Convenient preparation of chiral dipyrrolylmethanes containing a chiral moiety

Article abstract of DOI:10.1135/cccc20071046

A variety of chiral bis-pyrroles have been made readily accessible via acid-catalyzed condensation of chiral ketones with pyrrole. Three representative chiral ketones 2-4 taken from the chiral pool were transformed into the corresponding bis-pyrrole derivatives in a straightforward acid-catalyzed condensation. Chiral β-hydroxy ketone derivatives, prepared through proline-catalyzed aldol condensation of acetone and an aldehyde, are readily transformed into the corresponding dipyrrolylmethane by the acid-catalyzed condensation carried out in the same conditions. The crystal structure of the chiral dipyrrolylmethane 2 derived from the (-)-menthone was determined.

Full text of DOI:10.1135/cccc20071046

1046
Cozzi, Gambarotta, Monari, Zoli:
CONVENIENT PREPARATION OF CHIRAL DIPYRROLYLMETHANES
CONTAINING A CHIRAL MOIETY
b
a2
Pier Giorgio COZZIa1,*, Sandro GAMBAROTTA , Magda MONARI and
a3
Luca ZOLI
a
Dipartimento di Chimica “G. Ciamician”, Università di Bologna, Via Selmi 2,
40126, Bologna, Italy; e-mail: piergiorgio.cozzi@unibo.it, magda.monari@unibo.it,
1
2
3
zoli.luca@libero.it
b
Department of Chemistry, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada;
e-mail: sandro.gambarotta@uottawa.ca
Received March 2, 2007
Accepted July 13, 2007
Dedicated to Professor Štefan Toma on the occasion of his 70th birthday.
A variety of ch iral bis-pyrroles h ave been m ade readily accessible via acid-catalyzed con den -
sation of ch iral keton es with pyrrole. Th ree represen tative ch iral keton es 2–4 taken from th e
ch iral pool were tran sform ed in to th e correspon din g bis-pyrrole derivatives in a straigh tfor-
ward acid-catalyzed con den sation . Ch iral β-h ydroxy keton e derivatives, prepared th rough
prolin e-catalyzed aldol con den sation of aceton e an d an aldeh yde, are readily tran sform ed
in to th e correspon din g dipyrrolylm eth an e by th e acid-catalyzed con den sation carried out in
th e sam e con dition s. Th e crystal structure of th e ch iral dipyrrolylm eth an e 2 derived from
th e (–)-m en th on e was determ in ed.
Keyw ord s: Dipyrrom eth an es; Pyrroles; Calixpyrroles; Ch iral keton es; Organ ocatalysis;
Prolin e; Aldol con den sation .
Th e dipyrrolylm eth an e group is a versatile syn th on widely used as a build-
in g block for th e syn th esis of expan ded porph yrin s1 an d calixpyrroles2.
Th e sem in al work by Sessler3 an d Gale4 h as m arked im portan t m ileston es
in th e use of calixpolypyrroles in h ost–guest ch em istry an d for m olecular
recogn ition of an ion s. Som e dipyrrolylm eth an es h ave foun d application s as
flavors an d food additives5. Th ese com poun ds are gen erally obtain ed by
acid-catalyzed addition of pyrrole or pyrrole derivatives to carbon yl com -
poun ds6. In coordin ation ch em istry, dipyrrolylm eth an e h as been proven to
act as a versatile, dian ion ic ligan d due to th e η1/η5 bon din g ability of th e
pyrrolide m oiety7. Used in th e ch em istry of f-elem en ts, th is ligan d h as pro-
m oted un ique reactive aggregates8, capable of form in g reactive clusters,
Collect. Czech. Chem. Commun. 2007, Vol. 72, No. 8, pp. 1046–1056
© 2007 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc20071046

Chiral Dipyrrolylmethanes
1047
wh ich efficien tly stabilize h igh ly reactive low-valen t lan th an ides, yet boost-
in g th e reactivity of th e m etal cen ters with respect to m etallocen e an a-
logues9. Macrocyclic dipyrrolylm eth an e clusters of Sm (II), for exam ple, are
able to m ediate th e four-electron reduction of din itrogen by th e coopera-
tive one-electron oxidation of four Sm (II) centers10. Gam barotta has described
a few application s of dipyrrolylm eth an e ligan ds in th e organ om etallic
ch em istry of h igh ly reactive m etals, such as th orium 11 an d th ulium 12 in
low oxidation states. Love h as described in terestin g com plexes with early13
an d late14 tran sition m etals supported by dipyrrolylm eth an e ligan ds. In ad-
dition , h e h as reecen tly explored th e preparation of bin uclear m acrocyclic
clefts derived from dipyrrolylm eth an e15 able to activate sm all m olecule like
dioxygen 16
.
