Generation and Rearrangement of N,O-Dialkenylhydroxylamines for the Synthesis of 2-Aminotetrahydrofurans

Article abstract of DOI:10.1002/anie.201800908

A new diastereoselective route to 2-aminotetrahydrofurans has been developed from N,O-dialkenylhydroxylamines. These intermediates undergo a spontaneous C?C bond-forming [3,3]-sigmatropic rearrangement followed by a C?O bond-forming cyclization. A copper-catalyzed N-alkenylation of an N-Boc-hydroxylamine with alkenyl iodides, and a base-promoted addition of the resulting N-hydroxyenamines to an electron-deficient allene, provide modular access to these novel rearrangement precursors. The scope of this de novo synthesis of simple nucleoside analogues has been explored to reveal trends in diastereoselectivity and reactivity. In addition, a base-promoted ring-opening and Mannich reaction has been discovered to covert 2-aminotetrahydrofurans to cyclopentyl β-aminoacid derivatives or cyclopentenones.

Full text of DOI:10.1002/anie.201800908

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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International Edition
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Accepted Article
Title: Generation and Rearrangement of N,O-Dialkenylhydroxylamines
for the Synthesis of 2-Aminotetrahydrofurans
Authors: Jongwoo Son, Tyler W Reidl, Ki Hwan Kim, Donald J Wink,
and Laura L Anderson
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201800908
Angew. Chem. 10.1002/ange.201800908
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10.1002/anie.201800908
Angewandte Chemie International Edition
COMMUNICATION
Generation and Rearrangement of N,O-Dialkenylhydroxylamines
for the Synthesis of 2-Aminotetrahydrofurans
Jongwoo Son,+ Tyler W. Reidl,+ Ki Hwan Kim, Donald J. Wink, and Laura L. Anderson*[a]
Dedication ((optional))
Abstract: A new diastereoselective route to 2-aminotetrahydrofurans
has been developed from N,O-dialkenylhydroxylamines. These
intermediates undergo a spontaneous C–C bond-forming [3,3]-
allene 5a, which precipitates a spontaneous [3,3]-rearrangement
and cyclization sequence (Scheme 1C). The 2-amino-
tetrahydrofuran products that are accessible by this method are
highly-substituted and deoxygenated nucleoside analogues with
a simple carbamate base. Since nucleoside analogues are known
to be potent bioactive reagents, the development of this new
approach to these types of structures will assist in expanding the
chemical space around these important compounds, while further
advancing de novo strategies for the synthesis of furanosides.[7-9]
sigmatropic rearrangement followed by
a C–O bond-forming
cyclization. copper-catalyzed N-alkenylation of an N-Boc-
A
hydroxylamine with alkenyl iodides, and a base-promoted addition of
the resulting N-hydroxyenamines to an electron-deficient allene,
provide modular access to these novel rearrangement precursors.
The scope of this de novo synthesis of simple nucleoside analogues
has been explored to reveal trends in diastereoselectivity and
reactivity. In addition, a base-promoted ring-opening and Mannich
reaction has been discovered to covert 2-aminotetrahydrofurans to
cyclopentyl β-aminoacid derivatives or cyclopentenones.
A) Proposed synthesis of 2-aminotetrahydrofurans
O
O
O
NH
R1 R2
O
O
R5
R1
R4
R1
R5
N
N
R2
R5
R2
R4
R3
R4
R3
R3
O
Tetrahydrofurans are found in a variety of natural products and
biologically active molecules.[1] Due to the privileged nature of
these heterocycles, many methods have been developed to
access these important scaffolds.[2] One strategy that has not yet
been explored for the synthesis of tetrahydrofurans is the [3,3]-
sigmatropic rearrangement of N,O-dialkenylhydroxylamines
followed by cyclization of the initial rearrangement product
(Scheme 1A).[3] This approach is appealing because of the
potential to simultaneously set several contiguous stereocenters
in the tetrahydrofuran ring and the latent modularity of the
precursor. Analogous transformations have been reported for the
synthesis of dihydrobenzofurans from O-aryloxime ethers, which
are easily prepared via oxime arylation or condensation of the
corresponding O-arylhydroxylamine with the appropriate
ketone.[4,5] In contrast, the tetrahydrofuran synthesis has
remained elusive because of the difficulty in generating and
controlling the reactivity of N,O-dialkenylhydroxylamines
(Scheme 1B). Due to our interest in advancing the reactivity of
unsaturated hydroxylamines and nitrones, we wondered if we
could leverage our understanding of oxime and hydroxylamine
B) Synthesis of 2-aminodihydrobenzofurans via a [3,3]-rearrangement
O
H
N
O
O
O
N
H2N
TFAA
CH2Cl2, 0 °C
R = H, 94%
ref. 4a
MeOH, 25 °C
R = CN, 91%
ref. 4b
R
F3C
CN
n
2
C) Generation and rearrangement of N,O-dialkenylhydroxylamines - This work.
