Ammonium-directed dihydroxylation: Metal-free synthesis of the diastereoisomers of 3-aminocyclohexane-1,2-diol

Article abstract of DOI:10.1039/b808812h

The ammonium-directed, metal-free oxidation of 3-(N,N-dibenzylamino) cyclohex-1-ene with mCPBA in the presence of either trichloroacetic acid or tosic acid has been used as the key step to facilitate the synthesis of all the diastereoisomers of 3-aminocyc

Full text of DOI:10.1039/b808812h

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Ammonium-directed dihydroxylation: metal-free synthesis of the
diastereoisomers of 3-aminocyclohexane-1,2-diol†
Caroline Aciro,a Stephen G. Davies,*a Paul M. Roberts,a Angela J. Russell,a,b Andrew D. Smitha and
James E. Thomsona
Received 27th May 2008, Accepted 29th July 2008
First published as an Advance Article on the web 20th August 2008
DOI: 10.1039/b808812h
The ammonium-directed, metal-free oxidation of 3-(N,N-dibenzylamino)cyclohex-1-ene with mCPBA
in the presence of either trichloroacetic acid or tosic acid has been used as the key step to facilitate the
synthesis of all the diastereoisomers of 3-aminocyclohexane-1,2-diol, in >98% de in each case.
Introduction
The vicinal amino diol motif is ubiquitous throughout organic
chemistry due to the prevalence of this moiety in natural prod-
ucts and a variety of other biologically and pharmaceutically
important compounds.1 As such, a range of methodologies
for the synthesis of this unit in both racemic and homochiral
forms has been developed, with arguably the most common
methods being based upon dihydroxylation or epoxidation of
an allylic amine2 (or equivalent),3 or aminohydroxylation4 or
epoxidation5 of an allylic alcohol. In the preceding manuscript,
we reported the development of an ammonium-directed,
metal-free dihydroxylation protocol.6 Treatment of 3-(N,N-
dibenzylamino)cyclohex-1-ene 1 with trichloroacetic acid fol-
lowed by mCPBA furnished 1,2-anti-2,3-syn-1-trichloroacetoxy-
Scheme 1 Reagents and conditions: (i) Cl3CCO2H (5 eq), mCPBA, DCM
2-hydroxy-3-(N,N-dibenzylamino)cyclohexane 2 in 90% de, con-
rt, 21 h, then NaHCO3 (0.1 M, aq); (ii) TsOH (3 eq), mCPBA, DCM, rt,
sistent with initial ammonium-directed (hydrogen-bonded) epox-
21 h, then NaHCO3 (0.1 M, aq); (iii) DBU, DCM, rt, 24 h; (iv) Cl3CCO2H,
DCM, rt, 16 h, then NaHCO3 (0.1 M, aq); (v) K2CO3, MeOH, rt, 16 h;
(vi) Pd(OH)2/C, H2 (1 atm), MeOH, rt, 24 h.
idation occurring on the face of the olefin syn to the 3-N,N-
dibenzylamino group, with subsequent epoxide opening occurring
exclusively at the C(1)-position. In order to corroborate this
mechanistic proposal, treatment of 1 with tosic acid (TsOH)
followed by mCPBA gave 1,2-anti-2,3-syn-1-p-toluenesulfonyloxy-
2-hydroxy-3-(N,N-dibenzylamino)cyclohexane 3 in 90% de, which
underwent base-catalysed elimination of TsOH to give syn-epoxide
4, isolated in >98% de. Subsequent ring-opening of 4 with
Cl3CCO2H furnished 2 with complete regio- and stereocontrol.
Transesterification of 2 (90% de) upon treatment with methanolic
K2CO3 gave 5 in 90% de. Hydrogenolytic deprotection afforded
3-aminocyclohexane-1,2-diol 6–9 (Fig. 1), utilising 3 and 4 as the
key intermediates. We have previously communicated a method
to effect some of these transformations,7 although the methods
described were not found to be the most robust, reproducible
or generally applicable and we therefore describe herein our full
investigations into the development and application of a reliable
experimental protocol.
the corresponding primary amino diol 6 in 78% yield and 90% de
(Scheme 1).
