactivity of NHBoc with different substituents and ring
systems of allylic alcohols was examined first (Table 1). When tert-
alcohol 3a was treated with Mg(ClO4)2 (0.1 equiv) in CH3CN at
80 ꢁC, a smooth and fast reaction took place and the desired tet-
rahydroisoquinoline 4a was obtained in 98% yield (Table 1, entry 1).
Similarly, the secondary alcohol 3b also worked well and gave 4b in
94% yield, albeit a longer reaction time was needed (Table 1, entry
2). However, the reaction of primary alcohol 3c was sluggish even
with higher catalyst loadings (1 equiv), which gave the corre-
sponding product 4c in only 26% yield (Table 1, entry 3). The allylic
acetate 3d could enhance the reactivity and produce 4c in 50% yield
(Table 1, entry 4). The reaction also could be used to form the seven-
membered ring, which was difficult to obtain. Under the optimized
reaction conditions, compound 3e was converted to 4e in 41% yield.
b
CO2Me
N(Boc)2
CO2Me
1. Hg(OOCCF3)2, KI
I2, CH2Cl2, rt, 3 h
N(Boc)2
I
2. Boc2O, DMAP
MeCN
N
N
91%
Boc
14
Boc
15
CO2Me
N(Boc)2
Mg(ClO4)2, MeCN
80 °C, 1.5 h
OH
Pd(OAc)2, Ag2CO3
toluene, 2 h, 80 °C
90%
98%
N
OH
Besides the aromatic allylic alcohol, g- and d-amino allylic alcohol
derivatives 3k and 3l were trailed (Scheme 4). However, no desired
cyclized products 4k and 4l were detected.
Boc
16
CO2Me
NBoc
CO2Me
NBoc
O
OH
+
N
CO2Me
Troc
19
Cl
CO2Me
×
N
N
N
Boc
4k
Boc
Boc
NHBoc
3k
17b
17a
(1 : 1)
OH
CO2Me
NH
×
TMSOTf
N
1. 19, Et3N, CH2Cl2
NHBoc
Boc
2,6-Lutidine
0 °C, 12 h
3l
4l
17a
CH2Cl2, 0 °C
83%
2. Zn dust, CH3OH
reflux, 36 h
81%
N
Pd(OAc)2
Ag2CO3
Boc
OH
85%
O
O
18
5b
O
toluene
80 °C
NTs
O
O
N
NHTs
N
O
TFA, CH2Cl2
0 °C, 1.5 h
3m
Scheme 4.
4m
H
O
H
N
N
O
90%
N
N
H
The effects of the protecting group on the nitrogen were next
investigated. The N-tosyl derivatives, exhibiting stronger reactivity,
were chosed as substrates. When we attempted to prepare allylic
alcohol 3m by Heck reaction of 5b with 2-methyl-3-buten-2-ol, to
our great surprise, the cyclized product 4m was isolated in 85%
yield (Scheme 4). These results indicated that N-tosyl derivatives
exhibited stronger reactivity than carbamates.
Thus, more N-tosyl allylic alcohols were investigated as shown
in Table 1 (Table 1, entries 6e10). Although 3f gave 4f in almost the
same yield as those of 3b, 3g and its acetate 3h gave the corre-
sponding product in much higher yields compared with 3c and 3d
(Table 1, entries 7 and 8). Since selective cleavage of Boc group in
compounds 3i and 3j to produce the corresponding N-tosyl allylic
alcohols by using Mg(ClO4)2 is well-known. We planed to perform
Mg(ClO4)2-promoted deprotection/cyclization cascade reaction for
3i and 3j in one-pot manner, thus streamlining the synthesis.14
Gratefully, N-tosyl allylic alcohols 3i as a pair of diastereomers in
a ratio of 1:1.3 and 3j worked smoothly and gave the pyrrolidine 4i
(cis/trans¼1:1.3) in 82% yield and piperidine 4j in 95% yield, re-
spectively (Table 1, entries 9 and 10).
Boc
demethoxyfumitremorgin C (21)
20
O
N
CO2Me
NBoc
H
N
O
N
N
H
Boc
17b
22
Scheme 5. Total synthesis of demethoxyfumitremorgin C.
Tryptophan derivative 14 was treated with Hg(CF3CO2)2 and I2
to provide the desired iodide 15 (33%), together with 58% NHBoc
product.21 Treating the crude products with Boc2O and DMAP in
acetonitrile yielded 15 in 91% overall yield. Heck reaction of 15 with
2-methyl-3-buten-2-ol gave allylic alcohol 16 in 90% yield. Treat-
ment of 16 with Mg(ClO4)2 under our optimized conditions pro-
vided the diastereoisomers 17a and 17b in 98% yield with a trans to
cis ratio of 1:1, which could be separated by careful chromatogra-
phy. Conversion of 15 to 17a and 17b also could be done in a one-
pot manner.14 Since the relative configuration of 17a and 17b was
impossible to be determinated by NOESY studies at this stage, it had
to await completion of the synthesis of 21. Selective deprotection of
Boc in 17a with TMSOTf in the presence of 2,6-lutidine gave amine
2.3. Total synthesis of demethoxyfumitremorgin C
The utility of this new method is demonstrated by a rapid total
synthesis of demethoxyfumitremorgin C, a fungal inhibitor of
mammalian cell cycle progression at the G(2)/M transion.16 So far,
the groups of Ottenheijm,17 Nakagawa,18 Bailey,19 and Ganesan20
have finished the total synthesis of demethoxyfumitremorgin C,
all of which took advantage of the PicteteSpengler reaction as the
18 in 83% yield. Coupling 18 with -Troc-Pro-Cl 19, followed by
treatment of the corresponding product with Zn dust gave dike-
topiperazine 20 in 81% yield. Finally, deprotection of Boc with
L

4228
D. Jiang et al. / Tetrahedron 68 (2012) 4225e4232
CF3CO2H provided the target molecule demethoxyfumitremorgin C
(21) in 90% yield. The physical properties (1H, and 13C NMR, MS
data) of 21 are in accord with those described in the literature.17e20
Synthetic demethoxyfumitremorgin C had an optical rotation of
(ESI) m/z calcd for
C
18H25NNaO5 (MþNa)þ 358.1625, found
358.1628; IR (KBr) 3427, 3304, 3054, 2983, 2931, 2896, 1677, 1541,
1502, 1486, 1280, 1253, 1165, 1040, 954, 936, 872, 852, 663, 628,
603 cmꢀ1
.
½
a 2D8
ꢂ
þ4.0 (c 0.2, CHCl3), lit.: natural16
½
a 3D0
ꢂ
þ8.0 (c 0.2, CHCl3),
synthetic20a
½
a 2D4
ꢂ
þ16.4 (c 0.14, CHCl3).
4.2.3. tert-Butyl 2-(5-((E)-3-hydroxyprop-1-enyl)-benzo[d][1,3]di-
oxol-6-yl) ethylcarbamate (3c). Lithium hydroxide mono-hydrate
(50.0 mg, 1.19 mmol) was added to a solution of 3d (290 mg,
0.798 mmol) in 75% aqueous ethanol (8 mL). The solution was
stirred for 4 h at rt. Upon completion of reaction, the mixture was
partitioned between water and ethyl acetate, and the aqueous layer
was further extracted with ethyl acetate. The combined organic
layers were washed successively with saturated sodium hydrogen
carbonate, water, and brine, then dried over anhydrous magnesium
sulfate and evaporated to dryness. The residue was purified by FCC
(pet ether/EtOAc¼2:1) to provide 3c (184 mg, 72%) as a white solid,
The epimer 17b was readily converted to epi-demethoxyfumi-
tremorgin C 22 following the same synthetic scheme as described
for demethoxyfumitremorgin C. The physical properties (1H and 13
C
NMR, MS data) of 22 are in accord with those described in the lit-
erature.17a Synthetic epi-demethoxyfumitremorgin C had an optical
rotation of ½a 2D8
ꢂ
ꢀ312 (c 0.1, CH3OH), lit.: synthetic17a
½
a 2D2
ꢂ
ꢀ436
(c 0.1, CH3OH). These results also confirmed the absolute configu-
rations of 17a and 17b.
3. Conclusion
mp 147e149 ꢁC. 1H NMR (400 MHz, DMSO)
d 7.04 (s, 1H), 6.70 (d,
In summary, we have demonstrated that Mg(ClO4)2 could cat-
alyze direct intramolecular amination of allylic alcohols with a va-
riety of substrates. This method is the operational simplicity.
Inexpensive and non-toxic Mg(ClO4)2 was used as catalyst, which
render this methodology to be eco-friendly. Its utility can be seen in
the total synthesis of demethoxyfumitremorgin C.
