Intermolecular (4+3) cycloadditions of aziridinyl enolsilanes

Article abstract of DOI:10.1039/c3cc48266a

Upon activation by strong Bronsted acids, aziridinyl enolsilanes undergo (4+3) cycloadditions with dienes to afford aminoalkylated cycloheptenones as products. The use of a highly polar medium such as nitroalkane facilitates high cycloaddition yields of up to 99%. Optically pure aziridinyl enolsilanes react to yield (4+3) cycloadducts with up to 99% ee.

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Intermolecular (4+3) Cycloadditions of Aziridinyl Enolsilanes
Sze Kui Lam, Sarah Lam, Wing-Tak Wong, and Pauline Chiu*
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
First published on the web Xth XXXXXXXXX 200X
DOI: 10.1039/b000000x
5
Under activation by strong Brønsted acids, aziridinyl enolsilanes undergo (4+3) cycloadditions
with dienes to afford aminoalkylated cycloheptenones as products. The use of a highly polar
medium such as nitroalkane facilitates high cycloaddition yields of up to 99%. Optically pure
aziridinyl enolsilanes react to yield (4+3) cycloadducts with up to 99% ee.
10 Functionalized cycloheptanoids are common subunits in
natural products. There is a need for methods to construct
these motifs under mild reaction conditions, and to produce
them in a richly functionalized form with potential for further
stoichiometric amount of acid resulted in incomplete reaction.
We further reasoned that the formation of the protonated
electrophilic intermediate would be promoted by the use of a
polar medium.
The use of propionitrile instead of
elaborations, to address the syntheses of many natural product 55 dichloromethane as solvent indeed resulted in an improved
15 targets, including alkaloids.1
yield (Table 1, entry 2). Nitroethane promoted a significant
enhancement in yield to 86% when used as solvent (Table 1,
entry 3). These results underscored that a polar, nonꢀ
nucleophilic medium facilitates effective cycloadditions of
The (4+3) cycloaddition is an efficient method to prepare
functionalized cycloheptanes, where the classical reaction
generated and employed 2ꢀoxyallyl cations as dienophiles to
undergo [π4+π2] cycloaddition with dienes.2 Strategies to 60 aziridinyl enolsilanes 1.
20 afford optically pure (4+3) cycloadducts3 and novel methods
Table 1. Acidꢀmediated cycloaddition of 1a
to generate allyl cations as the threeꢀcarbon dienophile4 are
topics of ongoing research in this area.
We have reported on the silyl triflateꢀcatalyzed (4+3)
cycloaddition of epoxy enolsilanes reacting as dienophiles.5,6
25 Both interꢀ and intramolecular (4+3) cycloadditions with
cyclic dienes proceeded with facial and diastereoselectivity
with respect to the epoxide stereochemistry to yield
hydroxylated polycyclic ketones as products.
As an extension of this concept, we reasoned that strained
30 rings other than epoxides could display a similar reactivity,
and engender cycloaddition to afford alternatively
functionalized cycloadducts. The importance of alkaloids in
natural product chemistry led us to consider whether
aziridinyl enolsilanes such as 1a could also be similarly
35 activated to yield dienophiles for (4+3) cycloadditions to
afford amineꢀsubstituted cycloheptanones directly.7
Entry Solvent
m
5
5
5
5
5
5
3
1.5
5
Acid (n equiv)
TfOH (1.1)
TfOH (1.1)
TfOH (1.1)
TfOH (1.1)
TfOH (1.1)
TFA (5.0)
TFA (5.0)
TFA (5.0)
TFA (5.0)
TFA (5.0)
TFA (5.0)
TFA (5.0)
Yielda αꢀ4aa:β-4aa
T (°C)
−90
−90
−90
−78
−45
−90
−90
−90
−78
−90
−44
−90
1
2
CH2Cl2
EtCN
56%
68%
86%
80%
68%
99%
92%
84%
95%
99%
ꢀꢀb
60:40
38:62
50:50
52:48
62:38
55:45
57:43
60:40
55:45
50:50
ꢀꢀ
3
4
5
6
7
8
9
10
EtNO2
EtNO2
EtNO2
EtNO2
EtNO2
EtNO2
EtNO2
iꢀPrNO2
5
5
5
11 CF3CH2OH
12 CH2Cl2
27%c
52:48
However, while epoxy enolsilanes 2a yielded readily to
ring cleavage under activation by silyl triflates, aziridinyl
enolsilane 1a was unreactive. This was not surprising, as the
40 SiꢀO bond is much stronger than the SiꢀN bond, and silylation
would be more effective for activation of epoxides than for
aziridines. In fact, we could synthesize 1a from ketone 3a
using TESOTf/Et3N without concomitant decomposition of
the aziridine (Scheme 1).
a Isolated yields; b 92% yield of 3a isolated; c 72% yield of 3a isolated.
