Ammonium-directed dihydroxylation of 3-aminocyclohex-1-enes: Development of a metal-free dihydroxylation protocol

Article abstract of DOI:10.1039/b808811j

Treatment of 3-aminocyclohex-1-enes with mCPBA in the presence of trichloroacetic acid gives the corresponding 1,2-anti-2,3-syn-1- trichloroacetoxy-2-hydroxy-3-aminocyclohexane with high levels of diastereoselectivity (90% de). This is consistent with a mechanism of oxidation involving hydrogen-bonded delivery of the oxidant by the allylic ammonium ion formed in situ, followed by highly regioselective ring-opening of the intermediate epoxide by trichloroacetic acid. The effect of conformational constraints upon the oxidation reaction is also examined. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b808811j

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Ammonium-directed dihydroxylation of 3-aminocyclohex-1-enes: development
of a metal-free dihydroxylation protocol†‡
Caroline Aciro,a Timothy D. W. Claridge,a Stephen G. Davies,*a Paul M. Roberts,a Angela J. Russella,b 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/b808811j
Treatment of 3-aminocyclohex-1-enes with mCPBA in the presence of trichloroacetic acid gives the
corresponding 1,2-anti-2,3-syn-1-trichloroacetoxy-2-hydroxy-3-aminocyclohexane with high levels of
diastereoselectivity (90% de). This is consistent with a mechanism of oxidation involving
hydrogen-bonded delivery of the oxidant by the allylic ammonium ion formed in situ, followed by
highly regioselective ring-opening of the intermediate epoxide by trichloroacetic acid. The effect of
conformational constraints upon the oxidation reaction is also examined.
Introduction
The epoxidation of allylic alcohols is a widely studied synthetic
transformation in organic chemistry,1 with high levels of stereo-
control having been observed in substrate-directed epoxidation of
both cyclic2 and acyclic3 allylic alcohols. The related epoxidation
of allylic amines has been much less widely studied, presumably
due to facile N-oxidation upon treatment with oxidising agents,4
although examples employing carbamate, amide and sulfonamide
protecting groups have been reported.5 The chemoselective olefinic
oxidation of allylic amines6 has been achieved upon treatment of
the requisite amine with F3CCO2H followed by trifluoroperacetic
acid.7,8 More recently, Asensio et al. have shown that 1 undergoes
syn-directed oxidation upon treatment with mCPBA to give 2 in
>98% de.9 Aggarwal et al. have also demonstrated that oxidation
of the ammonium p-toluenesulfonate salt 3 with Oxone proceeds
with high levels of syn-selectivity (>90% de) to generate epoxide
4 in 73% yield.10 Additionally, Harrity et al. have demonstrated
Fig. 1 Ammonium-directed oxidations of allylic amines [Ar = p-ClC6H4].
that spiropiperidine ammonium trifluoroacetate salt 5 undergoes
diastereoselective epoxidation upon treatment with mCPBA11 to
give 6 (Fig. 1).
Results and discussion
We have previously communicated a method to effect the
dihydroxylation of 3-(N,N-dibenzylamino)cyclohex-1-ene upon
Development of an ammonium-directed oxidation protocol
treatment with Cl3CCO2H followed by mCPBA.12 However, the
method described was not found to be robust or generally
applicable. We therefore describe herein our full investigations
into the development of a reliable experimental protocol appli-
cable to the dihydroxylation of primary, secondary and tertiary
amines.
In order to probe the oxidation protocol, 3-(N,N-
dibenzylamino)cyclohex-1-ene 9 was chosen as model system for
reaction optimisation. Tertiary allylic amine 9 was synthesised
from cyclohexene via Wohl–Ziegler allylic bromination13 and
subsequent bromide displacement with dibenzylamine, giving 9
in 41% yield after chromatographic purification. However, a more
experimentally facile (and scalable) preparation of 9 involved
benzylation of secondary allylic amine 8 (prepared from 7 and
benzylamine) with benzyl bromide, with subsequent acid/base
extraction giving 9 in 70% yield on a >80 g scale (Scheme 1).
The formation of ammonium species 10 from tertiary allylic
amine 9 in the presence of Cl3CCO2H was examined. Amine 9
was added in 0.1 eq aliquots to a solution of Cl3CCO2H (1 eq)
in CDCl3, and the distribution of products was monitored by
1H NMR spectroscopy. A pronounced difference in dH of the
vinylic protons was observed (for 9, C(1)H and C(2)H appear
as a multiplet at dH 5.65–5.85 ppm), indicating the time-averaged
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
† Dedicated to Professor Gordon H. Whitham, to honour his 80th year.
‡ Electronic supplementary information (ESI) available: Additional ex-
perimental information. CCDC reference number 679350. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b808811j
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by aqueous work-up after 21 h, returned a mixture of products.
Similarly, when 9 was treated with either 1 eq or 2 eq of Cl3CCO2H
for 5 min, followed by the addition of mCPBA, a mixture of
products was observed. However, when 4 eq of Cl3CCO2H was
utilised, a 33 : 67 mixture of 9 and trichloroacetate 11 (90% de)15,16
was generated, although other minor unidentifiable by-products
1
were also noted in the H NMR spectrum of the crude reaction
mixture. Under the same conditions 5 eq of Cl3CCO2H gave a
crude reaction mixture whose 1H NMR spectrum indicated only
the presence of 9 and trichloroacetate 11 (90% de) in a 31 : 69 ratio.
Reaction optimisation showed that quantitative conversion to 11
was achieved when 9 in DCM (0.36 M) was treated with 5 eq of
Cl3CCO2H followed by 1.6 eq mCPBA (Scheme 2). The relative
1,2-anti-2,3-syn-configuration of 11 was initially assigned by a
combination of 1H NMR 3J coupling constant and NOE analyses
(assuming a chair conformation is adopted in which the N,N-
dibenzylamino moiety lies in an equatorial site), and subsequently
unambiguously proven via single crystal X-ray analysis‡ of the
trichloroacetate salt 12 (Fig. 3).
