Syntheses of chiral fluorine analogs of hematoporphyrin

Article abstract of DOI:10.1016/S0040-4020(01)00780-3

Four chiral fluorine analogs of hematoporphyrin, (R,R)-, (R,S)-, (S,R)-, and (S,S)-3,8-bis(2,2,2-trifluoro-1-hydroxyethyl)deuteroporphyrins, were synthesized starting from pyrroles with a chiral 2,2,2-trifluoro-1-hydroxyethyl (TFHE) group. This chiral TFHE group was obtained by asymmetric reduction of a trifluoroacetyl group. Among these chiral analogs of hematoporphyrin, the (S,S)-isomer showed higher affinity for cancer cells than other stereoisomers.

Full text of DOI:10.1016/S0040-4020(01)00780-3

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 8085±8094
Syntheses of chiral ¯uorine analogs of hematoporphyrin
Masaaki Omote, Akira Ando, Kazuyuki Sato and Itsumaro Kumadakip
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaotoge-cho, Hirakata 573-0101, Japan
Received 9 May 2001; accepted 27 July 2001
AbstractÐFour chiral ¯uorine analogs of hematoporphyrin, (R,R)-, (R,S)-, (S,R)-, and (S,S)-3,8-bis(2,2,2-tri¯uoro-1-hydroxyethyl)deutero-
porphyrins, were synthesized starting from pyrroles with a chiral 2,2,2-tri¯uoro-1-hydroxyethyl (TFHE) group. This chiral TFHE group was
obtained by asymmetric reduction of a tri¯uoroacetyl group. Among these chiral analogs of hematoporphyrin, the (S,S)-isomer showed
higher af®nity for cancer cells than other stereoisomers. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
with an acid gives a complex mixture of oligomers through
ether or ester bond-formation and some of the dehydration
products of the hydroxyethyl group to a vinyl group. We
have been engaged in synthesizing new porphyrin photo-
sensitizers that could be used for PDT as a substitute for
HpD.4 In the course of this research, we realized two
interesting phenomena. First, af®nity of porphyrins for a
tumor tissue depends on the con®guration of the substituents
on the porphyrin ring. Second, the porphyrins were
stabilized considerably by introducing ¯uorine atoms at a
proper position of the substituent. From these phenomena,
our attention was turned to a synthesis of ¯uorinated
porphyrins.
Recently, photodynamic therapy (PDT) using porphyrin
derivatives as a photosensitizer have attracted much
attention in the ®eld of diagnosis and therapy of cancer.1
Many research groups, especially in Europe and Asia,
have been engaged in this ®eld and a lot of photosensitizers
for PDT have been developed.2 Among these photo-
sensitizers, hematoporphyrin derivatives (HpD) obtained
by treating hematoporphyrin (HP) with sulfuric acid in hot
acetic acid still have been most widely used, although its
composition is changeable case by case.3 This dif®culty
might be due to the labile structure of HP: HP has two chiral
centers, and commercial HPs have different composition of
diastereomers. Further, owing to a strong electron-donating
effect of the porphyrin ring, the hydroxyl groups of HP are
eliminated easily to form cationic intermediates. This makes
isomerization of the chiral centers occur easily, and the
resulting cationic species produces oligomers through
ether or ester bonds formation. One of the possible trans-
formation of HP when treated with an acid is shown in
Scheme 1.
We have already synthesized hematoporphyrin derivatives
having achiral mono and bis-(2,2,2-tri¯uoro-1-hydroxy-
ethyl) (TFHE) group(S) at 3- and/or 8-positions by the
reaction of deuteroporphyrin dimethyl ester (DPDME)
with tri¯uoroacetaldehyde in the presence of a Lewis acid
(Scheme 2).5
The hydroxyl groups of these ¯uorine analogs are very
stable to heating, acidic and basic conditions and very dif®-
cult to be eliminated. This high stability of a TFHE group is
HP itself is a mixture of stereoisomers, and its treatment
Scheme 1.
Keywords: hematoporphyrin; pyrrole; stereoisomers; ¯uorine; tri¯uoromethyl.
