Anti-dioxylation of cyclohex-4-ene-1,2-diamine derivatives: Asymmetric routes to hydroxy- and amino-substituted cyclohexane and 7-azanorbornane

Article abstract of DOI:10.1002/ejoc.201301700

The highly diastereoselective anti-dioxylation of (1R,2R)-1,2-bis[(1S)- phenylethylamino]cyclohexene was accomplished through epoxidation of the double bond with m-chloroperbenzoic acid (mCPBA) in the presence of a sulfonic or trihaloacetic acid and ring opening of the epoxide in situ in the presence of sulfonate or carboxylate anions. The two procedures, after basic quenching and reductive removal of the N-substituents, provide stereoselective access to 2-exo-5-endo-5-amino-7-azabicyclo[2.2.1]heptan-2-ol and 4,5-diaminocyclohexane- 1,2-diol, respectively. The different outcomes are explained by differing chair conformations of the protonated diamine-epoxide intermediates, which undergo ring opening through a preferred anti-diaxial mechanism.

Full text of DOI:10.1002/ejoc.201301700

FULL PAPER
DOI: 10.1002/ejoc.201301700
anti-Dioxylation of Cyclohex-4-ene-1,2-diamine Derivatives: Asymmetric
Routes to Hydroxy- and Amino-Substituted Cyclohexane and 7-Azanorbornane
Diego Savoia,*[a] Davide Balestri,[a] Stefano Grilli,[a] and Magda Monari[a]
Keywords: Synthetic methods / Asymmetric synthesis / Diastereoselectivity / Oxidation / Alkenes
The highly diastereoselective anti-dioxylation of (1R,2R)-1,2-
bis[(1S)-phenylethylamino]cyclohexene was accomplished
through epoxidation of the double bond with m-chloroper-
benzoic acid (mCPBA) in the presence of a sulfonic or tri-
haloacetic acid and ring opening of the epoxide in situ in the
presence of sulfonate or carboxylate anions. The two pro-
cedures, after basic quenching and reductive removal of the
N-substituents, provide stereoselective access to 2-exo-5-
endo-5-amino-7-azabicyclo[2.2.1]heptan-2-ol and 4,5-di-
aminocyclohexane-1,2-diol, respectively. The different out-
comes are explained by differing chair conformations of the
protonated diamine-epoxide intermediates, which undergo
ring opening through a preferred anti-diaxial mechanism.
Introduction
Optically pure trans-cyclohex-4-ene-1,2-diamine deriva-
tives 1 are valuable chiral synthons for the construction of
more complex compounds through functionalization of the
C=C double bond (Scheme 1). For example, an unsymmet-
rically N,NЈ-disubstituted analogue of 1a was prepared by
catalytic ring-opening (meso-desymmetrization) of N-(3,5-
dinitrobenzoyl)cyclohexa-1,4-diene monoaziridine and then
converted into Tamiflu.[1,2] Recently, we have described hy-
droboration of the ditosylate salt of (1R,2R)-N,NЈ-bis[(S)-1-
phenylethyl]cyclohex-4-ene-1,2-diamine (1b)[3,4] to give the
diastereomeric 3,4-diaminocyclohexanol derivatives 2b and
2Јb, and the prevalent form 2Јb was first converted into
endo-7-azabicyclo[2.2.1]heptan-2-amine 3b and then into
3a.[5] The racemic endo-7-azabicyclo[2.2.1]heptan-2-amine
moiety is present in more complex, biologically and phar-
macologically active molecules.[6] Optically pure 2-endo-3-
exo-3-amino-2-arylsulfonyl-7-azanorbornenes were ob-
tained by a sequence involving cycloaddition reactions of
N-Boc-pyrrole and acetylenic sulfones and final resolution
by preparative chiral HPLC, and were shown to be potent
inhibitors of malarial aspartic protease.[7–9]
Scheme 1. Compounds derived from N,NЈ-disubstituted trans-cy-
clohex-4-ene-1,2-diamines.
benzoic acid (mCPBA) in NaHCO3-buffered CH2Cl2 gave
predominantly 5c, which bears axial hydroxy substituents,
via the corresponding epoxide 4c. On the other hand, dia-
stereomer 5Јc was prepared from cis-1,2-diol-trans-4,5-di-
aminocyclohexene by a sequence of steps.[10,11]
Enantiopure 4,5-diaminocyclohexane-1,2-diols have, to
the best of our knowledge, never been prepared, although
they represent high-value targets in medicinal chemistry.
Hence, we directed our efforts towards their synthesis.
Both cis and racemic trans-cyclohex-4-ene-1,2-diamine
1a were converted into 4,5-diaminocyclohexane-1,2-diols,
the PtCl2 complexes of which exhibited different solubility
and antitumor properties depending on the relative stereo-
chemistry of the amino and hydroxyl groups. Moreover,
epoxidation of the di-Cbz derivative 1c with m-chloroper-
[a] Dipartimento di Chimica “G. Ciamician”, Università di
Bologna,
via Selmi 2, 40126 Bologna, Italy
Results and Discussion
E-mail: diego.savoia@unibo.it
http://www.unibo.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301700
The use of peracids for the epoxidation of amino-substi-
tuted alkenes requires protection of the amine, as previously
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D. Savoia, D. Balestri, S. Grilli, M. Monari
FULL PAPER
reported for the preparation of the diamine-epoxide 4c.