Scheme 1 Reagents and conditions: (i) NBS, AIBN, CCl4, 80 ◦C, 1.5 h;
(ii) benzylamine, K2CO3, THF, 50 ◦C, 3 days; (iii) BnBr, Hu¨nig’s base,
DMAP, DCM, rt, 24 h; (iv) dibenzylamine, K2CO3, THF, 50 ◦C, 3 days.
signal and fast exchange between amine 9 and ammonium 10.
The difference in chemical shift (Dd) between the values of dH
for C(1)H and C(2)H increased with increasing equivalents of
Cl3CCO2H, although a plateau was noted at approximately 4–5
equivalents, suggesting that the equilibrium lies predominately to
the right and the ammonium 10 predominates in solution under
these conditions. This result suggests that 5 eq of Cl3CCO2H may
be sufficient to effect efficient N-protonation (Fig. 2).
A range of carboxylic acids, ranging in acid strength from acetic
acid to trifluoroacetic acid, was next screened for their efficacy in
promoting chemoselective olefinic oxidation. Here, 9 was treated
with an excess (5 eq) of the requisite carboxylic acid followed
by mCPBA (1.6 eq) over 21 h, followed by basification, and the
1
product distribution was analysed by H NMR spectroscopy.16
These results demonstrated that AcOH (pKa = 4.76)17 and
ClCH2CO2H (pKa = 2.86)17 were ineffective at promoting olefinic
oxidation, giving rise to complex mixtures of products. In the
The effect of number of equivalents of Cl3CCO2H on the
product distribution of the oxidation reaction was assessed. Initial
treatment of 9 in DCM (0.07 M) with 1.2 eq of mCPBA,14 followed
Fig. 2 Difference in chemical shift (Dd) between C(1)H and C(2)H upon addition of Cl3CCO2H to 9.
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Scheme 2 Reagents and conditions: (i) Cl3CCO2H, mCPBA, DCM, 21 h,
rt then NaHCO3 (0.1 M, aq).
Scheme 3 Reagents and conditions: (i) 9 (1 eq) in DCM (0.36 M), Brønsted
acid (5 eq), then mCPBA (1.6 eq), rt, 21 h, then NaHCO3 (0.1 M, aq);
(ii) 9 (1 eq) in DCM (0.36 M), TsOH (3 eq), then mCPBA (1.6 eq), rt, 21 h,
then NaHCO3 (0.1 M, aq); (iii) 9 (1 eq) in 1,4-dioxane (0.36 M), H2SO4 (5
eq), then mCPBA (1.6 eq), 0 ◦C to rt, 21 h, then NaHCO3 (0.1 M, aq) [a
Determined from analysis of the 1H NMR spectrum of the crude reaction
product. b First ionisation].
MeOH, gave the common 1,2-anti-2,3-syn-N-protected amino diol
1
3
16 in 90% de in each case. H NMR J coupling constant and
NOE analyses were supportive of the assigned 1,2-anti-2,3-syn-
configuration within 16 (Scheme 4).
Scheme 4 Reagents and conditions: (i) K2CO3, MeOH, rt, 16 h.
Fig. 3 Chem 3D representation of the X-ray crystal structure of 12 (some
H atoms and the Cl3CCO2 counterion omitted for clarity).
-
In order to probe the intermediacy of syn-epoxide 17 in this
oxidation reaction, it was envisaged that 17 could be prepared
through base-promoted elimination of TsOH from 15. Treatment
of 15 (90% de) with DBU gave a 95 : 5 mixture of syn-epoxide
17 (>98% de) and 1,2-anti-2,3-anti-tosylate 18 (>98% de)16
respectively, with chromatographic purification giving syn-epoxide
17 in 95% yield and >98% de. The observation that base-mediated
epoxide formation from 1,2-anti-2,3-syn-tosylate 15 is faster than
that from 1,2-anti-2,3-anti-tosylate 18 is consistent with the former
proceeding via a favourable chair-like transition state that places
the N,N-dibenzylamino group equatorial, whilst the latter would
presumably have to proceed via an unfavourable twist-boat-like
transition state (Scheme 5).
Treatment of 17 (>98% de) with TsOH (5 eq) proceeded with
complete regio- and diastereocontrol to give, after basification, 15
in >98% de and 86% yield. Epoxide opening of 17 with Cl3CCO2H
(5 eq) and basification furnished 11 in >98% de and quantitative
yield. An authentic sample of 14 was also prepared upon ring-
opening of 17 with F3CCO2H. Transesterification of either 11 or 14
with K2CO3/MeOH gave a sample of 16 in >98% de. Attempted
direct formation of 16 upon ring-opening of 17 with H2SO4 in
aqueous dioxane gave 72% conversion to 16 in >98% de, and
was accompanied by the formation of unidentified by-products.
It was also noted that treatment of 17 with meta-chlorobenzoic
case of Cl2CHCO2H (pKa = 1.29),17 however, the corresponding
dichloroacetate ester 13 was observed as the major product, in 87%
de. Oxidation in the presence of F3CCO2H (pKa = -0.25)17 gave a
53 : 47 mixture of trifluoroacetate 14 (90% de) and diol 16 (90%
de), presumably a result of the lability of the trifluoroacetate group
under the basic aqueous work-up conditions. The effectiveness of
N-protection with a sulfonic acid in this reaction was also assessed
via the application of TsOH (pKa = -6.5),17 giving 15 in 90% de
after aqueous work-up. In accordance with the increased acidity
of TsOH over Cl3CCO2H, optimisation studies revealed that only
3 eq of TsOH were necessary to effect efficient N-protonation
in this reaction protocol. The utility of mineral acids was also
examined, although treatment of 9 with aq HCl (pKa = -7)17 in
1,4-dioxane followed by mCPBA returned starting material, and
addition of aq H2SO4 (pKa1 = -9)17 gave a 9 : 61 : 30 mixture of
9, 1,2-anti-2,3-syn diol 16 (90% de) and syn-epoxide 17 (90% de)
respectively, along with other unidentifiable products (Scheme 3).
