Concise stereoselective synthesis of oxaspirocycles with 1-tosyl-1,2,3-triazoles: Application to the total syntheses of (±)-tuberostemospiroline and (±)-stemona-lactamr

Article abstract of DOI:10.1002/chem.201403756

A 4-substituted-1-tosyl-1,2,3-triazole-based stereoselective synthesis of structurally diverse oxaspirocycles is reported. The synthesis involves Rh-catalyzed loss of nitrogen from 4-substituted-1-tosyl-1,2,3-triazoles, Grignard reaction, and a ring-closing metathesis reaction as key steps. By employing readily available and stable 4-substituted-1-tosyl-1,2,3-triazoles as surrogates of diazo compounds and nitrogen sources, two types of oxaspirocycles were obtained. The latter compounds, which contain adjacent nitrogen stereocenters, could serve as the core structures of many natural products. This chemistry has been successfully applied to the total syntheses of (±)-tuberostemospiroline and (±)-stemona-lactamR.

Full text of DOI:10.1002/chem.201403756

DOI: 10.1002/chem.201403756
Full Paper
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Spiro Compounds
Concise Stereoselective Synthesis of Oxaspirocycles with 1-Tosyl-
1,2,3-triazoles: Application to the Total Syntheses of (Æ)-
Tuberostemospiroline and (Æ)-Stemona-lactam R
Junkai Fu,[a] Hongjuan Shen,[a] Yuanyuan Chang,[a] Chuangchuang Li,[a] Jianxian Gong,[a] and
Zhen Yang*[a, b]
Abstract: A 4-substituted-1-tosyl-1,2,3-triazole-based stereo-
selective synthesis of structurally diverse oxaspirocycles is re-
ported. The synthesis involves Rh-catalyzed loss of nitrogen
from 4-substituted-1-tosyl-1,2,3-triazoles, Grignard reaction,
and a ring-closing metathesis reaction as key steps. By em-
ploying readily available and stable 4-substituted-1-tosyl-
1,2,3-triazoles as surrogates of diazo compounds and nitro-
gen sources, two types of oxaspirocycles were obtained. The
latter compounds, which contain adjacent nitrogen stereo-
centers, could serve as the core structures of many natural
products. This chemistry has been successfully applied to
the total syntheses of (Æ)-tuberostemospiroline and (Æ)-ste-
mona-lactam R.
text, we have recently reported[9] the synthesis of dihydrofur-
an-3-one 13 from its precursor a-oxo gold carbenoid 11
through the intermediacy of ylide 12 (Figure 2b).
Introduction
Oxaspirocycles are valuable structural motifs that are found in
many biologically active natural products[1] (see 1–6 in
Figure 1). A longstanding problem in the synthesis of oxaspiro-
cycle compounds is the stereoselective formation of its oxy-
genated quaternary center, which is challenging by the exist-
ing methods.[2] Thus, the development of novel chemistry for
the synthesis of these motifs from readily accessible starting
materials remains highly desirable.
As a continuation of our previous studies on the utilization
of metal carbene species in synthesis transformation, we ex-
plored the generation of metal carbene species from their cor-
responding 4-substituted-1-tosyl-1,2,3-triazoles, and applied
this information to the stereoselective synthesis of oxaspirocy-
cles. It was hypothesized that triazole 14 (Figure 2c) could un-
dergo a stereochemically defined[10] [2,3]-sigmatropic rear-
rangement upon treatment with rhodium(II) catalyst[5a] to form
17 via oxonium ylide 16. The resultant imine 17 could be
trapped with Nu to form tetrahydrofuran-substituted N-tosyl
amine 18.[11] The vicinal chiral centers in 18 are expected to be
N-Sulfonyl-1,2,3-triazoles, which can be easily prepared from
terminal alkynes by copper-catalyzed 1,3-dipolar cycloaddition
with N-sulfonyl azides,[3] have recently received much attention
as precursors of a-imino metal carbenes[4] (Figure 2a), and
have been used in a series of intriguing transformations.[5]
Metal carbene species are powerful electrophiles that can
accept an electron from various nucleophiles such as water, al-
lylic alcohols, and allylic ethers.[5h,q,6] When an allylic ether is
the nucleophile, the formed oxonium ylide[7] can undergo in-
tramolecular [2,3]-sigmatropic rearrangement to afford a scaf-
fold bearing an oxygenated quaternary carbon.[8] In this con-
[a] J. Fu, H. Shen, Y. Chang, Prof. Dr. C. Li, Dr. J. Gong, Prof. Dr. Z. Yang
Laboratory of Chemical Genomics
School of Chemical Biology and Biotechnology
Peking University Shenzhen Graduate School, Shenzhen 518055 (China)
E-mail: zyang@pku.edu.cn
[b] Prof. Dr. Z. Yang
Key Laboratory of Bioorganic Chemistry
and Molecular Engineering of Ministry of Education
and Beijing National Laboratory for Molecular Science (BNLMS)
Peking-Tsinghua Center for Life Sciences
Peking University, Beijing 100871 (China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403756.
Figure 1. Naturally occurring biologically active products.
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entry 1). A screen of other rhodium(II) catalysts revealed that
Rh2(Oct)4 was most active, improving the yield to 75%
(entry 3). Halogenated solvents (entries 4–5), which had been
reported as the optimum solvent for carbenoid transforma-
tions of triazoles,[5a] were examined, and these gave a similar
result. To facilitate the following nucleophilic addition, toluene
was selected as a suitable solvent. Further investigation
showed that temperature played an important role in this
transformation. Even at ambient temperature, the reaction
gave the desired product in 35% yield with 75% conversion in
3 days (entry 6). Further elevation of temperature from 60 to
1008C led to significantly lower yields (entries 7–9). Interesting-
ly, when the reaction mixture was heated to reflux in toluene
for 4 h, the desired product 33 was isolated in 91% yield as
a single product (entry 10). The structure of 33 was unambigu-
ously established by using X-ray crystallographic analysis.[13] In-
creasing the concentration of substrate lowered the yield
(entry 11), and a control experiment without rhodium catalysts
did not give any desired product (entry 12).
