Catalytic asymmetric alkylation reactions for the construction of protected ethylene-amino and propylene-amino motifs attached to quaternary stereocentres

Article abstract of DOI:10.1002/chem.201203825

An efficient catalytic and stereoselective method for the direct construction of protected ethylene-amino and propylene-amino scaffolds attached to quaternary stereocentres is reported. Preliminary investigations revealed a mild base catalysed nucleophilic ring opening of N-sulfonyl aziridines using the commercially available phosphazene base 2-tert-butylimino-2-diethylamino-1,3- dimethyl-perhydro-1,3,2-diazaphosphorine (BEMP) was possible and resulted in highly efficient alkylation reactions with a range of methine carbon acids. This reaction could be rendered highly asymmetric (up to 97 % ee) by employing phase-transfer catalysis to control stereoinduction. Incorporation of alkyl substituents onto the aziridine electrophile, resulted in a highly diastereoselective (up to 30:1 d.r.) variant of this methodology. A further extension using N-protected cyclic sulfamidates as the electrophilic component was successful with a range of pro-nucleophiles (up to 96 % ee and 45:1 d.r.) and allowed a range of nitrogen protecting groups (carbamate, sulfonyl, phosphonyl, benzyl) to be incorporated into the alkylation adducts. Finally, the utility of the products have been demonstrated in the synthesis of useful heterocycles and compounds bearing structural components of natural products. Open sesame: The enantio- and diastereoselective nucleophilic ring opening of protected aziridines and cyclic sulfamidates using asymmetric phase-transfer catalysis (PTC) is reported. The ring-opening alkylation reactions create quaternary chiral centres containing ethylene- and propylene-amino motifs in good yields with good to excellent enantioselectivities (see scheme). These reactions are broad in scope and a wide range of pro-nucleophiles are tolerated. Copyright

Full text of DOI:10.1002/chem.201203825

FULL PAPER
DOI: 10.1002/chem.201203825
Catalytic Asymmetric Alkylation Reactions for the Construction of Protected
Ethylene-Amino and ACHTNUGRTENUNGPropylene-Amino Motifs Attached to
Quaternary Stereocentres
Thomas A. Moss,[a] David M. Barber,[b] Andrew F. Kyle,[b] and Darren J. Dixon*[b]
Abstract: An efficient catalytic and
stereoselective method for the direct
construction of protected ethylene-
amino and propylene-amino scaffolds
attached to quaternary stereocentres is
reported. Preliminary investigations re-
vealed a mild base catalysed nucleo-
philic ring opening of N-sulfonyl aziri-
dines using the commercially available
phosphazene base 2-tert-butylimino-2-
diethylamino-1,3-dimethyl-perhydro-
1,3,2-diazaphosphorine (BEMP) was
possible and resulted in highly efficient
alkylation reactions with a range of
methine carbon acids. This reaction
could be rendered highly asymmetric
(up to 97% ee) by employing phase-
transfer catalysis to control stereoin-
duction. Incorporation of alkyl sub-
stituents onto the aziridine electro-
phile, resulted in a highly diastereose-
lective (up to 30:1 d.r.) variant of this
using N-protected cyclic sulfamidates
as the electrophilic component was suc-
cessful with a range of pro-nucleophiles
(up to 96% ee and 45:1 d.r.) and al-
lowed a range of nitrogen protecting
groups (carbamate, sulfonyl, phospho-
AHCTUNGTRENNnGUN yl, benzyl) to be incorporated into the
alkylation adducts. Finally, the utility of
the products have been demonstrated
in the synthesis of useful heterocycles
and compounds bearing structural com-
ponents of natural products.
methodology.
A
further extension
Keywords: alkylation · asymmetric
synthesis · aziridines · phase-trans-
fer catalysis · sulfamidates
Introduction
been significant with highly enantioselective examples
known in both cases.[3,4] The impressive bioactivities of
many of these compounds encouraged us to investigate a
synthetic strategy that was simple in concept but broad in
applicability. We recognised a synthetically powerful route
to these compounds could involve a catalytic, and potential-
ly enantioselective alkylation reaction of a carbon acid with
a protected amino ethylene synthon, such as an N-protected
aziridine.[5] Furthermore, such a reaction would install di-
rectly a protected amino group and allow g-substituents to
be incorporated into the produced g-amino acid backbone.
Compounds containing the ethylene-amino and propylene-
amino group attached to a stereogenic quaternary carbon[1]
are widespread amongst natural products (Figure 1), and
Figure 1. Natural products containing the ethylene-amino and propylene-
amino scaffolds bonded to a quaternary carbon.
Results and Discussion
form the basis of potential building blocks for g-peptides
and foldamer chemistry.[2] Despite its prevalence, there is a
dearth of methods to introduce this important structural
motif catalytically and asymmetrically. To this end, develop-
ments in the field of enantioselective Michael additions of
carbonyl compounds to nitro-olefins and acrylonitriles have
Base catalysed alkylation using aziridines: Our synthetic
strategy (Scheme 1) required the base catalysed addition of
various pro-nucleophiles 1 to a suitably protected form of
aziridine 2. The proposed alkylation reaction would afford
the desired products 3 in a quick and efficient manner,
whilst also using relatively simple starting materials. N-Sub-
stituted aziridines have previously been employed as mildly
electrophilic reagents for the homologation of a range of
carbon and heteroatom nucleophiles. Their simple synthesis
[a] Dr. T. A. Moss
School of Chemistry, University of Manchester
Oxford Road, Manchester, M13 9PL (UK)
[b] D. M. Barber, A. F. Kyle, Prof. Dr. D. J. Dixon
Chemistry Research Laboratory, Department of Chemistry
University of Oxford, Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: darren.dixon@chem.ox.ac.uk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203825.
Scheme 1. Concept of a catalysed aziridine ring opening reaction.
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Table 1. Preliminary studies into a base catalysed alkylation of ethyl
AHCTUNGERTGpNNUN henylcyanoacetate 1a.
from readily available and inexpensive commercial materi-
als,[6] as well as their ease of handling makes them important
synthetic building blocks. Due to their modest reactivity,
and ability to polymerise under certain reaction conditions,
the synthetic community has focused on using harsh re-
agents when using aziridine electrophiles. These include stoi-
chiometric amounts of organometallics or reactive metal
enolates when employing a carbon-centred nucleophile. Ex-
ceptionally little attention has been dedicated to finding
mild and catalytic conditions for the ring opening of protect-
ed aziridine precursors.[7,8] It should be noted that until this
study, there were no reports of using carbon acids under
base catalysed conditions to facilitate the ring opening of
aziridines, enantioselective or otherwise.[5]
Entry[a]
PG
Base
t
Product
Yield
[%][b]
[h]
1
2
3
4
5
6
7
8
p-tosyl (2a)
p-tosyl (2a)
p-tosyl (2a)
SO2Mes (2b)
Cbz (2c)
DABCO
TMG
72
36
19
24
672
24
3a
3a
3a
3b
3c
–
69
83
93
98
BEMP
BEMP
BEMP
BEMP
BEMP
BEMP
For the proposed reaction to be catalytic in base, the reac-
tivity of the aziridine electrophile and the pKa values of all
the reaction components is critical; following the union of
aziridine 2 with carbanion 4, the resulting adduct 5 must be
basic enough to deprotonate another molecule of pro-nu-
83
p-nosyl (2d)
0[c,d]
0[d]
0[e]
PO
N
168
1
–
–
o-CF3C6H4SO2 (2 f)
[a] Reactions were performed on a 0.36 mmol scale in THF (0.8 mL) at
258C. [b] Isolated yield after purification. [c] Aziridine 2d was insoluble
in THF at 258C. [d] No reaction occurred. [e] Polymeric products were
obtained.
