A novel biomimetic route to the 3-acyl-5-hydroxy-3-pyrrolin-2-one and 3-acyl-3,4-epoxy-5-hydroxypyrrolidin-2-one ring systems

Article abstract of DOI:10.1021/jo048605r

Modified Moffat oxidation of alcohols 17, 22, and 25 afforded aldehydes that underwent intramolecular aldol reactions on treatment with a NaOH solution to yield 4-pyrrolin-2-ones 16, 23, and 26. Oxidation with DMDO at -40 °C provided 3-acyl-5-hydroxy-3-py

Full text of DOI:10.1021/jo048605r

CHART 1
A Novel Biomimetic Route to the
3-Acyl-5-hydroxy-3-pyrrolin-2-one and
3-Acyl-3,4-epoxy-5-hydroxypyrrolidin-2-one
Ring Systems
Barry B. Snider* and Bobbianna J. Neubert
Department of Chemistry MS 015, Brandeis University,
Waltham, Massachusetts, 02454-9110
snider@brandeis.edu
Received August 10, 2004
Abstract: Modified Moffat oxidation of alcohols 17, 22, and
25 afforded aldehydes that underwent intramolecular aldol
reactions on treatment with a NaOH solution to yield
4-pyrrolin-2-ones 16, 23, and 26. Oxidation with DMDO at
-40 °C provided 3-acyl-5-hydroxy-3-pyrrolin-2-ones 18, 24,
and 27 with the ring system of oteromycin (3), UCS1025A
(5), and related natural products. Further oxidation of 18
yielded 3-acyl-3,4-epoxy-5-hydroxy-pyrrolidin-2-one 19 with
the ring system of fusarin C (1) and epolactaene (2).
Dehydration of 18 afforded 20 with the talaroconvolutin A
(4) ring system.
(2),14 NG-391,15 azaspirene (6),16 PI-091,17 pramanicin,18
and the pyrrolidinone moieties of fusarin C (1)19 and
L-755,80720 have been reported. Kobayashi reported that
both enantiomers of epolactaene (2) and an analogue with
a simple dodecanoyl side chain, lacking the two methyl
groups, ester, and four double bonds of 2, had comparable
activity to 2 in inhibiting mammalian DNA polymerase
R and â, and human DNA topoisomerase II and in
inducing apoptosis in BALL-1 cells. This suggests that
the pyrrolidinone moiety is largely responsible for the
biological activity of these compounds.14g,21 The pyrroli-
dinone moiety is usually constructed by an intramolecu-
lar aldol reaction of a dicarbonyl compound with a
protected R-hydroxyaldehyde followed by ring closure of
a keto amide to form the 5-hydroxy-3-pyrrol-2-one or 3,4-
Over the past twenty years, a wide variety of biologi-
cally active natural products have been isolated that
contain either the 3-acyl-5-hydroxy-3-pyrrolin-2-one or
the 3-acyl-3,4-epoxy-5-hydroxypyrrolidin-2-one moiety.
These include fusarin C (1) and congeners,1 epolactaene
(2),2 oteromycin (3),3 talaroconvolutin A (4), ZG-1494R,
and congeners,4 UCS1025A (5),5 azaspirene (6) and CJ-
16,367,6 NG-391,7 lucilacataene,8 L-755,807,9 pramani-
cin,10 pyrrocidine A,11 and PI-09012 and acosalipyrrolid-
inone A (see Chart 1).13 Total syntheses of epolactaene
(1) (a) Gelderblom, W. C. A.; Marasas, W. F. O.; Steyn, P. S.; Thiel,
P. G.; van der Merwe, K. J.; van Rooyen, P. H.; Vleggaar, R.; Wessels,
P. L. J. Chem. Soc., Chem. Commun. 1984, 122-124. (b) Gaddamidi,
V.; Bjeldanes, L. F.; Shoolery, J. N. J. Agric. Food Chem. 1985, 33,
652-654. (c) Steyn, P. S.; Vleggaar, R. J. Chem. Soc., Chem. Commun.
1985, 1189-1191.
(2) Kakeya, H.; Takahashi, I.; Okada, G.; Isono, K.; Osada, H. J.
Antibiot. 1995, 48, 733-735.
(3) Singh, S. B.; Goetz, M. A.; Jones, E. T.; Bills, G. F.; Giacobbe, R.
A.; Herranz, L.; Stevens-Miles, S.; Williams, D. L., Jr. J. Org. Chem.
1995, 60, 7040-7042.