Boc
OTBS
K
Boc
OR
Boc
O
N
H
N
5a
CO2Me
N
CO2Me
1. cat. [Cu]
Cs2CO3, 95%
2. TBAF, 70%
1
•
Me
+
Me
K2CO3
I
6a
R = TBS, 3a
H, 4a
2a
MeO2C
‡
O
CO2Me
H
N
Boc
O
Boc
O
H
OMe
O
N
Me
N
Boc
Me
91%
from 4a
Me
H
8a
7a
(dr = >20:1)
Scheme
1.
Synthesis
of
2-Aminodihydrobenzofurans
and
2-
=
Aminotetrahydrofurans via [3,3]-Sigmatropic Rearrangements. TFAA
trifluoroacetic anhydride, TBS = t-butyldimethylsilyl, Boc = t-butyloxycarbonyl,
TBAF = tetrabutylammonium fluoride.
alkenylation
to
design
a
modular route to N,O-
dialkenylhydroxylamines.[6] Herein we describe the synthesis of 2-
aminotetrahydrofurans such as 8a with three contiguous carbon
stereocenters through a copper-catalyzed N-alkenylation of N-
Boc-siloxyamine 1, followed by generation of N,O-dialkenyl-
hydroxylamine 6a via deprotection of 3a and addition of 4a to
We initiated our studies towards the generation of N,O-
dialkenylhydroxylamines
6 for the synthesis of 2-amino-
tetrahydrofurans 8 through the development of conditions for the
N-alkenylation of N-Boc-siloxyamine 1. Using previous studies of
hydrazodiformates as
a
starting point, copper-catalyzed
conditions for the N-alkenylation of 1 were optimized and the
reaction was determined to work best in the presence of 10 mol %
CuI and DMEDA (N,N’-dimethylethylenediamine) (Scheme
2).[10,11] The scope of the synthesis of 3 was then investigated and
shown to work well for both cyclic and linear E-alkenyliodides 2.
Cyclohexenyl- and cycloheptenyl N-siloxyenamines 3a and 3b
were prepared in excellent yield and acetal-substituted
cyclohexenyl enamine 3c and β-tetralone-derived 3d were also
[a]
J. Son, T. W. Reidl, K. H. Kim, Dr. D. J. Wink, Prof. L. L. Anderson
Department of Chemistry
University of Illinois at Chicago
845 W Taylor St., Chicago, IL USA
E-mail: lauralin@uic.edu
[+]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201800908
Angewandte Chemie International Edition
COMMUNICATION
shown to be easily accessible. Heterocyclic alkenyl iodides were
tolerated by the transformation for the preparation of N-
siloxyenamines 3e and 3f, as well as 3g and 3h with more
complicated substitution patterns. E-Disubstituted linear alkenyl
iodides were used to form 3i and 3j; however, Z-4-octenyl iodide
was unreactive. Monosubstituted alkenyl iodides were also
tolerated with substitution at either the α- or β-position to give 3k
and 3l. Silyl ether deprotection and conversion of 3 to 4 was
achieved for all of the substrates shown in Scheme 2 using TBAF.
The range of N-hydroxyenamines prepared in Scheme 2 was then
used to facilitate our further study of N,O-dialkenylhydroxylamine
generation and 2-aminotetrahydrofuran synthesis.
