Chiral base route to functionalised cyclopentenyl amines: Formal synthesis of the cyclopentene core of nucleoside Q

Article abstract of DOI:10.1016/j.tetlet.2004.10.043

A chiral base route to a range of highly functionalised amino cyclopentenes has been developed. The key asymmetric step involved the chiral lithium amide base-mediated rearrangement of a protected trans-4-hydroxy cyclopentene oxide to give an allylic alcohol (88% ee). Subsequent Overman rearrangement gave a protected trans-1,2-aminocyclopentenol whereas Mitsunobu substitution with BocNHNs gave a protected cis-amino cyclopentenol. Both are proven intermediates for natural product synthesis. The protected cis-aminocyclopentenol was transformed in a few steps into a precursor of the cyclopentene core of nucleoside Q, a natural product whose deficiency in animals is related to tumour growth.

Full text of DOI:10.1016/j.tetlet.2004.10.043

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9053–9055
Chiral base route to functionalised cyclopentenyl amines:
formal synthesis of the cyclopentene core of nucleoside Q
Sally J. Oxenford,a Peter OÕBriena,* and Mark R. Shiptonb
aDepartment of Chemistry, University of York, Heslington, York YO10 5DD, UK
bGlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
Received 14 September 2004; accepted 6 October 2004
Abstract—A chiral base route to a range of highly functionalised amino cyclopentenes has been developed. The key asymmetric step
involved the chiral lithium amide base-mediated rearrangement of a protected trans-4-hydroxy cyclopentene oxide to give an allylic
alcohol (88% ee). Subsequent Overman rearrangement gave a protected trans-1,2-aminocyclopentenol whereas Mitsunobu substi-
tution with BocNHNs gave a protected cis-amino cyclopentenol. Both are proven intermediates for natural product synthesis.
The protected cis-aminocyclopentenol was transformed in a few steps into a precursor of the cyclopentene core of nucleoside Q,
a natural product whose deficiency in animals is related to tumour growth.
Ó 2004 Elsevier Ltd. All rights reserved.
Our group has an ongoing interest in the use of chiral
base methodology for the synthesis of cyclic allylic
amines.1–4 Recently, we turned our attention to develop-
ing a chiral base route to the cyclopentene fragment of
nucleoside Q.5 Nucleoside Q, also known as queuosine,
is widely distributed in tRNAs of plants and animals6
and is of current interest since deficiency of nucleoside
Q is related to tumour growth.7 Recent synthetic
work8–11 has culminated in two enantioselective synthe-
ses of the cyclopentene core, independently developed
by Kim and Miller10 and Trost and Sorum.11 The
penultimate compound in MillerÕs route was amino
alcohol 112 which was mesylated and eliminated using
a dilute solution of DBU to give an allylic amine suit-
able for nucleoside Q synthesis.10 Racemic 1 and its
Boc-deprotected version have also been utilised in routes
to antiviral carbocyclic nucleoside analogues13,14 and
the antitumour compound neoplanacin A.15
Our proposed route to the key intermediate, amino alco-
hol 1, is outlined below. Amino alcohol 1 would be
derived from amino cyclopentenol 2,16 itself obtained
by a Mitsunobu reaction on allylic alcohol 3 using an
appropriate nitrogen source. The chiral base-mediated
rearrangement of epoxide trans-4 would be used to
produce the required allylic alcohol 3. Although much
is known on the rearrangement of the corresponding
cis-cyclopentene oxides,17,18 we were surprised to find
that the best enantioselectivity for rearrangement of
epoxide trans-4 (P = TBS) was only 73% ee.18e,f This
observation encouraged us to implement this particular
chiral base strategy for the synthesis of amino alcohol 1.
H N
2
NH
OP
OH
OP
OP
O
OH
OH
N
O
O
N
N
O
H
HO
HO
O
Boc NH
Boc NH
OH
Nucleoside Q
HO
1
2
3
trans-4
Keywords: Chiral bases; Epoxides; Rearrangement; Amino cyclopentenes; Nucleoside Q.
*
Corresponding author. Tel.: +44 01904 432535; fax: +44 01904 432516; e-mail: paob1@york.ac.uk
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.043

