Ammonium-directed oxidation of cyclic allylic and homoallylic amines

Article abstract of DOI:10.1021/jo9012783

(Chemical Equation Presented) The ammonium-directed olefinic oxidation of a range of cyclic allylic and homoallylic amines has been investigated. Functionalization of a range of allylic 3-(N,N-dibenzylamino)cycloalk-1-enes with m-CPBA in the presence of Cl3CCO2H gives exclusively the corresponding syn-epoxide for the 5-membered ring (>99:1 dr), the anti-epoxide for the 8-membered ring (>99:1 dr), and predominantly the anti-epoxide for the 7-membered ring (94:6 dr). Oxidation of the homoallylic amines 3-(Nbenzylamino) methylcyclohex-1-ene and 3-(N,N-dibenzylamino)methylcyclohex-1-ene gave, in both cases, the correspondingN-protected 1,2-anti-2,3-syn-3-aminomethylcyclohexane- 1,2-diol with high levels of diastereoselectivity (g90:10 dr). The versatile synthetic intermediates resulting from these oxidation reactions are readily transformed into a range of amino diols.

Full text of DOI:10.1021/jo9012783

pubs.acs.org/joc
Ammonium-Directed Oxidation of Cyclic Allylic and Homoallylic Amines
Christopher W. Bond, Alexander J. Cresswell, Stephen G. Davies,* Ai M. Fletcher,
Wataru Kurosawa, James A. Lee, Paul M. Roberts, Angela J. Russell, Andrew D. Smith,
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 June 17, 2009
The ammonium-directed olefinic oxidation of a range of cyclic allylic and homoallylic amines has
been investigated. Functionalization of a range of allylic 3-(N,N-dibenzylamino)cycloalk-1-enes with
m-CPBA in the presence of Cl3CCO2H gives exclusively the corresponding syn-epoxide for the
5-membered ring (>99:1 dr), the anti-epoxide for the 8-membered ring (>99:1 dr), and predominantly
the anti-epoxide for the 7-membered ring (94:6 dr). Oxidation of the homoallylic amines 3-(N-
benzylamino)methylcyclohex-1-ene and 3-(N,N-dibenzylamino)methylcyclohex-1-ene gave, in both
cases, the corresponding N-protected 1,2-anti-2,3-syn-3-aminomethylcyclohexane-1,2-diol with high
levels of diastereoselectivity (g90:10 dr). The versatile synthetic intermediates resulting from these
oxidation reactions are readily transformed into a range of amino diols.
Introduction
diastereoselective oxidation of 3-(N,N-dibenzylamino)cyclo-
hex-1-ene 1 could be achieved by in situ protection of the
amine with either Cl3CCO2H or TsOH, followed by treatment
withm-CPBA.5 This methodologywasutilizedtofacilitatethe
synthesis of the diastereoisomericsyn- andanti-epoxides2 and
3 and all four diastereoisomers of 3-(N,N-dibenzylamino)-
cyclohexane-1,2-diol 4-7 (Figure 1).6 As part of our ongoing
research program concerning the synthesis of the amino diol
motif for application in the de novo asymmetric synthesis of
unnatural amino sugars and derivatives,7 we have further
Substrate-directed transformations are valuable synthetic
processes.1 Within this arena, the olefinic oxidation of an
allylic alcohol by a peracid (Prileschajew oxidation)2 under
hydrogen-bonded control of the hydroxyl group has been
extensively studied1,3 and utilized.1 In contrast, oxidations of
the corresponding homoallylic substrates have been much less
well investigated.4 We recently reported that the chemo- and
(1) For a review on substrate-directed reactions, see: Hoveyda, A. H.;
Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307.
(2) Prileschajew, N. Chem. Ber. 1909, 42, 4811.
(5) Aciro, C.; Claridge, T. D. W.; Davies, S. G.; Roberts, P. M.; Russell,
A. J.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 3751.
(3) Bartlett, P. D. Rec. Chem. Prog. II 1950, 47. Henbest, H. B.; Wilson,
R. A. L. J. Chem. Soc. 1957, 1958. Dryuk, V. G. Tetrahedron 1976, 32, 2855.
Singleton, D. A.; Merrigan, S. R.; Liu, J.; Houk, K. N. J. Am. Chem. Soc.
1997, 119, 3385. Houk, K. N.; Liu, J.; DeMello, N. C.; Condroski, K. R. J.
Am. Chem. Soc. 1997, 119, 10147. Okovytyy, S.; Gorb, L.; Leszczynski, J.
Tetrahedron Lett. 2002, 43, 4215.
(6) Aciro, C.; Davies, S. G.; Roberts, P. M.; Russell, A. J.; Smith, A. D.;
Thomson, J. E. Org. Biomol. Chem. 2008, 6, 3762.
(7) 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.;
(4) For a discussion of the stereochemistry of epoxidation in some
ꢀ
ꢁ
homoallylic cyclohexene alcohols, see: Kocovsky, P. J. Chem. Soc., Perkin
Trans. 1 1994, 1759. For examples concerning the oxidative functionalization
of homoallylic substrates, see ref 1 and: Garside, P.; Halsall, T. G.; Hornby,
G. M. J. Chem. Soc. C 1969, 716. Ye, D.; Fringuelli, F.; Piermatti, O.; Pizzo,
F. J. Org. Chem. 1997, 62, 3748. de Sousa, S. E.; Kee, A.; O’Brien, P.;
Watson, S. T. Tetrahedron Lett. 1999, 40, 387. Donohoe, T. J.; Mitchell, L.;
Waring, M. J.; Helliwell, M.; Bell, A.; Newcombe, N. J. Org. Biomol. Chem.
2003, 1, 2173.
ꢁ
Nicholson, R. L.; Perkins, J. H.; Roberts, P. M.; Russell, A. J.; Sanchez-
Fernandez, 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.
Aciro, C.; Davies, S. G.; Kurosawa, W.; Roberts, P. M.; Russell, A. J.;
Thomson, J. E. Org. Lett. 2009, 11, 1333.
DOI: 10.1021/jo9012783
r
Published on Web 07/31/2009
J. Org. Chem. 2009, 74, 6735–6748 6735
2009 American Chemical Society

Bond et al.
JOCArticle
SCHEME 1a
aReagents and conditions: (i) NBS (0.25 equiv), (PhCO2)2 (cat.), CCl4,
reflux, 1 h;(ii) Bn2NH, 0 °C tort, 12h;(iii) NBS (1 equiv), (PhCO2)2 (cat.),
CCl4, reflux, 1 h; (iv) Bn2NH, K2CO3, 60 °C, 35 h.
FIGURE 1. Ammonium-directed olefinic oxidation of 3-(N,N-
dibenzylamino)cyclohex-1-ene 1.
products, including syn-epoxide 20 and the corresponding
ring-opened trichloroacetate adduct 21 in a 62:38 ratio,
respectively, was obtained (Scheme 2). This product distri-
bution suggests a slower rate of epoxide ring-opening as
compared to the 6-membered ring system,5 which is consis-
tent with the observed slower rate of ring-opening of cyclo-
pentene oxide versus cyclohexene oxide with a variety of
nucleophiles.9 This may be due in part to relief of torsional
strain during a half-chair to chair conformational change in
the ring-opening of cyclohexene oxide; during ring-opening
of cyclopentene oxide an envelope conformation is retained
and no such relief occurs. Optimization of the reaction
conditions revealed that using only 1.05 equiv of m-CPBA
gave syn-epoxide 20 as the only product after 3.5 h, and in
>99:1 dr, as determined by peak integration of the 1H NMR
spectrum of the crude reaction mixture. Purification gave
20 in 99% yield and >99:1 dr. The relative syn-configura-
tion within 20 was unambiguously established by single-
crystal X-ray analysis. The complete syn-diastereoselectivity
observed in the epoxidation of the ammonium 17 is
in accordance with the very high syn-selectivities re-
ported for the peracid epoxidations of cyclopent-2-enol,10
N-(cyclopent-2-enyl)acetamide,11 N-(cyclopent-2-enyl)benz-
amide,11b N-(cyclopent-2-enyl)formamide,12 and N-(cyclo-
pent-2-enyl)trichloroacetamide.13 In these cases, the efficient
syn-selectivity has been typically ascribed to an intermolecular
probed the generality of this transformation by application to
a range of cyclic allylic and homoallylic amines, as delineated
herein.
Results and Discussion
Oxidation of Allylic Amines: Diastereoselective Epoxida-
tion of 3-(N,N-Dibenzylamino)cycloalk-1-enes. A range of
3-(N,N-dibenzylamino)cycloalk-1-enes 14-16, comprising
5-, 7-, and 8-membered rings, was prepared via Wohl-
Ziegler allylic bromination8 of the corresponding cycloalk-
enes 8-10 followed by amination with dibenzylamine
(Scheme 1).
In order to effect in situ protection of the amines, the
formation of the corresponding ammonium species 17-19
from amines 14-16 in the presence of Cl3CCO2H was
examined by 1H NMR spectroscopy. Cl3CCO2H was added
in 1 equiv portions to a solution of the requisite amine 14-16
in CD2Cl2, and in all cases a pronounced difference in δH of
the vinylic protons was observed, indicating the time-aver-
aged signal and fast exchange between the amine 14-16 and
corresponding ammonium 17-19. The difference in chemi-
cal shift (Δδ) between the values of δH for C(1)H and C(2)H
increased with increasing amounts of Cl3CCO2H, although a
plateau was noted at approximately 4-5 equiv, suggesting
the equilibrium lies predominately to the right and the
ammonium species 17-19 predominate in solution under
these conditions. These results suggest that 5 equiv of
Cl3CCO2H may be sufficient to effect efficient N-proton-
ation of 14-16 and are in accordance with our analo-
gous study on 3-(N,N-dibenzylamino)cyclohex-1-ene 15
(Figure 2).
(9) (a) For example, see: Iranpoor, N.; Shekarriz, M.; Shiriny, F. Synth.
Commun. 1998, 28, 347. (b) Yoo, D.-W.; Yoo, S.-K.; Kim, C.; Lee, J.-K. J.
Chem. Soc., Dalton Trans. 2002, 3931. (c) Iranpoor, N.; Firouzabadi, H.;
Aghapour, G.; Nahid, A. Bull. Chem. Soc. Jpn. 2004, 77, 1885. (d) Han, J. H.;
Hong, S. J.; Lee, E. Y.; Lee, J. H.; Kim, H. J.; Kwak, H.; Kim, C. Bull. Korean
Chem. Soc. 2005, 26, 1434. (e) Singh, M. C.; Peddinti, R. K. Tetrahedron Lett.
2007, 48, 7354.
ꢀ
(10) Steyn, R.; Sable, H. Z. Tetrahedron 1969, 25, 3579. Kocovsky, P.
ꢁ
Tetrahedron Lett. 1988, 29, 2475.
(11) (a) Haseqawa, A.; Sable, H. Z. J. Org. Chem. 1966, 31, 4154. (b)
Vince, R.; Daluge, S. J. Med. Chem. 1974, 17, 578.
(12) Baldwin, J. E.; Adlington, R. M.; Chondrogianni, J.; Edenborough,
M. S.; Keeping, J. W.; Ziegler, C. B. J. Chem. Soc., Chem. Commun. 1985,
816.
The oxidation of 5-membered ring substrate 14 upon
treatment with 5 equiv of Cl3CCO2H followed by 1.6 equiv
of m-CPBA was investigated.5 After 12 h, a mixture of
(13) O’Brien, P.; Childs, A. C.; Ensor, G. J.; Hill, C. L.; Kirby, J. P.;
Dearden, M. J.; Oxenford, S. J.; Rosser, C. M. Org. Lett. 2003, 5, 4955.
(8) Djerassi, C. Chem. Rev. 1959, 71, 349.
6736 J. Org. Chem. Vol. 74, No. 17, 2009

