Ammonium directed dihydroxylation of N,N-dibenzylaminocyclohex-2-ene: Metal-free syntheses of the diastereoisomers of 3-dibenzylamino-1,2- dihydroxycyclohexane

Article abstract of DOI:10.1039/b509088a

Treatment of N,N-dibenzylaminocyclohex-2-ene with mCPBA in the presence of CCl₃CO₂H gives 1,2-anti-2,3-syn-1-trichloroacetoxy-2- hydroxy-3-N,N-dibenzylaminocyclohexane with high diastereoselectivity; this methodology has been used to

Full text of DOI:10.1039/b509088a

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Ammonium directed dihydroxylation of N,N-dibenzylaminocyclohex-2-
ene: metal-free syntheses of the diastereoisomers of 3-dibenzylamino-
1
,2-dihydroxycyclohexane
Stephen G. Davies,* Marcus J. C. Long and Andrew D. Smith
Received (in Cambridge, UK) 29th June 2005, Accepted 18th July 2005
First published as an Advance Article on the web 9th August 2005
DOI: 10.1039/b509088a
1
4
Treatment of N,N-dibenzylaminocyclohex-2-ene with mCPBA
in the presence of CCl CO H gives 1,2-anti-2,3-syn-1-trichloro-
yield. To probe further the mechanism of this transformation,
the crude reaction product from oxidation of amine 1 with
3
2
mCPBA (containing
a single product) was purified on
acetoxy-2-hydroxy-3-N,N-dibenzylaminocyclohexane with high
diastereoselectivity; this methodology has been used to facilitate
the metal-free stereoselective syntheses of all the diastereo-
isomers of 3-dibenzylamino-1,2-dihydroxycyclohexane.
alumina, giving 1,2-anti-2,3-syn-1-trichloroacetoxy-2-hydroxy-3-
N,N-dibenzylaminocyclohexane 2 in 40% yield and . 98% d.e.
The low (40%) isolated yield in the isolation of 2 from the crude
reaction product is presumably due to facile trichloroacetate
hydrolysis to 3 upon purification; consistent with this hypothesis
when 2 was stirred over silica, or subjected to chromatographic
purification on silica, amino diol 3 was formed in quantitative
yield. The 1,2-anti-2,3-syn-arrangement within amino diol 3 is
consistent with the mechanism of this transformation involving
initial protonation of the amine to give the corresponding
ammonium ion, which upon subsequent oxidation with mCPBA
directs epoxidation to the syn-face of the allylic CLC, presumably
The epoxidation of allylic alcohols is a widely studied synthetic
transformation in organic chemistry, with the tartrate directed
asymmetric epoxidation by Sharpless et al. arguably the most
1
valuable synthetic protocol developed within this area. High levels
2
of stereocontrol are observed in the substrate directed epoxidation
3
4
of both cyclic and acyclic allylic alcohols, with the most widely
recognised examples in this area being the hydroxyl directed syn-
epoxidation of cyclohex-2-enol, or anti-epoxidation of O-protected
15
5
via a hydrogen bonded transition state. The resulting syn-epoxide
cyclohex-2-enol derivatives upon oxidation with mCPBA.
9
is subsequently opened regioselectively with trichloroacetic acid
The related asymmetric epoxidation reaction of allylic amines
6
has been much less widely studied, presumably due to facile
in a trans-diaxial manner, with chromatographic purification on
silica promoting hydrolysis of the acetate and giving the amino
diol 3. Alternatively, treatment of amine 1 with TsOH and
subsequent oxidation with mCPBA gave 1,2-anti-2,3-syn-1-para-
7
N-oxidation upon treatment with oxidising agents. Although
Asensio et al. have shown that ammonium salts undergo stereo-
selective syn-directed epoxidation upon treatment with mCPBA or
8,9
toluenesulfonate-2-hydroxy-3-N,N-dibenzylaminocyclohexane
4
dioxiranes, this protocol is not applicable for the oxidation of
in . 98% d.e. and in 85% isolated yield, with subsequent
O-acetylation giving 5. To invert the configuration at C(2) within
tertiary allylamines, and the product epoxides are susceptible to
10
decomposition at ambient temperature. Harrity et al. have also
5
, neighbouring group participation of the acetate using a modified
shown that a spiropiperidine ammonium salt undergoes stereo-
16
11
Winstein procedure was followed, giving a 50 : 50 mixture of the
separable 1,2-syn-2,3-syn-acetates 6 and 7 in . 98% d.e. in each
case and 65% overall yield (two steps) after purification.