(4) (a) Suzuki, S.; Hosoe, T.; Nozawa, K.; Kawai, K.-i.; Yaguchi, T.;
Udagawa, S.-i. J. Nat. Prod. 2000, 63, 768-772. (b) West, R. R.; Van
Ness, J.; Varming, A.-M.; Rassing, B.; Biggs, S.; Gasper, S.; McKernan,
P. A.; Piggott, J. J. Antibiot. 1996, 49, 967-973.
(5) Agatsuma, T.; Akama, T.; Nara, S.; Matsumiya, S.; Nakai, R.;
Ogawa, H.; Otaki, S.; Ikeda, S.-i.; Saitoh, Y.; Kanda, Y. Org. Lett. 2002,
4, 4387-4390.
(6) (a) Asami, Y.; Kakeya, H.; Onose, R.; Yoshida, A.; Matsuzaki,
H.; Osada, H. Org. Lett. 2002, 4, 2845-2848. (b) Sugie, Y.; Hirai, H.;
Kachi-Tonai, H.; Kim, Y.-J.; Kojima, Y.; Shiomi, Y.; Sugiura, A.;
Sugiura, A.; Suzuki, Y.; Yoshikawa, N.; Brennan, L.; Duignan, J.;
Huang, L. H.; Sutcliffe, J.; Kojima, N. J. Antibiot. 2001, 54, 917-925.
(7) Sugawara, T.; Shinonaga, H.; Simura, H.; Yoshikawa, R.; Yama-
moto, K. Japanese Kokai Tokkyo Koho JP 08 319,289, 1996; Chem.
Abstr. 1997, 126, 103149e.
(12) Kawashima, A.; Yoshimura, Y.; Sakai, N.; Kamirgoori, K.;
Mizutani, T.; Omura, S. Japanese Kokai Tokkyo Koho JP 02 62,859,
1990; Chem. Abstr. 1990, 113, 113856d.
(13) Osterhage, C.; Kaminksy, R.; Ko¨nig, G. M.; Wright, A. D. J.
Org. Chem. 2000, 65, 6412-6417.
(14) (a) Hayashi, Y.; Narasaka, K. Chem. Lett. 1998, 313-314. (b)
Marumoto, S.; Kogen, H.; Naruto, S. J. Org. Chem. 1998, 63, 2068-
2069. (c) Marumoto, S.; Kogen, H.; Naruto, S. Tetrahedron 1999, 55,
7129-7144. (d) Marumoto, S.; Kogen, H.; Naruto, S. Tetrahedron 1999,
55, 7145-7156. (e) Kuramochi, K.; Nagata, S.; Itaya, H.; Takao, K.-i.;
Kobayashi, S. Tetrahedron Lett. 1999, 40, 7371-7374. (f) Hayashi, Y.;
Kanayama, J.; Yamaguchi, J.; Shoji, M. J. Org. Chem. 2002, 67, 9443-
9448. (g) Kuramochi, H.; Nagata, S.; Itaya, H.; Matsubara, Y.; Sunoki,
T.; Uchiro, H.; Takao, K.-i.; Kobayashi, S. Tetrahedron 2003, 59, 9743-
9758. (h) Aoki, S.-y.; Oi, T.; Shimizu, K.; Shiraki, R.; Takao, K.-i.;
Tadano, K.-i. Heterocycles 2004, 62, 161-166.
(15) Hayashi, Y.; Yamaguchi, J.; Shoji, M. Tetrahedron 2002, 58,
9839-9846.
(16) Hayashi, Y.; Shoji, M.; Yamaguchi, J.; Sato, K.; Yamaguchi, S.;
Mukaiyama, T.; Sakai, K.; Asami, Y.; Kakeya, H.; Osada, H. J. Am.
Chem. Soc. 2002, 124, 12078-12079.
(8) Kakeya, H.; Kageyama, S.-i.; Nie, L.; Onose, R.; Okada, G.;
Beppu, T.; Norbury, C. J.; Osada, H. J. Antibiot. 2001, 54, 850-854.
(9) Lam, T. Y. K.; Hensens, O. D.; Ransom, R.; Giacobbe, R. A.;
Polishook, J.; Zink, D. Tetrahedron 1996, 52, 1481-1486.
(10) 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.
(17) Shiraki, R.; Sumino, A.; Tadano, K.-i.; Ogawa, S. J. Org. Chem.
1996, 61, 2845-2852.
(18) Barrett, 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.
(19) Williams, R. M.; Esslinger, C. S. Tetrahedron Lett. 1991, 32,
3635-3638.