J¼16.0 Hz, 1H), 6.68 (s, 1H), 6.14 (dt, J¼5.0, 16.0 Hz, 1H), 5.94 (s, 2H),
4.08 (d, J¼5.0 Hz, 2H), 3.00 (t, J¼7.4 Hz, 2H), 2.66 (t, J¼7.4 Hz, 2H),
1.35 (s, 9H); 13C NMR (100 MHz, DMSO)
d 155.5, 146.4, 146.2, 130.5,
130.4, 129.1, 125.6, 109.7, 105.2, 100.8, 77.6, 61.8, 41.1, 32.6, 28.3;
HRMS (ESI) m/z calcd for C17H23NNaO5 (MþNa)þ 344.1468, found
344.1469; IR (KBr) 3733, 3398, 3261, 3073, 2978, 2928, 2872, 1680,
1561, 1503, 1487, 1299, 1257, 1164, 1040, 1003, 978, 956 cmꢀ1
.
4. Experimental section
4.1. General
4.2.4. tert-Butyl 2-(5-((E)-3-acetoxyprop-1-enyl)-benzo[d][1,3]dioxol-
6-yl) ethylcarbamate (3d). Isolated yield 78% as white solid, mp
93e94 ꢁC.1H NMR (400 MHz, CDCl3)
d
6.96 (s,1H), 6.84 (d, J¼15.6 Hz,
Infrared spectra were recorded on Thermo Nicolet Nexus-470
FT-IR spectrometers. Mass spectra were recorded on a Bruker
APEX IV FT-MS (ESI) spectrometer. 1H NMR and 13C NMR spectra
were recorded on Bruker Avance III 400 MHz spectrometer.
Chemical shifts (in parts per million) were referenced to tetrame-
1H), 6.63 (s, 1H), 6.05 (dt, J¼6.4, 15.6 Hz, 1H), 5.94 (s, 2H), 4.72 (d,
J¼6.4 Hz, 2H), 4.58 (br s, 1H), 3.26 (br d, J¼6.8 Hz, 2H), 2.80 (t,
J¼6.8 Hz, 2H), 2.10 (s, 3H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3)
d
170.7, 155.7, 147.5, 146.6, 131.2, 130.8, 128.7, 123.3, 109.8, 105.8, 101.0,
79.1, 65.2, 41.5, 33.3, 28.3, 20.9; HRMS (ESI) m/z calcd for
C19H25NNaO6 (MþNa)þ 386.1574, found 386.1579; 3340, 3033, 2978,
2928, 2880,1734,1701,1682,1527,1504,1486,1455,1392,1366,1288,
thylsilane (
d
¼0 ppm) in the deuterated solvent as an internal
standard. Flash column chromatography was performed using sil-
ica gel (200e300 mesh) with solvents distilled prior to use. Visu-
alization was achieved under a UV lamp (254 nm and 365 nm), and
by developing the plates with phosphomolybdic acid in ethanol.
1243, 1167, 1135, 1040, 971, 956, 931, 872 cmꢀ1
.
4.2.5. tert-Butyl
carbamoyl) methylcarbamate (3e). Isolated yield 80% as yellow oil.
1H NMR (400 MHz, CDCl3)
8.40 (s, 1H), 7.73 (br s, 1H), 7.34 (d,
(2-((E)-3-hydroxy-3-methylbut-1-enyl)phenyl-
4.2. Preparation of allylic alcohols 3aej
d
J¼7.2 Hz, 1H), 7.20 (t, J¼7.2 Hz, 1H), 7.10 (t, J¼7.2 Hz, 1H), 6.67 (d,
J¼15.6 Hz,1H), 6.21 (d, J¼15.6 Hz,1H), 5.72 (br s,1H), 3.91 (br s, 2H),
2.46 (br s, 1H), 1.44 (s, 9H), 1.40 (s, 6H); 13C NMR (100 MHz, CDCl3)
A suspension of 5a (270 mg, 0.69 mmol), 2-methyl-3-buten-2-ol
(0.72 mL, 6.9 mmol), Pd(OAc)2 (22.5 mg, 0.069 mmol), and Ag2CO3
(114 mg, 0.42 mmol) in toluene (1.75 mL) was heated at 80 ꢁC for
13 h. The reaction mixture was filtered and evaporated. The residue
was purified by FCC to afford 3a (221 mg, 92%).
d
168.6, 156.5, 141.7, 134.0, 130.3, 127.8, 126.8, 125.5, 123.8, 121.2,
80.5, 71.0, 45.1, 29.7, 28.3; HRMS (ESI) m/z calcd for C18H30N3O4
(MþNH4)þ 352.2231, found 352.2226; IR (KBr) 3396, 2974, 2930,
1685, 1528, 1453, 1368, 1257, 1164, 1101, 1052, 968, 909, 864,
4.2.1. tert-Butyl 2-(5-((E)-3-hydroxy-3-methylbut-1-enyl)benzo[d]
755 cmꢀ1
.
[1,3]dioxol-6-yl) ethylcarbamate (3a). Isolated yield 92% as yellow
oil. 1H NMR (400 MHz, CDCl3)
d
6.92 (s, 1H), 6.91 (d, J¼16.0 Hz, 1H),
4.2.6. (E)-4-(5-(2-(Tosylamino)ethyl)benzo[d][1,3]-dioxol-6-yl)but-
6.60 (s, 1H), 6.09 (d, J¼16.0 Hz, 1H), 5.91 (s, 2H), 4.81 (br s, 1H), 3.20
3-en-2-ol (3f). Isolated yield 21% as yellow oil. 1H NMR (400 MHz,
(q, J¼7.2 Hz, 2H), 3.04 (br s, 1H), 2.78 (t, J¼7.6 Hz, 2H), 1.44 (s, 9H),
CDCl3)
d
7.68 (d, J¼8.0 Hz, 2H), 7.25 (d, J¼8.0 Hz, 2H), 6.87 (s, 1H),
1.41 (s, 6H); 13C NMR (100 MHz, CDCl3)
d
155.9, 146.7, 146.6, 138.7,
6.69 (d, J¼15.6 Hz, 1H), 6.49 (s, 1H), 5.96 (dd, J¼6.0, 15.6 Hz, 1H),
5.89 (s, 2H), 5.09 (br s, 1H), 4.45 (br s, 1H), 3.05 (br s, 2H), 2.82 (dd,
J¼7.2, 13.8 Hz, 1H), 2.74 (dd, J¼7.2, 13.8 Hz, 1H), 2.61 (br s, 1H), 2.39
130.2, 130.0, 123.4, 109.8, 106.2, 100.8, 79.5, 70.9, 41.5, 34.6, 29.9,
28.4; HRMS (ESI) m/z calcd for C19H27NO5Na (MþNa)þ 372.1781,
found 372.1778; IR (KBr) 3420, 2973, 2930, 1691, 1482, 1366, 1245,
(s, 3H), 1.33 (d, J¼6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 147.1,
1164, 1038 cmꢀ1
.
146.8, 143.3, 137.0, 134.8, 129.7, 129.6, 129.3, 126.9, 126.0, 109.7,
106,1, 101.0, 68.6, 44.0, 33.6, 23.3, 21.4; HRMS (ESI) m/z calcd for
C20H23NNaO5S (MþNa)þ 412.1189, found 412.1195; IR (KBr) 3517,
3281, 2968, 2923, 2884, 1717, 1503, 1484, 1325, 1158, 1040, 662,
4.2.2. tert-Butyl
oxol-6-yl) ethylcarbamate (3b). Isolated yield 54% as while solid,
mp 86e89 ꢁC. 1H NMR (400 MHz, CDCl3)
6.91 (s, 1H), 6.83 (d,
2-(5-((E)-3-hydroxybut-1-enyl)-benzo[d][1,3]di-
d
551 cmꢀ1
.