Hence, we choose to perform the oxidation of cyclohex-4-
ene-1,2-diamine 1b by the same procedure that Davies ap-
plied to N,N-dibenzyl- and N-benzylcyclohex-3-en-
amine[12–14] making use of mCPBA in the presence of an
excess of acid HA (p-toluenesulfonic or trichloroacetic
acid). This protocol is clearly advantageous because protec-
tion of the amino groups can be avoided in the acidic me-
dium, and the intermediate protonated epoxide undergoes
attack by the oxyanion A– leading to the dioxylated prod-
uct. Reactions of 1b with mCPBA (2 equiv.) in the presence
of variable amounts of p-toluenesulfonic acid monohydrate
(TsOH) were carried out in CH2Cl2 at room temperature,
and were quenched at different times to establish the opti-
mal conditions. In all cases, the reaction mixture was
washed with aqueous solutions of Na2SO3 and then
NaHCO3, and the crude organic product was analyzed by
1H NMR spectroscopy. Column chromatography was used
to separate the products. We could ascertain that the start-
ing compound 1b was almost completely consumed after
4 h when 6 equiv. TsOH/H2O and 2 equiv. mCPBA were
used, whereas either extending the reaction time or increas-
ing the amount of acid led to more complex mixtures and
decreased yields of isolated products. Under the optimized
conditions, two to four main products were obtained
(Scheme 2 and Table 1). Minor amounts of epoxide 4b (9%)
and mono-O-tosyl diol 7A (6%) were first eluted together
by column chromatography. Then the main products, di-
aminodiol 5Јb (27%) and 2-exo-5-endo-5-amino-7-azabicy-
clo[2.2.1]heptan-2-ol 6 (29%), were eluted together. How-
ever, when a mixture of 5Јb and 6 was treated with PPh3/
diisopropyl azodicarboxylate (DIAD) in tetrahydrofuran
(THF) at room temperature, complete conversion of 5Јb
into 6 was achieved (overall 55% yield of 6). Similarly, basic
treatment of the 4b/7A mixture [1,8-diazabicyclo[5.4.0]un-
dec-7-ene (DBU), CH2Cl2, room temp., 12 h] resulted in
Scheme 2. Reactions of cyclohexenediamine 1b with mCPBA and
sulfonic acids.
Table 1. Dioxylation of 1b with mCPBA (2 equiv.) in the presence
of sulfonic acids.
Entry Brønsted acid [equiv.] Products (Yield [%])[b]
1
2
3
4
5
TsOH[a] (6)
TsOH[a] (8)
TfOH (6)
MsOH (6)
MsOH (6)
5Јb (27), 6 (29), 4b (9), 7A (6)
5Јb (25), 6 (25), 4b (12), 7A (12)
5Јb (20), 6 (19), 4b (34)
6 (40), 4b (10), 7C (20)
6 (90)[c]
[a] Monohydrate form. [b] Yield of products isolated by column
chromatography. [c] After microwave irradiation of the crude reac-
tion product at 150 °C in a sealed tube.
complete conversion into epoxide 4b. The structures of the
1
products were determined by H NMR spectroscopy and oxide 4c. In the latter case, hydrolysis with aq. HCl gave
the exo-orientation of the hydroxyl group in bicyclic com- mainly diol 5c[9] through the preferred anti-diaxial mode via
pound 6 was confirmed by NOE experiments (see the Sup- a chair-like transition state, according to the Fürst–Plattner
porting Information).
rule.[15–18]
The analogous reaction performed on 1b with MsOH
Several features of the reactions described above are
worth comment. It is worth noting that bicyclic exo-alcohol gave the bridged bicyclic compound 6, which was isolated
6 does not derive from rearrangement of epoxide 4b alone in 40% yield after chromatographic separation from
through intramolecular nucleophilic attack of the trans-dis- a mixture of monoprotected diol 7C (20%) and epoxide 4b
posed amino group, because this reaction would produce (10%). However, microwave irradiation of the crude prod-
bicyclic endo-alcohol. The ratios (5Јb + 6)/(4b + 7) reflects uct in a sealed tube (150 W, 10 min, T up to 150 °C) in the
the regioselectivity of the epoxide ring-opening step. Di- presence of a catalytic amount of MsOH for 16 min, re-
aminodiol 5Јb, which has equatorial hydroxy and amino sulted in clean conversion into bicyclic compound 6, which
substituents on the cyclohexane ring, was presumably was isolated in a remarkable yield of 90% (Table 1, entry 5).
formed by ring opening of the protonated epoxide by water The higher yield obtained in the MW-assisted reaction (en-
present in the sulfonic acid. Diaxial diol 5b (see below) was try 5 vs. 4) was possible because chromatographic separa-
not observed in any chromatographic fractions because of tion of the diverse products could be avoided. We suppose
its higher polarity as compared to 5Јb, nevertheless, it might that MW irradiation induces rapid equilibration between
have been formed in minor amounts (see below). This out- the two diastereomeric mono-O-mesylate diols 7C and 7ЈC
come indicates that the hydrolytic ring opening of the pro- via epoxide 4b. Only 7ЈC, which displays trans-1,4-orienta-
tonated epoxide occurred with very high regioselectivity, tion of the amino and OMs groups, can undergo cyclization
which, unexpectedly, was opposite to that observed with ep- by intramolecular substitution to give bicyclic compound 6
1908
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Asymmetric Dihydroxylations
Scheme 4. Reactions of cyclohexenediamine 1b with mCPBA and
trihaloacetic acids.