Corresponding author. Tel.: 181-72-866-3140; fax: 181-72-850-7020; e-mail: kumadaki@pharm.setsunan.ac.jp
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00780-3

8086
M. Omote et al. / Tetrahedron 57 ,2001) 8085±8094
Scheme 2.
in an outstanding contrast with that of the labile hydroxy-
ethyl groups of HP. To investigate the af®nity of these
TFHE-porphyrins, each sodium salt was added to a culture
medium of human liver cancer cells, JTC-16, and incubated
for 48 h. The cells were washed with buffer solution and
extracted with diisopropylamine±methanol.6 The intensity
of ¯uorescence of this extract was measured. From the
results shown in Fig. 1, the cancer cells af®nity of the
three were obviously different and the bis substituted
compounds, HFHPNa, showed the highest af®nity. The
af®nity of porphyrins increased by introduction of
the TFHE groups and was in¯uenced by their positions on
the porphyrin ring.
HP, namely, a ¯uorine atom is as small as a hydrogen
atom. Replacement of hydrogen atoms with ¯uorine atoms
does not change the form of the original compound so large,
and the ¯uorine analog behaves similarly in an organism as
the non-¯uorinated one. A TFHE group is very stable, and
its chirality is reserved through many steps of reactions. Bis-
TFHE-DP, hexa¯uoro analog of HP (HFHP), seemed to be
the best model compound for investigation of HP. Achiral
HFHP was found to show high af®nity for cancer cells, as
shown above. If it were synthesized in a chiral form, the
chirality would be stable due to the effect of ¯uorine atoms.
The chiral and stable model compound will be useful in
understanding the mechanism of the af®nity of HP for
tumor tissue at the molecular level.
Racemic porphyrins are used for the experiments so far. A
chiral compound would show different biological activity
from its enantiomer. Thus, we thought that investigation
using enantiometrically pure HPs was essential to under-
stand biological activity of HP. However, HP itself is not
stereochemically stable, since the hydroxyethyl groups of
HP loses the hydroxyl group easily in the presence of a very
weak acid through the mechanism shown in Scheme 1.
This paper discusses enantioselective syntheses of ¯uorine
analogs of four stereoisomers of hematoporphyrin and also
brie¯y their af®nity to cancer cells.
2. Results and discussion
Our strategy for the syntheses of the chiral porphyrins is
similar to the previous route to dimethyl ethers of HFHP-
DME.7 A pyrrole with a chiral TFHE group was obtained by
We decided to use ¯uorine analogs of HP as model
compounds for investigation of biological properties of
Figure 1.
Scheme 3.

M. Omote et al. / Tetrahedron 57 ,2001) 8085±8094
8087
that we had used methylated TFHE-pyrroles, while an
acetyl group, which is much easier to remove, was used
for protection of the hydroxyl group of the TFHE group
(Scheme 5).
The methyl group at position 5 of compound 4 was oxidized
to an acetoxymethyl group with lead(IV) acetate to give
compound (R)- and (S)-5 in 77 and 95% yields, respectively,
without any decrease of enantiomeric excess. Compound 5
corresponds to the ring A of the desired porphyrin.
Scheme 4.
On the other hand, the hydroxyl group of compound (R)-4
was acetylated with acetyl chloride in the presence of
4-dimethylaminopyridine to give an acetate (R)-6 in a
95% yield. The methyl group at position 5 of (R)-6 was
oxidized by the reaction with sulfuryl chloride, followed
by hydrolysis to give carboxylic compound in 99% yield.
Esteri®cation of the carboxyl group with diazomethane gave
benzyl methyl ester (R)-7 in 75% yield. Hydrogenolysis of
the benzyl ester with 5% palladium on activated carbon
gave the corresponding carboxylic acid (R)-8 quantitatively.