9054
S. J. Oxenford et al. / Tetrahedron Letters 45 (2004) 9053–9055
Me
Ph
Li
N
OTBDPS
HSCH CO H, LiOH
N
OTBDPS
OTBDPS
O
OTBDPS
BocNHNs, DIAD, PPh
(1S,2R)-7
m-CPBA, rt, 16 h
cyclohexane
64%
Me
3
2
2
DMF, rt, 16 h
87%
→
rt, 4 h
THF, 0 ˚C
toluene, rt, 72 h
80%
Boc
N
then rt, 22 h
HO
Boc NH
Ns
trans-6
76%
8 88% ee
9
10
TBDPSO
Ns = o-NO C H SO –
2
6
3
2
Me
Ph
Li
N
5
OTBDPS
HSCH CO H, LiOH
N
OTBDPS
O
OTBDPS
OTBDPS
(1R,2S)-7
BocNHNs, DIAD, PPh
toluene, rt, 72 h
m-CPBA, rt, 16 h
CH Cl
Me
3
2
2
DMF, rt, 16 h
89%
THF, 0 ˚C →rt, 4 h
2
2
Boc
N
then rt, 22 h
40%
HO
11
Boc NH
76%
Ns
cis-6
54%
85% ee
12
13
Furthermore, we also developed syntheses of a range of
functionalised amino cyclopentenes that have been suc-
cessfully employed in a range of synthetic endeavours by
other groups (vide infra). Herein we describe our results.
sor from a benzoate ester of ent-10;16f Miller and co-
workers described the conversion of an acetate ester of
ent-10 into (+)-uracilpolyoxin C25 and Schaudt and
Blechert converted the N-allylated amino alcohol of 13
into (+)-astrophylline.16b Our route to these key inter-
mediates is notable since either enantiomer of 8–13
can be obtained simply by using the appropriate enantio-
mer of chiral base 7 and epoxide trans- or cis-6.
To start with, commercially available 3-cyclopenten-1-
ol19 was TBDPS-protected and epoxidised using
m-CPBA in cyclohexane to give a good (64%) isolated
yield of epoxide trans-6. The trans-selectivity was
much lower in dichloromethane but this produced the
highest isolated yield of the diastereomeric epoxide
cis-6 (40%).18f,20 Next, the key chiral base-mediated
rearrangements were investigated. After a screen of alco-
hol protecting group and chiral base structure, we found
that rearrangement of the TBDPS-protected epoxides
trans- and cis-6 using our21 norephedrine-derived chiral
bases (1S,2R)-7 and (1R,2S)-7 were optimal in terms of
yield and enantioselectivity. Reaction of epoxide trans-6
using (1S,2R)-7 gave allylic alcohol 8 {[a]D +56.7 (c 1.0,
CHCl3)} in 76% yield and 88% ee (by MosherÕs ester
formation). Significantly, this is a 15% ee improvement
on the highest previously reported enantioselectivity
for rearrangement of a protected trans-4-hydroxycyclo-
pentene oxide.18e,f Under similar conditions, epoxide
cis-6 was rearranged using (1R,2S)-7 to give allylic alco-
hol 11 {[a]D +22.0 (c 1.0, CHCl3)} in 54% yield and 85%
ee. Similarly high enantioselectivity for the rearrange-
ment of other protected cis-4-hydroxycyclopentene
oxides has been reported by other groups.18c–f
Further transformations into other useful compounds
were also explored. Thus, Overman rearrangement26 of
allylic alcohol 8 gave a 54% yield of allylic amide 14,
analogous to a compound used by Johnson and co-
workers in the synthesis of natural 3-hydroxyproline.27
Alternatively, deprotection of amino ether 10 using
TBAF gave amino alcohol 15 {[a]D ꢀ56.3 (c 1.0,
CHCl3), 88% ee} of known absolute stereochemistry
{[a]D ꢀ69.0 (c 1.0, CHCl3) for 15 of 98% ee28} thus con-
firming the stereochemical assignments in this series of
compounds. Dess–Martin periodinane oxidation of 15
then generated amino ketone 16 {[a]D ꢀ51.1 (c 1.0 in
CHCl3) (lit.,16a [a]D +69.6 (c 2.6 in CHCl3) for ent-16
of >99% ee)} which has recently been used by Lee
and Miller to prepare 4-acylamino analogues of
LY35474028 and by Roberts and co-workers for the
synthesis of some novel prostaglandin analogues.29
OTBDPS
1. Cl CCN, DBU
TBDPSO
3
H
CH Cl , rt, 16 h
2
2
N
CCl
3
Although allylic alcohol 8 was of more interest due to
our proposed nucleoside Q synthesis, we converted both
allylic alcohols 8 and 11 into their corresponding amino
ethers. For this, a Mitsunobu protocol using BocNHNs
(Ns = o-NO2C6H3SO2–), independently developed by
ourselves4,22 and Fukuyama and co-workers,23 was
2. K CO , xylene
2 3
150 ˚C, 16 h
O
HO
8 88% ee
14
54%
OTBDPS
OH
O
Dess-Martin
periodinane
TBAF, THF
used. Thus, reaction of allylic alcohol
8 with
rt, 16 h
64%
CH Cl , rt
30 min
BocNHNs/PPh3/DIAD gave amino ether 9 which was
smoothly deprotected using mercaptoacetic acid to give
partially deprotected amino ether 10, suitable for nucleo-
side Q synthesis. In the same way, allylic alcohol 11
gave amino ether 12 and thence NHBoc amino ether
13. Each of 8–13 are useful synthetic building blocks.
As examples, Ogasawara and co-workers used a differ-
ently protected version of ent-10 in a concise route to
(-)-kainic acid;24 Trost et al. prepared a carbovir precur-
2
2
Boc NH
Boc NH
Boc NH
80%
10
15
16
With a range of synthetically useful compounds pre-
pared, we then completed our planned synthesis of Mill-
erÕs nucleoside Q intermediate, amino alcohol 1. Thus,
amino ether 10 (easily prepared in five steps from com-
mercially available 3-cyclopenten-1-ol19) was subjected