The relative configurations within the major diastereoisomers
13, 14 and 15 were assigned by analogy to that unambiguously
1
3
proven for 11. Additionally, H NMR J coupling constant and
NOE analyses were supportive of the relative 1,2-anti-2,3-syn-
configuration within 15, and transesterification of 11, 13 and 14
(as a 53 : 47 mixture of 14:16) upon treatment with K2CO3 in
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=
syn-face of the allylic C C, via a hydrogen-bonded transition
state 19 analogous to the Bartlett18 and Henbest19 studies on
the corresponding allylic alcohol, to give syn-epoxide 17 as the
corresponding ammonium trichloroacetate salt 20. This presum-
ably resides in the more stable conformation 20A, where the
N,N-dibenzylammonium moiety lies equatorial. This conformer
favours nucleophilic attack by the conjugate base of the Brønsted
acid protecting agent at the C(1)-oxirane carbon, giving a chair-
like transition state leading to the trans-diaxial product 11, in
accordance with the Fu¨rst–Plattner rule.20 This is also consistent
with the acid-catalysed ring-opening of epoxides proceeding via a
late transition state,21 thus promoting attack at the C(1)-oxirane
carbon where the electron-withdrawing inductive effect of the
N,N-dibenzylammonium moiety is lower (Fig. 4).
Scheme 5 Reagents and conditions: (i) DBU, DCM, rt, 24 h.
acid returned only starting material, whilst addition of a 1.6 : 5
mixture of meta-chlorobenzoic acid/Cl3CCO2H gave, after basic
work-up, 11 only, indicating that no competitive ring-opening of
17 by meta-chlorobenzoic acid was occurring under the oxidation
reaction conditions (Scheme 6).
Conformational effects upon reaction diastereoselectivity and rate
In order to probe the effect of conformation upon the reaction
diastereoselectivity, the oxidations of the diastereoisomers of 3-
(N,N-dibenzylamino)-5-tert-butylcyclohex-1-ene syn-21 and anti-
22 (both prepared from 4-tert-butylcyclohexanol)22 were investi-
gated. Treatment of syn-21 with 5 eq of Cl3CCO2H and mCPBA
followed by basic aqueous work-up and transesterification with
K2CO3 in MeOH gave 1,2-anti-2,3-syn-23 as a single diastereoiso-
mer in quantitative yield. The relative stereochemistry within 23
was assigned by 1H NMR 3J coupling constant analysis, assuming
that 23 preferentially adopts a chair ground-state conformation
in solution which places both the bulky tert-butyl and N,N-
dibenzylamino groups in equatorial sites. Analogous treatment
of anti-22 gave a 22 : 78 mixture of epoxide 24 and its ring-
opened product 1,2-anti-2,3-syn-25 as single diastereoisomers in
each case, and in quantitative yield. The stereochemistry within
1
3
25 was assigned on the basis of H NMR J coupling constant
analysis, assuming that 25 preferentially adopts a distorted chair
conformation in solution which places the tert-butyl group in an
equatorial site, and the N,N-dibenzylamino group midway be-
tween an axial and equatorial site.23 These results suggest that both
positions for the N,N-dibenzylamino group (an equatorial site in
syn-21 and midway between an axial and equatorial site in anti-
22) are equally effective in promoting a highly diastereoselective
syn-oxidation reaction (Scheme 7).
Scheme 6 Reagents and conditions: (i) TsOH, DCM, rt, 16 h, then
NaHCO3 (0.1 M, aq); (ii) X3CCO2H, DCM, rt, 16 h, then NaHCO3 (0.1 M,
aq); (iii) K2CO3, MeOH, rt, 16 h.
The 1,2-anti-2,3-syn-arrangement within the major di-
astereoisomeric N,N-dibenzylamino diol 16 resulting from this
oxidation protocol is consistent with a mechanism involving initial
protonation of the amine 9 to give the corresponding ammonium
10. Subsequent oxidation with mCPBA directs epoxidation to the
Fig. 4 Postulated mechanism for the oxidation of 9 with Cl3CCO2H and mCPBA [Ar = m-ClC6H4].
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and mCPBA (0.58 M). These data were used to determine the rate
coefficient (k) by application of the integrated form of the rate law
for a second-order reaction,24 giving k = 3.5 ¥ 10-4
(
0.2 ¥ 10-4)
mol-1 dm3 s-1 (Fig. 5).
The oxidation of syn-21 was next monitored by 1H NMR
spectroscopy. Addition of 5 eq of Cl3CCO2H to syn-21 gave
ammonium 26. Upon addition of mCPBA the consumption
of ammonium 26 was monitored by calculating an average
integration of the peaks due to C(1)H (dH 6.24–6.32 ppm) and
C(2)H (dH 5.84–5.93 ppm), and the consumption of peracid was
monitored in an analogous fashion to that previously described.
The generation of ammonium 27 was monitored by calculating
an average integration of the peaks due to C(1)H (dH 5.20–5.24
ppm), C(3)H (dH 3.64–3.72 ppm), and N(CHAHBPh)2 (dH 5.33–
5.41 ppm). Analogous treatment of the data to that described for
oxidation of 9 gave k = 3.3 ¥ 10-4 ( 0.2 ¥ 10-4) mol-1 dm3 s-1 (Fig. 6).
Similarly, the oxidation of anti-22 was monitored by 1H NMR
spectroscopy. Addition of 5 eq of Cl3CCO2H to anti-22 gave
ammonium 28. Upon addition of mCPBA the consumption
of ammonium 28 was monitored by calculating an average
integration of the peaks due to C(1)H (dH 6.51–6.60 ppm) and
C(2)H (dH at 5.95–6.05 ppm), and the consumption of peracid was
monitored in an analogous fashion to that previously described.
The generation of ammonium 30 was monitored by integration of
the peaks due to N(CHAHBPh)2 (dH 5.25–5.32 ppm). The growth
and decay of a signal at dH 3.68–3.73 ppm was attributed as
arising from C(3)H within the intermediate epoxide ammonium
29, consistent with 29 being an intermediate en route to 30. In this
Scheme 7 Reagents and conditions: (i) Cl3CCO2H, mCPBA, DCM, rt,
21 h, then K2CO3, MeOH, rt, 16 h.