J¼15.4 Hz,1H), 6.59 (s, 1H), 6.01 (dd, J¼5.2,15.4 Hz,1H), 5.90 (s, 2H),
4.77 (br s, 1H), 4.48 (br s, 1H), 3.19 (dt, J¼6.2, 7.2 Hz, 2H), 2.96 (br s,
1H), 2.76 (t, J¼7.2 Hz, 2H), 1.43 (s, 9H), 1.34 (d, J¼6.4 Hz, 3H); 13C
4.2.7. (E)-3-(5-(2-(Tosylamino)ethyl)benzo[d][1,3]-dioxol-6-yl)prop-
2-en-1-ol (3g). As yellow solid, mp 76e78 ꢁC. 1H NMR (400 MHz,
NMR (100 MHz, CDCl3)
d
155.9, 146.9, 146.6, 134.8, 130.1, 129.8,
CDCl3)
d
7.69 (d, J¼8.2 Hz, 2H), 7.28 (d, J¼8.2 Hz, 2H), 6.92 (s, 1H),
126.0, 109.8, 106.1, 100.9, 79.5, 68.4, 41.5, 34.2, 28.4, 23.3; HRMS
6.76 (d, J¼15.6 Hz, 1H), 6.51 (s, 1H), 6.11 (dt, J¼5.6, 15.6 Hz, 1H), 5.93

D. Jiang et al. / Tetrahedron 68 (2012) 4225e4232
4229
(s, 2H), 4.46 (t, J¼6.0 Hz, 1H), 4.30 (d, J¼5.6 Hz, 2H), 3.10 (dt, J¼6.0,
6.8 Hz, 2H), 2.82 (t, J¼6.8 Hz, 2H), 2.42 (s, 3H); 13C NMR (100 MHz,
under reduced pressure. The residue was purified by flash column
chromatography (PE/EtOAc¼6:1) to provide 11 (7.3 g, 84%) as col-
CDCl3)
d
147.3, 147.0, 143.4, 137.1, 129.9, 129.8, 129.7, 129.3, 127.9,
orless oil. 1H NMR (400 MHz, CDCl3)
d
7.76 (d, J¼8.0 Hz, 2H), 7.30 (d,
127.0, 109.8, 106.3, 101.1, 63.6, 44.1, 33.6, 21.5; HRMS (ESI) m/z calcd
for C19H21NNaO5S (MþNa)þ 398.1033, found 398.1037; IR (KBr)
3443, 2963, 2926,1730, 1599,1503,1484,1261,1095,1023, 865, 802,
J¼8.0 Hz, 2H), 4.93 (t, J¼6.0 Hz, 1H), 3.53 (t, J¼6.4 Hz, 2H), 2.92 (dt,
J¼6.7, 6.8 Hz, 2H), 2.42 (s, 3H), 1.42e1.51 (m, 4H), 1.28e1.34 (m, 2H),
0.94 (t, J¼8.0 Hz, 9H), 0.57 (q, J¼8.0 Hz, 6H); 13C NMR (100 MHz,
708, 665 cmꢀ1
.
CDCl3) d 143.2, 137.0, 129.6, 127.0, 62.4, 43.1, 32.1, 29.2, 22.8, 21.4,
6.7, 4.3; HRMS (ESI) m/z calcd for C18H34NO3SSi (MþH)þ 372.2023,
found 372.2025; IR (KBr) 3560, 3283, 3031, 2951, 2875, 2734, 1916,
1807, 1726, 1599, 1459, 1417, 1327, 1238, 1160, 1094, 1013, 813, 729,
4.2.8. (E)-3-(5-(2-(Tosylamino)ethyl)benzo[d][1,3]-dioxol-6-yl)allyl
acetate (3h). Isolated yield 34% as yellow solid, mp 134e135 ꢁC. 1H
NMR (400 MHz, CDCl3)
d
7.69 (d, J¼8.0 Hz, 2H), 7.28 (d, J¼8.0 Hz,
664, 573, 552 cmꢀ1
.
2H), 6.89 (s, 1H), 6.72 (d, J¼15.6 Hz, 1H), 6.51 (s, 1H), 5.98 (dt, J¼6.4,
15.6 Hz, 1H), 5.93 (s, 2H), 4.68 (dd, J¼0.8, 6.4 Hz, 2H), 4.45 (t,
J¼6.0 Hz, 1H), 3.10 (dt, J¼6.0, 7.2 Hz, 2H), 2.78 (t, J¼7.2 Hz, 2H), 2.42
Compound 12: to a stirred solution of 11 (7.26 g, 11.6 mmol)
and DMAP (477 mg, 3.9 mmol) in dry CH3CN (40 mL) was added
(Boc)2O (4.69 g, 21.5 mmol) at rt. After the mixture was stirred
for 2 h, more (Boc)2O (4.69 g, 21.5 mmol) was added and the
mixture was additionally stirred overnight. The solvent was
evaporated, and the residue was purified by silica gel column
chromatography (PE/EtOAc¼14:1) to afford the desired product
(8.8 g, 96%).
(s, 3H), 2.10 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 170.9, 147.6, 146.9,
143.3, 137.0, 131.1, 129.6, 129.5, 128.9, 127.0, 123.9, 109.8, 106.1, 101.1,
65.1, 43.8, 33.3, 21.4, 21.0; HRMS (ESI) m/z calcd for C21H27N2O6S
(MþNH4)þ 435.1584, found 435.1587; IR (KBr) 3278, 2920, 2862,
1738, 1504, 1487, 1327, 1250, 1159, 1041, 936, 697, 548 cmꢀ1
.
To a solution of oxalyl chloride (0.5 mL, 5.9 mmol) in CH2Cl2
(10 mL) cooled at ꢀ78 ꢁC was added dropwise a solution of DMSO
(0.84 mL, 11.8 mmol) in CH2Cl2 (10 mL). After 30 min, a solution of
the above product (2.54 g, 5.38 mmol) in CH2Cl2 (30 mL) was added.
The reaction mixture was then stirred for 1.5 h at ꢀ78 ꢁC and
triethylamine (3.74 mL, 26.9 mmol) was added in one portion. The
mixture was allowed to warm to rt to react 3 h and quenched with
saturated aqueous solution of NH4Cl and extract with CH2Cl2 and
washed with brine. The organic solution was dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography to afford aldehyde 12 (1.21 g,
98%) as colorless oil and the starting material (800 mg). 1H NMR
4.2.9. Compound (3i). The aldehyde 7 (1.29 g, 3.23 mmol), 2-
oxopropyltriphenylphosphonium chloride 8 (1.72 g, 4.84 mmol),
and sodium carbonate (390 mg, 3.68 mmol) were stirred with
40 mL tetrahydrofuran and 10 mL water at reflux for 15 h. Ether
was added, the layers were separated, and the organic material
was washed with brine and dried over magnesium sulfate. Evap-
oration of the solvent was followed by the addition of hexane and
gravity filtration to remove the crystalline tri-phenylphosphine
oxide. The hexane was evaporated and the residue was purified
by silica gel column chromatography (PE/EtOAc¼4:1) to afford 9
(3.23 g, 68%) as yellow oil. ½a D17
ꢂ
ꢀ64 (c 0.2, CH3OH); 1H NMR
(400 MHz, CDCl3)
d
7.93 (d, J¼8.0 Hz, 2H), 7.33 (d, J¼8.0 Hz, 2H),
(400 MHz, CDCl3)
d
9.79 (t, J¼1.4 Hz, 1H), 7.77 (d, J¼8.4 Hz, 2H), 7.31
6.88 (dt, J¼6.4, 16.0 Hz, 1H), 6.17 (d, J¼16.0 Hz, 1H), 5.07 (dd, J¼4.4,
(d, J¼8.0 Hz, 2H), 3.84 (t, J¼7.2 Hz, 2H), 2.52 (dt, J¼1.4, 7.3 Hz, 2H),
9.4 Hz, 1H), 3.72 (s, 3H), 2.45 (s, 3H), 2.36e2.49 (m, 3H), 2.26 (s,
2.44 (s, 3H), 1.77e1.84 (m, 2H), 1.67e1.74 (m, 2H), 1.25 (s, 9H); 13C
3H), 2.23 (m, 1H), 1.30 (s, 9H); 13C NMR (100 MHz, CDCl3)
d
198.4,
NMR (100 MHz, CDCl3) d 202.0, 150.9, 144.1, 137.3, 129.2, 127.7, 84.2,
170.0, 149.8, 146.3, 144.4, 136.4, 132.0, 129.0, 128.6, 85.1, 58.7, 52.4,
29.1, 28.9, 27.7, 26.8, 21.5; HRMS (ESI) m/z calcd for C21H29NNaO7S
(MþNa)þ 462.1557, found 462.1565; IR (KBr) 3471, 2981, 2951,
1744, 1675, 1631, 1449, 1361, 1293, 1255, 1150, 1088, 1041, 978, 719,
46.6, 43.3, 29.5, 27.8, 21.5, 19.0; HRMS (ESI) m/z calcd for
C17H25NO5NaS (MþNa)þ 378.1346, found 378.1352; IR (KBr) 3035,
2967, 2873,1723,1597,1427,1395,1357,1289,1249,1157,1106,1087,
1003, 675, 584, 547 cmꢀ1
.
663, 585, 548 cmꢀ1
.
