Stereocontrolled synthesis of 1,3-diamino-2-ols by aminohydroxylation of bicyclic methylene-aziridines

Article abstract of DOI:10.1002/ejoc.201300416

Nitrogen-containing stereotriads, which are defined as compounds with three adjacent stereodefined carbon atoms, are common structural motifs in several biologically relevant compounds. The 1,3-diamino-2-ol motif in particular is an important pharmacophore for which there are limited stereoselective synthetic approaches. In this communication, we describe the aminohydroxylation of a series of bicyclic methylene-aziridines obtained from the aziridination of a series of homoallenic carbamates. The unusual electronic and steric features of these useful heterocyclic scaffolds render the Os-catalyzed aminohydroxylation of the exocyclic alkene highly regio- and stereoselective. Rearrangement of the proposed N,O-aminal intermediate to a 1,3-diamino-2-one is followed by reduction with NaBH₄ to deliver the desired 1,3-diamino-2-ols in good yields with high diastereomeric ratios. Complex amine-containing stereotriads are recurring motifs in a number of bioactive and pharmacologically important molecules. The regio- and stereocontrolled aminohydroxylation of bicyclic methylene-aziridines can be followed by carbonyl reduction to deliver 1,3-diamino-2-ols in good yields with good diastereoselectivities (Ts = para-tolylsulfonyl, Bs = phenylsulfonyl, Boc = tert-butoxycarbonyl). Copyright

Full text of DOI:10.1002/ejoc.201300416

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300416
Stereocontrolled Synthesis of 1,3-Diamino-2-ols by Aminohydroxylation of
Bicyclic Methylene-Aziridines
Cale D. Weatherly,[a] Ilia A. Guzei,[a] and Jennifer M. Schomaker*[a]
Keywords: Aziridination / Allenes / Strained molecules / Oxidation / Osmium
Nitrogen-containing stereotriads, which are defined as com-
pounds with three adjacent stereodefined carbon atoms, are
common structural motifs in several biologically relevant
compounds. The 1,3-diamino-2-ol motif in particular is an
homoallenic carbamates. The unusual electronic and steric
features of these useful heterocyclic scaffolds render the Os-
catalyzed aminohydroxylation of the exocyclic alkene highly
regio- and stereoselective. Rearrangement of the proposed
important pharmacophore for which there are limited stereo- N,O-aminal intermediate to a 1,3-diamino-2-one is followed
selective synthetic approaches. In this communication, we
describe the aminohydroxylation of a series of bicyclic meth-
ylene-aziridines obtained from the aziridination of a series of
by reduction with NaBH4 to deliver the desired 1,3-diamino-
2-ols in good yields with high diastereomeric ratios.
We hypothesized that allene aziridination might be used
to access 1,3-diamino-2-ols, a motif found in many natural
products and biologically active molecules (Figure 1). These
include the HIV protease inhibitor Darunavir,[4a] the endur-
acididine components of the antibiotic mannopeptimycin
β,[4b] Mipralden,[4c] a rare and potent binder of Mcl-1 and
Bcl-X(L), as well as compounds that inhibit BACE-1.[4d]
The synthesis of the nitrogen–oxygen–nitrogen stereotriads
found in these molecules often require significant manipula-
tion of chiral starting materials and multistep synthetic se-
quences.[5]
Introduction
The development of catalytic methods for the oxidation
of olefins to compounds containing vicinal heteroatom-
bearing stereocenters is one of the central developments of
organic chemistry in the past three decades.[1] However,
these methods are limited to the introduction of two hetero-
atoms by virtue of the substrate and can suffer from issues
with regioselectivity if two different heteroatoms are in-
stalled. Efficient regio-, chemo-, and stereoselective routes
to nitrogen-containing arrays of three or more carbon–het-
eroatom bonds (“stereotriads”) through the oxidation of
allenes could help to address some of the shortcomings as-
sociated with olefin oxidation and streamline the syntheses
of these useful motifs.[2] Allenes present several advan-
tageous features for stereotriad construction, as they are
easily synthesized, their axial chirality can be transferred
to point chirality, and they possess three adjacent sites for
functionalization.[3] Our group has recently described the
efficient synthesis of stereotriads of the form C–Nu/C–N/
C–E (Nu = nucleophile, E = electrophile) from homoallenic
sulfamates through allene aziridination as a key step.[2e] Al-
though this approach offers diverse choices for the Nu and
E groups of the product, the placement of nitrogen atom
remains restricted to the central carbon atom of the
stereotriad. To gain access to other valuable nitrogen-con-
taining stereotriads, alternative strategies to harness the
unique reactivity of bicyclic methylene-aziridines were
desired.