Scheme 3. Proposed mechanism for the conversion of 7C into 6 by
MW irradiation.
uents occupied pseudoequatorial positions in the crystal
structure of the cyclohex-4-ene-1,2-diamine dihydrochloride
(Scheme 3). Simple heating of the crude mixture in MeCN 1b·2HCl (see the Supporting Information), as observed in
at reflux for 8 h did not give satisfactory results. the previously reported X-ray structures of several trans-
Finally, the effect of the nature of the carboxylic acids cyclohexane-1,2-diamine salts.[20–23] We assumed that no
on the reaction outcome was investigated (Scheme 4). The change would occur upon substituting chloride for sulfon-
oxidation reactions of 1b with mCPBA in the presence of ate or carboxylate anions. However, it must be considered
10 equiv. of either trifluoroacetic acid (TFA) or tri- that equilibration of the alternative half-chair conforma-
chloroacetic acid (TCA) afforded mixtures of diols 5Јb and tions of substituted cyclohexenes requires less energy with
5b (Scheme 4) in excellent yields, with the former predomi- respect to those of the corresponding substituted cyclohex-
1
nating (dr ca. 90:10 by H NMR analysis of the crude mix- anes. As a matter of fact, the equatorial conformers of 4-
ture); only traces of impurities were observed. The main methylcyclohexene and 4-bromocyclohexene are only
diastereoisomer 5Јb was easily separated by column slightly favored, with the axial isomers being higher in en-
chromatography from the more polar 5b, which was ob- ergy by 1 kcal/mol or less, because the presence of the
tained in very low yield that did not allow complete charac- double bond eliminates one of the 1,3-interactions with the
terization. We think that in these reactions the two diols C4-substituent, which is slightly shifted from the vertical
were formed by ready hydrolysis of the corresponding elus- towards the double bond.[24,25] The half-chair conformation
ive mono-O-trihaloacetate derivatives. On the other hand, is also preferred for cyclohexene oxide.[26,27]
1
cyclization of the intermediate mono-O-trihaloacetate of
We carried out H NMR titration studies following ad-
5Јb to give bicyclic compound 6 was not a competitive pro- dition of acid to 1b to gain information on the course of
cess because the trihaloacetate anion is not a sufficiently the dioxylation reaction. Thus, we observed that addition
labile leaving group. It should be underlined that the reac- of 2 equiv. TsOH was sufficient to achieve complete double
tions performed with trihaloacetic acids took place with su- protonation of diamine 1b; none of the signals any of the
perior regio-/stereoselectivity with respect to those that used N-CH protons moved further downfield upon further ad-
sulfonic acids, and gave direct access to all-equatorial diam- dition of acid. On the other hand, at least 3 equiv. TFA
inodiol 5Јb.
was required to ensure complete protonation of 1b (see the
The outcomes of the previously described dioxylation re- Supporting Information). An analogous study with the iso-
actions were clearly affected by the nature of the acid; lated diamine-epoxide 4b gave more revealing information
TfOH led to lower (5Јb + 6)/(4b + 7) ratio with respect on the conformation of the doubly protonated diamine-ep-
to TsOH, whereas TFA and TCA gave a high 5Јb/5b ratio. oxide (see Scheme 5) and a plausible explanation for the
1
Notably, the reactions performed with acetic acid under a regioselectivity of the epoxide ring opening. The H NMR
variety of experimental conditions were unsatisfactory, re- spectrum of 4b showed distinct absorptions for the two O-
sulting in very low conversion to more complex mixtures of CH protons at δ = 3.00 (m) and 3.08 (m) ppm. The progress
1
compounds, which were discharged. In conclusion, the of the epoxide ring opening was monitored by H NMR
course of the reaction and the regioselectivity of the epoxide spectroscopy following consecutive additions of TFA ali-
ring opening were apparently governed by the strength of quots to 4b, which caused the downfield shifts of the N-
the acid, not by the steric properties of the acid or its CH*-CH*-N ring protons, observed as superimposed mul-
anion.[19]
tiplets at 2.2–2.4 ppm in the free base (Figure 1). After the
We hypothesized that the variable regioselectivity in the addition of two equivalents of TFA, these protons appeared
epoxide ring opening was affected by conformational as quartets at δ = 3.28 and 3.37 ppm, with an apparent
changes of the substituted cyclohexane ring, following mul- coupling constant of 5.9 Hz.[28] This multiplicity indicated
tiple protonation. We observed that the ammonium substit- that conformer 8 of the doubly protonated diamine-epoxide
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D. Savoia, D. Balestri, S. Grilli, M. Monari
FULL PAPER
Scheme 5. Proposed mechanism of the dioxylation reaction of 1b.