Bond et al.
JOCArticle
FIGURE 2. Differences in chemical shift (Δδ) between C(1)H and C(2)H upon addition of Cl3CCO2H to 14-16.
SCHEME 2a
SCHEME 3a
aReagents and conditions: (i) Cl3CCO2H (5 equiv), CH2Cl2, rt, 5 min,
then m-CPBA (1.05 equiv), rt, 3.5 h; (ii) Cl3CCO2H (5 equiv), CH2Cl2, rt,
5 min, then m-CPBA (1.6 equiv), rt, 12 h.
aReagents and conditions: (i) TsOH (5 equiv), CH2Cl2, 40 °C, 4.5 h; (ii)
Cl3CCO2H (5 equiv), CH2Cl2, 40 °C, 12 h; (iii) AcOH, 50 °C, 66 h; (iv)
H2SO4 (3 M aq), THF, 40 °C, 20 h; (v) K2CO3, MeOH, rt, 12 h.
hydrogen bond in the transition state, although minimization
of torsional strain may also contribute.14
Ring-opening of syn-epoxide 20 upon treatment with
anhydrous Cl3CCO2H at 40 °C gave 21 as the major product
(>90%) along with trace amounts of unidentifiable species.
Transesterification of 21 by treatment with K2CO3 in MeOH
gave 24 in 89% isolated yield and 97:3 dr (Scheme 3). The
preferential ring-opening at C(1) of epoxide 20 to give the
1,2-anti-2,3-syn-diastereoisomer 21 is consistent with the
acid-catalyzed ring-opening proceeding via a late (product-
like) transition state with substantial carbocationic character
at the oxirane carbon undergoing nucleophilic attack.15 This
promotes attack at the C(1)-oxirane carbon where the in-
ductively electron-withdrawing influence of the N,N-diben-
zylammonium group is lower. In order to investigate the
(14) Several instances of syn-selective osmylation and epoxidation reac-
tions of 3-substituted cyclopentenes which proceed in the absence of any
obvious associative interactions (e.g., hydrogen bonding) in the transition
state have been reported; see: (a) Donohoe, T. J.; Blades, K.; Moore, P. R.;
Waring, M. J.; Winter, J. J. G.; Helliwell, M.; Newcombe, N. J.; Stemp, G. J.
Org. Chem. 2002, 67, 7946. (b) Ward, S. E.; Holmes, A. B.; McCague, R.
Chem. Commun. 1997, 2085. (c) Aggarwal, V. K.; Monteiro, N. J. Chem.
Soc., Perkin Trans. 1 1997, 2531. Poli has proposed a model to account for
these observations, in which attack on the syn-face is favoured due to
minimization of torsional strain in the transition state; see: Poli, G.
Tetrahedron Lett. 1989, 30, 7385. Houk has coined the term “torsional
steering” for this effect; see: Cheong, P. H.-Y.; Yun, H.; Danishefsky, S. J.;
Houk, K. N. Org. Lett. 2006, 8, 1513.
(15) Parker, R. E.; Isaacs, N. S. Chem. Rev. 1959, 59, 737. Addy, J. K.;
Parker, R. E. J. Chem. Soc. 1963, 915.
J. Org. Chem. Vol. 74, No. 17, 2009 6737