The effect of conformational constraints on the rate of the
oxidation reaction was next determined. Initially, the progress of
the oxidation of 3-(N,N-dibenzylamino)cyclohexene 9 was studied
by 1H NMR spectroscopy. Treatment of 9 with 5 eq of Cl3CCO2H
gave ammonium 10. Upon subsequent addition of mCPBA, the
consumption of ammonium 10 was monitored by calculating an
average integration of the peaks due to C(1)H (dH 6.27–6.36 ppm)
and C(2)H (dH 5.87–5.94 ppm), whilst the consumption of peracid
was monitored by calculating an average integration of the peaks at
dH 7.86–7.89 and 7.93–7.96 ppm. The generation of ammonium 12
was monitored by calculating an average integration of the peaks
due to C(1)H (dH 5.10–5.17 ppm), C(3)H (dH 3.65–3.72 ppm), and
N(CHAHBPh)2 (dH 5.31–5.41 ppm). The integral values obtained
from the 1H NMR spectra were converted to concentration values
using the known initial concentrations of 10 (0.36 M), 12 (0 M),
case the rate coefficient was calculated as k = 5.9 ¥ 10-4
( 0.2 ¥
10-4) mol-1 dm3 s-1 (Fig. 7).
1
Fig. 5 Real-time H NMR measurements for Cl3CCO2H- and mCPBA-promoted dihydroxylation of 9 [R = COCCl3; for brevity, for 10 and 12, the
-
Cl3CCO2 counterions are not shown].
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Fig. 6 Real-time 1H NMR measurements for Cl3CCO2H- and mCPBA-promoted dihydroxylation of syn-21 [R = COCCl3; for brevity, for 26 and 27,
-
the Cl3CCO2 counterions are not shown].
Fig. 7 Real-time 1H NMR measurements for Cl3CCO2H- and mCPBA-promoted dihydroxylation of anti-22 [R = COCCl3; for brevity, for 28–30, the
-
Cl3CCO2 counterions are not shown].
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Whitham and co-workers investigated the preferred geometry
of the transition state proposed by Henbest for the epoxidation
of cyclohex-2-enol 31 by performing the oxidation of the di-
astereoisomers of 5-tert-butylcyclohex-2-enol syn-32 (having the
hydroxyl group locked in an pseudoequatorial site of a half-chair
conformation) and anti-33 (having the hydroxyl group locked in a
pseudoaxial site of a half-chair conformation).25 Very high levels
of syn-diastereoselectivity were achieved for epoxidation of 31
and syn-32 (>95% de) but were lower for anti-33 (66% de). Fur-
thermore, the relative rates of oxidation of 31:syn-32:anti-33 were
determined to be 5 : 7 : 1. These rate data suggest that the pseudoe-
quatorial hydroxyl group in syn-32 is efficient at promoting a rapid,
highly diastereoselective oxidation reaction, whilst the pseudoax-
ial hydroxyl group within anti-33 is much less effective, presumably
due to the conformational restriction preventing adoption of
the optimal reactive geometry in the transition state.26 The
intermediate rate of oxidation of 31 is consistent with this species
existing as a mixture of the two possible half-chair conformations
in solution. In the ammonium-directed oxidation of 9, syn-21
and anti-22, very high levels of syn-diastereoselectivity (≥90% de)
were observed in each case, and the relative rates of oxidation of
9:syn-21:anti-22 were determined to be 1 : 1 : 2. The similarity in
the rates of oxidation of 9 and syn-21 in this system presumably
reflects the similarity in the preferred half-chair conformations of
each species, with the bulky N,N-dibenzylamino group showing a
pronounced preference to adopt a pseudoequatorial site within a
half-chair conformation for 9, and both the tert-butyl and N,N-
dibenzylamino substituents adopting pseudoequatorial sites in a
half-chair conformation for syn-21. The faster rate of oxidation
for anti-22 is in contrast to the results obtained by Whitham on
the analogous allylic alcohol system, but is consistent with the
preferred conformation of anti-22 (and therefore ammonium 28)
being a distorted half-chair which places the ammonium in a more
optimal reactive geometry within the hydrogen-bonded transition
state originally proposed by Henbest (Fig. 8).
Fig. 8 Relative rates of oxidation of allylic alcohols 31–33, and allylic
amines 9, 21 and 22.
In order to investigate this hypothesis, MacroModel molec-
ular modelling27 was carried out on ammonium syn-26, for
which a half-chair conformation was predicted with the N,N-
dibenzylammonium substituent occupying a pseudoequatorial
site. For anti-28 a distorted half-chair conformation was predicted,
with the N,N-dibenzylammonium substituent midway between a
pseudoaxial and pseudoequatorial site28 (Fig. 9).
The conformations of epoxide ammoniums 34 (derived from
syn-21) and 29 (derived from anti-22) were modelled, and found
at minima of -42.2 and -37.5 kJ mol-1 respectively. From analysis
of these minimised energy conformations the ring-opening of
34 at C(1) would traverse a chair-like transition state, while
the ring-opening of 29 at C(1) would traverse a twist-boat-
like transition state. This is consistent with the observation
by 1H NMR spectroscopy of an epoxide intermediate in the
oxidation of anti-22, presumably due to a longer lifetime of this
intermediate arising from a slower rate of ring-opening in situ
(Fig. 10).
Fig. 9 Chem 3D representation of the MacroModel global energy predictions of for ammoniums 26 and 28 (some H atoms omitted for clarity).
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Fig. 10 Chem 3D representation of the MacroModel global energy predictions of for epoxide ammoniums 34 and 29 (some H atoms omitted for clarity).
“One-pot” dihydroxylation: Application to tertiary, secondary and
primary amines
The viability of a “one-pot” dihydroxylation procedure was next
examined. After treatment of allylic amine 9 with Cl3CCO2H and
mCPBA for 21 h, sat aq Na2SO3, followed by MeOH and then
K2CO3, were added to the crude reaction mixture, affording N,N-
Scheme 9 Reagents and conditions: (i) Cl3CCO2H (5 eq), mCPBA, DCM,
dibenzylamino diol 16 directly, in quantitative yield and 90% de,
rt, 21 h, then Na2SO3 (sat aq), then K2CO3, MeOH, rt, 16 h; (ii) H2
on a >10 g scale. Subsequent hydrogenolytic N-debenzylation gave
3-aminocyclohexane-1,2-diol 35 in 78% overall yield and 90% de
(1 atm), Pd(OH)2/C, MeOH, rt, 24 h.
