Unsymmetrical ozonolysis of a Diels-Alder adduct: Practical preparation of a key intermediate for heme total synthesis

Full text of DOI:10.1021/jo001732c

J . Org. Chem. 2001, 66, 2515-2517
2515
Sch em e 1
Un sym m etr ica l Ozon olysis of a Diels-Ald er
Ad d u ct: P r a ctica l P r ep a r a tion of a Key
In ter m ed ia te for Hem e Tota l Syn th esis
Douglass F. Taber* and Katsumasa Nakajima
Department of Chemistry and Biochemistry, University of
Delaware, Newark, Delaware 19716
taberdf@udel.edu
Received December 12, 2000
In tr od u ction
In the course of other work, we needed to prepare gram
quantities of the pyrrole 3, an important precursor for
the preparation of hemes and porphyrins.1 Although the
pyrrole 3 has been known for many years, the prepara-
tion is somewhat tedious.1 It occurred to us that if the
simple Diels-Alder-derived ketal 1 could be selectively
ozonolyzed to the aldehyde 2, ketal removal followed by
condensation and formylation could give 3.
Resu lts
Un sym m etr ica l Ozon olysis. The key question was
whether the ozonolysis of 1 would be regioselective.
Unsymmetrical ozonolysis, first reported by Schreiber et
al. in 19822 and subsequently employed by others,3
provides terminally differentiated products from cyclo-
alkenes. When an unsymmetrical cycloalkene is ozono-
lyzed, two products can be formed. There were only six
prior examples of selective cleavage of an unsymmetrical
disubstituted cycloalkene such as 1 (Scheme 1). An
electron-withdrawing acetoxy group at the allylic position
in both cyclohexene 4 and cyclopentene 7 directed the
alkene cleavage, to give the intermediate methoxy hy-
droperoxide predominantly on the distal carbon. This
effect was still observed with 10, despite the alkyl
branching at the other allylic position. However, in
cyclopentene 13, the effect of the allylic dimethyl sub-
stitution became dominant, reversing the regioselectivity
of the cleavage. The only other examples were those first
reported by Schreiber et al., 16 and 19. It seemed likely
in this pair of examples that the influence of the acetoxy
group was steric, rather than electronic.
With these scanty results in hand, it was desirable to
investigate the directing effects of other substituents. We
have found, as described below, that the unsymmetrical
ozonolysis of 1 indeed proceeds with significant regiose-
lectivity, opening a simple route to the target pyrrole 3.
P r ep a r a tion of Keta l 1. Following the literature
precedent,4a cycloaddition of piperylene and methyl vinyl
ketone in the presence of BF3‚OEt2 provided a mixture
of endo and exo adduct 22 in a ratio of 96:4 (1H NMR
integration). Ketalization (Scheme 2) with concomitant
epimerization then produced 1 as a 3:1 diastereomeric
mixture, based on 1H NMR integration of the methyl
doublets at δ 1.11 and δ 0.99, respectively (the trans
diastereomer, δ 1.11, was dominant). Since the two
stereogenic centers at C-3 and C-4 become sp2 centers in
the target pyrrole 3, the separation of the diastereomeric
ketals was not required.
Ozon olysis of Keta l 1. Ozonolysis of 1 in CH2Cl2-
alcohol in the presence of NaHCO3 followed by treatment
with acetic anhydride and triethylamine afforded an
inseparable mixture of 2a and 25a (Scheme 2). This
mixture contained four diastereomeric and constitutional
(1) For leading references, see: (a) Davies, J . L. J . Chem. Soc. (C)
1968, 1392. (b) Al-Hazimi, H. M. G.; J ackson, A. H.; Knight, D. W.;
Lash, T. D. J . Chem. Soc., Perkin Trans. 1 1987, 265. (c) Padney, R.
K.; Leung, S. H.; Smith, K. M. Tetrahedron Lett. 1994, 35, 8093. (d)
Lash, T. D.; Mani, U. N.; Lyons, E. A.; Thientanavanich, P.; J ones, M.
A. J . Org. Chem. 1999, 64, 478.
(2) (a) Schreiber, S. L.; Claus, R. E.; Reagan, J . Tetrahedron Lett.
1982, 23, 3867. (b) Claus, R. E.; Schreiber, S. L. Organic Synthesis;
Wiley: New York, 1990; Collect. Vol. VII, p 168.
(4) (a) Gu¨ner, O. F.; Ottenbrite, R. M.; Shillady, D. D.; Alston, P. V.