It was anticipated that this transformation could be applied as
the key step to facilitate the synthesis of all the diastereoisomers of
aDepartment of Chemistry, Chemistry Research Laboratory, University of
Oxford, Mansfield Road, Oxford, OX1 3TA, UK.
E-mail: steve.davies@chem.ox.ac.uk
bDepartment of Pharmacology, University of Oxford, Mansfield Road,
Oxford, OX1 3QT, UK
† Electronic supplementary information (ESI) available: Additional ex-
perimental information. CCDC reference number 681276. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b808812h
Fig. 1 The diastereoisomers of 3-amino-cyclohexane-1,2-diol 6–9.
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Results and discussion
Preparation of 1,2-syn-2,3-syn-3-(N,N-
dibenzylamino)cyclohexane-1,2-diol
Initial studies focused on the synthesis of 1,2-syn-2,3-syn-11 from
1,2-anti-2,3-syn-3, via C(2)-acetylation and subsequent inversion
of configuration at C(1), employing a neighbouring group par-
ticipation reaction first described by Winstein et al.,8 to give the
corresponding 1,2-syn-2,3-syn relationship (Fig. 2).
Scheme 3 Reagents and conditions: (i) EtOH–H2O (6 : 1), reflux, 48 h,
then K2CO3, MeOH, rt, 16 h; (ii) EtOH–H2O (6 : 1), CaCO3, reflux, 48 h,
then K2CO3, MeOH, rt, 16 h.
Fig. 2 Proposed strategy for the synthesis of 11.
Acetylation of 3 (90% de, generated from TsOH promoted,
ammonium-directed oxidation of 1 with mCPBA) gave 10 in 90%
de and quantitative yield. Alternatively, treatment of syn-epoxide
4 (>98% de) with TsOH followed by Ac2O gave 10 in quantitative
yield and >98% de (Scheme 2).
the minor 1,2-anti-2,3-anti-diastereoisomer present in the starting
material (vide infra).
An alternative procedure reported by Winstein et al.8 was there-
fore investigated. Treatment of 10 (>98% de) in EtOH–H2O (6 : 1)
with KOAc (1.5 eq) at reflux gave a mixture of products, containing
the regioisomeric monoacetates 12 and 13. Transesterification
of this mixture upon treatment with K2CO3 in MeOH gave a
4:7:89 mixture of 4:5:11. After column chromatography the major
product 11 was isolated in >98% de and 74% yield, along with syn-
epoxide 4 in >98% de and 4% yield, and 5 in >98% de and 7% yield.
The stereochemistry within 11 was assigned by a combination
1
3
of H NMR NOE and J coupling constant analyses, assuming
that in solution 11 resides preferentially in a chair conformation
with the N,N-dibenzylamino group occupying an equatorial site9
(Scheme 4).
Scheme 2 Reagents and conditions: (i) TsOH (3 eq), mCPBA (1.6 eq),
DCM, rt, 21 h, then NaHCO3 (0.1 M, aq); (ii) TsOH, DCM, rt, 16 h, then
NaHCO3 (0.1 M, aq); (iii) Ac2O, DMAP, DCM–pyridine (1 : 1), rt, 24 h,
then NaHCO3 (0.1 M, aq).
In order to effect a Winstein reaction, 10 (90% de) was subjected
to reflux in EtOH–H2O (6 : 1), and gave a complex mixture of
products which, after transesterification with MeOH/K2CO3 and
column chromatography, gave a 97 : 3 mixture of 11:5 (94% de) in
13% yield. Modification of the experimental procedure by addition
of CaCO3 also gave a complex mixture of products, although
transesterification followed by column chromatography allowed
access to 11 in >98% de and an improved 60% yield, along with the
diastereoisomers 5 in >98% de and 13% yield, and 14 in >98% de
and 4% yield (Scheme 3). The observation of the diastereoisomeric
diol 5 in this reaction protocol is indicative of a competing reaction
pathway: plausibly 5 arises from acetate hydrolysis of 10 under the
basic reaction conditions and subsequent syn-epoxide formation
followed by trans-diaxial ring-opening with hydroxide. 1,2-syn-2,3-
anti-14 can be envisaged as originating from a Winstein reaction on
Scheme 4 Reagents and conditions: (i) EtOH–H2O (6 : 1), KOAc, reflux,
48 h, then K2CO3, MeOH, rt, 16 h.