(Scheme 8).
spectroscopically identical to those samples prepared from tertiary
amine 9 and secondary amine 8 (Scheme 10).
Scheme 8 Reagents and conditions: (i) Cl3CCO2H (5 eq), mCPBA, DCM,
rt, 24 h, then Na2SO3 (sat aq), then K2CO3, MeOH, rt, 24 h; (ii) H2
(1 atm), Pd(OH)2/C, MeOH.
Scheme 10 Reagents and conditions: (i) Cl3CCO2H (5 eq), rt; (ii) mCPBA
(1.6 eq), rt, 21 h, then K2CO3, MeOH, rt, 16 h.
The applicability of this oxidation protocol to secondary and
primary amines was next investigated. Thus, 3-(N-benzylamino)-
cyclohex-1-ene 8 was treated under the optimum oxidation and
transesterification conditions, followed by column chromatogra-
phy on neutral alumina to give 1,2-anti-2,3-syn-36 in 90% de
and 94% yield. The relative configuration within 36 was assigned
by analogy to the tertiary amine case, and subsequently proven
through hydrogenolysis to furnish amino diol 35 in 90% de and
84% yield (Scheme 9).
In order to access the corresponding primary amine, N-
deprotection of 37 with Cl3CCO2H (5 eq) generated trichloroac-
etate salt 38 in situ. To this mixture was added mCPBA giving,
after transesterification and column chromatography on neutral
alumina, amino diol 35 in 90% de and 34% yield, which was
Conclusion
In conclusion, primary, secondary and tertiary 3-aminocyclohex-
1-enes are susceptible to highly chemo- and diastereoselective
olefinic dihydroxylation upon treatment with either Cl3CCO2H
or TsOH and mCPBA. The high levels of stereoselectivity
observed are consistent with the formation of an ammonium
ion in situ that directs epoxidation with mCPBA to the syn-
face, with subsequent regio- and stereoselective trans-diaxial
epoxide opening and hydrolysis generating the corresponding 1,2-
anti-2,3-syn-3-aminocyclohexane-1,2-diol. The application of this
protocol to facilitate the synthesis of all the diastereoisomers of
3-aminocyclohexane-1-2-diol is reported in the following paper.
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H]+, 100%); HRMS (ESI+) C22H2535Cl3NO3 ([M + H]+) requires
456.0895; found 456.0891.
+
Experimental
General experimental
Rate studies of the ammonium-directed dihydroxylation reaction
R
Water was purified by an Elixꢀ UV-10 system. mCPBA was sup-
plied as a 70–77% slurry in water (Aldrich) and titrated according
to the procedure of Swern14 immediately before use. All other
solvents were used as supplied (analytical or HPLC grade) without
prior purification. Organic layers were dried over MgSO4. Thin
layer chromatography 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.
A solution of 9 (15 mg, 0.054 mmol) in CDCl3 (0.15 mL) was
prepared in a 3 mm NMR tube. Cl3CCO2H (44 mg, 0.27 mmol)
was added and the tube was shaken for 5 min. mCPBA (87% by
wt, 17 mg, 0.087 mmol) was then added, and the progress of the
reaction was monitored by 1H NMR spectroscopic analysis.
X-Ray crystal structure determination for 12
Data were collected using an Enraf-Nonius k-CCD diffractometer
with graphite-monochromated Mo-Ka radiation using standard
procedures at 150 K. The structure was solved by direct methods
(SIR92); all non-hydrogen atoms were refined with anisotropic
thermal parameters. Hydrogen atoms were added at idealised
positions. The structure was refined using CRYSTALS.29
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.
12: C17.5H18Cl6.67N0.67O4.67, M = 548.69, monoclinic, space group
˚
˚
˚
C2/c, a = 24.5125(2) A, b = 9.82110(10) A, c = 30.9595(4) A, b
◦
3
-1
˚
= 106.7096(5) , V = 7138.47(13) A , Z = 12, m = 0.823 mm ,
colourless plate, crystal dimensions = 0.2 ¥ 0.2 ¥ 0.3 mm3. A total
of 7984 unique reflections were measured for 5 < q < 27 and 5826
reflections were used in the refinement. The final parameters were
wR2 = 0.095 and R1 = 0.092 [I>3s(I)]. CCDC 679350.‡
(1RS,2RS,3RS)-1-p-Toluenesulfonyloxy-2-hydroxy-3-(N,N-
dibenzylamino)cyclohexane 15
General procedure for ammonium-directed dihydroxylation
The requisite acid was added to a stirred solution of the requisite
allylic amine in DCM, and the resultant solution was stirred
at rt for 5 min. Freshly titrated mCPBA was then added and
the solution was stirred at rt for 21 h. The mixture was then
diluted with DCM and washed with sat. aq. Na2SO3 until starch–
iodide paper indicated that no mCPBA was present. The organic
layer was washed four times with 0.1 M aq. NaHCO3, dried and
concentrated in vacuo.
Following the general procedure, TsOH (206 mg, 1.08 mmol), 9
(100 mg, 0.36 mmol) in DCM (1 mL), and mCPBA (87%, 117 mg,
0.58 mmol) gave 15 as a green oil (167 mg, quant, 90% de); nmax
(film) 3050 (O–H), 2946 (C–H); dH (400 MHz, CDCl3) 1.43–1.85
(6H, m, C(4)H2, C(5)H2, C(6)H2), 2.44 (3H, s, ArCH3), 2.92–3.13
(2H, br m, C(3)H, OH), 3.77 (4H, AB system, N(CH2Ph)2), 4.03–
4.09 (1H, m, C(2)H), 4.75–4.79 (1H, m, C(1)H), 7.23–7.37 (12H,
m, Ar, Ph), 7.75–7.81 (2H, d, J 7.8, Ar); dC (100 MHz, CDCl3) 19.2
(CH2), 21.7 (ArCH3) 23.4, 25.1 (CH2), 54.6 (N(CH2Ph)2), 58.4
(C(3)), 67.4 (C(2)), 80.1 (C(1)), 127.0, 127.8, 128.5, 128.6, 129.9,
133.9, 139.8, 144.8 (Ar, Ph); m/z (ESI+) 466 ([M + H]+, 100%);
HRMS (ESI+) C27H32NO4S+ ([M + H]+) requires 466.2047; found
466.2045.