Bond et al.
JOCArticle
SCHEME 4a
the preferred solid-state conformations of both allylic amine
16 and epoxide 25 reveal that both display the characteristic
chair-boat conformation,20 with the N,N-dibenzylamino
group occupying a pseudobowsprit position, which may
account for the very slow rate of ring-opening of 25.
Furthermore, the complete anti-selectivity (>99:1 dr) in the
epoxidation of ammonium 19 parallels the peracid epoxida-
tion of both cis-cyclooct-2-en-1-ol21 and cis-cyclooct-2-en-1-
yl methyl ether22 which have also been reported as proceed-
ing with complete anti-selectivity, which is usually ascribed
to oxidation on the least hindered face of the olefin with the
cyclooctene ring in the preferred low energy chair-boat
conformation.20 In order to probe the role of hydrogen
bonding in this reaction, N-methylammonium triflate spe-
cies 26 was prepared in 23% yield by treatment of 16 with
methyl triflate. Oxidation of 26 under conditions analogous
to those employed for oxidation of 16 (1.05 equiv of m-
CPBA in the presence of 5 equiv of Cl3CCO2H) gave 4%
conversion to epoxide 27 as the only detectable diastereo-
isomer. The relative configuration within 27 was unambigu-
ously established by N-methylation of 25 upon treatment
with methyl triflate, which gave 27 as a single diastereoi-
somer. These results suggest that an intermolecular hydro-
gen bond need not be invoked to explain the observed anti-
selectivity but may be involved in stabilizing the transition
state and thereby accelerating the rate of reaction, which is
consistent with the relatively close proximity of the N,N-
dibenzylamino group to the anti-face of the olefin. In the case
of oxidation of 26, shielding of the anti-face by the bulky
N-methyl-N,N-dibenzylammonium group, as well as its
deactivating electron-withdrawing influence on the olefin,
may account for the low reaction conversion.
Attention next turned to oxidation of the 7-membered ring
substrate 15. Under the conditions employed for epoxidation
of 5- and 8-membered ring substrates 14 and 16, respectively,
oxidation of 15 gave 88% conversion to a 94:6 mixture of
epoxides anti-28:syn-29. Chromatographic purification gave
the major anti-epoxide 28 in 69% yield and >99:1 dr, and the
minor syn-epoxide 29 in 4% yield and >99:1 dr as crystalline
solids (Scheme 5). The relative anti-configuration within 28
was assigned unambiguously by single-crystal X-ray analy-
sis. It is notable that unreacted starting material 15 is present
after 3.5 h, indicating that the rate of epoxidation of the
ammonium 18 is slower than that of the ammoniums 17
and 19, derived from the 5- and 8-membered ring substrates
14 and 16, respectively. The epoxidation of cyclohept-2-enol
has been reported to proceed with only low levels of
syn-diastereoselectivity (∼2:1 dr) with various peracids.19,21
These low diastereoselectivities suggest that the 7-membered
ring is conformationally ill-defined, consistent with the
known conformational lability of cycloheptene itself.23
This contrasts with the relatively high anti-diastereo-
selectivity observed in the epoxidation of ammonium 18,
aReagents and conditions: (i) Cl3CCO2H (5 equiv), CH2Cl2, rt, 5 min,
then m-CPBA (1.05 equiv), rt, 3.5 h; (ii) MeOTf, Et2O, rt, 2 h.
generality of this regioselectivity, syn-20 was treated with a
range of Brønsted acids (aq H2SO4, TsOH and AcOH). In
each case, ring-opening proceeded preferentially via attack
at C(1) to give the corresponding 1,2-anti-2,3-syn-diastereoi-
somer as the major product.16 In the case of 1-acetoxy 22, the
regioselectivity of ring-opening and relative configuration
was unambiguously established by single-crystal X-ray ana-
lysis of the corresponding HBF4 salt.17 Transesterification of
22 with K2CO3 in MeOH gave 24 in 97% yield and >99:1 dr,
thus confirming the assigned relative configuration within
24. Ring-opening of epoxide syn-20 with aq H2SO4 gave 24 as
the major product (96:4 dr), while ring-opening with anhy-
drous TsOH gave 23 as a single diastereoisomer in 88%
isolated yield. The regioselectivity of the ring-opening pro-
moted by TsOH was assigned by analogy to that unambigu-
ously established for ring-opening promoted by aq H2SO4,
Cl3CCO2H, and AcOH (Scheme 3).
Epoxidation of the 8-membered ring substrate 16 gave
epoxide anti-25 as the sole product in >99:1 dr and quanti-
tative yield after 3.5 h (Scheme 4). The relative anti-config-
uration within 25 was determined unambiguously by single-
crystal X-ray analysis. The observation that epoxide anti-25
is cleanly isolable without competing ring-opening by
Cl3CCO2H parallels the known, extremely slow intermole-
cular nucleophilic ring-opening of cis-cyclooctene oxide.18 It
has been proposed that the chair-boat conformation of cis-
cyclooctene oxide presents an extremely hindered approach
to nucleophilic attack on the epoxide moiety,19 though
development of transannular and bond-widening strain
upon epoxide opening may also contribute. Comparison of
(16) Ring-opening of 20 by TsOH gave 23 as a single diastereoisomer
(>99:1 dr). Ring-opening of 20 by aq H2SO4 gave a 96:4 ratio of 24:35. Ring-
opening of 20 by AcOH gave an 84:6:5:5 mixture of 22 and three other
unidentified acetate-containing species [δH 4.94 (dd, J 7.7, 4.2), 4.97-5.03
(m), 5.29 (dd, J 6.2, 2.9)]. Purification of the crude reaction mixture gave 22 in
83% yield and >99:1 dr, while transesterification of the crude reaction
mixture gave an 89:11 mixture of 24:35.
(17) A range of Brønsted acids were screened for their ability to promote
crystallization of 22 as the corresponding ammonium salt, with HBF4 giving
crystals of suitable quality for X-ray analysis.
(20) For a discussion of the conformation of cyclooctane derivatives such
as cis-cyclooctene, see: Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 3981.
(21) Itoh, T.; Kaneda, K.; Teranishi, S. Chem. Commun. 1976, 421. Cope,
A. C.; Keough, A. H.; Peterson, P. E.; Simmons, H. E.; Wood, G. W. J. Am.
Chem. Soc. 1957, 79, 3900.
(18) See ref 9d and: Iranpoor, N.; Shekarriz, M.; Shiriny, F. Synth.
Commun. 1998, 28, 347. Jacobsen, E. N. Acc. Chem. Res. 2000, 33, 421.
(19) Denmark, S. E.; Barsanti, P. A.; Wong, K.-T.; Stavenger, R. A. J.
Org. Chem. 1998, 63, 2428.
(22) Chamberlain, P.; Roberts, M. L.; Whitham, G. H. J. Chem. Soc.
1970, 1374.
(23) Leong, M. K.; Mastryukov, V. S.; Boggs, J. E. J. Mol. Struct. 1998,
445, 149.
6738 J. Org. Chem. Vol. 74, No. 17, 2009

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JOCArticle
SCHEME 5a
SCHEME 6a
aReagents and conditions: (i) MsCl, Et3N, DMAP, CH2Cl2, 0 °C to rt,
2 h; (ii) K2CO3, MeOH/THF (7:3), rt, 2 h; (iii) H2SO4 (3 M aq), THF,
40 °C, 24 h.
aReagents and conditions: (i) Cl3CCO2H (5 equiv), CH2Cl2, rt, 5 min,
then m-CPBA (1.05 equiv), rt, 3.5 h; (ii) MeOTf, Et2O, rt, 2 h.
suggesting that the sterically demanding N,N-dibenzylam-
monium group may be enforcing a more well-defined con-
formation, which is reflected in the transition state for the
epoxidation. In the solid-state structures of both allylic
amine 15 and epoxide 28 the 7-membered ring adopts a
chair-type conformation, and studies have shown that both
cycloheptene23 and cycloheptene oxide24 favor this confor-
mation in solution. A comparison of solid-state structures of
the allylic amines and the derived anti-epoxides in both the
7- and 8-membered ring systems suggests that the origin of
the anti-selectivity in the formation of epoxide anti-28 may lie
in epoxidation on the sterically more accessible face of the
olefin. Treatment of 15 with methyl triflate gave the corre-
sponding N-methylammonium 30 in 21% yield, with sub-
sequent treatment with 1.05 equiv of m-CPBA and 5 equiv of
Cl3CCO2H giving 44% conversion to a 50:50 mixture of the
diastereoisomeric epoxides anti-31 and syn-32. The relative
configuration within anti-epoxide 31 was unambiguously
established through N-methylation of anti-epoxide 28. These
observations suggest that, in contrast to the 8-membered
ring, an intermolecular hydrogen bond in the oxidation of 15
may not only provide stabilization of the transition state, but
also play a crucial role in determining the high facial
selectivity of the epoxidation reaction.
ferential attack of H2O25 at C(1) where the electron-with-
drawing influence of the N,N-dibenzylammonium moiety is
lower.
With both the 1,2-anti-diastereoisomers of 3-(N,N-
dibenzylamino)cyclopentane-1,2-diol in hand, the 1,2-syn-
diastereoisomers were targeted. It was envisaged that the 1,2-
syn-2,3-anti-diastereoisomer 39 would be available from
acetoxy mesylate 33 utilizing a neighboring group participa-
tion reaction originally reported by Winstein et al.26 Under
literature conditions, 33 was suspended in EtOH/H2O and
treated with KOAc which gave a 7:9:84 mixture of the
regioisomeric acetates 36 and 37 and dibenzylamine 38,
respectively.27 When EtOH/H2O was replaced by AcOH/
H2O (in which 33 proved soluble) a mixture of products,
including a 34:12:54 mixture of 36:37:38, was obtained.27
Transesterification of the crude reaction mixture and purifica-
tion by chromatography gave 39 in 44% yield and >99:1 dr28
(Scheme 7). The relative configuration within 39 was unam-
biguously established by single-crystal X-ray analysis of the
corresponding 2-methyl-5-nitrobenzenesulfonic acid salt.29
A plausible mechanistic rationale for the formation of
dibenzylamine 38 in this reaction involves competing ring-
opening of the acetoxonium ion intermediate 40 to give
(25) Alternatively, ring-opening by either HSO4- or SO42- (followed by
hydrolysis) may occur. For a very recent example, see: Cavdar, H.;
Saracoglu, N. Tetrahedron 2009, 65, 985.
(26) Winstein, S.; Hess, H. V.; Buckles, R. E. J. Am. Chem. Soc. 1942, 64,
2157. Roberts, J. D.; Young, W. G.; Winstein, S. J. Am. Chem. Soc. 1942, 64,
2796.
(27) The regiochemistry within 36 and 37 was arbitrarily assigned.
(28) The relative 1,2-syn-configurations within 39 and 47 were unam-
biguously established by dihydroxylation of 14 with OsO4/NMO, which gave
a 91:9 mixture of 39:47. Chromatographic purification gave 39 in 46% yield
and >99:1 dr (reagents and conditions: (i) OsO4 (1 mol %), NMO (3 equiv),
acetone/H2O (4:1), rt, 4 h, then satd aq Na2SO3).
The synthetic utility of the epoxide products 20 and 28 was
next demonstrated by their elaboration to 3-amino-1,2-diols.
In the 5-membered ring system, ring-opening of syn-epoxide
20 with aq H2SO4 allowed direct access to 1,2-anti-2,3-syn-
N,N-dibenzylamino diol 24 (vide supra), and it was envi-
saged that the 1,2-anti-2,3-anti-diastereoisomer 35 would be
available from analogous ring-opening of the corresponding
anti-epoxide 34. anti-Epoxide 34 was prepared via mesyla-
tion of 22 to furnish acetoxy mesylate 33, followed by
treatment with K2CO3 in MeOH (Scheme 6). The relative
configurations within 33 and 34 were established unambigu-
ously by single-crystal X-ray analysis. Ring-opening of anti-
epoxide 34 with 3 M aq H2SO4 gave 35 in >99:1 dr, with
purification giving 35 in 83% yield and >99:1 dr (Scheme 6).
The production of 35 as the only diastereoisomer in this
reaction is consistent with ring-opening proceeding via pre-
(29) A range of Brønsted acids were screened for their ability to promote
crystallization of 39 as the corresponding ammonium salt, with 2-methyl-5-
nitrobenzenesulfonic acid giving crystals of suitable quality for X-ray
analysis.
(24) Abraham, R. J.; Castellazzi, I.; Sancassan, F.; Smith, T. A. D. J.
Chem. Soc., Perkin Trans. 2 1999, 99.
J. Org. Chem. Vol. 74, No. 17, 2009 6739