It was also observed, however, that the strongly acidic
65 reaction conditions induced polymerization that consumed the
furan, and thus an excess of the diene was required for good
cycloaddition yields. We then explored whether acids weaker
than TfOH (pKa −14.9) could promote the same cycloaddition
with less detrimental polymerization.
After some
70 investigations, we found that TFA (pKa +0.3) was a suitable
acid. In the presence of 5 equivalents of TFA and using
nitroethane as solvent, a near quantitative yield of 4aa was
obtained (Table 1, entry 6). The diene could be reduced from
a 5.0 equivalent excess to 1.5 equivalents and still afford an
75 84% yield of cycloadducts, due to decreased polymerization
and consumption of the diene under these conditions (Table 1,
entries 7ꢀ8). Increasing the temperature to −78 °C resulted in
a slightly diminished yield but further warming resulted in
deleterious effects (Table 1, entries 3ꢀ5, 9). Nitroalkanes are
45
Scheme 1. Synthesis of aziridinyl enolsilanes.
Ultimately, we found that 1a could be induced to undergo
(4+3) cycloaddition by activation with
a stoichiometric
amount of TfOH, to afford a moderate yield of the endo and
50 exoꢀcycloadducts αꢀ4aa and βꢀ4aa (Table 1, entry 1).8 A subꢀ
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good solvents, but trifluoroethanol did not promote the
desired reaction to any extent (Table 1, entries 10ꢀ11). Using
TFA in dichloromethane resulted in mainly desilylation
instead of cycloaddition (Table 1, entry 12).
substituents at C1, C2 and C4 of the enol ether (Figure 1).
Table 3. (4+3) Cycloadditions of 1h-m
Entry 1
Diene
Cycloadducts
Yielda (dr)
5
With the optimized reaction conditions in hand, we
explored the scope of aziridinyl enolsilanes 1 and dienes for
the (4+3) cycloaddition. A range of sulfonylated aziridines
1a-d were found to engage in cycloaddition, where increasing
the steric bulkiness of sulfonyl group resulted in a slight
1
2
3
1h
CpH
56% (60:40)b
X=CH2; αꢀ4hb X=CH2; βꢀ4hb
10 decrease in the yield, but without any significant impact on
the cycloadduct endo/exo ratios (Table 2, entries 1ꢀ6).
1i
1j
CpH
CpH
99% (60: 40)c
86% (65:35)c
X=CH2; αꢀ4ib X=CH2; βꢀ4ib
Table 2. Scope of the TFAꢀmediated (4+3) cycloaddition of 1a-g
X=CH2; αꢀ4jb
X=O; αꢀ4ka
X=O; βꢀ4jb
X=O; βꢀ4ka
Entry
1
Diene
Yielda
α:β
R′
H
Me
H
H
H
H
H
H
H
H
H
H
H
X
1
2
3
4
5
6
7
8
9
10
11
12
13
1a, P= Ts
CH2
O
(CH2)2
O
4ab, 93%
4ac, 25% b
4ad, 63%c
4ba, 94%
4ca, 85%
4da, 84%
4ea, 53%d
4eb, 75%d
4ee, 69%d
4fa, 54%d
4fb, 79%d
4ga, 39%d
4gb, 72%d
54:46
79:21
41:59
52:48
57:43
57:43
53:47
59:41
83:17
51:49
58:42
49:51
58:42
4
5
1k
1k
Furan
CpH
94% (87:13)
68% (47:53)
1a
1a
X=CH2; αꢀ4kb X=CH2; βꢀ4kb
1b, P= Ms
1c, P= MesSO2
1d, P= Trisyl
1e, P= Boc
1e
O
O
O
CH2
(CH2)2C
O
CH2
O
6
7
1k 2ꢀMeꢀfuran
36% (87:13)
74% (51:49)
αꢀ4kf
αꢀ4lb
βꢀ5kf
βꢀ4lb
1e
1f, P= CBz
1f
1g, P= Piv
1g
CH2
1l
CpH
a Isolated yields; b 11% alkylated furan also obtained; c Isolated and
15 methylated for separation, see SI; d Reaction promoted by 1.2 equiv. TFA.