ACHTUNGTRENNUNGcleoACHTUNGTRENNUNGphile 1, thus completing the catalytic cycle (Scheme 2).
more basic phosphazene reagent BEMP (2-tert-butylimino-
2-diethylACTHNUTRGNEaUNG mino-1,3-dimethyl-perhydro-1,3,2-diazaphosphor-
ine)[9] led to almost quantitative formation of product 3a in
19 h at 258C (Table 1, entry 3). N-p-Nosyl aziridine (2d) was
found to have poor solubility whilst N-diethylphosphonate
aziridine (2e) was unreactive under our conditions; both
gave no observable alkylation products. Interestingly, when
the o-(trifluoromethyl)benzenesulfonyl aziridine (2 f) was
used as the electrophile under base catalysed conditions,
only poACTHNUGRTNENUGlymHCATUNGTRENNeNGU risation products were obtained (Table 1,
entry 8). The various reaction pathways presented in
Scheme 2 can rationalise this observation. If the ring opened
adduct 5 is reasonably stable (as one could envisage due to
the ortho placement of the trifluoromethyl group on the ar-
ylsulfonyl protecting group), then proton transfer between
adduct 5 and the parent acid 1 is disrupted, thus allowing
the polymerisation of the aziridine to become the dominant
reaction pathway. Successful alkylation using the carbamate
protected aziridine 2c was observed, however, the reaction
was prohibitively slow (Table 1, entry 5). Despite the long
reaction time, no significant polymerisation of aziridine 2c
was observed, this suggests that proton transfer in the cata-
lytic cycle was fast, the lethargic reaction presumably being
caused by the weaker inductive activation of the carbamate
protected aziridine in comparison to its sulfonyl analogues.
The reaction efficiency was further enhanced when N-mesi-
tylsulfonyl aziridine (2b) was employed (Table 1, entry 4),
possibly due to a suppression of the aziridine polymerisation
pathway through steric effects. Overall, the optimal condi-
tions employed aziridine 2b (1 equiv), pro-nucleophile 1a
(2 equiv) with BEMP (10 mol%) in THF at 258C.
Scheme 2. Initiation, propagation and polymerisation pathways in the
base catalysed alkylation of carbon acids with aziridine electrophiles.
As adduct 5 is also nucleophilic at the nitrogen atom, the
equiACHTUNGTRENNUNGlibACHTUNGTRENNUNGrium must favour carbanion 4 to suppress the possi-
ble polymerisation pathway of aziridine 2. We postulated
that by careful choice of aziridine N-protecting group, pro-
nucleophile and base catalyst, a mild aziridine alkylation re-
action would be possible using base catalysis. Preliminary
studies using a range of N-sulfonyl aziridines (2a–f) with
ethyl phenACHTUNGTRENNUNGylcyanoacetate 1a as a representative pro-nucleo-
phile were performed to assess the feasibility of our concept
(Table 1). Using catalytic DABCO, the alkylation adduct 3a
was furnished in an encouraging 69% yield, but only after
72 h at 258C (Table 1, entry 1). To address the need for
higher reactivity, we screened more basic catalytic systems.
TMG afforded the product in an improved yield and short-
ened reaction time (Table 1, entry 2). Employing the even
With the optimal conditions in hand, the scope of the azir-
idine alkylation reaction was probed by modifying the pro-
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Protected Ethylene- and Propylene-Amino Motifs
FULL PAPER
nucleophile coupling partner. A range of carbonyl com-
pounds 1b–n including esters, lactams, acetates and nitriles,
in addition to cyanoacetates, amides and oxindoles were
screened. Pleasingly, the nature of the electron withdrawing
substituent had little bearing on the reaction, with acetates,
amides, nitriles and a range of esters all reacting efficiently
(Scheme 3). Yields ranged from 73–99% and in many cases
Scheme 4. Manipulation of alkylation adducts 3d and 3b.
two-step process; first by reduction of 3d to the correspond-
ing diol 7a, which was then transformed into the N-protect-
ed spiro adduct 7b (d.r. 2:1) by a one-pot tosylation/cyclisa-
tion reaction. Cyclisation of acyclic adducts was somewhat
more facile; treatment of cyanoacetate 3b with LiHMDS re-
sulted in smooth cyclisation onto the nitrile affording func-
tionalised amidine 9 in good yield.
Sulfonamide protecting groups are notoriously difficult to
cleave, but as sulfonyl protection was necessary for accepta-
ble levels of reactivity, we began investigations into its cleav-
age under non-destructive conditions. Of the various meth-
ods reported,[10] we found the trifluoroacetamide exchange
protocol of Moussa and Romo to be the most productive
(Scheme 4). Subjection of adducts 3b and 3d to a one-pot
activation/cleavage reaction using TFAA and SmI2,[11] result-
ed in smooth substitution of the sulfonamide protecting
group to the synthetically useful trifluoroacetamide protect-
ed compounds 8a and 8b in good yields (74 and 73%, re-
spectively).
Enantioselective alkylation using aziridines: The construc-
tion of enantioenriched g-amino butyric acid derivatives
through the nucleophilic ring opening of aziridines is a
barely explored field,[5] and thus with parameters for a base
catalysed reaction established,[12] we next sought to develop
an asymmetric variant of our methodology. Preliminary
studies were conducted using N-mesitylsulfonyl aziridine
(2b) and tert-butyl indanone carboxylate 1k as a representa-
tive pro-nucleophile (Table 2). Initially, we screened for ac-
tivity in the alkylation reaction using the bifunctional cin-
chona derived catalysts 10a and 10b (Table 2, entries 1 and
2).[13] Pleasingly, at room temperature, using CH2Cl2 as sol-
vent, both catalysts 10a and 10b were observed to afford
the desired adduct 3h. However, the reactions were found
to be prohibitively slow with only 15% conversion (Table 2,
entry 1) and 10% conversion (Table 2, entry 2) after 48 h.
The alkylation adducts were also obtained in low enantiose-
lectivity (10 and 6% ee, respectively). This led us to con-
clude that aziridines bearing a N-sulfonyl protecting group
were unsuitable electrophiles for use with the bifunctional
organocatalysts 10a and 10b. In an attempt to enhance the
reactivity of the alkylation reaction, we screened a variety
of bases in conjunction with a selection of phase-transfer
catalysts (10c–f).[14–17] Initially, pro-nucleophile 1k was treat-
ed with aziridine 2b using 10 mol% of phase-transfer cata-
Scheme 3. Base catalysed alkylation reactions with N-sulfonyl aziridines
2a and 2b. Reactions were performed on a 0.36 mmol scale in THF
(0.8 mL) at 258C. Isolated yield after purification. [a] Reaction was per-
formed at 658C. [b] 23% Oxygen-alkylation product was isolated.
were quantitative, with the exception of 3k (44%); in this
case appreciable oxygen-alkylation was also observed when
conducting the reaction at 658C. Pleasingly, oxindole nu-
ACHTUNGTRENNUNGcleoACHTUNGTRENNUNGphiles reacted efficiently furnishing the product 3p in
98% yield. Other reactive functional groups, such as the
indole substituted 3q, did not affect the chemical yield
(91%).
With the scope of the reaction established, the synthetic
potential of the alkylation products was investigated
(Scheme 4). Firstly, adducts 3d and 3b were synthesised on
gram scale with no reduction in chemical yield. Direct lac-
tamisation of cyclic derivatives, such as 3d, proved to be
challenging, however, azaspirocycles could be accessed in a
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D. J. Dixon et al.
