Highly diastereoselective anti-dihydroxylation of 3-N,N- dibenzylaminocyclohex-1-ene N-oxide

Article abstract of DOI:10.1021/ol900114b

Oxidation of 3-N,N-dibenzylaminocyclohex-1-ene N-oxide in the presence of Cl₃CCO₂H proceeds with high levels of anti- diastereoselectivity (97% de), with no competing side reactions, allowing access to 1,2-anti-2,3-anti-3-aminocycloh

Full text of DOI:10.1021/ol900114b

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1333-1336
Highly Diastereoselective
anti-Dihydroxylation of
3-N,N-Dibenzylaminocyclohex-1-ene
N-Oxide
Caroline Aciro, Stephen G. Davies,* Wataru Kurosawa, Paul M. Roberts,
Angela J. Russell, and James E. Thomson
Department of Chemistry, Chemistry Research Laboratory, UniVersity of Oxford,
Mansfield Road, Oxford OX1 3TA, U.K.
steVe.daVies@chem.ox.ac.uk
Received January 19, 2009
ABSTRACT
Oxidation of 3-N,N-dibenzylaminocyclohex-1-ene N-oxide in the presence of Cl3CCO2H proceeds with high levels of anti-diastereoselectivity
(97% de), with no competing side reactions, allowing access to 1,2-anti-2,3-anti-3-aminocyclohexane-1,2-diol after deprotection.
Tertiary amine N-oxides have long been known within
organic chemistry.1 They have found use as intermediates
in, for example, [1,2]- and [2,3]-Meisenheimer rearrange-
ments,2 Cope eliminations,3 and Polonovski reactions4 and
are well-known in alkaloid chemistry (e.g., within the
strychnos, ergoline, and opium families), often facilitating
structure elucidation or promoting interesting skeletal rear-
rangements.5 Nonetheless, their utility in synthesis remains
underdeveloped.1,6 As part of our ongoing research program
directed toward the synthesis of the amino diol motif,7-9
and recognizing that N-oxidation of allylic amines competes
with oxidative functionalization of the olefin, we recently
achieved the highly chemo- and diastereoselective, am-
monium-directed epoxidation of 3-N,N-dibenzylaminocy-
(5) Bentley, K. W. The Chemistry of the Morphine Alkaloids; Oxford
University Press: Oxford, 1954; Albini, A. Heterocycles 1992, 34, 1973.
(6) For selected examples of the use of N-oxides in synthesis, see: Tokitoh,
N.; Okazaki, R. Chem. Lett. 1985, 241. O’Neil, I. A.; Turner, C. D.;
Kalindjian, S. B. Synlett 1997, 777. O’Neil, I. A.; Bhamra, I.; Gibbons,
P. D. Chem. Commun. 2006, 4545. Oh, K.; Ryu, J. Tetrahedron Lett. 2008,
49, 1935.
(1) For a review of the synthetic utility of tertiary amine N-oxides, see:
Albini, A. Synthesis 1992, 263.
(7) Aciro, C.; Claridge, T. D. W.; Davies, S. G.; Roberts, P. M.; Russell,
A. J.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 3751.
(2) Meisenheimer, J. Chem. Ber. 1919, 52, 1667. For selected synthetic
applications, see: Davies, S. G.; Smyth, G. D. J. Chem. Soc., Perkin Trans.
1 1996, 2467. Majumdar, K. C.; Jana, G. H. J. Org. Chem. 1997, 62, 1506.
Arnone, A.; Metrangolo, P.; Novo, B.; Resnati, G. Tetrahedron 1998, 54,
7831. Buston, J. E. H.; Coldham, I.; Mulholland, K. R. J. Chem. Soc., Perkin
Trans. 1 1999, 2327.
(8) Aciro, C.; Davies, S. G.; Roberts, P. M.; Russell, A. J.; Smith, A. D.;
Thomson, J. E. Org. Biomol. Chem. 2008, 6, 3762.
(9) For selected recent examples, see: Cailleau, T.; Cooke, J. W. B.;
Davies, S. G.; Ling, K. B.; Naylor, A.; Nicholson, R. L.; Price, P. D.;
Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E. Org. Biomol.
Chem. 2007, 5, 3922. Abraham, E.; Davies, S. G.; Millican, N. L.; Nicholson,
R. L.; Roberts, P. M.; Smith, A. D. Org. Biomol. Chem. 2008, 6, 1655.
Abraham, E.; Brock, E. A.; Candela-Lena, J. I.; Davies, S. G.; Georgiou,
M.; Nicholson, R. L.; Perkins, J. H.; Roberts, P. M.; Russell, A. J.; Sa´nchez-
Ferna´ndez, E. M.; Scott, P. M.; Smith, A. D.; Thomson, J. E. Org. Biomol.
Chem. 2008, 6, 1665. Davies, S. G.; Durbin, M. J.; Goddard, E. C.; Kelly,
P. M.; Kurosawa, W.; Lee, J. A.; Nicholson, R. L.; Price, P. D.; Roberts,
P. M.; Russell, A. J.; Scott, P. M.; Smith, A. D. Org. Biomol. Chem. 2009,
7, 761.
(3) Cope, A. C.; LeBel, N. A. J. Am. Chem. Soc. 1960, 82, 4656. For
a review, see: Gallagher, B. M.; Pearson, W. H. Chemtracts: Org. Chem.
1996, 9, 126. For selected synthetic applications, see: O’Neil, I. A.; Ramos,
V. E.; Ellis, G. L.; Cleator, E.; Chorlton, A. P.; Tapolczay, D. J.; Kalindjan,
S. B. Tetrahedron Lett. 2004, 45, 3659. Henry, N.; O’Neil, I. A. Tetrahedron
Lett. 2007, 48, 1691.
(4) Polonovski, M.; Polonovski, M. Bull. Soc. Chim. Fr. 1927, 41, 1190.
For a review, see: Grierson, D. Org. React. 1990, 39, 85.
10.1021/ol900114b CCC: $40.75
Published on Web 02/11/2009
2009 American Chemical Society

