Stereoselective oxygenation of bicyclic lactams

Article abstract of DOI:10.1016/j.tetasy.2004.03.008

Stereoselective syntheses of the epoxy and diol derivatives of a bicyclic lactam derived from pyroglutamic acid are reported, and their reactivity is discussed.

Full text of DOI:10.1016/j.tetasy.2004.03.008

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1239–1242
Stereoselective oxygenation of bicyclic lactams
Ian F. Cottrell,a Philip J. Davisb and Mark G. Moloneyb,*
aDepartment of Process Research, Merck Sharp and Dohme Research Laboratories, Hertford Rd, Hoddesdon, Herts EN11 9BU, UK
bThe Department of Chemistry, University of Oxford, Central Research Laboratory, Mansfield Rd, Oxford OX1 3TA, UK
Received 28 January 2004; revised 27 February 2004; accepted 2 March 2004
Abstract—Stereoselective syntheses of the epoxy and diol derivatives of a bicyclic lactam derived from pyroglutamic acid are
reported, and their reactivity is discussed.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Pyrrolidines are widely occurring structural sub-units in
natural products, and recently hydroxylated examples
have begun to emerge as an important structural sub-
type with diverse biological activity. Examples include
pramanicin, an antibiotic and antifungal agent,1 epo-
lactaene, a nerve growth factor,2 anisomycin, an anti-
protozoal and antifungal agent,3 plakoridine, a cytoxic
agent4 and polyhydroxylated pyrrolidine and pyrrolizi-
dine alkaloids such as the broussonetines5 and radic-
amines,6 which are highly effective competitive
glycosidase inhibitors. Aside from the obvious route for
the synthesis of these compounds from carbohydrate
precursors, one possibility is the introduction of oxygen
functionality onto a pre-existing lactam ring. Barratt
et al. in their synthesis of pramanicin achieved this indi-
rectly by introduction and subsequent interconversion
of silicon functionality.7 Meyers et al. have demon-
strated that direct epoxidation of chiral unsaturated
lactams of type 1 using NMO in excellent yield is pos-
sible provided that the alkene is also activated with an
ester function (Fig. 1).8 Although the epoxidation9;10 of
unactivated lactam 2a to give 3a has also been previ-
ously reported, carefully optimised reaction conditions
were required for successful conversion.11 Surprisingly,
no investigation of similar reactions of the activated
system 2b have been made, although conjugate addition
of carbon12;13 and nitrogen14;15 nucleophiles have been
described, and this communication reports our findings
in this regard.
Application of the Herdeis conditions (t-BuOOH/
nBu4NF/K2CO3/DMF)10 to the activated lactam 2b
gave only a 20% yield of the expected product 3b, and
examination of a large number of alternative conditions
to improve the yield (e.g., NMO,8 alkaline hydrogen
peroxide,16 hydrogen peroxide–Triton B,17 and hydro-
gen peroxide–t-BuLi18) were unsuccessful (Scheme 1).
Frustrated by this lack of success, a series of experi-
ments was conducted in which lactam 2b was treated
with hydrogen peroxide in dichloromethane, and buf-
fered at pH 3, 5, 7 and 9, with vigorous stirring for 24 h;
at pH 9 (sodium tetraborate–HCl), it was found that
yields of epoxide 3b of up to 70% were readily
obtained.19 At lower pH, the epoxidation reaction was
markedly slower and at pH 3 the sole product was dimer
4. These results were surprising, since we had found
earlier that enone 2b rapidly dimerised on storage20 or
under basic conditions14 to give dimer 4. The stereo-
structure of 3b was initially established by NOE analysis
(which exhibited clear enhancement in the series H-
2 fi H-4endo fi H-6, indicating their cis-, endo-relation-
ship, see Fig. 2) and later confirmed by X-ray analysis.21
This compound was readily deprotected to give pyro-
glutaminol 5 in quantitative yield.
MeO2C
R1
O
O
N
R2
1 R1= Ph, Me; R2=Ph, iPr
Figure 1.