Reaction of 8 with iodine, sodium iodide and sodium hydro-
gen carbonate gave an iodide (R)-9 in 77%. The iodine of
compound (R)-9 was removed by Adams catalyst to give
a-unsubstituted pyrrole (R)-10 in a 98% yield. Finally, the
methyl ester of compound 10 was converted to a benzyl
ester by transesteri®cation with sodium bis(trimethylsilyl)-
amide in benzyl alcohol. Simultaneous deacetylation took
place to give compound (R)-11 in an 80% yield. Compound
11 corresponds to the ring B of the desired porphyrin. By the
same procedure, (S)-11 was obtained from (S)-4. The yield
in each step is shown in Scheme 5. Decrease in enantiomeric
excess was not observed at all through these transfor-
mations. This suggested that the TFHE group was so stable
through these transformations and that any precautions to
avoid the racemization of the chiral TFHE groups were not
required in further transformations.
enantioselective reduction of a tri¯uoroacetyl group.8
This pyrrole compound was transformed to the A and B
rings of porphyrin, and these were converted to the
desired chiral porphyrin derivatives by the MacDonald
condensation.
Thus, tri¯uoroacetylpyrrole 2 was obtained by the oxidation
of the pyrrole 1 with Dess±Martin reagent9 in 98% yield, as
shown in Scheme 3.
The enantioselective reduction proceeded effectively using
Corey's oxazaborolidine catalyst (Scheme 4). High enantio-
selectivity was attained by using bulkier catecholborane10 in
the place of BH3±THF.11 When the (S)-catalyst was used,
(R)-TFHE product (4) was obtained with more than 95% ee
in a yield of 99%. Similarly, the enantiomer of 4 with (S)
con®guration was obtained quantitatively and more than
95% ee using the catalyst of the opposite con®guration
(Scheme 4). The con®gurations of both products were deter-
mined by X-ray analysis of (1S)-camphanyl esters of (S)-4.8
Now, we carried out the transformation of (R)- and (S)-4,
obtained in high enantiomeric excesses, to the suitable
chiral TFHE-pyrroles for synthesis of the ring A and B of
HP. The strategy that we used for this transformation was
similar to our previous route7 with achiral pyrroles except
Pyrroles (R)-5 and (R)-11 were condensed effectively to a
dipyrrylmethane (R,R)-12 in a 88% yield as shown in
Scheme 5.

8088
M. Omote et al. / Tetrahedron 57 ,2001) 8085±8094
Scheme 6.
Scheme 6. Diastereomeric excess of (R,R)-12 was found to
be very high by the NMR analysis of its MTPA ester. The
enantiomeric excess of (R,R)-12 was higher than expected
from the ees of (R)-5 and (R)-11. This might be due to
the removal of other isomers during puri®cation by
column chromatography. Other dipyrrylmethanes ((R,S)-,
(S,R)- and (S,S)-12) were also obtained in high
diastereomeric excesses by the same method, as shown in
Scheme 6.
3. Conclusion
A chiral (2,2,2-tri¯uoro-1-hydroxyethyl)pyrrole (4) was
obtained in high enantiomeric excess in a quantitative
yield by reduction of a tri¯uoroacetylpyrrole in the presence
of Corey's oxazaborolidine catalyst with catecholborane.
An absolute con®guration of 4 was determined by X-ray
analysis of its (1S)-camphanyl ester. Both (R)- and (S)-4
were transformed to corresponding precursors (R)- and
(S)-5 (A ring of porphyrin) and (R)- and (S)-11 (B ring of
porphyrin) without loss of enantiomeric excesses. Reaction
of the chiral pyrrole (R)- or (S)-5 with the another chiral
pyrrole (R)- or (S)-11 gave four dipyrrylmethanes (R,R)-,
(R,S)-, (S,R)- and (S,S)-12. Decarboxylation of these
dipyrrylmethanes followed by MacDonald condensation
gave (R,R)-, (R,S)-, (S,R)- and (S,S)-HFHP-DME with
high enantiomeric excesses. Preliminary tests of biological
assay showed that the (S,S)-isomer was most effectively
taken up by cancer cells of four isomers. This is the
®rst experiment showing enantioselective recognition of
porphyrin derivatives. We are convinced that these chiral
porphyrins will help understanding of biological activities
of porphyrins in PDT and other ®elds.
HFHP-DME with both (R) con®gurations was synthesized
from (R,R)-dipyrrylmethane 12, as follows: (R,R)-12 was
hydrogenolyzed to dicarboxylic acid (R,R)-13. Decarboxyl-
ation of (R,R)-13 proceeded effectively by heating a solution
of (R,R)-13 in ethanolamine to give a,a0-unsubstituted
dipyrrylmethane, (R,R)-14, which was used for the next
MacDonald condensation12 without further puri®cation.
