cis- and trans-Stereoselective Epoxidation of N-Protected 2-Cyclohexen-1-ylamines

Article abstract of DOI:10.1021/ol035873n

(Equation Presented) The first systematic study of the cis and trans stereoselectivity in the m-CPBA epoxidation of N-protected cyclic allylic amines has been completed. Mono-N-protected systems gave epoxides with cis stereochemistry (amides are better ci

Full text of DOI:10.1021/ol035873n

ORGANIC
LETTERS
2003
Vol. 5, No. 26
4955-4957
cis- and trans-Stereoselective
Epoxidation of N-Protected
2-Cyclohexen-1-ylamines
Peter O’Brien,* Amanda C. Childs, Gareth J. Ensor, Cheryl L. Hill,
Jonathan P. Kirby, Michael J. Dearden, Sally J. Oxenford, and Clare M. Rosser
Department of Chemistry, UniVersity of York, Heslington, York YO10 5DD, UK
paob1@york.ac.uk
Received September 25, 2003
ABSTRACT
The first systematic study of the cis and trans stereoselectivity in the m-CPBA epoxidation of N-protected cyclic allylic amines has been
completed. Mono-N-protected systems gave epoxides with cis stereochemistry (amides are better cis directors than sulfonamides or carbamates)
whereas di-N-protected systems gave trans-epoxides (TsNBoc protection gave complete trans stereoselectivity).
The success of strategies for total synthesis continues to
depend on high levels of stereoselectivity being observed in
substrate-controlled diastereoselective reactions.1 In this
context, one of the more widely used processes is alkene
epoxidation, and although much has been reported on the
diastereoselectivity of epoxidation of cyclic alkenes with an
O-allylic directing group (following Henbest’s pioneering
contribution2), it turns out that there have been only a few
reports on the epoxidation of N-protected cyclic allylic
amines.3,4
(presumably via a “Henbest-like” hydrogen-bonding interac-
tion). More recent work by Murray et al. has established
that a benzamide-protected allylic amine can be preferentially
converted into a cis-epoxide using DMDO.3e Asensio and
co-workers have also shown that alkenes containing an allylic
trialkylammonium substituent undergo cis-stereoselective
epoxidations with m-CPBA or dioxiranes.3f By way of con-
trast, we have found only one example of the epoxidation
of a cyclic N-diprotected allylic amine, and this showed trans
selectivity, presumably due to steric factors.5 In this paper,
we now report on the first systematic study of the m-CPBA
epoxidation of a wide range of mono- and di-N-protected
cyclic allylic amines 1 (Scheme 1). We also report on the
For example, epoxidation of mono-N-protected alkenes
(carbamate,3c,3d amide,3a-c sulfonamide5 protecting group)
with peracids gives an unquantified degree of cis selectivity
(1) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307.
(2) Henbest, H. B.; Wilson, R. A. L. J. Chem. Soc. 1957, 1958.
(3) (a) Goodman, L.; Winstein, S.; Boschan, R. J. Am. Chem. Soc. 1958,
80, 4312. (b) Baldwin, J. E.; Adlington, R. M.; Chondrogianni, J.;
Edenborough, M. S.; Keeping, J. W.; Ziegler, C. B. J. Chem. Soc., Chem.
Commun. 1985, 816. (c) Kocovsky, P.; Stary, I. J. Org. Chem. 1990, 55,
3236. (d) Brouillette, W. J.; Saeed, A.; Abuelyaman, A.; Hutchison, T. L.;
Wolkowicz, P. E.; McMillin, J. B. J. Org. Chem. 1994, 59, 4297. (e) Murray,
R. W.; Singh, M.; Williams, B. L.; Moncrieff, H. M. J. Org. Chem. 1996,
61, 1830. (f) Asensio, G.; Mello, R.; Boix-Bernardini, C.; Gonza´lez-Nu´n˜ez,
M. E.; Castellano, G. J. Org. Chem. 1995, 60, 3692. (g) Comin, M. J.;
Rodriguez, J. B. Tetrahedron 2000, 56, 4639.
Scheme 1
10.1021/ol035873n CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/27/2003