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JOCArticle
SCHEME 7a
SCHEME 8a
aReagents and conditions: (i) KOAc, AcOH/H2O (6:1), 80 °C, 18 h; (ii)
K2CO3, MeOH, rt, 12 h.
aReagents and conditions: (i) Ac2O, Et3N, DMAP, CH2Cl2, rt, 6 h; (ii)
KOAc, EtOH/H2O (6:1), 80 °C, 6 h; (iii) K2CO3, MeOH, rt, 12 h.
SCHEME 9a
FIGURE 3. Postulated mechanism for the formation of dibenzyla-
mine 38 and cyclopentenone 43.
enamine 41, which may be in equilibrium with iminium 42;
subsequent hydrolysis and E1CB-type elimination of AcOH
(although not necessarily in that order) gives dibenzylamine 38
and cyclopentenone 43. Consistent with this hypothesis, when
the reaction was carried out in AcOH-d4/D2O mixture and
analyzed by 1H NMR spectroscopy, the formation of 43-d3 was
observed. Deuteration at both C(2) and C(5) of 43 potentially
arises from tautomerization and deuteration of enamine 41
or the corresponding ketone (Figure 3).
aReagents and conditions: (i) H2 (1 atm), Pd(OH)2/C (50% w/w),
MeOH, 4 h, rt, then HCl (conc, aq).
In order to access 1,2-syn-2,3-syn-47, a neighboring group
participation strategy was also employed. Thus, acetylation of
23 was followed by exposure of the resultant acetoxy tosylate
44 to Winstein’s conditions,26 affording a 69:31 mixture of
regioisomeric acetates 45 and 46.30 Subsequent transesterifi-
cation with K2CO3 in MeOH gave 47 in 94% yield as a single
diastereoisomer28 (Scheme 8). This reaction sequence also
serves to further confirm the structural assignment of 23.
With all diastereoisomers of 3-(N,N-dibenzylamino)-
cyclopentane-1,2-diol in hand, N-debenzylation to give the
diastereoisomers of 3-aminocyclopentane-1,2-diol was in-
vestigated. In each case, hydrogenolysis of 24, 35, 39, and
47 mediated by Pearlman’s catalyst [Pd(OH)2/C] followed by
acidification of the crude reaction mixture with HCl gave the
corresponding diastereoisomers of 3-aminocyclopentane-
1,2-diol as the hydrochloride salts 48-51, in good yield as
single diastereoisomers. The spectroscopic properties of 48-
51 were in agreement to those previously reported in the
literature31 (Scheme 9).
Manipulation of anti-epoxide 28, derived from oxidation
of the 7-membered substrate 15 was next investigated. Ring-
opening of 28 with anhydrous TsOH or anhydrous
Cl3CCO2H gave the corresponding 1,2-anti-2,3-anti-diaster-
eoisomers 52 and 53, resulting from regioselective epoxide
opening at C(1), as the major products32 (Scheme 10).
(31) Whitten, J. P.; McCarthy, J. R.; Whalon, M. R. J. Org. Chem. 1985,
50, 4399.
(32) Ring-opening of 28 by anhydrous TsOH gave 52 in >99:1 dr. Ring-
opening of 28 by Cl3CCO2H gave 53 as the major product (>95%) along with
trace amounts of unidentifiable species. Recrystallization of the crude
reaction mixture gave 53 in 87% yield and >99:1 dr, while transesterification
gave 54 in >95:5 dr.
(30) The regiochemistry within 45 and 46 was arbitrarily assigned.
6740 J. Org. Chem. Vol. 74, No. 17, 2009

Bond et al.
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SCHEME 10a
SCHEME 12a
aReagents and conditions: (i) H2 (1 atm), Pd(OH)2/C (50% w/w),
MeOH, 4 h, rt, then HCl (conc, aq).
aReagents and conditions: (i) TsOH (5 equiv), CH2Cl2, 40 °C, 4.5 h; (ii)
Cl3CCO2H (5 equiv), CH2Cl2, 40 °C, 12 h; (iii) K2CO3, MeOH, rt, 12 h.
which were isolated as the hydrochloride salts 59 and 60 in
good yield and >99:1 dr in both cases (Scheme 12).
SCHEME 11a
These studies demonstrate that the ammonium-directed
oxidation protocol (that has previously been reported by us
within a 6-membered ring scaffold)5,6 is general for the
oxidation of a range of cyclic (5-, 7-, and 8-membered ring)
allylic amines. In these latter cases, the ring-opening of the
intermediate epoxide is sufficiently slow as to allow its
isolation by modification of the reaction conditions, and
the epoxide products (within the 5- and 7-membered ring
systems) are readily derivatized into a range of vicinal amino
diol motifs. The extension of this methodology to a more
challenging homoallylic system was next probed.
Oxidation of Homoallylic Amines: Diastereoselective Oxi-
dation of N-Protected 3-Aminomethylcyclohex-1-enes. 3-Hy-
droxymethylcyclohex-1-ene 62 and N-protected 3-amino-
methylcyclohex-1-enes 64 and 65 were prepared from cyclo-
hexene 61. Treatment of 61 with Schlosser’s base35 followed
by paraformaldehyde gave alcohol 62 in 86% yield.36 Under
optimized conditions, treatment of 62 with NBS and triphe-
nylphosphine37 gave bromide 63 in 74% yield, with subse-
quent bromide displacement with benzylamine followed by
benzylation of the resultant secondary amine 64 with benzyl
bromide giving tertiary amine 65 in 53% yield over two steps
from 6338 (Scheme 13).
The ability of the hydroxyl functionality to enable a
diastereoselective oxidation of the olefin within 62 was
first investigated. Treatment of alcohol 62 with m-CPBA
(1.5 equiv) gave a 76:24 mixture of epoxides syn-66 and anti-
67. The major diastereoisomer was assigned the relative syn-
configuration on the assumption that the reaction proceeds
predominantly under hydrogen-bonded substrate control. In
support of this hypothesis, protection of the hydroxyl group
upon treatment with NaH followed by methyl iodide gave
methyl ether 68 which upon oxidation withm-CPBA provided
a 58:42 mixture of diastereoisomeric epoxides syn-69 and anti-
70. The major product from this reaction was assigned as the
syn-diastereoisomer 69 by chemical correlation, through
O-methylation of a 76:24 mixture of syn-66:anti-67 which
gave a 76:24 mixture of syn-69:anti-70 (Scheme 14).
aReagents and conditions: (i) Ac2O, Et3N, DMAP, CH2Cl2, rt, 18 h; (ii)
KOAc, EtOH/H2O (6:1), 80 °C, 12 h; (iii) K2CO3, MeOH, rt, 12 h.
The relative configurations within 52 and 53 were established
unambiguously by single-crystal X-ray analysis. Transester-
ification of 53 gave 1,2-anti-2,3-anti-54 in 83% yield as a
single diastereoisomer (Scheme 10).
The 1,2-syn-2,3-anti-diastereoisomer 58 was accessed
using the neighboring group participation reaction.26 Acet-
ylation of 52 provided acetoxy tosylate 55 in >99:1 dr and
80% yield, and treatment with KOAc in EtOH/H2O gave a
75:25 mixture of hydroxy acetates 56 and 57.33 Transester-
ification of the crude reaction mixture with K2CO3 in MeOH
gave 58 in quantitative yield and >99:1 dr34 (Scheme 11).
Catalytic hydrogenolysis of 54 and 58 gave the corre-
sponding diastereoisomers of 3-aminocycloheptane-1,2-diol
(33) The regiochemistry within 56 and 57 was arbitrarily assigned.
(34) The relative 1,2-syn-configuration within 58 was unambiguously
established by dihydroxylation of 15 with OsO4/NMO, which gave an
83:17 mixture of 58:97. Chromatographic purification gave 58 in 24% yield
and >99:1 dr, and 97 in 4% yield and >99:1 dr (reagents and conditions:
(i) OsO4 (1 mol %), NMO (3 equiv), acetone/H2O (4:1), rt, 4 h, then satd aq
Na2SO3).
(35) Schlosser, M. J. Organomet. Chem. 1967, 8, 9.
(36) Clausen, R. P.; Bols, M. J. Org. Chem. 2000, 65, 2797.
(37) Borcherding, D. R.; Narayanan, S.; Hasobe, M.; McKee, J. G.;
Keller, B. T.; Borchardt, R. T. J. Med. Chem. 1988, 31, 1729.
(38) Direct formation of N,N-dibenzyl-protected amine 65 from bromide
63 via displacement with dibenzylamine was not as efficacious.
J. Org. Chem. Vol. 74, No. 17, 2009 6741