1
Figure 1. Monitoring the ring opening of epoxide 4b by H NMR spectroscopic analysis after addition of TFA.
had been converted into conformer 8Ј, which displays equa- ration of the positively charged ring substituents. Moreover,
torial hydrogen atoms and axially disposed ammonium we believe that a hydrogen bond is established between the
groups. This conformation should be partly stabilized by oxygen and the faced axial ammonium ion, at the same time
the relative anti orientation, and hence lead to larger sepa- stabilizing 8Ј and activating the epoxide-opening process.
1910
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Asymmetric Dihydroxylations
Further shifts of the O-CH and N-CH protons were ob- tained, nucleophilic attack is expected to occur through the
served upon further addition of TFA, up to ten equivalents, anti-diaxial mode, according to the Fürst–Plattner rule,
resulting in a rapid opening of the epoxide by trifluoroacet- thus giving intermediate diammonium salt 10.
ate anion to give, ultimately, the fully protonated diamine-
This regioselectivity is consistent with a previous report
diol mono-O-triflate 10Ј. In this product, the four O-CH describing the acidic hydrolysis of epoxide 4c to give trans-
(4.30 and 5.25 ppm) and N-CH (3.60 and 3.67 ppm) cyclo- diaxial diol 5c.[9] Successive basic treatment converts 10 into
hexane ring protons appeared as broad multiplets, as ex- the mono-O-protected derivative. In the case of sulfonyl de-
pected for their equatorial orientation in a chair conforma- rivatives 7A/7C, partial conversion into epoxide 4b occurs,
tion. The ring-opening reaction of epoxide 4b with TsOH whereas the trihaloacetate derivatives undergo hydrolysis to
could not be monitored by 1H NMR spectroscopic analysis, the diol 5b. Nucleophilic attack to the protonated epoxide
analogously to the titration study using TFA, because of 9 with the opposite regioselectivity would occur through
the increased complexity of the reaction mixture and the a less favorable twist-boat-like transition state to give all-
broadened signals of the relevant protons.
equatorially substituted compounds 7Ј or 11, which are pre-
cursors of bicyclic exo-alcohol 6 and diol 5Јb, respectively.
The prevalent formation of compounds 5Јb and 6, espe-
cially when using trihaloacetic acids, is difficult to explain
considering that triprotonated diamine-epoxide 9 is the
principal intermediate. Instead, we think that the doubly
protonated diamine-epoxide 8Ј is the most reactive interme-
diate when trihaloacetic acids, weaker than sulfonic acids,
are used. Then, the epoxide ring opening of 8Ј takes place
by the favored anti-diaxial mechanism to give mono-O-sub-
stituted diol 10Ј. In the presence of an excess of acid, fur-
ther protonation of the oxy-functionalities occur. Basic
treatment of 10Ј afforded the mono-O-protected diols 7Ј or
11, depending on the nature of the acid/nucleophile. The
mono-sulfonylated diol 7Ј then undergoes ring closure by
nucleophilic displacement of the sulfonate group by the op-
posite trans-amino function to give the bridged bicyclic exo-
alcohol 6. On the other hand, free diamino-diol 5Јb is pro-
duced by ready hydrolysis of mono-O-trihaloacetate diol
11.
A monodimensional ROESY[29] study was conducted on
10Ј in situ (Figure 2). After irradiation at the frequency of
the CHOTf proton (δ = 5.27 ppm), similar NOE enhance-
ments were observed for the absorptions of three vicinal
protons (CH-O and methylene protons). This demonstrates
that the irradiated proton H* is in an equatorial position
because, in this case, all the H*···H distances are compar-
able. Conversely, by irradiation of an axial proton, the sig-
nal enhancement of an equatorial vicinal proton would be
greater than that of a vicinal axial proton. These observa-
tions strongly support the hypothesis that the amino sub-
stituents are already in axial positions in the reactive half-
chair conformer 8Ј of the protonated diamine-epoxide. Only
after basic treatment does the cyclohexane ring of the free-
base 11 assume the chair conformation with all-equatorial
substituents.
Following the expeditious and efficient synthesis of all-
equatorial diaminodiol 5Јb from diaminocyclohexene 1b by
the application of the mCPBA/TFA protocol, we converted
5Јb into the 7-azanorbornane derivative 6 by Mitsunobu
reaction with the PPh3/DIAD system. The hydrogenolysis
of the N-benzylic substituents in compounds 6 and 5Јb was
then achieved over 20% Pd/C in MeOH/HCl, so obtaining
the optically pure 4,5-diaminocyclohexane-1,2-diol 5Јa and
5-amino-7-azabicyclo[2.2.1]heptan-2-ol 12 as dihydro-
chlorides in good yields (Scheme 6).
Figure 2. 1D selective ROESY analysis of 10Ј.
A plausible, complete mechanism for the acid-promoted
dioxylation reactions of 1b is depicted in Scheme 5. We as-
sume that the epoxidation of the doubly protonated di-
aminocyclohexene 1b to give 8 is the rate-determining step.
