Synthesis of vicinal aminoalcohols by stereoselective aza-wacker cyclizations: Access to (-)-acosamine by redox relay

Article abstract of DOI:10.1002/anie.201305926

Diastereoselective aza-Wacker cyclization of O-allyl hemiaminals under aerobic conditions enables efficient access to 1,2-aminoalcohol derivatives from allylic alcohols. The scope of this method is presented and its utility is highlighted in a streamlined

Full text of DOI:10.1002/anie.201305926

Angewandte
Chemie
DOI: 10.1002/anie.201305926
Synthetic Methods
Synthesis of Vicinal Aminoalcohols by Stereoselective Aza-Wacker
Cyclizations: Access to (À)-Acosamine by Redox Relay**
Adam B. Weinstein, David P. Schuman, Zhi Xu Tan, and Shannon S. Stahl*
The stereoselective synthesis of vicinal aminoalcohols from
simple starting materials is a prominent challenge in organic
chemistry. The prevalence of the vicinal aminoalcohol moiety
in biologically active molecules, as well as the challenge in
accessing the 1,2-oxidation pattern, has justified the develop-
ment of a diverse array of synthetic approaches to this
functionality.[1] Intermolecular oxidative difunctionalization
of alkenes is an appealing strategy for the generation of the
1,2-aminooxygenation pattern, but methods with a combina-
tion of high stereo- and regioselectivity, and diverse scope
remain elusive. Examples include Sharpless asymmetric
aminohydroxylation,[2] metal-catalyzed activation of oxazir-
idines,[3] and palladium-catalyzed aminoacetoxylation reac-
tions which employ hypervalent iodine oxidants.[4] Our
interest in palladium-catalyzed aerobic oxidation of alkenes
(Wacker-type reactions) prompted us to investigate new
methods for the synthesis of vicinal aminoalcohols from
readily available, stereochemically defined starting materials.
Herein, we employ a detachable, tethered nitrogen nucleo-
phile to generate the 1,2-aminooxygenation pattern from
allylic alcohols by an aza-Wacker cyclization (Scheme 1a).[5–7]
The cyclization step forms five-membered oxazolidine prod-
ucts and exhibits high levels of diastereoselectivity. This
strategy is amenable to the de novo synthesis of aminosugars,
which are key substructures of several antibiotic and anti-
cancer natural products (Scheme 1b).[8] Implementation of
a redox-relay approach[9] enables rapid synthesis of (À)-
acosamine and highlights the utility of this method.
We began our studies with an assessment of the reactivity
and diastereoselectivity of the Wacker cyclization when using
distinct tethering units for the attachment of oxygen or
nitrogen nucleophiles to secondary allylic amine or allylic
alcohol substrates (Table 1). These efforts included the allylic
N-tosyl carbamate 1 (entries 1–3) and N-allyl hemiaminal 3
(entries 4–6) substrates, which were reported previously by
Bꢀckvall and co-workers[5f] and Hiemstra and co-workers,[5a]
as well as the O-allyl hemiaminal 5a. Assessment of a variety
of catalyst conditions for aerobic oxidative cyclization
Scheme 1. a) Detachable tethered nucleophile approach for the syn-
thesis of vicinal aminoalcohols from allylic alcohols. b) Aminosugars
in natural product antibiotic and anticancer agents. Z=benzyloxycar-
bonyl (Cbz) or tert-butoxycarbonyl (Boc).
Table 1: Evaluation of diastereoselective oxidative cyclization of sub-
strates derived from an allylic alcohol or an allylic amine.
Entry
Substrate
Major
product
Cond.[a]
Yield
[%]
d.r.[b]
1
2
3
A
B
C
0
11
0
n.d.
3.5:1[c]
n.d.
