Stereocontrolled synthesis of β-amino alcohols from lithiated aziridines and boronic esters

Article abstract of DOI:10.1002/anie.200805272

(Chemical Equation Presented) β-Amino alcohols have been prepared with high selectivity by the addition of lithiated aziridines to boronic esters. The regioselectivity of lithiation for aryl aziridines is sensitive to the reaction conditions and to the ba

Full text of DOI:10.1002/anie.200805272

Angewandte
Chemie
DOI: 10.1002/anie.200805272
Amino Alcohols
Stereocontrolled Synthesis of b-Amino Alcohols from Lithiated
Aziridines and Boronic Esters**
Frank Schmidt, Florian Keller, Emeline Vedrenne, and Varinder K. Aggarwal*
From natural products to ligands for asymmetric catalysis, the
b-amino alcohol motif is ubiquitous.[1] The importance of this
motif to such a broad spectrum of chemistry has prompted the
development of a range of methodologies for its synthesis
which include Sharpless aminohydroxylation[2] as well as the
addition of nucleophiles to aminocarbonyls,[3] imines,[4] epox-
ides, and aziridines.[5] We considered a conceptually different
route to prepare this class of compound: namely, the
lithiation/borylation[6] of aziridines[7] (Scheme 1, pathway a).
Although most studies have focused on lithiation and
trapping of N-sulfonyl aziridines,[9,12] we were attracted to the
N-Boc aziridines because: 1) they could be easily prepared in
enantiomerically enriched form (either from the correspond-
ing amino acid[13] or by Jacobsenꢀs kinetic resolution of
terminal epoxides[14] using Boc-NH2[15]), and 2) the N-Boc
amino alcohol products provide more useful functionality for
further manipulation downstream. However previous studies
had shown that lithiated aziridines bearing an N-Boc group
undergo a rapid intramolecular [1,2] anionic rearrangement
to give aziridinyl esters 7, a useful reaction in its own right
(Scheme 1, pathway b).[8] This rearrangement pathway made
it virtually impossible to trap the C-lithiated aziridine with
any external electrophile, including MeOD. However, if the
electrophile was already present during the deprotonation
step, it would be theoretically possible to trap the lithiated
aziridine prior to the migration of the Boc group.[16] As we
believed that most boronic esters/boranes would also be
compatible with the hindered base (LTMP) required for
deprotonation, this provided the possibility of using N-Boc
aziridines in the lithiation–borylation reaction, without
migration of the Boc group. This analysis gave us the
motivation to embark on the following study.
Scheme 1. Lithiation/borylation of terminal aziridines. LTMP=lithium
2,2,6,6-tetramethylpiperidide, pin=pinacolato.
To maximize the rate of the bimolecular trapping (and
therefore minimize the migration rate of the Boc group), the
reactions were conducted at the maximum concentration that
was practical. Thus, slow addition of a THF solution of LTMP
to a solution of N-Boc aziridine 1a and ethyl boronic ester 2a
(1.5 equiv) at ꢀ788C followed by warming to 08C and
oxidative workup gave a mixture of amino alcohol 6 and the
aziridine 7, in 40% and 20% yield, respectively (Scheme 1).
This result showed that the rates of trapping and of rearrange-
ment of the lithiated aziridine were similar, even at high
concentration. However, on increasing the stoichiometry of
the boronic ester to 3 equivalents none of the aziridine
derivative where the Boc group has migrated was detected.
These optimized reaction conditions were found to be general
for a broad range of alkyl (Table 1, entries 1–5), vinyl
(Table 1, entries 6 and 7), and aryl boronic esters (Table 1,
entries 8 and, 9). The process was further extended to other
alkyl and unsaturated aziridines thus demonstrating its scope
(Table 1, entries 10–12).
In all cases b-amino alcohols 6 were obtained in high yield
and as single diastereoisomers. The relative configuration of
6k was proven by X-ray analysis,[17] and that of 6j was
confirmed by correlation with the literature.[18] The config-
uration of the product is consistent with the mechanism
shown in Scheme 1, which involves lithiation trans to the
aziridine substituent, reaction with the boronic ester with
retention of configuration, migration of the boron substituent
This route was attractive because: 1) it combines readily
ꢀ
available aziridines 1 and boronic esters 2, and creates a C C
bond, 2) high stereoselectivity for the overall process could be
expected since lithiation of N-Boc[8] (tert-butoxycarbonyl)
and N-Bus[9] (tert-butylsulfonyl) aziridines[10] had been shown
to occur trans to the aziridine substituent, and the subsequent
steps (3 ! 4 ! 5 ! 6) were expected to be stereospecific,
3) there existed the potential to create quaternary stereogenic
centers through lithiation at the internal position.[11]
[*] Dr. F. Schmidt, Dr. F. Keller, Dr. E. Vedrenne, Prof. Dr. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
Fax: (+44)117-929-8611
E-mail: v.aggarwal@bristol.ac.uk
Homepage: http://www.chm.bris.ac.uk/org/aggarwal/
aggarhp.html
[**] F. Schmidt and F. Keller thank the DAAD and the DFG for
postdoctoral fellowships. V.K.A. thanks The Royal Society for a
Wolfson Research Merit Award and EPSRC for support of this work
and for a Senior Research Fellowship. We thank Frontier Scientific
for the generous donation of boronic acids and boronic esters. We
thank the EPSRC National Crystallography Service and Dr. Jonathan
Charmant for X-ray analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200805272.