Alth ough plan ar ch iral dipyrrolylm eth an e ligan ds [η5-(C4H3N)(η5-Cp*Fe)]2-
CH2 described by Fu17 h ave foun d in terestin g application in en an tio-
selective catalysis18, ch iral dipyrrolylm eth an es as ligan ds were scarcely con -
sidered19. Given th e versatility of th is class of com poun ds, it is surprisin g
th at ch iral derivatives, to th e best of our kn owledge, rem ain un kn own .
Con versely, ch iral dipyrrolylm eth an e derivatives m ay h ave an in terestin g
poten tial sin ce could be used in th e preparation of ch iral m etal com plexes
as well as in th e syn th esis of ch iral calixpyrrole derivatives20. As a part of
our research program devoted to th e study of n ew ch iral calixpyrrole deriv-
atives, we describe h erein a sim ple access to ch iral bis-pyrrole buildin g
blocks.
RESULTS AND DISCUSSION
As m en tion ed above, th e coordin ation ch em istry of dipyrrolylm eth an e h as
been explored with ach iral derivatives readily available from arom atic an d
aliph atic keton es th rough acid-catalyzed con den sation 10–18. In order to
study th e syn th esis of ch iral dipyrrolylm eth an e derivatives, a suitable, com -
m ercially available ch iral keton e was ch osen . We h ave perform ed th e reac-
tion with (–)-m en th on e (1) un der th e reaction con dition s em ployed with
various aliph atic an d arom atic keton es, with out success in th e isolation of
th e ch iral dipyrrolylm eth an e. Th e con den sation of (–)-m en th on e (1) with
pyrrole was carefully in vestigated by varyin g th e acid catalyst (HCl,
MeSO3H, TsOH, CF3COOH, CH3COOH), th e solven ts (EtOH, ben zen e, tolu-
en e, CHCl3, AcOEt, CH2Cl2), an d perform in g th e reaction s at various tem -
peratures. We h ave foun d th at stron g acids (HCl, MeSO3H), wh en used in
an am oun t of 5–10%, can cause th e form ation of in tractable red tars in
pure pyrrole, wh ile in oth er solven ts, th e form ation of polypyrrole oc-
Collect. Czech. Chem. Commun. 2007, Vol. 72, No. 8, pp. 1046–1056

1048
Cozzi, Gambarotta, Monari, Zoli:
curred. Am on g th e large variety of reaction con dition s an d solven ts tested,
we foun d th at th e m ost con ven ien t syn th etic route for th e preparation of
th e desired ch iral dipyrrolylm eth an e in volves th e use of pyrrole as solven t
an d trifluoroacetic acid as th e acid catalyst, an d perform in g th e reaction at
room tem perature (Sch em e 1).
NH
O
pyrrole, 8-10 equiv., r.t.