The epoxide ring opening can take place after protonation
of epoxide 4b to give the triprotonated species 9. In this
Scheme 6. Preparation of N,NЈ-unsubstituted diaminodiol 5Јa and
case, if the conformation of the cyclohexane ring is main- 5-amino-7-azabicyclo[2.2.1]heptan-2-ol 12.
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D. Savoia, D. Balestri, S. Grilli, M. Monari
FULL PAPER
sure. Flash chromatography of the residue over SiO2 column elut-
ing with solvent mixtures of increasing polarity [from cyclohexane/
EtOAc (2:8) to EtOAc/MeOH (7:3)] gave mixtures of products or
pure compounds, depending on the sulfonic acid used.
Conclusions
The course and the regio-/stereoselectivity of the di-
oxylation reaction of (R,R)-cyclohex-4-ene-1,2-diamine 1b
with mCPBA is dependent on the nature of the protic acid
used, which, at the same time, protects the diamine func-
Microwave-Assisted Preparation of (4R,5R)-7-[(S)-1-Phenylethyl]-5-
[(S)-1-phenylethylamino]-7-azabicyclo[2.2.1]heptan-2-ol (6): The
tions, activates the epoxide ring and provides the nucleo- crude material obtained by reaction of 1b (170 mg, 0.52 mmol) with
mCPBA and MsOH (Table 1, entry 5) was dissolved in CH2Cl2
(20 mL) and a catalytic amount of MsOH (5 μL) was added. The
mixture was introduced into a 75 mL PTFE-sealed reaction vessel
equipped with a fiber optic system and inserted in a microwave
apparatus. The reaction mixture was irradiated at 150 W to reach
an internal temperature of 150 °C in 10 min, then the temperature
was maintained by pulsed irradiation for an additional 6 min. After
cooling to room temperature, the mixture was diluted in CH2Cl2
washed twice with 1 m NaOH, the solvent was dried with anhy-
drous Na2SO4 and removed under reduced pressure. Compound 6
philic oxyanion for epoxide ring opening. The use of rela-
tively strong sulfonic acids led to mixtures of products/dia-
stereomers as a consequence of the low degree of regioselec-
tivity in the epoxide ring opening. In fact, the sulfonyloxy
group introduced in the cyclohexane ring could act as a
leaving group, undergoing intramolecular substitution by
the opposite amine to ultimately give the 2-exo-5-endo-5-
amino-7-azabicyclo[2.2.1]heptan-2-ol structure. Excellent
yield of the bicyclic compound 6 was obtained by MW irra-
diation (150 W, 150 °C) of the crude mixture obtained in (157 mg, 0.47 mmol, 90%) was obtained after purification on SiO2
column (EtOAc/MeOH, 7:3) as a viscous oil. [α]2D0 = –128.0 (c =
the presence of MsOH.
0.34, CHCl ). IR (KBr): ν = 3386, 3060, 3026, 2970, 2930, 2869,
˜
3
On the other hand, 1b was cleanly converted into the
4,5-diaminocyclohexane-1,2-diol moiety, obtained as a 9:1
mixture of the (1S,2S,4R,5R)- and (1R,2R,4R,5R)-4,5-di-
aminocyclohexane-1,2-diol, by the same oxidative protocol
but using trifluoro- or trichloroacetic acid. In these reac-
tions, the intermediate epoxide underwent highly regioselec-
tive ring opening by the trihaloacetate anion, and the tri-
haloacetate ester function underwent hydrolysis during
1492, 1453, 1369, 1306, 1200, 1111, 1078, 763, 701 cm–1. H NMR
1
(400 MHz, CDCl3, 25 °C): δ = 7.37–7.25 (m, 10 H), 3.76 (q, J =
6.4 Hz, 1 H), 3.65 (q, J = 6.4 Hz, 1 H), 3.61 (d, J = 6.0 Hz, 1 H),
3.36–3.30 (m, 1 H), 3.11 (app. t, J = 4.2 Hz, 1 H), 2.85 (d, J =
6.0 Hz, 1 H), 2.37 (dd, J = 13.6, 7.2 Hz, 1 H), 2.23–2.16 (m, 1 H),
1.38 (d, J = 6.4 Hz, 3 H), 1.34–1.26 (m, 1 H), 1.21 (d, J = 6.4 Hz,
3 H), 0.69 (dd, J = 13.2, 5.2 Hz, 1 H) ppm. 13C NMR (100.8 MHz,
CDCl3, 25 °C): δ = 145.6, 145.3, 128.5, 128.4, 127.2, 126.8, 126.7,
basic workup. The unexpected selectivity of the anti-di- 73.7, 65.5, 58.8, 58.3, 55.0, 54.4, 35.0, 31.2, 24.0, 22.1 ppm. MS
(ESI): m/z = 337 [M + H]+. C22H28N2O calcd. C 78.53, H 8.39, N
8.33; found C 78.22, H 8.42, N 8.30.
oxylation reaction in the presence of trihaloacetic acids was
explained by assuming that the N,NЈ-diprotonated diamine-
Azabicyclic compound 6 was also prepared from 1b by using
MsOH (Table 1, entry 4). The product was isolated as a pure com-
pound in 40% yield, whereas in the presence of TsOH (Table 1,
entry 1) a mixture of 5Јb and 6 was produced, from which pure 6
was obtained with overall 55% yield by applying the Mitsunobu
protocol as described for 5Јb.
epoxide is the reactive intermediate existing in the half-chair
conformation in which the ammonium groups occupy axial
positions, and one faces the epoxide and activates it
through an intramolecular hydrogen bond. Attack by nu-
cleophilic carboxylate can then take place by the favored
anti-diaxial mechanism.