(1RS,2RS,3RS)-1-Trichloroacetoxy-2-hydroxy-3-(N,N-
dibenzylamino)cyclohexane 11
(1RS,2RS,3RS)-3-(N,N-Dibenzylamino)cyclohexane-1,2-diol 16
Following the general procedure, Cl3CCO2H (294 mg, 1.81 mmol),
9 (100 mg, 0.36 mmol) in DCM (1 mL), and mCPBA (81%, 122 mg,
0.58 mmol) gave 11 as a colourless oil (165 mg, quant, 90% de); nmax
=
(film) 3424 (O–H), 2941 (C–H), 1762 (C O); dH (400 MHz, CDCl3)
1.50–1.97 (6 H, m, C(4)H2, C(5)H2, C(6)H2), 2.91 (1 H, br s, OH),
2.99–3.08 (1 H, m, C(3)H), 3.74 (1 H, d, J 14.4, N(CHAHBPh)2),
3.94 (1 H, d, J 14.4, N(CHAHBPh)2), 4.14–4.19 (1 H, m, C(2)H),
5.14–5.20 (1 H, m, C(1)H), 7.22–7.38 (10 H, m, Ph); dC (100 MHz,
CDCl3) 19.8, 22.6, 24.2 (C(4), C(5), C(6)), 54.9 (N(CH2Ph)2), 57.5
K2CO3 (500 mg) was added to a stirred solution of 11 (164 mg,
0.36 mmol) in MeOH (5 mL), and the resultant suspension was
stirred at rt for 16 h then concentrated in vacuo. H2O (10 mL) was
added and the mixture was extracted with DCM (4 ¥ 10 mL). The
combined organic extracts were then washed with brine (50 mL),
dried and concentrated in vacuo. Purification via flash column
(C(3)), 67.8 (C(2)), 77.9 (C(1)), 89.9 (CCl3), 127.0 (p-Ph), 128.5,
+
=
128.6 (o-, m-Ph), 139.8 (i-Ph), 161.0 (C O); m/z (ESI ) 456 ([M +
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chromatography (gradient elution, eluent 0%→100% EtOAc in
40–60 ◦C petrol) gave 16 as a viscous, pale yellow oil (112 mg,
quant, 90% de); nmax (film) 3407 (O–H), 3027, 2937 (C–H); dH
(400 MHz, CDCl3) 1.43–1.89 (6H, m, C(4)H2, C(5)H2, C(6)H2),
2.14 (1H, br s, OH), 3.10–3.20 (1H, m, C(3)H), 3.69–3.78 (2H,
d, J 14.4, N(CHAPh)2), 3.81–3.91 (3H, m, C(2)H, N(CHBPh)2),
3.99–4.06 (1H, m, C(1)H), 7.22–7.38 (10H, m, Ph); dC (100 MHz,
CDCl3) 19.9, 23.8, 28.1 (C(4), C(5), C(6)), 55.0 (N(CH2Ph)2), 58.3
(C(3)), 70.5 (C(1)), 71.1 (C(2)), 127.0 (p-Ph), 128.5, 128.7 (o-, m-
Ph), 139.8 (i-Ph); m/z (ESI+) 312 ([M + H]+, 100%); HRMS (ESI+)
Cl3CCO2H (44 mg, 0.27 mmol) was added to a solution of syn-
21 (13 mg, 0.039 mmol) in CDCl3 (0.15 mL) in a 3 mm NMR
tube. After 5 min, mCPBA (87% by wt, 17 mg, 0.086 mmol)
was added and the progress of the reaction monitored by 1H
NMR spectroscopy. After completion the reaction mixture was
transferred to a round-bottom flask and sat. aq. Na2SO3 was added
until starch–iodide paper indicated that no mCPBA remained.
MeOH (1 mL) and K2CO3 (50 mg) were added and the suspension
stirred for 24 h before being concentrated in vacuo. H2O (2 mL) was
added and the mixture was extracted with DCM (4 ¥ 2 mL). The
combined organic extracts were washed with brine (10 mL), dried,
and concentrated in vacuo to give 23 as a colourless oil (14 mg,
quant, >95% de); nmax (film) 3376 (O–H), 3085, 3063, 3028, 2950,
2689 (C–H); dH (400 MHz, CDCl3) 0.81 (9H, s, CMe3), 1.06–
1.17 (1H, app q, J 12.1, C(4)Hax), 1.40 (1H, br tt, J 12.3, 2.8,
C(5)H), 1.50 (1H, td, J 13.0, 2.8, C(6)Hax), 1.59–1.66 (1H, m,
C(6)Heq), 1.72–1.80 (1H, m, C(4)Heq), 3.06 (1H, br dt, J 12.1, 3.0,
C(3)H), 3.77 (2H, d, J 16.0, N(CHAHBPh)2), 3.87 (2H, d, J 16.0
N(CHAHBPh)2), 4.01 (1H, app br t, J 2.5, C(2)H), 4.15 (1H, app q,
J 3.0, C(1)H), 7.19–7.40 (10H, m, Ph); dC (100 MHz, CDCl3) 25.7
(C(4)), 27.4 (CMe3), 28.4 (C(6)), 32.2 (CMe3), 40.2 (C(5)), 54.9
(N(CH2Ph)2), 59.9 (C(3)), 69.3 (C(2)), 70.2 (C(1)), 126.9 (p-Ph),
128.4, 128.5 (o-, m-Ph), 139.2 (i-Ph); m/z (ESI+) 368 ([M + H]+,
C20H26NO2 ([M + H]+) requires 312.1958; found 312.1952.