Subsequent acetate hydrolysis of 6, or 7, or the 50 : 50 mixture
of 6 and 7, gave 1,2-syn-2,3-syn-amino diol 8 in quantitative yield
and in . 98% d.e. in each case (Scheme 1).
selective directed epoxidation. We communicate herein an ammo-
nium directed, metal-free dihydroxylation protocol of allylamines
that has been applied to the preparation of all the diastereoisomers
12,13
of 3-dibenzylamino-1,2-dihydroxycyclohexane.
Our strategy in this area centred upon protection of the amine
by protonation prior to oxidation, with ammonium ion formation
proposed to negate N-oxidation upon treatment with an oxidising
agent. This ammonium ion would simultaneously provide a
hydrogen bond donor capable of directing the subsequent
epoxidation, the epoxide from which would be capable of regio-
and stereoselective ring opening with a suitable nucleophile. To
investigate this proposed reaction manifold, the oxidation of
N,N-dibenzylaminocyclohex-2-ene 1 was used as a model system
for optimisation. Treatment of amine 1 with trichloroacetic acid
and subsequent addition of mCPBA at rt gave, after chromato-
graphic purification on silica, 1,2-anti-2,3-syn-3-amino-1,2-dihy-
droxycyclohexane 3 as the sole product in . 98% d.e. and in 80%
With the 2,3-syn-stereoisomeric combinations of 3-dibenzyl-
amino-1,2-dihydroxycyclohexane in hand, the preparation of the
corresponding 2,3-anti-stereoisomers was pursued. Treatment of
tosylate 4 with DBU gave the syn-epoxide 9 in . 98% d.e., which
upon regio- and stereoselective opening with TsOH gave tosylate
4, consistent with the syn-epoxide 9 being an intermediate in the
oxidation protocol. Alternatively, treatment of syn-epoxide 9 with
AcOH and subsequent O-mesylation gave 10 in quantitative yield.
Application of the modified Winstein procedure inverted the
configuration at C(2) within 10, giving 1,2-syn-2,3-anti-3-amino-1-
acetoxy-11 in . 98% d.e. and 80% yield, with subsequent acetate
hydrolysis giving the 1,2-syn-2,3-anti-amino diol 12 in quantitative
yield. The formation of a 50 : 50 mixture of acetates 6 and 7 from
The Department of Organic Chemistry, University of Oxford, Chemistry
Research Laboratory, Mansfield Road, Oxford, UK OX1 3TA.
E-mail: steve.davies@chem.ox.ac.uk
5, and of a single acetate 11 from 10, presumably reflects the
relative thermodynamic preference of each system. Alternatively,
4
536 | Chem. Commun., 2005, 4536–4538
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Scheme 1 Reagents and conditions: (i). CCl
purification on alumina; (iv). TsOH, DCM, rt, 30 min then mCPBA, rt; (v). Ac
DCM, rt; (ix). AcOH, D; (x). MsCl, NEt , DMAP, DCM, rt; (xi). EtOH, H O, D; (xii). K
3
CO
2
H, DCM, rt, 30 min then mCPBA, rt; (ii). chromatographic purification on silica; (iii). chromatographic
O, DMAP, pyridine, rt; (vi). EtOH, D; (vii). DBU, DCM, rt; (viii). TsOH,
CO , MeOH, rt; (xiii). CCl CO H, D.
2
3
2
2
3
3
2
acetate hydrolysis of mesylate 10 and concomitant intramolecular
mesylate displacement allowed the isolation of the anti-epoxide 13
in quantitative yield without the need for purification. Treatment
of epoxide 13 with trichloroacetic acid gave 14 as the major
component of a 92.5 : 7.5 mixture of regioisomers in quantitative
yield, which upon chromatographic purification on silica gave 1,2-
anti-2,3-anti-amino diol 15 as the major component of a 92.5 : 7.5
mixture of 1,2-anti-2,3-anti-15 : 1,2-anti-2,3-syn-3 (85% d.e.) in
quantitative yield (Scheme 1). The relative configuration within
each diastereoisomeric series was confirmed using NMR spectro-
scopic analysis, consistent in each case with the assumption that
the N,N-dibenzylamino group preferentially adopts a pseudo-
equatorial position in a chair conformation. Furthermore, the
selective preparation of the four diastereoisomeric amino diols 3, 8,
levels of stereoselectivity observed in this reaction are consistent
with in-situ formation of an ammonium ion that directs
epoxidation with mCPBA to the syn-face, with subsequent regio-
and stereoselective trans-diaxial epoxide opening and hydrolysis
generating 1,2-anti-2,3-syn-3-N,N-dibenzylamino-1,2-dihydroxy-
cyclohexane derivatives. Further protecting group manipulations
facilitate the stereoselective synthesis of the four diastereoisomers
of 3-dibenzylamino-1,2-dihydroxycyclohexane. 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.