(1R,3R,4R,6S)-N,NЈ-Bis[(S)-1-phenylethyl]-7-oxabicyclo[4.1.0]-
heptane-3,4-diamine (4b): The mixture of compounds 4b (16.8 mg,
0.050 mmol) and 7A (18.2 mg, 0.036 mmol), obtained by reaction
of 1b with TsOH (Table 1, entry 2), was dissolved in anhydrous
CH2Cl2 (1 mL), and DBU (6.6 mg, 6.5 μL, 1.2 equiv. with respect
to 7A) was added. After stirring overnight at room temperature,
5% aq. CuSO4 (5 mL) was added and the organic phase was ex-
tracted with CH2Cl2 (3ϫ 10 mL). The collected organic layers were
dried with anhydrous Na2SO4 and concentrated under reduced
pressure to give epoxide 4b (25 mg, 87%) with a good purity. Fur-
ther purification could be achieved by flash chromatography over
SiO2 (cyclohexane/EtOAc, 6:4) to give the product as a viscous oil.
Hence, the two complementary dioxylation procedures of
cyclohex-4-ene-1,2-diamine 1b provide access to optically
pure, all-equatorial 4,5-diaminocyclohexane-1,2-diol and 5-
endo-2-exo-5-amino-7-azabicyclo[2.2.1]heptan-2-ol, which
are interesting polyfunctionalized molecules that are poten-
tially useful for the preparation of even more complex com-
pounds and pharmacologically active drugs. It is note-
worthy that racemic 2-exo,3-exo,5-endo-5-amino-7-azabicy-
clo[2.2.1]heptane-2,3-diol was active as a glycosidase inhibi-
tor.[30]
[α]2D0 = –86.0 (c = 0.20, CHCl ). IR (KBr): ν = 3306, 3025, 2961,
˜
3
2924, 2852, 1732, 1493, 1452, 1368, 1261, 1119, 1027, 762,
Experimental Section
1
701 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 7.35–7.22 (m,
Reaction of Epoxide 1b with mCPBA in the Presence of a Sulfonic
Acid: To a solution of cyclohexenediamine 1b (100 mg, 0.31 mmol)
in anhydrous CH2Cl2 (0.5 mL), sulfonic acid (see Table 1, molar
equivalents as in entries 1–4), then mCPBA (160 mg, 0.62 mmol)
were added. The mixture was magnetically stirred at room tempera-
ture for 4 h (a white precipitate formed), then quenched with satu-
rated aq. Na2SO3 (2 mL). After 10 min, THF (1 mL) and 10%
NaHCO3 (5 mL) were added and the mixture was stirred for 4 h.
After extraction with EtOAc (3ϫ 10 mL), the collected organic
layers were washed twice with 1 m NaOH then dried with anhy-
drous Na2SO4 and the solvent was removed under reduced pres-
10 H), 3.82 (q, J = 6.7 Hz, 1 H), 3.80 (q, J = 6.7 Hz, 1 H), 3.08–
3.06 (m, 1 H), 3.01 (app. t, J = 4.8 Hz, 1 H), 2.51 (ddd, J = 14.8,
J = 4.8, 2.1 Hz, 1 H), 2.36–2.25 (m, 2 H), 2.06–1.99 (m, 1 H), 1.72
(br., 2 H, NH), 1.54 (dd, J = 15.2, 9.4 Hz, 1 H), 1.39–1.33 (m, 1
H), 1.33 (d, J = 6.7 Hz, 3 H), 1.30 (d, J = 6.7 Hz, 3 H) ppm. 13C
NMR (100.8 MHz, CDCl3, 25 °C): δ = 145.6, 145.4, 128.5, 126.9,
126.6, 126.5, 54.8, 54.5, 52.7, 52.7, 51.2, 50.9, 30.9, 30.1, 25.6,
25.4 ppm. EI-MS (70 eV): m/z (%) = 336 (2) [M+], 231 (9) [M+
–
CH(Ph)CH3], 202 (15), 120 (15), 105 (100), 77 (28). MS (ESI): m/z
= 337 [M + H+]. C22H28N2O calcd C 78.53, H 8.39, N 8.33; found
C 78.72, H 8.41, N 8.31.
1912
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Eur. J. Org. Chem. 2014, 1907–1914

Asymmetric Dihydroxylations
(1R,2R,4R,5R)-2-Hydroxy-4,5-bis[(S)-1-phenylethylamino]cyclo-
hexyl Methanesulfonate (7C): Obtained as an inseparable mixture
with epoxide 4b from dioxylation reaction of 1b with MsOH
(Table 1, entry 4) as a viscous oil. From NMR spectra of the mix-
ture 7C/4b (65:35) the following absorptions were assigned to 7C.