Compound 13: isolated yield 72% as colorless oil. 1H NMR
(400 MHz, CDCl3)
To a stirred solution of ketone 9 (889 mg, 2 mmol) in methanol
(18 mL) was added cerium chloride heptahydrate (1.12 g, 3 mmol).
After 5 min, the mixture was cooled to 0 ꢁC, and NaBH4 (84 mg,
2.2 mmol) was added. The reaction mixture was stirred at 0 ꢁC until
total consumption of starting material (30 min). The reaction was
quenched by adding a few drops of 50% acetic acid to neutral pH.
Water and CH2Cl2 were added, and the heterogeneous mixture was
extracted with CH2Cl2. The organic layer was washed with water
and brine. The combined organic layer was dried over MgSO4, and
the solvent was removed under reduced pressure. The residue was
purified by silica gel column chromatography to afford 3i (810 mg,
92%) as a pair of diastereomers in a ratio of 1:1.3 (yellow oil). 1H
d
7.76 (d, J¼8.0 Hz, 2H), 7.31 (d, J¼8.0 Hz, 2H), 6.81
(dt, J¼6.8, 16.0 Hz, 1H), 6.10 (d, J¼16.0 Hz, 1H), 3.84 (t, J¼7.2 Hz, 2H),
2.44 (s, 3H), 2.30 (dt, J¼6.8, 6.9 Hz, 2H), 2.25 (s, 3H), 1.78e1.84 (m,
2H), 1.52e1.59 (m, 2H), 1.33 (s, 9H); 13C NMR (100 MHz, CDCl3)
d
198.5, 150.9, 147.5, 144.1, 137.5, 131.6, 129.2, 127.7, 84.2, 46.7, 31.9,
29.6, 27.8, 26.9, 25.1, 21.5; HRMS (ESI) m/z calcd for C20H29NO5NaS
(MþNa)þ 418.1659, found 418.1663; IR (KBr) 3634, 2979, 2935,
2866, 1725, 1674, 1628, 1598, 1456, 1356, 1288, 1256, 1154, 1088,
999.8, 848, 813, 772, 721, 674, 576, 545 cmꢀ1
.
Compound 3j: isolated yield 86% as colorless oil. 1H NMR
(400 MHz, CDCl3)
d
7.76 (d, J¼8.4 Hz, 2H), 7.30 (d, J¼8.4 Hz, 2H),
5.63 (dt, J¼6.4, 15.4 Hz, 1H), 5.55 (dd, J¼6.0, 15.4 Hz, 1H), 4.27 (m,
1H), 3.81 (t, J¼8.0 Hz, 2H), 2.44 (s, 3H), 2.06e2.11 (m, 2H), 1.73e1.81
(m, 2H), 1.68 (d, J¼3.6 Hz, 1H), 1.42e1.49 (m, 2H), 1.32 (s, 9H), 1.26
NMR (400 MHz, CDCl3). Mixture of diastereomers
d 7.92e7.94 (m,
2H), 7.32 (d, J¼8.4 Hz, 2H), 5.61e5.73 (m, 2H), 5.08 (m, 1H), 4.31 (m,
1H), 3.72 (s, 1.7H), 3.71 (s,1.3H), 2.45 (s, 3H), 2.01e2.42 (m, 4H), 1.70
(br s, 2H), 1.30 (s, 4.0H), 1.29 (s, 5.0H), 1.26e1.28 (m, 3H); 13C NMR
(d, J¼6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 151.0, 144.0, 137.5,
134.8, 130.1, 129.2, 127.7, 84.1, 68.8, 46.9, 31.5, 29.4, 27.8, 25.9, 23.3,
21.5; HRMS (ESI) m/z calcd for C20H31NNaO5S (MþNa)þ 420.1815,
found 420.1822; IR (KBr) 3548, 3421, 2971, 2931, 2865, 1726, 1598,
1455, 1356, 1287, 1259, 1157, 1088, 1043, 1018, 812, 721, 674, 579,
(100 MHz, CDCl3). Mixture of diastereomers
d 170.5, 150.0, 144.3,
136.6, 135.9, 129.2, 129.0, 128.9, 128.7, 85.0, 68.9, 68.8, 58.6, 58.5,
52.4, 29.9, 29.8, 28.9, 28.8, 27.8, 23.2, 23.1, 21.6.
546 cmꢀ1
.
4.2.10. Compound (3j). Compound 11: TESCl (6 mL, 35 mmol) were
sequentially added to a stirred solution of alcohol (6 g, 23.3 mmol)
in CH2Cl2 (80 mL) at 0 ꢁC. The resulting mixture was stirred at 0 ꢁC
overnight. Then EtOAc was added to dilute the reaction mixture,
which was further washed with water and brine. The organic so-
lution was dried over Na2SO4, filtered, and the solvent was removed
4.3. General procedure for the direct amination of allylic
alcohols
A stirred solution of 3a (61 mg, 0.175 mmol) and Mg(ClO4)2
(4 mg, 0.0175 mmol) in CH3CN (1.75 mL) was heated to reflux for

4230
D. Jiang et al. / Tetrahedron 68 (2012) 4225e4232
8 h. The reaction was allowed to cool and evaporated. The residue
was purified by FCC to afford 4a (56.8 mg, 98%).
3.80 (m, J¼2.3, 6.0, 13.6 Hz, 1H), 3.29 (m, J¼4.2, 11.4, 13.6 Hz, 1H),
2.49 (m, J¼6.0, 11.4, 16.2 Hz, 1H), 2.45 (m, J¼2.3, 4.2, 16.2 Hz, 1H),
2.37 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 146.7, 146.0, 143.1, 137.8,
4.3.1. tert-Butyl 7,8-dihydro-5-(2-methylprop-1-enyl)-[1,3]dioxolo
137.3, 129.4, 127.1, 126.9, 126.6, 117.6, 108.4, 107.6, 100.9, 58.1, 39.2,
27.6, 21.4; HRMS (ESI) m/z calcd for C19H20NO4S (MþH)þ 358.1108,
found 358.1111; IR (KBr) 3400, 3077, 3032, 2962, 2926, 2896, 2845,
[4,5-g]isoquinoline-6(5H)-carboxylate (4a). Isolated yield 98% as
white solid, mp 54e56 ꢁC. 1H NMR (400 MHz, CDCl3)
d 6.55 (s, 1H),
6.47 (s, 1H), 5.88 (m, 2H), 5.66 (br s, 1H), 5.31 (dt, J¼1.6, 9.6 Hz, 1H),
4.16 (br s, 1H), 3.12 (t, J¼12.0, 1H), 2.82 (m, J¼4.4, 12.0, 16.0 Hz, 1H),
2.58 (d, J¼4.4, 16.0 Hz, 1H), 1.93 (s, 3H), 1.72 (s, 3H), 1.47 (s, 9H); 13C
1730, 1632, 1597, 1484, 1333, 1229, 837, 806, 669, 543 cmꢀ1
.
4.3.7. (2S,5R)-Methyl 5-((E)-prop-1-enyl)-1-tosylpyrrolidine-2-
NMR (100 MHz, CDCl3)
d
154.4, 146.0, 132.7, 130.5, 127.3, 124.8,
carboxylate (4i-cis). As yellow solid, mp 89e90 ꢁC. ½a D17
ꢀ11 (c
ꢂ
108.3, 107.1, 100.7, 79.6, 52.4, 37.7, 28.9, 28.5, 25.7, 18.6; HRMS (ESI)
m/z calcd for C19H26NO4 (MþH)þ 332.1856, found 332.1860; IR
(KBr) 2974, 2925, 1690, 1481, 1415, 1237, 1162, 1106, 1038, 931, 859,
0.21, CH3OH); 1H NMR (400 MHz, CDCl3)
d
7.74 (d, J¼8.0 Hz, 2H),
7.28 (d, J¼8.0 Hz, 2H), 5.68 (dq, J¼6.4, 15.0 Hz, 1H), 5.32 (ddq, J¼1.4,
7.0, 15.0 Hz, 1H), 4.44 (t, J¼6.8 Hz, 1H), 4.19 (dd, J¼7.0, 13.6 Hz, 1H),
3.74 (s, 3H), 2.42 (s, 3H), 1.97e2.02 (m, 2H), 1.82 (m, 1H), 1.67 (m,
834, 767 cmꢀ1
.