NH
CF3COOH
yield 22 %
Me
Me
2
1
SCHEME 1
As reported by Sessler3 an d Gale4, th e con den sation of pyrrole with ke-
ton es usually affords calixtetrapyrrole (Fig. 1) as th e th erm odyn am ically
m ore stable com poun ds. In fact, un der our optim ized reaction con dition s
th e yields of dipyrrolylm eth an e 2 are gen erally rath er poor, ran gin g be-
tween 20 an d 30%. In addition , it is kn own from literature th at dipyrrolyl-
m eth an es are often con tam in ated by th e form ation of isolable tripyrrolyl-
m eth an e6b. Non eth eless, in th e case of th e con den sation between
(–)-m en th on e an d pyrrole both m aterials are in expen sive an d available th us
allowin g large-scale preparation s. Th e excess of pyrrole can be recovered by
low-pressure distillation . Th e ch iral 2,2′-(p-m en th on e-3,3-diyl)dipyrrole (2)
can be isolated after ch rom atograph y an d purified furth er by crystallization
in pen tan e at –15 °C. Suitable crystals for th e X ray structure determ in ation
were obtain ed by crystalization with pen tan e. Figure 2 presen ts two dif-
feren t views foun d in th e asym m etric un it. Com poun d 2 crystallizes in th e
ch iral space group P212121, with two ch em ically equivalen t an d crystallo-
graph ically in depen den t m olecules A an d B in th e asym m etric un it. Th e
R
R
R
R
NH
NH
R
R
R
R
NH
HN
NH HN
dipyrrolylmethane
R
R
calixtetrapyrrole
FIG. 1
Calixtetrapyrrole an d dipyrrolylm eth an e
Collect. Czech. Chem. Commun. 2007, Vol. 72, No. 8, pp. 1046–1056

Chiral Dipyrrolylmethanes
1049
two in depen den t m olecules are con form ation al isom ers arisin g from differ-
en t orien tation s of th e isopropyl groups an d pyrrole rin gs. In both con for-
m ation s A an d B m olecules are in volved in in term olecular N–H···π (pyrrole)
h ydrogen bon ds with th e form ation of A···B pairs in th e solid state.
In order to probe th e gen erality of th e reaction con dition s we h ave tested
oth er ch iral carbon yl substrates such 1,2:5,6-di-O-isopropyliden e-α-D-ribo-
3-h ex-3-ribofuran ose (3) derived from a carboh ydrate an d th e steroid
keton e 5α-ch olestan -3-on e (4), both com m ercially available (Sch em e 2). In
both cases we h ave successfully isolated th e desired products 5 an d 6 by
flash ch rom atograph y.
Th e yields of 6 were particularly prom isin g, givin g th e establish ed poten -
tial of th ese derivatives for recogn ition ch em istry of an ion s in m em bran e
layers. Recen tly, Lee reported th e preparation of strapped calixtetrapyrrole
startin g from th e con den sation of 4-h ydroxy-butan -2-on e19. Th e bis-pyrrole
con gen er is an in terestin g buildin g block for th e preparation of fun ction al-
ized bis- an d calix[n]polypyrroles. Ch iral 3-h ydroxy keton es are suitable
substrates for obtain in g ch elatin g bis-pyrroles in wh ich th e h ydroxy group
can act as eith er addition al coordin atin g h eteroatom or as a reactive fun c-
tion for in corporation of th e ch iral bis-pyrrole m oiety in to m ore com plex
arch itectures20. A con ven ien t syn th esis of ch iral 3-h ydroxy keton es could
be realized takin g con siderable advan tage from organ ocatalytic m eth odolo-
gies21. Syn th eses of ch iral β-h ydroxy keton es were reported by List an d
Lern er, in th eir pion eerin g studies of th e aldol con den sation prom oted by
FIG. 2
Differen t view in th e asym m etric un it of th e ch iral dipyrrolylm eth an e 2
Collect. Czech. Chem. Commun. 2007, Vol. 72, No. 8, pp. 1046–1056

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Cozzi, Gambarotta, Monari, Zoli:
O
O
O
O
O
O
O
O
O
O
pyrrole
CF3COOH
23%
N
H
O
HN
3
5
pyrrole
CF3COOH
76%
N
H
O
6
4
HN
SCHEME 2
prolin e22. Several auth ors h ave n ow con siderably expan ded th ese fin d-
in gs23, en largin g th e scope of th e reaction by subtle adjustm en ts of th e sys-
tem . Man y prolin e derivatives h ave been reported as en h an cin g th e
en an tiom eric excesses of th e reaction . In addition , th e use of differen t sol-
ven ts, such as water24 or ion ic liquids25, h ave been tested in organ ocatalytic
reaction s. Fin ally, as th e h igh loadin g of organ ocatalytic reaction som e-
tim es h am pered th eir application in in dustry, th e supported prolin e h as th e
advan tage of bein g recyclable26. With th e purpose of testin g optically active
β-h ydroxy keton es in our con den sation reaction , we h ave em ployed th e
con dition s described by List, an d perform ed th e reaction with aceton e in
th e presen ce of prolin e. Th e syn th esis is in expen sive if aceton e is used both
as a solven t an d a reagen t. Also com m ercially available aldeh ydes can be
used an d prolin e acts as a catalyst. By en h an cin g th e scale, we h ave pre-
pared th e h ydroxy keton es illustrated in Sch em e 3 in m oderate en an tio-
m eric excesses. Th e optically active keton es were subjected to th e CF3COOH-
prom oted acid con den sation in n eat pyrrole, an d th e com poun ds 11–14
were isolated after ch rom atograph ic purification . HPLC an alysis perform ed
with com poun ds 13 an d 14 con firm ed th e reten tion of en an tiom eric excess
durin g th e acid-catalyzed con den sation . Th e isolated yields were in th e
ran ge of th ose obtain ed with oth er ch iral keton es. As reported by Lee for h is
preparation of calixpyrrole, th e acid-catalyzed con den sation could be per-
form ed with un protected alcoh ols, also usin g CF3COOH an d n eat pyrrole.