Preparation of 1,2-anti-2,3-anti-3-(N,N-
dibenzylamino)cyclohexane-1,2-diol
With the 2,3-syn-stereoisomeric combinations of 3-(N,N-
dibenzylamino)cyclohexane-1,2-diol 5 and 11 in hand, the prepa-
ration of the corresponding 2,3-anti-stereoisomers was pursued.
It was proposed that the ring-opening of syn-epoxide 4 with acetic
acid would give 15. Subsequent activation of the C(2)-hydroxyl as
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a leaving group, followed by base-promoted acetate hydrolysis, was
then anticipated to facilitate the preparation of anti-epoxide 17.
Subsequent acid-promoted epoxide opening was then predicted to
give 18 (Fig. 3).
Scheme 5 Reagents and conditions: (i) AcOH, 50 ◦C, 24 h, then NaHCO3
(0.1 M, aq); (ii) MsCl, DMAP, Et3N, DCM, -10 ◦C, 48 h; (iii) K2CO3,
MeOH, rt, 16 h.
Fig. 3 Proposed strategy for the synthesis of 18.
Although treatment of 4 with 10% AcOH (aq) in DCM at rt
returned predominantly starting material, with only a trace of
the desired ring-opened product (<2%), upon exposure to neat
AcOH (5 eq) at 50 ◦C followed by 0.1 M aq NaHCO3, 15 was
furnished in >98% de and quantitative yield. The regiochemistry
of epoxide opening, and hence the relative stereochemistry within
15, was assigned by analogy to that observed during the ring-
opening of 4 with Cl3CCO2H and TsOH;6 1H NMR NOE data
obtained on 15 supported this assignment. With 15 in hand,
studies focused on the conversion of the C(2)-hydroxyl group to
a leaving group. Initial attempts to synthesise the ◦corresponding
tosylate via treatment with TsCl at either rt or 50 C, or Ts2O at
50 ◦C, were all unsuccessful and returned starting material in each
case. Presumably, steric hindrance from the 3-N,N-dibenzylamino
substituent has a pronounced effect in these reactions. While
attempted mesylation of 15 at rt generated an intractable mixture
of products, mesylation at -78 ◦C gave 34% conversion to the
desired product 16 and at -42 ◦C, 84% conversion was obtained.
Consequently mesylation at -10 ◦C was attempted, giving 16
in >98% de and quantitative yield. Transesterification of 16
promoted concomitant ring closure, giving anti-epoxide 17 in
>98% de, which was isolated in >98% de and 46% yield after
column chromatography (Scheme 5).
The regioselectivity of ring-opening of anti-epoxide 17 upon
treatment with a range of Brønsted acids was next investigated
as it was predicted that this would facilitate the preparation of
the desired 1,2-anti-2,3-anti relative stereochemistry. It was also
anticipated that this would unambiguously establish the nature of
the minor diastereoisomeric products observed in studies into the
ammonium-directed oxidation protocol, reported in the preceding
paper.6 Thus, in order to access 18 directly, 17 was treated with
H2SO4 (pKa1 = -9)10 in 1,4-dioxane, with ring-opening proceeding
with complete regio- and diastereocontrol to give 18 in >98% de
and 44% yield after basification and column chromatography. 1H
NMR NOE and 3J coupling constant analyses were supportive of
the assigned configuration of 18 (Scheme 6).
Scheme 6 Reagents and conditions: (i) H2SO4, 1,4-dioxane, rt, 16 h, then
NaHCO3 (0.1 M, aq).
Brønsted acid employed, with the complete C(1)-regioselectivity
(as observed with H2SO4) being eroded with decreasing strength
of the acid. Upon treatment of 17 (>98% de) with TsOH (pKa =
-6.5)10 complete regio- and diastereocontrol was observed giving,
after basification, 19 in >98% de and quantitative yield. The
relative stereochemistry within 19 was assigned by a combination
of 1H NMR NOE and 3J coupling constant analyses11 (Scheme 7).