1H), 1.58 (dd, J¼1.4, 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 172.7,
4.3.2. tert-Butyl 7,8-dihydro-5-((E)-prop-1-enyl)-[1,3]dioxolo[4,5-g]
143.3, 136.4, 131.0, 129.3, 127.9, 127.8, 63.0, 61.4, 52.3, 32.4, 29.3,
21.5, 17.5; HRMS (ESI) m/z calcd for C16H22NO4S (MþH)þ 324.1264,
found 324.1265; IR (KBr) 2961, 2923, 1752, 1345, 1215, 1163, 1088,
isoquinoline-6(5H)-carboxylate (4b). Isolated yield 94% as colorless
oil. 1H NMR (400 MHz, CDCl3)
d 6.57 (s, 2H), 5.90 (s, 2H), 5.47e5.59
(m, 2H), 5.38 (br s, 1H), 4.05 (br s, 1H), 3.13 (br s, 1H), 2.80 (m, 1H),
667, 594, 551 cmꢀ1
.
2.60 (m, 1H), 1.68 (d, J¼5.2 Hz, 3H), 1.48 (s, 9H); 13C NMR (100 MHz,
CDCl3)
d
154.6, 146.2, 145.9, 130.8, 128.9, 127.9, 127.2, 108.4, 107.8,
4.3.8. (2S,5S)-Methyl 5-((E)-prop-1-enyl)-1-tosylpyrrolidine-2-
a 17
100.8, 79.7, 55.9, 37.6, 28.8, 28.5, 17.6; HRMS (ESI) m/z calcd for
C18H24NO4 (MþH)þ 318.1700, found 318.1702; IR (KBr) 3504, 3367,
2974, 2929, 1692, 1503, 1484, 1417, 1242, 1164, 1039, 945, 929, 861,
carboxylate (4i-trans). As colorless oil. ½ ꢂD ꢀ26 (c 0.19, CH3OH);
1H NMR (400 MHz, CDCl3)
d
7.67 (d, J¼8.4 Hz, 2H), 7.25 (d, J¼8.4 Hz,
2H), 5.57 (dq, J¼6.4, 15.0 Hz, 1H), 5.05 (ddq, J¼1.2, 8.8, 15.0 Hz, 1H),
4.47 (t, J¼8.0 Hz,1H), 4.38 (dd, J¼1.2, 8.8 Hz,1H), 3.74 (s, 3H), 2.41 (s,
3H), 2.35 (m, 1H), 2.20 (m, 1H), 1.95 (m, 1H), 1.66 (m, 1H), 1.54 (d,
822, 766, 674, 632, 540, 463 cmꢀ1
.
4.3.3. tert-Butyl
line-6(5H)-carboxylate (4c). Isolated yield 26% and 50% as yellow
oil. 1H NMR (400 MHz, CDCl3)
6.59 (s,1H), 6.58 (s, 1H), 5.91 (s, 2H),
7,8-dihydro-5-vinyl-[1,3]dioxolo-[4,5-g]isoquino-
J¼1.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 173.1, 143.0, 138.2, 130.1,
129.0, 128.1, 127.8, 62.3, 60.9, 52.3, 31.6, 29.1, 21.5, 17.4; HRMS (ESI)
d
m/z calcd for C16H22NO4S (MþH)þ 324.1264, found 324.1266; IR
5.90 (m, J¼5.9, 10.4, 16.8 Hz, 1H), 5.39 (br s, 1H), 5.15 (d, J¼10.4 Hz,
(KBr) 2953, 2920, 1747, 1449, 1343, 1204, 1155, 1097, 671, 594 cmꢀ1
.
1H), 5.06 (d, J¼16.8 Hz, 1H), 4.08 (br s, 1H), 3.16 (br s, 1H), 2.81(m,
1H), 2.61 (m, 1H), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl3)
d
154.6,
4.3.9. 2-((E)-Prop-1-enyl)-1-tosylpiperidine (4j). Isolated yield 95%
as yellow solid, mp 148e151 ꢁC. 1H NMR (400 MHz, CDCl3)
7.65 (d,
146.4, 146.0, 137.6, 128.1, 115.7, 108.4, 107.7, 100.8, 79.8, 56.9, 38.2,
28.7, 28.5; HRMS (ESI) m/z calcd for C17H22NO4 (MþH)þ 304.1543,
found 304.1538; IR (KBr) 3086, 2976, 2928, 2768, 1693, 1503, 1483,
d
J¼8.0 Hz, 2H), 7.25 (d, J¼8.0 Hz, 2H), 5.55 (m, 1H), 5.33 (dd, J¼6.4,
15.3 Hz, 1H), 4.54 (br s, 1H), 3.67 (d, J¼13.2 Hz, 1H), 2.93 (t,
J¼12.2 Hz, 1H), 2.41 (s, 3H), 1.57 (d, J¼6.4 Hz, 3H), 1.39e1.52 (m,
1415, 1366, 1241, 1223, 1165, 1140, 929 cmꢀ1
.
6H); 13C NMR (100 MHz, CDCl3)
d 142.6, 137.8, 129.2, 128.2, 127.4,
4.3.4. tert-Butyl
benzo[e][1,4]diazepine-4(5H)-carboxylate (4e). Isolated yield 41% as
yellow oil. 1H NMR (400 MHz, CDCl3)
8.19 (s, 0.5H) 8.03 (s, 0.5H),
7.21 (m, 2H), 7.04 (t, J¼7.6 Hz, 1H), 6.89 (d, J¼7.6 Hz, 1H), 5.93 (s,
0.5H), 5.62 (s, 0.5H), 5.35 (s, 0.5H), 5.33 (s, 0.5H), 4.73 (s, 0.5H), 4.50
(s, 0.5H), 4.15 (s, 0.5H), 4.11 (s, 0.5H), 1.76 (s, 6H), 1.40 (s, 9H); 13C
2,3-dihydro-5-(2-methylprop-1-enyl)-2-oxo-1H-
127.4, 54.8, 41.6, 30.4, 25.1, 21.4, 19.0, 17.7; HRMS (ESI) m/z calcd for
C15H22NO2S (MþH)þ 280.1366, found 280.1367; IR (KBr) 3543,
2939, 2859, 2732, 1920, 1730, 1668, 1599, 1495, 1451, 1337, 1305,
d
1290, 1187, 1159, 1093, 1057, 1017, 935, 815, 719, 661, 603, 547 cmꢀ1
.
4.3.10. 5,6,7,8-Tetrahydro-5-(2-methylprop-1-enyl)-6-tosyl-[1,3]di-
NMR (100 MHz, CDCl3)
d
171.9,154.1,139.5,134.6,132.2,130.1,128.3,
oxolo[4,5-g]isoquinoline (4m). Isolated yield 85% as white solid, mp
123.9, 121.7, 120.5, 80.9, 57.2, 47.3, 28.3, 25.7, 18.3; HRMS (ESI) m/z
141e143 ꢁC. 1H NMR (400 MHz, CDCl3)
d
7.61 (d, J¼8.0 Hz, 2H), 7.20
calcd for C18H25N2O3 (MþH)þ 317.1860, found 317.1860; IR (KBr)
(d, J¼8.0 Hz, 2H), 6.47 (s, 1H), 6.41(s, 1H), 5.88 (d, J¼1.2 Hz, 1H), 5.86
(d, J¼1.2 Hz,1H), 5.63 (d, J¼10.0 Hz,1H), 5.03 (dt, J¼1.2, 10.0 Hz,1H),
3.92 (m, J¼1.5, 6.0, 13.0 Hz, 1H), 3.19 (m, J¼3.6, 12.0, 13.0 Hz, 1H),
2.83 (m, J¼6.0, 12.0, 16.0 Hz, 1H), 2.56 (m, J¼1.5, 3.6, 16.0 Hz, 1H),
2.38 (s, 3H), 1.91 (d, J¼1.2 Hz, 3H), 1.55 (s, 3H); 13C NMR (100 MHz,
3216, 2976, 2920, 1698, 1160, 757 cmꢀ1
.
4.3.5. 5,6,7,8-Tetrahydro-5-((E)-prop-1-enyl)-6-tosyl-[1,3]dioxolo
[4,5-g]isoquinoline (4f). Isolated yield 90% as white solid, mp
93e95 ꢁC. 1H NMR (400 MHz, CDCl3)
d
7.65 (d, J¼8.0 Hz, 2H), 7.20
CDCl3) d 146.3, 146.2, 142.8, 137.8, 134.0, 129.4, 129.1, 127.1, 126.0,
(d, J¼8.0 Hz, 2H), 6.49 (s, 1H), 6.44 (s, 1H), 5.89 (s, 1H), 5.88 (s, 1H),
5.41e5.49 (m, 2H), 5.35 (d, J¼5.6 Hz, 1H), 3.83 (dd, J¼5.7, 13.3 Hz,
1H), 3.25 (m, J¼4.3, 12.0, 13.3 Hz, 1H), 2.68 (m, J¼5.7, 12.0, 15.8 Hz,
1H), 2.50 (br d, J¼15.8 Hz, 1H), 2.37 (s, 3H), 1.60 (d, J¼5.6 Hz, 3H);
123.2, 108.3, 106.9, 100.8, 53.8, 39.4, 28.6, 25.6, 21.4, 18.4; HRMS
(ESI) m/z calcd for C21H24NO4S (MþH)þ 386.1421, found 386.1425;
IR (KBr) 3435, 3043, 2978, 2913, 2878, 2772, 1670, 1599, 1506, 1488,
1337, 1234, 1157, 1093, 1038, 755, 678, 569, 552 cmꢀ1
.