Investigation of the ring opening chemistry of epoxide
3b indicated an unexpected lack of reactivity under
acidic,22–24 nucleophilic (PhSeNa, AcOH, EtOH)25 or
* Corresponding author. Fax: +44-01865-275-674; e-mail: mark.
moloney@chem.ox.ac.uk
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.03.008

1240
I. F. Cottrell et al. / Tetrahedron: Asymmetry 15 (2004) 1239–1242
Ph
O
R
O
R
EtO2C
N
6
H2O2, pH 9, DCM
O
O
O
N
N
4
O
2
O
O
N
CO2Et
Ph
Ph
3a R = H
3b R = CO2Et
O
2a R = H
Ph
4
2b R = CO2Et
For 2b: KMnO4 (1.2eq),
For 3b: NaN3, NH4Cl,
MeOH, H2O, 14%
TFA, THF,
H2O, 100%
18-crown-6 (0.04eq),
pH 9, DCM, 31%
X
OH
O
OH
N
OR
O
O
EtO2C
O
EtO2C
O
O
N
N
H
Ph
HO
Ph
6a X = N3
6b X = I
5
Ac2O, py,
7a R = H
DMAP, DCM,
RT, 90%
7b R = Ac
Scheme 1.
obtained after purification by column chromatogra-
phy.21 The diol 7a was successfully acetylated with acetic
anhydride to give the monoacetylated product 7b,29 as
evidenced by a significant downfield shift of C(6)H (to d
5.17 from d 4.34 in the starting material) but oxidation
of 7a to the corresponding ketone proved not to be
possible under several conditions (Swern, PCC and
RuCl3/NaIO4), perhaps due to steric hindrance at this
position.
OH
N
OH
O
N
N3
H
N
EtO2C
O
OH
H
H
EtO2C
O
H
H
H
H
H
H
H
O
H
H
H
O
H
O
O
H
6a
Ph
Ph
H
Ph
3b
7a
Figure 2.
9;10
or LiAlH426) conditions, but sodium
Thus, diastereocontrolled oxygenation of the ring of
bicyclic lactams derived from pyroglutamic acid has
proved to be possible, leading to highly functionalised
derivatives, although these products have displayed
unexpected reactivity.
reductive (SmI2
azide/methanol/water gave the trans-azido alcohol 6a in
low yield (14%), whose stereochemistry was confirmed
by NOE studies (Fig. 2); this material was the same as
that obtained from reaction of epoxide 3a under previ-
ously reported identical reaction conditions.10 Similar
lack of reactivity of epoxides of this type has been pre-
viously reported: the nucleophilic opening of the epox-
ide 3a is difficult, and apart from the azide opening
outlined above, could only be achieved with NaI/
NaOAc/HOAc to give iodide 6b.10 The formation of
epoxides in the reactions of related bicyclic piperidi-
nones has also been reported by Amat et al. who also
found that the epoxide exhibited low reactivity to
nucleophilic opening.27
Acknowledgements
We acknowledge the use of the EPSRC Chemical
Database Service at Daresbury30 and the EPSRC Na-
tional Mass Spectrometry Service Centre at Swansea.
We acknowledge the EPSRC and Merck Sharp &
Dohme for a CASE studentship for PJD.
Attention was then turned towards the synthesis of di-
hydroxylated lactam 7a. There is literature precedent for
the cis-dihydroxylation of lactam 2a using osmium
tetroxide under standard conditions.11 However, these
conditions failed with lactam 2b, and it was desirable to
identify suitable reagents that could be used with the
same conditions that had proved so successful for the
epoxidation reaction (DCM buffered at pH 9). One such
reagent is potassium permanganate,28 and application of
this reagent in conjunction with 18-crown-6 ether yield-
ed the required dihydroxylated product 7a in 30%
yield.29 The stereochemistry was initially established by
NOE analysis in dry d6-DMSO, which enabled resolu-
tion of the C(6) and C(7) hydroxyl groups (Fig. 2) and
confirmed by X-ray analysis of the white crystals
References and notes
1. Schwartz, R. E.; Helms, G. L.; Bolessa, E. A.; Wilson, K.
E.; Giacobbe, R. A.; Tkacz, J. S.; Bills, G. F.; Liesch, J.
M.; Zink, D. L.; Curotto, J. E.; Pramanik, B.; Onishi, J. C.
Tetrahedron 1994, 50, 1675–1686.
2. Kakeya, H.; Takahashi, I.; Okada, G.; Isono, K.; Osada,
H. J. Antibiot. 1995, 48, 733–735.
3. Chang, M. Y.; Chen, S. T.; Chang, N. C. Heterocycles
2003, 60, 1203–1209.