Table 1. Optimization of Addition and Rearrangement Reaction
Boc
Boc
OH
NH
N
CO2Me
O
conditions
•
+
Me
CO2Me
H
H
Me
4a
5a
8a (dr = >20:1)
Entry[a]
Base
none
Solvent
T (°C)
t (h)
% Yield[b]
1
CH2Cl2
CH2Cl2
PhMe
0
0
0
0
0
25
0
0
0
0
0
0
1
nr
2
Cs2CO3 (1 equiv)
Cs2CO3 (1 equiv)
Cs2CO3 (1 equiv)
Cs2CO3 (1 equiv)
Cs2CO3 (1 equiv)
K2CO3 (1 equiv)
Li2CO3 (1 equiv)
K3PO4
1
57
3
1
55
CuI (10 mol %)
DMEDA (10 mol %)
Boc
OTBS
R2
Boc
OH
R2
I
N
N
Boc
OTBS
TBAF
THF
N
H
+
R1
R1
R1
4
MeCN
THF
1
38
Cs2CO3 (2 equiv)
PhMe, 65 °C
R2
1
4
2
3
5
1
50
3 (R = TBS), 4 (R = H)
Boc
OR
Boc
6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1
29
OR
Boc
OR
O
Boc
OR
N
N
N
N
7
1
83
8
1
54
O
3a (95%)
4a (70%
3c (83%)
4c (60%)
3d (99%)
4d (88%)
3b (96%)
4b (54%
9
1
nr
Boc
OR
Boc
OR
Boc
Boc
OR
OR
10
11
12
K2CO3 (20 mol %)
K2CO3 (1 equiv)
K2CO3 (1 equiv)
1
69
N
N
N
N
3h (87%)
4h (80%)
2
80
O
Cl
O
S
O
0.5
93 (91)[c]
Cl
Cl
3e (93%)
4e (62%)
3g (46%)
4g (83%)
3f (52%)
4f (54%)
[a] Conditions: 4a (1 equiv), 5a (2 equiv), 0.1 M in solvent. [b] % Yield
determined by 1H NMR spectroscopy using CH2Br2 as a reference. [c]
Isolated yield.
Boc
N
OR
Boc
H
OR
Boc
OR
Boc
OR
N
N
N
n-Pr
Ph
n-Bu
n-Pr
MeO
Ph
Ph
3i (76%)
4i (79%)
3j (92%)
4j (95%)
3k (95%)
4k (61%)
3l (86%)
4l (72%)
N-Hydroxyenamines 4 were paired with electron-deficient
allenes
aminotetrahydrofurans 8. As shown in Scheme 3, N-
hydroxyenamines with cycloalkenyl or heterocyclic N-
5 to explore the scope of the synthesis of 2-
Scheme 2. N-Boc-Hydroxylamine Silyl Ether N-Alkenylation and Deprotection.
4
substituents underwent the addition and rearrangement to give 8a
– 8c and 8e – 8g in good to excellent yield with high
diastereoselectivity. In comparison, the facial selectivity for the
formation of 8d and 8h were attenuated, which may be caused by
the increased planarity of the starting materials. Substrates 4i –
4l with linear alkenyl substituents gave good yields of the
corresponding 2-aminotetrahydrofurans, but low to moderate
Conditions for the generation of N,O-dialkenylhydroxylamines
6 and their conversion to 2-aminotetrahydrofurans 8 were initially
tested with N-hydroxyenamine 4a and allenoate 5a. As shown in
Table 1, treatment of 4a with 5a in the absence of a base resulted
in no reaction but when these reagents were combined in the
presence of Cs2CO3, rapid formation of 8a was observed with high
diastereoselectivity (Table 1, entries 1 – 2). The favored
diastereomer was identified as the cis-fused ring system through
X-ray crystallography.[12] A solvent screen indicated that CH2Cl2
was the optimal solvent for this transformation and subsequent
screening of similar carbonate and phosphate bases showed that
K2CO3 gave the highest yield of 8a (Table 1, entries 2 – 9).[13] The
use of 20 mol % K2CO3 gave the desired product in attenuated
yield and the addition and rearrangement reaction was shown to
be sensitive to reaction time and temperature with the optimal
conditions determined to be 30 min at 0 °C (Table 1, entries 6 and
10 – 12).[14] These conditions were used to investigate the scope
of this transformation using N-hydroxyenamines 4.