With the optimal conditions in hand, triazoles 23–32, which
were prepared by CuI-catalyzed Huisgen cycloaddition of the
corresponding alkynes with TsN3,[3] were converted into the
corresponding products 34–43 in moderate to excellent yields
with diastereomeric ratios in the range of 4:1 to 20:1. It is
noteworthy that aryl substrates bearing electron-withdrawing
groups such as Cl-, F-, or CF3- (Table 2, entries 3–6) gave better
results than those bearing electron-donating groups, such as
BnO- and MeO- (Table 2, entries 7–9), which indicated that the
presence of an electron-rich aromatic moiety reduced the elec-
trophilicity of the rhodium carbenoid and retarded the forma-
tion of the oxonium ylide.
Figure 2. Synthetic analysis.
generated in a diastereoselective manner by consideration of
the fact that 17 might adopt the preferable conformation
shown in 17-1 which is caused by the electronic repulsion be-
tween the oxygen and nitrogen atoms (see 3D structure of 17-
1 in Figure 2). As a result, the Nu could approach the imine
from its upper face. We also envisioned that if the Nu moiety
in 18 was an alkyl group, the N-tosyl amine could
We then proceeded to investigate the chemistry required for
the synthesis of type-I oxaspirocycles. Thus, amines 33 and 42
react with an organic halide bearing a terminal
double bond, and the resultant diene 19 could un-
Table 1. Screening conditions for carbenoid transformation of 4-substituted-1-tosyl-
dergo a ring-closing-metathesis (RCM) reaction[12] to
give type-I oxaspirocycle 20. Alternatively, if the Nu
moiety in 18 is a vinyl, allyl, or homoallyl group, the
substrate might undergo direct RCM reaction to
afford type-II oxaspirocycle 21. Through the use of
this strategy, the readily available N-sulfonyl-1,2,3-tri-
azoles could be used not only as surrogates of diazo
compounds, but also as nitrogen sources, and the
two types of oxaspirocycles formed, which contain
adjacent nitrogen atoms, would provide efficient
access to the core structures of many natural prod-
ucts.
1,2,3-triazoles followed by Grignard reaction.
Entry
Catalyst
Solvent[a]
Temp. [8C]
Time [h]
Yield 33 [%][b]
1
2
3
4
5
6
7
8
9
Rh2(OAc)4
Rh2(O2CtBu)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
none
toluene
toluene
toluene
CHCl3
140
140
140
140
120
RT
5
5
4
4
4
3 d
10
6
6
4
70
64
75
85[c]
84[c]
35[d]
83
67
44
91
80
DCE
toluene
toluene
toluene
toluene
toluene
toluene
toluene
60
80
Results and Discussion
100
reflux
reflux
reflux
10
11[e]
12
We initiated our studies with N-sulfonyl 1,2,3-triazole
22 as a model substrate. When this compound was
treated with a catalytic amount of Rh2(OAc)4 in tolu-
ene at 1408C for 5 h, to our delight, 33 was pro-
duced in 70% isolated yield after nucleophilic addi-
tion with methylmagnesium bromide (Table 1,
4
4
0
[a] All reactions were carried out in 0.04m solvent with 5 mol% catalyst. [b] Yield of
isolated product. [c] The yield of imine was determined by using biphenyl as internal
standard. [d] 75% conversion. [e] The reaction was carried out in 0.10m solvent.
DCE=1,2-dichloroethane.
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Table 2. Synthesis of compounds 33–43.
Table 3. Synthesis of type-I oxaspirocycles 48--51.
Product[a]
Yield
[%][a,b]
Entry
Substrate
Product[a]
Yield [%]
(d.r.)[b]
Entry Substrate Product
Yield
[%][a,b]
1
2
33
33
91
52
93
90
1
2
3
4
5
6
7
8
9
22, R=H
33, R=H
91 (>20:1)[c]
89 (14:1)
89 (7:1)
81 (20:1)
95 (>20:1)
94 (>20:1)[c]
80 (17:1)
75 (15:1)
60 (>20:1)
23, R=3-Me
24, R=4-Cl
25, R=3-Cl
26, R=2-F
27, R=3-CF3
28, R=3-OMe
29, R=3-OBn
30, R1 =3-OMe
R2 =4-OMe
34, R=3-Me
35, R=4-Cl
36, R=3-Cl
37, R=2-F
38, R=3-CF3
39, R=3-OMe
40, R=3-OBn
41, R1 =3-OMe
R2 =4-OMe
3
4
42
42
92
55
91
91
10
11
95 (>20:1)
93 (4:1)
[a] Isolated yield. [b] For 45 and 47 Cs2CO3 was used as base, see the Sup-
porting Information.
[a] Isolated yield. [b] The diastereoselectivity was determined by 1H NMR
spectroscopic analysis. [c] The structures of 33 and 38 were confirmed by
X-ray crystallographic analysis.[13]
Table 4. Synthesis of type-II oxaspirocycles 58–63.
were selected as model substrates, and alkylation with allyl
bromide or 4-bromo-butene in the presence of base gave
dienes 44–47 in good yields (Table 3). Subsequent treatment
of these dienes with Grubbs 2nd generation catalyst gave the
corresponding oxaspirocycles 48–51 in excellent yields.
Entry Nucleophile Product
Yield [%]
(d.r.)[a,b]
Product
Yield
[%][a,b]
1
2
80 (>20:1)
93
94
We then turned our attention to the preparation of the
type-II oxaspirocycles. Oxaspirocycles with different ring sizes
are present in a wide variety of natural products, therefore, we
decided to synthesize such compounds including 5,5-, 5,6-,
and 5,7-ring systems. In addition, the amine group can be
transformed into other functional groups, which would allow
for the synthesis of a range of structurally diverse natural prod-
ucts. With this in mind, we attempted to trap the imine with
several Grignard species, including vinyl-, allyl-, and 3-butenyl-
magnisium bromide. Triazole 22 was selected as a model sub-
strate for these experiments, and this compound was heated
to reflux with Rh2(Oct)4 in toluene to give the imine. Trapping
with vinyl-, allyl-, and 3-butenyl-magnesium bromides gave the
corresponding dienes 52–54 in good yields. Further treatment
of dienes 52--54 with Grubbs 2nd generation catalyst in tolu-
ene at 608C gave type-II oxaspirocycles 58–60 in excellent
yields (Table 4).