J . Org. Chem. 1988, 53, 5348. For 1H NMR data of 22, see: (b)
Bonnesen, P. V.; Puckett, C. L.; Honeychuck, R. V.; Hersh, W. H. J .
Am. Chem. Soc. 1989, 111, 6070.
(3) (a) Bunnelle, W. H.; Isbell, T. A. J . Org. Chem. 1992, 57, 729.
(b) Kawamura, S.; Yamakoshi, H.; Nojima, M. J . Org. Chem. 1996,
61, 5953.
10.1021/jo001732c CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/09/2001

2516 J . Org. Chem., Vol. 66, No. 7, 2001
Notes
Sch em e 2
Sch em e 3
2a . The 1H NMR, 13C NMR and mp of 3 were in excellent
agreement with the literature data.1d No attempt was
made to locate the product or products from 25a .
Con clu sion
Ta ble 1. Yield of 2 a n d 25 fr om Ozon olysis of 1
entry
R
yield (%)
ratio of 2 and 25
We have observed regioselective ozonolytic cleavage of
1 in the presence of an alcohol, to give 2 as the major
product. We have found the overall procedure described
here to be very satisfactory for the preparation of 3, a
key intermediate for porphyrin and heme syntheses.8
1
2
3
4
5
Me (a )
Et (b)
i-Pr (c)
Bn (d )
t-Bu (e)
68
71
73
75
48
3.6:1
3.6:1
3.6:1
4.8:1
6.0:1
Exp er im en ta l Section
isomers. The ratio of 2a and 25a (3.6:1) was determined
by 1H NMR integration of the aldehyde signals, doublets
from 2a (δ 9.64), and triplets from 25a (δ 9.77, δ 9.76).
This regioselectivity was favorable for the subsequent
conversion to pyrrole 3, which can be obtained only from
2.5
We have briefly explored the use of other alcohols
(entries 2-5 in Table 1) in this unsymmetrical ozonolysis.
Although tert-butyl alcohol appears to show enhanced
regioselectivity, the lower yield leaves open the possibility
that the improved ratio is due to selective loss of the
minor regioisomer. In contrast to the results from the
ozonolysis of 1 in the presence of methanol (Scheme 2), a
control experiment in which methanol was added after
the formation of the ozonide from 1 in CH2Cl2 did not
lead to the formation of 2a or 25a . This suggested that
the alcohol trapping likely is occurring prior to the
formation of the secondary ozonide.
The conversion of the intermediate alkoxyhydroperox-
ides 23 and 24 (Scheme 2) to the esters was found to
proceed smoothly in only 1 h at room temperature. This
was in contrast to the literature procedure,3b which with
the same solvents and concentrations specified a room-
temperature reaction for 20 h.
P yr r ole Syn th esis. The inseparable mixture of 2a
and 25a (3.6:1 ratio) was subjected to ketal hydrolysis
(Scheme 3) in acetone-water with catalytic pyridinium
p-toluenesulfonate (PPTS). The resulting keto aldehyde
mixture was immediately heated with ammonium car-
bonate to effect the Paal-Knorr pyrrole synthesis.6 The
resulting crude methyl 2,4-dimethyl-1H-pyrrole-3-pro-
panoate 261b was then formylated at C-2 with trimethyl
orthoformate in TFA to afford 37 in 39% overall yield from
Gen er a l. 1H NMR and 13C NMR spectra were obtained as
solutions in deuteriochloroform (CDCl3) at 400 MHz (1H NMR),
with tetramethylsilane ) 0.00 as in internal standard. 13C
multiplicities were determined with the aid of a J VERT pulse
sequence, differentiating the signals for methyl and methine
carbons as “d”, from methylene and quaternary carbons as “u”.
The infrared (IR) spectra were determined as neat oils. Mass
spectra (MS) were obtained at an ionizing potential of 15 eV.
Substances for which C, H analyses are not reported were
purified as specified and gave spectroscopic data consistent with
being >95% the assigned structure. Rf values indicated refer to
thin-layer chromatography (TLC) on 2.5 × 10 cm, 250 µm
analytical plates coated with silica gel GF, unless otherwise
noted, and developed in the solvent system indicated. Column
chromatography was carried out with Merck 35-60 µm silica
gel, following the procedure described by Taber.9 The solvent
mixtures used are volume/volume mixtures. All glassware was
flame dried under a dry nitrogen stream immediately before use.