diastereoselectivity for the formation of 8i
– 8l. Minor
diastereomers of 8d and 8h – 8l were determined to have inverted
stereochemistry at the hemiaminal ether.[15] Within this set of
substrates, it was observed that changing the size and shape of
the N-alkenyl group from 4i to 4j resulted in an increase in
diastereomeric ratio between 8i and 8j. For monosubstituted N-
alkenyl substrates 4k and 4l, the substituent at the β-position had
a
greater influence on the diastereoselectivity of the 2-
aminotetrahydrofuran synthesis. Further investigation of the
method involved varying the electron-withdrawing and alkyl
substituents on the allene. As shown for 8m – 8p, several
alkylated allenoates are tolerated for the transformation. All
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10.1002/anie.201800908
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COMMUNICATION
methyl-substituted allenoate addition and rearrangement
products were obtained in high yield (see 8m – 8n); however, as
the size of the alkyl substituent increased, the yield of the addition
and rearrangement reaction decreased (see 8o – 8p).[16] The use
of cyano-substituted allene 5g resulted in a moderate yield of 8r,
but ketone- and Weinreb amide-substituted allenes 5f and 5h
were well-tolerated for the formation of 8q and 8s, respectively.
These studies illustrate the scope of the addition and
rearrangement reaction to provide a small library of new 2-
aminotetrahydrofurans 8 for reactivity studies.
treatment of 8a with MeI in the presence of K2CO3, resulted in
tetrahydrofuran ring-opening, alkylation, and Mannich addition to
form β-amino-cyclopentenone 9a with high diastereoselectivity
(Scheme 4). The preferred conformation of this product was
confirmed by X-ray crystallography.[12] This transformation was
consistent for other 2-aminotetrahydrofurans as shown for 9b and
9d, as well as other electrophiles as shown for 9c.[19] In the
absence of an electrophile, an adventitious proton source gave
9e. Cyclopentyl β-amino acid derivatives such as 9 are important
scaffolds in a variety of biologically active molecules and this new
route to highly substituted examples from 2-aminotetrahydro-
furans 8 will help to broaden the accessibility of these privileged
compounds.[20] Under longer reaction times, and in the absence
of an electrophile, the base-promoted tetrahydrofuran ring-
opening and Mannich cyclization was also observed to occur with
an elimination process to give cyclopentenones 10. These
transformations were similarly diastereoselective as shown for
10a and 10b. The conversion of 8i to 10c also resulted in an
increase in the diastereomeric ratio of the product in comparison
to the starting material.[21] Cyclopentenones 10 have the opposite
electronic substitution pattern to Nazarov rearrangement products
and provide an opportunity to continue to expand structural
diversity around this structure for synthetic applications.[22]
Boc
R1
NH
H
Boc
OH
R2
N
EWG
H
K2CO3 (1 equiv)
O
R3
•
EWG
+
R1
CH2Cl2, 0 °C
30 min - 2 h
E = CO2Me
R2
5
R3
4
8
Boc
Boc
Boc
NH
Boc
NH
NH
HN
H
E
H
E
H
E
H
E
H
O
O
O
O
O
H
H
O
H
Me
8a
Me
Me
Me
8d
8b
8c
(91%, dr = >20:1)
(89%, dr = 12:1)
(73%, dr = >20:1)
(71%, dr = >20:1)
Boc
Boc
NH
NH
Boc
NH
Boc
NH
E
O
O
E
O
E
E
O
O
Cl
O
H
H
O
S
H
Boc
H
H
Me
H
El
Me
EWG
H
El-I
NH
H
Me
Cl
Me
EWG
O
R1
R2
R1
K2CO3 (1 equiv)
K2CO3 (1 equiv)
Cl
8e
8f
8g
8h
8
O
(94%, dr = >20:1) (78%, dr = >20:1) (89%, dr = >20:1)
18-crown-6 (1 equiv)