+
“One-pot” dihydroxylation protocol
Cl3CCO2H (29.5 g, 0.18 mol) was added to a stirred solution of
9 (10 g, 36 mmol) in DCM (100 mL) and the resultant solution
was stirred at rt for 5 min. Freshly titrated mCPBA (87%, 11.5 g,
58 mmol) was then added and the solution was stirred at rt for
21 h. Sat. aq. Na2SO3 was then added until starch–iodide paper
indicated that no mCPBA was present. MeOH (500 mL) and
K2CO3 (10 g) were then added and the resultant suspension was
stirred at rt for 16 h before being concentrated in vacuo. H2O
(500 mL) was then added and the mixture was extracted with
DCM (4 ¥ 500 mL). The combined organic extracts were washed
with brine (1 L), dried and concentrated in vacuo to give 16 as a
viscous, pale yellow oil (11.4 g, quant, 90% de).
100%); HRMS (ESI+) C24H34NO2 ([M + H]+) requires 368.2584;
+
found 368.2584.
(1RS,2RS,3RS,5RS)-3-(N,N-Dibenzylamino)-5-tert-
butylcyclohexane-1,2-diol 25
(1RS,2SR,3SR)-1,2-Epoxy-3-(N,N-dibenzylamino)-
cyclohexane 17
Cl3CCO2H (44 mg, 0.27 mmol) was added to a solution of anti-
22 (18 mg, 0.054 mmol) in CDCl3 (0.15 mL) in a 3 mm NMR
tube. After 5 min, mCPBA (87% by wt, 17 mg, 0.086 mmol)
was added and the progress of the reaction monitored by 1H
NMR spectroscopy. After completion the reaction mixture was
transferred to a round-bottom flask and sat. aq. Na2SO3 was added
until starch–iodide paper indicated that no mCPBA remained.
MeOH (1 mL) and K2CO3 (50 mg) were added and the suspension
stirred for 24 h before being concentrated in vacuo. H2O (2 mL)
was added and the mixture was extracted with DCM (4 ¥ 2 mL).
The combined organic extracts were washed with brine (10 mL),
dried, and concentrated in vacuo to give a 22 : 78 mixture of 24:25
as a colourless oil (20 mg); nmax (film) 3354 (O–H), 3068, 3032,
2956, 2871 (C–H); m/z (ESI+) 368 ([M + H]+, 25, 100%), 350
DBU (7.94 mL, 52.8 mmol) was added to a stirred solution of 15
(22.3 g, 49 mmol, 90% de) in DCM (100 mL) at rt and the reaction
mixture was stirred for 24 h. 10% aq. CuSO4 (500 mL) was added
and the mixture was extracted with DCM (3 ¥ 500 mL). The
combined organic extracts were washed with H2O (3 ¥ 500 mL),
dried and concentrated in vacuo. Purification via flash column
chromatography (gradient elution, eluent 0%→100% Et2O in 40–
60◦C petrol) gave 17 as a colourless oil (13.6 g, 95%, >98% de); nmax
(film) 3061, 2938 (C–H); dH (400 MHz, CDCl3) 1.11–1.39 (1H, m,
C(5)HA), 1.55–1.96 (5H, m, C(4)H2, C(5)HB, C(6)H2), 3.00–3.10
(1H, m, C(3)H), 3.11–3.17 (1H, m, C(1)H), 3.37 (1H, app d, J 4.0,
C(2)H), 3.75 (2H, d, J 14.1, N(CHAHBPh)2), 3.96 (2H, d, J 14.1,
N(CHAHBPh)2), 7.24–7.53 (10H, m, Ph); dC (100 MHz, CDCl3)
19.3, 21.6, 23.1 (C(4), C(5), C(6)), 51.7 (C(1)), 54.7 (N(CH2Ph)2),
55.0 (C(2)), 55.7 (C(3)), 126.7 (p-Ph), 128.2, 128.6 (o-, m-Ph),
140.7 (i-Ph); m/z (ESI+) 294 ([M + H]+, 100%); HRMS (ESI+)
C20H24NO+ ([M + H]+) requires 294.1852; found 294.1853.
+
([M + H]+, 24, 74%); HRMS (ESI+) C24H34NO2 ([M + H]+, 25)
requires 368.2584; found 368.2582.
Data for 24: dH (400 MHz, CDCl3) [selected peaks] 0.84 (9H, s,
CMe3), 3.67 (2H, d, J 12.0, N(CHAHBPh)2), 3.97 (2H, d, J 12.0,
N(CHAHBPh)2).
Data for 25: dH (400 MHz, CDCl3) 0.93 (9H, s, CMe3), 1.03
(1H, app q, J 12.5, C(6)Hax), 1.17–1.37 (1H, m, C(4)Hax), 1.57
(1H, br tt, J 12.9, 3.4, C(5)H), 2.05 (1H, br ddd, J 12.4, 6.8,
3.0, C(6)Heq), 2.15–2.23 (1H, m, C(4)Heq), 3.21 (1H, dd, J 9.6,
7.3, C(2)H), 3.33 (1H, app t, J 6.6, C(3)H), 3.43 (2H, d, J 13.1,
N(CHAHBPh)2), 3.85 (1H, ddd, J 11.4, 9.6, 4.3, C(1)H), 3.95 (2H,
d, J 13.1, N(CHAHBPh)2), 7.20–7.45 (10H, m, Ph); dC (100 MHz,
(1RS,2RS,3RS,5SR)-3(-N,N-Dibenzylamino)-5-tert-
butylcyclohexane-1,2-diol 23
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CDCl3) 23.5 (C(4)), 27.3 (CMe3), 32.3 (C(6)), 32.8 (CMe3), 43.0
(C(5)), 56.1 (C(3)), 56.4 (N(CH2Ph)2), 73.4 (C(1)), 75.0 (C(2)),
127.5 (p-Ph), 128.6, 129.0 (o-, m-Ph), 138.8 (i-Ph).