clohex-1-ene 1 with mCPBA employing a strategy reliant
on in situ N-protection against oxidation via protonation with
Cl3CCO2H. Epoxide ring opening by Cl3CCO2H, followed
by transesterification, gave 3-N,N-dibenzylaminocyclohex-
ane-1,2-diol 2 in 90% de (Scheme 1).7 We hypothesized that
Olefinic oxidation of N-oxide 3 in the presence of
Cl3CCO2H was next investigated. In situ treatment of a
freshly prepared sample of 3 with 1 equiv of Cl3CCO2H
followed by 3 equiv of mCPBA gave a complex mixture of
products. Transesterification with K2CO3 in MeOH gave a
55:15:30 mixture of epoxide 6 and diols 8 and 9, respectively,
suggesting that the ring opening of epoxide 7 by Cl3CCO2H
is much faster than that of epoxide 6. When 5 equiv of
Cl3CCO2H were employed, 68% de in favor of diol 8 was
noted; when 10 equiv of Cl3CCO2H were used, 8 was
produced in 97% de. No traces of 6 or 7 were noted in either
case, consistent with an increased rate of epoxide ring
opening with increasing concentration of Cl3CCO2H. Re-
crystallization of the crude reaction mixture gave 8 in >98%
de and 63% yield (Scheme 3). The relative configuration
Scheme 1. Ammonium-Directed Dihydroxylation of
3-N,N-Dibenzylaminocyclohex-1-ene 1
an alternative diastereoselective olefin functionalization
protocol would be available through N-oxidation of 3-N,N-
dibenzylaminocyclohex-1-ene 1 to give the corresponding
N-oxide followed by further oxidation of the olefin. We
delineate herein our results within this area.
Scheme 3. anti-Dihydroxylation of
3-N,N-Dibenzylaminocyclohex-1-ene N-Oxide 3 in the Presence
of Trichloroacetic Acid
Our initial studies were directed toward preparation of
N-oxide 3. Treatment of amine 1 with mCPBA (1.5 equiv) at
0 °C in CD2Cl2 gave N-oxide 3 as a mixture with excess
mCPBA and m-chlorobenzoic acid (mCBA). As expected,
attempted basic aqueous workup and purification on basic
alumina gave an impure sample of N-oxide 3 as a mixture with
mCBA (∼6%), and hydroxylamines 4 (6%) and 5 (80%) as
the major products. This suggests that a Meisenheimer rear-
rangement (to give hydroxylamine 4) or Cope elimination (to
give hydroxylamine 5 and cyclohexa-1,3-diene) was occurring,
indicating that the presence of acid is necessary to suppress
rearrangement or fragmentation of 3, presumably by protonation
on, or by hydrogen bonding to, the oxygen atom.10,11 With
N-oxide 3 in hand, olefinic dihydroxylation was investigated.
Treatment of 3 with 3 equiv of mCPBA gave 68% conversion
after 48 h to a 73:27 mixture of the diastereoisomeric
epoxides anti-6 and syn-7 (Scheme 2). The relative configu-
rations within 6 and 7 were assigned by comparison to
authentic samples (vide infra).
within the major diastereoisomer 8 resulting from this
oxidation protocol was unambiguously established by single
crystal X-ray analysis (Figure 1). Within the solid-state
structure, hydrogen bonding is observed between the C(2)-
hydroxyl substituent and the oxygen atom of the N-oxide
group, which is consistent with the known stabilizing effect
of hydrogen bonding on the N-oxide moiety.11,12 Meanwhile,
the relative configuration within the minor diastereoisomer
9 was unambiguously established through the synthesis of
an authentic sample by N-oxidation of the known N,N-
dibenzylamino diol 28 (Scheme 4) and subsequent analysis
by X-ray crystallography (Figure 2). N-Oxide 9 cocrystallized
Scheme 2
.
Epoxidation of 3-N,N-Dibenzylaminocyclohex-1-ene
N-Oxide 3
(10) Aliphatic amine N-oxides have long been known to form stable
salts with organic acids; for a recent example of the use of acid to suppress
rearrangement of an N-oxide, see: Bernier, D.; Blake, A. J.; Woodward, S.
J. Org. Chem. 2008, 73, 4229. Indeed, a sample of N-oxide 3 in CD2Cl2
(prepared via treatment of amine 1 with mCPBA) was found to be largely
unchanged after 10 days, although the formation of ∼5% of N-oxide epoxide
6 was observed.
1334
Org. Lett., Vol. 11, No. 6, 2009