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SCHEME 13a
SCHEME 15a
aReagents and conditions: (i) Cl3CCO2H (4 equiv), CH2Cl2, rt, 5 min,
then m-CPBA (1.6 equiv), rt, 21 h; (ii) K2CO3, MeOH, rt, 12 h.
aReagents and conditions: (i) KOtBu, BuLi, 0 °C to rt, 18 h, then
(CH2O)n, 60 °C, 3 h; (ii) NBS, PPh3, CH2Cl2, 0 °C to rt, 17 h; (iii)
BnNH2, NaI, 50 °C, 20 h; (iv) BnBr, iPr2NEt, CH2Cl2, 40 °C, 2 h.
SCHEME 14a
FIGURE 4. Postulated mechanism for the oxidation of 64 with
Cl3CCO2H and m-CPBA.
aReagents and conditions: (i) m-CPBA, CH2Cl2, 0 °C to rt, 1 h; (ii) NaH,
MeI, THF/DMF (3:1), rt, 48 h; (iii) m-CPBA, CH2Cl2, 0 °C to rt, 2.5 h.
SCHEME 16a
The ability of a homoallylic amino substituent to promote
diastereoselective oxidation of the olefin within this scaffold was
next probed. Oxidation of secondary amine 64 upon treatment
with 4 equiv of Cl3CCO2H39 and 1.6 equiv of m-CPBA,5
followed by transesterification with K2CO3 in MeOH, gave
1,2-anti-2,3-syn-N-benzylamino diol 71 in 95:5 dr (Scheme 15).
Although attempted assignment of the relative configuration
1
3
aReagents and conditions: (i) Cl3CCO2H (5 equiv), CH2Cl2, rt, 30 min,
then m-CPBA (1.5 equiv), rt, 21 h; (ii) K2CO3, MeOH, rt, 12 h.
within 71 by H NMR J coupling constant analysis proved
inconclusive, it was subsequently established unambiguously by
chemical correlation (vide infra). The level of stereoselectivity in
this oxidation process is similar to that observed in the analo-
gous 6-membered ring allylic amine system5 and is consistent
with a highly diastereoselective syn-epoxidation under hydrogen
bond control, followed by regioselective ring-opening of the
Analogous oxidation of tertiary amine 65 in the presence
of 5 equiv of Cl3CCO2H39 gave, after transesterification, a
90:10 mixture of N,N-dibenzylamino diols 75 and 76, respec-
tively. Purification via flash column chromatography gave
the major diastereoisomer 75 in 55% yield and >99:1 dr and
a sample of the minor diastereoisomer 76 (contaminated
with trace amounts of unknown impurities) in ∼4% yield
(Scheme 16). The relative configuration within 75 was un-
ambiguously established by single-crystal X-ray analysis,
and the relative configuration within 76 was assigned from
protonated intermediate epoxide syn-73 at C(1), in a trans-
40
diaxial manner according to the Furst-Plattner rule, via a
chair-like transition state which places the sterically demanding,
protonated N-benzylaminomethyl group in an equatorial site
(Figure 4).
€
3
1H NMR J coupling constant analysis of a pure sample
(39) The stoicheiometry of Cl3CCO2H or TsOH required to effect the
efficient protection of homoallylic amines 64 and 65 was determined in each
case by an analogous 1H NMR “titration experiment” as described for allylic
amines 14-16.
(40) Furst, A.; Plattner, P. A. 12th Int. Congress Pure Appl. Chem. New
York, 1951, p 409.
(vide infra). There are two possible chair conformations
available for 75: 75A, which places the N,N-dibenzylamino-
methyl group axial, and 75B, which places the N,N-dibenzy-
laminomethyl group equatorial (Figure 5). Quite clearly, an
€
6742 J. Org. Chem. Vol. 74, No. 17, 2009

Bond et al.
JOCArticle
SCHEME 17a
aReagents and conditions: (i) TsOH (3 equiv), CH2Cl2, rt, 30 min, then m-CPBA (1.6 equiv), rt, 22 h; (ii) DBU, CH2Cl2, 0 °C to rt, 15 h.
SCHEME 18a
FIGURE 5. Conformations of 75.
intramolecular hydrogen-bonding network between the
C(1)- and C(2)-hydroxyl groups and the nitrogen atom
within 75A can serve to stabilize this conformation.41 The
alternative chair conformation 75B results in both hydroxyl
groups occupying axial sites where formation of one intra-
molecular hydrogen bond becomes impossible; furthermore,
the formation of a hydrogen bond between the axial C(2)-
aReagents and conditions: (i) TsOH (3 equiv), CH2Cl2, rt, 3 h; (ii) AcOH,
rt, 12 h; (iii) Cl3CCO2H (5 equiv), CH2Cl2, rt, 2 h; (iv) K2CO3, MeOH, rt,
12 h.
hydroxyl group and the nitrogen atom of the molecule in this
conformation results in the N,N-dibenzylaminomethyl
group experiencing unfavorable syn-pentane interactions.
Within the solid state, 75 exists in conformation 75A, and
an identical conformational preference in solution was
imate 10:75:15 mixture of diol 75 and hydroxy tosylates 77
and 78,43 respectively. Presumably, hydroxy tosylates 77 and
78 result from ring-opening of the intermediate syn- and anti-
epoxides 79 and 80 at C(1), respectively (vide infra), while
diol 75 results from ring-opening of syn-epoxide 79 at C(1) by
inferred from 1H NMR 3J coupling constant analysis.42
The stereochemical outcome of the oxidation reaction is
consistent with our proposed mechanism for oxidation of
secondary amine 64 although, in comparison, the diastereos-
adventitious water. This implies that the diastereoisomeric
electivity of the two-step epoxidation/ring-opening process
with tertiary amine 65 is lower.
tertiary homoallylic amine 65 with m-CPBA in the presence
To probe this observation further, the syn- and anti-
diastereoisomers of the intermediate epoxide were prepared
in order that the regioselectivity of their ring-opening could
be subsequently investigated. Oxidation of 65 with m-CPBA
in the presence of 3 equiv of TsOH39 furnished an approx-
ratio of epoxides syn-79:anti-80 formed in the oxidation of
of TsOH is ∼85:15. Treatment of the crude reaction mixture
(10:75:15, 75:77:78) with DBU gave a 10:4:75:11 mixture of
diol 75, hydroxy tosylate 78, and the diastereoisomeric
epoxides syn-79 and anti-80, respectively. This product dis-
tribution is consistent with the elimination of TsOH from 77
being faster than that from 78; this is presumably a result of
(41) A “strong” hydrogen bond is observed between C(2)O-H N, and
3 3 3
ring closure of 77 proceeding via a favored chair-like transi-
tion state which places the N,N-dibenzylaminomethyl moi-
ety in an equatorial position, while ring closure of 78
proceeds either via a disfavored twist-boat-like transition
state, or from a disfavored chair conformation with all the
substituents occupying axial sites. Exhaustive purification of
the crude reaction mixture enabled partial separation of the
epoxide products, giving a diastereoisomerically pure sample
a “weak” hydrogen bond is observed between C(1)O-H O-C(2); see:
3 3 3
Desiraju, G. R. The Weak Hydrogen Bond in Structural Chemistry and
Biology; Desiraju, G. R., Steiner, T., Eds.; Oxford University Press: Oxford,
1999; p 13.
(42) The multiplet due to C(2)H appears as a doublet of doublets (J2,1 9.1,
J2,3 4.6); in addition, it is notable that both OH protons are observable,
appearing as broad singlets at δH 2.55 and 6.75.
(43) The stereo- and regiochemistries within 77 and 78 were subsequently
established by comparison with authentic samples prepared via ring-opening
of syn- and anti-epoxides 79 and 80, respectively.
J. Org. Chem. Vol. 74, No. 17, 2009 6743