The ring closure proceeded under conventional condition
of MacDonald condensation to give (R,R)-HFHP-DME
(16) with a high enantiomeric excess (Scheme 7). (R,S)-,
(S,R)- and (S,S)-HFHP-DME (16) were obtained in high
enantiomeric excesses by the same method, as shown in
Scheme 7.
All these stereoisomers 16 were hydrolyzed to sodium salts
of sterically pure HFHPs. Detailed studies on biological
behaviors of these isomers are now going on, but their pre-
liminary tests showed that the (S,S)-isomer was most
effectively taken up by human gastric cancer cells, KATO
III. This suggests that chiral centers of HpD must play an
important role in biological activity.
4. Experimental
4.1. General procedure
Melting points were measured on a micro melting point
apparatus, Model MP (Yanagimoto, Kyoto, Japan) and a
Scheme 7.

M. Omote et al. / Tetrahedron 57 ,2001) 8085±8094
8089
melting point apparatus (Ishii Shoten, Tokyo, Japan) with-
out correction. Optical rotations were measured on JASCO
DIP-140 digital polarimeter. 1H NMR spectra were recorded
on JEOL FX90Q and JNM-GX400 spectrometers. Tetra-
methylsilane was used as an internal standard. 19F NMR
spectra were measured on Hitachi R-1500 and JEOL
FX90Q spectrometers. Trichloro¯uoromethane was used
as an internal standard and the lower ®eld is shown by 1.
Abbreviations are: s, singlet; d, doublet; m, multiplet; bs,
broad singlet; q, quartet. Mass spectra were recorded on a
JEOL JMS-DX300.
oxazaborolidine (270 mg, 0.97 mmol) in anhydrous THF
(30 mL) at room temperature and the mixture was stirred
for another 30 min. To the mixture was added a solution of 3
(3.0 g, 9.23 mmol) in anhydrous THF (30 mL) over 75 min
at 2808C and the mixture was stirred for 37 h at 2308C.
After the mixture was worked up as in the case of (R)-4, the
crude product was separated by column chromatography
(SiO2, Et2O±CH2Cl2, 5:95), and recrystallized from hex-
ane±CH2Cl2 to give (S)-4 (2.87 g, 95%, .95% ee). (S)-4:
colorless crystals (CH2Cl2±hexane). Mp 109±1108C.
[a]D ˆ127.68 (c 2.07, CH2Cl2). MS (EI) m/z: 327 (M1).
20
HRMS C16H16F3NO3: 327.108 (M1). Found: 327.108.
4.1.1. Benzyl 3,5-dimethyl-4--tri¯uoroacetyl)pyrrole-2-
carboxylate -3). In a stream of Ar, a solution of benzyl
3,5-dimethyl-4-(2,2,2-tri¯uoro-1-hydroxyethyl)pyrrole-2-
carboxylate (2, 10 g, 30.6 mmol) in CH2Cl2 (20 mL) was
added to a suspension of Dess±Martin reagent (20 g,
47.2 mmol) in anhydrous CH2Cl2 (20 mL) under ice-
cooling. After stirring for 30 h at room temperature, the
excess reagent was decomposed with saturated Na2S2O3
and NaHCO3 (7:1). The mixture was stirred for another
1 h and the whole was extracted with CH2Cl2. The CH2Cl2
layer was washed with H2O then dried over with anhydrous
MgSO4. After evaporation of the solvent under vacuum, the
residue was separated by column chromatography (SiO2,
CH2Cl2), and recrystallized from hexane±CH2Cl2 to give
3 (9.77 g, 98%). 3: colorless crystals. Mp 125±1278C. MS
(EI) m/z: 325 (M1). HRMS C16H14F3NO3: 325.093 (M1).
Found: 325.093. IR (KBr) nmax 3295, 1686, 1666 cm21. 1H
NMR (CDCl3) d: 9.75 (1H, bs), 7.39 (5H, m), 5.35 (2H, s),
2.56 (3H, s), 2.50 (3H, s). 19F NMR (CDCl3) d: 274.68 (3F,
s).