Notably, we also found that aziridines protected by Boc
(1e), CBz (1f) and Piv (1g) not only underwent reaction with
acceptable yields and without concomitant deprotection, their
cycloadditions were promoted without the need for a large
20 excess of acid (Table 2, entries 7ꢀ13). For example, the
treatment of 1e with 1.2 equivalents of TFA and
cyclopentadiene in nitroethane afforded a 75% yield of
cycloadducts 4eb, whereas the reaction of 1a was largely
incomplete under the same conditions. This can be attributed
25 to the higher basicity of the aziridine protected as a carbamate
or an amide, and hence are more effectively protonated and
8
9
1m
1m
Furan
CpH
71% (93:7)
72% (50:50)
αꢀ4ma
αꢀ4mb
βꢀ4ma
βꢀ4mb
aIsolated yields; b5% epiꢀ4hb also obtained; cReaction with1.2 equiv. TFA
All of aziridinyl enolsilanes yielded to cycloaddition under
40 treatment with TFA, and most proceeded with good to
excellent yields. Two diastereomeric cycloadducts from endo
and exo modes of cycloaddition are generally obtained.
Although many of the reactions showed no particular
diastereoselectivity, a higher preference for endo product was
activated compared with a sulfonamide. However, 1 in which 45 observed in the cycloadditions of substituted enolsilanes 1k
and 1m, where the dr was as high as 93:7 (Table 3, entries 4ꢀ
6,8ꢀ9). This might be explained by steric preferences in the
reactions of hindered substrates, as found previously for
epoxides as well.5 On the other hand, in analogy to the
50 possible dienophiles in the corresponding reactions of the
epoxy enolsilanes (Figure 2),6 cycloaddition via the
P= Bn did not yield to cycloaddition. The scope of the dienes
that underwent cycloaddition included cyclopentadiene,
30 spirocyclopentadiene, cyclohexadiene, as well as substituted
furans.
intermediacy of
a
softer, more oxyallyl cationꢀlike
intermediate C3 in the continuum, rather than through a hard,
electrophilic intermediate such as C1, could also explain the
55 higher endo selectivity. This would be consistent with the
observation that significant endo selectivity was found only in
the cycloadditions with furan, but not with cyclopentadiene
(Table 3, entries 4 vs. 5, 8 vs 9), for which the minimization
Figure 1. Substituted aziridinyl enolsilanes investigated
We also prepared and studied the cycloadditions of
35 aziridinyl enolsilanes 1h-m to examine the effects of
2
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of the dipoles of the oxyallyl cation and furan in the transition 35 Therefore the cycloadditions of 1m probably proceeded
state has been proposed as the rationale for endo selectivity.
through an intermediate with significant oxyallyl cation
character, favoured due to additional substituents that stabilize
C3 (Figure 2, R= Me). The endo selectivity was also a result
of a more C3ꢀlike intermediate engaging in cycloaddition with
40 furan.
5
Figure 2. Possible dienophiles in the (4+3) cycloaddition
To differentiate between these explanations, and coinciding
with the next stage of our program aimed at procuring
optically enriched cycloadducts, we examined the
Scheme 4. Cycloaddition of (ꢀ)ꢀ1m
We have shown for the first time that, promoted by
Brønsted acid in nitroethane as solvent, aziridinyl enolsilanes
45 react as dienophiles in the (4+3) cycloaddition with dienes, to
directly afford amineꢀsubstituted cycloadducts with yields up
to 99%. Enantiomericallyꢀenriched cycloadducts of up to
99% ee could be obtained from optically enriched aziridinyl
enolsilanes. Our efforts to understand the mechanism of the
50 cycloaddition by experiment and computations, and to apply
these cycloadditions to obtain chiral intermediates for the
synthesis of bioactive alkaloids will be reported in due course.
We thank the Research Grants Council of Hong Kong SAR
(GRF HKU 7015/10P), the State Key Laboratory of Synthetic
55 Chemistry, and the HKU Small Project Funding for support.
cycloadditions of enantiomerically pure 1.