89 (1.4:1)
3
76 (>20:1)
91
4
5
6
92 (>20:1)
73 (4:1)
94
92
89
79 (>20:1)
Encouraged by these results, we proceeded to investigate
the application of this methodology to aliphatic substrates
(Table 4, entries 4–6). Notably, b-hydride elimination represents
a potential competitive reaction for rhodium carbenoid inter-
[a] Isolated yield; [b] The diastereoselectivity was determined by 1H NMR
spectroscopic analysis; [c] The structures of 52 and 58 were confirmed by
X-ray crystallographic analysis.[13]
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mediates and, in some cases, this reaction can lead to the for-
mation of a,b-unsaturated N-tosyl imines, unless the procedure
is conducted under basic conditions.[5g,h,q] Triazole 32 was se-
lected as a model substrate to evaluate this reaction. Pleasing-
ly, treatment of 32 with Rh2(Oct)4 under the optimized condi-
tions gave the expected imine, which was captured with vinyl-,
allyl-, and 3-butenyl magnesium bromide to give the corre-
sponding dienes 55–57, respectively, in good to excellent
yields (Table 4, entries 4–6). Furthermore, no b-hydride elimina-
tion by-products were observed in these reactions, which sug-
gested that the formation of the oxonium ylide was much
faster than the b-hydride elimination of the rhodium carbenoid
intermediates in all three cases. The dienes were then subject-
ed to an RCM reaction, which gave the corresponding oxa-
spirocycles 61–63 in excellent yields.
Upon completion of our survey of these transformations of
triazoles into oxaspirocycles, we applied this methodology to
the total syntheses of tuberostemospiroline (2) and stemona-
lactam R (3) with triazole 31 as the starting substrate.
Compounds 2 and 3 were isolated recently from Stemona-
ceae,[1b,d] which has been used as traditional medicines for the
treatment of respiratory disorders in China for many centu-
ries.[14] Structurally, 2 and 3 are composed of a spiro-g-butyro-
lactone scaffold, which is attached to a pyrido[1,2-a]azepine.
Since the first synthesis of (+)-croomine was completed by
Williams and co-workers by using iodine-induced cyclization,
several strategies, including Martin’s vinylogous Mannich reac-
tion and Figueredo’s 1,3-dipolar cycloaddition, have been de-
veloped for the synthesis of this type of scaffold.[15] The bioac-
tivity, along with the increasing number of Stemona alkaloids,
make it meaningful to develop a new flexible route to con-
struct these nature products, and we anticipate that our newly
Scheme 1. Diastereoselective total syntheses of (Æ)-tuberostemo-spiroline
(2) and (Æ)-stemona-lactam R (3). Reagents and conditions: a) Rh2(Oct)4, tol-
uene, reflux, (3,3-dimethoxypropyl)magnesium bromide, À608C, 3 h, 83%,
64/65=7:1; b) Rh2(Oct)4, toluene, reflux, (3,3-dimethoxypropyl)magnesium
bromide, RT, 3 h, 80%, 64/65=1:20; c) NaH, allyl bromide, THF, 08C to RT,
8 h, 95%. d) Hoveyda–Grubbs catalyst, toluene, 808C, 6 h, 90%; e) Pd/C, H2,
MeOH, RT, 10 h; f) Jones reagent, acetone, 08C, 4 h; g) CH2N2, THF, 08C, 1 h,
91% for three steps; h) RuCl3, NaIO4, CCl4/MeCN/H2O, RT, 12 h, 45%, 65%
brsm; i) Na, naphthalene, DME, À708C, 15 min, 85%; j) LHMDS, MeI, THF,
À788C to À208C, 4 h, 64%; k) LHMDS, PhSeBr, THF, À788C, 4 h, then H2O2,
CH2Cl2, 08C, 3 h, 55% for two steps; l) RuCl3, NaIO4, CH3CO2Et/MeCN/H2O,
08C, 10 min; m) SmI2, (CH2OH)2, HMPA, THF, RT, 3 h, 49% for two steps.
developed strategy will provide
a useful complementary
method for accessing natural products belonging to this struc-
tural class.
Our route for the total syntheses of (Æ)-tuberostemospiro-
line (2) and (Æ)-stemona-lactam R (3) is shown in Scheme 1. To
synthesize amine 65, triazole 31 was initially heated with
Rh2(Oct)4 to reflux in toluene, followed by reaction of the re-
sulting imine with (3,3-dimethoxypropyl) magnesium bromide
at À608C. To our surprise, product 64 was obtained as a major
isomer with the undesired newly generated chiral center.
When the reaction was conducted at room temperature, prod-
uct 65 was formed as the major isomer in a ratio of 20:1 with
64 and a combined yield of 80%.[16]
Allylation of 65 with allyl bromide in the presence of NaH af-
forded diene 66 in 95% yield, which was treated with the Hov-
eyda–Grubbs catalyst at 808C to give the annulated product
67 in 90% yield. The double bond in 67 was then reduced by
catalytic hydrogenation, and the ketal moiety was then sub-
jected to Jones oxidation followed by methylation to give the
corresponding ester 68 in a yield of 91% over three steps. Sub-
sequent RuCl3-catalyzed oxidation of the tetrahydrofuran in 68
in the presence of NaIO4 resulted in the formation of lactone
69 in 45% yield (65% based on recovered starting material).
The relative stereochemistry of 68 was confirmed by its X-ray
crystallographic analysis.[13]
Treatment of 69 with sodium in the presence of naphtha-
lene in 1,2-dimethoxyethane (DME) at À708C led to the cleav-
age of the N-tosyl group, and the resulting secondary amine
underwent intramolecular lactamization in situ to give lactam
70 in 85% yield. Selective a-methylation of lactone 70 with
MeI in the presence of LiHMDS completed the total synthesis
of (Æ)-tuberostemospiroline (2) in 64% isolated yield, together
with its diastereoisomer (21% yield).