(11) He, H.; Yang, H. Y.; Bigelis, R.; Solum, E. H.; Greenstein, M.;
Carter, G. T. Tetrahedron Lett. 2002, 43, 1633-1636.
(20) Marumoto, S.; Kogen, H.; Naruto, S. Tetrahedron: Asymmetry
1999, 10, 675-678.
10.1021/jo048605r CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/06/2004
8952
J. Org. Chem. 2004, 69, 8952-8955

epoxy-5-hydroxypyrroldin-2-one.14a-d,f,15,20 Oxidations of
furans to give pyrrolidinones have also been used.17,19
Kobayashi has developed a general procedure using the
aldol reaction of a lactone-derived oxiranyl anion to
construct the skeleton.14e,g
We envisaged that the functionalized pyrrolidinone
ring system could be easily constructed by a biomimetic
route that has not been previously reported.22 3,4-
Epoxypyrrolidin-2-one (7) should be accessible by oxida-
tion of 3-pyrrolin-2-one 8, which should be formed
spontaneously from epoxide 9, which in turn should be
accessible by oxidation of enamide 10. An intramolecular
aldol reaction of aldehyde 12 should give adduct 11,
which will tautomerize to the more stable enamide 10
(see Scheme 1).
Reaction of phenylalaninol with diketene and Et3N in
CH2Cl2 for 16 h at 25 °C afforded 72% of acetoacetamide
17 (see Scheme 3). Attempts to improve the yield by using
more diketene led to mixtures of 17 and the bis ester
amide that could be hydrolyzed with K2CO3 in MeOH to
give comparable yields of 17. Modified Moffat oxidation24
of 17 with EDC and Cl2CHCO2H in 1:1 DMSO/toluene
provided aldehyde 14 that was taken up in EtOAc and
shaken for 5 min with 1 M aqueous NaOH to give 61%
of 16 after recrystallization. We were delighted to find
that oxidation of 16 with dimethyldioxirane (DMDO)25
in acetone/CH2Cl2 at -40 °C for 2 h gave the desired
3-pyrrolin-2-one 18 in quantitative yield. Further oxida-
tion of 18 with H2O2 and NaOH in MeOH for 2 h at 25
°C afforded a 64% yield of a 1:3 mixture of fusarin C (1)
and epolactaene (2) models 19a and 19b, whose stereo-
chemistry was established by NOE experiments. Alter-
natively, oxidation of 18 with DMDO generated in situ
with Oxone, Na2EDTA, and NaHCO3 in acetone at 0 °C26
for 12 h provided a mixture of 19a and 19b. The
conversion of 16 to 19 could be accomplished in a single
step by oxidation with DMDO generated in situ as
described above to give exclusively 19a, which isomerized
to give a 3:1 mixture of 19a and 19b in 58% yield during
flash chromatography on silica gel. Attempted asym-
metric oxidation of 16 with Shi’s fructose-derived ketone27
afforded a 3:1 mixture of 19a and 19b in 40% yield with
[R]D -2.6, suggesting that the epoxidation occurred with
only modest enantioselectivity. Finally, treatment of 18
with TFA in CH2Cl2 for 12 h gave diene 20 with the
talaroconvolutin A (4)4a ring system in quantitative yield.
SCHEME 1. Retrosynthesis of
Epoxypyrrolidinones and Pyrrolinones
As part of their model studies for the synthesis of
cytochalasins, Schmidlin and Tamm prepared 16 in 66%
yield by hydrolysis of acetal 13 with HCl in aqueous THF,
followed by treatment of freshly prepared aldehyde 14
in a CH2Cl2/ether mixture with 2 M aqueous NaOH to
give 15, which tautomerized to 16 (see Scheme 2).23 We
SCHEME 3. Synthesis of 18, 19, and 20
SCHEME 2. Schmidlin and Tamm’s Synthesis of
16
chose to explore a variation of this route in which the
aldehyde was constructed by oxidation of an alcohol
rather than by hydrolysis of the somewhat inaccessible
acetal.