13C NMR (100 MHz, CDCl3)
d 146.5, 146.0, 142.9, 138.0, 130.3, 129.3,
129.0, 127.7, 127.2, 126.6, 108.3, 107.6, 100.8, 57.8, 39.1, 27.9, 21.4,
17.5; HRMS (ESI) m/z calcd for C20H22NO4S (MþH)þ 372.1264, found
372.1266; IR (KBr) 3493, 3438, 3357, 2915, 1486, 1332, 1229, 1159,
4.4. Total synthesis of demethoxyfumitremorgin C
4.4.1. Compound 16. It was prepared from 15 (220 mg,
0.342 mmol) and 2-methylbut-3-en-2-ol (0.720 mL, 6.84 mmol)
according to the standard conditions. The crude product was pu-
rified by FCC (PE/EtOAc¼3:1) to provide 16 (186 mg, 90%) as col-
1091, 1031, 968, 930, 807, 558 cmꢀ1
.
4.3.6. 5,6,7,8-Tetrahydro-6-tosyl-5-vinyl-[1,3]dioxolo[4,5-g]isoquino-
line (4g). Isolated yield 73% and 76% as white solid, mp 128e131 ꢁC.
orless oil. ½a 3D3
ꢂ
ꢀ107 (c 1.04, CH3OH); 1H NMR (400 MHz, CDCl3)
1H NMR (400 MHz, CDCl3)
2H), 6.51 (s, 1H), 6.44 (s, 1H), 5.90 (s, 1H), 5.89 (s, 1H), 5.85 (m, 1H),
d
7.65 (d, J¼8.0 Hz, 2H), 7.19 (d, J¼8.0 Hz,
d
8.10 (d, J¼7.6 Hz, 1H), 7.47 (d, J¼7.6 Hz, 1H), 7.25 (t, J¼7.6 Hz, 1H),
7.19 (t, J¼7.6, Hz, 1H), 6.72 (d, J¼16.0 Hz, 1H), 6.02 (d, J¼16.0 Hz, 1H),
5.13 (dd, J¼4.0, 10.4 Hz, 1H), 3.75 (s, 3H), 3.62 (dd, J¼4.0, 14.8 Hz,
5.41 (d, J¼6.4 Hz,1H), 5.16 (d, J¼10.0 Hz,1H), 5.05 (d, J¼16.8 Hz,1H),

D. Jiang et al. / Tetrahedron 68 (2012) 4225e4232
4231
1H), 3.52 (dd, J¼10.4,14.8 Hz,1H), 2.19 (br s,1H), 1.64 (s, 9H), 1.46 (s,
3H), 1.44 (s, 3H), 1.29 (s, 18H); 13C NMR (100 MHz, CDCl3)
170.6,
J¼3.5, 15.6 Hz, 1H), 2.77 (dd, J¼10.8, 15.6 Hz, 1H), 1.86 (br s, 1H), 1.80
(s, 3H), 1.70 (s, 3H), 1.60 (s, 9H); 13C NMR (100 MHz, CDCl3)
173.4,
d
d
152.1, 150.3, 141.6, 135.7, 135.1, 130.3, 124.2, 122.6, 118.7, 118.4, 116.0,
115.3, 83.7, 82.8, 70.7, 59.0, 52.3, 29.5, 29.3, 28.3, 27.7, 25.1; HRMS
(ESI) m/z calcd for C32H50N3O9 (MþNH4)þ 620.3542, found
149.9, 137.3, 136.6, 136.4, 128.7, 125.4, 124.0,122.4, 117.9, 115.4,114.7,
83.4, 55.2, 52.0, 51.8, 28.0, 26.5, 25.7, 18.6; HRMS (ESI) m/z calcd for
C22H29N2O4 (MþH)þ 385.2122, found 385.2129; IR (KBr) 3433,
620.3557; IR (KBr) 3480, 2076, 1638, 473 cmꢀ1
.
2916, 1736, 1365, 1321, 1261, 1139, 1030, 736 cmꢀ1
.
To a solution of compound 14 (3.07 g, 5.94 mmol) in dry CH2Cl2
(60 mL) was added mercury (II) trifluoroacetate (3.29 g, 7.71 mmol).
The solution was stirred at rt for 30 min, washed with a saturated
aqueous solution of potassium iodide, dried over Na2SO4, filtered
and then treated with iodine (2.26 g, 8.91 mmol). The resulting
purple solution was stirred for 3 h and filtered. The filtrate was next
successively washed with a 10% wt aqueous sodium thiosulfate
solution and brine, dried over Na2SO4, filtered and concentrated.
The residue was then purified by flash chromatography over silica
gel to afford compound 15 (1.25 g, 33%) and NHBoc product (1.86 g,
58%). Then to the solution of NHBoc compound (1.86 g, 3.4 mmol)
and DMAP (84 mg, 0.68 mmol) in dry CH3CN (25 mL) was added
(Boc)2O (0.89 g, 4.1 mmol) at rt. The mixture was stirred overnight.
The solvent was evaporated, and the residue was purified by silica
gel column chromatography to afford compound 15 quantitatively
4.4.4. Compound 20. To a solution of compound 18 (154 mg,
0.40 mmol) in CH2Cl2 (3 mL) was added Et3N (0.12 mL, 0.86 mmol)
at 0 ꢁC under nitrogen. A solution of acid chloride 19 (186 mg,
0.60 mmol) in 2 mL CH2Cl2 was added slowly dropwise. The mix-
ture was allowed to react at 0 ꢁC overnight and extracted with
CH2Cl2. The combined organic extracts were washed with saturated
brine, dried (Na2SO4), filtered, and evaporated. The residue was
purified by FCC (PE/EtOAc¼4:1). The acid amide was dissolved in
methanol (5 mL), and zinc dust (85 mg) was added. The mixture
was stirred at reflux under nitrogen for 36 h. The reaction mixture
was filtered, washed with methanol. The residue was purified by
FCC (PE/EtOAc¼1:1) to provide 20 (144 mg, 81%) as white solid.
½
a 2D6
ꢂ
ꢀ34.7 (c 0.167, CH3OH); 1H NMR (400 MHz, CDCl3)
d 8.00 (dd,
J¼1.6, 7.2 Hz, 1H), 7.53 (dd, J¼1.8, 7.2 Hz, 1H), 7.29 (dt, J¼1.6, 7.2 Hz,
1H), 7.26 (dt, J¼1.8, 7.2 Hz, 1H), 6.98 (d, J¼9.6 Hz, 1H), 4.79 (br d,
J¼9.6 Hz,1H), 4.09e4.17 (m, 2H), 3.61e3.65 (m, 2H), 3.53 (dd, J¼5.0,
16.2 Hz, 1H), 3.07 (dd, J¼11.8, 16.2 Hz, 1H), 2.42 (m, 1H), 2.31 (m,
1H), 2.08 (m, 1H), 1.96 (m, 1H), 2.00 (br s, 3H), 1.69 (s, 9H), 1.61 (s,
a 32
as yellow oil. Compound 15: ½ ꢂD ꢀ85.3 (c 0.4, CH3OH); 1H NMR
(400 MHz, CDCl3)
d
8.06 (d, J¼1.0, 7.2 Hz, 1H), 7.47 (dd, J¼1.0, 7.2 Hz,
1H), 7.20 (dt, J¼1.0, 7.2 Hz, 1H), 7.16 (dt, J¼1.0, 7.2 Hz, 1H), 5.23 (dd,
J¼5.2, 9.3 Hz,1H), 3.79 (s, 3H), 3.57 (dd, J¼9.3,14.8 Hz,1H), 3.52 (dd,
J¼5.2, 14.8 Hz, 1H), 1.70 (s, 9H), 1.28 (s, 18H); 13C NMR (100 MHz,
3H); 13C NMR (100 MHz, CDCl3)
d 168.3, 165.7, 149.7, 136.3, 136.0,
CDCl3)
d
170.6, 151.6, 149.2, 138.0, 130.1, 125.8, 124.3, 122.7, 118.2,
136.0, 127.8, 124.3, 122.8, 118.2, 115.8, 114.2, 84.3, 59.5, 56.2, 50.7,
45.4, 28.4, 28.2, 26.1, 23.2, 21.5, 18.8; HRMS (ESI) m/z calcd for
C26H32N3O4 (MþH)þ 450.2387, found 450.2385; IR (KBr) 3420,
2966, 2924, 2854, 1736, 1668, 1455, 1369, 1159, 1144, 1119,
115.4, 85.0, 82.8, 79.9, 58.0, 52.3, 28.4, 28.2, 27.6; HRMS (ESI) m/z
calcd for C27H37NaN2O8I (MþNa)þ 667.1487, found 667.1484; IR
(KBr) 3433, 2980, 2933, 1797, 1741, 1700, 1600, 1477, 1448, 1369,
1315, 1254, 1143, 1096, 1059, 1013, 759 cmꢀ1
.