molecules and both the C(2)-hydroxyl group and the oxygen
atom of the N-oxide.11,13
Treatment of the known epoxides anti-108 and syn-117
with mCPBAgave authentic samples of 6 and 7. Addition
of 2 equiv of Cl3CCO2H to syn-7 and transesterification after
22 h gave 9 in >98% de. Analogous ring opening of anti-6
was found to occur much more slowly and required treatment
with 5 equiv of Cl3CCO2H over 3 days to achieve complete
conversion. Transesterification with K2CO3/MeOH gave 8
in >98% de (Scheme 5). These results demonstrate that the
Scheme 5
.
Regio- and Stereoselective Ring Opening of N-Oxide
Epoxides 6 and 7 by Trichloroacetic Acid
Figure 1
. Chem 3D representation of the X-ray crystal structure
of 8 (some H atoms omitted for clarity).
Scheme 4. Preparation of an Authentic Sample of
3-N,N-Dibenzylaminocyclohexane-1,2-diol N-Oxide 9
ring openings of both anti-6 and syn-7 by Cl3CCO2H are
highly regioselective and are consistent with the ring opening
of 7 proceeding via a chair-like transition state with the N,N-
dibenzylamino N-oxide group in a pseudoequatorial site to
give the trans-diaxial product,14 with ring opening of 6
proceeding via a twist-boat-like transition state (vide infra).
The production of mixtures of 8 and 9 upon olefinic oxidation
of N-oxide 3 in the presence of 1 or 5 equiv of Cl3CCO2H
is therefore consistent with loss of stereoselectivity in the
initial epoxidation step rather than erosion of regioselectivity
in the epoxide ring opening step.
with two molecules of mCBA in the asymmetric unit, and
within the crystal lattice hydrogen bonding is observed
between the carboxylic acid group of one of the mCBA
Stereoselective anti-epoxidation of 3 in the presence of
10 equiv of Cl3CCO2H suggests that the protonated N,N-
dibenzylamino N-oxide group15 does not participate in
hydrogen-bonded delivery of the oxidant to the syn-face of
the olefin.16,17 The stereochemical outcome is consistent with
the oxidation proceeding either under steric control or
through minimization of the dipoles of the protonated amine
N-oxide and the peracid18 to give protonated anti-epoxide
(11) The stabilization of N-oxides through intramolecular hydrogen-
bonding has been documented; for instance, see: O’Neil, I. A.; Potter, A. J.
Chem. Commun. 1998, 1487, and references cited therein.
(12) A similar solution phase conformation for N-oxide 8 in CDCl3 was
inferred from determination of the interproton distances by analysis of the
NOE build-up curves; see: Esposito, G.; Pastore, A. J. Magn. Reson. 1988,
76, 331. Claridge, T. D. W. High-Resolution NMR Techniques in Organic
Chemistry, 2nd ed.; Elsevier Science Ltd: Oxford, 1999; Chapter 8.
(13) The second molecule of mCBA within the asymmetric unit of the
crystal structure of N-oxide 9 is involved with hydrogen bonding with the
C(1)-hydroxyl substituent of 9.
Figure 2. Chem 3D representation of the X-ray crystal structure
of 9 (some H atoms and both mCBA molecules omitted for clarity).
(14) Fu¨rst, A.; Plattner, P. A. 12th Int. Congr. Pure Appl. Chem. New
York 1951, 409.
Org. Lett., Vol. 11, No. 6, 2009
1335