MeCN, 3 h
18-crown-6 (1 equiv)
MeCN, 1 h
(82%, dr = 2:1)
R2
R3
R3
Boc
NH
Boc
Boc
10
9
H
N
NH
NH
E
O
E
H
Ar
O
E
H
n-Pr
E
O
Ph
O
Boc
Et
Boc
Boc
O
O
Boc
O
Me
H
Boc
Me
Me
NH
H
n-Pr
Ph
NH
NH
CO2Me
H
CO2Me
O
n-Bu
NH
Me
H
CO2Me
Ph
O
Me
8i
(73%, dr = 2:1)
Me
Me
8l
(46%, dr = 8:1)
Ar = p-OMe(C6H4)
8k
(61%, dr = 2:1)
Ph
O
O
8j
O
(68%, dr = 7:1)
H
Me
H
Me
9a
(86%, dr = >20:1) (75%, dr = >20:1)
Me
O
H
Me
9b
9c
(51%, dr = >20:1)
9d
Boc
Boc
NH
R = t-Bu, 8m
R = Bn, 8o
NH
(50%, dr = >20:1)
(86%, dr = >20:1)
CO2R
H
E
(65%, dr = >20:1)
R = i-Pr, 8p
(34%, dr = >20:1)
O
O
Boc
O
CO2Me
O
CO2Me
CO2Me
R =
O
, 8n
H
NH
H
n-Pr
Ph
O
H
H
R
(90%, dr = >20:1)
Me
O
O
O
n-Pr
O
Boc
Boc
NH
Boc
NH
H
H
O
H
O
OMe
H
Me
10a
Me
Me
10c
NH
O
Me
Ph
CN
H
N
Me
O
O
9e
10b
(51%, dr = >20:1) (64%, dr = >20:1)
(53%, dr = >20:1)
(55%, dr = 15:1)
H
H
H
H
H
Me
Me
8r
Me
8s
(73%, dr = >20:1)
Scheme 4. Ring-Opening of
8 and Mannich Ring-Closure Under Basic
8q
Conditions.
(72%, dr = >20:1) (48%, dr = >20:1)
Scheme 3. Scope of N,O-Dialkenylhydroxylamine Generation and 2-
Aminotetrahydrofuran Synthesis.
In summary, by targeting the generation of N,O-
dialkenylhydroxylamines under mild conditions, we have
developed a new modular route to 2-aminotetrahydrofurans. A
copper-catalyzed N-alkenylation of N-Boc-siloxyamine 1 has
been optimized for the synthesis of N-siloxyenamines 3. These
intermediates have been shown to readily undergo silyl
deprotection and deprotonation for the addition to electron-
The development of mild conditions for the generation of N,O-
dialkenylhydroxyamine 6, which initiated
a
spontaneous
rearrangement and cyclization sequence to form 2-
aminotetrahydrofurans 8, provided an opportunity to explore the
unknown rearrangement reactivity of these novel heterocycles.
As expected, exposure of 8a to acidic conditions resulted in
pyrrole formation.[17] In contrast, we anticipated that mild basic
conditions might cleave the tetrahydrofuran C–O bond and
convert 8 to highly-substituted cyclopentanone products via a
formal aza-Petasis-Ferrier rearrangement.[18] Gratifyingly,
deficient allenes
5 and the generation of N,O-dialkenyl-
hydroxylamines 6. These intermediates then undergo
a
spontaneous [3,3]-sigmatropic rearrangement and cyclization to
form 2-aminotetrahydrofurans 8. Taken together, these results
provide a new, novel, and diastereoselective route to simple
nucleoside analogues from modular precursors. In addition, this
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10.1002/anie.201800908
Angewandte Chemie International Edition
COMMUNICATION
World J. Gastroenterol. 2015, 21, 10485; e) J. J. McGowan, J. E.
Tomaszewski, C. James, H. Daniel, K. G. Charles, S. Broder, H. Mitsuya,
Rev. Infect. Dis. 1990, 12, S513; f) X.-W. Zhang, Y.-X. Ma, Y. Sun, Y.-B.
Cao, Q. Li, C.-A. Xu, Targeted Oncol. 2017, 12, 309.
study has also lead to the discovery that 2-aminotetrahydrofurans
can be used to access cyclopentyl β-amino acid derivatives and
cyclopentenones under basic conditions.
[8]
[9]
For nucleoside analogue synthesis see: a) T. Tejero, I. Delso, P. Merino
in Chemical Synthesis of Nucleoside Analogues, (Ed. P. Merino), John
Wiley & Sons, Inc., Hoboken, 2013, pp 699; b) O. Sari, V. Roy, L. A.
Agrofoglio in Chemical Synthesis of Nucleoside Analogues, (Ed. P.
Merino), John Wiley & Sons, Inc., Hoboken, 2013, pp 49.
Acknowledgements
We are grateful to the National Science Foundation for their
generous financial support (NSF-CHE 1464115). We thank Mr.
