Aminodiols via stereocontrolled oxidation of methyleneaziridines

Article abstract of DOI:10.1021/ol5003576

A highly diastereoselective Ru-catalyzed oxidation/reduction sequence of bicyclic methyleneaziridines provides a facile route to complex 1-amino-2,3-diol motifs. The relative anti stereochemistry between the amine and the vicinal alcohol are proposed to result from 1,3-bischelation in the transition state by the C1 and C3 heteroatoms.

Full text of DOI:10.1021/ol5003576

Letter
pubs.acs.org/OrgLett
Aminodiols via Stereocontrolled Oxidation of Methyleneaziridines
Jared W. Rigoli, Ilia A. Guzei, and Jennifer M. Schomaker*
Department of Chemistry, University of WisconsinMadison, Madison Wisconsin 53706, United States
S
* Supporting Information
ABSTRACT: A highly diastereoselective Ru-catalyzed oxida-
tion/reduction sequence of bicyclic methyleneaziridines pro-
vides a facile route to complex 1-amino-2,3-diol motifs. The
relative anti stereochemistry between the amine and the vicinal
alcohol are proposed to result from 1,3-bischelation in the
transition state by the C1 and C3 heteroatoms.
minodiols are ubiquitous in a host of bioactive molecules
and natural products (Figure 1).1 Popular approaches to
Scheme 1. Allene Functionalization Strategies
A
Figure 1. Bioactive molecules containing NOO stereotriads.
these motifs often employ starting materials from the chiral
pool or utilize the ring-opening of chiral epoxy alcohols with
amine nucleophiles.2,3 These strategies work well when the
target aminodiol is relatively simple, but accessing more
complex and densely substituted motifs can be difficult.
While the dihydroxylation of chiral allylic amines addresses
this challenge to some extent, high loadings of OsO4 and
variable dr are drawbacks.4
Our group has developed new methods that introduce three
new sp3 carbon−heteroatom bonds into an allene in a
sterecontrolled manner. Rapid access to C−Nu/C−N/C−E
stereotriads (motifs containing three contiguous chiral carbons,
Ic, Scheme 1) from homoallenic sulfamates is enabled through
the intermediacy of bicyclic methyleneaziridines Ia.5 This
method offers diversity in the choices for the Nu and E groups
of Ic but restricts the placement of nitrogen to the central
carbon of the stereotriad. The utility of allene oxidation could
be expanded if amine-containing stereotriads of other
substitution patterns could be accessed. Herein, we report a
highly diastereoselective formation of C−N/C−O/C−O
(NOO) triads from simple homoallenic carbamates.
The initial step of our strategy employs allene aziridination to
a methyleneaziridine IIa (Scheme 1).6 The bicyclic nature of
IIa was expected to promote dihydroxylation to a hemiaminal
IIb in high dr. Unraveling of IIb to a 1,3-hydroxyaminated
ketone IIc, followed by reduction, would yield either IId or IIe,
depending on the nature of the reductant.
exocyclic double bond was problematic. Treatment of
homoallenic carbamate 1a (Table 1) with OsO4 and NMO
gave no reaction; however, a 1 mol % loading of RuCl3 in the
presence of NaIO4 as the terminal oxidant (“flash dihydrox-
ylation”) cleanly provided the desired ketone 2aE (IIc, Scheme
1 for general structure).7 The key to achieving excellent
conversion and minimizing oxidative cleavage was to employ
CeCl3 as an additive.7d,g Under these conditions, the ketone
2aE was obtained as a single diastereomer, indicating excellent
facial selectivity in the dihydroxylation. Immediate reduction of
the ketone with NaBH4 in MeOH yielded the 1-amino-2,3-diol
3aE in >20:1 dr (Table 1, entry 1).
The scope of the reaction was investigated (Table 1).5,6 In all
cases, the 1-amino-2,3-diol was obtained in >20:1 dr, with both
We initially attempted to use homoallenic sulfamates as
substrates, but aziridine ring-opening prior to reaction of the
Received: February 5, 2014
Published: March 11, 2014
© 2014 American Chemical Society
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Letter
Table 1. Stereocontrolled Transformation of gem-Dimethyl Bicyclic Methyleneaziridines to NOO Stereotriads
a
b
c
Combined yield of E and Z. dr of both the E and Z products. The E and Z methyleneaziridines were separated, and only E was used in the
d
reaction. 100 mol % CeCl3 and 3.0 equiv of NaIO4 were employed in the oxidation, while Zn(BH4)2 in Et2O at 0 °C was used in the reduction.
Table 2. Expanding the Scope of NOO Stereotriad Synthesis*
*
Conditions A: 1 mol % of RuCl3, 50 mol % of AcOH, 1.5 equiv of NaIO4, 2:1 MeCN/H2O. Conditiosn B: 1 mol % of RuCl3, 20 mol % of H2SO4,
a
b
1.5 equiv of NaO4. 3:3:1 EtOAc/MeCN/H2O. Yield of the product from the E isomer. dr of the product from the E methyleneaziridine.
aryl (entries 1−3) and alkyl (entries 4−8) groups tolerated at
C3 of the substrate. The presence of an EWG on the arene
decreased the yield but did not impact the dr (Table 1,
compare entry 3 to entries 1 and 2). The 1-amino-2,3-diols
obtained from E methyleneaziridines contained the 1,2-anti:2,3-
syn stereochemistry, as verified by X-ray crystallography of 3cE.
The structures of 3aE and 3bE were assigned by analogy to 3cE
(Supporting Information). The anti relationship between the
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Letter
C1 amine and the C2 alcohol was also observed when C3 was
achiral (entries 4 and 5). When the two substituents at C3 of
the allene were very similar, the mixtures of E and Z