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Table 1: b-amino alcohol synthesis.[a]
Finally, phenylaziridines were investigated as an extension
of the methodology. Lithiation of aziridine 1e is known to
occur adjacent to the phenyl group and so this has the
potential to generate quaternary stereogenic centers
(Scheme 3).[11] However, lithiation with LTMP and trapping
Entry
R1 (aziridine 1)
R2 (boronic ester 2)
Yield [%][b]
1
2
3
4
5
6
7
8
iPr (1a)
iPr (1a)
iPr (1a)
iPr (1a)
iPr (1a)
iPr (1a)
iPr (1a)
iPr (1a)
iPr (1a)
Me (1b)
nBu (1c)
Et (2a)
iPr (2b)
cPr (2c)
Cy (2d)
PhCH2CH2 (2e)
vinyl (2 f)
76 (6a)
75 (6b)
79 (6c)
81 (6d)
73 (6e)
93 (6 f)
83 (6g)
76 (6h)
70 (6i)
63 (6j)
86 (6k)
75 (6l)
Scheme 3. Proposed lithiation and trapping of aryl-substituted aziri-
dines.
=
nBuCH CH (2g)
Ph (2h)
pMeOPh (2i)
Ph (2h)
Ph (2h)
Ph (2h)
9
10
11
12
of the N-Boc aziridine 1e with boronic ester 2h only gave the
product 10 where the Boc group has migrated.[19] Presumably,
the phenyl group has the effect of slowing down the trapping
of the carbanion with the boronic ester as a result of increased
steric demands and increased electronic stabilization of the
carbanion. To inhibit this migration we decided to replace the
N-Boc group with the less labile N-Bus group. Although
substantial studies have been performed on lithiated N-Bus
aziridines bearing alkyl substituents, particularly in relation to
their carbenoid character,[8b,9c] there were no reports on
lithiation and trapping of N-Bus aziridines bearing aryl
substituents. We therefore studied the deprotonation/boryla-
tion of these more robust aziridine derivatives.
Treatment of N-Bus aziridine 8 with LTMP in the
presence of different aryl and vinyl boronic esters gave the
corresponding alcohols 11 in good yield and with complete
diastereoselectivity (Table 2, entries 1–3). No racemization of
the labile benzylic center was detected. Surprisingly, the use
of alkyl boronic esters (Table 2, entries 4–7) led to an
approximate 3.5:1 mixture of the secondary/tertiary alcohols
(11/9), again with complete control over enantio- and
diastereoselectivity. We had expected lithiation to occur
=
CH2 CH(CH2)2 (1d)
[a] All reactions were performed on a 0.5 mmol scale using boronic ester
2 (3 equiv), LTMP (0.6m; 3 equiv) in THF (1 mL) at ꢀ788C for
90 minutes, then warming to 08C and subsequent oxidation. [b] Yield
of isolated product. Cy=cyclohexyl.
ꢀ
anti to the C N bond, and finally retention of configuration in
the oxidation step. The very high diastereoselectivity
observed, even with the smallest of substituents (R1 = Me;
Table 1, entry 10) is indicative of a very high degree of
selectivity in the lithiation step trans to the aziridine
substituents and complete selectivity in trapping 3 with the
boronic ester.
The process was easily extended to the enantioenriched
series. Thus, treatment of (S)-1a with phenyl boronic ester 2h
gave 6h in 99% ee (Scheme 2). Furthermore, the reaction of
(S)-1a and (R)-1a with the enantioenriched boronic ester (S)-
2j[6a] gave the amino alcohols (S,S,S)-6m and (R,R,S)-6m with
complete diastereo- and enantioselectivity in 68% and 72%
yield, respectively. This outcome shows that there are no
matched/mismatched issues here, which can often complicate
reaction outcomes.
Table 2: Synthesis of b-amino alcohols from phenylaziridine 8.[a]
Entry R2 (boronic ester 2) Yield [%][b] Yield [%][b] e.r. 11[c] e.r. 9[c]
of 11
of 9
1
2
3
4
5
6
7
vinyl (2 f)
Ph (2h)
pMeO-Ph (2i)
allyl (2j)
Et (2a)
73 (11 f)
83 (11h)
87 (11i)
60 (11j)
63 (11a)
70 (11k)
61 (11d)
<5
<5
<5
>99:1
>99:1
>99:1
>99:1 >99:1
>99:1 >99:1
>99:1 >99:1
>99:1 >99:1
–
–
–
23 (9j)
15 (9a)
20 (9k)
20 (9d)
nBu (2k)
Cy (2d)
[a] All reactions were performed using boronic ester 2 (1.2 equiv), LTMP
(0.5m; 1.2 equiv) in THF at ꢀ788C for 1 hour, then at room temperature
for a further 1 hour and subsequent oxidation. [b] Yield of isolated
product (see the Supporting Information). [c] The enantiomeric ratio
(e.r.) was determined by HPLC on a chiral stationary phase using a
Chiralcel OD-H or AD column.