Figure 1. Bioactive molecules with N–O–N stereotriads.
Results and Discussion
[a] Department of Chemistry, University of Wisconsin, Madison,
1101 University Avenue, Madison, WI 53706, U.S.A
Fax: +1-608-265-3454
Our first strategy to obtain 1,3-diamino-2-ols from all-
enes employed a five-step, one-pot conversion of homoall-
enic carbamate 1a into N–O–N stereotriad 1d (Scheme 1).
This first-generation synthesis proceeded by way of an in-
E-mail: schomakerj@chem.wisc.edu
Homepage: http://www.chem.wisc.edu/users/schomakerj
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300416.
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C. D. Weatherly, I. A. Guzei, J. M. Schomaker
SHORT COMMUNICATION
tramolecular aziridination to form bicyclic methylene-azir- 5 and 81% yield of 6 (Table 1, entry 6). The PTC was para-
idine 1b, intermolecular aziridination to form 1,4-diaza- mount to the success of the reaction, as its absence (Table 1,
spiro[2.2]pentane 1c, ring-opening with an acetate nucleo- entries 7 and 8) gave no conversion to 6.
phile, rearrangement, and reduction (Scheme 1, top). Al-
Table 1. Optimization of the aminohydroxylation.
though the individual steps of this approach were high
yielding, cleavage of the N–N bond in the final product was
difficult.[2d]
Scheme 1. Syntheses of 1,3-diamino-2-ols from allenes (tpa = tri-
phenylacetate, Phth = phthalyl, Ts = para-tolylsulfonyl, Bs = phen-
ylsulfonyl, Boc = tert-butoxycarbonyl).
To address this limitation and to improve the efficiency
of the sequence, we wanted to investigate the direct amino-
hydroxylation of bicyclic methylene-aziridine 1b as a poten-
tial route to N–O–N stereotriads 2b (Scheme 1, bottom).[6]
The successful implementation of this second-generation
synthesis required achieving a stereo- and regioselective
aminohydroxylation to form an N,O-aminal intermediate
[a] dr was Ͼ19:1 unless noted. [b] dr was 3:1.
capable of stereoselective rearrangement to 1,3-diami-
Chloramine B could also be employed as the nitrogen
noketone 2a. As our previous reports on the reactivity of source to provide 6 in 74 and 79% yield (Table 1, entries 10
methylene-aziridines demonstrated that the concavity of and 11), and this reagent offered the advantage of being
this unusual fused heterocycle can promote highly dia- more labile than the tosyl group. Attempts to enhance the
stereoselective reactions of the exocyclic olefin, this strategy reaction rate by using several amine additives, including hy-
warranted further investigation.[2c]
droquinidine 1,4-phthalazinediyl diether [(DHDQ)2PHAL],
Early reports from the Sharpless group described four pyridine, and N,N,NЈ,NЈЈ-tetramethyl-1,2-ethylenediamine
primary sets of conditions for the osmium-catalyzed amino- (TMEDA), were not successful (Table 1, entries 8, 9, 12–
hydroxylation of alkenes.[7] These conditions were applied 14).[8] The use of BocNNaCl as the nitrogen source
to the transformation of methylene-aziridine 5 into 1,3-di- (Table 1, entry 15) resulted in decreased conversion and
aminated ketones 6 and 6a (Table 1). Biphasic systems con- yield.