Table 2. Preliminary studies into the enantioselective alkylation of tert-
butyl indanone carboxylate 1k with aziridine electrophiles.
ed aziridines, they do not suffer from low solubility and are
stable at room temperature, whereas more reactive systems
such as N-triflimide aziridines are known to be susceptible
to self-polymerisation. In a screen of various cinchona alka-
loid-derived phase-transfer catalysts (10c–f; Table 2, entries
5–8), 10 f bearing the bulky adamantoyl ester was found to
be the most selective affording the alkylation adduct 3r in
good yield, and in 94% ee when the reaction was conducted
at 08C with 50% aq. Cs2CO3 as the base. A slight increase
in the selectivity of the alkylation was observed by cooling
the reaction mixture to À208C (95% ee; Table 2, entry 9). A
further enhancement of stereocontrol was found when using
a milder 50% aq. K2HPO4 solution as the base (97% ee;
Table 2, entry 10). Conversely, when the more strongly basic
50% aq. K3PO4 solution was used, reduced reaction times
but diminished enantioselectivity was observed (86% ee;
Table 2, entry 11).
With optimal conditions in hand, the scope of the reaction
was then probed (Scheme 5). A range of substituted inda-
none pro-nucleophiles bearing bulky ester moieties were
Entry[a] Aziridine Cat. Conditions[b]
Conv.[c] ee [%][d]
1
2
3
4
5
6
7
8
2b
2b
2b
2b
2 f
2 f
2 f
2 f
2 f
2 f
2 f
10a RT, CH2Cl2
10b RT, CH2Cl2
15
10
100
35
100
80
100
100
10
6
10 f BEMP (10 mol%), RT
10 f 50% aq. Cs2CO3, RT
10c 50% aq. Cs2CO3, 08C
10d 50% aq. Cs2CO3, 08C
10e 50% aq. Cs2CO3, 08C
10 f 50% aq. Cs2CO3, 08C
33
91
24
21
51
94
95
97
86
9
10
11
10 f 50% aq. Cs2CO3, À208C 100
10 f 50% aq. K2HPO4, À208C 100[e]
10 f 50% aq. K3PO4, À208C
100
[a] Reactions were performed on a 0.13 mmol scale. [b] Entries 4–11
were performed with base (1.5 equiv) and catalyst (10 mol%) in toluene/
1
CHCl3 (9:1, 1.0 mL). [c] Determined by H NMR spectroscopy after 48 h.
[d] Determined by HPLC analysis. [e] Conversion after 72 h.
lyst 10 f[18] in the presence of 10 mol% BEMP,[17] and inda-
none adduct 3h was afforded in an encouraging 33% ee
(Table 2, entry 3). Anticipating a prevalent background reac-
tion using the strongly basic BEMP, we opted to use the
more mildly basic Cs2CO3 as a 50% aq. solution. Gratifying-
ly, the alkylation reaction was found to have excellent ster-
eocontrol, forming adduct 3h in 91% ee (Table 2, entry 4),
although the reaction was slow (35% conversion after
2 days).
The ability to tune the reactivity of the electrophilic aziri-
dine motif by judicious choice of the N-protecting group
adds to the versatility of aziridine chemistry. By modifying
the mesityl protected aziridine 2b to the o-(trifluoromethyl)
benzenesulfonyl substituted aziridine 2 f, a dramatic increase
in reactivity was observed, with complete conversion to al-
kylation adduct 3r in 48 h at 08C whilst also exhibiting ex-
cellent enantioselectivity (94% ee; Table 2, entry 8). The o-
(trifluoromethyl)benzenesulfonyl protecting group offers
significant advantages over other sulfonamide groups com-
monly employed to protect aziridines. These 2-carbon elec-
trophiles are highly reactive compared to N-p-tosyl protect-
Scheme 5. Enantioselective ring opening of unsubstituted aziridines with
phase-transfer catalyst 10 f. Reactions were performed on a 0.13 mmol
scale in toluene/CHCl3 (9:1, 1 mL) at À208C. Isolated yield after purifi-
cation. Enantiomeric excess was determined by HPLC analysis. [a] For
deprotection of 3r, see the Supporting Information. [b] Reaction was per-
formed at 08C using 50% aq. Cs2CO3 as the base.
subjected to the alkylation conditions, with high enantiose-
lectivities and good yields being obtained in all cases (91–
97% ee; 3r–u). The indanone pro-nucleophile could easily
tolerate both electron-withdrawing (3s, 85%, 97% ee) and
electron-donating (3t, 85%, 95% ee) substituents on the ar-
omatic ring. The tert-butyl ester group could also be ex-
changed for the bulky adamantly group with only a small
decrease in enantioselectivity. tert-Butyl cyclopentanone car-
boxylate was also found to be a good substrate leading to
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Protected Ethylene- and Propylene-Amino Motifs
FULL PAPER
the alkylated product 3v in good yield and enantiomeric
excess (78%, 82% ee) when using 50% aq. Cs2CO3 at 08C.
In order to determine the absolute stereochemistry imparted
by phase-transfer catalyst 10 f, the reaction between tert-
butyl indanone carboxylate 1k and aziridine 2 f was scaled
up and the product 3r recrystallised (>99% ee). Single crys-
tal X-ray analysis revealed the absolute stereochemistry of
3r to be S, which was consistent with the stereochemical
outcomes for related systems (Figure 2).[18] Accordingly, the
related indanone structures 3s–u and cyclopentanone
adduct 3v were assigned by analogy assuming the presence
of a bulky tert-butyl ester was the major factor in governing
the facial selectivity.
Scheme 6. Proposed origin of stereoselectivity through a catalyst control-
led matched and mis-matched pathway. Reactions were performed on a
0.25 mmol scale in toluene/CHCl3 (9:1, 2 mL) at 08C. Isolated yield after
purification. Yield based on 2 f.
er, attempts to synthesise even more reactive electrophiles,
such as 2g, led to problems of dimerisation in the aziridine
formation step (Scheme 7). Anticipating that dimerisation
occurred via aziridine formation, we reasoned that if a suita-
Figure 2. Absolute stereochemistry of 3r determined to be S by single
crystal X-ray crystallography (see the Supporting Information).
To extend this methodology, a pro-nucleophile bearing an
additional stereocentre was employed in the alkylation reac-
tion (Scheme 6). Due to the presence of the extra stereocen-
tre in the pro-nucleophile, effective molecular recognition
was observed. Using an excess (4 equiv) of racemic tert-
butyl 3-phenylindanone-2-carboxylate (1r) as the pro-nu-
Scheme 7. In situ aziridine formation/nucleophilic trapping.
ACHTUNGTRENNUNGcleoACHTUNGTRENNUNGphile, predominantly one enantiomer was reactive
toward 2 f and resulted in the efficient production of 3w in
high enantioselectivity (92% ee) as a single diastereoisomer.
We propose that a high level of substrate control directs ad-
dition of the aziridine electrophile to the face of the enolate
opposite to the phenyl group.[19] When a chiral catalyst (Q*+
ClÀ) is employed, the diastereofacial selectivity arising from
the substrate can be matched or mis-matched to the enolate–
catalyst ion pair formed. In the matched case alkylation is
fast; in the mis-matched case the alkylation is blocked by
the bulky phenyl group and is significantly slower. As for-
mation of the ammonium enolate ion pair is reversible, one
enantiomer of the nucleophile is more reactive than the
other, affording the alkylation product in high diastereo-
and enantioselectivity.
ble aziridine precursor 11 was used as the electrophile,
forming the reactive aziridine 2g in situ, and trapping with a
pro-nucleophile could give the alkylation adduct without the
need to isolate the aziridine electrophile. Pleasingly, this was
indeed found to be the case, treatment of tert-butyl inda-
none carboxylate 1k with 11 and catalyst 10 f (10 mol%) led
to the formation of the alkylation adduct 3x in high enantio-
selectivity (93% ee) but in poor yield due to the formation
of dimer 12.
Nucleophilic ring opening of aziridines is generally regio-
selective towards the less hindered carbon of the aziridine.