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JOCArticle
SCHEME 19a
SCHEME 20a
aReagents and conditions: (i) MsCl, Et3N, CH2Cl2, 0 °C, 1 h; (ii) K2CO3,
MeOH, rt, 12 h.
of syn-79 in 17% yield from 65 and a mixed fraction (86:14,
79:80) in 31% yield from 65 (Scheme 17).
aReagents and conditions: (i) TsOH (3 equiv), CH2Cl2, rt, 2 h; (ii)
Cl3CCO2H (5 equiv), CH2Cl2, rt, 14 h, then K2CO3, MeOH, rt, 12 h; (iii)
AcOH, rt, 13 h. [acrude; bpurified, isolated yield of single diastereoi-
somer (>99:1 dr); creaction proceeded to 82% conversion; da mixed
fraction containing both 84 and 85 was also obtained in 68% yield; the
combined yield of both products was therefore 80%.]
Treatment of diastereoisomerically pure syn-epoxide 79
with AcOH gave the C(1) ring-opened product 81 in 95:5 dr,
with purification giving 81 in 90% yield and >99:1 dr
(Scheme 18). The regioselectivity of ring-opening and relative
configuration within 81 were unambiguously determined by
single-crystal X-ray analysis. The solid-state conformation of
81 is analogous to that of 75, with the N,N-dibenzylamino-
methyl group occupying an axial site in order to avoid un-
favorable syn-pentane interactions when forming an intra-
molecular hydrogen bond between the C(2)-hydroxyl group
and the nitrogen atom. However, 1H NMR 3J coupling
constant analysis was suggestive of the alternative chair con-
formation which places the bulky N,N-dibenzylaminomethyl
group equatorial being favored in solution. The inability of 81
(versus 75) to form an additional intramolecular hydrogen
bond between the C(1) and C(2) hydroxy groups may account
for this difference in conformational preference. Ring-opening
of 79 by TsOH gave a single diastereoisomer 77, with the
relative configuration within 77 being assigned by analogy to
diastereoisomerically pure syn- and anti-epoxides 79 and 80,
respectively, with Cl3CCO2H, the epoxide ratio resulting from
the ammonium-directed oxidation of tertiary amine 65 in the
presence of Cl3CCO2H can be inferred as ∼9:1.) Both of these
results indicate that ring-opening at C(1) is marginally pre-
ferred. Treatment of 80 with AcOH gave 82% conversion to a
29:71 mixture of C(1):C(2) ring-opened products, hydroxy
acetates 84 and 85, suggesting that ring-opening at C(2) is
slightly preferred (Scheme 20). The C(1) and C(2) ring-opened
products proved separable by column chromatography in
each case. The relative configurations within 76, 78, and 83-
85 were assigned by 1H NMR 3J coupling constant analyses
assuming, in each case, that the preferred conformation in
solution was a chair which places the N,N-dibenzylamino-
methyl group equatorial; in the case of 85, the relative config-
uration was proven unambiguously by single-crystal X-ray
analysis. Within the solid state, 85 preferentially adopts a chair
conformation which places the N,N-dibenzylaminomethyl
group equatorial and both the C(1)-hydroxyl and C(2)-acet-
oxy functionalities axial. This preference is readily accounted
for due to the inability of 85 (versus 75 and 81) to form an
intramolecular hydrogen bond to the nitrogen atom. The
modest levels of and variation in regioselectivity observed
upon ring-opening of anti-epoxide 80 with TsOH, AcOH,
and Cl3CCO2H parallels the observations of Crotti et al.
concerning the ring-opening of anti-1,2-epoxy-3-benzyloxy-
methylcyclohexane by a range of nucleophiles.44 Assuming
that anti-epoxide 80 exists in solution in one of two possible
half-chair conformers, 80A which has the N,N-dibenzylami-
nomethyl group in a pseudoequatorial site, and 80B which has
the N,N-dibenzylaminomethyl group in a pseudoaxial site,
then trans-diaxial ring-opening resulting from attack at C(2)
of 80A may be anticipated, since this results in a chair-like
transition state with the protonated N,N-dibenzylamino-
methyl group equatorial. However, the necessary approach
trajectory of the nucleophile may be hindered by the steric
bulk of the amino substituent, thus promoting trans-diaxial
ring-opening via attack at C(1) of 80B, giving an alternative
chair-like transition state but with the protonated N,N-diben-
zylaminomethyl group in an axial site. Variations in the
1
3
that unambiguously proven for 81; H NMR J coupling
constant analysis, assuming that 77 preferentially adopts a
conformation in solution which places the bulky N,N-diben-
zylaminomethyl group equatorial, was supportive of this
assignment (Scheme 18). Ring-opening of 79 by Cl3CCO2H
and transesterification gave diol 75 in 95:5 dr. Additionally,
transesterification of hydroxy acetate species 81 (>99:1 dr)
gave diol 75 in 79% yield and >99:1 dr (Scheme 18). These
results demonstrate that ring-opening of epoxide syn-79 pro-
ceeds with very high (g95:5 dr) levels of regioselectivity for
attack at C(1) for a range of acids. This predilection presum-
ably arises due to the ring-opening reaction proceeding
preferentially via a chair-like transition state which places the
N,N-dibenzylaminomethyl group equatorial to give the trans-
diaxial product.40
anti-Epoxide 80 was prepared from hydroxy acetate 81 via
mesylation to give 82, isolated in 97% yield after chroma-
tography, and subsequent treatment with K2CO3 in MeOH,
giving diastereoisomerically pure 80 in 85% yield. 1H NMR
3J coupling constant analysis of acetoxy mesylate 82 indi-
cated that the favored solution-phase conformation is a
chair which places the N,N-dibenzylaminomethyl group
equatorial (Scheme 19).
The regioselectivity observed upon ring-opening of anti-
epoxide 80 with TsOH, AcOH and Cl3CCO2H was investi-
gated. Treatment of 80 with TsOH (3 equiv) gave a 64:36
mixture of hydroxy tosylates 78 and 83, whilst ring-opening
with Cl3CCO2H followed by transesterification gave a 56:44
mixture of diols 76 and 75. (From the 95:5 and 56:44 ratios of
C(1):C(2) ring-opened products obtained upon treatment of
(44) Chini, M.; Crotti, P.; Flippin, L. A.; Gardelli, C.; Macchia, F. J. Org.
Chem. 1992, 57, 1713.
6744 J. Org. Chem. Vol. 74, No. 17, 2009

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JOCArticle
SCHEME 22a
FIGURE 6. Proposed rationale for variation in regioselectivity of
ring-opening of epoxide 80 with TsOH, Cl3CCO2H, and AcOH.
aReagents and conditions: (i) Ac2O, pyridine, DMAP, CH2Cl2, 0 °C to rt,
2 h; (ii) KOAc, EtOH/H2O (6:1), 80 °C, 12 h; (iii) MeOH, K2CO3, rt, 12 h.
SCHEME 21a
SCHEME 23a
aReagents and conditions: (i) KOAc, EtOH/H2O (6:1), 80 °C, 12 h; (ii)
K2CO3, MeOH, rt, 12 h.
regioselectivity of ring-opening with the identity of the nucleo-
phile may therefore be expected44,45 (Figure 6).
In addition to providing mechanistic insight into this
oxidative transformation, these studies also facilitated the
preparation of the diastereoisomeric 1,2-anti-configured
N,N-dibenzylamino diols 75 and 76. The corresponding
1,2-syn-configured diols were next prepared via the inversion
strategy of Winstein, reliant on formation of an acetoxonium
intermediate.26 Treatment of acetoxy mesylate 82 with
KOAc in aqueous EtOH at reflux for 12 h afforded a 75:25
mixture of hydroxy acetates 86 and 87.46 Transesterification
gave 88 as a single diastereoisomer (>99:1 dr) in 82% yield
aReagents and conditions: (i) H2 (1 atm), Pd(OH)2/C (50% w/w),
MeOH, 6 h, rt.
(45) Hydrogen-bonded delivery of the conjugate base to C(2) by the
protonated N,N-dibenzylaminomethyl group may also be important in
determining the regioselectivity of the ring-opening reaction.
(46) The regiochemistry within 86 and 87 was arbitrarily assigned.
(47) The relative 1,2-syn-configuration within 88 was also established by
dihydroxylation of 65 with OsO4/TMEDA, which gave 88 in 83% isolated
yield and >99:1 dr (reagents and conditions: (i) OsO4, TMEDA, CH2Cl2,
-78 °C, 2 h, then MeOH, HCl, rt, 24 h).
and >99:1 dr47 after purification (Scheme 21). The relative
configuration within 88 was unambiguously established by
single-crystal X-ray analysis. In the solid state, both the N,N-
dibenzylaminomethyl group and the C(2)-hydroxyl substi-
tuent within 88 are able to adopt equatorial sites within a
chair conformation, and an intramolecular hydrogen bond is
observed between them. 1H NMR 3J coupling constant
analysis of 88 was indicative of an identical solution-phase
conformational preference.
In a similar manner, acetylation of hydroxy tosylate 77
(>99:1 dr) gave acetoxy tosylate 89 in 60% yield, with
subsequent treatment with KOAc in aq EtOH giving a 55:45
J. Org. Chem. Vol. 74, No. 17, 2009 6745