4. Takeuchi, S.; Ishibashi, M.; Kobayashi, J. J. Org. Chem.
1994, 59, 3712–3713.
5. Shibano, M.; Kitagawa, S.; Kusano, G. Chem. Pharm.
Bull. 1997, 45, 505–508.

I. F. Cottrell et al. / Tetrahedron: Asymmetry 15 (2004) 1239–1242
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6. Shibano, M.; Tsukamoto, D.; Masuda, A.; Tanaka, Y.;
Kusano, G. Chem. Pharm. Bull. 2001, 49, 1362–1365.
7. Barratt, A. G. M.; Head, J.; Smith, M. L.; Stock, N. S.;
White, A. J. P.; Williams, D. J. J. Org. Chem. 1999, 64,
6005–6018.
8. Andres, C. J.; Spetseris, N.; Norton, J. R.; Meyers, A. I.
Tetrahedron Lett. 1995, 36, 1613–1616.
9. Panday, S. K.; Langlois, N. Synth. Commun. 1997, 27,
1373–1384.
10. Herdeis, C.; Hubmann, H. P.; Lotter, H. Tetrahedron:
Asymmetry 1994, 5, 119–128.
11. Hamada, Y.; Hara, O.; Kawai, A.; Ohno, Y.; Shiori, T.
Tetrahedron 1991, 47, 8635–8652.
12. Bailey, J. H.; Cherry, D.; Dyer, J.; Moloney, M. G.;
Bamford, M. J.; Keeling, S.; Lamont, R. B. J. Chem. Soc.,
Perkin Trans. 1 2000, 2783–2792.
13. Dyer, J.; Keeling, S.; King, A.; Moloney, M. G. J. Chem.
Soc., Perkin Trans. 1 2000, 2793–2804.
14. Chan, P. W. H.; Cottrell, I. F.; Moloney, M. G. J. Chem
Soc, Perkin Trans. 1 2001, 2997–3006.
15. Chan, P. W. H.; Cottrell, I. F.; Moloney, M. G. J. Chem.
Soc., Perkin Trans. 1 2001, 3007–3012.
16. Piers, E.; Renaud, J. J. Chem. Soc., Chem. Commun. 1990,
1324.
17. Mori, K.; Tamura, H. Liebigs Ann. Chem. 1988, 97, 97.
18. Meth-Cohn, O.; Moore, C.; Taljaard, H. C. J. Chem Soc.,
Perkin Trans. 1 1988, 2663.
19. Procedure for (2R,5R,6R,7R)-6,7-epoxy-7-ethoxycar-
bonyl-8-oxo-2-phenyl-1-aza-3-oxabicyclo[3.3.0]octane 3b:
To a solution of enone 2b (1.90 g, 7.0 mmol) in DCM
(200 mL) were added pH 9 buffer solution (200 mL) and
hydrogen peroxide (4.00 g, 35 mmol, 35% aq), and the
biphasic mixture was stirred rapidly for 16 h. The organic
layer was separated, dried (MgSO4), filtered and concen-
trated in vacuo. The crude was purified by flash column
chromatography eluting with EtOAc–petrol (1:1) to yield
232469. 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
email: deposit@ccdc.cam.ac.uk].
Crystal data and data collection parameters for compound
7a: C15H17NO6, T ¼ 150 K, M ¼ 307:30, orthorhombic,
ꢀ
a ¼ 5:8907ð2Þ, b ¼ 10:4767ð4Þ, c ¼ 23:5621ð8Þ A, V ¼
3
ꢀ
1454:1 A . Space group
P
21 21 21, Z ¼ 4, Dx ¼
1:404 mg mꢁ3, l ¼ 0:109 mmꢁ1. The compound was crys-
tallised from EtOH. Crystallographic data (excluding
structure factors) for this structure have been deposited
with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC232468. 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 email: deposit@ccdc.cam.
ac.uk].
22. Griffart-Brunet, D.; Langlois, N. Tetrahedron Lett. 1994,
35, 2889–2890.
23. Burley, I.; Hewson, A. T. Tetrahedron Lett. 1994, 35, 7099.
24. Severino, E. A.; Correia, C. R. D. Org. Lett. 2000, 2, 3039.
25. Miyashita, M.; Suzuki, T.; Yoshikoshi, A. Tetrahedron
Lett. 1987, 28, 4293.