7 J. Quick, Y. Khandelwal, P. C. Meltzer and J. S. Weinberg, J. Org. Chem.,
1983, 48, 5199; J. Quick, C. Mondello, M. Humora and T. Brennan,
J. Org. Chem., 1978, 43, 2705; W. D. Emmons, A. S. Pagano and J. P.
Freeman, J. Am. Chem. Soc., 1954, 76, 3472; L. Gil, D. Compe`re,
B. Guilloteau-Bertin, A. Chiaroni and C. Marazano, Synthesis, 2000,
2117; G. V. Grishina, A. A. Borisenko, I. S. Veselov and A. M. Petrenko,
Russ. J. Org. Chem., 2005, 41, 272.
(1RS,2RS,3RS)-3-Aminocyclohexane-1,2-diol 35
8 The Lewis acid BF3 has also been reported to protect the N-atom of
tertiary alkenylamines from oxidation by dioxiranes; see: M. Ferrer,
F. Sanchez-Baeza, A. Messeguer, A. Diez and M. Rubiralta, J. Chem.
Soc., Chem. Commun., 1995, 293.
9 G. Asensio, R. Mello, C. Boix-Bernardini, M. E. Gonza´lez-Nu´n˜ez and
G. Castellano, J. Org. Chem., 1995, 60, 3692; G. Asensio, C. Boix-
Bernardini, C. Andreu, M. E. Gonza´lez-Nu´n˜ez, R. Mello, J. O. Edwards
and G. Castellano, J. Org. Chem., 1999, 64, 4705; G. Asensio, M. E.
Gonza´lez-Nu´n˜ez, C. B. Bernardini, R. Mello and W. Adam, J. Am.
Chem. Soc., 1993, 115, 7250.
10 V. K. Aggarwal and G. Y. Fang, Chem. Commun., 2005, 3448.
11 A. S. Edwards, R. A. J. Wybrow, C. Johnstone, H. Adams and J. P. A.
Harrity, Chem. Commun., 2002, 1542.
Pd(OH)2/C (50 mg) was added to a vigorously stirred suspension
of 16 (100 mg, 0.32 mmol) in degassed MeOH (1 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 35 as
a pale yellow solid (33 mg, 78%, 90% 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), C(6)), 49.9 (C(3)), 70.0 (C(1)),
74.2 (C(2)); m/z (ESI+) 132 ([M + H]+, 100%); HRMS (ESI+)
12 S. G. Davies, M. J. C. Long and A. D. Smith, Chem. Commun., 2005,
4536.
13 C. Djerassi, Chem. Rev., 1959, 71, 349.
14 mCPBA was supplied as a 70–77% slurry in water (Aldrich). It was
titrated according to the procedure outlined by Swern immediately
before use; see: D. Swern, Org. React., 1953, VII, 392.
15 Reaction diastereoselectivities were assessed by peak integration of the
1H NMR spectrum of the crude reaction mixture.
C6H14NO2 ([M + H]+) requires 132.1019; found 132.1022.
+
16 The minor diastereoisomers in these oxidation protocols were shown,
in each case, to be the corresponding 1,2-anti-2,3-anti-stereoisomers
via an independent chemical synthesis; see: C. Aciro, S. G. Davies,
P. M. Roberts, A. J. Russell, A. D. Smith and J. E. Thomson,
Org. Biomol. Chem., 2008, 6, DOI: 10.1039/b808812h (following
manuscript).
17 J. F. J. Dippy, S. R. C. Hughes and A. Rozanski, J. Chem. Soc.,
1959, 2942; M. B. Smith and J. March, in March’s Advanced Organic
Chemistry – Reactions, Mechanisms, and Structure, 2001, 5th edn, New
York, John Wiley & Sons Inc., p. 329.
Acknowledgements
The authors thank Research Councils UK, for a Fellowship
(A. J. R.).
References and notes
18 P. D. Bartlett, Rec. Chem. Prog., 1950, 47.
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19 H. B. Henbest and R. A. L. Wilson, J. Chem. Soc., 1957, 1958.
20 A. Fu¨rst and P. A. Plattner, Proceedings of the 12th International
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21 R. E. Parker and N. S. Isaacs, Chem. Rev., 1959, 59, 737; J. K. Addy
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22 Full details describing the preparation of syn-21 and anti-22 are
contained within the ESI.
23 An axial substituent in a chair form of cyclohexane ring will tend to
bend away from the axial hydrogen atoms, and in doing so results in
deformation (flattening) of the ring; see: J. B. Hendrickson, J. Am.
Chem. Soc., 1962, 84, 3355.
24 The integrated form of the rate law for a second order reaction is k2t =
{1/[B0 - A0]}ln[(A0B)/(B0A)] where A and B refer to concentrations.
25 P. Chamberlain, M. L. Roberts and G. H. Whitham, J. Chem. Soc. B,
1970, 1374.
26 The reduced reactivity of the olefin within anti-33 has been postulated
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Evans and G. C. Fu, Chem. Rev., 1993, 93, 1307.
4 S. Miyano, L. D.-L. Lu, S. M. Viti and K. B. Sharpless, J. Org. Chem.,
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6 For the epoxidation of a g-amino-a,b-unsaturated ester with tBuOOH
see: M. T. Reetz and E. H. Lauterbach, Tetrahedron Lett., 1991, 32,
4477. For the epoxidation of a tertiary allylic amine with NBS in
aqueous dioxane see: H. J. M. Gijsen, M. J. A. De Cleyn, C. J. Love,
M. Surkyn, S. F. A. Van Brandt, M. G. C. Verdonck, L. Moens, J.
Cuypers and J.-P. R. M. A. Bosmans, Tetrahedron, 2008, 64, 2456.
For the epoxidation of a tertiary allylic amine with NaOCl see: D. R.
Boyd, R. J. H. Davies, L. Hamilton, J. J. McCullough and H. P. Porter,
J. Chem. Soc., Perkin Trans. 1, 1991, 2189.
27 Meastro-MacroModel software, version 7.0.110. Conformational
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28 Similar solution phase conformations for amines syn-21 and anti-22
were inferred from 1H NMR NOE studies.
29 P. W. Betteridge, J. R. Carruthers, R. I. Cooper, C. K. Prout and
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The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3751–3761 | 3761
©