3-Oxoamide 22 with a more complex side chain was
prepared in 62% yield by heating 21,28 which was
prepared from Meldrum’s acid and cyclohexanecarbonyl
(21) (a) Mizushina, Y.; Kobayashi, S.; Kuramochi, K.; Nagata, S.;
Sugawara, F.; Sakaguchi, K. Biochem. Biophys. Res. Commun. 2000,
273, 784-788. (b) Nakai, J.; Kawada, K.; Nagata, S.; Kuramochi, K.;
Uchiro, H.; Kobayashi, S.; Ikekita, M. Biochim. Biophys. Acta 2002,
1581, 1-10. (c) Kuramochi, K.; Mizushina, Y.; Nagata, S.; Sugawara,
F.; Sakaguchi, K.; Kobayashi, S. Bioorg. Med. Chem. 2004, 12, 1983-
1989. (d) Nagumo, Y.; Kakeya, H.; Yamaguchi, J.; Uno, T.; Shoji, M.;
Hayashi, Y.; Osada, H. Bioorg. Med. Chem. Lett. 2004, 14, 4425-4429.
(22) An intact serine is incorporated into an acyltetramic acid in
the biosynthesis of pramanicin: Harrison, P. H. M.; Duspara, P. A.;
Jenkins, S. I.; Kassam, S. A.; Liscombe, D. K.; Hughes, D. W. J. Chem.
Soc., Perkin Trans 1 2000, 4390-4402.
(24) Akahoshi, F.; Ashimori, A.; Sakashita, H.; Yoshimura, R.;
Imada, T.; Nakajima, M.; Mitsutomi, N.; Kuwahara, S.; Ohtsuka, T.;
Fukaya, C.; Miyazaki, M.; Nakamura, N. J. Med. Chem. 2001, 44,
1286-1296.
(25) Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Ber. 1991, 124,
2377.
(26) Frohn, M.; Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 6425-
6426.
(27) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am.
Chem. Soc. 1997, 119, 11224-11235.
(23) Schmidlin, T.; Tamm, C. Helv. Chim. Acta 1980, 63, 121-127.
J. Org. Chem, Vol. 69, No. 25, 2004 8953

chloride, with phenylalaninol in toluene at 65 °C for 18
h (see Scheme 4).29 The modified Moffat oxidation and
aldol reaction afforded crude 23, which was treated with
DMDO25 at -40 °C to provide oteromycin (3) model 24
in 35% overall yield from 22. The lower yields in this
sequence result in part from purification difficulties. Both
16 and 23 are not very stable to chromatography, but 16
can easily be purified by recrystallization while the oily
23 was carried on without purification.
24, and 27 and further oxidation of 18 yielded 3-acyl-
3,4-epoxy-5-hydroxypyrrolidin-2-one 19. Dehydration of
18 afforded 20 with the talaroconvolutin A (4) ring
system.
Experimental Section
General. NMR spectra were recorded at 400 MHz in CDCl3.
Chemical shifts are reported in δ and coupling constants in Hz.
IR spectra are reported in cm-1
.
N-(1-Hydroxymethyl-2-phenylethyl)-3-oxobutyramide
(17). To a stirred solution of (R)-(+)-2-amino-3-phenyl-1-propanol
(0.51 g, 3.4 mmol) and Et3N (0.61 mL, 4.4 mmol) in CH2Cl2 (7.6
mL) at 0 °C was added a solution of diketene (0.24 mL, 3.1 mmol)
in CH2Cl2 (3.1 mL). The reaction was stirred at 25 °C for 16 h
and a solution of 5% aqueous HCl (10 mL) was added. The
aqueous layer was extracted with CH2Cl2 (5 × 15 mL). The
combined organic layers were washed with brine (50 mL), dried
over MgSO4, and concentrated to give a red oil. Flash chroma-
tography on silica gel (24:1 CH2Cl2/MeOH) gave 520 mg (72%)
of 17 as a white solid: mp 74-76 °C; 1H NMR 7.33-7.22 (m, 5),
7.12-7.10 (br, 1, NH), 4.24-4.20 (m, 1), 3.74-3.70 (m, 1), 3.60
(ddd, 1, J ) 11.0, 5.5, 5.5), 3.41 (d, 1, J ) 17.1), 3.36 (d, 1, J )
17.1), 2.92 (dd, 1, J ) 14.0, 7.3), 2.85 (dd, 1, J ) 14.0, 7.3), 2.55
(t, 1, J ) 5.5, OH), 2.22 (s, 3); 13C NMR 204.5, 166.1, 137.5, 129.2
(2 C), 128.5 (2 C), 126.6, 64.0, 53.1, 49.8, 37.0, 30.8; IR (KBr)
3500-3100, 1717, 1646; HRMS (DCI/NH3) calcd for C13H18NO3
(MH+) 236.1287, found 236.1280.