Tetrahydrofuran (THF), diethyl ether, and 1,2-dimethoxyethane
(DME) were distilled from sodium metal/benzophenone ketyl
under dry nitrogen. Dichloromethane (CH2Cl2) and toluene were
distilled from calcium hydride under dry nitrogen. MTBE is
methyl tert-butyl ether. All reaction mixtures stirred magneti-
cally, unless otherwise noted.
Keton e 22. A mixture of piperylene (60% cis-trans isomers,
90 mL, 0.54 mol) and methyl vinyl ketone (95% grade, 15 mL,
0.18 mol) was cooled to 0 °C, and BF3‚OEt2 (3.0 mL, 24 mmol)
was slowly added. An exothermic reaction was observed, and
polymeric materials precipitated to the bottom of the flask. The
mixture was stirred at room temperature for 1 h and then
concentrated in vacuo. The residual oil was subjected to a bulb-
to-bulb distillation (bp 35 °C (pot)/0.1 mm) to afford 18.3 g (76%)
of 22 as a colorless oil: 1H NMR δ 5.71-5.62 (m, 2 H), 2.75-
(7) We also prepared 3 from 22 by sequential ozonolysis in CH2-
Cl2-MeOH, esterification with Ac2O and Et3N, Paal-Knorr pyrrole
synthesis with ammonium carbonate and formylation. This was a
shorter path to 3, but resulted in a poorer yield (15% overall), due to
a lower yield and poorer regioselectivity for the ozonolysis step.
(8) For leading references to alternative approaches to pyrroles and
porphyrins, see (a) Liu, D.; Williamson, D. A.; Kennedy, M. L.;
Williams, T. D.; Morton, M. M.; Benson, D. R. J . Am. Chem. Soc. 1999,
121, 11798. (b) Cho, D. H.; Lee, J . H.; Kim, B. H. J . Org. Chem. 1999,
64, 8048.
(5) Previously, a similar keto aldehyde had been prepared by
ozonolysis of a silyl enol ether, prepared by Diels-Alder cycloaddition
to a silyloxy diene: J acobi, P. A.; Cai, G. Heterocycles 1993, 35, 1103.
(6) (a) Bean, G. P. In The Chemistry of Heterocyclic Compounds;
J ones, R. A., Ed.; Wiley: New York, 1990; Vol. 48, Part 1, p 206. (b)
Wasserman, H. H.; Gosselink, E.; Keith, D. D.; Nadelson, J .; Sykes,
R. J . Tetrahedron 1976, 32, 1863.
(9) Taber, D. F. J . Org. Chem. 1982, 47, 1351.

Notes
J . Org. Chem., Vol. 66, No. 7, 2001 2517
2.62 (m, 2 H), 2.16 (s, 3 H), 2.15-1.93 (m, 2 H), 1.79-1.60 (m,
2 H), 0.94 (d, J ) 7.1 Hz, 3 H for exo 22), 0.84 (d, J ) 7.0 Hz, 3
H, for endo 22). This was in excellent agreement with literature
data.4b
1.70 (m, 6 H), 1.35-1.08 (a mixture of singlets and doublets, 12
H); 13C NMR signals for a major isomer δ δ 203.4, 67.6, 47.1,
46.0, 22.7, 21.7, 9.6, u 172.5, 111.2, 63.8 (2 C), 33.2, 22.9; IR
2886, 2715, 1727, 1182 cm-1; MS (CI) m/z 273 (M+H+, 15), 213
(100); HRMS calcd for C14H25O5 (M + H+) 273.1702, obsd
273.1333.
Keta l 1. A mixture of ketone 22 (13.8 g, 0.100 mol), p-
toluenesulfonic acid monohydrate (1.89 g, 9.95 mmol), and
ethylene glycol (56 mL, 1.0 mol) in benzene (150 mL) was heated
to reflux for 24 h in a flask equipped with a Dean-Stark water
separator. After cooling to room temperature, the mixture was
partitioned between MTBE and saturated aqueous K2CO3. The
combined organic extract was dried (MgSO4) and concentrated
in vacuo to give a brown oil. Bulb-to-bulb distillation (bp 55 °C
(pot)/0.1 mm) afforded 15.9 g (87%) of 1 as a colorless oil, TLC
Rf (5% MTBE-petroleum ether) ) 0.50 and 0.69. The ratio of
the isomers was determined by 1H NMR: common signals
assigned to both isomers δ 5.70-5.45 (m, 2 H), 4.00-3.85 (m, 4
H), 2.25-1.83 (m, 4 H), 1.50-1.30 (m, 2 H); the major isomer δ
1.29 (s, 3 H), 1.11 (d, J ) 6.9 Hz, 3 H); the minor isomer δ 32 (s,
3 H), 0.99 (d, J ) 7.0 Hz, 3 H); 13C NMR: the major isomer δ
134.0, 125.5, 48.0, 31.9, 21.9, 20.3, u 112.4, 64.3, 63.6, 24.8, 24.1;
the minor isomer δ d 133.6, 125.3, 45.9, 30.2, 22.4, 16.2, u 111.4,
65.1, 63.8, 26.3, 17.4; IR 1455, 1216 cm-1; MS (CI) m/z 183
(M + H+, 100), 167 (50); HRMS calcd for C11H18O2 (M+) 182.1307,
obsd 182.1300.