1028 cmꢀ1
.
4.4.2. Compound 17a and 17b. They were prepared from 16
(134 mg, 0.220 mmol) according to general procedure. The residue
was purified by FCC to provide 17a (53 mg, 49%) and 17b (53 mg,
4.4.5. Demethoxyfumitremorgin C (21). A solution of 20 (23.0 mg,
0.05 mmol) and TFA (0.4 mL) in CH2Cl2 (1.6 mL) was stirred at 0 ꢁC
for 1.5 h. The reaction mixture was evaporated to dryness and the
residue was extracted with EtOAc. The combined organic layers
were washed with water and brine, dried over Na2SO4 and evap-
orated to dryness. The residue was purified by FCC (PE/EtOAc¼1:1)
49%). Compound 17a: as colorless oil. ½a D26
ꢂ
þ71.9 (c 0.2, CH3OH); 1H
NMR (400 MHz, CDCl3)
d
8.08 (d, J¼7.2 Hz, 1H), 7.46 (d, J¼7.2 Hz,
1H), 7.21e7.29 (m, 2H), 6.50 (br s, 1H), 5.48 (s, 1H), 4.99 (d, J¼6.8 Hz,
1H), 3.61 (s, 3H), 3.36 (br d, J¼13.6 Hz, 1H), 2.97 (dd, J¼7.6, 16.0 Hz,
1H), 1.76 (s, 3H), 1.68 (s, 3H), 1.63 (s, 9H), 1.54 (s, 9H); 13C NMR
to provide 21 (16.1 mg, 90%) as pale yellow solid. ½a D28
þ4.0 (c 0.2,
ꢂ
CHCl3), lit.: natural16
½
a 3D0
ꢂ
þ8.0 (c 0.2, CHCl3), synthetic20a
½ ꢂ
a 2D4
(100 MHz, CDCl3)
d
172.7, 154.8, 149.7, 136.9, 136.1, 128.6, 124.2,
þ16.4 (c 0.14, CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.84 (br s, 1H),
123.1, 122.6, 118.1, 115.4, 112.8, 83.5, 81.1, 51.9, 49.4, 28.4, 28.0, 26.3,
20.6, 18.8; HRMS (ESI) m/z calcd for C27H37N2O6 (MþH)þ 485.2646,
found 485.2662; IR (KBr) 3454, 2978, 2932, 1739, 1694, 1458, 1142,
7.58 (d, J¼7.6 Hz, 1H), 7.35 (d, J¼7.6 Hz, 1H), 7.20 (dt, J¼1.1, 7.6 Hz,
1H), 7.15 (dt, J¼1.1, 7.6 Hz, 1H), 6.03 (br d, J¼9.6 Hz, 1H), 4.92 (br d,
J¼9.6 Hz, 1H), 4.20 (br dd, J¼5.0, 11.8 Hz, 1H), 4.12 (br dd, J¼7.5,
8.0 Hz, 1H), 3.63e3.67 (m, 2H), 3.57 (dd, J¼5.0, 15.7 Hz, 1H), 3.13 (br
d, J¼11.7, 15.7 Hz, 1H), 2.42 (m, 1H), 2.24 (m, 1H), 2.08 (m, 1H), 2.01
869, 749 cmꢀ1. Compound 17b: as colorless oil. ½a 2D6
ꢀ91.8 (c 0.2,
ꢂ
CH3OH); 1H NMR (400 MHz, CDCl3)
d
8.20 (d, J¼7.2 Hz, 1H), 7.45 (d,
J¼7.2 Hz,1H), 7.23e7.31 (m, 2H), 6.41 (s, 0.5H), 6.31 (s, 0.5H), 5.21 (s,
1H), 4.14 (d, J¼8.8 Hz, 1H), 3.78 (s, 3H), 3.31 (s, 0.5H), 3.19 (s, 0.5H),
2.95 (d, J¼16.4 Hz, 1H), 1.84 (s, 3H), 1.76 (s, 3H), 1.63 (s, 9H), 1.43 (s,
(s, 3H), 1.95 (m, 1H), 1.65 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 169.5,
165.7,136.2,134.3,133.5,126.3,124.0,122.2,120.1,118.4,111.2,106.5,
59.3, 56.9, 51.0, 45.4, 28.6, 25.7, 23.1, 21.9,18.1; HRMS (ESI) m/z calcd
for C21H24N3O2 (MþH)þ 350.1863, found 350.1863; IR (KBr) 3424,
9H); 13C NMR (100 MHz, CDCl3)
d 171.1, 154.8, 149.7, 138.7, 136.4,
128.7, 124.3, 123.0, 122.8, 117.9, 115.7, 114.6, 83.9, 81.3, 53.2, 51.9,
29.3, 25.9, 22.8, 22.0, 18.6; HRMS (ESI) m/z calcd for C27H37N2O6
(MþH)þ 485.2646, found 485.2662; IR (KBr) 3435, 2979, 2933,
2963, 2924, 2863, 1723, 1650, 1452, 1375, 1161 cmꢀ1
.
4.4.6. epi-Demethoxyfumitremorgin C 22. Intermediate 1: isolated
1736, 1700, 1457, 1367, 1160, 1137, 750 cmꢀ1
.
yield 83% as yellow solid, mp 65e68 ꢁC. ½a D31
ꢂ
ꢀ79 (c 0.2, CH3OH); 1H
NMR (400 MHz, CDCl3)
d
8.05 (br d, J¼7.6 Hz, 1H), 7.42 (br d,
4.4.3. Compound 18. To
a
vigorously stirred solution of 17a
J¼7.6 Hz, 1H), 7.27 (t, J¼7.6 Hz, 1H), 7.22 (t, J¼7.6 Hz, 1H), 5.39 (d,
J¼7.6 Hz, 1H), 5.35 (d, J¼7.6 Hz, 1H), 3.95 (dd, J¼4.8, 10.0 Hz, 1H),
3.80 (s, 3H), 3.07 (dd, J¼4.8, 15.6 Hz, 1H), 2.83 (dd, J¼10.0, 15.6 Hz,
1H), 2.31 (br s, 1H), 1.81 (s, 3H), 1.71 (s, 3H), 1.61 (s, 9H); 13C NMR
(164 mg, 0.337 mmol) and 2,6-lutidine (0.20 mL, 1.69 mmol) in
CH2Cl2 (3.00 mL) at 0 ꢁC was added TMSOTf (0.250 mL, 1.35 mmol).
After 1 h, the reaction mixture was quenched with saturated
NaHCO3 and then extracted with CH2Cl2, The combined organic
extracts were washed with saturated brine, dried (Na2SO4), filtered.
The residue was purified by FCC (PE/EtOAc¼10:1 then 5:1) to
(100 MHz, CDCl3)
d 173.8, 149.9, 137.2, 136.2, 136.0, 129.1, 125.5,
124.0, 122.5, 117.8, 115.4, 113.7, 83.5, 52.0, 51.3, 50.4, 28.1, 25.9, 25.4,
18.6; HRMS (ESI) m/z calcd for C22H29N2O4 (MþH)þ 385.2122,
found 385.2128; IR (KBr) 3435, 2975, 2930, 1732, 1455, 1363, 1292,
provide 18 (108 mg, 83%) as yellow solid, mp 87e88 ꢁC. ½a D30
ꢀ87.3
ꢂ
(c 0.2, CH3OH); 1H NMR (400 MHz, CDCl3)
d
7.97 (d, J¼7.6 Hz, 1H),
1263, 1214, 1142, 1116, 1018, 746 cmꢀ1
.