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Chiral Dipyrrolylmethanes
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As m an y oth er organ ocatalytic reaction s h ave been in troduced in recen t
years for th e syn th esis of a pleth ora of ch iral carbon yl derivatives, our
con den sation reaction could be, in prin ciple, applied to oth er h igh ly
fun ction alized en an tio-en rich ed carbon yl derivatives27. It is worth y to em -
ph asize th at th e con den sation with pyrrole could be perform ed un der very
m ild con dition s, usin g on ly catalytic am oun ts of CF3COOH. Th e acid is
quen ch ed with an addition of Et3N or sim ply evaporated un der reduced
pressure. Th e pyrrole used in excess is recovered from th e reaction m ixture
by a sim ple distillation . No in ert con dition s an d n itrogen atm osph ere are
required.
OH
O
L-proline
acetone
RCHO
R
R
%
ee%
68
7
8
Ph
46
48
42
48
4-O2NC6H4
cyclohexyl
1-naphthyl
76
9
42
10
70
NH
OH
O
HN
HO
R
pyrrole
R
CF3COOH
R
%
11
12
13
14
Ph
23
22
15
34
4-O2NC6H4
cyclohexyl
1-naphthyl
SCHEME 3
We h ave described a straigh tforward preparation of ch iral bis-pyrrole
derivatives, poten tially useful buildin g blocks in coordin ation ch em istry,
ch iral recogn ition an d asym m etric syn th esis usin g an acid-catalyzed con -
den sation perform ed in n eat pyrrole. Differen t en an tiopure keton es from
th e ch iral pool, an d en atio-en rich ed β-h ydroxy keton es un dergoes th e
acid-catalyzed con den sation , affordin g th e desired products in low to m od-
erate yields. Th e use of th ese ch iral buildin g blocks in preparation of ch iral
calixtetrapyrrole will be th e focus of furth er in vestigation s.
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Cozzi, Gambarotta, Monari, Zoli:
EXPERIMENTAL
1H NMR spectra were m easured on Varian 220 an d 300 MHz spectrom eters. Ch em ical sh ifts
are reported in ppm (δ-scale) from tetram eth ylsilan e with th e solven t reson an ce as th e in ter-
n al stan dard. Data are reported as follows: ch em ical sh ifts, m ultiplicity, couplin g con stan ts
(J) in Hz. 13C NMR spectra were recorded on a Varian 50 MHz an d Varian 75 MHz spectrom -
eters with com plete proton decouplin g. Ch em ical sh ifts are reported in ppm (δ-scale) from
tetram eth ylsilan e with th e solven t as th e in tern al stan dard (deuteroch loroform : δ 77.0).