4
5
6
A
B
C
34
51
67
1.6:1
1.6:1
1.8:1
7
8
9
A
B
C
93
94
77
9:1
8:1
5:1
[*] A. B. Weinstein, D. P. Schuman, Z. X. Tan, Prof. S. S. Stahl
Department of Chemistry, University of Wisconsin-Madison
1101 University Avenue, Madison, WI 53706 (USA)
E-mail: stahl@chem.wisc.edu
[a] Catalyst conditions A: 5 mol% Pd(TFA)2, 20 mol% DMSO, 20 mol%
NaOBz, 3 ꢀ M.S., THF (0.1m), 258C, 24 h, 1 atm O2. Catalyst
conditions B: 5 mol% Pd(TFA)2, 20 mol% NaOBz, 3 ꢀ M.S., DMSO
(0.1m), 608C, 24 h, 1 atm O2. Catalyst conditions C: 5 mol% Pd(OAc)2,
DMSO (0.1m), 608C, 24 h, 1 atm O2. [b] Yield/diastereomeric ratio
based on 1H NMR spectroscopic analysis of the crude reaction mixture
with phenyltrimethylsilane as the internal standard. [c] Yield of the
isolated product. Diastereomeric ratio based on 1H NMR analysis of the
purified products. Boc=tert-butoxycarbonyl, Bz=benzoyl, Cbz=ben-
zyloxycarbonyl, DMSO=dimethylsulfoxide, M.S.=molecular sieves,
THF=tetrahydrofuran, TFA=trifluoroacetic acid, Ts=4-toluenesulfonyl.
Homepage: stahl.chem.wisc.edu
[**] We thank the NIH (R01 GM67173) and Organic Syntheses (ACS
Division of Organic Chemistry fellowship for A.B.W.) for financial
support of this work. Spectroscopic instrumentation was partially
funded by the NSF (CHE-1048642, CHE-0342998, CHE-9208463).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201305926.
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Table 2: Diastereoselective synthesis of oxazolidines from cyclization of
secondary O-allyl hemiaminals.
revealed palladium(II)/dimethylsulfoxide-based catalysts to
be the most promising.[10] Effective catalyst systems included
[Pd(DMSO)2(TFA)2] in THF,[10c] which is effective at ambient
temperatures (conditions A), Pd(TFA)2 in DMSO, which is
compatible with higher reaction temperatures (conditions B),
and Pd(OAc)2 in DMSO, which resemble conditions origi-
nally discovered by Larock and Hightower[10a] and Hiemstra
and co-workers[10b] (conditions C). The allylic N-tosyl carba-
mate substrate 1 was susceptible to decomposition under
these direct aerobic reoxidation conditions.[11] When cycliza-
tion to the oxazolidinone 2 occurred (e.g., entry 2), only
modest diastereoselectivity was observed. The N-allyl hemi-
aminal 3 cyclized to the corresponding oxazolidine 4 in
moderate yields, but the diastereoselectivity of the trans-
formation was poor.[12] O-Allyl hemiaminals are an appealing
class of substrates because they may be synthesized directly
from allylic alcohols, but they have not been tested previously
in Wacker-type cyclizations. The benzyl carbamate (Cbz)
derivative 5a underwent cyclization in excellent yield and
good diastereoselectivity to afford the trans-oxazolidine 6a
(entries 7–9). Conditions A and B were particularly effective.
The three-step detachable tethered nucleophile approach
for the conversion of a trans-crotyl alcohol into the vicinal
aminoalcohol derivative 8 is illustrated in Scheme 2. Trans-
crotyl alcohol is readily converted into the corresponding O-
allyl hemiaminal, and aza-Wacker cyclization proceeds
Entry
Substrate
Product
Cond.[a] Yield
[%]
d.r.[b]
1
2
A
B
86
88
12:1
11:1
3
B
73
>20:1
4
5
A
B
72
85
>20:1
>20:1
6
B
75
>20:1
7
8
9
B
B
B
78
59
53
>20:1
>20:1
>20:1
10
B
62
9:1
Scheme 2. Transformation of primary allylic alcohols into vicinal ami-
noalcohols. PPTS=pyridinium p-toluenesulfonate.
11
12
B
B
74
75
19:1
9:1
smoothly at ambient temperature (condition A). The oxazo-
lidine ring is unmasked under acidic conditions. Several
additional primary O-allyl hemiaminal substrates were sim-
ilarly effective. Comparison of benzyl- (Cbz) and tert-butyl
carbamate (Boc) O-allyl hemiaminals revealed that the Cbz-
derived nitrogen nucleophile is more effective (6c versus 6d).
A propyl-substituted alkene produced the oxazolidine 6e
with negligible alkene isomerization.[13] Finally, reaction with
[a] See Table 1 for descriptions of catalyst conditions A and B. [b] Yields of
the isolated products. Diastereomeric ratio based on 1H NMR spectro-
scopic analysis of the isolated material. Relative configurations of 6a and
6j were assigned by NOESY-1D spectroscopic analysis (other structures
assigned by analogy).