optimal protecting groups for the synthesis of epoxides cis-2
or trans-2.
(and should be avoided in synthesis), and of the sulfon-
amides investigated, a p-NO2C6H4SO2 gave the highest cis
selectivity (Table 1, entry 4). The best compromise of high
cis-selectivity and ease of protecting group introduction/
removal involved the use of either a p-NO2C6H4SO2 or
trichloroactamide N-protecting group for the epoxidation of
cyclohexene-derived allylic amines.
Initially, a wide range of mono-N-protected cyclic allylic
amines 3a-j were prepared using standard methods. The
key synthetic intermediates were trichloroacetamide 3h
(prepared by Overman rearrangement6) and 2-cyclohexen-
1-ylamine (formed by hydrolysis7 of 3h and isolated as the
hydrochloride salt8). N-Protection of 2-cyclohexen-1-ylamine
gave sulfonamides 3a-d, carbamates 3e-g, and amides 3i,j
(see the Supporting Information). The epoxidation of alkenes
3a-j was carried out under standard conditions (0.5 mmol
scale): 2 equiv of m-CPBA/NaHCO3, CH2Cl2, rt, 19 h
followed by workup with aq Na2SO3 (Table 1). In each case,
Next, we prepared five di-N-protected cyclic allylic amines
5a-e. Alkenes 5a, 5b, and 5e were prepared by protection
of N-(cyclohex-2-enyl)-4-methoxybenzylamine,9 whereas a
Mitsunobu approach was used for the synthesis of alkenes
5c and 5d (see the Supporting Information).10 The epoxida-
tion results with 5a-e are shown in Table 2. With di-N-
protected allylic amines, trans-epoxides were obtained as the
major products and this was established as follows. Reaction
of the 90:10 mixture of epoxides cis- and trans-4b (of known
relative stereochemistry5) with p-methoxybenzyl chloride
(K2CO3, MeCN, reflux) gave a major product which, by
Table 1. Stereoselective Epoxidation of Mono-N-protected
Alkenes 3a-j
1
comparison of H NMR spectra, was clearly the minor
product (epoxide cis-6a) from the epoxidation of alkene 5a.
Epoxide 6b was assigned in the same way. In addition,
separate Boc-protection of the 90:10 mixtures of cis- and
trans-4b and -4c identified trans-6c and -6d, respectively.
Proof of stereochemistry in epoxides trans-6c-e was pro-
vided by their rearrangement to oxazolidinones 7a-c (via
participation of the Boc carbonyl group and subsequent loss
of the tert-butyl group3e,4) under acidic conditions (e.g., silica
gel/MeOH, TFA/CH2Cl2) or even under the epoxidation
conditions for trans-6c or trans-6e (Scheme 2). Indeed, a
reduced epoxidation time for alkene 5c was required to
prevent any rearrangement occurring during the reaction. In
contrast, we could not stop rearrangement with epoxide trans-
6e, and oxazolidinone 7c was isolated as the only product
(93% yield) after chromatography.
entry
R
alkene
epoxidea
cis/transb
1
2
3
4
5
6
7
8
9
Ms
Ts
3a
3b
3c
3d
3e
3f
3g
3h
3i
4a
4b
4c
4d
4e
4f
4g
4h
4i
90:10
90:10
90:10
>95:5
90:10
90:10
85:15
95:5
o-Nsc
p-Nsd
CO2Me
CO2Bn
t
CO2 Bu
Cl3CC(O)
PhC(O)
tBuC(O)
>98:2
>98:2
10
3j
4j
a Epoxidation conditions: m-CPBA, NaHCO3, CH2Cl2, rt, 19 h. b Ratio
determined by 1H NMR spectroscopy on the crude product mixture.
c o-NO2C6H4SO2-. d p-NO2C6H4SO2-.
Scheme 2
quantitative crude yields of mixtures of epoxides cis- and
trans-4a-j were obtained, and the ratio of epoxides was
determined from the 1H NMR spectrum of the crude product
mixture. The major products were identified as epoxides cis-
4a-j by analogy with the known stereochemistry of cis-
4b,5 cis-4f,3d and cis-4i.3e
All these epoxidations were cis selective but our results
show that amides are the best cis directors for the m-CPBA-
mediated epoxidation of mono-N-protected cyclohexene-
derived allylic amines (Table 1, entries 8-10). Notably, a
Boc group gave the worst cis selectivity (Table 1, entry 7)
The results in Table 2 indicate that very high levels of
trans stereoselectivity are obtained from the epoxidation of
di-N-protected cyclic allylic amines containing a Boc group
and either a sulfonamide or p-methoxybenzyl group (Table
2, entries 3-5). The stereoselectivity is governed by steric
factors. If the epoxide product is required from N-Boc-
protected allylic amines 5c-e, the reaction time of the
(4) For a systematic study of N-protecting group in some acyclic allylic
amines, see: Roush, W. R.; Straub, J. A.; Brown, R. J. J. Org. Chem. 1987,
52, 5127.
(5) Ba¨ckvall, J.-E.; Oshima, K.; Palermo, R. E.; Sharpless, K. B. J. Org.
Chem. 1979, 44, 1953.
(6) (a) Overman, L. E.; J. Am. Chem. Soc. 1976, 98, 2901. (b) Nishikawa,
T.; Asai, M.; Ohyabu, N.; Isobe, M. J. Org. Chem. 1998, 63, 188.
(7) Demay, S.; Kotschy, A. Knochel, P. Synthesis 2001, 863.
(8) (a) Tsushima, S.; Yamada, Y. Onami, T.; Oshima, K.; Chaney, M.
O.; Jones, N. D.; Swartzendruben, J. K. Bull. Chem. Soc. Jpn 1989, 62,
1167. (b) Murahashi, S.-I.; Taniguchi, Y.; Imada, Y.; Tanigawa, Y. J. Org.
Chem. 1989, 54, 3292.
(9) Ikeda, M.; Hamada, M.; Yamashita, T.; Matsui, K.; Sato, T.; Ishibashi,
H. J. Chem. Soc., Perkin Trans. 1 1999, 1949.
(10) (a) Henry, J. R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.;
Harris, G. D.; Weinreb, S. M. Tetrahedron Lett. 1989, 30, 5709. (b)
Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373.
4956
Org. Lett., Vol. 5, No. 26, 2003