4.1.4. Benzyl 5-acetoxymethyl-3-methyl-4---R)-2,2,2-
tri¯uoro-1-hydroxyethyl)pyrrole-5-carboxylate --R)-5).
In a stream of Ar, lead(IV) acetate (1.00 g, 2.26 mmol)
was added to a solution of (R)-4 (300 mg, 0.92 mmol) in
acetic acid (7.0 mL), and the mixture was stirred for 4 h at
658C. After the excess of lead(IV) acetate was decomposed
by ethylene glycol, the mixture was poured into ice-H2O and
extracted with CH2Cl2. The CH2Cl2 layer was washed with
H2O and dried over anhydrous MgSO4. After evaporation of
the solvent under vacuum, the residue was puri®ed by
column chromatography (SiO2, Et2O±CH2Cl2, 5:95) to
give (R)-5 (350 mg, 99%, .95% ee by NMR analysis of
Mosher's ester). (R)-5: colorless crystals (CH2Cl2±hexane).
20
Mp 87±898C. [a]D ˆ264.18 (c 0.948, CH2Cl2). MS (EI)
m/z: 385 (M1). HRMS C18H18F3NO5: 385.114 (M1). Found:
1
385.114. IR (KBr) nmax 3475, 3308, 1721, 1666 cm21. H
NMR (CDCl3) d: 9.32 (1H, bs), 7.43±7.32 (5H, m), 5.34
(1H, d, Jˆ13.5 Hz), 5.32 (2H, s), 5.13 (1H, qd, Jˆ7.0,
4.0 Hz), 5.08 (1H, d, Jˆ13.5 Hz), 3.50 (1H, d, Jˆ4.0 Hz),
2.35 (3H, s), 2.07 (3H, s). 19F NMR (CDCl3) d: 274.37 (3F,
d, Jˆ7.0 Hz).
4.1.2.
Benzyl
3,5-dimethyl-4---R)-2,2,2-tri¯uoro-1-
hydroxyethyl)pyrrole-2-carboxylate --R)-4). In a stream
of Ar, catecholborane (1.95 mL, 18.3 mmol) was added to a
solution of (S)-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-
oxazaborolidine (270 mg, 0.97 mmol) in anhydrous THF
(30 mL) at room temperature and the mixture was stirred
for another 30 min. To the mixture was added a solution of 3
(3.00 g, 9.23 mmol) in anhydrous THF (30 mL) over 30 min
at 2808C and the mixture was stirred for 24 h at 2308C.
The reaction was quenched with an alkaline H2O2 solution
(10% NaOH±30% H2O2ˆ1:1, 40 mL) and the mixture was
stirred for 1 h at room temperature. The whole was extracted
with CH2Cl2, and the CH2Cl2 layer was washed with H2O
and 5% aqueous NaOH, then dried over anhydrous MgSO4.
After evaporation of the solvent under vacuum, the residue
was separated by column chromatography (SiO2, Et2O±
CH2Cl2, 5:95), and recrystallized from hexane±CH2Cl2 to
give (R)-4 (3.00 g, 99%, .95% ee). (R)-4: colorless crys-
4.1.5. Benzyl 4---R)-1-acetoxy-2,2,2-tri¯uoroethyl)-3,5-
dimethylpyrrole-2-carboxylate --R)-6). In a stream of
Ar, acetyl chloride (457 mL, 6.43 mmol) was added to a
solution of (R)-4 (0.96 g, 2.94 mmol) and 4-(dimethyl-
amino)pyridine (0.78 g, 6.39 mmol) in anhydrous CH2Cl2
(44 mL) at room temperature, and the mixture was stirred
for 1.5 h at the same temperature. After evaporation of the
solvent under vacuum, the residue was separated by column
chromatography (SiO2, CH2Cl2) to give (R)-6 (1.03 g, 95%)
20
as a colorless syrup. (R)-6: [a]D ˆ257.18 (c 2.44, CH2Cl2).