Mass spectra were perform ed at an ion izin g voltage of 70 eV. Ch rom atograph ic purification
was m ade with 240–400 m esh silica gel. An alytical gas ch rom atograph y (GC) was perform ed
on a Hewlett–Packard HP 6890 gas ch rom atograph , with a flam e ion ization detector an d
split-m ode capillary in jection system , usin g a crosslin ked 5% PH ME Siloxan e (30 m ) col-
um n . An alytical h igh perform an ce liquid ch rom atograph y (HPLC) was perform ed on a HP
1090 liquid ch rom atograph equipped with a variable wavelen gth UV detector (deuterium
lam p 190–600 n m ), usin g a Daicel Ch iralcel OD colum n (0.46 × 25 cm ) (Daicel In c.) an d a
Daicel Ch iralcel AD colum n (0.46 × 25 cm ) (Daicel In c.). HPLC grade isopropyl alcoh ol
an d h exan e were used as th e elutin g solven ts. IR spectra (waven um bers in cm –1) were m ea-
sured on a FT-IR Nicolet 380 spectrom eter. All th e reaction s were carried out un der n itrogen
atm osph ere in flam e-dried glassware, usin g stan dard in ert tech n iques to in troduce reagen ts
an d solven ts. All keton es were used as received. All th e aldeh ydes were distilled un der re-
duced pressure prior to th eir use. CF3COOH an d pyrrole were used as received. An h ydrous
CH2Cl2, dieth yl eth er, toluen e an d THF were purch ased from Fluka (SureSeal bottle).
2,2′-(p-Men th on e-3,3-diyl)dipyrrole (2)
CF3COOH (0.6 m l) was added to a solution of (–)-m en th on e (3.5 g) in pyrrole (6.5 m l) an d
th e reaction m ixture was stirred at room tem perature for 72 h . Th e reaction was quen ch ed
by th e addition of Et3N (0.5 m l) an d th e excess pyrrole evaporated un der reduced pressure.
Th e crude residue was carefully purified by flash ch rom atograph y (cycloh exan e–Et2O
9:1–8:2) an d th e resultin g yellow oil was dissolved in a m in im um am oun t of pen tan e. Th e
solution was kept at –15 °C for 5 days affordin g wh ite crystals of 2. Yield 23%; m .p. 90 °C;
[α]D –9.5 (c 1, CHCl3). 1H NMR (200 MHz, CDCl3): 7.83 bs, 1 H (NH); 7.78 bs, 1 H (NH);
6.66–6.62 m , 2 H (pyrrole); 6.31–6.29 m , 1 H (pyrrole); 6.18–6.13 m , 2 H (pyrrole);
6.03–6.00 m , 1 H (pyrrole); 2.22–1.90 m , 1 H; 2.10 sept, 1 H, J = 6.6 (MeCHMe); 1.92 m ,
1 H; 1.90–1.80 m , 2 H; 1.60–1.30 m , 3 H; 1.00–0.90 m , 1 H; 0.88 d, 6 H, J = 6.6 (CH3);
0.26 d, 3 H, J = 6.6 (CH3). 13C NMR (50 MHz, CDCl3,): 139.8, 133.4, 116.1, 115.9, 108.3
(2 C); 103.6 (2 C); 51.2, 49.9, 45.5, 35.4, 29.6, 27.9, 24.2, 23.0, 22.8, 17.5. For C18H26N2
(270.4) calculated: 79.95% C, 9.69% H, 10.36% N; foun d: 79.89% C, 9.60% H, 10.44% N.
Com poun d 5
A m ixture of pyrrole (0.432 m l, 6.2 m m ol) an d keton e 3 (0.4 g, 1.56 m m ol) was treated with
CF3COOH (0.11 m l), wh ich was added dropwise in to th e reaction vessel. Th e reaction m ix-
ture was stirred at room tem perature for 48 h . Th e reaction was quen ch ed by th e addition of
Et3N (0.1 m l) an d th e excess pyrrole evaporated un der reduced pressure. Th e residue was
carefully purified by flash ch rom atograph y (dieth yl eth er) to give a yellow solid. Yield
0.135 g (23%); m .p. 130 °C; [α]D +101 (c 0.54, CHCl3). 1H NMR (200 MHz, CDCl3): 9.40 bs,
1 H (NH); 8.40 bs, 1 H (NH); 6.77–6.67 m , 2 H (pyrrole); 6.25–6.17 m , 2 H (pyrrole);
Collect. Czech. Chem. Commun. 2007, Vol. 72, No. 8, pp. 1046–1056

Chiral Dipyrrolylmethanes
1053
6.07–6.05 m , 1 H (pyrrole); 6.00 d, 1 H, J = 3.2 (pyrrole); 4.89 d, 1 H, J = 3.4 (CHO); 4.58 d,
1 H, J = 8 (CHO); 3.85–3.61 m , 4 H; 1.35 s, 6 H (Me); 1.54 s, 6 H (Me). 13C NMR (50 MHz,
CDCl3): 129.1, 127.9, 117.4, 117.2, 112.3, 108.4, 108.3, 108.2, 107.0, 104.3 (2 C); 87.2, 81.8,
70.6, 64.5, 54.7, 26.9, 26.8, 26.3 (2 C). IR (Nujol): 2921, 2843, 1459, 1371, 1090. For
C
20H26N2O5 (374.4) calculated: 64.15% C, 7.00% H, 7.48% N; foun d: 64.10% C, 6.93% H,
7.39% N.