À
a trisubstituted alkene affords a tertiary C N bond (6 f);
conditions B was more effective than condition A in this
reaction.
higher diastereoselectivity can be achieved with the cis
substrate. Increasing the size of the secondary allylic sub-
stituent improves the diastereoselectivity, and conditions B
provides higher reactivity with these more sterically encum-
bered substrates (entries 4–6). The cyclic O-allyl hemiaminals
5j and 5k yield the cis-ring-fused products in good yields
(entries 7 and 8). Allylic alcohols derived from aldol additions
to crotonaldehyde also provide effective O-allyl hemiaminal
We next explored the scope of the diastereoselective
cyclization of O-allyl hemiaminals derived from secondary
alcohols (Table 2). Both trans- and cis-allylic alcohols are
good substrates and afford the same trans-4,5-disubstituted
oxazolidine (entries 2 and 3). The effectiveness of the trans-
allylic alcohol substrate is noteworthy because such substrates
are more readily accessible than the cis analogue. However,
2
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substrates (entries 9–12). The ketone adduct 5l is prone to
decomposition under the reaction conditions and provides
only modest yield of the oxazolidine 6l, but the Weinreb
amide 5m, ethyl ester 5n, and dimethylamide 5o are well-
tolerated.
The aldol reaction is one of many potential routes to
enantioenriched allylic alcohols[14] and thus can provide
access to enantioenriched aminoalcohol derivatives in con-
nection with our method. An asymmetric aldol reaction
enabled the synthesis of the enantioenriched allylic alcohol 9
from crotonaldehyde,[15] which was converted into the corre-
sponding O-allyl hemiaminal 5p and cyclized cleanly to the
oxazolidine 6p (Scheme 3). The oxazolidine 6p was obtained
with exquisite diastereoselectivity and no epimerization of
the a-methyl stereocenter.
Scheme 5. Synthesis of (À)-N-Cbz-O-methylacosamine. TBDPS=tert-
butyldiphenylsilyl, TBS=tert-butyldimethylsilyl.
lidine ring was opened under acidic conditions with concom-
itant formation of the methyl-protected cyclic acetal 16 [(À)-
N-Cbz-O-methylacosamine]. This rapid and redox econom-
Scheme 3. Transformation of enantioenriched allylic alcohol to the
oxazolidine with no epimerization. rsm = recovered starting material.
ical synthesis of (À)-acosamine illustrates
a versatile
approach which could be applied to a variety of other
aminosugar derivatives.
The utility of this method is illustrated in the synthesis of
the 2-deoxy-3-aminosugar (À)-acosamine.[16] 2-Deoxy-3-ami-
nosugars can be obtained by synthesis of the corresponding
acyclic 1,3-aminoaldehyde precursor. We envisioned that the
aminoaldehyde could be accessed rapidly by employing our
cyclization in a redox-relay sequence, whereby cyclization of
an O-allyl hemiaminal derived from a bis(allylic alcohol)
precursor would generate a masked aldehyde intermediate
(Scheme 4). Transfer of the olefin redox equivalent by b-
hydride elimination from the second allylic alcohol position
would form an enol ether and expedite elaboration of the
oxazolidine to the desired aminosugar target.
In summary, we have demonstrated that aza-Wacker
cyclizations can be used to synthesize stereodefined vicinal
aminoalcohols from allylic alcohol precursors by employing
a detachable tethered nucleophile approach. These oxidative
functionalization reactions are operationally simple and the
catalytic reactions give clean conversion of starting material
into desired product. The diversity of methods for the
asymmetric synthesis of allylic alcohols makes the diastereo-
selective transformation described here particularly apt for
application to a variety of contexts.
Received: July 8, 2013
Published online: && &&, &&&&
Keywords: amination · oxidation · palladium · stereoselectivity ·
.
synthetic methods
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Communications
Synthetic Methods
A. B. Weinstein, D. P. Schuman, Z. X. Tan,
S. S. Stahl*
&&&& — &&&&
Synthesis of Vicinal Aminoalcohols by
Stereoselective Aza-Wacker Cyclizations:
Access to (À)-Acosamine by Redox Relay
Diastereoselective aza-Wacker cyclization
of O-allyl hemiaminals under aerobic
conditions enables efficient access to 1,2-
aminoalcohol derivatives from allylic
alcohols. The scope of this method is
presented and its utility is highlighted in
a streamlined synthesis of the biologically
important aminosugar (À)-acosamine.
Cbz=benzyloxycarbonyl, TBDPS=tert-
butyldiphenylsilyl, TBS=tert-butyldime-
thylsilyl.
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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