Scheme 7 Reagents and conditions: (i) TsOH, DCM, rt, 16 h, then 0.1 M
NaHCO3 (aq).
Treatment of 17 (>98% de) with Cl3CCO2H (pKa 0.65)10
followed by basification gave an 80 : 20 mixture of 20 and
21 in quantitative combined yield. The minor product 21 was
assigned as arising from regioisomeric ring-opening of 17 at C(2)
based on 1H NMR analysis, which indicated the presence of
a multiplet corresponding to C(2)H at dH 5.36–5.42 ppm: this
high dH value is not consistent with the presence of the hydroxyl
substituent but rather indicates the more electron withdrawing
trichloroacetoxy substituent at C(2). Ring-opening of 17 (>98%
de) with Cl2CHCO2H (pKa 1.29),10 gave a 75:25 mixture of 22
and 23 after basification. The minor product 23 exhibited a
complex multiplet at dH 5.46-5.51 ppm for C(2)H, indicating
the presence of the dichloroacetoxy substituent at C(2). In both
cases the identity of the major 1,2-anti-2,3-anti-diastereoisomers
20 and 22 was established on the basis of 1H NMR NOE and 3J
coupling constant analyses.12 The isomeric composition of 20:21
Subsequent investigations into the ring-opening of 17 with a
range of acids revealed that the regioselectivity [ring-opening
at C(1) versus C(2)] is highly dependent on the strength of the
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and 22:23 was supported by transesterification of the mixtures,
which generated 80 : 20 and 75 : 25 diastereoisomeric mixtures of
18:5, respectively (Scheme 8).
and plausibly originates from an acyl-transfer reaction of 24,
due to the lability of the trifluoroacetyl group under the reaction
conditions. 26 was identical by 1H NMR spectroscopic analysis to
the major diastereoisomeric product observed upon F3CCO2H-
promoted ammonium-directed oxidation of 1, and presumably
originates from an acyl-transfer reaction of isomer 27, where 27
is generated from ring-opening of 17 at C(2). The absence of 27
and the presence of 26 in this mixture may reflect an equilibrium
distribution of these species. The observation of diols 18 and 5 is
presumably the result of partial trifluoroacetate ester hydrolysis of
24, 25 and 26 upon aqueous work-up (Fig. 4).
The isomeric composition of this mixture was supported by
transesterification, giving an 81 : 19 (i.e. [24+25+18]:[26+5] = 81 :
19) mixture of diastereoisomeric diols 18:5 (Scheme 10).
Finally, ring-opening of 17 with AcOH (pKa 4.76)10 was investi-
gated, and gave a 44 : 36 : 11 : 9 mixture of 28:29:30:31 respectively
(Scheme 11). The stereochemical assignment of 1,2-anti-2,3-anti-
28 was made by chemical correlation to the corresponding diol
18, whilst 30 and 31 were identical to the products of a Winstein
reaction on mesylate 16 (vide infra). 1,2-anti-2,3-syn-29 exhibited
a complex multiplet at dH 3.09–3.16 ppm for C(1)H and a complex
multiplet at dH 5.17–5.22 ppm for C(2)H. Thus, the regioselectivity
of the ring-opening process is reflected in the ratio of 28 and 29 (i.e.
the ratio of products resulting from opening at C(1) versus C(2) is
approximately 1.25 : 1). The observation of the minor 1,2-syn-2,3-
anti products 30 and 31 in this case could support a competing
pathway which traverses an aziridinium intermediate 33, giving
rise to monoacetate 31 which may be able to undergo acyl-transfer
to give a mixture of 30 and 31 (Fig. 5).13 This is consistent with
observations reported in the preceding manuscript that attempted
AcOH-promoted ammonium-directed oxidation of tertiary allylic
amine 1 does not result in efficient protonation of the nitrogen
atom.6
Scheme 8 Reagents and conditions: (i) Cl3CCO2H, DCM, rt, 16 h, then
NaHCO3 (0.1 M, aq); (ii) Cl2CHCO2H, DCM, rt, 16 h, then NaHCO3
(0.1 M, aq); (iii) K2CO3, MeOH, rt, 16 h.