MS (EI) m/z: 369 (M1). HRMS C18H18F3NO3: 369.119
(M1). Found: 369.120. IR (KBr) nmax 3307, 1761,
1
1670 cm21. H NMR (CDCl3) d: 9.11 (1H, bs), 7.42±7.30
(5H, m), 6.17 (1H, q, Jˆ7.6 Hz), 5.30 (2H, s), 2.39 (3H, s),
2.31 (3H, s), 2.14 (3H, s). 19F NMR (CDCl3) d: 271.39 (3F,
d, Jˆ7.6 Hz).
20
tals. Mp 109±1108C. [a]D ˆ227.68 (c 2.14, CH2Cl2). MS
(EI) m/z: 327 (M1). HRMS C16H16F3NO3: 327.108 (M1).
Found: 327.109. IR (KBr) nmax 3529, 3256, 1666 cm21. 1H
NMR (CDCl3) d: 8.92 (1H, bs), 7.37 (5H, m), 5.29 (2H, s),
5.05 (1H, qd, Jˆ7.3, 4.0 Hz), 2.56 (1H, d, Jˆ4.0 Hz), 2.35
(3H, s), 2.32 (3H, s). 19F NMR (CDCl3) d: 273.77 (3F, d,
Jˆ7.3 Hz).
4.1.6. Benzyl 4---R)-1-acetoxy-2,2,2-tri¯uoroethyl)-5-
methoxycarbonyl-3-methylpyrrole-2-carboxylate --R)-
7). In a stream of Ar, sulfuryl chloride (0.93 mL,
11.6 mmol) was added to a solution of (R)-6 (1.03 g,
2.79 mmol) in anhydrous CH2Cl2±Et2O (6.7 mL, 10 mL)
at room temperature, and the mixture was stirred for 1.5 h.
The mixture was concentrated under vacuum, and the
residue was dissolved in acetone (15 mL) and H2O
(3.1 mL). After the mixture was re¯uxed for 40 min,
acetone was evaporated, and the residue was treated with
ice-H2O and hexane. The crystals, separated between two
4.1.3.
Benzyl
3,5-dimethyl-4---S)-2,2,2-tri¯uoro-1-
hydroxyethyl)pyrrole-2-carboxylate --S)-4). In a stream
of Ar, catecholborane (1.95 mL, 18.3 mmol) was added to
a solution of (R)-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-

8090
M. Omote et al. / Tetrahedron 57 ,2001) 8085±8094
layers, were collected by ®ltration. The crystals were
dissolved in 2 M NH4OH, then the solution was acidi®ed
by acetic acid to give a carboxylic compound (1.10 g, 99%).
Colorless crystals (CH2Cl2±hexane). Mp 143±1458C. MS
(EI) m/z: 399 (M1). HRMS C18H16F3NO6: 399.093 (M1).
4.1.9. Methyl 3---R)-1-acetoxy-2,2,2-tri¯uoroethyl)-4-
methylpyrrole-2-carboxylate --R)-10). A solution of (R)-
9 (3.21 g, 7.93 mmol) in MeOH (39 mL) was stirred in an
atmosphere of H2 in the presence of platinum(IV) oxide
(52 mg) and anhydrous sodium acetate (1.99 g,
24.3 mmol) until absorption of H2 was no longer observed.
After the catalyst was ®ltered off, H2O was added to the
mixture and the whole was extracted with CH2Cl2. The
CH2Cl2 layer was washed with H2O and dried over
anhydrous MgSO4. After evaporation of the solvent under
vacuum, the residue was separated by column chroma-
tography (SiO2, Et2O±CH2Cl2, 3:97) to give (R)-10
(2.15 g, 97%). (R)-10: colorless crystals (CH2Cl2±hexane).
1
Found: 399.094. H NMR (CDCl3) d: 9.98 (1H, bs), 9.75
(1H, bs), 7.54 (5H, s), 7.25 (1H, q, Jˆ7.3 Hz), 5.45 (2H, s),
2.55 (3H, s), 2.20 (3H, s). 19F NMR (CDCl3) d: 270.83 (3F,
d, Jˆ7.3 Hz).