These
10 enantiomerically enriched aziridines were synthesized from
optically pure serine.†
NHP
NHP
OTES
Furan, TFA (1.2 equiv)
EtNO2, -90 °C
O
O
+
O
O
NP
( )-1e, P= Boc, 99% ee
( )-1f, P= CBz, 99% ee
( )-1g, P= Piv, 99% ee
-4ea, 78% ee
-4fa, 84% ee
-4ga, 82% ee
-4ea, 98% ee
-4fa, 93% ee
-4ga, 99% ee
53% yield, 53:47
54% yield, 51:49
39% yield, 49:51
NHP
NHP
OTES
CpH, TFA (1.2 equiv)
EtNO2, -90 °C
+
O
O
NP
-4eb, 99% ee
-4fb, 98% ee
-4gb, 99% ee
( )-1e, P= Boc, 99% ee
( )-1f, P= CBz, 99% ee
( )-1g, P= Piv, 99% ee
-4eb, 98% ee
-4fb
, 98% ee
-4gb, 99% ee
75% yield, 59:41
79% yield, 58:42
72% yield, 58:48
Notes and references
a Department of Chemistry and State Key Laboratory of Synthetic
Chemistry, The University of Hong Kong, Pokfulam Rd., Hong Kong, PR
China. Fax: 852-28571586; Tel: 852-28598949; E-mail: pchiu@hku.hk
60 † Electronic Supplementary Information (ESI) available: Experimental
procedures and full characterization of all new compounds. See
DOI: 10.1039/b000000x/
Scheme 2. Cycloadditions of (ꢀ)ꢀ1e-g
Indeed the cycloadditions of 1e-g with either furan or
15 cyclopentadiene generated optically enriched cycloadducts
with up to 99% ee (Scheme 2), confirming the mechanism of
this cycloaddition as proceeding through intermediates C1 or
C2 with retention of stereochemical information, and not
through the classical and necessarily achiral oxyallyl cations
20 C3 (Figure 2, R= H). Therefore this aziridinyl enolsilane
(4+3) cycloaddition constitutes a method to secure optically
enriched, amineꢀsubstituted oxabicyclic and carbobicyclic
ketones for asymmetric synthesis.
The (4+3) cycloadditions with furan were consistently
25 lower in ee than with cyclopentadiene. This could be because
furan is a less reactive diene and could not intercept C1 or C2
as effectively as cyclopentadiene. The enantiomeric excess
can be partially recovered, however, by the use of a less polar
1
M. A. Battiste, P. M. Pelphrey and D. L. Wright, Chem. Eur. J. 2006,
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70
75
80
85
90
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Selected reviews: H. M. R. Hoffmann, Angew. Chem. Int. Ed. 1984,
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3
4
medium than nitroethane (Scheme 3).
The absolute
30 stereochemistry of (−)ꢀβꢀ4aa was confirmed by xꢀray.9
5
6
7
2ꢀMethyleneaziridines have been used in (4+3) cycloadditions: G.
Prié, N. Prévost, H. Twin, S. A. Fernandes, J. F. Hayes and M.
Shipman, Angew. Chem., Int. Ed. 2004, 43, 6517.
Cu(OTf)2, La(OTf)3, Sc(OTf)3, Yb(OTf)3, and Zn(OTf)2 all failed to
induce (4+3) cycloaddition.
Scheme 3. Cycloadditions of (+)ꢀ1a
8
9
The cycloaddition of scalemic 1m, however, produced
cycloadducts 4ma and 4mb with almost no optical activity.
Crystal data for (−)ꢀβꢀ4aa: C15H17NO4S, Mw=307.36, Orthorhombic,
space group P 212121 (#19), a = 5.0949 (2) Å, b = 12.0655 (4) Å, c =
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24.2090 (7) Å, β = 90.00°, V = 1488.19 (9) Å3, Z = 4, Dx = 1.372
Mg mꢀ3, ꢁ(Mo Kα)= 0.23 mmꢀ1, F(000)= 648, T=296 K; crystal
dimensions: 0.16 mm × 0.18 mm × 0.36 mm. Of the 11344
reflections that were collected, 2616 reflections were unique. (Rint =
0.0336); equivalent reflections were merged. All nonꢀH atoms were
refined anisotropically. R1 = 0.034, wR2 = 0.077. Crystallographic
data for (−)ꢀβꢀ4aa have been deposited at the Cambridge
Crystallographic Data Center, CCDC 976137.
5
4
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