The ring-opening of anti-epoxide 17 with F3CCO2H (pKa
=
-0.25)10 was next investigated and gave, after basification, a 22 :
4 : 55 : 17 : 2 mixture of 24:25:18:26:5, respectively (Scheme 9).
1H NMR analysis was used to elucidate the identities of the
components of this mixture. 24 was spectroscopically identical to
the minor diastereoisomeric product observed upon F3CCO2H-
promoted ammonium-directed oxidation of tertiary allylic amine
1.6 25 exhibited a complex multiplet at dH 5.07–5.14 ppm for C(2)H
Scheme 9 Reagents and conditions: (i) F3CCO2H, DCM, rt, 16 h, then NaHCO3 (0.1 M, aq).
Fig. 4 Ring-opening of 17 upon treatment with F3CCO2H.
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Scheme 10 Reagents and conditions: (i) K2CO3, MeOH, rt, 16 h.
Scheme 11 Reagents and conditions: (i) AcOH, DCM, 50 ◦C, 24 h, then NaHCO3 (0.1 M, aq).
Fig. 5 Postulated mechanism for the formation of 30 and 31 upon
ring-opening of 17 with AcOH.
Scheme 12 Reagents and conditions: (i) K2CO3, MeOH, rt, 16 h.
The isomeric composition of the mixture was confirmed by
subsequent transesterification of the mixture of 28:29:30:31 to
give a 44 : 36 : 20 mixture of 18:5:14 (Scheme 12).
is presumably disfavoured on steric grounds due to the requirement
of the large N,N-dibenzylammonium group to occupy a pseudo-
axial position. However, with decreasing acid strength, attack at
C(2) with the epoxide in the favoured conformation 32A competes,
with ring-opening proceeding via a chair-like transition state to
give the trans-diaxial product, in accordance with the Fu¨rst–
Plattner rule15 (Fig. 6).
With the highly diastereoselective synthesis of 1,2-anti-2,3-anti-
18 achieved, the concluding 1,2-syn-2,3-anti arrangement was
tackled.
These results are in contrast to ring-openings of syn-epoxide
4, which proceed exclusively at C(1) regardless of the strength
of the Brønsted acid employed, as rationalised in the preceding
manuscript.6 The regioselectivity observed upon ring-opening of
17 in the case of strong acids such as H2SO4 or TsOH, however,
is consistent with attack at C(1) being favoured electronically.
The ring-opening of epoxides in Brønsted acidic conditions is
known to proceed via a late transition state:14 the oxirane car-
bon atom undergoing nucleophilic attack possesses considerable
carbocationic character, which presumably favours nucleophilic
attack at C(1) where the effects of the electron-withdrawing N,N-
dibenzylammonium moiety are minimised. C(1) attack on epoxide
ammonium 32 presumably occurs in the favoured conformation
32A, resulting in a twist-boat-like transition state. The alternative
attack on C(1), with the epoxide ammonium in conformation 32B,
Preparation of 1,2-syn-2,3-anti-3-(N,N-
dibenzylamino)cyclohexane-1,2-diol
It was envisaged that inversion of the configuration at C(2) of
1,2-anti-2,3-syn-16 via a Winstein protocol would give access to
the 1,2-syn-2,3-anti relationship. Thus, application of the Winstein
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In an alternative preparation of 14 it was predicted that, under
Winstein conditions, 19 (prepared from ring-opening of 17 with
TsOH) could be used to access the 1,2-syn-2,3-anti relationship,
which would also serve to further corroborate the assigned relative
stereochemistry. In accordance with this hypothesis, acetylation of
19 liberated 34 in >98% de and 72% yield. Treatment of 34 with
KOAc in EtOH–H2O generated a mixture containing the regioiso-
meric monoacetates 30 and 31. Transesterification of this mixture
with K2CO3 in MeOH provided 14 as a single diastereoisomer in
57% yield, with identical spectroscopic properties to that prepared
from mesylate 16 (Scheme 14).