Bond et al.
JOCArticle
mixture of hydroxy acetates 90 and 91.48 Transesterifica-
tion of this mixture with K2CO3 in MeOH gave 92 in 28%
yield and >99:1 dr. The relative configurations within 89
ether/EtOAc, 96:4); mp 58-60 °C (iPrOH); νmax (KBr) 3084,
3061, 3027, 2951, 2802 (C-H), 1602, 1494, 1453; δH (400 MHz,
CDCl3) 1.45-1.59 (3H, m, C(4)HA, C(5)H2), 2.00-2.11 (1H, m,
C(4)HB), 3.25-3.31 (1H, m, C(3)H), 3.34 (1H, app d, J 2.7, CH,
epoxide), 3.47 (1H, app d, J 2.7, CH, epoxide), 3.74 (2H, d, J
14.3, N(CHAHBPh)2), 3.86 (2H, d, J 14.3, N(CHAHBPh)2),
7.22-7.46 (10H, m, Ph); δC (100 MHz, CDCl3) 17.9 (C(5)), 25.7
(C(4)), 53.7, 55.5, 56.4 (C(1), C(2), N(CH2Ph)2), 61.4 (C(3)),
126.8 (p-Ph), 128.2, 128.5 (o-, m-Ph), 140.4 (i-Ph); m/z (ESI+)
280 ([M + H]+, 100); HRMS (ESI+) C19H22NO+ ([M+H]+)
requires 280.1696, found 280.1692. Anal. Calcd for C19H21NO:
C, 81.7; H, 7.6; N, 5.0. Found: C, 81.5; H, 7.7; N, 4.9.
X-ray Crystal Structure Determination for 20. Data were
collected using an Enraf-Nonius κ-CCD diffractometer with
graphite-monochromated Mo KR radiation using standard
procedures at 150 K. The structure was solved by direct methods
(SIR92); all non-hydrogen atoms were refined with aniso-
tropic thermal parameters. Hydrogen atoms were added at
idealized positions. The structure was refined using CRYS-
TALS.49
1
3
and 92 were assigned on the basis of H NMR J coupling
constant analyses, assuming in each case that the preferred
conformation in solution is a chair which places the
N,N-dibenzylaminomethyl group in an equatorial site
(Scheme 22).
Hydrogenolysis of N-benzylamino diol 71 and N,N-diben-
zylamino diols 75, 76, 88, and 92 gave the corresponding
diastereoisomers of 3-aminomethylcyclohexane-1,2-diol
93-96 in good yield. Hydrogenolysis of secondary amine 71
(95:5 dr) and tertiary amine 75 gave the same diastereoiso-
meric product 93, thus unambiguously confirming the relative
configuration within secondary amine 71 (Scheme 23).
Conclusion
In conclusion, the oxidative functionalization of a range of
allylic 3-(N,N-dibenzylamino)cycloalk-1-enes with m-CPBA
in the presence of Cl3CCO2H gives exclusively the corre-
sponding syn-epoxide for the 5-membered ring (>99:1 dr),
the anti-epoxide for the 8-membered ring (>99:1 dr), and
predominantly the anti-epoxide for the 7-membered ring
(94:6 dr). Oxidation of homoallylic amines 3-(N-benzylamino)-
methylcyclohex-1-ene and 3-(N,N-dibenzylamino)methyl-
cyclohex-1-ene gave, in both cases, the corresponding N-pro-
tected 1,2-anti-2,3-syn-3-aminomethylcyclohexane-1,2-diol
with high levels of diastereoselectivity (g90:10 dr). The
versatile synthetic intermediates resulting from these oxida-
tion reactions are readily transformed into a range of amino
diols.
X-ray crystal structure data for 20 [C19H21NO]: M = 558.76,
˚
monoclinic, space group P21, a=12.444(3) A, b=7.8733(16)
3
˚
˚
˚
A, c = 16.766(3) A, β =109.74(3)°, V = 1546.1(6) A , Z = 4,
μ = 0.073 mm-1, colorless block, crystal dimensions = 0.2 Â
0.2 Â 0.2 mm3. A total of 3651 unique reflections were
measured for 5 < θ < 27, and 3651 reflections were used in
the refinement. The final parameters were wR2 = 0.214 and
R1 = 0.092 [I >-3.0σ(I)]. Crystallographic data (excluding
structure factors) has been deposited with the Cambridge Crys-
tallographic Data Centre as supplementary publication number
CCDC 733891. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-mail: deposit@
ccdc.cam.ac.uk].
(1RS,2SR,3RS)-1,2-Epoxy-3-(N,N-dibenzylamino)cyclooctane
(25).
Experimental Section
(1RS,2SR,3SR)-1,2-Epoxy-3-(N,N-dibenzylamino)cyclopentane
(20).
Cl3CCO2H (26.7 g, 164 mmol) was added to a stirred
solution of 16 (10 g, 32.7 mmol) in CH2Cl2 (109 mL, 0.3 M
with respect to 16), and the resultant mixture was stirred at rt
for 5 min. m-CPBA (74%, 8.02 g, 34.4 mmol) was then added
in one portion, and the reaction mixture was stirred at rt for
3.5 h. The mixture was diluted with CH2Cl2 (100 mL), and
satd aq Na2SO3 was added until starch-iodide paper in-
dicated no remaining peracid. Saturated aq NaHCO3 (200 mL)
was added, and the layers were separated. The organic
layer was washed with satd aq NaHCO3 (2 Â 200 mL) and
then dried, filtered through a short plug of silica gel (eluent
CH2Cl2), and concentrated in vacuo to give 25 as a white
crystalline solid (10.4 g, quant, >99:1 dr): mp 104 °C
(EtOH); νmax (KBr) 2972, 2926, 2854 (C-H), 1602, 1493,
1454; δH (400 MHz, CDCl3) 0.85-0.99 (1H, m, C(8)HA),
1.11-1.21 (1H, m, CH2), 1.34-1.61 (5H, m, CH2), 1.65-
1.75 (2H, m, C(4)H2), 2.10 (1H, app dq, J 13.7, 3.9, C(8)HB),
2.68 (1H, app td, J 9.5, 6.7, C(3)H), 2.89 (1H, app dt, J 10.4,
4.4, C(1)H), 3.08 (1H, dd, J 9.5, 4.4, C(2)H), 3.79 (4H, AB
Cl3CCO2H (31.0 g, 190 mmol) was added to a stirred solution
of 14 (10 g, 38.0 mmol) in CH2Cl2 (127 mL, 0.3 M with respect
to 14), and the resultant mixture was stirred at rt for 5 min. m-
CPBA (73%, 9.43 g, 39.9 mmol) was then added in one
portion, and the reaction mixture was stirred at rt for 3.5 h.
The mixture was diluted with CH2Cl2 (100 mL), and satd aq
Na2SO3 was added until starch-iodide paper indicated no
remaining peracid. Saturated aq NaHCO3 (200 mL) was
added, and the layers were separated. The organic layer was
washed with satd aq NaHCO3 (2 Â 200 mL) and then dried,
filtered through a short plug of silica gel (eluent CH2Cl2), and
concentrated in vacuo to give 20 in >99:1 dr. Purification via
recrystallization (iPrOH) gave 20 as a white crystalline solid.
Concentration of the mother liquors and purification of the
residue via flash column chromatography (gradient elution,
1%f8% EtOAc in 40-60 °C petroleum ether) gave 20 as a
colorless oil that solidified on standing to a white crystalline solid
(10.5 g combined, 99%, >99:1 dr): Rf 0.12(40-60 °Cpetroleum
(49) Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, C. K.;
Watkin, D. J. CRYSTALS 2001, issue 11, Chemical Crystallography
Laboratory, University of Oxford, UK.
(48) The regiochemistry within 90 and 91 was arbitrarily assigned.
6746 J. Org. Chem. Vol. 74, No. 17, 2009