Figure 3. Postulated mechanism for the dihydroxylation of tertiary allylic amine N-oxide 3 in the presence of Cl3CCO2H.
N-oxide 13. This presumably resides in conformation 13A,
with the protonated C(3)-N,N-dibenzylamino N-oxide group
occupying a pseudoequatorial position. Regioselective ring
opening of 13A at C(1) followed by transesterification gives
8. The acid catalyzed ring opening of epoxides is known to
proceed via a late transition state19 which, in this case, favors
attack at C(1) of 13A where the electron-withdrawing
inductive effect of the protonated N,N-dibenzylamino N-
oxide moiety is lower. This presumably overrides any
propensity of 13 to undergo ring opening through a chair-
like transition state via attack at C(2) of 13A to give the
corresponding trans-diaxial product14 (Figure 3).
Treatment of 8 with activated zinc dust gave the known
N,N-dibenzylamino diol 15,8 while hydrogenolysis of 8 gave
the known amino diol 16,8 in quantitative yield and >98%
de in both cases (Scheme 6).
In conclusion, stereoselective anti-dihydroxylation of 3-N,N-
dibenzylaminocyclohex-1-ene N-oxide offers a short, high
Scheme 6. N-Deprotection of
3-N,N-Dibenzylaminocyclohexane-1,2-diol N-Oxide 8
yielding route for the preparation of 1,2-anti-2,3-anti-3-
aminocyclohexane-1,2-diol after global hydrogenolytic depro-
tection. The stereochemical outcome is complementary to
the selectivity previously reported by us in the corresponding
ammonium-directed case and is consistent with epoxidation
proceeding under steric or dipolar control on the face anti
to the tertiary amine N-oxide group. Evaluation of the scope
and utility of this novel transformation, for example in the
application to the total asymmetric synthesis of amino sugars,
is ongoing within this laboratory.
(15) Protonation of N-oxide 3 by Cl3CCO2H is to be expected due to
the differences in pKa of the two species (for Cl3CCO2H, pKa ) 0.65; for
a tertiary amine N-oxide, pKa ∼4.5); see: Bell, R. P.; Higginson, W. C. E.
Pro. Royal Soc. 1949, 197, 141. Dippy, J. F. J.; Hughes, S. R. C.; Rozanski,
A. J. Chem. Soc. 1959, 2492.
Acknowledgment. We thank Ajinomoto Co., Inc. for
(16) For a discussion of the stereochemistry of epoxidation in some
homoallylic cyclohexene alcohols, see: Koe`ovsky, P. J. Chem. Soc., Perkin
Trans. 1 1994, 1759.
funding (W.K.).
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of 1H and 13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) Trost recently reported the syn-epoxidation of 3-[(4′-methylpyridin-
2′-yl)methyl]cyclohex-1-ene N-oxide by mCPBA; see: Trost, B. M.;
Thaisrivongs, D. A. J. Am. Chem. Soc. 2008, 130, 14092.
(18) Crossley, N. S.; Darby, A. C.; Henbest, H. B.; McCullough, J. J.;
Nicholls, B.; Stewart, M. F. Tetrahedron Lett. 1961, 2, 398.
(19) Parker, R. E.; Isaacs, N. S. Chem. ReV. 1959, 59, 737. Addy, J. K.;
Parker, R. E. J. Chem. Soc. 1963, 915.
OL900114B
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