A solution of CH2N2 in Et2O was added to a solution of the
carboxylic acid obtained above (5.82 g, 14.6 mmol) in
CH2Cl2 (50 mL) at room temperature. After the excess of
CH2N2 was decomposed with AcOH, the mixture was
poured into ice-H2O then extracted with CH2Cl2. The
CH2Cl2 layer was washed with H2O and dried over
anhydrous MgSO4. After evaporation of the solvent under
vacuum, the crude product was separated by column
chromatography (SiO2, CH2Cl2) to give (R)-7 (4.54 g,
20
Mp 139±1408C. [a]D ˆ226.38 (c 2.54, CH2Cl2). MS (EI)
m/z: 279 (M1). HRMS C11H12F3NO4: 279.072 (M1). Found:
1
279.071. IR (KBr) nmax 3392, 1748, 1702 cm21. H NMR
(CDCl3) d: 9.05 (1H, bs), 7.17 (1H, q, Jˆ7.6 Hz), 6.70 (1H,
d, Jˆ3.0 Hz), 3.89 (3H, s), 2.19 (3H, s), 2.17 (3H, s). 19F
NMR (CDCl3) d: 271.15 (3F, d, Jˆ7.6 Hz).
20
75%) as a colorless syrup. (R)-7: [a]D ˆ210.58 (c 1.30,
CH2Cl2). MS (EI) m/z: 413 (M1). HRMS C19H18F3NO6:
413.109 (M1). Found: 413.108. IR (KBr) nmax 3307,
4.1.10. Benzyl 4-methyl-3---R)-2,2,2-tri¯uoro-1-hydroxy-
ethyl)pyrrole-2-carboxylate --R)-11). In a stream of Ar,
a solution of NaN(Si(CH3)3)2 (1.0 M in THF, 1.0 mL) was
added dropwise to a solution of (R)-10 (100 mg, 0.36 mmol)
in anhydrous PhCH2OH (1.0 mL) at 808C, and the mixture
was re¯uxed for 5 min at the same temperature. The mixture
was poured into ice-H2O and the whole was extracted with
CH2Cl2. The CH2Cl2 layer was washed with H2O, and dried
over anhydrous MgSO4. After evaporation of the solvent
under vacuum, the residue was separated by column chro-
matography (SiO2, Et2O±CH2Cl2, 5:95) to give (R)-11
(90 mg, 80%). (R)-11: colorless crystals (CH2Cl2±hexane).
1757, 1717 cm21 1H NMR (CDCl3) d: 9.67 (1H, bs),
.
7.45±7.35 (5H, m), 7.16 (1H, q, Jˆ7.3 Hz), 5.34 (2H, s),
3.93 (3H, s), 2.47 (3H, s), 2.16 (3H, s). 19F NMR (CDCl3) d:
270.91 (3F, d, Jˆ7.3 Hz).
4.1.7. 4---R)-1-Acetoxy-2,2,2-tri¯uoroethyl)-5-methoxy-
carbonyl-3-methylpyrrole-2-carboxylic acid --R)-8). A
solution of (R)-7 (4.46 g, 10.8 mmol) in THF (76 mL) was
shaken in an atmosphere of H2 in the presence of 5% Pd-C
(365 mg) until absorption of H2 was no longer observed.
After the catalyst was ®ltered off, the solvent was evapo-
rated under vacuum. The residue was dissolved in 2 M
NH4OH, then the solution was ®ltered and acidi®ed with
acetic acid to give colorless crystals of (R)-8 (3.43 g,
98%). (R)-8: colorless crystals (CH2Cl2±hexane). Mp
184±1868C. MS (EI) m/z: 323 (M1). HRMS
20
Mp 99±1008C. [a]D ˆ224.68 (c 1.93, CH2Cl2). MS (EI)
m/z: 313 (M1). HRMS C15H14F3NO3: 313.092 (M1). Found:
313.092. IR (KBr) nmax 3328, 3220, 1672, 1404, 1354,
1
1284 cm21. H NMR (CDCl3) d: 9.00 (1H, bs), 7.42±7.35
(5H, m), 6.81 (1H, d, Jˆ11.6 Hz), 6.70 (1H, d, Jˆ3.0 Hz),
5.34 (1H, d, Jˆ12.2 Hz), 5.30 (1H, d, Jˆ12.2 Hz), 5.06 (1H,
dq, Jˆ11.6, 7.3 Hz), 2.07 (3H, s). 19F NMR (CDCl3) d:
274.32 (3F, d, Jˆ7.3 Hz).