Selenylation of 2 with LiHMDS/PhSeBr followed by oxidative
elimination with H2O2 gave a,b-unsaturated lactone 71 in 55%
yield. Subsequent dihydroxylation with NaIO4 in the presence
of catalytic RuCl3, followed by SmI2-mediated dehydroxylation
of the resultant diol 72 gave (Æ)-stemona-lactam R (3) in
1
a yield of 49% over two steps. The H and 13C NMR spectra of
the synthesized tuberostemospiroline (2) and stemona-lac-
tam R (3) were in good agreement with those reported in the
literature.[1b,d]
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Compound 64
Conclusion
Rh2(Oct)4 (197 mg, 0.25 mmol, 0.03 equiv) was added to a solution
of triazole 31 (2.70 g, 8.41 mmol, 1.0 equiv) in anhydrous toluene
(210 mL) at ambient temperature. The mixture was degassed with
Ar, and heated to reflux for 4 h. The reaction mixture was then
cooled to À608C, and (3,3-dimethoxy-propyl) magnesium bro-
mide[18] (1.0m in THF, 12.6 mL, 12.6 mmol, 1.5 equiv) was added
dropwise. The reaction was maintained at that temperature for 3 h,
then quenched with saturated aqueous ammonium chloride, ex-
tracted twice with ethyl acetate, dried over Na2SO4, filtered, and
concentrated in vacuo. Purification by flash column chromatogra-
phy (hexane/EtOAc=8:1–2:1) afforded 64 (2.77 g, 6.98 mmol, 83%
We have developed a novel approach to the diastereoselective
synthesis of oxaspirocycles through Rh-catalyzed loss of nitro-
gen from 4-substituted-1-tosyl-1,2,3-triazoles,[17] a Grignard re-
action, and an RCM reaction as key steps. By using the devel-
oped chemistry, the total syntheses of tuberostemospiroline
(2) and stemona-lactam R (3) have been achieved for the first
time. Further application of the chemistry in synthesizing chal-
lenging natural products with biologically significance can be
envisioned.
1
overall yield); ratio 64/65=7:1. H NMR (400 MHz, CDCl3): d=7.73
(d, J=8.0 Hz, 2H), 7.27 (d, J=8.0 Hz, 2H), 5.73 (td, J=16.8, 7.2 Hz,
1H), 5.07–4.98 (m, 2H), 4.82 (d, J=8.8 Hz, 1H), 4.20 (t, J=5.4 Hz,
1H), 3.63–3.58 (m, 1H), 3.49–3.43 (m, 1H), 3.35–3.30 (m, 1H), 3.19
(s, 6H), 2.38 (s, 3H), 2.20 (d, J=7.2 Hz, 2H), 1.88–1.72 (m, 3H),
1.72–1.61 (m, 2H), 1.51–1.38 (m, 2H), 1.27–1.18 ppm (m, 1H);
13C NMR (100 MHz, CDCl3): d=142.8, 138.9, 133.9, 129.3, 126.9,
118.0, 104.1, 86.3, 68.2, 59.9, 52.7, 52.7, 40.9, 31.6, 29.4, 26.1, 26.0,
21.4 ppm; IR (film): n˜max =3248, 2960, 1650, 1625, 1435, 1373, 1150,
Experimental Section
Synthesis of products 33–43: general procedure
Rh2(Oct)4 (15.9 mg, 0.020 mmol, 0.05 equiv) was added to a solution
of triazole 22 (150 mg, 0.41 mmol, 1.0 equiv) in anhydrous toluene
(10 mL) at ambient temperature. The mixture was degassed by Ar,
and then heated to reflux. After 4 h, the reaction mixture was
cooled to 08C, and methylmagnesium bromide (0.27 mL,
0.82 mmol, 2.0 equiv, 3.0m in Et2O) was added dropwise. The reac-
tion mixture was warmed to ambient temperature slowly during
4 h, then the reaction was quenched with saturated aqueous am-
monium chloride, extracted twice with ethyl acetate, dried over
Na2SO4, filtered, and concentrated in vacuo. Purification by flash
column chromatography (hexane/EtOAc=8:1–2:1) afforded the
desired amine product 33 (133 mg, 0.37 mmol, 91% overall yield);
d.r.> 20:1. 1H NMR (400 MHz, CDCl3): d=7.78 (d, J=8.3 Hz, 2H),
7.35–7.22 (m, 4H), 7.20–7.12 (m, 1H), 7.09–7.02 (m, 1H), 5.45 (ddt,
J=17.1, 10.2, 7.2 Hz, 1H), 5.03 (d, J=12.4 Hz, 1H), 4.98 (d, J=
12.4 Hz, 1H), 4.95–4.85 (m, 2H), 4.71 (d, J=10.0 Hz, 1H), 3.71 (td,
J=10.0, 6.8 Hz, 1H), 2.80 (dd, J=14.3, 7.5 Hz, 1H), 2.47 (dd, J=
14.3, 7.5 Hz, 1H), 2.42 (s, 3H), 0.71ppm (d, J=6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=143.1, 140.3, 139.8, 138.7, 132.7, 129.6, 128.0,
127.5, 126.9, 121.5, 121.0, 118.4, 92.7, 73.8, 56.6, 42.3, 21.5,
16.8 ppm; IR (film): n˜max =3276, 3282, 1769, 1643, 1432, 1332, 1161,
1092, 1038, 918, 761, 664, 562 cmÀ1; HRMS (ESI): m/z calcd for
C20H23NNaO3S: 380.1291 [M+Na]+; found: 380.1293.
1048, 932, 819, 750, 580 cmÀ1
; HRMS (ESI): m/z calcd for
C20H31NNaO5S: 420.1815 [M+Na]+; found: 420.1817.