Fig. 6 Ring-opening of 17 in the presence of acid [R = conjugate base of
the Brønsted acid].
protocol to 16 gave a mixture containing regioisomeric monoac-
etates 30 and 31. Subsequent transesterification gave 14 in >98%
1
3
de and 43% yield (Scheme 13). H NMR NOE and J coupling
constant analyses of 14 facilitated initial assignment of the relative
stereochemistry, and this was subsequently unambiguously proven
by single-crystal X-ray analysis† (Fig. 7).
Scheme 14 Reagents and conditions: (i) Ac2O, DMAP, DCM–pyridine
(1 : 1), rt, 24 h, then NaHCO3 (0.1 M, aq); (ii) EtOH–H2O (6 : 1), KOAc,
reflux, 72 h; (iii) K2CO3, MeOH, rt, 16 h.
N-Deprotection: Synthesis of the diastereoisomers of
3-aminocyclohexane-1,2-diol
With samples of 3-(N,N-dibenzylamino)cyclohexane-1,2-diols 11,
14 and 18 in hand, hydrogenolytic deprotection to the parent
amino diols was investigated. By analogy to the hydrogenolysis of
5 (90% de) to 6 reported in the preceding paper, treatment of 5, 11,
14 or 18 (>98% de in each case) with Pd(OH)2/C under 1 atm of H2
gave the corresponding diastereoisomer of 3-aminocyclohexane-
1,2-diol 6–9 in >98% de and good to excellent yield (Scheme 15).
Scheme 13 Reagents and conditions: (i) EtOH–H2O (6 : 1), KOAc, reflux,
48 h, then K2CO3, MeOH, rt, 16 h.
Conclusion
In conclusion, in this manuscript we have demonstrated that
the highly diastereoselective, ammonium-directed oxidation of 3-
(N,N-dibenzylamino)cyclohex-1-ene facilitates the stereoselective
synthesis of the four diastereoisomers of 3-aminocyclohexane-1,2-
diol, in >98% de in each case (Scheme 16). A full evaluation
of the scope and limitations of this metal-free dihydroxylation
protocol, the development of an enantioselective variant, and
the application of this methodology toward amino carbohydrate
synthesis are currently under investigation within our laboratory.
Experimental
General experimental
Reactions involving moisture-sensitive reagents were carried out
under a nitrogen or argon atmosphere using standard vacuum
line techniques and glassware that was flame-dried and cooled
Fig. 7 Chem 3D representation of the X-ray crystal structure of 14 (some
H atoms omitted for clarity).
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was performed on aluminium plates coated with 60 F254 silica.
Plates were visualised using UV light (254 nm), iodine, 1% aq
KMnO4, or 10% ethanolic phosphomolybdic acid. Flash column
chromatography was performed either on Kieselgel 60 silica on
a glass column, or on a Biotage SP4 automated flash column
chromatography platform.
Melting points were recorded on a Gallenkamp Hot Stage
apparatus and are uncorrected. IR spectra were recorded on a
Bruker Tensor 27 FT-IR spectrometer as either a thin film on NaCl
plates (film) or a KBr disc (KBr), as stated. Selected characteristic
peaks are reported in cm-1. NMR spectra were recorded on
Bruker Avance spectrometers in the deuterated solvent stated.
The field was locked by external referencing to the relevant
deuteron resonance. Low-resolution mass spectra were recorded
on either a VG MassLab 20-250 or a Micromass Platform 1
spectrometer. Accurate mass measurements were run on either
a Bruker MicroTOF internally calibrated with polyalanine, or
a Micromass GCT instrument fitted with a Scientific Glass
Instruments BPX5 column (15 m ¥ 0.25 mm) using amyl acetate
as a lock mass.
(1RS,2RS,3RS)-3-Aminocyclohexane-1,2-diol 6
Scheme 15 Reagents and conditions: (i) Pd(OH)2/C, H2 (1 atm), MeOH,
rt, 24 h.
under nitrogen before use. Solvents were dried according to
the procedure outlined by Grubbs and co-workers.16 Water was
R
purified by an Elixꢀ UV-10 system. All other solvents were used
Pd(OH)2/C (78 mg) was added to a vigorously stirred solution
of 5 (157 mg, 0.50 mmol) in degassed MeOH (2 mL) and the
resultant suspension was stirred at rt under H2 (1 atm) for 24 h.
as supplied (analytical or HPLC grade) without prior purification.