Ald eh yd e Ben zyl Ester s 2d a n d 25d . TLC Rf (30% MTBE-
petroleum ether) ) 0.31. An oil (4.8:1 ratio); 1H NMR δ 9.72 (t,
J ) 1.5 Hz, 1 H), 9.69 (t, J ) 1.3 Hz, 1 H), 9.58 (d, J ) 0.6 Hz,
1 H), 7.40-7.28 (m, 5 H), 5.15-5.08 (m, 2 H), 4.00-3.72 (m, 4
H), 2.70-1.68 (m, 6 H), 1.30-1.07 (a mixture of singlets and
doublets, 6 H); 13C NMR signals for a major isomer δ d 203.4,
128.4 (2 C), 128.2 (2 C), 128.1, 47.1, 46.1, 22.7, 9.6, u 172.8, 135.7,
111.1, 66.1, 63.78, 63.76, 32.9, 22.8; IR 2887, 2718, 1731, 1170
cm-1; MS (CI) m/z 321 (M + H+, 35), 229 (75), 113 (100); HRMS
calcd for C18H25O5 (M + H+) 321.1702, obsd 321.1347.
Ald eh yd e ter t-Bu tyl Ester s 2e a n d 25e. TLC Rf (30%
MTBE-petroleum ether) ) 0.55. An oil (6.0:1 ratio); 1H NMR δ
9.76 (t, J ) 1.4 Hz, 1 H), 9.63 (s, 1 H), 3.92-3.76 (m, 4 H), 2.65-
1.70 (m, 6 H), 1.46 (s, 9 H), 1.44 (s, 9 H), 1.32 (s, 3 H), 1.12 (d,
J ) 7.1 Hz, 3 H); 13C NMR signals for a major isomer δ 203.6,
47.2, 46.1, 28.0, 22.9, 9.6, u 172.5, 111.3, 80.4, 63.9 (2 C), 34.2,
23.1; IR 2887, 2715, 1725, 1154 cm-1; MS (CI) m/z 213 (M+
t-BuOH, 100); HRMS calcd for
213.1127, obsd 213.1117.
-
C
11H17O4 (M+ - t-BuOH)
Ald eh yd e Meth yl Ester s 2a a n d 25a . An ozone stream was
bubbled through a suspension of ketal 1 (3.40 g, 18.7 mmol) and
NaHCO3 (6.31 g, 75.1 mmol) in a 5:1 mixture of CH2Cl2:MeOH
(36 mL) at -78 °C until complete consumption of 1 was observed
by TLC analysis. The mixture was then flushed with nitrogen,
and NaHCO3 was removed by filtration. The filtrate was
concentrated in vacuo to give the crude mixture of 23 and 24 as
a colorless oil, which was taken up in CH2Cl2 (30 mL). The
mixture was cooled to 0 °C, and acetic anhydride (8.8 mL, 93
mmol) and triethylamine (3.9 mL, 28 mmol) were added. The
mixture was stirred at room temperature for 1 h and then
partitioned between MTBE and, sequentially, 3 M aqueous HCl,
3 M aqueous KOH, and brine. The combined organic extract was
dried (MgSO4) and concentrated in vacuo. Chromatography of
the crude product afforded 3.11 g (68%) of an inseparable
mixture of 2a and 25a as a colorless oil, TLC Rf (30% MTBE-
petroleum ether) ) 0.26. The ratio of 2a and 25a (3.6:1) was
P yr r ole 3. A solution of the mixture of 2a and 25a (3.6:1 ratio,
830 mg, 3.40 mmol) and pyridinium p-toluenesulfonate (256 mg,
1.02 mmol) in a 3:1 mixture of acetone:water (8 mL) was heated
to reflux for 4 h. After cooling to room temperature, the mixture
was diluted with acetone (8 mL), and ammonium carbonate (6.60
g, 68.8 mmol) was added. The acetone was carefully removed
by rotatory evaporation. DMF (12 mL) was added to the residue,
and the mixture was stirred at 120 °C for 30 min. Sublimed
ammonium carbonate had to be pushed back into the flask from
the reflux condenser periodically through the reaction. The
cooled mixture was partitioned between MTBE and water. The
combined organic extract was dried (MgSO4) and concentrated
in vacuo to give the crude methyl 2,4-dimethyl-1H-pyrrole-3-
propanoate 261b as an orange oil. This was taken up in TFA (4.0
mL). Trimethyl orthoformate (2.0 mL, 18 mmol) was added
dropwise, and the mixture was stirred at room temperature for
10 min. The resulting product was partitioned between CHCl3
and, sequentially, water, 10% aqueous NH4OH and water. The
combined organic extract was dried (MgSO4) and concentrated.