(1S,2S,4R,5R)-4,5-Diaminocyclohexane-1,2-diol Dihydrochloride
(5Јa·2HCl): Diaminodiol 5Јb (100 mg, 0.28 mmol) was dissolved in
freshly distilled MeOH (10 mL) in a glass reactor. 2 m HCl in Et2O
(0.84 mmol, 420 μL) was added, followed by 20% Pd/C (50 mg)
and the reactor was submitted to 45 psi of H2 pressure in a Parr
1H NMR (400 MHz, CD3OD, 25 °C): δ = 7.38–7.27 (m, 10 H, apparatus for 24 h at room temperature. The mixture was filtered
+4b), 4.69–4.66 (m, 1 H), 3.95–3.89 (m, 1 H), 3.87–3.83 (m, 2 H,
+4b), 2.99 (s, 3 H), 2.50–2.42 (m, 1 H), 2.40–2.30 (m, 1 H), 2.29–
2.13 (m, 1 H, +4b), 2.11–2.05 (m, 1 H), 1.75–1.65 (m, 1 H),1.53–
through Celite and the solution was discarded, then 5Јa·2HCl (in-
soluble in methanol) was recovered by washing the Celite pad with
water (10 mL). After solvent evaporation under reduced pressure,
1.48 (m, 1 H, +4b), 1.35 (d, J = 6.8 Hz, 6 H, +4b) ppm. 13C NMR the solid residue was triturated three times with cyclohexane, then
(100.8 MHz, CD3OD, 25 °C): δ = 80.9 (C-OMs), 68.0 (C-OH), 38.4 dried under vacuum over P2O5 for 24 h to afford the product
(CH3SO2), 33.1 (CH2), 30.8 (CH2) ppm.
(52 mg, 0.24 mmol, 85%) as a white solid, no m.p. (dec.). [α]2D0
23.7 (c = 0.20, H O). IR (KBr): ν = 3284, 2812, 1629, 1589, 1454,
=
˜
2
Reactions of Epoxide 1b with mCPBA in the Presence of Trihalo-
carboxylic Acids: The trihalocarboxylic acid (10 equiv.) and then
mCPBA (160 mg, 0.62 mmol, 2 equiv.) were added to a solution of
cyclohexenediamine 1b (100 mg, 0.31 mmol) in anhydrous CH2Cl2
(0.5 mL). The mixture was magnetically stirred at room tempera-
ture for 4 h (a white precipitate formed), then the reaction was
quenched with saturated aq. Na2SO3 (2 mL). After 10 min, THF
(1 mL) and 10% aq. NaHCO3 (5 mL) were added and the mixture
was stirred for 2 h. After extraction with EtOAc (3ϫ 10 mL), the
collected organic layers were washed with 1 m NaOH then dried
with anhydrous Na2SO4 and the solvent was removed under re-
duced pressure. The two diastereomeric diols 5Јb and 5b (dr
ca. 90:10 by 1H NMR analysis) were separated by flash chromatog-
raphy over SiO2 column by using solvent mixtures of increasing
polarity [from EtOAc to EtOAc/MeOHl (1:1)].
1445, 1405, 1109, 1066, 1033 cm–1 1H NMR (400 MHz, D2O,
.
25 °C): δ = 3.71–3.61 (m, 4 H), 2.43 (dt, J = 13.2, 3.7 Hz, 2 H),
1.78–1.66 (m, 2 H) ppm. 13C NMR (100.8 MHz, D2O, 25 °C): δ =
7 0 . 8 , 5 0 . 1 , 3 3 . 7 p p m . M S ( E S I ) : m / z = 1 4 7 . 2 [ M –
– +
HCl2 ] .C6H16Cl2N2O2 calcd. C 32.89, H 7.36, N 12.79; found C
32.79, H 7.38, N 12.74.
(1R,2S,4R,5R)-5-Amino-7-azabicyclo[2.2.1]heptan-2-ol Dihydro-
chloride (12): Bicyclic diamino alcohol 6 (120 mg, 0.35 mmol) was
dissolved in freshly distilled MeOH (15 mL) in a glass reactor. 2 m
HCl in Et2O (0.89 mmol, 450 μL) was added, followed by 20% Pd/
C (70 mg) and the reactor was submitted to 45 psi of H2 pressure
in a Parr apparatus for 30 h at room temperature. H2O (10 mL)
was then added to the mixture and filtered through a Celite pad,
then washed twice with H2O/MeOH (1:1, 2ϫ 10 mL). After solvent
evaporation under reduced pressure, the solid residue was triturated
three times with cyclohexane, then dried under vacuum over P2O5
for 24 h to afford the product 12 (58 mg, 0.29 mmol, 83%) as an
off-white solid. Further purification was achieved by stepwise ad-
dition of a solution of the product in MeOH (1.5 mL) to THF
(15 mL) while stirring, and by recovering the white solid by vacuum
filtration. [α]2D0 = 6.1 (c = 0.18, MeOH). 1H NMR (400 MHz, D2O,
25 °C): δ = 4.60–4.56 (m, 1 H), 4.34 (d, J = 7.2 Hz, 1 H), 4.24 (d,
J = 6.0 Hz, 1 H), 4.00–3.97 (m, 1 H), 2.63–2.56 (m, 2 H), 1.98
(1S,2S,4R,5R)-4,5-Bis[(S)-1-phenylethylamino]cyclohexane-1,2-diol
(5Јb): Yield 90 mg (0.25 mmol, 82%); white crystalline solid; m.p.