SCHEME 4. Synthesis of Oteromycin Model 24
Attempts to improve the yield by using more diketene led to
mixtures ranging from 100:0 to 50:50 of 17 and the bis ester
amide, which could be separated by flash chromatography on
silica gel (99:1 to 24:1 CH2Cl2/MeOH). Selective hydrolysis of
the bis ester amide was achieved with K2CO3 (6 equiv) in MeOH
(0.1 M) for 12 h followed by treatment with 1 M HCl until the
pH was neutral. The aqueous layer was extracted with EtOAc,
washed with brine, dried over Na2SO4, and concentrated to give
17. Flash chromatography on silica gel (24:1 CH2Cl2/MeOH) gave
17 as a white solid in 95-99% yield from the bis ester amide.
The overall yield of 17 ranged from 65% to 72%.
Finally, we prepared UCS1025A (5) model 27 from 21
and prolinol. Heating in toluene with DMAP afforded 25
in 98% yield (see Scheme 5). Modified Moffat oxidation
and aldol condensation gave crude 26, which was treated
with DMDO25 at -40 °C to provide 27 in 11% yield from
25. The spectral data for 27 correspond well with those
for the open form of UCS1025A (5).5
(Z)-1,3-Dihydro-3-(1-hydroxyethylidene)-5-phenylmeth-
yl-2H-pyrrol-2-one (16). EDC (0.49 g, 2.55 mmol) and dichlo-
roacetic acid (84 µL, 1.0 mmol) were added to a solution of 17
(0.12 g, 0.51 mmol) in toluene (3 mL) and DMSO (3 mL). The
reaction was stirred at 25 °C for 16 h and 2 M aqueous HCl (6
mL) was added. The acidic aqueous layer was extracted with
EtOAc (3 × 10 mL) to give a solution of the aldehyde.
SCHEME 5. Synthesis of UCS1025A Model 27
The EtOAc solution of the crude aldehyde was shaken with 1
M NaOH (40 mL) for 5 min. The basic aqueous layer was
extracted with Et2O (4 × 40 mL) and the combined organic layers
were washed with brine (100 mL), dried over MgSO4, and
concentrated to give a yellow-green solid. Recrystallization from
Et2O, CH2Cl2, and pentane (1:1:0.2) yielded 67 mg (61%) of 16
as white needles: mp 139-141 °C (lit. mp 139-141 °C);23 1H
NMR 8.53 (br, 1, NH), 7.33-7.21 (m, 5), 5.49 (s, 1), 3.69 (s, 2),
2.14 (s, 3); 13C NMR 171.9, 171.0, 137.0, 132.4, 128.8 (2 C), 128.7
(2 C), 126.9, 107.1, 98.4, 34.7, 19.2; IR (KBr) 3200-3100, 1672,
1629. The data are identical with those reported by Tamm and
Schmidlin.23
1,5-Dihydro-5-hydroxy-3-(1-oxoethyl)-5-phenylmethyl-
2H-pyrrol-2-one (18). DMDO (7.5 mL, 0.46 mmol, 0.07 M
solution in acetone)25 was added to a solution of 16 (100 mg,
0.46 mmol) in CH2Cl2 (5 mL) at -40 °C. The solution was stirred
for 2 h and then concentrated to yield 0.107 g (100%) of 18 as a
yellow oil: 1H NMR 7.54 (d, 1, J ) 2.4), 7.36-7.25 (m, 5), 6.21
(br, 1, NH), 3.20 (d, 1, J ) 13.4), 3.04 (d, 1, J ) 13.4), 2.49 (s, 3);
13C NMR 194.2, 168.1, 155.3, 134.9, 134.0, 130.4 (2 C), 128.5 (2
C), 127.5, 86.5, 43.8, 29.2; IR (neat) 3400-3200, 1716, 1614;
HRMS (CI/NH3) calcd for C13H17N2O3 (MNH4+) 249.1239, found
249.1243.
4-Hydroxy-1-(1-oxoethyl)-4-phenylmethyl-6-oxa-3-
azabicyclo[3.1.0]hexan-2-one (19a and 19b). A 30% solution
of H2O2 (81 µL, 0.71 mmol) was added to a solution of 18 (54.8
mg, 0.24 mmol) in MeOH (2.4 mL) in a 15-20 °C water bath.