The authors thank New College, Oxford for a Junior Research
Fellowship (A. D. S.).
12 and 15 using this methodology confirms the assigned relative
configurations within each series.
Notes and references
To demonstrate further the utility of these amino diols in
synthesis, N-deprotection of 3 to the corresponding primary amine
1 S. S. Woodard, M. G. Finn and K. B. Sharpless, J. Am. Chem. Soc.,
1991, 113, 106; M. G. Finn and K. B. Sharpless, J. Am. Chem. Soc.,
1
6 was investigated. Hydrogenolysis of 3 upon treatment with
Pearlman’s catalyst and H gave the desired 1,2-anti-2,3-syn-amino
diol 16 in 65% yield as a single stereoisomer after purification
Scheme 2).
1991, 113, 113; Y. Gao, J. M. Klunder, R. M. Hanson, H. Masamune,
2
S. Y. Ko and K. B. Sharpless, J. Am. Chem. Soc., 1987, 109, 5765;
K. B. Sharpless, S. S. Woodard and M. G. Finn, Pure Appl. Chem.,
1983, 55, 1823.
(
2
3
For a thorough review on substrate directed transformations see:
A. H. Hoveyda, D. A. Evans and G. C. Fu, Chem. Rev., 1993, 93, 1307.
For selected directed metal catalysed epoxidations see (a) T. J. Donohoe,
K. Blades, P. R. Moore, M. J. Waring, J. J. G. Winter, M. Halliwell,
N. J. Newcombe and G. Stemp, J. Org. Chem., 2002, 67, 7946; (b)
K. B. Sharpless and R. C. Michaelson, J. Am. Chem. Soc., 1973, 95,
In conclusion, we have demonstrated that N,N-dibenzylcyclo-
hex-2-ene is susceptible to stereoselective dihydroxylation upon
3 2
treatment with either CCl CO H or TsOH and mCPBA. The high
6136; (c) T. Otoh, K. Kaneda and S. Teranishi, J. Chem. Soc., Chem.
Commun., 1976, 421; (d) R. B. Dehnel and G. H. Whitham, J. Chem.
Soc., Perkin Trans. 1, 1979, 953.
With mCPBA see M. R. Johnson and Y. Kishi, Tetrahedron Lett., 1979,
4
20, 4347; for selected metal catalysed processes see S. Tanaka,
H. Yamamoto, H. Nozaki, K. B. Sharpless, R. C. Michaelson and
J. D. Cutting, J. Am. Chem. Soc., 1974, 96, 5254; E. D. Mihelich,
Tetrahedron Lett., 1979, 20, 4733.
Scheme 2 Reagents and conditions: (i). Pd(OH)
2 2
on C, MeOH, H
(5 atm).
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 4536–4538 | 4537

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5
6
H. B. Henbest and R. A. Wilson, J. Chem. Soc., 1957, 1958;
H. B. Henbest, Proc. Chem. Soc., 1963, 159.
A. Messeguer, A. Diez and M. Rubiralta, J. Chem. Soc., Chem.
Commun., 1995, 293.
11 A. S. Edwards, R. A. J. Wybrow, C. Johnstone, H. Adams and
J. P. A. Harrity, Chem. Commun., 2002, 1542.
12 For related stereoselective oxidations within this laboratory see
S. G. Davies, M.-S. Key, H. R. Solla, H. J. Sanganee, E. D. Savory
and A. D. Smith, Synlett, 2003, 1659.
13 For a related topic see L. Gil, D. Comp e` re, B. Guilloteau-Bertin,
A. Chiaroni and C. Marazano, Synthesis, 2000, 2117.
14 Experimental procedure: 1 (100 mg, 0.36 mmol) was dissolved in DCM
The directed syn-epoxidation of mono-N-protected cyclic allylic amides
has also been explored with the use of carbamate, amide and
sulfonamide N-protecting groups; P. Kocovsky and I. Stary, J. Org.