Compound 65
Obtained in 80% overall yield (64/65=1:20) by following the
above procedure, except that the Grignard reaction was carried
1
out at ambient temperature for 3 h. H NMR (400 MHz, CDCl3): d=
7.73 (d, J=8.0 Hz, 2H), 7.27 (d, J=8.0 Hz, 2H), 5.71 (ddt, J=16.8,
10.0, 7.0 Hz, 1H), 5.13–5.05 (m, 2H), 4.75 (d, J=9.2 Hz, 1H), 4.15 (t,
J=4.8 Hz, 1H), 3.68–3.63 (m, 2H), 3.33–3.28 (m, 1H), 3.18 (s, 6H),
2.40 (s, 3H), 2.27 (dd, J=14.0, 6.4 Hz, 1H), 2.17 (dd, J=14.0, 7.6 Hz,
1H), 1.92–1.71 (m, 4H), 1.59–1.46 (m, 2H), 1.45–1.26 ppm (m, 2H);
13C NMR (100 MHz, CDCl3): d=142.9, 138.9, 133.4, 129.4, 126.8,
118.6, 104.2, 86.5, 68.6, 59.5, 52.6, 52.5, 41.5, 32.9, 28.9, 26.3, 25.9,
21.4 ppm; IR (film): n˜max =3297, 2960, 1645, 1600, 1442, 1331, 1160,
1125, 1093, 1053, 914, 816, 733, 665, 550 cmÀ1; HRMS (ESI): m/z
calcd for C20H31NNaO5S: 420.1815 [M+Na]+; found: 420.1813.
Compound 66
NaH (196 mg, 4.91 mmol, 1.5 equiv, 60% w/w) was added to
a stirred solution of amine 65 (1.30 g, 3.27 mmol, 1.0 equiv) in THF
(30 mL) at 08C. The reaction mixture was allowed to warm to am-
bient temperature, and stirred for 30 min. Allyl bromide (0.55 mL,
6.54 mmol, 2.0 equiv) was added, followed by the addition of tetra-
butyl ammonium iodide (121 mg, 0.33 mmol, 0.1 equiv). When TLC
showed complete consumption of the starting material (ca. 8 h),
the reaction was quenched with saturated aqueous ammonium
chloride, extracted twice with ethyl acetate, dried over Na2SO4, fil-
tered, and concentrated in vacuo. Purification by flash column
chromatography (hexane/EtOAc=10:1–4:1) afforded the desired
RCM reactions: general procedure
To a solution of 44 (160 mg, 0.40 mmol, 1.0 equiv) in anhydrous
toluene (40 mL) was added Grubbs 2nd generation catalyst
(33 mg, 0.040 mmol, 0.1 equiv). The reaction was degassed with
argon four times and then stirred at 608C for 10 h. After cooling to
ambient temperature, the mixture was concentrated in vacuo and
the residue was purified by flash column chromatography (hexane/
EtOAc=8:1–2:1) to afford 48 (137 mg, 0.37 mmol, 93%). 1H NMR
(500 MHz, CDCl3): d=7.77 (d, J=8.1 Hz, 2H), 7.35–7.23 (m, 4H),
7.23–7.15 (m, 1H), 7.13 (dd, J=7.6, 4.8 Hz, 1H), 5.89–5.64 (m, 1H),
5.52–5.29 (m, 1H), 5.12 (d, J=12.5 Hz, 1H), 5.07 (d, J=12.5 Hz, 1H),
4.32 (dd, J=18.0, 6.2 Hz, 1H), 4.28–4.23 (m, 1H), 4.03 (dd, J=18.0,
1.5 Hz, 1H), 2.52–2.39 (m, 1H), 2.42 (s, 3H), 2.22 (dd, J=17.0,
7.7 Hz, 1H), 0.89 ppm (d, J=6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=144.0, 143.0, 138.3, 138.2, 129.3, 128.2, 127.8, 127.4, 127.1,
126.4, 121.0, 120.9, 93.6, 73.6, 61.8, 42.1, 39.6, 21.5, 13.1 ppm; IR
(film): n˜max =3470, 2414, 1766, 1652, 1435, 1314, 1124, 960, 781,
1
diene 66 (1.36 g, 3.11 mmol, 95%). H NMR (400 MHz, CDCl3): d=
7.69 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 5.84–5.71 (m, 2H),
5.20–5.02 (m, 4H), 4.17 (t, J=5.6 Hz, 1H), 4.00–3.86 (m, 3H), 3.76 (t,
J=6.7 Hz, 2H), 3.17 (s, 3H), 3.15 (s, 3H), 2.39 (s, 3H), 2.31 (dd, J=
14.1, 6.0 Hz, 1H), 2.22 (dd, J=14.1, 8.5 Hz, 1H), 2.01–1.85 (m, 3H),
1.82–1.59 (m, 3H), 1.25–1.17 ppm (m, 2H); 13C NMR (100 MHz,
CDCl3): d=143.0, 138.3, 135.7, 133.8, 129.2, 127.7, 118.2, 117.1,
104.1, 88.2, 66.9, 62.1, 52.6, 52.4, 47.3, 42.6, 31.4, 30.2, 25.6, 22.5,
21.4 ppm; IR (film): n˜max =2948, 1742, 1454, 1336, 1245, 1157, 1125,
550 cmÀ1
; HRMS (ESI): m/z calcd for C21H23NNaO3S: 392.1291
[M+Na]+; found: 392.1290.
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1091, 1050, 916, 817, 733, 662, 579, 547 cmÀ1; HRMS (ESI): m/z
calcd for C23H35NNaO5S: 460.2128 [M+Na]+; found: 460.2130.
3.26 (br, 1H), 2.47 (br, 2H), 2.39 (s, 3H), 1.95–1.40 ppm (m, 12H);
13C NMR (100 MHz, CDCl3): d=173.9, 142.5, 137.7, 128.9, 128.1,
86.1, 66.9, 63.4, 51.6, 43.6, 38.0, 35.3, 31.1, 26.7, 25.9, 24.4, 21.4,
21.1 ppm; IR (film): n˜max =2937, 1737, 1437, 1328, 1165, 1091, 1048,
; HRMS (ESI): m/z calcd for
C20H29NNaO5S: 418.1659 [M+Na]+; found: 418.1660.