Com poun d 6
A m ixture of pyrrole (0.430 m l, 6.2 m m ol) an d keton e 4 (0.3 g, 0.78 m m ol) was treated with
CF3COOH (0.045 m l, 0.58 m m ol), wh ich was in troduced dropwise in to th e reaction vessel.
Th e reaction m ixture was stirred at room tem perature for 48 h . Th e reaction was quen ch ed
by th e addition of Et3N (0.1 m l) an d th e excess pyrrole evaporated un der reduced pressure.
Th e residue was carefully purified by ch rom atograph y (cycloh exan e–Et2O 7:3) to give a yel-
low solid. Yield 0.33 g (78%); m .p. 150 °C; [α]D +35.3 (c 0.92, CHCl3). 1H NMR (200 MHz,
CDCl3): 7.85 bs, 1 H (NH); 7.60 bs, 1 H (NH); 6.71–6.69 m , 1 H (pyrrole); 6.52–6.50 m , 1 H
(pyrrole); 6.22–6.19 m , 2 H (pyrrole); 6.11–6.08 m , 1 H (pyrrole); 6.02–6.00 m , 1 H (pyrrole);
2.20–1.00 m , 34 H; 0.90–0.85 m , 12 H. 13C NMR (50 MHz, CDCl3,): 141.1, 135.0, 117.1,
116.1, 107.8, 106.4, 101.6 (2 C); 56.4, 56.2, 53.9, 42.5, 42.0, 39.9, 39.5, 36.1, 36.0, 35.9,
35.8, 35.4, 35.3, 32.9, 31.7, 28.6, 28.2, 27.9, 24.1, 23.8, 22.8, 22.5, 20.8, 18.6, 12.1, 12.0.
IR (n eat): 2929, 2843, 1460, 1382. For C35H54N2 (502.8) calculated: 83.60% C, 10.82% H,
5.57% N; foun d: 83.52% C, 10.79% H, 5.52% N.
Preparation of Hydroxy Keton es 7, 8, 9 an d 10
Com poun ds 7–10 were obtain ed followin g th e gen eral procedure described by List an d
Barbas22
.
(4R)-4-Hydroxy-4-phenylbutan-2-one 7. Yield 46%. 1H NMR (200 MHz, CDCl3): 7.20–7.10 m ,
5 H (Ph ); 4.95 m , 1 H (Ph CHOH); 3.78 bs, 1 H (OH); 2.65 m , 2 H (CH2CHOH); 2.00 s, 3 H
(CH3). HPLC (Daicel OJ, h exan e–i-PrOH 95:5, flow rate 1 m l/m in ) tR(m ajor) 35.76 m in ,
tR(m in or) 38.50 m in ; ee 58%.
(4R)-4-Hydroxy-(4-nitrophenyl)butan-2-one 8. Yield 48%. 1H NMR (200 MHz, CDCl3): 8.20 d,
2 H, J = 7.0 (Ar); 7.52 d, 2 H, J = 7 (Ar); 5.25 m , 1 H (ArCHOH); 3.56 d, 1 H, J = 3.2 (OH);
2.83 m , 2 H (CH2CHOH); 2.21 s, 3 H (CH3). HPLC (Daicel AD h exan es–i-PrOH 97:3, flow
rate 1 m l/m in ) tR(m ajor) 18.76 m in , tR(m in or) 22.56 m in ; ee 74%.