Thus, if suitably substituted chiral aziridines were used as
electrophiles, product substitution patterns could be ob-
tained that would not normally be accessible by the com-
monly employed b-substituted nitro-olefin Michael reac-
tions.[3,4] Furthermore, we envisaged that if the chiral elec-
Although activated aziridine 2 f proved to be a suitable
electrophile for reactive indanone and cyclopentanone sys-
tems, the reaction turnover was poor in other cases. Howev-
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D. J. Dixon et al.
trophiles themselves imparted a degree of substrate control-
led diastereoselectivity, finding matched pairs of electro-
phile/phase-transfer catalyst could result in higher diastereo-
selectivities in the products than might be expected from the
enantioselective reaction with the same pro-nucleophile.[20]
In an initial proof-of-concept, indanone 1k was treated with
N-p-nosyl aziridines bearing both small (13a, PG=p-Ns,
R4 =Me, R5 =H) and bulky (13b, PG=p-Ns, R4 =iPr, R5 =
H; 13c, PG=p-Ns, R4 =H, R5 =iPr; 13d, PG=Tf, R4 =iPr,
R5 =H) substituents, with solid Cs2CO3 and 10 mol% of
phase-transfer catalyst 10 f (Scheme 8). Pleasingly, we were
N-p-Nosyl substituted sulfonamides can be readily cleaved
under mildly nucleophilic conditions.[21] Alkylation adduct
14b was treated with thiophenol and K2CO3, which under-
went smooth desulfonylation at room temperature, followed
by intramolecular condensation to give tricyclic imine 15 in
high yield (Scheme 9). We reasoned that as the deprotection
Scheme 9. One-pot alkylation/cyclisation sequences for the synthesis of
functionalised cyclic imines and spiro-lactams.
proceeds with weak inorganic bases, this process could be
telescoped with the alkylation process, thus circumventing
the purification of the alkylation intermediate. Accordingly
we synthesised heterocyclic compound 15 in a one-pot se-
quence from the corresponding pro-nucleophile 1k by an in-
itial alkylation with 13b followed by addition of thiophenol.
Pleasingly the overall yield was comparable to the two-step
process. Although direct lactamisation onto esters was chal-
lenging in cyclic examples, this incompatibility could be
overcome by activating the nucleophile as the hexafluoroiso-
propyl ester. Treatment of activated cyclopentanone pro-nu-
cleophile 1u with aziridine 13d and catalyst 10 f resulted in
rapid and irreversible intramolecular lactamisation following
initial diastereoselective alkylation, giving the spiro-lactam
16 in moderate yield but in good diastereomeric ratio.
Scheme 8. Diastereoselective ring opening of chiral aziridines 13a–d with
phase-transfer catalyst 10 f. Reactions were performed on a 0.25 mmol
scale in toluene/CHCl3 (9:1, 1 mL) at 08C. Isolated yield after purifica-
tion. Diastereomeric ratio was determined by 1H NMR spectroscopy of
the crude product. [a] Reaction performed at 258C. [b] Product obtained
in d.r. 2:1 when 10 f was replaced with TBAB (10 mol%). [c] Relative
stereochemistry of 14c was determined by single crystal X-ray crystallog-
raphy (see the Supporting Information).
Enantioselective alkylation using cyclic sulfamidates: Stud-
ies to this point had identified the sulfonyl protecting group
as a vital component for acceptable levels of reactivity in
aziridine electrophiles.[22] Although in some cases it was
found that the sulfonyl group could be cleaved under mild
conditions, we believed a method encompassing a wider
range of nitrogen protecting groups would be desirable. Ad-
ditionally, access to the “propylene-amino” unit
(CH2CH2CH2NHPG) remained elusive. Accordingly, we
considered cyclic sulfamidates as potential 2- and 3-carbon
electrophiles.[23,24] Seminal work by Lubell[25] and Gallagh-
er[26] have demonstrated that 5- and 6-membered cyclic sul-
famidates are valuable intermediates for the synthesis of al-
kaloid natural products. However, to the best of our knowl-
edge, there have been no previous reports of opening sulf-
able to obtain the matched enantiopure alkylation adducts
(14a and 14b) in good yields and high diastereoselectivities
(d.r. 30:1 in both cases). In the mis-matched case, catalyst
control outweighed the weak natural substrate control and
14c was afforded in good diastereomeric excess (d.r. 12:1).
N-p-Nosyl protected aziridine 13b was found to exhibit
poor reactivity with pro-nucleophiles that were not inda-
none based. By substituting the N-p-nosyl group with the
corresponding N-trifluoromethylsulfonyl aziridine 13d, we
were able to significantly enhance the reactivity of the al
ation reaction when using indanones (14d), cyclopentanones
(14e), tetralones (14 f) lactams (14g) and succinimides (14h
and 14i) as the pro-nucleophiles, giving the alkylation prod-
ACHTUNGTNERkNUNG yl-
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
ucts in high yields and in moderate to high diastereoselectiv-
ities (d.r. 9:2 to 30:1).
ACHTUNGTRENNUNG
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Protected Ethylene- and Propylene-Amino Motifs
FULL PAPER
Table 3. Enantioselective ring opening of N-protected cyclic sulfamidates
17a–e with indanone nucleophile 1k.
Table 4. Synthesis of various tert-butyl carboxylate substituted pro-nu-
philes.[a]
ACHUTGTNRENNUGcleoACHTUNGTRENNUGN
Starting
material
Method
Product
Yield
[%][b]
Entry[a]
17
PG
n
Product
Yield
[%][b]
ee
[%][c]
A
A
A
70[c]
85
1
2
a
b
c
d
e
Boc
Cbz
o-CF3C6H4SO2
1
1
1
1
2
18a
18b
3r
18c
18d
75 (18)
54 (31)
80
55 (33)
65 (20)
93
94
96
45
92
3[d]
4
PO
N
5
Boc
[a] Reactions were performed on a 0.40 mmol scale in xylene (2 mL) at
À208C. [b] Isolated yield after purification (yield of oxygen-alkylation
product shown in parentheses). [c] Determined by HPLC analysis.
[d] Reaction performed at 08C due to low solubility of 17c.
92
A
A
A
A
82
88
85
90
In an initial electrophile screen, tert-butyl indanone car-
boxylate (1k) was treated with 5- and 6-membered cyclic
sulfamidates (17a–e) bearing a range of nitrogen protecting
groups under phase-transfer catalysis (Table 3). Carbamate
(Table 3, entries 1 and 2), sulfonyl (entry 3) and phospho-
nate (entry 4) protected electrophiles were screened for re-
activity in the alkylation reaction, and in all but one case,
the alkylation products were obtained in excellent enantio-
selectivity (up to 96% ee) following mild acid hydrolysis. In
some cases, low to moderate degrees of competitive oxygen-
alkylation was also observed (Table 3, entries 1, 2, 4 and 5).
We were pleased to observe that the 6-membered electro-
phile reacted efficiently (entry 5) giving the alkylation
adduct bearing the protected “propylene-amino” scaffold
(previously unobtainable using our established methodolo-
gy)[22] in good yield and with excellent stereocontrol (92%
ee), thus giving access to a much wider spectrum of potential
synthetic targets. In a test of the scale-up potential of our
methodology, tert-butyl indanone carboxylate (1k) was
treated on gram scale with sulfamidate 17a at reduced cata-
lyst loading (4 mol%). Pleasingly, the alkylation adduct 18a
was afforded in 65% yield and in 82% ee, after 24 h at 08C
(see the Supporting Information).
A
B
B
73[d,e]
85
81
B
B
88[d,f]
55[d,f]
With optimal conditions established, the scope of this re-
action was investigated with respect to the pro-nucleophile.