Compound 67
922, 816, 660, 576, 550 cmÀ1
Hoveyda–Grubbs catalyst (119 mg, 0.19 mmol, 0.05 equiv) and ben-
zoqinone (41 mg, 0.38 mmol, 0.1 equiv) were added to a solution
of 66 (1.66 g, 3.80 mmol, 1.0 equiv) in anhydrous toluene (200 mL).
The reaction mixture was degassed by argon four times, then
stirred at 808C for 6 h. After cooling to ambient temperature, the
mixture was concentrated in vacuo, and the residue was purified
by flash column chromatography (hexane/EtOAc=10:1–4:1) to
Compound 69
MeCN (40 mL) and H2O (60 mL) were added to a solution of 68
(2.37 g, 6.00 mmol, 1.0 equiv) in CCl4 (40 mL), then NaIO4 (4.49 g,
21.0 mmol, 3.5 equiv), NaHCO3 (2.02 g, 24.0 mmol, 4.0 equiv), and
RuCl3·3H2O (470 mg, 1.80 mmol, 0.3 equiv) were added sequentially
at ambient temperature. The mixture was stirred at ambient tem-
perature for 12 h, then diluted with H2O and extracted three times
with CH2Cl2. The combined organic layer was washed with brine,
dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by flash column chromatography (hexane/EtOAc=
4:1–2:1) to afford lactone 69 (1.11 g, 2.70 mmol, 45% yield; 65%
yield based on recycled starting material). 1H NMR (400 MHz,
CDCl3): d=7.87 (d, J=7.7 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 4.42 (br,
1H), 3.71 (s, 3H), 3.40 (br, 1H), 3.25 (br, 1H), 2.66–2.57 (m, 2H),
2.57–2.47 (m, 2H), 2.42 (s, 3H), 2.30 (br, 1H), 2.01–1.70 (m, 6H),
1.61 (s, 3H), 1.60–1.38 ppm (m, 3H); 13C NMR (100 MHz, CDCl3): d=
175.4, 173.4, 143.3, 136.7, 129.4, 128.2, 89.0, 62.4, 51.8, 42.7, 35.8,
33.1, 30.3, 28.5, 26.6, 22.5, 21.5, 20.6 ppm; IR (film): n˜max =3451,
2937, 1771, 1737, 1645, 1442, 1322, 1180, 1154, 1091, 914, 814,
733, 660, 579, 547 cmÀ1; HRMS (ESI): m/z calcd for C20H27NNaO6S:
432.1451 [M+Na]+; found: 432.1415.
1
afford 67 (1.40 g, 3.42 mmol, 90%). H NMR (400 MHz, CDCl3): d=
7.76 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 5.48–5.37 (m, 2H),
4.36 (t, J=3.9 Hz, 1H), 4.16–3.95 (m, 2H), 3.80–3.72 (m, 1H), 3.68–
3.56 (m, 2H), 3.28 (s, 3H), 3.27 (s, 3H), 2.35 (s, 3H), 2.23 (dd, J=
16.8, 4.0 Hz, 1H), 1.99 (dd, J=16.8, 4.4 Hz, 1H), 1.87–1.76 (m, 3H),
1.74–1.57 (m, 4H), 1.57–1.47 ppm (m, 1H); 13C NMR (100 MHz,
CDCl3): d=142.5, 138.2, 128.9, 128.4, 127.6, 126.4, 104.2, 85.9, 66.9,
63.5, 53.0, 53.0, 41.2, 36.9, 34.8, 29.5, 26.3, 22.2, 21.3 ppm; IR (film):
n˜max =2925, 1737, 1457, 1380, 1331, 1245, 1151, 1120, 1094, 1053,
920, 813, 714, 650, 548 cmÀ1
; HRMS (ESI): m/z calcd for
C21H31NNaO5S: 432.1815 [M+Na]+; found: 432.1816.
Compound 68
Pd/C (43 mg, 0.41 mmol, 0.15 equiv, palladium 10% on carbon)
was added to a solution of 67 (1.12 g, 2.74 mmol, 1.0 equiv) in an-
hydrous methanol (5.0 mL). The reaction mixture was aspirated by
hydrogen four times and stirred at ambient temperature under
a hydrogen balloon for 10 h. The mixture was then filtered through
Celite, and the filtrate was concentrated in vacuo. The residue was
Compound 70
1
used directly for the next step without further purification. H NMR
Sodium metal (0.12 g, 5.0 mmol) was added to a solution of naph-
thalene (0.72 g, 5.5 mmol) in DME (5 mL) and the mixture was
stirred at ambient temperature for 2 h to give a dark-green solu-
tion. Lactone 69 (460 mg, 1.12 mmol, 1.0 equiv) was dissolved in
anhydrous DME (10 mL), and cooled to À708C, and the prepared
Na-naphthalenide solution was added dropwise to the reaction
mixture until the mixture became dark-green. The reaction was
maintained at that temperature for 15 min, and then quenched
with water. After warming to ambient temperature, the reaction
was extracted four times with ethyl acetate. The combined organic
layer was dried over Na2SO4, filtered, and concentrated in vacuo.
Further purification through flash column chromatography (DCM/
MeOH/Et3N=20:1:0.1–5:1:0.1) afforded lactam 70 (210 mg,
(400 MHz, CDCl3): d=7.87 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.4 Hz,
2H), 4.38 (br, 1H), 4.06 (br, 1H), 3.82–3.71 (m, 2H), 3.37 (br, 1H),
3.31 (s, 3H), 3.30 (s, 3H), 3.14 (br, 1H), 2.39 (s, 3H), 1.92–1.47 ppm
(m, 15H); 13C NMR (100 MHz, CDCl3): d=142.4, 138.2, 128.9, 128.1,
104.2, 86.3, 66.7, 63.8, 53.2, 53.1, 42.5, 37.6, 35.6, 30.0, 27.1, 26.0,
23.0, 21.4, 20.57 ppm; IR (film): n˜max =2943, 1742, 1451, 1376, 1325,
1246, 1154, 1120, 1088, 1050, 920, 814, 713, 650, 585, 550 cmÀ1
;
HRMS (ESI): m/z calcd for C21H33NNaO5S: 434.1972 [M+Na]+; found:
434.1969.