(4R)-4-Cycloh exyl-4-h ydroxybutan -2-on e 9
Cycloh exan ecarbaldeh yde (0.36 m l, 3 m m ol) was added to a suspen sion of L-prolin e (0.1 g,
0.9 m m ol) in aceton e (2 m l). Th e reaction m ixture was stirred at room tem perature for 48 h
an d th en quen ch ed with a saturated solution of NH4Cl. Th e m ixture was diluted with di-
eth yl eth er (10 m l) an d th e organ ic ph ase was separated. Th e aqueous ph ase was extracted
with dieth yl eth er. Th e com bin ed organ ic ph ases were dried with an h ydrous Na2SO4 an d
evaporated un der reduced pressure. Th e resultin g oil was purified by flash ch rom atograph y
(cycloh exan e–Et2O 1:1). Yield 0.19 g (42%). 1H NMR (200 MHz, CDCl3): 3.80 m 1 H
(CHCHOH); 2.89 bs, 1 H (OH); 2.55 m , 2 H (CH2CHOH); 2.18 s, 3 H (CH3); 1.77–1.62 m , 5 H;
1.25–0.97 m , 6 H. HPLC (Daicel AD, h exan e–i-PrOH 97:3), flow rate 1 m l/m in , tR(m ajor)
12.94 m in , tR(m in or) 15.30 m in ; ee 74%.
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1054
Cozzi, Gambarotta, Monari, Zoli:
(4R)-4-Hydroxy-4-(1-naphthyl)butan-2-one 10. Yield 48%. 1H NMR (200 MHz, CDCl3):
7.82 m , 4 H (Ar); 7.45 m , 3 H (Ar); 5.34 m , 1 H (CHCHOH); 3.44 bs, 1 H (OH); 2.95 m , 2 H
(CH2CHOH); 2.21 s, 3 H (CH3). HPLC (Daicel AD, h exan es–i-PrOH 92.5:7.5), flow rate
1 m l/m in , tR(m ajor) 18.64 m in , tR(m in or) 22.85 m in ; ee 73%.
Syn th esis of Com poun ds 11–14. Gen eral Procedure
CF3COOH (0.2 m m ol) was added at room tem perature to a m ixture of h ydroxy keton e
(2 m m ol) in pyrrole (14 m m ol). Th e tem perature of th e reaction m ixture in creased im m edi-
ately an d pyrrole started refluxin g in th e flask. Th e m ixture was stirred for addition al 24 h
an d th en quen ch ed with 1 M NaOH (10 m l). After extraction with CH2Cl2, th e solven t was
evaporated un der reduced pressure an d th e excess of pyrrole rem oved by distillation at low
pressure. Th e residue was purified by flash ch rom atograph y (cycloh exan e–Et2O) givin g th e
desired dipyrrolylm eth an e derivatives.
Compound 11. Yield 23%; [α]D +8.8 (c 1, CHCl3). 1H NMR (200 MHz, CDCl3): 10.29 bs,
1 H (NH); 10.4 bs 1 H (NH); 7.30–7.20 m , 5 H (Ph ); 6.72–6.54 m , 2 H (pyrrole); 6.22–6.18 m ,
4 H (pyrrole); 4.80–4.78 m , 1 H (CHCHOH); 2.48 dd, 1 H, J = 14.8, 9.6 (CH2CHOH);
2.26 dd, 1 H, J = 14.8, 2.6 (CH2CHOH); 2.08 bs, 1 H (OH); 1.78 s, 3 H (CH3). 13C NMR
(50 MHz, CDCl3): 145.1, 137.5, 136.9, 128.3, 127.2, 125.5, 117.3, 117.1, 107.9, 107.8, 100.7
(2 C); 71.6, 50.8, 38.7, 28.1. IR (Nujol): 2924, 2851, 1550, 1470, 1379. For C18H20N2O
(280.4) calculated: 77.11% C, 7.19% H, 9.99% N; foun d: 77.15% C, 7.65% H, 9.91% N.