Wishing to expand the general synthetic utility of our meth-
odology, we synthesised a range of cyclic pro-nucleophiles
bearing a tert-butyl ester substituent. On searching the liter-
ature, we found general methods for the direct introduction
of tert-butyl esters were lacking; cyanoformate reagents
have been used with some success,[18d] although the forma-
tion of cyanide by-products and the absence of a commer-
cially available reagent makes this reaction potentially haz-
ardous and impractical on large scale. Other methods, such
as metal catalysed transesterification[27] and Dieckmann cy-
[a] Method A: NaHMDS (2.0 equiv), Boc2O (1.0 equiv), THF, À788C,
0.5–3 h. Method B: NaH (2.0 equiv), N-Boc pyrrole (1.2 equiv), THF,
reflux, 3–6 h. [b] Isolated yield after purification. [c] Yield based on re-
covered starting material. [d] Diastereomeric ratio determined by
1H NMR spectroscopy of the crude product. [e] d.r. 5:2. [f] d.r.>20:1.
ally gave highly efficient and selective mono-acylation for
heterocyclic nucleophiles, even in cases such as succinimides
and glutarimides in which there is more than one reactive
carbonyl present. Under these conditions, indanone derived
nucleophiles gave predominantly the oxygen-acylated prod-
ucts. However, in these cases direct esterification could be
performed by using N-Boc pyrrole[29] as the electrophile and
heating with NaH in THF (Table 4, Method B).
ACHTUNGTRENNUNGcliACHTUNGTRENNUNG
sation,[28] have been used, but these are generally narrow
in scope. After extensive optimisation, we found the combi-
nation of Boc2O and NaHMDS (Table 4, Method A) gener-
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3077

D. J. Dixon et al.
phile the product 18k was obtained in good yield and in an
impressive 93% ee. N-Butyl glutarimide 18n showed dimin-
ished stereoinduction (55% ee) compared to the N-Me ana-
logue 18e (85% ee) using 10 f as the catalyst. Pro-nucleo-
philes bearing an additional stereocentre could also be uti-
lised. By using 2 equiv of the pro-nucleophile to 1 equiv of
the sulfamidate 17a, 3-phenyl succinimide (18p) gave a high
level of diastereocontrol (d.r. 20:1), but the yield was mod-
erate and the enantioselectivity was low (59%, 23% ee for
the major isomer). More remote stereogenic centres could
also influence diastereoselectivity, albeit moderately. For ex-
ample, lactone pro-nucleophile 1ac gave the alkylation
products 18q as a mixture of diastereomers (d.r. 5:2) in
good yield but with moderate enantioselectivity (69%, 45%
ee for the major isomer). The combination of ring sizes
available in both nucleophile and electrophile partners, and
the mild reaction conditions allows a diverse range of prod-
ucts to be synthesised easily and with exceptional stereocon-
trol.
To extend our developed methodology to diastereoselec-
tive alkylation reactions, we wanted to implement enantio-
pure cyclic sulfamidates (Figure 3). Using alanine and phen-
Figure 3. Enantiopure cyclic sulfamidates used in diastereoselective al
ation studies.
ACHTUNGTRENNUNGkyl-
AHCTUNGTRENNUNG
Scheme 10. Enantioselective ring opening of unsubstituted cyclic sulfami-
dates under phase-transfer catalysis. Reactions were performed on a
0.40 mmol scale in xylene (2 mL) at 08C. Isolated yield after purification.
Enantiomeric excess was determined by HPLC analysis. [a] Reaction was
performed at À208C in xylene/CHCl3 (2 mL). [b] Reaction was per-
formed on a 0.20 mmol scale. Yield based on the starting sulfamidate.
ACHUTNGRENyNUG lACTHUNGRTENaUNG lanine as convenient chiral building blocks, both enan-
tiomers of sulfamidates 17 f and 17g were synthesised in the
hope that matched and mis-matched combinations of sub-
strate and catalyst could be observed. Using TBAB as an
achiral phase-transfer catalyst (Table 5), substrate control
from (S)-alanine-derived sulfamidate (S)-17 f was found to
be highly dependent on the nature of the nucleophile,[20]
varying from good with succinimide 1z (d.r. 9:1) to poor
with lactone 1aa (d.r. 1:1). Lactam derived nucleophile 1t
gave the alkylated product 19a with moderate diastereose-
lectivity (d.r. 7:2) when TBAB was used as the catalyst,
which in the matched case with sulfamidate (R)-17g and 10 f
was enhanced (d.r. 7:1). In the mis-matched case using the
enantiomeric electrophile (S)-17g, diastereoselectivity was
eroded (d.r. 2:1), however, it could be boosted (d.r. 11:2) by
employing the matched pseudoenantiomeric catalyst 10 f’
(Figure 4). The lactone pro-nucleophile 1aa had previously
displayed no substrate control with TBAB, but when used in
conjunction with catalyst 10 f, the alkylation adducts 19b
and 19c were afforded in high yields and moderate dia-
DiaACHTUNGTRENNUNG
stereomeric ratio was determined by 1H NMR spectroscopy of the
crude product.
With a range tert-butyl ester pro-nucleophiles in hand, we
subjected them to the optimal reaction conditions
(Scheme 10). Pleasingly, the alkylation adducts were afford-
ed in good to high enantioselectivities[30] using a range of 5-
and 6-membered cyclic[31] systems, several of which are
novel substrates in asymmetric phase-transfer catalysis. Sub-
stituents could be introduced onto the aryl ring of the inda-
none scaffold, with electron-rich (18 f) and electron-poor
(18g) substituents being tolerated without considerably af-
fecting the stereocontrol (90% ee and 85% ee, respectively,
cf. 93% ee in 18a). The succinimide derived (18h and 18m)
and lactone derived (18i and 18l) pro-nucleophiles were
found to perform well, giving the alkylation products after
16 h at 08C in high yields (87–91%) and in good to high
levels of enantioselectivity (up to 86% ee). N-Methyl glu-
A
ACHTUNGTRENsNUGN electivity (d.r. 5:1, in both cases). This level of dia-
A
ACHTUNGTRENNUNG
strate with regard to generating high levels of stereoinduc-
ACHTUNGTRENNUNG
tion (18e and 18k). For example, using 17e as the electro-
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Protected Ethylene- and Propylene-Amino Motifs
FULL PAPER
Table 5. Diastereoselective ring opening of chiral cyclic sulfamidates
under phase-transfer catalysis.[a]
eochemistry of 19e was determined by single crystal X-ray
diffraction (see the Supporting Information). Acyclic pro-
nucleophile 1af displayed both poor catalyst and substrate
directed selectivity; with the alkylation adduct 19d being
obtained in good overall yield, but with disappointing dia-
A
ACHTUNGERTNsNUNG electivity (d.r. 3:2).
Sulfamidate
Product
Catalyst
(10 mol%)
Yield
[%][b]
d.r.[c]
known to be completely regioselective. Exploiting this, we
postulated that we could access alkylation products that
have 1,2- or 1,3-substitution patterns (Scheme 11). Having
AHCTUNGTRENNUNG
TBAB
10 f
82
80
7:2
7:1
(R)-17g
TBAB
10 f
10 f’
84
78
81
7:2
2:1
11:2
(S)-17g
(S)-17 f
(R)-17 f
(S)-17 f
(R)-17 f
(S)-17 f
TBAB
10 f
84
82
1:1
5:1
Scheme 11. Divergent synthetic strategies available from cyclic sulfami-
date electrophiles.
TBAB
10 f
83
86
1:1
5:1
established that C2-substituted cyclic sulfamidates were re-
active towards our conditions, C1-substituted variants were
then investigated. Chiral sulfamidate 17h was synthesised in
racemic form and as single S enantiomer. Initial alkylation
studies were carried out using NMP derived nucleophile 1af
(Scheme 12). Pleasingly, treatment of 1af with sulfamidate
TBAB
10 f
10g
85
84
82
1.1:1
3:2
1.3:1
TBAB
10 f
10g
36
traces
51
9:1
n.d.