Table 2. Stereoselective Epoxidation of Di-N-protected Alkenes 5a-e
entry
R1
R2
time (h)
alkene
epoxidea
trans/cisb
1
2
3
4
5
Ts
p-MeOC6H4CH2
p-MeOC6H4CH2
19
19
7.5e
19
5a
5b
5c
5d
5e
6a
6b
6c
6d
6ef
85:15
90:10
>98:2
>98:2
>98:2
o-Nsc
p-Nsd
o-Nsc
t
CO2 Bu
t
CO2 Bu
t
p-MeOC6H4CH2
CO2 Bu
7.5
a Epoxidation conditions: m-CPBA, NaHCO3, CH2Cl2, rt. b Ratio determined by 1H NMR spectroscopy on the crude product mixture. c o-NO2C6H4SO2-.
d p-NO2C6H4SO2-. e If the epoxidation was left for 19 h, some rearrangement to oxazolidinone 7a was observed. f Epoxide trans-6e not isolated: the only
product of this reaction was the rearranged oxazolidinone 7c (see Scheme 2).
In summary, complementary routes to cis- and trans-
epoxides from protected cyclic allylic amines have been
Scheme 3
established. With mono-N-protected alkenes, it has been
demonstrated that amides and a p-NO2C6H4SO2 group are
the best cis directors of epoxidation (g95:5 cis/trans). The
presence of an NBoc substituent is crucial for high stereo-
selectivity (>98:2 trans/cis) in the epoxidation of di-N-
protected alkenes. These results are consistent with our results
with 4-amino-substituted cyclopentenes.12 Finally, rearrange-
ment of epoxides trans-6c-e (diprotected, possessing a NBoc
group) either in situ (6e) or after treatment with acid (6c,d)
generates oxazolidinones 7a-c, which appear to be very
useful, stereodefined synthetic building blocks.
Acknowledgment. We thank Pfizer for an undergraduate
epoxidation must be carefully monitored; otherwise, rear-
summer bursary (to A.C.C. and J.P.K.), the BBSRC for a
rangement to the oxazolidinones 7a-c occurs.
We have also carried out a preliminary study on epoxi-
dation of five-membered ring N-protected allylic amines
quota award (to M.J.D.), and the EPSRC and GlaxoSmith-
Kline for CASE awards (to S.J.O. and C.M.R.).
(Scheme 3). Epoxidation of trichloroacetamide-protected
alkene 8 furnished a single diastereomeric epoxide, assigned
as cis-9. This result is consistent with our previous report of
the cis directing effect of an allylic NHBoc group in the
Supporting Information Available: Outline details of
the routes used to synthesize compounds 3a,b and 5a-e,
1
general epoxidation procedure, key H NMR spectroscopy
data for all epoxides 4a-j and 6a-d, characterization data
epoxidation of a substituted cyclopentene system (during the
for oxazolidinones 7a-c, and copies of 1H NMR spectra of
development of a route to the agelastatins).11 In contrast,
all epoxides and oxazolidinones. This material is available
epoxidation of TsNBoc-diprotected alkene 10 with m-CPBA
free of charge via the Internet at http://pubs.acs.org.
for 6 h gave epoxide trans-11 (>98:2 trans/cis). With an
extended reaction time (19 h), there was evidence for the
formation of some oxazolidinone 12.
OL035873N
(11) Baron, E.; O’Brien, P.; Towers, T. D. Tetrahedron Lett. 2002, 43,
723.
(12) Barrett, S.; O’Brien, P.; Steffens, H. C.; Towers, T. D.; Voith, M.
Tetrahedron 2000, 56, 9633.
Org. Lett., Vol. 5, No. 26, 2003
4957