Chem., 1990, 55, 3236; L. Goodman, S. Winstein and R. Boschan,
J. Am. Chem. Soc., 1958, 80, 4312; A. Hasegawa and H. Z. Sable,
J. Org. Chem., 1966, 31, 4154; J. E. Baldwin, R. M. Adlington,
J. Chondrogianni, M. S. Edenborough, J. W. Keeping and C. B. Ziegler,
J. Chem. Soc., Chem. Commun., 1985, 816; R. W. Murray, M. Singh,
B. L. Williams and H. M. Moncrieff, J. Org. Chem., 1996, 61, 1830;
J. E. B a¨ ckvall, K. Oshima, R. E. Palermo and K. B. Sharpless, J. Org.
Chem., 1979, 44, 1953 and ref. 3(a). For a study using acyclic carbamates
see A. Jenmalm, W. Berts, K. Luthman, I. Cs o¨ regh and U. Hacksell,
J. Org. Chem., 1995, 60, 1026. O’Brien et al. have reported recently the
diastereoselective trans-epoxidation of di-N-protected cyclic allylic
amines using combinations of the same protecting groups; P. O’Brien,
A. C. Childs, G. J. Ensor, C. L. Hill, J. P. Kirby, M. J. Dearden,
S. J. Oxenford and C. M. Rosser, Org. Lett., 2003, 5, 4955.
(1 mL) and CCl
30 minutes at rt. mCPBA (102 mg, 0.41 mmol) was added and the
mixture stirred at rt overnight. Aqueous NaHCO was added to the
3
COOH (310 mg, 1.81 mmol) was added and stirred for
3
reaction mixture and the phases separated and extracted with DCM
(3 6 50 mL). The combined organic extracts were dried, filtered and
concentrated in vacuo to yield the crude amino diol. Purification by
chromatography on SiO
colourless oil. d (400 MHz, CDCl
C(6)H ), 1.84–1.93 (1H, m, C(6)H
(2H, d, J 13.1, (CH Ph) ), 4.85–4.94 (3H, m, C(1)H, (CH
4.10 (1H, m, C(2)H), 7.18–7.50 (10H, m, Ph); d (100 MHz, CDCl
20.3, 24.1, 28.5 (C(4), C(5), C(6)), 55.5 ((CH Ph) ), 58.9 (C(3)), 71.0
(C(1)), 71.5 (C(2)), 127.3, 127.6, 128.6, 128.9, 129.2, 139.8 (Ph); m/z
2
(50% Et
2
O in petrol) gave 3 (90 mg, 80%) as a
) 1.40–1.82 (5H, m, C(4)H , C(5)H
), 3.08–3.19 (1H, s, C(3)H), 3.83
Ph) ), 4.00–
H
3
2
2
,
A
B
7
Sharpless et al. have used the susceptibility of amines to N-oxidation to
effect kinetic resolution by enantioselective N-oxide formation; see
S. Miyano, L. D.-L. Lu, S. M. Viti and K. B. Sharpless, J. Org. Chem.,
1983, 48, 3608; S. Miyano, L. D.-L. Lu, S. M. Viti and K. B. Sharpless,
J. Org. Chem., 1985, 50, 4350.
A
2
B
2
C
3
)
2
2
+
+
+
2
(ESI ) 312 (100% MH ). HRMS found 312.1969; C20H26NO (MH )
8
9
G. Asensio, R. Mello, C. Boix-Bernardini, M. E. Gonz a´ lez-N u´ n˜ ez and
G. Castellano, J. Org. Chem., 1995, 60, 3692; G. Asensio, C. Boix-
Bernardini, C. Andreu, M. E. Gonz a´ lez-N u´ n˜ ez, R. Mello, J. O. Edwards
and G. Castellano, J. Org. Chem., 1999, 64, 4705.
calculated 312.1964; nmax (film) 3412 (O–H).
15 In this analysis, it is assumed that the pseudoequatorial ammonium
ion is more efficient at directing epoxidation than the pseudoaxial
conformer; this has been postulated in the analogous directed
epoxidation of allylic alcohols with mCPBA; P. Chamberlain,
M. L. Roberts and G. H. Whitham, J. Chem. Soc. (B), 1970, 1374.
16 S. Winstein, C. Hanson and E. Grunwald, J. Am. Chem. Soc., 1948, 70,
812.
G. Asensio, M. E. Gonz a´ lez-N u´ n˜ ez, C. B. Bernardini, R. Mello and
W. Adam, J. Am. Chem. Soc., 1993, 115, 7250.
0 BF has been reported to protect the N-atom of tertiary alkenylamines
1
3
from oxidation by dioxiranes; see M. Ferrer, F. Sanchez-Baeza,
4
538 | Chem. Commun., 2005, 4536–4538
This journal is ß The Royal Society of Chemistry 2005