7:1
TBAB
10 f
10g
41
59
65
9:1
45:1
9:1
[a] Reactions were performed on a 0.40 mmol scale in xylene (2 mL) at
08C. [b] Isolated yield of product, [c] Determined by 1H NMR spec
tros-
copy of the crude product. [d] The relative stereochemistry of 19e was
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
determined by single crystal X-ray crystallography (see the Supporting
Information).
Scheme 12. Nucleophile controlled alkylation/lactamisation.
(Æ)-17h (1 equiv) in the presence of catalytic TBAB and
Cs2CO3 for 6 h at 508C, followed by acid hydrolysis and sub-
sequent lactamisation afforded the spiro-lactams 20a and
20b as a 1:1 mixture of diastereomers (d.r. 3:2, when 10 f
was used in place of TBAB). In order to obtain a higher
degree of stereocontrol we chose chiral pro-nucleophile (R)-
1ag with the intention of obtaining a degree of substrate
control from the nucleophile. Pleasingly, treatment of (R)-
1ag with one equivalent of sulfamidate (S)-17h in the pres-
ence of catalytic TBAB and Cs2CO3 for 24 h at 408C, fol-
lowed by acid hydrolysis and lactamisation[26] afforded the
spiro-lactam 21 in good yield and diastereoselectivity (68%,
d.r. 20:1). Pleasingly, using catalyst 10 f further enhanced the
diastereoselectivity of the reaction (d.r. 40:1); this suggested
a matched pairing of catalyst and nucleophile. In compari-
Figure 4. Other phase-transfer catalysts used in diastereoselective alkyla-
tion studies.
selectivity, furnishing 19e (d.r. 45:1) with a minor amount of
the oxygen-alkylation side-product. Interestingly, the mis-
matched pair of catalyst 10 f and sulfamidate (R)-17 f result-
ed in almost exclusive oxygen-alkylation. The relative ster-
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3079

D. J. Dixon et al.
and extracted with EtOAc (25 mL). The organic phase was washed with
brine, dried over Na2SO4, filtered and concentrated. The resulting residue
was purified by flash column chromatography to yield the desired prod-
uct.
son, when the pseudoenantiomeric catalyst 10 f’ was used in
the synthesis of lactam 21, there was a decrease in the dia-
stereoselectivity of the reaction (d.r. 10:1), thus suggesting
that these were a mis-matched combination (see the Sup-
porting Information).[32]
General procedure for the phase-transfer catalysed sulfamidate ring
opening reaction: Solid Cs2CO3 (0.600 mmol) was added to a solution of
pro-nucleophile (0.400 mol), sulfamidate (0.420 mmol) and catalyst 10 f
(0.040 mmol) in xylene (2.0 mL) at 08C. Following completion of the re-
action (usually 16–72 h), 1N HCl (2 mL) was added and the mixture was
stirred for 10 min. CH2Cl2 (5 mL) was added and the layers were separat-
ed. The aqueous layer was extracted with CH2Cl2 (5 mL), the combined
organic phases were dried over Na2SO4, filtered and concentrated. The
resulting residue was purified by flash column chromatography to yield
the desired product.
Conclusion
In conclusion, we have developed highly efficient catalytic
and enantioselective alkylation methodologies for creating
quaternary carbon stereogenic centres attached to ethylene-
amino and propylene-amino motifs. Using commercially
available phosphazene reagents, it is possible to perform
base catalysed ring opening on a range of substrates in gen-
erally high yields. Then, through asymmetric phase-transfer
catalysis this reaction can be rendered highly enantioselec-
tive and diastereoselective. To address the need for a wider
variety of nitrogen protecting groups to be tolerated, we
then applied the reaction to the ring opening of 1,2- and 1,3-
cyclic sulfamidates with various substitution patterns and
protecting groups.[33] Manipulation of the alkylation adducts,
including spiro-cyclisation and intramolecular condensation
for the efficient synthesis of multicyclic systems has also
been demonstrated.
Acknowledgements
We gratefully acknowledge the EPSRC (studentships to T.A.M., D.M.B.,
A.F.K. and Leadership Fellowship to D.J.D.), Pfizer Global Research and
Development (studentship to T.A.M.), AstraZeneca (studentship to
D.M.B.) and GlaxoSmithKline (studentship to A.F.K.). We thank Dr.
John Ward (School of Chemistry, University of Manchester) for prelimi-
nary investigations into the synthesis of tert-butyl ester pro-nucleophiles.
We also thank Dr. M. Helliwell (School of Chemistry, University of Man-
chester) and Dr. Katherine Bogle for X-ray structure determination and
the Oxford Chemical Crystallography Service for the use of the instru-
mentation.
[1] For selected examples from our group of reactions forming quater-
nary stereocentres, see: a) A. W. Pilling, J. Boehmer, D. J. Dixon,
Angew. Chem. 2007, 119, 5524–5526; Angew. Chem. Int. Ed. 2007,
46, 5428–5430; b) C. L. Rigby, D. J. Dixon, Chem. Commun. 2008,
3798–3800; c) M. Li, D. J. Dixon, Org. Lett. 2010, 12, 3784–3787;
d) P. Jakubec, D. M. Cockfield, P. S. Hynes, E. Cleator, D. J. Dixon,
Tetrahedron: Asymmetry 2011, 22, 1147–1155.
Experimental Section
General procedure for the BEMP catalysed aziridine ring opening reac-
tion: BEMP (10.4 mL, 0.036 mmol) was added to a solution of pro-nu-
ACHTUNGTRENNUNGcleoACHTUNGTRENNUNGphile (0.720 mmol) in THF (0.8 mL) and the resulting solution was
stirred at 258C for 10 minutes. The aziridine (0.360 mmol) was added and
the mixture was stirred at 258C until completion (usually 16–48 h). The
solution was concentrated and the residue was purified by flash column
chromatography to yield the desired product.
[2] For a review, see: C. M. Goodman, S. Choi, S. Shandler, W. F. De-
Grado, Nat. Chem. Biol. 2007, 3, 252–262.
[3] For selected reviews, see: a) H. Pellissier, Tetrahedron 2007, 63,
9267–9331; b) M. Santanu, J. Yang, S. Hoffmann, B. List, Chem.
Rev. 2007, 107, 5471–5569; c) D. Almas¸i, D. A. Alonso, C. Nꢁjera,
Tetrahedron: Asymmetry 2007, 18, 299–365; d) Y. Takemoto, H.
Miyabe, Chimia 2007, 61, 269–275.
General procedure for the phase-transfer catalysed aziridine ring opening
reaction: K2HPO4 (0.200 mmol in 35 mL H2O) was added to a solution of
pro-nucleophile (0.130 mmol), aziridine (0.160 mmol) and catalyst 10 f
(0.013 mmol) in a 9:1 toluene/CHCl3 mixture (1 mL) at À208C. Following
completion of the reaction (usually 16–72 h), CH2Cl2 (5 mL) and 1N HCl
(2 mL) were added and the layers were separated. The aqueous layer
was extracted with CH2Cl2 (5 mL), the combined organic phases were
dried over Na2SO4, filtered and concentrated. The resulting residue was
purified by flash column chromatography to yield the desired product.
[4] For recent examples of secondary amine catalysed Michael additions
of aldehydes to nitro-olefins, see: a) Y. Chi, L. Guo, N. A. Kopf,
S. H. Gellman, J. Am. Chem. Soc. 2008, 130, 5608–5609; b) M.
Wiesner, J. D. Revell, S. Tonazzi, H. Wennermers, J. Am. Chem. Soc.
2008, 130, 5610–5611; c) P. Garcꢂa-Garcꢂa, A. LapꢃpÞche, R.
Halder, B. List, Angew. Chem. 2008, 120, 4797–4799; Angew. Chem.