NaOH (6 M, 20 µL, 0.12 mmol) was added over 1 h keeping the
In conclusion, we have developed a short and efficient
route to 3-acyl-5-hydroxy-3-pyrrolin-2-ones 18, 24, and
27 with the ring system of oteromycin (3), UCS1025A
(5), and related natural products and 3-acyl-3,4-epoxy-
5-hydroxypyrrolidin-2-one 19 with the ring system of
fusarin C (1) and epolactaene (2). Modified Moffat oxida-
tion of alcohols 17, 22, and 25 afforded aldehydes that
underwent intramolecular aldol reactions on treatment
with a NaOH solution to give 4-pyrrolin-2-ones 16, 23,
and 26. Oxidation with DMDO at -40 °C provided 18,
(28) Sørensen, U. S.; Falch, E.; Krogsgaard-Larsen P. J. Org. Chem.
2000, 65, 1003-1007.
(29) Pak, C. S.; Yang, H. C.; Choi, E. B. Synthesis 1992, 1213-1214.
8954 J. Org. Chem., Vol. 69, No. 25, 2004

water bath between 20 and 25 °C. The reaction was stirred for
2 h and poured into H2O (5 mL). The aqueous layer was
extracted with Et2O (4 × 5 mL), and the combined organic layers
were washed with H2O (15 mL), dried over MgSO4, and
concentrated to give 51 mg (87%) of a 1:3 mixture of crude 19a
and 19b as a yellow oil. Flash chromatography on silica gel (19:1
CH2Cl2/MeOH) yielded 38 mg (64%) of a 1:3 mixture of 19a and
19b as a clear oil.
with 2 M NaOH (5 mL) for 5 min. Ice was added and the aqueous
layer neutralized with 2 M HCl. The organic layer was removed
and the neutral aqueous layer was extracted with CH2Cl2 (3 ×
5 mL). The combined organic layers were washed with 2.5 M
NaCl solution (5 × 5 mL), dried over MgSO4, and concentrated
to give 32 mg (84%) of 80-90% pure 23 as a bluish oil: 1H NMR
7.52-7.21 (m, 5), 5.59 (s, 1), 3.48 (br, 2), 2.50-2.40 (m, 1), 1.85-
1.55 (m, 8), 1.35-1.29 (m, 2).
3-Cyclohexanecarbonyl-1,5-dihydro-5-hydroxy-4-phen-
ylmethyl-2H-pyrrol-2-one (24). A crude solution of 23 (32 mg,
0.11 mmol) in CH2Cl2 (0.35 mL) was cooled to -40 °C and a
solution of DMDO (2.4 mL, 0.07 M in acetone) was quickly
added. The bright yellow solution was stirred for 3 h. The
solution was then concentrated to a yellow oil. Flash chroma-
tography on silica gel deactivated with 5% H2O (13:7 CH2Cl2/
EtOAc) yielded 13 mg (35% from 24) of 22 as a yellow oil: 1H
NMR 7.38 (s, 1), 7.31-7.21 (m, 5), 6.82 (s, 1, NH), 3.83 (s, 1,
OH), 3.20 (d, 1, J ) 13.4), 3.11 (d, 1, J ) 13.4), 3.07-2.95 (m,
1), 1.71-1.54 (m, 4), 1.30-1.04 (m, 6); 13C NMR 200.3, 167.9,
154.3, 135.5, 134.0, 130.4 (2 C), 128.5 (2 C), 127.4, 86.7, 48.4,
43.8, 28.0, 27.7, 25.8, 25.4, 25.3; IR (neat) 3500-3200; 1713,
1681; HRMS (DCI/NH3) calcd for C18H22NO3 (MH+) 300.1600,
found 300.1610.
N-(3-Cyclohexyl-1,3-dioxopropyl)-2-(hydroxymethyl)-
pyrrolidine (25). DMAP (30 mg, 0.25 mmol) and 21 (0.13 g,
0.49 mmol) were added to a solution of (S)-prolinol (50 mg, 0.49
mmol) in toluene (12 mL). The cloudy solution was heated to 70
°C for 16 h. The clear solution was cooled to 25 °C and poured
into a solution of saturated NH4Cl (12 mL). The aqueous layer
was extracted with CH2Cl2 (3 × 10 mL). The combined organic
layers were washed with 1 M HCl (2 × 20 mL). The combined
acidic layers were extracted with CH2Cl2 (10 mL). The combined
organic layers were washed with brine (30 mL), dried over
MgSO4, and concentrated to yield 0.123 g (98%) of oily 25 as a
complex mixture of four keto, enol, and amide tautomers: 1H
NMR 4.97-4.95, 4.85-4.83, 4.58-4.54, 4.28-4.19, and 3.83-
3.37 (5 m, 7 H for keto, 6 H for enol), 2.54-2.48 (m, 1), 2.12-
1.62 and 1.41-1.18 (2 m, 14 H); IR (neat) 1710, 1626; HRMS
(DCI/NH3) calcd for C14H24NO3 (MH+) 254.1756, found 254.1753.