sisting of mixtures of tBuOH or CH3CN/H2O using Chlor-
With successful conditions for the aminohydroxylation
amine T as the nitrogen source gave low yields of desired in hand, the next step was to explore stereocontrol in the
6 (Table 1, entries 1 and 2) and significant byproduct for- reduction of 1,3-diamino-2-one 6a. To the best of our
mation. Switching the solvent to benzene and employing knowledge, no systematic investigations on the reduction
BnEt3NBr as a phase-transfer catalyst (PTC) gave low con- of acyclic α,αЈ-diaminated ketones have been undertaken.
version, but mainly to the desired product (Table 1, en- Reduction of 6a with NaBH4 in CH2Cl2 gave 1,3-diamino-
try 3). Increasing the temperature of the reaction gave 70% 2-ol 7 in excellent yield and stereoselectivity (Table 2, en-
conversion, but only 25% yield of 6 (Table 1, entry 4). try 1). Attempts to conduct the aminohydroxylation/re-
Changing the solvent to chloroform gave the product in duction sequence in a single pot gave comparable overall
both moderate conversion and yield (Table 1, entry 5). This yield (64%) but a significant decrease in the dr (5:1dr single
system was further optimized by increasing the loading of pot, 10:1dr two pots). A series of reductions in solvents of
the catalyst from 5 to 7.5 mol-% to give full conversion of differing polarities (Table 2, entries 2–4) demonstrated that
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Stereocontrolled Synthesis of 1,3-Diamino-2-ols
a larger dr was obtained in less polar solvents. The relative group at C3 of the substrate, silyl-protected alcohols (TIPS
1,2-anti/2,3-syn stereochemistry of 7 was confirmed by X- = triisopropylsilyl), and remote aryl groups (Table 4, en-
ray crystallography of a derivative (see the Supporting In- tries 3–6), provided optimized conditions were employed
formation for further details) and is consistent with Felkin– (Table 4, conditions B). For more electron-rich methylene-
Anh control by C1.[9]
aziridines (Table 4, entries 3 and 4), trace amounts (Ͻ10%)
of overoxidized product c were also observed. Application
of conditions C to aryl-substituted methylene-aziridines
gave moderate yields of the desired products (Table 4, en-
tries 7–9), although one electron-rich substrate did not react
(Table 4, entry 10), yields for these types of aminohydroxyl-
ations are typically moderate, but this is offset by the high
yield and dr of the reduction, which leads to a rapid in-
crease in the stereochemical complexity.
Table 2. Reduction of the 1,3-diaminated ketone.
Table 4. Scope of the N–O–N stereotriad formation.
[a] Isolated yield. [b] NMR yield calculated by using mesitylene as
an internal standard.
The standard aminohydroxylation conditions from
Table 1 were unsuccessfully applied to phenyl-substituted
methylene-aziridine 8 (Table 3, entry 1). The use of carb-
amate-derived chloramine salts, commonly used for the
aminohydroxylation of styrenes, substantially improved the
yield to 55% (Table 3, entry 5).[10] Reduction of 8b was best
carried out in CHCl3/H2O (1:1) with sonication to give 8c
in 88% yield and Ͼ19:1dr.
Table 3. Synthesis of aryl-substituted N–O–N stereotriads.
[a] Conditions A, aminohydroxylation: K2OsO2(OH)4 (7.5 mol-%),
Chloramine T, 33 °C; reduction: NaBH4 in CH2Cl2. Conditions B,
aminohydroxylation: OsO4 (10 mol-%), Chloramine B, 37 °C; re-
duction: NaBH4 in CH2Cl2. Conditions C, aminohydroxylation:
OsO4 (7.5 mol-%), BocNNaCl, 30 °C; reduction: NaBH4 in CHCl3/
H2O (1:1) with sonication. A dr of Ͼ19:1 for all substrates.
[b] Ͻ10% dihydroxylation product was observed. [c] 60% based on
recovered starting material. [d] No reaction upon heating to 50 °C.
The excellent regioselectivity of the aminohydroxylation
may be attributed to the preference of the chloramine nitro-
gen atom to bind to the less substituted and/or more elec-
tron-rich carbon atom of the methylene-aziridine,[11] as the
[a] Based on recovered starting material.