S. J. Oxenford et al. / Tetrahedron Letters 45 (2004) 9053–9055
9055
´
9. Ovaa, H.; Codee, J. D. C.; Lasldrager, B.; Overkleeft, H.
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nide formation. In this way, acetonide 17 was obtained
as a single diastereomer in 84% yield over the two steps.
The steric bulk and the cis arrangement of the NHBoc
and silyl ether groups in 10 ensured a highly diastereo-
selective dihydroxylation process.30 Finally, TBAF
deprotection of the silyl ether in 17 produced amino
alcohol 1 of 88% ee, [a]D ꢀ18.6 (c 1.0 in CH2Cl2)
{lit.,12 [a]D ꢀ20.2 (c 0.95, CH2Cl2) for 1 of >98% ee},
identical in all respects to that previously described.12,14
10. Kim, K.-H.; Miller, M. J. Tetrahedron Lett. 2003, 44,
4571.
11. Trost, B. M.; Sorum, M. Org. Process Res. Dev. 2003, 7,
432.
12. Shireman, B. T.; Miller, M. J. Tetrahedron Lett. 2000, 41,
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´
15. Jung, M.; Offenbacher, G.; Retey, J. Helv. Chim. Acta
1983, 66, 1915.
OTBDPS
OTBDPS
3 steps
16. For other routes to cis-aminoalcohols 2 (P = H; other N-
protecting groups), see: (a) Davis, F. A.; Yongzhong, W.
Org. Lett. 2004, 6, 1269; (b) Schaudt, M.; Blechert, S. J.
Org. Chem. 2003, 68, 291; (c) Asami, M.; Ogawa, M.;
Inoue, S. Tetrahedron Lett. 1999, 40, 1563; (d) Ramesh, N.
G.; Klunder, A. J. H.; Zwanenburg, B. J. Org. Chem.
1999, 64, 3635; (e) Mulvihill, M. J.; Gage, J. L.; Miller, M.
J. J. Org. Chem. 1998, 63, 3357; (f) Trost, B. M.;
Stenkamp, D.; Pulley, S. R. Chem. Eur. J. 1995, 1, 568;
(g) see Ref. 1.
O
trans-6
Boc NH
10
1. OsO , NMO, rt, 16 h
acetone-water
4
84% 2. 4:1 acetone-
Me C(OMe)
2
2
p-TsOH, rt, 16 h
OH
OTBDPS
17. For reviews, see: (a) Eames, J. Eur. J. Org. Chem. 2002,
393; (b) OÕBrien, P. J. Chem. Soc., Perkin Trans. 1 1998,
1439.
TBAF, THF
O
O
rt, 16 h
72%
O
O
18. (a) Brookes, P. C.; Milne, D. J.; Murphy, P. J.; Spolaore,
B. Tetrahedron 2002, 58, 4675; (b) Saravanan, P.; Bisai,
A.; Baktharaman, S.; Chandrasekhar, M.; Singh, V. K.
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son, S. K.; Andersson, P. G. J. Am. Chem. Soc. 2000, 122,
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Org. Chem. 1996, 61, 6108; (e) Asami, M.; Inoue, S.
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19. 3-Cyclopenten-1-ol is commercially available from Asta-
tech Inc., Philadelphia, USA.
20. de Sousa, S. E.; Kee, A.; OÕBrien, P.; Watson, S. T.
Tetrahedron Lett. 1999, 40, 387.
BocHN
Boc NH
17
1
In summary, the chiral base-mediated rearrangement of
an epoxide (trans-6 ! 8) is the key step in a new route to
amino alcohol 1, an important intermediate in the
synthesis of the cyclopentene fragment of nucleoside
Q, carbocyclic nucleoside analogues and neoplanacin
A. A range of other stereodefined, functionalised
cyclopentenyl amine building blocks have also been
prepared.
21. (a) de Sousa, S. E.; OÕBrien, P.; Steffens, H. C. Tetrahedron
Lett. 1999, 40, 8423; (b) Colman, B.; de Sousa, S. E.;
OÕBrien, P.; Towers, T. D.; Watson, W. Tetrahedron:
Asymmetry 1999, 10, 4175.
Acknowledgements
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1301; (b) Kan, T.; Fukuyama, T. Chem. Commun. 2004,
353.
We thank the EPSRC and GlaxoSmithKline for a
CASE award (to S.J.O.).
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