26. Griffart-Brunet, D.; Langlois, N. Tetrahedron Lett. 1994,
35, 119–122.
27. Amat, M.; Llor, N.; Hidalgo, J.; Hernandez, A.; Bosch, J.;
Molins, E.; Miravitlles, C. Tetrahedron: Asymmetry 1996,
7, 2501–2504.
28. Casighari, G.; Rassu, G. Synthesis 1995, 607–626.
29. Procedure for (2R,5R,6R,7R)-7-ethoxycarbonyl-8-oxo-2-
phenyl-6,7-dihydroxy-1-aza-3-oxabicyclo[3.3.0]octane 7a:
To enone 2b (245 mg, 0.90 mmol) in DCM (20 mL) was
added pH 9 buffer solution (20 mL), potassium perman-
ganate (221 mg, 1.08 mmol) and 18-crown-6 ether (12 mg,
0.04 mmol), and the biphasic mixture was stirred rapidly at
room temperature for 3 h. Sodium sulfite solution was
added (satd aq 5.0 mL), and the mixture was neutralised
with citric acid solution (5% aq). The dark brown mixture
was then allowed to stand, with occasional stirring, until
all the precipitate had dissolved, leaving a colourless
mixture (1–3 days). The whole mixture was extracted with
DCM (3 · 30 mL) and EtOAc (3 · 30 mL), the organics
were combined, dried (MgSO4) and concentrated in
vacuo. The crude product was purified by flash column
chromatography eluting with EtOAc–Petrol (1:1) to yield
the title compound as white crystals (1.39 g, 69%).
22
D
Rf ¼ 0:34 (petrol–EtOAc (1:1)); ½aꢀ ¼ þ20:9 (c ¼ 1:0 in
CHCl3); mp 138–140 ꢁC;
m
max/cmꢁ1 (film) 1751 (br,
2 · C@O); dH (400 MHz, DMSO-d6) 1.25 (3H, t, J 7.1,
CH3CH2), 3.57 (1H, dd, J 8.5, 1.0, C(4)Hendo), 4.19–4.25
(1H, m, C(4)Hexo), 4.25–4.29 (2H, m, CH3 CH2), 4.30–4.35
(1H, m, C(5)H), 4.83 (1H, s, C(6)H), 6.14 (1H, s, C(2)H),
7.33–7.44 (5H, m, ArH); dC (100.6 MHz, DMSO-d6) 14.76
(OCH2CH3), 58.78 (C(7)), 59.44 (C(5)), 62.87
(OCH2CH3), 63.91 (C(6)), 66.61 (C(4)), 88.71 (C(2)),
126.83, 129.35, 129.64, 139.26 (ArC), 163.51, 171.26
(C@O); m/z (APCIþ) 290 ([M+H]þ, 100%); HRMS
(ESþ) 290.1023, C15H16NO5 requires 290.1028.
the title compound as white crystals (110 mg, 31%).
22
Rf ¼ 0:19 (EtOAc–Petrol (1:1); ½aꢀ ¼ þ127 (c ¼ 1:0 in
D
CHCl3); mp 109–113 ꢁC; mmax/cmꢁ1 (film) 3400 (br w, OH),
1750 (br s, 2 · C@O); dH (500 MHz, DMSO-d6) 1.21 (3H,
t, J 4.0, OCH3CH2), 3.84–3.88 (1H, m, C(4)Hendo), 4.03–
4.07 (1H, m, C(5)H), 4.18–4.22 (1H, m, OCH3CH2), 4.23–
4.29 (1H, C(4)Hexo), 4.32–4.36 (1H, m, C(6)H), 5.92 (1H,
d, J 6.4, C(6)OH), 6.17 (1H, s, C(2)H), 6.65 (1H, s,
C(7)OH), 7.36–7.45 (5H, m, ArH); dC (125.7 MHz,
DMSO-d6) 15.0 (OCH3CH2), 62.1 (OCH3CH2), 63.6
(C(5)), 70.2 (C(4)), 77.3 (C(6)), 84.9 (C(2)), 86.9 (C(7)),
127.1, 129.3, 129.7, 130.1 (ArC), 171.1, 172.7 (C@O); m/z
(APCIþ) 308 ([M+H]þ, 100%); HRMS (EIþ) 308.1136,
C15H18NO6 ([M+H]þ) requires 308.1134. Procedure for
(2R,5R,6R,7R)-6-acetoxy-7-ethoxycarbonyl-8-oxo-2-phen-
yl-7-hydroxy-1-aza-3-oxa-bicyclo[3.3.0] octane 7b: Diol
7a (30 mg, 0.098 mmol) was stirred overnight with DCM
(10 mL), acetic anhydride (9.2 lL, 0.098 mmol), pyridine
(15.8 lL, 0.196 mmol) and DMAP (11.9 mg, 0.98 mmol).