The residue was dissolved in acetone (40 mL), and the mixture was
cooled to 08C. Jones reagent (1.26m, 17.4 mL, 21.9 mmol,
8.0 equiv) was added dropwise, and the reaction was stirred at 08C
for 4 h. After addition of isopropanol (3 mL), the reaction was
stirred for 10 min, then the mixture was warmed to ambient tem-
perature, filtered through Celite, and the filtrate was extracted
three times with ethyl acetate. The combined organic layer was
washed with brine, dried over Na2SO4, filtered, and concentrated in
vacuo. The crude acid was also used directly for the next step with-
out further purification.
1
0.95 mmol, 85%). H NMR (400 MHz, CD3OD): d=4.02 (dd, J=9.6,
7.2 Hz, 1H), 3.79 (dd, J=14.0, 4.0 Hz, 1H), 3.08 (t, J=12.4 Hz, 1H),
2.77–2.67 (m, 1H), 2.51 (ddd, J=14.0, 5.4, 1.8 Hz, 1H), 2.45–2.31
(m, 2H), 2.22–2.16 (m, 2H), 2.09–1.99 (m, 1H), 1.92–1.82 (m, 2H),
1.82–1.57 (m, 4H), 1.57–1.44 ppm (m, 1H); 13C NMR (100 MHz,
CD3OD): d=178.7, 177.4, 91.1, 68.5, 42.9, 33.8, 30.9, 30.6, 29.4, 28.2,
23.6, 22.3 ppm; IR (film): n˜max =3451, 2925, 1774, 1662, 1554, 1457,
1420, 1260, 1211, 1165, 962, 740, 492 cmÀ1; HRMS (ESI): m/z calcd
for C12H17NNaO3: 246.1101 [M+Na]+; found: 246.1100.
The above acid was dissolved in THF (15 mL) and cooled to 08C.
Diazald (1.89 g, 8.22 mmol, 3.0 equiv) dissolved in diethyl ether
(10 mL) was added dropwise to a stirring solution of KOH (2.0 g,
35.7 mmol) in water (2.5 mL), ethanol (2.5 mL) and diethyl ether
(5.0 mL) at 708C. The generated CH2N2 was cooled through a con-
denser tube and added into the reaction mixture. After stirring for
1 h at 08C, the mixture was slowly warmed to RT, and stirred for
20 min. The mixture was concentrated in vacuo, and the residue
was purified by flash column chromatography (hexane/EtOAc=
8:1–4:1) to afford ester 68 (980 mg, 2.49 mmol, 91% yield for three
steps). 1H NMR (400 MHz, CDCl3): d=7.83 (d, J=8.0 Hz, 2H), 7.24
(d, J=8.0 Hz, 2H), 4.06 (br, 1H), 3.73–3.62 (m, 5H), 3.34 (br, 1H),
Tuberostemospiroline (2)
LHMDS (1.0m in THF, 0.86 mL, 0.86 mmol, 1.8 equiv) was added
dropwise to a solution of lactam 70 (107 mg, 0.48 mmol, 1.0 equiv)
in anhydrous THF (12 mL) at À788C. The reaction was slowly
warmed to À608C, and stirred for 1 h. After recooling to À788C,
MeI (0.12 mL, 1.92 mmol, 4.0 equiv) was added and the mixture
was slowly warmed to À208C, and maintained at that temperature
for 3 h. The reaction was quenched with saturated aqueous ammo-
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nium chloride, extracted four times with ethyl acetate, dried over
Na2SO4, filtered, and concentrated in vacuo. Purification by flash
column chromatography (DCM/MeOH/Et3N=20:1:0.1–5:1:0.1) af-
forded a mixture of tuberostemospiroline 2 with its isomer 2’
(d.r.=3:1, 97 mg, 0.41 mmol) in 85% overall yield. Further purifica-
tion (petroleum ether/EtOAc/Et2NH, 1:1:0.1) gave the natural prod-
(0.1m in THF, 4.5 mL, 0.447 mmol, 5.0 equiv) was added, and the
reaction was stirred at that temperature for 3 h. The mixture was
diluted with saturated NaHCO3 solution, extracted four times with
ethyl acetate, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by chromatography on silica gel (DCM/MeOH/
Et3N=15:1:0.1–5:1:0.1) to give the natural product stemona-lac-
tam R 3 (11 mg, 0.0438 mmol, 49% yield for two steps).[19] 1H NMR
(500 MHz, [D5]pyridine): d=7.82 (d, J=6.0 Hz, 1H), 4.25 (dd, J=
10.0, 5.5 Hz, 1H), 4.17 (d, J=13.6 Hz, 1H), 3.78 (dd, J=9.8, 6.8 Hz,
1H), 2.92 (dq, J=10.0, 7.0 Hz, 1H), 2.88 (t, J=13.0 Hz, 1H), 2.39–
2.29 (m, 2H), 2.29–2.20 (m, 2H), 2.18–2.12 (m, 1H), 1.78 (t, J=
13.0 Hz, 1H), 1.74–1.70 (m, 1H), 1.60–1.52 (m, 2H), 1.49–1.43 (m,
1H), 1.40 ppm (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, [D5]pyridine):
d=175.3, 173.6, 87.5, 77.2, 67.3, 40.7, 40.6, 30.1, 29.3, 25.7, 21.7,
21.2, 12.2 ppm; IR (film): n˜max =3410, 2916, 1760, 1671, 1442, 1265,
1105, 870, 560 cmÀ1; HRMS (ESI): m/z calcd for C13H20NO4: 254.1387
[M+H]+; found: 254.1390.