Organic layers were dried over MgSO4. Thin layer chromatography
Scheme 16 Reagents and conditions: (i) TsOH (3 eq), mCPBA, DCM rt, 21 h, then NaHCO3 (0.1 M, aq); (ii) DBU, DCM, rt, 24 h; (iii) TsOH, DCM, rt,
16 h, then NaHCO3 (0.1 M, aq); (iv) Cl3CCO2H, DCM, rt, 16 h, then NaHCO3 (0.1 M, aq); (v) K2CO3, MeOH, rt, 16 h; (vi) Cl3CCO2H (5 eq), mCPBA,
DCM, rt, 21 h, then K2CO3, MeOH, rt, 16 h; (vii) Ac2O, DMAP, DCM–pyridine (1 : 1), rt, 24 h, then NaHCO3 (0.1 M, aq); (viii) EtOH–H2O (6 : 1),
KOAc, reflux, 48 h, then K2CO3, MeOH, rt, 16 h; (ix) AcOH, 50 ◦C, 24 h, then NaHCO3 (0.1 M, aq); (x) MsCl, DMAP, Et3N, DCM, -10 ◦C, 48 h; (xi)
H2SO4, 1,4-dioxane, rt, 16 h, then NaHCO3 (0.1 M, aq); (xii) Pd(OH)2/C, H2 (1 atm), MeOH, rt, 24 h.
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The suspension was then filtered through a pad of Celite (eluent
MeOH) and the filtrate was concentrated in vacuo to give 6 as a
pale yellow solid (53 mg, 80%, >98% de); mp 115–116 ◦C; nmax
(KBr) 3355 (O–H), 2936, 2867 (C–H); dH (400 MHz, d4-MeOH)
1.34–1.46 (1H, m, C(6)HA), 1.47–1.66 (4H, m, C(4)H2, C(5)H2),
1.74–1.87 (1H, m, C(6)HB), 3.02–3.12 (1H, m, C(3)H), 3.52 (1H,
dd, J 5.3, 3.3, C(2)H), 3.74–3.82 (1H, m, C(1)H); dC (100 MHz,
d4-MeOH) 18.6, 29.2 (C(4), C(5)), 47.4 (C(6)), 49.9 (C(3)), 70.0
(C(1)), 74.2 (C(2)); m/z (ESI+) 132 ([M + H]+, 100%); HRMS
(ESI+) C6H14NO2+ ([M + H]+) requires 132.1019; found 132.1022.
resultant suspension was stirred at rt under H2 (1 atm) for 24 h.
The suspension was then filtered through a pad of Celite (eluent
MeOH) and the filtrate was concentrated in vacuo to give 9 as a
white solid (47 mg, quant, >98% de); mp 45–46 ◦C; nmax (KBr) 3356
(O–H), 2934, 2868 (C–H); dH (400 MHz, d4-MeOH) 1.25–1.46
(3H, m, C(4)HA, C(5)HA, C(6)HA), 1.71–1.81 (1H, m, C(5)HB),
1.88–2.02 (2H, m, C(4)HB, C(6)HB), 2.75 (1H, app td, J 10.3, 3.7,
C(3)H), 3.12 (1H, app t, J 9,2, C(2)H), 3.30–3.43 (1H, m, C(1)H);
dC (100 MHz, d4-MeOH) 21.3 (C(5)), 30.5, 32.9 (C(4), C(6)), 54.6
(C(3)), 73.6 (C(1)), 78.6 (C(2)); m/z (ESI+) 132 ([M + H]+, 100%);
HRMS (ESI+) C6H14NO2 ([M + H]+) requires 132.1019; found
+
(1RS,2SR,3SR)-3-Aminocyclohexane-1,2-diol 7
132.1022.
Acknowledgements
The authors thank New College, Oxford, for a Junior Research
Fellowship (A. D. S.) and Research Councils UK, for a Fellowship
(A. J. R.).
Pd(OH)2/C (121 mg) was added to a vigorously stirred solution
of 11 (243 mg, 0.78 mmol) in degassed MeOH (2 mL) and the
resultant suspension was stirred at rt under H2 (1 atm) for 24 h.