The reaction mixture was washed with pH 5 buffer
solution, dried over MgSO4 and concentrated in vacuo.
The crude product was purified by flash column chroma-
tography eluting with EtOAc–petrol (1:1) to yield the title
compound as a colourless oil. Rf ¼ 0:25 (petrol–EtOAc
20. Bailey, J. H.; Cherry, D. T.; Crapnell, K. M.; Moloney, M.
G.; Shim, S. B.; Bamford, M.; Lamont, R. B. Tetrahedron
1997, 53, 11731–11744.
21. Diffraction data were measured using an Enraf-Nonius
KappaCCD diffractometer (graphite-monochromated
ꢀ
Mo Ka radiation, k ¼ 0:71073 A). Intensity data were
processed using the DENZO-SMN package.31 The struc-
ture was solved using the direct-methods program
SIR92,32 which located all nonhydrogen atoms. Subse-
quent full-matrix least-squares refinement was carried out
using the CRYSTALS program suite.33
Crystal data and data collection parameters for compound
3b: C15H15NO5, T ¼ 298 K, M ¼ 289:29, orthorhombic,
ꢀ
a ¼ 6:3547ð1Þ, b ¼ 7:7537ð2Þ, c ¼ 28:1695ð6Þ A, V ¼
3
ꢀ
1388:0 A . Space group
P
21 21 21, Z ¼ 4, Dx ¼
1:384 mg mꢁ3, l ¼ 0:105 mmꢁ1. The compound was crys-
tallised from EtOAc–petrol. Crystallographic data
(excluding structure factors) for this structure have been
deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC-

1242
I. F. Cottrell et al. / Tetrahedron: Asymmetry 15 (2004) 1239–1242
22
D
(1:1)); ½aꢀ ¼ þ2:9 (c ¼ 0:025 in CHCl3); mmax/cmꢁ1 (film)
30. Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J. Chem.
Inf. Comput. Sci. 1996, 36, 746–749.
31. Otwinowski, Z.; Minor, W. Processing of X-ray diffraction
data collected in oscillation mode. In Methods Enzy-
mol; Carter, C. W., Sweet, R. M., Eds.; Academic:
New York, 1997.
32. Altomare, A.; Cascarano, G.; Giacovazzo, G.; Guagliardi,
A.; Burla, M. C.; Polidori, G.; Camalli, M. J. Appl. Cryst.
1994, 27, 435.
33. Watkin, D. J.; Prout, C. K.; Carruthers, J. R.; Betteridge,
P. W.; Cooper, R. I. CRYSTALS issue 11; Chemical
Crystallography Laboratory, Oxford, UK, 2001.
3400 (br s, OH), 1610 (br s, 2 · C@O); dH (400 MHz,
DMSO-d6) 1.23 (3H, t, J 7.0, OCH2 CH3), 2.06 (3H, s,
COCH3), 4.82–4.91 (1H, m, C(4)Hendo), 4.17–4.22 (2H, m,
OCH2 CH3), 4.30–4.35 (2H, m, C(5)H, C(4)Hexo), 5.17
(1H, d, J 5.5, C(6)H), 6.16 (1H, s, C(2)H), 7.07 (1H, s,
OH), 7.34–7.42 (5H, m, ArH); dC (100.6 MHz, DMSO-d6)
14.76 (OCH2CH3), 21.22 (COCH3), 61.64 (C(5)), 62.29
(OCH2CH3), 70.63 (C(4)), 76.38 (C(6)), 83.59 (C(7)), 87.24
(C(2)), 127.22, 129.40, 138.63 (ArC), 169.80, 170.72,
170.90 (C@O); m/z (APCIþ) 350 ([M+H]þ, 35%); HRMS
(EIþ) 350.1240, C17H20NO7 ([M+H]þ) requires 350.1240.