Chromatography of the crude product over silica gel (deactivated
with Et3N) provided a light brown solid (242 mg, mp 118-121
°C), TLC Rf (50% MTBE-petroleum ether) ) 0.30. Recrystalli-
zation from CHCl3-petroleum ether afforded 218 mg (39%
overall based on 2a content) of 3 as yellow crystals: mp 123-
124 °C (lit.1d 125-127 °C; lit.1b 123-125 °C; lit.1a 128-129 °C);
1H NMR δ 9.41 (br, 1 H). 9.46 (s, 1 H), 3.67 (s, 3 H), 2.72 (t, J )
7.7 Hz, 2 H), 2.45 (t, J ) 7.7 Hz, 2 H), 2.28 (s, 3 H), 2.27 (s, 3 H);
13C NMR δ 175.6, 51.6, 11.4, 8.7, u 173.3, 136.7, 132.6, 127.8,
120.9, 34.5, 19.2.
1
determined by H NMR of their aldehyde signals δ 0.77 (t, J )
1.5 Hz, 1 H), 9.76 (t, J ) 1.3 Hz, 1 H), 9.64 (d, J ) 0.7 Hz, 1 H),
4.00-3.79 (m, 4 H), 3.69 (s, 3 H), 3.67 (s, 3 H), 2.66-1.70 (m, 6
H), 1.38-1.10 (a mixture of singlets and doublets, 6 H); 13C
NMR: (Only signals corresponding to the major isomer are
described.) δ d 203.5, 51.5, 47.3, 46.1, 22.7, 9.7, u 173.5, 111.2,
63.9, 63.8, 32.8, 22.8; IR 2888, 2725, 1732, 1211 cm-1; MS (CI)
m/z 245 (M + H+, 70), 229 (100); HRMS calcd for C12H21O5
(M + H+) 245.1389, obsd 245.1025.
Following the same procedure for 2a and 25a , aldehyde esters
2b-e and 25b-e were prepared, and their data are described
below.
Ald eh yd e Eth yl Ester s 2b a n d 25b. TLC Rf (30% MTBE-
petroleum ether) ) 0.36. An oil (3.6:1 ratio); 1H NMR δ 9.77 (t,
J ) 1.6 Hz, 1 H), 9.76 (t, J ) 1.3 Hz, 1 H), 9.64 (d, J ) 0.8 Hz,
1 H), 4.20-4.05 (m, 2 H), 4.00-3.78 (m, 4 H), 2.70-1.68 (m, 6
H), 1.30-1.10 (a mixture of singlets, doublets and triplets, 9 H);
13C NMR signals for a major isomer δ d 203.3, 47.1, 46.0, 22.6,
14.0, 9.5, u 172.9, 111.1, 63.74, 63.70, 60.2, 32.9, 22.7; IR 2889,
2719, 1729, 1181 cm-1; MS (CI) m/z 259 (M + H+, 65), 229 (100);
HRMS calcd for C13H23O5 (M + H+) 259.1545, obsd 259.1170.
Ald eh yd e Isop r op yl Ester s 2c a n d 25c. TLC Rf (30%
MTBE-petroleum ether) ) 0.47. An oil (3.6:1 ratio); 1H NMR δ
9.761 (t, J ) 1.6 Hz, 1 H), 9.757 (t, J ) 1.4 Hz, 1 H), 9.63 (d,
J ) 0.5 Hz, 1 H), 5.03-4.92 (m, 1 H), 4.00-3.76 (m, 4 H), 2.65-
When this reaction was scaled up (5.27 g of 2a and 25a ), 1.05
g of 3 was obtained.
Ack n ow led gm en t. We thank the NIH (GM60287)
for support of this work.
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H and
13C NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O001732C