2-Cyclohexyl(hydroxy)methylene-2,5,6,7-tetrahydro-3H-
pyrrolizin-3-one (26). To a solution of 25 (39 mg, 0.15 mmol)
in toluene (1.0 mL) and DMSO (1.0 mL) was added EDC (0.15
g, 0.77 mmol) and dichloroacetic acid (25 µL, 0.31 mmol). The
solution was stirred for 36 h and 2 M HCl (3 mL) was added.
The aqueous layer was extracted with Et2O/CH2Cl2 (3:1, 3 × 5
mL). The combined organic layers were stirred with 2 M NaOH
(5 mL) for 5 min. Ice was added and the aqueous layer
neutralized with 2 M HCl. The organic layer was removed and
the neutral aqueous layer was extracted with CH2Cl2 (3 × 5 mL).
The combined organic layers were washed with 2.5 M NaCl
solution (5 × 5 mL), dried over MgSO4, and concentrated to give
28 mg (76%) of 80-90% pure 26 as a bluish oil: 1H NMR 5.51
(s, 1), 3.65 (t, 2, J ) 7.3), 2.65 (t, 2, J ) 7.3), 2.49-2.42 (m, 1),
2.35 (tt, 2, J ) 7.3, 7.3), 1.85-1.55 (m, 8), 1.39-1.20 (m, 2).
2-Cyclohexanecarbonyl-7a-hydroxy-5,6,7,7a-tetrahydro-
3H-pyrrolizin-3-one (27). A solution of crude 26 (28 mg, 12
mmol) in CH2Cl2 (0.35 mL) was cooled to -40 °C and a solution
of DMDO (1.60 mL, 0.07 M in acetone) was quickly added. The
bright yellow solution was stirred for 3 h. The solution was then
concentrated to provide a yellow oil. Flash chromatography on
silica gel deactivated with 5% H2O (13:7 CH2Cl2/EtOAc) yielded
4 mg (11% from 25) of >90% pure 27 as a yellow oil: 1H NMR
7.63 (s, 1), 3.56 (ddd, 1, J ) 8.5, 8.5, 8.5), 3.39-3.30 (m, 1), 3.28-
3.20 (m, 1), 2.62-2.54 (m, 1), 2.40-2.25 (m, 1), 2.19-2.14 (m,
1), 1.80-1.60 (m, 5), 1.66-1.58 (m, 1), 1.41-1.23 (m, 5); 13C NMR
200.0, 170.1, 153.1, 135.9, 95.4, 48.2, 42.3, 34.0, 28.5, 27.72,
27.71, 25.8, 25.6, 25.3; IR (neat) 3418, 1694.
Data for 19b were determined from the mixture: 1H NMR
7.38-7.26 (m, 5), 7.36 (br, 1, NH), 4.66 (s, 1, OH), 4.05 (d, 1, J
) 2.4), 3.13 (d, 1, J ) 13.4), 3.07 (d, 1, J ) 13.4), 2.11 (s, 3); 13
C
NMR 199.6, 168.1, 134.4, 130.5 (2 C), 128.6 (2 C), 127.3, 85.1,
64.8, 61.2, 41.3, 26.2; IR (neat) 3200-3000, 1700, 1680; HRMS
(DCI/NH3) calcd for C13H14NO4 (MH+) 248.0923, found 248.0924.
NOESY 1D irradiation of the absorption at δ 4.05 showed
small enhancements to δ 7.36, 4.66, and 2.11 and very small
enhancements to δ 3.13 and 3.07.
4-Hydroxy-1-(1-oxoethyl)-4-phenylmethyl-6-oxa-3-
azabicyclo[3.1.0]hexan-2-one (19a and 19b). A solution of
16 (42 mg, 0.20 mmol) in aqueous Na2(EDTA) (4 × 10-4 M, 1.6
mL) was cooled to 0 °C and acetone (1.6 mL, 21.8 mmol) was
added. A mixture of NaHCO3 (130 mg, 1.56 mmol) and Oxone
(0.60 g, 0.98 mmol) was added over a period of 1 h. The solution
was stirred for an additional 6 h at 0 °C. The reaction mixture
was filtered and concentrated under reduced pressure to remove
the acetone. The resulting aqueous layer was extracted with
CH2Cl2 (4 × 5 mL), which was dried over MgSO4 and concen-
trated to yield 30 mg (63%) of crude 19a. Flash chromatography
on silica gel (19:1 CH2Cl2/MeOH) yielded 28 mg (58%) of a 3:1
mixture of 19a and 19b.