Int. Ed. 2008, 47, 4719–4721; d) Y. Hayashi, T. Itoh, M. Ohkubo, H.
Ishikawa, Angew. Chem. 2008, 120, 4800–4802; Angew. Chem. Int.
Ed. 2008, 47, 4722–4724; e) M. Durini, F. A. Sahr, M. Kuhn, M.
Civera, C. Gennari, U. Piarulli, Eur. J. Org. Chem. 2011, 5599–5607.
[5] For reviews on ring opening of aziridines, including asymmetric
methods, see: a) X. E. Hu, Tetrahedron 2004, 60, 2701–2743;
b) I. D. G. Watson, L. Yu, A. K. Yudin, Acc. Chem. Res. 2006, 39,
194–206; c) M. Pineschi, Eur. J. Org. Chem. 2006, 4979–4988; d) C.
Schneider, Angew. Chem. 2009, 121, 2116; Angew. Chem. Int. Ed.
General procedure for the synthesis of tert-butyl ester substituted pro-nu-
cleophiles with Boc2O (Method A): NaHMDS (2m in THF, 10 mL) was
added dropwise to a solution of carbonyl compound (10.0 mmol) in THF
(40 mL) at À788C. Following addition of base, Boc2O (10.0 mmol) in
THF (5 mL) was added and the mixture was stirred at À788C until com-
pletion (usually 0.5–3 h). The reaction was quenched with sat. aq. NH4Cl
and extracted with EtOAc (25 mL). The organic phase was washed with
brine, dried over Na2SO4, filtered and concentrated. The resulting residue
was purified by flash column chromatography to yield the desired prod-
uct.
´
2009, 48, 2082; e) S. Stankovic, M. D’hooghe, S. Catak, H. Eum, M.
Waroquier, V. V. Speybroeck, N. D. Kimpe, H.-J. Ha, Chem. Soc.
Rev. 2012, 41, 643–665.
General procedure for the synthesis of tert-butyl ester substituted inda-
none pro-nucleophiles with N-Boc pyrrole (Method B): Indanone
(5.0 mmol) was added to a suspension of NaH (10.0 mmol, 60% in min-
eral oil washed with hexane) in THF (20 mL) at RT. Following warming
to relux, N-Boc pyrrole (10.0 mmol) in THF (5 mL) was added dropwise
and the solution was further warmed to reflux until completion (usually
3–6 h). The reaction mixture was cooled to RT, quenched with 1N HCl
[6] For methodologies in aziridine synthesis, see: a) J. E. G. Kemp, in
Comprehensive Organic Synthesis, Vol. 7 (Eds.: B. M. Trost, I. Flem-
ing, L. Lwowski), Pergamon, Oxford, 1991, p. 469; b) K. M. L. Rai,
A. Hassner, Adv. Strain. Interest. Org. Mol. 2000, 8, 187–257; c) S. S.
Murphree, A. Padwa, Prog. Heterocycl. Chem. 2001, 13, 52–70;
d) A. L. Williams, J. N. Johnston, J. Am. Chem. Soc. 2004, 126,
3080
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Protected Ethylene- and Propylene-Amino Motifs
FULL PAPER
1612–1613; e) X. Zeng, X. Zeng, Z. Xu, M. Lu, G. Zhong, Org.
Lett. 2009, 11, 3036–3039; f) L. D. S. Yadav, R. Kapoor, Garima,
Synlett 2009, 3123–3126.
M. Bell, K. A. Jørgensen, Angew. Chem. 2006, 118, 6701–6704;
Angew. Chem. Int. Ed. 2006, 45, 6551–6554; d) T. B. Poulsen, L.
Bernardi, J. Aleman, J. Overgaard, K. A. Jørgensen, J. Am. Chem.
Soc. 2007, 129, 441–449; e) L. Bernardi, J. Cantarero, B. Neiss,
K. A. Jørgensen, J. Am. Chem. Soc. 2007, 129, 5772–5778.
[19] H.-F. Cui, K.-Y. Dong, G.-W. Zhang, L. Wang, J.-A. Ma, Chem.
Commun. 2007, 2284–2286.
[20] For electrophile directed diastereoselective alkylation, see: a) L.
Overman, J. F. Larrow, B. A. Stearns, J. M. Vance, Angew. Chem.
2000, 112, 219–221; Angew. Chem. Int. Ed. 2000, 39, 213–215;
b) S. B. Hoyt, L. Overman, Org. Lett. 2000, 2, 3241–3244; c) T.
Emura, T. Esaki, T. Kazutaka, M. Shimizu, J. Org. Chem. 2006, 71,
8559–8564; d) S. P. Marsden, R. Newton, J. Am. Chem. Soc. 2007,
129, 12600–12601.
[7] a) H. Stamm, V. Gailius, Chem. Ber. 1981, 114, 3599–3608; b) T.
Baumann, B. Buckholz, H. Stamm, Synthesis 1995, 44–46.
[8] For a phase-transfer catalysed example, see: a) E. V. Blyumin, H. J.
Gallon, A. K. Yudin, Org. Lett. 2007, 9, 4677–4680. For a Lewis
base catalysed example, see: b) S. Minakata, Y. Okada, Y. Oderao-
toshi, M. Komatsu, Org. Lett. 2005, 7, 3509–3512. For a Lewis acid
catalysed example, see: c) I. Ungureanu, P. Klotz, A. Mann, Angew.
Chem. 2000, 112, 4790–4792; Angew. Chem. Int. Ed. 2000, 39, 4615–
4617; d) J. S. Yadav, B. V. S. Reddy, S. Abraham, G. Sabitha, Tetrahe-
dron Lett. 2002, 43, 1565–1567.
[9] R. Schwesinger, J. Willaredt, H. Schlemper, M. Keller, D. Schmitt,
H. Fritz, Chem. Ber. 1994, 127, 2435–2454.
[10] D. A. Alonso, P. G. Andersson, J. Org. Chem. 1998, 63, 9455–9461,
and references cited therein.
[11] Z. Moussa, D. Romo, Synlett 2006, 3294–3298.
[12] T. A. Moss, A. Alba, D. Hepworth, D. J. Dixon, Chem. Commun.
2008, 2474–2476.
[13] For seminal work on bifunctional cinchona-derived organocatalysis,
see: a) H. Li, Y. Wang, L. Tang, L. Deng, J. Am. Chem. Soc. 2004,
126, 9906–9907; b) S. H. McCooey, S. J. Connon, Angew. Chem.
2005, 117, 6525–6528; Angew. Chem. Int. Ed. 2005, 44, 6367–6370;
c) B. Vakulya, S. Varga, A. Csꢁmpai, T. Soꢄs, Org. Lett. 2005, 7,
1967–1969; d) J. Ye, D. J. Dixon, P. S. Hynes, Chem. Commun. 2005,
4481–4483; e) B. Li, L. Jiang, M. Liu, Y. Chen, L. Ding, Y. Wu, Syn-
lett 2005, 603–606.
[14] For reviews of phase-transfer catalysis, see: a) K. Maruoka, T. Ooi,
Chem. Rev. 2003, 103, 3013–3028; b) B. Lygo, B. I. Andrews, Acc.
Chem. Res. 2004, 37, 518–525; c) M. J. O’Donnell, Acc. Chem. Res.
2004, 37, 506–517; d) T. Ooi, K. Maruoka, Angew. Chem. 2007, 119,
4300–4345; Angew. Chem. Int. Ed. 2007, 46, 4222–4266; e) T. Ha-
shimoto, K. Maruoka, Chem. Rev. 2007, 107, 5656–5682.
[15] For selected examples of phase-transfer catalysis, see: a) R. He, X.