Scheme 2. Synthesis of enantiopure b-amino alcohols.
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predominantly at the benzylic position as observed by Florio
et al.,[11] who used sBuLi as the base and so expected to obtain
predominantly the tertiary alcohol 9 (Scheme 3). Evidently,
when the more hindered base LTMP is employed, steric
factors outweigh electronic factors and lithiation occurs at the
less acidic terminal position. However, it was surprising that
the site of lithiation (which determines the product ratio) was
dependent on the nature of the boronic ester employed: aryl
and vinyl boronic esters resulted in lithiation at the terminal
position, whereas alkyl boronic esters gave an approximate
3.5:1 ratio of terminal/benzylic lithiation.
esters furnished the tertiary alcohols in high yield and with
complete stereocontrol (Table 3). These hindered amino
alcohols are especially difficult to make by other routes,
including Sharpless aminohydroxylation, but are nevertheless
an extremely important class of bioactive compounds.[21]
However, aryl boronic esters were much less well behaved
and gave mixtures of products which included alkenes.[22]
Table 3: Synthesis of amino alcohols bearing quaternary stereogenic
centers.[a]
Mechanistic studies have been undertaken to shed light on
the factors affecting the regioselectivity of lithiation with
LTMP. To determine whether the lithiated aziridine species
could isomerize, aziridine 8 was treated with LTMP for
10 seconds, 2 minutes, and 1 hour before addition of MeOD.
These experiments gave a 1:2.4 (27% deuterium incorpora-
tion), 1:3 (41% deuterium incorporation), and 1:8 (92%
deuterium incorporation) ratio of products 12/13, respectively
(Scheme 4). The reactions were clean and there were no
Entry
R2 (boronic ester 2)
Yield [%][b]
e.r.[c]
1
2
3
Cy (2l)[d]
allyl (2j)
nBu (2k)
84 (9d)
87 (9j)
80 (9k)
>99:1
>99:1
>99:1
[a] All reactions were performed using boronic ester 2 (1.2 equiv), nBuLi
(1.2 equiv) in Et2O at ꢀ788C. [b] Yield of isolated product. [c] The
enantiomeric ratio (e.r.) was determined by HPLC on a chiral stationary
phase using a Chiralcel AD column. [d] The neopentyl boronic ester was
used instead of the pinacol boronic ester.[23] TMEDA=N,N,N’,N’-
tetramethylethylenediamine.
In conclusion, we have presented a conceptually new
route to b-amino alcohols, a common motif found across a
wide spectrum of molecules in chemistry. This associative
route employs terminal N-Boc aziridines which are lithiated
and trapped with boronic esters to give syn-b-amino alcohols
with complete diastereoselectivity. The process is easily
rendered asymmetric and can be used to create carbon
chains with multiple stereogenic centers with control over
relative and absolute stereochemistry. The process can be
further extended to the generation of 1,2-amino alcohols
bearing quaternary stereogenic centers, thus providing a
useful route to this especially challenging motif.
Scheme 4. Mechanistic studies to probe the site of lithiation and
potential for equilibration.
products from dimerization of the lithiated aziridine species.
Furthermore, lithiation with LTMP for 1 hour and subsequent
addition of boronic ester 2k gave a 1:3 ratio of adducts 11k/
9k, whereas trapping with the same boronic ester in situ gave
a 3.5:1 ratio (Table 2, entry 6). Taken together, these results
show that, in the absence of a boronic ester, LTMP favors
benzylic lithiation and that the terminal lithiated aziridine
equilibrates to the thermodynamically more stable benzylic
lithiated aziridine over time. Possibly, the base forms a
complex with the reactive boronic esters (aryl, vinyl) and
therefore the more hindered complex leads to lithiation at the
terminal position. In the presence of aliphatic boronic esters,
the base LTMP may lead to a “looser complex” which gives
an approximate 3.5:1 mixture of lithiated aziridine species
(Table 2). That the regiochemical outcome of the lithiation
process is dependent on the nature of the boronic ester is
further illustrated by the fact that LTMP deprotonation of
aziridine 8 in the presence of the less hindered ethyl
neopentyl boronic ester gave an approximate 1:1 mixture of
11/9 whereas the ethyl pinacol boronic ester (2a) gave an
approximate 4:1 mixture (Table 2, entry 5).[20]
Received: October 28, 2008
Published online: December 29, 2008
Keywords: amino alcohols · asymmetric synthesis ·
.
borate esters · lithiated aziridines · quaternary centers
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