Furong Sun (UIUC) for high resolution mass spectrometry data.
For the de novo synthesis of furanosides see: a) M. Peifer, R. Berger, V.
W. Shurtleff, J. C. Conrad, D. W. C. MacMillan, J. Am. Chem. Soc. 2014,
136, 5900; b) M. Kim, S. Kang, Y. H. Rhee, Angew. Chem. Int. Ed. 2016,
55, 9733; c) J. Stambasky, V. Kapras, M. Stefko, O. Kysilka, M. Hocek,
A. V. Malkov, P. Kocovsky, J. Org. Chem. 2011, 76, 7781; d) Shi, P.;
O'Doherty, G. A. in Selective Glycosylations: Synthetic Methods and
Catalysts, (Ed. C. S. Bennett), Wiley-VCH, Weinheim, 2017, pp 327.
Keywords: sigmatropic rearrangement • allenoate •
hydroxylamine • tetrahydrofuran • aza-Petasis-Ferrier
[10] See the Supporting Information for a table describing optimization of
conditions for the N-alkenylation of 1 with alkenyliodides.
[1]
[2]
a) E. J. Kang, E. Lee, Chem. Rev. 2005, 105, 4348; b) M. M. Faul, B. E.
Huff, Chem. Rev. 2000, 100, 2407; c) M. Saleem, H. J. Kim, M. S. Ali, Y.
S. Lee, Nat. Prod. Rep. 2005, 696.
[11] For related N-alkenylation reactions of carbazates and N-arylation
reactions of O-alkyl hydroxamates see a) M. R. Rivero, S. L. Buchwald,
Org. Lett. 2007, 9, 973; b) C. Zhou, D. Ma, Chem. Commun. 2014, 50,
3085; c) T. Kukosha, N. Trufilkina, S. Belyakov, M. Katkevics, Synthesis
2012, 44, 2413; d) Y. Yang, X. Wu, J. Han, S. Mao, X. Qian, L. Wang,
Eur. J. Org. Chem. 2014, 6854.
a) J. P. Wolfe, M. B. Hay, Tetrahedron 2007, 63, 261; b) A. de la Torre,
C. Cuyamendous, V. Bultel-Ponce, T. Durand, J. M. Galano, C. Oger,
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Albericio, M. Álvarez, Chem. Rev. 2013, 113, 4567; d) C. C. Jing, D. Xing,
L. X. Gao, J. Li, W. H. Hu, Chem. Eur. J. 2015, 21, 19202; e) A. Tikad, J.
A. Delbrouck, S. P. Vincent, Chem. Eur. J. 2016, 22, 9456.
[12] CCDC 1814362, and CCDC 1814364 contain the supplementary
crystallographic data for compounds 8a and 9a, respectively. These data
can be obtained free of charge from The Cambridge Crystallographic
Data Center via www.ccdc.cam.ac.uk/data_request/cif.
[3]
For related approaches to pyrrole synthesis see: a) B. C. Milgram, K.
Eskildsen, S. M. Richter, W. R. Scheidt, K. A. Scheidt, J. Org. Chem.
2007, 72, 3941; b) B. A. Trofimov, O. A. Tarasova, A. I. Mikhaleva, N. A.
Kalinina, L. M. Sinegovskaya, J. Henkelmann, Synthesis, 2000, 1585; c)
H.-Y. Wang, D. S. Mueller, R. M. Sachwani, R. Kapadia, H. N. Londino,
L. L. Anderson, J. Org. Chem. 2011, 76, 3203.
[13] DABCO and DBU were also tested as bases for the addition of 4a to 5a
but gave 8a in less than 25% yield. See Supporting Information for an
expanded Table 1.
[14] At longer reaction times and higher temperatures, treatment of 4a with
5a in the presence of K2CO3 gave competing formation of a pyrrolidine.
Formation of 9a or 10a was not observed. See Supporting Information.
[15] See Supporting Information for details.
[4]
[5]
a) N. Takeda, O. Miyata, T. Naito, Eur. J. Org. Chem. 2007, 1491; b) N.
Takeda, M. Ueda, S. Kagehira, H. Komei, N. Tohnai, M. Miyata, T. Naito,
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Shono, O. Miyata, Chem. Eur. J. 2014, 20, 6763.
[16] Treatment of 4a with methyl 2,3-butadienoate favoured formation of a
pyrrolidine. See Supporting Information for details.