Data for 19a were determined from the mixture: 1H NMR
7.39-7.25 (m, 5), 7.26 (br, 1, NH), 6.28 (s, OH), 3.98 (d, 1, J )
2.4), 3.22 (d, 1, J ) 13.4), 3.13 (d, 1, J ) 13.4), 1.96 (s, 3); 13C
NMR 196.6, 167.0, 133.0, 130.6 (2 C), 128.8 (2 C), 127.7, 84.5,
63.5, 62.8, 43.5, 27.4; IR (neat) 3200-3000, 1700, 1680; HRMS
(DCI/NH3) calcd for C13H14NO4 (MH+) 248.0923, found 248.0924.
NOESY 1D irradiation of the absorption at δ 3.98 showed
small enhancements of δ 7.26 and 1.96 and larger enhancements
of δ 3.22 and 3.13.
(Z)-1,5-Dihydro-3-(1-oxoethyl)-5-(phenylmethylene)-2H-
pyrrol-2-one (20). To a solution of 18 (9 mg, 0.04 mmol) in CH2-
Cl2 (0.5 mL) was added TFA (3 µL, 0.04 mmol). The solution
was stirred for 12 h and then poured into H2O (3 mL). The
aqueous layer was neutralized with 1 M NaOH and extracted
with CH2Cl2 (3 × 3 mL). The combined organic layers were
washed with H2O (5 mL), dried over MgSO4, and concentrated.
Flash chromatography on silica gel (49:1 CH2Cl2/MeOH) yielded
8 mg (100%) of 20 as a yellow solid: 1H NMR 8.51 (br, 1, NH),
7.73 (d, 1, J ) 2.4), 7.51-7.38 (m, 5), 6.41 (s, 1), 2.62 (s, 3); 13C
NMR 193.6, 169.4, 144.1, 134.7, 134.1, 131.6, 129.6, 129.4 (2 C),
129.3 (2 C), 120.2, 29.3; IR (KBr) 3456, 1698, 1671, 1636; HRMS
(DEI) calcd for C13H11NO2 (M+) 213.0790, found 213.0790.
N-(1-Hydroxymethyl-2-phenylethyl)-3-cyclohexyl-3-oxo-
propionamide (22). (R)-(+)-2-Amino-3-phenyl-1-propanol (30
mg, 0.20 mmol) was added to a solution of 21 (50 mg, 0.20 mmol)
in toluene (2 mL). The cloudy solution was heated at 70 °C for
18 h giving a clear solution that was concentrated to afford a
yellow oil. Flash chromatography on silica gel (1:4 hexanes/
EtOAc) yielded 37 mg (62%) of 22 as a white solid: mp 77-79
°C; 1H NMR 7.30-7.20 (m, 5), 4.21-4.18 (m, 1), 3.68 (dd, 1, J )
11, 5), 3.57 (dd, 1, J ) 11, 5), 3.41 (d, 1, J ) 16), 3.37 (d, 1, J )
16), 2.90 (dd, 1, J ) 13, 7), 2.83 (dd, 1, J ) 13, 7), 2.41-2.35 (m,
1), 1.82-1.61 (m, 4), 1.34-1.15 (m, 6); 13C NMR 209.9, 166.3,
137.6, 129.2 (2 C), 128.4 (2 C), 126.5, 63.9, 53.1, 51.5, 47.0, 36.9,
27.89, 27.88, 25.6, 25.32, 25.29; IR (KBr) 3303, 1708, 1645;
HRMS (DCI/NH3) calcd for C18H26NO3 (MH+) 304.1913, found
304.1909.
(Z)-3-(Cyclohexyl(hydroxy)methylene)-1,3-dihydro-5-
phenylmethyl-2H-pyrrol-2-one (23). To a solution of 22 (41
mg, 0.14 mmol) in toluene (1.0 mL) and DMSO (1.0 mL) was
added EDC (0.13 g, 0.68 mmol) and dichloroacetic acid (22 µL,
0.27 mmol). The solution was stirred for 36 h and 2 M HCl (3
mL) was added. The aqueous layer was extracted with Et2O/
CH2Cl2 (3:1, 3 × 5 mL). The combined organic layers were stirred
Acknowledgment. We thank the NIH (GM50151)
for generous financial support.
Supporting Information Available: 1H and 13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO048605R
J. Org. Chem, Vol. 69, No. 25, 2004 8955