1
uct tuberostemospiroline 2 as a white solid; m.p. 1178C; H NMR
(400 MHz, CD3OD): d=4.03 (dd, J=8.8, 7.4 Hz, 1H), 3.66 (ddd, J=
12.6, 6.4, 2.6 Hz, 1H), 3.23–3.17 (m, 1H), 2.90–2.83 (m, 1H), 2.53
(dd, J=13.5, 10.0 Hz, 1H), 2.40–2.37 (m, 2H), 2.23–2.16 (m, 1H),
2.00–1.88 (m, 3H), 1.79–1.65 (m, 3H), 1.60–1.54 (m, 2H), 1.30 ppm
(d, J=7.1 Hz, 3H); 13C NMR (100 MHz, CD3OD): d=181.2, 177.5,
89.2, 67.7, 43.3, 38.7, 38.5, 36.5, 30.9, 28.6, 23.5, 23.0, 17.4 ppm; IR
(film): n˜max =2950, 1759, 1440, 1328, 1160, 1085, 1040, 921, 886,
656, 579, 547 cmÀ1; HRMS (ESI): m/z calcd for C13H20NO3: 238.1437
[M+H]+; found: 238.1438.
Compound 71
LHMDS (1.20 mL, 1.20 mmol, 3.0 equiv, 1.0m in THF) was added
dropwise to a solution of the 2 and 2’ mixture (94 mg, 0.40 mmol,
1.0 equiv) in anhydrous THF (10 mL) at À788C. The reaction was
stirred at À788C for 1.5 h, then PhSeBr (142 mg, 0.60 mmol,
1.5 equiv) in THF (1.0 mL) was added. The reaction was maintained
at that temperature for 4 h, then quenched with saturated aque-
ous ammonium chloride. The mixture was extracted four times
with ethyl acetate, and the combined organic layer was washed
with brine. Dried over Na2SO4, filtered, and concentrated in vacuo,
to give a residue that was used directly for the next step.
Acknowledgements
The authors thank the National Basic Research 973 Program of
China (Grant Nos. 2010CB833201, 2012CB722602), the National
863 Program (Grant No. 2013AA092903), Natural Science Foun-
dation of China (Grant No. 21372016) and Shenzhen Basic Re-
search Program (Grant Nos. JCYJ20130329180217059,
GJHS20120628101219325,
ZYC201105170335A,
ZYC201105170358A) for financial support. We also thank Pro-
fessor Yefeng Tang of Tsinghua University for helpful discus-
sions.
The above residue was dissolved in CH2Cl2 (4.0 mL), the mixture
was cooled to 08C, and H2O2 (30% solution, 7.0 mL) was added
dropwise. The reaction was stirred vigorously for 3 h, then diluted
with CH2Cl2. The aqueous phase was extracted three times with
CH2Cl2, and the combined organic layer was washed with brine,
dried over Na2SO4, filtered, and concentrated in vacuo. Purification
by flash column chromatography (DCM/MeOH/Et3N=20:1:0.1–
5:1:0.1) afforded 71 (51 mg, 0.22 mmol, 55% yield for two steps).
1H NMR (400 MHz, CD3OD): d=7.34 (d, J=1.5 Hz, 1H), 3.94 (t, J=
7.3 Hz, 1H), 3.79 (ddd, J=13.8, 7.1, 3.4 Hz, 1H), 3.28–3.20 (m, 1H),
2.35–2.26 (m, 2H), 2.10–2.02 (m, 1H), 1.98–1.88 (m, 6H), 1.88–1.77
(m, 1H), 1.76–1.62 ppm (m, 3H); 13C NMR (100 MHz, CD3OD): d=
177.5, 174.6, 151.2, 132.1, 90.9, 67.0, 43.6, 35.8, 31.0, 28.5, 24.2,
22.7, 10.6 ppm; IR (film): n˜max =3468, 2937, 1757, 1677, 1456, 1371,
1268, 1140, 1040, 985, 888, 762 cmÀ1; HRMS (ESI): m/z calcd for
C13H17NNaO3: 258.1101 [M+Na]+; found: 258.1115.
Keywords: carbenes
·
oxaspirocycles
·
sigmatropic
rearrangement · spiro compounds · total synthesis
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Stemona-lactam R (3)
RuCl3·3H2O (27 mg, 0.129 mmol) was added to a solution of NaIO4
(274 mg, 1.27 mmol) in H2O (3.6 mL), and the solution became
dark-orange upon dissolution (this reagent had a shelf life of at
least 2 h). Compound 71 (21 mg, 0.0894 mmol, 1.0 equiv) was dis-
solved in ethyl acetate (1.8 mL) and acetonitrile (1.8 mL), and
cooled to 08C. The prepared stock dark-orange solution (0.60 mL)
was then added to the reaction, and allowed to react for 10 min
before being quenched with saturated Na2S2O3. The mixture was
diluted with ethyl acetate, and the aqueous phase was extracted
four times with ethyl acetate. The combined organic layer was
washed with brine, dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was quickly passed through a short column,
and used directly for the next step.
A
solution of above residue in THF (1.5 mL), HMPA (47 mL,
0.268 mmol, 3.0 equiv), and ethylene glycol (39 mL, 0.715 mmol,
8.0 equiv) was degassed with argon four times. Samarium diiodide
Chem. Eur. J. 2014, 20, 1 – 9
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Received: May 30, 2014
Published online on && &&, 0000
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Chem. Eur. J. 2014, 20, 1 – 9
www.chemeurj.org
8
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
FULL PAPER
&
Spiro Compounds
J. Fu, H. Shen, Y. Chang, C. Li, J. Gong,
Z. Yang*
&& – &&
Concise Stereoselective Synthesis of
Oxaspirocycles with 1-Tosyl-1,2,3-
triazoles: Application to the Total
Syntheses of (Æ)-
Triazole not diazo: A 4-substituted-1-
tosyl-1,2,3-triazole-based stereoselective
synthesis of structurally diverse oxas-
pirocycles is reported (see scheme). The
synthesis involves a Rh-catalyzed loss of
nitrogen from 4-substituted-1-tosyl-
1,2,3-triazoles, a Grignard reaction, and
a ring-closing metathesis reaction as
key steps. This chemistry has been ap-
plied to the total syntheses of (Æ)-tu-
berostemospiroline (1) and (Æ)-stemo-
na-lactam R (2).
Tuberostemospiroline and (Æ)-
Stemona-lactam R
Chem. Eur. J. 2014, 20, 1 – 9
www.chemeurj.org
9
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