For the preparation of O-aryloxime ethers see: a) X.-H.; Feng, G.-Z.
Zhang, C.-Q. Chen, M.-Y. Yang, X.-Y. Xu, G.-S. Huang, Synth. Commun.
2009, 39, 1768; b) P. De, K. Pandurangan, U. Maitra, S. Wailes, Org.
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2010, 132, 9990; e) H. M. Petrassi, K. B. Sharpless, J. W. Kelly, Org. Lett.
2001, 3, 138; f) F. Contiero, K. M. Jones, E. A. Matts, A. Porzelle, N. C.
O. Tomkinson, Synlett 2009, 3003 and reference 4.
[17] See Supporting Information for the conversion of 8a to a pyrrole.
[18] For aza-Petasis-Ferrier rearrangements see: a) M. Terada, Y. Toda, J.
Am. Chem. Soc. 2009, 131, 6354; b) M. Terada, T. Komuro, Y. Toda, T.
Korenaga, J. Am. Chem. Soc. 2014, 136, 7044; c) H. Frauenrath, T.
Arenz, G. Raabe, M. Zorn, Angew. Chem. Int. Ed. 1993, 32, 83.
[19] Formation of 9 or 10 as byproducts was not observed under the reaction
conditions described in Scheme 3 for 4a – 4l. One example of 4 with an
aryl substituent at the β-position was observed to give 9 when treated
with 5a in low yield. See Supporting Information for details.
[6]
[7]
a) A. S. Patil, D.-L. Mo, H.-Y. Wang, D. S. Mueller, L. L. Anderson,
Angew. Chem. Int. Ed. 2012, 51, 7799; b) D.-L. Mo, D. J. Wink, L. L.
Anderson, Org. Lett. 2012, 14, 5180; c) H.-Y. Wang, L. L. Anderson, Org.
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Anderson, Org. Lett. 2013, 15, 4830; e) T. W. Reidl, J. Son, D. J. Wink,
L. L. Anderson, Angew. Chem. Int. Ed. 2017, 56, 11579.
[20] a) Y. Deng, M. V. Yglesias, H. Arman, M. P. Doyle, Angew. Chem. Int.
Ed. 2016, 55, 10108 and references within.
[21] This observation is consistent with the assignment of the minor
diastereomer of 4d and 4h – 4l exhibiting inversion at the hemiaminal
ether stereocenter. Conversion of 8d and 8h to corresponding 9 as single
diastereomers was also observed. See Supporting Information.
[22] a) D. Leboeuf, J. Huang, V. Gandon, A. J. Frontier, Angew. Chem. Int.
Ed. 2011, 50, 10981; b) J. Huang, D. Leboeuf, A. J. Frontier, J. Am.
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For bioactive nucleoside analogues see: a) M. F. Chellat, R. Riedl,
Angew. Chem., Int. Ed. 2017, 56, 13184; b) J. Deval, M. Gotte in Antiviral
Research: Strategies in Antiviral Drug Discovery, (Ed. R. L. LaFemina),
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c) R. Diab, G. Degobert, M. Hamoudeh, C. Dumontet, H. Fessi, Expert
Opin. Drug Deliv. 2007, 4, 513; d) K. Fujiwara, S. Yasui, O. Yokosuka,
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10.1002/anie.201800908
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Jongwoo Son+, Tyler W. Reidl+, Ki Hwan
Kim, Donald J. Wink, and Laura L.
Anderson*
MeO2C
I
K
H
Boc
O
Boc
OTBS
•
N
CO2Me
N
H
O
H
N
Boc
Me
Me
H
CO2Me
Me
Page No. – Page No.
Generation and Rearrangement of
N,O-Dialkenylhydroxylamines for the
Synthesis of 2-
A new approach to the synthesis of 2-aminotetrahydrofurans has been designed
using an N,O-dialkenylhydroxylamine precursor, which undergoes a [3,3]-
rearrangement and cyclization cascade sequence to form the desired heterocycle.
This new route provides diastereoselective access to highly-substituted and
deoxygenated nucleoside analogues with a simple carbamate base from N-Boc-
hydroxylamine, alkenyl iodides, and electron-deficient allenes.
Aminotetrahydrofurans
This article is protected by copyright. All rights reserved.