Wang, T. Hashimoto, K. Maruoka, Angew. Chem. 2008, 120, 9608–
9610; Angew. Chem. Int. Ed. 2008, 47, 9466–9468; b) D. Uraguchi,
Y. Ueki, T. Ooi, J. Am. Chem. Soc. 2008, 130, 14088–14089; c) V.
Rauniyar, A. D. Lackner, G. L. Hamilton, F. D. Toste, Science 2011,
334, 1681–1684; d) E. E. Maciver, P. C. Knipe, A. P. Cridland, A. L.
Thompson, M. D. Smith, Chem. Sci. 2012, 3, 537–540; e) K. M.
Johnson, M. S. Rattley, F. Sladojevich, D. M. Barber, M. G. NuÇez,
A. M. Goldys, D. J. Dixon, Org. Lett. 2012, 14, 2492–2495; f) C. D.
Fiandra, L. Piras, F. Fini, P. Disetti, M. Moccia, M. F. A. Adamo,
Chem. Commun. 2012, 48, 3863–3865.
[21] T. Fukuyama, C.-K. Jow, M. Cheung, Tetrahedron Lett. 1995, 36,
6373–6374.
[22] a) T. A. Moss, D. R. Fenwick, D. J. Dixon, J. Am. Chem. Soc. 2008,
130, 10076–10077; b) M. W. Paix¼o, M. Nielsen, C. B. Jacobsen,
K. A. Jørgensen, Org. Biomol. Chem. 2008, 6, 3467–3470.
[23] For a review on the synthesis and reactions of cyclic sulfamidates,
see: R. E. Melꢃndez, W. D. Lubell, Tetrahedron 2003, 59, 2581–
2616.
[24] For seminal work in this area, see: a) J. E. Baldwin, A. C. Spivey,
C. J. Schofield, Tetrahedron: Asymmetry 1990, 1, 881–884; b) G. J.
White, M. E. Garst, J. Org. Chem. 1991, 56, 3178–3181; c) G. F.
Cooper, K. E. McCarthy, M. G. Martin, Tetrahedron Lett. 1992, 33,
5895–5896; d) L. T. Boulton, H. T. Stock, J. Raphy, D. C. Horwell, J.
Chem. Soc. Perkin Trans. 1 1999, 1421–1430; e) J. J. Posakony, T. J.
Tewson, Synthesis 2002, 859–864.
[25] L. Wei, W. D. Lubell, Can. J. Chem. 2001, 79, 94–104.
[26] a) J. F. Bower, J. Svenda, A. J. Williams, J. P. H. Charmant, R. M.
Lawrence, P. Szeto, T. Gallagher, Org. Lett. 2004, 6, 4727–4730;
b) J. F. Bower, P. Szeto, T. Gallagher, Chem. Commun. 2005, 5793–
5795; c) J. F. Bower, S. Chakthong, J. Svenda, A. J. Williams, R. M.
Lawrence, P. Szeto, T. Gallagher, Org. Biomol. Chem. 2006, 4,
1868–1877; d) J. F. Bower, T. Riis-Johannessen, P. Szeto, A. J.
Whitehead, T. Gallagher, Chem. Commun. 2007, 728–730; e) J. F.
Bower, A. J. Williams, H. L. Woodward, P. Szeto, R. M. Lawrence,
T. Gallagher, Org. Biomol. Chem. 2007, 5, 2636–2644; f) J. F.
Bower, P. Szeto, T. Gallagher, Org. Lett. 2007, 9, 4909–4912.
[27] M. Nakajima, S. Yamamoto, Y. Yamaguchi, S. Nakamura, S. Hashi-
moto, Tetrahedron 2003, 59, 7307–7313.
[28] M. E. Bunnage, S. G. Davies, R. M. Parkin, P. M. Roberts, A. D.
Smith, J. M. Withey, Org. Biomol. Chem. 2004, 2, 3337–3354.
[29] For examples of reactions using pyrrole reagents, see: a) M. S. Scott,
C. A. Luckhurst, D. J. Dixon, Org. Lett. 2005, 7, 5813–5816; b) R. D.
Richardson, F. A. Hernandez-Juan, D. J. Dixon, Synlett 2006, 77–80.
[30] The stereochemistry of indanone adducts 18a–d, 18 f and 18g were
assigned by analogy to compound 3r (absolute configuration deter-
mined by X-ray analysis). Compounds 18i and 18l were assigned by
analogy to the cyclopentanone system (see ref. [18c]). Succinimide
products 18h and 18m were assigned by comparison to compound
19e in the matched system with (S)-17 f and catalyst 10 f (relative
configuration determined by X-ray analysis). Glutarimide adducts
18e and 18k were assigned by analogy to the succinimide and cyclo-
hexanone (see ref. [18c]) systems.
[16] For selected examples of phase-transfer catalysed alkylation reac-
tions forming
a quaternary stereocentre, see: a) T. B. K. Lee,
G. S. K. Wong, J. Org. Chem. 1991, 56, 872–875; b) T. Ooi, T. Miki,
M. Taniguchi, M. Shiraishi, K. Maruoka, Angew. Chem. 2003, 115,
3926–3928; Angew. Chem. Int. Ed. 2003, 42, 3796–3798; c) E. J.
Park, M. H. Kim, D. Y. Kim, J. Org. Chem. 2004, 69, 6897–6899;
d) S.-S. Jew, Y.-J. Lee, J. Lee, M. J. Kang, B.-S. Jeong, J.-H. Lee, M.-
S. Yoo, M.-J. Kim, S.-H. Choi, J.-M. Ku, H.-G. Park, Angew. Chem.
2004, 116, 2436–2439; Angew. Chem. Int. Ed. 2004, 43, 2382–2385;
e) T. Ooi, K. Fukumoto, K. Maruoka, Angew. Chem. 2006, 118,
3923–3926; Angew. Chem. Int. Ed. 2006, 45, 3839–3842; f) D. Ura-
guchi, Y. Asai, T. Ooi, Angew. Chem. 2009, 121, 747–751; Angew.
Chem. Int. Ed. 2009, 48, 733–736; g) K. Ohmatsu, M. Kiyokawa, T.
Ooi, J. Am. Chem. Soc. 2011, 133, 1307–1309; h) S. Hong, J. Lee, M.
Kim, Y. Park, C. Park, M.-H. Kim, S.-S. Jew, H.-G. Park, J. Am.
Chem. Soc. 2011, 133, 4924–4929.
[31] Subjection of acyclic pro-nucleophile tert-butyl-2-methylacetoacetate
to our optimal conditions resulted in a 2:3 inseparable mixture of
oxygen- and carbon-alkylated products, respectively.
[32] When the reaction was conducted with (Æ)-17h, a 1:1 mixture of
major diastereomers were obtained, in a 20:1 ratio with their respec-
tive minor diastereomers (d.r. 20:1:20:1).
[17] a) M. J. O’Donnell, F. Delgado, R. Hostettler, R. Schwesinger, Tetra-
hedron Lett. 1998, 39, 8775–8778; b) Y.-J. Lee, J. Lee, M.-J. Kim, B.-
S. Jeong, J.-H. Lee, T.-S. Kim, J. Lee, J.-M. Ku, S.-S. Jew, H.-G. Park,
Org. Lett. 2005, 7, 3207–3209.
[33] T. A. Moss, B. Alonso, D. Fenwick, D. J. Dixon, Angew. Chem. 2010,
122, 578–581; Angew. Chem. Int. Ed. 2010, 49, 568–571.
[18] For seminal work, see: a) E. J. Corey, F. Xu, M. C. Noe, J. Am.
Chem. Soc. 1997, 119, 12414–12415; b) B. Lygo, P. G. Wainwright,
Tetrahedron Lett. 1997, 38, 8595–8598; c) T. B. Poulsen, L. Bernardi,
Received: October 25, 2012
Published online: January 17, 2013
Chem. Eur. J. 2013, 19, 3071 – 3081
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3081