119–120 °C (dec); [α]2D0 = –112.0 (c = 0.19, methanol). IR (KBr): ν
˜
= 3383, 3147, 2968, 2924, 2851, 1629, 1456, 1082, 1068, 1041, 765,
1
701 cm–1. H NMR (400 MHz, CD3OD, 25 °C): δ = 7.38–7.32 (m,
8 H), 7.28–7.23 (m, 2 H), 3.84 (q, J = 6.6 Hz, 2 H), 3.13–3.08 (m,
2 H), 2.24–2.20 (m, 2 H), 2.03–2.00 (m, 2 H), 1.32 (d, J = 6.6 Hz,
6 H), 1.00–0.94 (m, 2 H) ppm. 13C NMR (100.8 MHz, CD3OD,
25 °C): δ = 143.4, 130.2, 129.3, 128.2, 73.6, 56.9, 56.5, 35.1,
23.6 ppm. MS (ESI): m/z = 355 [M + H+]. C22H30N2O2 calcd. C
74.54, H 8.53, N 7.90; found C 74.51, H 8.55, N 7.88.
(br. d, J = 14.8 Hz, 1 H), 1.65 (dd, J = 14.8, 4.4 Hz, 1 H) ppm. 13
C
NMR (100.8 MHz, D2O, 25 °C): δ = 70.1, 65.9, 58.8, 47.6, 32.0,
26.9 ppm. MS (ESI): m/z = 129.2 [M – HCl2–]+. C6H14Cl2N2O
calcd. C 35.84, H 7.02, N 13.93; found C 35.75, H 7.05, N 13.89.
(1R,2R,4R,5R)-4,5-Bis[(S)-1-phenylethylamino]cyclohexane-1,2-diol
(5b): Obtained in very low yield as a viscous oil that could not be
fully characterized. 1H NMR (400 MHz, CD3OD, 25 °C): δ = 7.38–
7.25 (m, 10 H), 3.92 (q, J = 6.8 Hz, 2 H), 3.74 (br. s, 2 H), 2.49–
2.47 (m, 2 H), 2.05–2.00 (m, 2 H), 1.58–1.50 (m, 2 H), 1.36 (d, J
= 6.8 Hz, 6 H) ppm. MS (ESI): m/z = 355 [M + H+].
Supporting Information (see footnote on the first page of this arti-
cle): 1H NMR titration studies of the protonation of diamine 1b
and ring opening of epoxide 4b by addition of acids, NMR spectra
of all new compounds, X-ray diffraction structure, crystal data, and
details of data collection of compound 1b·2HCl.[20]
Preparation of (4R,5R)-7-[(S)-1-Phenylethyl]-5-[(S)-1-phenyleth-
ylamino]-7-azabicyclo[2.2.1]heptan-2-ol (6) by Mitsunobu Protocol:
Compound 5Јb (70 mg, 0.20 mmol) was dissolved in anhydrous
THF (5 mL) under an N2 atmosphere, then PPh3 (142 mg,
0.54 mmol) and DIAD (109 mg, 0.54 mmol) were added sequen-
tially, and the mixture was stirred at room temperature for 24 h.
After addition of 3 m NaOH (10 mL), the mixture was stirred for
3 h, then the organic material was extracted with ethyl acetate (3ϫ
10 mL). The collected organic layers were dried (Na2SO4) and then
concentrated under reduced pressure. 1 m HCl (50 mL) was added
and the aqueous phase was washed with ethyl acetate (2ϫ 10 mL),
then made basic by addition of 3 m NaOH. The organic products
were extracted with EtOAc (3ϫ 10 mL), and the collected organic
layers were dried (Na2SO4) and concentrated under reduced pres-
sure to give the crude bicyclic compound 6 (61 mg, 90%) with a
good purity. Further purification was achieved by gradient flash
chromatography over SiO2 using solvent mixtures of increasing po-
larity (from EtOAc to 30:70 MeOH/EtOAc).
Acknowledgments
This work was supported by the Ministero dell’Istruzione, dell’Uni-
versità e della Ricerca (MIUR) and carried out as part of the
national PRIN program: Sintesi e stereocontrollo di molecole or-
ganiche mediante metodologie innovative.
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Eur. J. Org. Chem. 2014, 1907–1914
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1913

D. Savoia, D. Balestri, S. Grilli, M. Monari
FULL PAPER
[6]
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[20] X-ray diffraction of compound 1b·2HCl: CCDC-916853
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467.
[28] To explain the quartet-like multiplicity, we assume that both
CHN protons experienced three similar J3 coupling constants,
one of these being generated from the HC-N+H coupling (typi-
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M. Badertscher, in: Structure Determination of Organic Com-
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[29] Performed in CDCl3 at 400 MHz by using a 60 Hz selective
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Received: November 12, 2013
Published Online: January 23, 2014
1914
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Eur. J. Org. Chem. 2014, 1907–1914