Bond et al.
JOCArticle
system, JAB 13.7, N(CH2Ph)2), 7.19-7.46 (10H, m, Ph); δC
(100 MHz, CDCl3) 25.2, 25.5, 26.8, 27.1, 31.2 (C(4)-C(8)),
53.4 (C(1)), 54.6 (N(CH2Ph)2), 55.7 (C(2)), 55.8 (C(3)), 126.7
(p-Ph), 128.1, 128.7 (o-, m-Ph), 140.5 (i-Ph); m/z (ESI+) 322
([M+H]+, 100); HRMS (ESI+) C22H28NO+ ([M+H]+)
([M+H]+, 100); HRMS (ESI+) C21H26NO+ ([M+H]+)
requires 308.2009, found 308.2005. Further elution gave 28 as
a colorless oil which solidified on standing to a white crystal-
line solid (1.49 g, 69%, >99:1 dr): Rf 0.17 (40-60 °C
petroleum ether/Et2O, 90:10); mp 69-70 °C; νmax (KBr)
3084, 3061, 3028, 2926, 2851, 2804 (C-H), 1602, 1494,
1454; δH (400 MHz, CDCl3) 1.02-1.12 (1H, m, C(7)HA),
1.15-1.34 (2H, m, CH2), 1.60-1.73 (2H, m, C(4)H2), 1.83-
1.92 (2H, m, CH2), 2.22 (1H, app ddd, J 13.7, 6.8, 6.5,
C(7)HB), 2.66 (1H, app dd, J 10.4, 7.5, C(3)H), 3.00 (1H,
ddd, J 8.0, 6.5, 5.0, C(1)H), 3.24 (1H, dd, J 7.5, 5.0, C(2)H),
3.77 (4H, AB system, JAB 13.9, N(CH2Ph)2), 7.21-7.46 (10H,
m, Ph); δC (100 MHz, CDCl3) 24.0, 29.3, 29.8, 31.2 (C(4)-
C(7)), 52.7 (C(3)), 54.6 (N(CH2Ph)2), 55.6 (C(1)), 60.7 (C(2)),
126.8 (p-Ph), 128.1, 128.8 (o-, m-Ph), 140.1 (i-Ph); m/z (ESI+)
308 ([M+H]+, 100); HRMS (ESI+) C21H26NO+ ([M+H]+)
requires 308.2009, found 308.2006.
requires 322.2165, found 322.2161.
X-ray Crystal Structure Determination for 25. Data were
collected using an Enraf-Nonius κ-CCD diffractometer with
graphite-monochromated Mo KR radiation using standard
procedures at 150 K. The structure was solved by direct methods
(SIR92); all non-hydrogen atoms were refined with aniso-
tropic thermal parameters. Hydrogen atoms were added at
idealized positions. The structure was refined using CRYS-
TALS.49
X-ray crystal structure data for 25 [C22H27NO]: M = 642.93,
˚
monoclinic, space group P21/c, a = 14.8507(4) A, b =
˚
˚
14.8824(4) A, c = 16.6996(4) A, β = 94.0401(18)°, V=
3681.67(17) A , Z = 8, μ = 0.070 mm-1, colorless plate, crystal
3
˚
dimensions=0.2 Â 0.2 Â 0.3 mm3. A total of 8288 unique
reflections were measured for 5 < θ < 27, and 3748 reflections
were used in the refinement. The final parameters were wR2 =
0.133 and R1 = 0.151 [I > 3.0σ(I)]. Crystallographic data
(excluding structure factors) has been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary publica-
tion number CCDC 733893. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk].
X-ray Crystal Structure Determination for 28. Data were
collected using an Enraf-Nonius κ-CCD diffractometer with
graphite-monochromated Mo KR 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 idealized
positions. The structure was refined using CRYSTALS.49
X-ray crystal structure data for 28 [C21H25NO]: M =
˚
307.44, monoclinic, space group P21/c, a = 9.6786(2) A, b =
˚
˚
15.6935(4) A, c = 11.6781(4) A, β = 92.0417(10)°, V =
1772.67(8) A , Z = 4, μ = 0.070 mm-1, colorless block, crystal
3
˚
(1RS,2SR,3RS)- and (1RS,2SR,3SR)-1,2-Epoxy-3-(N,N-
dibenzylamino)cycloheptane (28 and 29).
dimensions=0.1 Â 0.1 Â 0.1 mm3. A total of 4010 unique
reflections were measured for 5 < θ < 27, and 1988 reflections
were used in the refinement. The final parameters were wR2 =
0.035 and R1=0.034 [I > 3.0σ(I)]. Crystallographic data
(excluding structure factors) has been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary pub-
lication number CCDC 733894. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax: +44(0)-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
Cl3CCO2H (5.74 g, 35.2 mmol) was added to a stirred
solution of 15 (2.05 g, 7.03 mmol) in CH2Cl2 (23 mL, 0.3 M
with respect to 15), and the resultant mixture was stirred at
rt for 5 min. m-CPBA (74%, 1.72 g, 7.38 mmol) was then
addedinoneportion, andthe reaction mixturewasstirredatrt
for 3.5 h. The mixture was diluted with CH2Cl2 (25 mL), and
satd aq Na2SO3 was added until starch-iodide paper indi-
cated no remaining peracid. Saturated aq NaHCO3 (25 mL)
was added, and the layers were separated. The organic
layer was washed with satd aq NaHCO3 (2 Â 25 mL) and
then dried, filtered through a short plug of silica gel (eluent
CH2Cl2), and concentrated in vacuo to give a 94:6 mixture of
28:29. Purification via flash column chromatography
(gradient elution, 2%f20% Et2O in 40-60 °C petroleum
ether) gave 29 as a colorless oil which solidified on standing
toa whitecrystallinesolid (94 mg, 4%, >99:1 dr): Rf 0.28 (40-
60 °C petroleum ether:Et2O, 90:10); mp 54 °C; νmax
(film) 3084, 3062, 3027, 2926, 2849, 2803 (C-H), 1603, 1494,
1453; δH (400 MHz, CDCl3) 0.59-0.70 (1H, m, CH2), 1.26-
1.65 (4H, m, CH2), 1.74-1.82 (1H, m, CH2), 1.84-1.91 (1H,
m, CH2), 2.22-2.31 (1H, m, CH2), 2.89 (1H, app dd, J 11.6,
2.8, C(1)H), 3.06 (1H, app t, J 5.3, C(3)H), 3.35 (1H, dd, J
4.8, 1.0, C(2)H), 3.59 (2H, d, J 13.9, N(CHAHBPh)2), 3.90
(2H, d, J 13.9, N(CHAHBPh)2), 7.21-7.42 (10H, m, Ph); δC
(100 MHz, CDCl3) 23.4, 24.1, 27.1, 28.0 (C(4)-C(7)), 53.3
(C(3)), 54.3 (N(CH2Ph)2), 58.4 (C(1)), 60.7 (C(2)), 126.7 (p-
Ph), 128.1, 128.5 (o-, m-Ph), 140.4 (i-Ph); m/z (ESI+) 308
(1RS,2RS,3SR)-3-(N,N-Dibenzylamino)methylcyclohexane-
1,2-diol (75).
Dihydroxylation of 65. Cl3CCO2H (4.20 g, 25.7 mmol) was
added to a stirred solution of 65 (1.5 g, 5.15 mmol) in CH2Cl2
(14 mL), and the resultant mixture was stirred at rt for
30 min. m-CPBA (70%, 1.90 g, 7.71 mmol) was then added
in one portion, and the reaction mixture was stirred at rt for
21 h. The mixture was then diluted with CH2Cl2 (20 mL), and
satd aq Na2SO3 was added until starch-iodide paper
indicated no remaining peracid. Saturated aq NaHCO3
(150 mL) was then added, and the layers were separated.
The organic layer was washed with satd aq NaHCO3 (2Â
100 mL), dried, and concentrated in vacuo. Following the
general procedure, transesterification with K2CO3 (3.55 g,
25.7 mmol) in MeOH (80 mL) gave 75 in 90:10 dr. Purifica-
tion via exhaustive flash column chromatography (gradient
elution, 7%f60% EtOAc in 30-40 °C petroleum ether)
gave 75 as a white solid (916 mg, 55%, >99:1 dr) and a
sample of 76 contaminated with trace amounts (<5%) of
unknown impurities (63 mg, ∼4%).
J. Org. Chem. Vol. 74, No. 17, 2009 6747

Bond et al.
JOCArticle
Data for 75: mp 83-85 °C; νmax (film) 3356 (O-H); δH (400
MHz, CDCl3) 1.09-1.14 (2H, m, C(5)H2), 1.26-1.29 (1H, m,
C(6)HA), 1.43-1.49 (2H, m, C(4)H2), 1.71-1.78 (1H, m,
C(6)HB), 2.20-2.24 (1H, m, C(3)H), 2.55-2.60 (1H, br s,
OH), 2.60-2.70 (2H, m, C(3)CH2N), 3.07-3.15 (3H, m, C(1)H,
N(CHAHBPh)2), 3.36-3.39 (1H, m, C(2)H), 4.05-4.09 (2H,
m, N(CHAHBPh)2), 6.78-6.99 (1H, br s, OH), 7.27-7.42 (10H,
m, Ph); δC (100 MHz, CDCl3) 19.9 (C(5)), 28.5 (C(4)), 31.7
(C(6)), 33.7 (C(3)), 54.7 (C(3)CH2N), 58.9 (N(CH2Ph)2), 70.6
(C(1)), 76.7 (C(2)), 127.7 (p-Ph), 128.6, 129.6 (o-, m-Ph), 137.4
(i-Ph); m/z (ESI+) 326 ([M + H]+, 100); HRMS (ESI+)
C21H28NO2+ ([M+H]+) requires 326.2115, found 326.2114.
X-ray Crystal Structure Determination for 75. Data were
collected using an Enraf-Nonius κ-CCD diffractometer with
graphite-monochromated Mo KR 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 idealized
positions. The structure was refined using CRYSTALS.49
X-ray crystal structure data for 75 [C21H27NO2]: M = 325.45,
dimensions=0.3 Â 0.3 Â 0.3 mm3. A total of 4097 unique
reflections were measured for 5 < θ < 27, and 2235 reflections
were used in the refinement. The final parameters were wR2 =
0.037 and R1 =0.038 [I > 3.0σ(I)]. Crystallographic data
(excluding structure factors) has been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary publica-
tion number CCDC 733901. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk].
Acknowledgment. We thank Ajinomoto Co., Inc. for
funding (W.K.), New College, Oxford, for a Junior Research
Fellowship (A.D.S.), and the Oxford Chemical Cry-
stallography Service for the use of their X-ray diffract-
ometers.
Supporting Information Available: Full details of all experi-
C
mental procedures, characterization data, copies of 1H and 13
˚
monoclinic, space group P21/n, a = 10.9893(3) A, b =
˚
NMR spectra, and crystallographic information files (for struc-
tures CCDC 733888-733904). This material is available free of
charge via the Internet at http://pubs.acs.org.
˚
13.7910(3) A, c = 12.2178(4) A, β = 102.4024(11)°, V =
1808.44(9) A , Z = 4, μ = 0.076 mm-1, colorless block, crystal
3
˚
6748 J. Org. Chem. Vol. 74, No. 17, 2009