methyleneaziridines were difficult to separate (entries 6−8).
However, the reaction could be carried out on the 70:30 E/Z
mixtures and the resulting isomers separated to give the
diastereomeric triads 3f−hE and 3f−hZ in excellent dr (E
shown). Separating ketones 2gE and 2gZ and independently
subjecting them to reduction clearly showed the dr of the
reduction was >20:1. The relative stereochemistries of both
3gE and 3gZ were verified by X-ray crystallography as 1,2-
anti:2,3-syn (Supporting Information) for 3gE and 1,2-anti:2,3-
anti for 3gZ.
The 1,3-disubstituted methyleneaziridine 1i (entry 9) was
challenging, as overoxidation to the diketone using Ru catalysis
was problematic.7 Increasing the amount of CeCl3 improved
the selectivity for 2i, but at the cost of conversion. The use of a
full equivalent of CeCl3 and portionwise addition of 3.0 equiv
of NaIO4 gave a 66% yield of the desired product with minimal
overoxidation.
To expand the reaction scope and shed light on the factors
responsible for stereocontrol in the ketone reduction,
methyleneaziridines lacking the gem-dimethyl group were
explored (Table 2). These compounds were susceptible to
ring-opening when the conditions described in Table 1 were
employed. Substitution of AcOH or H2SO4 for CeCl3 as the
additive improved both the conversions and the yields in the
dihydroxylation.
Figure 2. Possible α,α′-chelation models for stereocontrol.
Oxidation of E-4a (Table 2, entry 1) gave the ketone 5a in
98% yield as a single diastereomer. Reduction of 5a with
NaBH4 in MeOH gave the 1,2-anti:2,3-syn stereoisomer 7a in
80% yield (verified by X-ray crystallography) and 5.7:1 dr,
along with the minor isomer 8a. The dialkyl-substituted
methyleneaziridines 4b and 4c were not easily separable, but
the diastereomers could be resolved at either the ketone or the
1-amino-2,3-diol stage to give the products in dr of 7.1−8.3:1
(entries 2 and 3). Substrates with identical substituents at C3
(entries 4 and 5) exhibited a 1,2-anti relationship between the
C1 amine and the C2 alcohol.
The unexpected stereochemical outcomes were initially
puzzling. While Felkin−Anh and Cram chelation models are
often invoked to explain stereochemical outcomes in the
addition of nucleophiles to α-substituted carbonyls, control
when a ketone is flanked by two different potential chelating
groups is poorly understood.8,9 We propose the −NH and the
−OH of ketones of the general form 9 (Figure 2) participate in
1,3-bis-chelation to give a trans decalin-type intermediate 10.
Reduction of the ketone from the top face should be favored to
yield the 1,2-anti:2,3-syn relationship observed in the products.
To determine how well this hypothesis fit our data, the
reduction of ketones of several substitution patterns were
examined more closely. In the case of 3fE and 3fZ, formed
from the E and Z stereoisomers of 2f, an anti relationship
between C1 and C2 was noted in both of the products (Table
1, entry 6 and Figure 2, A and B), ruling out stereocontrol of
the reduction by C3. The observed results could be rationalized
either by our proposed model or by assuming that the amine at
C1 is responsible for controlling the reduction outcome. If C1
were solely responsible for stereocontrol of the reduction, the
removal of a substituent from C3 of 2i (Table 1, entry 9 and
Figure 2, C) would not be expected to influence the dr.
However, we found that the dr of 3iE decreased to 2.2:1 using
NaBH4 in MeOH. Switching to a less polar solvent and a lower
temperature increased the dr, while substitution of Zn(BH4)2
for NaBH4 restored the dr to 7.9:1 with a 1,2-anti relationship
as verified by X-ray crystallography. Chelation control through
the C3 oxygen would be expected to yield the 1,2-syn:2,3-anti
triad; thus, we propose that a tighter transition state exists in C
when M = Zn (van der Waal radius of Zn2+ = 0.88 Å), as
compared to M = Na (Na+ = 1.16 Å), leads to an increase in dr.
In addition, the trans decalin transition state in C is disfavored
by the need to place the alkyl group in the pseudoaxial position,
a situation that is less favorable in the presence of a highly polar
solvent and/or a large cation. Removal of the gem-dimethyl
groups in 5a (Figure 2, D) lowered the dr, perhaps due to the
lack of assistance from the Thorpe−Ingold effect in enforcing
the trans decalin transition state.
In conclusion, rapid and diastereoselective conversion of
homoallenic carbamates to 1-amino-2,3-diols has been
achieved. Stereoselectivity in the reduction of the α,α′-
substituted ketones depends on the specific substitution pattern
of the substrate but often exhibits dr > 10:1. Coupled with our
previous observations that the axial chirality of an allene can be
transferred to point chirality, this protocol permits rapid access
to densely functionalized, enantioenriched aminodiols.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and full characterizations are available
for all new compounds. X-ray crystallographic data is available
for compounds 3cE, 3gE, 3gZ, 7aE, and 3iE (CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: schomakerj@chem.wisc.edu.
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Letter
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The NMR facilities at UWMadison are funded by the NSF
(CHE-9208463, CHE-9629688) and NIH (RR08389-01).
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