The scope of the aminohydroxylation/reduction of bicy- carbamate of the substrate likely serves as an inductively
clic methylene-aziridines to 1,3-diamino-2-ols was investi- electron-withdrawing group. The failure of two substrates,
gated (Table 4). The reaction was highly stereoselective, as β-carboxyethyl-substituted 13 and p-MeO-phenyl-substi-
E methylene-aziridine 5 (Table 4, entry 1) and Z isomer 9 tuted 16, to react in the aminohydroxylation supports elec-
(Table 4, entry 2) were shown to yield 1,3-diamino-2-ols 6 tronic control of both reactivity and regioselectivity. The
and 9b epimeric at C3. The relative 1,2-anti/2,3-anti stereo- former withdraws electron density from the less-substituted
chemistry of 9b was confirmed by X-ray crystallography of C3 carbon atom of the reactive site, whereas the latter do-
a derivative (see the Supporting Information for further de- nates electron density to the more substituted C2 carbon
tails). The transformation tolerated branching in the alkyl atom.
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Conclusions
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In summary, we have developed a highly stereoselective
method for the synthesis of 1,3-diamino-2-ols through Os-
catalyzed aminohydroxylation/reduction of bicyclic methyl-
ene-aziridines. The reaction proceeds with excellent regiose-
lectivity and diastereoselectivity to rapidly deliver these use-
ful structural motifs.
Experimental Section
Synthesis of 1,3-Diamino-2-ones from Bicyclic Methylene-Aziridines
[3] a) H. Kim, L. J. Williams, Curr. Opin. Drug Discov. Devel. 2008,
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Procedure A: A 0.05 m solution of the methylene-aziridine (1 equiv.)
and potassium osmate (0.075 equiv.) in CHCl3 was treated with
an equal volume of an aqueous solution of the chloramine salt
(3.1 equiv.) and the phase-transfer catalyst (0.05 equiv.). The flask
was fitted with a reflux condenser, and the mixture was heated to
33 or 37 °C by using an oil bath. After 20 h, the reaction mixture
was cooled to room temperature and extracted with CH2Cl2 (3ϫ).
The combined organic layer was dried with Na2SO4 and concen-
trated under reduced pressure, and the residue was purified by flash
chromatography (hexane/ethyl acetate gradient) to give the ketone.
Procedure B: An aqueous solution of 2% (w/v) OsO4 (0.05 equiv.)
was substituted for potassium osmate. Two further portions of 2%
(w/v) OsO4 solution (0.025 equiv.) were added at 4 h intervals.
[5] For selected approaches to the synthesis of 1,3-diamino-2-ols,
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[6] For recent reviews on the aminohydroxylation of alkenes, see:
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Reduction of 1,3-Diamino-2-ones to 1,3-Diamino-2-ols
Procedure A: NaBH4 (6 equiv.) was added to the ketone, followed
by enough CH2Cl2 to yield a 0.066 m solution in substrate. The
mixture was allowed to stir for 12 h, quenched with aqueous
NH4Cl, and extracted with CH2Cl2. The combined organic layer
was dried with Na2SO4, concentrated in vacuo, and purified by
flash chromatography (hexanes/ethyl acetate) to give the 1,3-di-
amino-2-ol.
Procedure B: NaBH4 (6 equiv.) was added to the ketone, followed
by enough CH2Cl2 to yield a 0.066 m solution in substrate. An
equal volume of deionized water was added and the mixture soni-
cated until the reduction was complete, typically 5–7 h.
CCDC-931790 (for 7c) and -931791 (for 9c) contain the supplemen-
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, characterization data, and copies of the
1H NMR and 13C NMR spectra for all new compounds.
[9] a) N. T. Anh, O. Eisenstein, Nouv. J. Chim. 1977, 1, 61; b) N. T.
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[11] L. Kurti, B. Czako (Eds.), Sharpless Asymmetric Aminohydrox-
ylation: Strategic Applications of Named Reactions in Organic
Synthesis Elsevier, Amsterdam, 2005.
Acknowledgments
The authors thank the University of Wisconsin-Madison for finan-
cial support. Michael Freidberg (UW-Madison) is thanked for as-
sistance with substrate synthesis.
Received: February 26, 2013
Published Online: May 6, 2013
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