7.42 (d, J¼7.6 Hz, 1H), 7.27 (t, J¼7.6 Hz, 1H), 7.22 (t, J¼7.6 Hz, 1H),
5.19 (br s, 2H), 3.83 (dd, J¼3.5, 10.8 Hz, 1H), 3.81 (s, 3H), 3.06 (dd,
Intermediate 2: isolated yield 73% as white solid, mp
186e188 ꢁC. ½a 3D0
ꢂ
ꢀ220 (c 0.167, CH3OH); 1H NMR (400 MHz, CDCl3)

4232
D. Jiang et al. / Tetrahedron 68 (2012) 4225e4232
Schmidt, S.; Keller, M.; Breit, B. Org. Lett. 2008, 10, 1207e1210; (c) Kinoshita, H.;
d
8.06 (d, J¼7.4 Hz, 1H), 7.42 (d, J¼7.4 Hz, 1H), 7.29 (t, J¼7.4 Hz, 1H),
Shinokubo, H.; Oshima, K. Org. Lett. 2004, 6, 4085e4088; (d) Shue, Y.-J.; Yang,
S.-C.; Lai, H.-C. Tetrahedron Lett. 2003, 44, 1481e1485; (e) Ozawa, F.; Okamoto,
H.; Kawagishi, S.; Yamamoto, S.; Minami, T.; Yoshifuji, M. J. Am. Chem. Soc. 2002,
124, 10968e10969 For Pt- or Au-catalyzed amination using simple amines or
anilines as nucleophiles, see: (f) Ohshima, T.; Miyamoto, Y.; Ipposhi, J.; Naka-
hara, Y.; Utsunomiya, M.; Mashima, K. J. Am. Chem. Soc. 2009, 131, 14317e14328;
(g) Utsunomiya, M.; Miyamoto, Y.; Ipposhi, J.; Ohshima, T.; Mashima, K. Org.
Lett. 2007, 9, 3371e3374; (h) Mukherjee, P.; Widenhoefer, R. A. Org. Lett. 2011,
13, 1334e1337 For Brønsted acids-catalyzed amination using simple amines or
anilines as nucleophiles, see: (i) Motokura, K.; Nakagiri, N.; Mizugaki, T.; Ebi-
tani, K.; Kaneda, K. J. Org. Chem. 2007, 72, 6006e6015; (j) Yokoyama, Y.; Hikawa,
H.; Mitsuhashi, M.; Uyama, A.; Hiroki, Y.; Murakami, Y. Eur. J. Org. Chem. 2004,
1244e1253; (k) Yokoyama, Y.; Matsumoto, T.; Murakami, Y. J. Org. Chem. 1995,
60, 1486e1487 For asymmetric amination, see: (l) Roggen, M.; Carreira, E. M. J.
Am. Chem. Soc. 2010, 132, 11917e11919; (m) Defieber, C.; Ariger, M. A.; Moriel, P.;
Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 3139e3143; (n) Yamashita, Y.;
Gospalarathnam, A.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 7508e7509.
6. For Pd(II)-catalyzed amination using carbamates or sulfonamides as nucleo-
philes, see: (a) Hande, S. M.; Kawai, N.; Uenishi, J. J. Org. Chem. 2009, 74,
244e253; (b) Banfi, L.; Basso, A.; Cerulli, V.; Guanti, G.; Riva, R. J. Org. Chem.
2008, 73, 1608e1611; (c) Ku, J.-M.; Jeong, B.-S.; Jew, S.-s.; Park, H.-g. J. Org.
Chem. 2007, 72, 8115e8118; (d) Eustache, J.; de Weghe, P. V.; Le Nouen, D.;
Uyehara, H.; Kabuto, C.; Yamamoto, Y. J. Org. Chem. 2005, 70, 4043e4054; (e)
Yokoyama, H.; Ejiri, H.; Miyazawa, M.; Yamaguchi, S.; Hirai, Y. Tetrahedron:
Asymmetry 2007, 18, 852e856; (f) Makabe, H.; Kong, L. K.; Hirota, M. Org. Lett.
2003, 5, 27e29; (g) Yokoyama, H.; Otaya, K.; Kobayashi, H.; Miyazawa, M.;
Yamaguchi, S.; Hirai, Y. Org. Lett. 2000, 2, 2427e2429; (h) Yokoyama, H.; Otaya,
K.; Yamaguchi, S.; Hirai, Y. Tetrahedron Lett. 1998, 39, 5971e5974; (i) Harrington,
P. J.; Hegedus, L. S.; McDaniel, K. F. J. Am. Chem. Soc. 1987, 109, 4335e4338; (j)
Chien, C.-W.; Shi, C.; Lin, C.-F.; Ojima, I. Tetrahedron 2011, 67, 6513e6523; (k)
Shi, C.; Ojima, I. Tetrahedron 2007, 63, 8563e8570.
7.24 (t, J¼7.4 Hz, 1H), 7.10 (d, J¼8.0 Hz, 1H), 5.23 (d, J¼8.0 Hz, 1H),
4.50 (dd, J¼5.0, 11.0 Hz, 1H), 4.15 (m, 1H), 3.95 (m, 1H), 3.52 (dd,
J¼5.0, 16.0 Hz, 1H), 3.45 (m, 1H), 2.84 (dd, J¼11.0, 16.0 Hz, 1H), 2.51
(m, 1H), 1.81e2.09 (m, 3H), 1.84 (s, 3H), 1.70 (s, 3H), 1.65 (s, 9H); 13C
NMR (100 MHz, CDCl3)
d 164.7, 163.9, 149.5, 139.4, 136.0, 133.9,
128.3, 124.4, 122.8, 121.9, 118.1, 115.5, 112.8, 84.0, 59.3, 52.8, 48.3,
45.0, 30.1, 28.1, 26.0, 21.6, 19.4; HRMS (ESI) m/z calcd for
C26H32N3O4 (MþH)þ 450.2387, found 450.2382; IR (KBr) 3435,
2971, 2932, 1741, 1665, 1456, 1421, 1366, 1307, 1256, 1224, 1165,
1145, 1122 cmꢀ1
.
epi-Demethoxyfumitremorgin C 22: isolated yield 96% as yellow
solid, mp 144e146 ꢁC. ½a D28
ꢂ
ꢀ312 (c 0.1, CH3OH), lit.: synthetic17a
½
a 2D2
ꢂ
ꢀ436 (c 0.1, CH3OH); 1H NMR (400 MHz, CDCl3)
d 7.78 (s,
1H), 7.51 (d, J¼7.6, 1H), 7.31 (d, J¼7.6 Hz, 1H), 7.18 (t, J¼7.6 Hz, 1H),
7.12 (t, J¼7.6 Hz, 1H), 6.43 (d, J¼9.6 Hz, 1H), 5.24 (d, J¼9.6 Hz, 1H),
4.45 (dd, J¼3.3, 11.3 Hz, 1H), 4.14 (m, 1H), 3.93 (m, 1H), 3.66 (dd,
J¼3.3, 15.7 Hz, 1H), 3.49 (m, 1H), 2.85 (dd, J¼11.3, 15.7 Hz, 1H), 2.50
(m, 1H), 2.05 (m, 1H), 2.05 (3H), 1.84e1.96 (m, 2H), 1.77 (s, 3H); 13C
NMR (100 MHz, CDCl3)
d 165.0, 164.3, 138.0, 136.4, 131.7, 126.6,
122.3, 121.1, 119.9, 118.4, 110.9, 106.7, 59.3, 54.7, 48.7, 45.1, 30.1, 27.9,
25.9, 21.5, 18.7; HRMS (ESI) m/z calcd for C21H24N3O2 (MþH)þ
350.1863, found 350.1863; IR (KBr) 3526, 3452, 3272, 2974, 2921,
1728, 1650, 1622, 1440, 1323, 1300, 749 cmꢀ1
.
7. (a) Kothandaraman, P.; Foo, S. J.; Chan, P. W. H. J. Org. Chem. 2009, 74,
5947e5952; (b) Guo, S.; Song, F.; Liu, Y. Synlett 2007, 964e968.
8. (a) Guerinot, A.; Serra-Muns, A.; Gnamm, C.; Bensoussan, C.; Reymond, S.;
Acknowledgements
ꢀ
Cossy, J. Org. Lett. 2010, 12, 1808e1811; (b) Jana, U.; Maiti, S.; Biswas, S. Tetra-
hedron Lett. 2008, 49, 858e862.
This research was supported by the National Natural Science
Foundation of China (Nos. 20972007, 20802005), the National Basic
Research Program of China (973 Program, NO. 2010CB833200), and
NCET.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2012.03.097.
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