The suspension was then filtered through a pad of Celite (eluent
MeOH) and the filtrate was concentrated in vacuo to give 7 as
a colourless oil (103 mg, quant, >98% de); nmax (film) 3385 (O–
H), 2941, 2867 (C–H); dH (400 MHz, d4-MeOH) 1.11–1.76 (6H,
m, C(4)H2, C(5)H2, C(6)H2), 2.59–2.74 (1H, m, C(3)H), 3.46–
3.59 (1H, m, C(1)H), 3.75–3.81 (1H, m, C(2)H); dC (100 MHz,
d4-MeOH) 21.0, 27.6, 28.2 (C(4), C(5), C(6)), 52.2 (C(3)), 71.8
(C(1)), 73.2 (C(2)); m/z (ESI+) 132 ([M + H]+, 100%); HRMS
(ESI+) C6H14NO2+ ([M + H]+) requires 132.1019; found 132.1020.
References and notes
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Pd(OH)2/C (25 mg) was added to a vigorously stirred solution
of 14 (54 mg, 0.17 mmol) in degassed MeOH (2 mL) and the
resultant suspension was stirred at rt under H2 (1 atm) for 24 h.
The suspension was then filtered through a pad of Celite (eluent
MeOH) and the filtrate was concentrated in vacuo to give 8 as a
white solid (14 mg, 64%, >98%); mp 134–135 ◦C; nmax (KBr) 3384
(O–H), 2940, 2871 (C–H); dH (400 MHz, d4-MeOH) 1.14–1.27
(1H, m, C(4)HA), 1.44–1.57 (2H, m, C(5)HA, C(6)HA), 1.63–1.78
(1H, m, C(5)HB), 1.79–1.97 (2H, m, C(4)HB, C(6)HB), 2.92–3.03
(1H, m, C(3)H), 3.21 (1H, dd, J 9.6, 3.1, C(2)H), 4.00 (1H, app q,
J 3.0, C(1)H); dC (100 MHz, d4-MeOH) 18.7 (C(5)) 31.4 (C(6)),
32.2 (C(4)), 50.4 (C(3)), 67.0 (C(1)), 77.3 (C(2)); m/z (ESI+) 132
([M + H]+, 55%); HRMS (ESI+) C6H14NO2 ([M + H]+) requires
+
132.1019; found 132.1022.
(1RS,2RS,3SR)-3-Aminocyclohexane-1,2-diol 9
8 S. Winstein, H. V. Hess and R. E. Buckles, J. Am. Chem. Soc., 1942, 64,
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Pd(OH)2/C (55 mg) was added to a vigorously stirred solution
of 18 (110 mg, 0.35 mmol) in degassed MeOH (2 mL) and the
11 Tosylate 19 was spectroscopically identical to the minor diastereoiso-
meric product observed upon TsOH-promoted ammonium-directed
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oxidation of tertiary allylic amine 1, thus confirming unambiguously
the nature of the minor diastereoisomer in this process; see ref. 6.
12 The major diastereoisomers 20 and 22 were spectroscopically identical
to the minor diastereoisomeric products observed upon Cl3CCO2H-
and Cl2CHCO2H-promoted ammonium-directed oxidation of tertiary
allylic amine 1 respectively, thus confirming unambiguously the nature
of the minor diastereoisomers in these processes; see ref. 6.
monoacetate 30, which may be able to undergo acetyl-transfer to give
a mixture of 30 and 31, or a combination of both pathways.
14 R. E. Parker and N. S. Isaacs, Chem. Rev., 1959, 59, 737; J. K. Addy
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15 A. Fu¨rst and P. A. Plattner, Proceedings of the 12th Interna-
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13 An alternative plausible rationale could involve the formation of
an azetidinium intermediate, with subsequent ring-opening to form
16 A. B. Pangborn, M. A. Giardello, R. H. Grubbs, R. K. Rosen and F. J.
Timmers, Organometallics, 1996, 15, 1518.
3770 | Org. Biomol. Chem., 2008, 6, 3762–3770
This journal is
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©