Compound 12. Yield 22%; [α]D +6.8 (c 0.74, CHCl3). 1H NMR (200 MHz, CDCl3): 10.29 bs,
1 H (NH); 10.4 bs, 1 H (NH); 8.17 d, 2 H, J = 8.8 (Ar); 7.42 d, 2 H, J = 8.8 (Ar); 6.72–6.68 m ,
2 H (pyrrole); 6.22–6.14 m , 4 H (pyrrole); 4.93–4.87 m , 1 H (CHCHOH); 2.46 dd, 1 H, J =
14.8, 9.2 (CH2CHOH); 2.27 dd, 1 H, J = 14.6, 2.2 (CH2CHOH); 2.10 bs, 1 H (OH); 1.77 s, 3 H
(CH3). 13C NMR (75 MHz, CDCl3): 147.1, 140.0, 132.4, 133.3, 128.5, 123.7, 117.4, 117.2,
108.1, 107.8, 104.4, 103.1, 68.5, 51.2, 30.3, 27.4. IR (n eat): 2918, 2845, 1464, 1372. For
C
18H19N3O3 (325.4) calculated: 66.45% C, 5.89% H, 12.91% N; foun d: 66.48% C, 5.86% H,
12.84% N.
Compound 13. Yield 15%; [α]D –6 (c 0.9, CHCl3). 1H NMR (200 MHz, CDCl3): 8.22 bs, 2 H
(NH); 6.68–6.63 m , 2 H (pyrrole); 6.16–6.11 m , 4 H (pyrrole); 3.60–3.51 m , 1 H (CHCHOH);
2.20–2.00 m , 3 H (CH2CHOH, OH); 1.80–1.60 m , 5 H; 1.67 s, 3 H (CH3); 1.40–1.00 m , 6 H.
13C NMR (75 MHz, CDCl3): 136.8, 136.3, 117.4, 117.1, 108 (2 C); 104.8, 104.2, 67.6, 45.5,
44.6, 42.9, 38.3, 28.9, 28.3, 27.6, 26.8, 26.5. HPLC (Daicel AD, h exan es–i-PrOH 99.05:05 to
90:10 in 20 m in ), flow rate 0.7 m l/m in , tR(m ajor) 16.25 m in , tR(m in or) 20.29 m in ; ee 74%.
IR (n eat): 3388, 3098, 2932, 2839, 1560, 1454, 1255, 1089, 1029. For C18H26N2O (286.4) cal-
culated: 75.48% C, 9.15% H, 9.78% N; foun d: 75.51% C, 9.10% H, 9.72% N.
Comound 14. Yield 34%; [α]D + 7.4 (c 0.74, aceton e). 1H NMR (200 MHz, CDCl3): 10.2 bs,
2 H (NH); 7.80–7.40 m , 7 H (Ar); 6.73–6.60 m , 2 H (pyrrole); 6.20–6.15 m , 4 H (pyrrole);
4.94–4.85 m , 2 H (CHCHOH, OH); 2.56 dd, 1 H, J = 14.6, 9.2 (CH2CHOH); 2.40 dd, 1 H, J =
14.6, 2.5 (CH2CHOH); 1.78 s, 3 H (CH3). 13C NMR (50 MHz, DMSO): 145.7, 139.8, 138.1,
133.3, 132.5, 128.0, 127.8, 126.2, 125.7, 125.1, 123.9, 117.1, 116.9, 106.8, 106.7, 104.9,
103.9, 70.8, 50.9, 31.1, 26.5. HPLC (Daicel AD, h exan es–i-PrOH 99.5:0.5 to 90:10 in 20 m in ),
flow rate 0.7 m l/m in , tR(m ajor) 30.82 m in , tR(m in or) 40.39 m in ; ee 73%. IR (Nujol): 2931,
2847, 1461, 1371, 1095. For C22H22N2O (330.4): 79.97% C, 6.71% H, 8.48% N; foun d:
80.00% C, 6.68% H, 8.44% N.
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Chiral Dipyrrolylmethanes
1055
PRIN 2005 (Progetto Nazionale: Sintesi e Stereocontrollo di Molecole Organiche per lo Sviluppo di
Metodologie Innovative di Interesse Applicativo) and Bologna University are acknowledged for
financial support of this research. The consortium CIMPRIS is acknowledged for financial support.
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