1
C12H12F3NO6: 323.062 (M1). Found: 323.062. H NMR
(CDCl3) d: 10.53 (1H, bs), 9.92 (1H, bs), 7.17 (1H, q,
Jˆ7.0 Hz), 4.01 (3H, s), 2.52 (3H, s), 2.24 (3H, s). 19F
NMR (CDCl3) d: 270.88 (3F, d, Jˆ7.0 Hz).
4.1.11. Benzyl 5-acetoxymethyl-3-methyl-4---S)-2,2,2-
tri¯uoro-1-hydroxyethyl)pyrrole-5-carboxylate --S)-5).
A solution of (S)-4 (300 mg, 0.92 mmol) in acetic acid
(7.0 mL) was treated similarly with Pb(OAc)4, and the
mixture was worked up similarly as in the case of (R)-5
to give (S)-5 (351 mg, 99%, .95% ee from NMR
analysis of Mosher's ester). (S)-5: mp 90±918C (CH2Cl2±
4.1.8. Methyl 4---R)-1-acetoxy-2,2,2-tri¯uoroethyl)-2-
iodo-3-methylpyrrole-5-carboxylate --R)-9). A solution
of I2 (3.59 g, 14.1 mmol) and NaI (3.89 g, 26.0 mmol) in
H2O (20 mL) was added to a mixture of (R)-8 (3.43 g,
10.6 mmol) and NaHCO3 (2.76 g, 32.9 mmol) in
CH2ClCH2Cl±H2O (20 mL, 20 mL), and the mixture was
re¯uxed for 40 min. After the excess of iodine was reduced
by saturated NaHSO3, the mixture was extracted with
CH2Cl2. The CH2Cl2 layer was washed with H2O and
dried over anhydrous MgSO4. After evaporation of the
solvent under vacuum, the residue was separated by column
chromatography (SiO2, CH2Cl2), and recrystallized from
hexane±CH2Cl2 to give (R)-9 (3.30 g, 77%). (R)-9: color-
20
hexane). [a]D ˆ165.88 (c 1.16, CH2Cl2). MS (EI) m/z: 385
(M1). HRMS C18H18F3NO5: 385.114 (M1). Found:
385.114.
4.1.12. Benzyl 4---S)-1-acetoxy-2,2,2-tri¯uoroethyl)-3,5-
dimethylpyrrole-2-carboxylate --S)-6). In a stream of
Ar, acetyl chloride (435 mL, 6.12 mmol) was added to a
solution of (S)-4 (919 mg, 2.81 mmol) and 4-dimethyl-
aminopyridine (739 mg, 6.05 mmol) in anhydrous CH2Cl2
(42 mL) at room temperature, and the mixture was stirred
for 1.5 h at the same temperature. After the mixture was
worked up as in the case of (R)-6, the crude product was
separated by column chromatography (SiO2, CH2Cl2) to
give (S)-6 (998 mg, 96%) as a colorless syrup. (S)-6:
20
less crystals. Mp 109±1118C. [a]D ˆ210.28 (c 2.17,
CH2Cl2). MS (EI) m/z: 405 (M1). HRMS C11H11F3INO4:
404.969 (M1). Found: 404.968. IR (KBr) nmax 3308,
1
1772, 1696, 1448, 1398, 1384 cm21. H NMR (CDCl3) d:
9.26 (1H, bs), 7.13 (1H, q, Jˆ7.6 Hz), 3.91 (3H, s), 2.17
(3H, s), 2.14 (3H, s). 19F NMR (CDCl3) d: 270.98 (3F, d,
Jˆ7.6 Hz).
20
[a]D ˆ156.98 (c 2.58, CH2Cl2). MS (EI) m/z: 369

M. Omote et al. / Tetrahedron 57 ,2001) 8085±8094
8091
(M1). HRMS C18H18F3NO4: 369.119 (M1). Found:
369.119.
(566 mg, 83%). (S)-11: mp 99±1008C (CH2Cl2±hexane).
20
[a]D ˆ124.38 (c 2.39, CH2Cl2). MS (EI) m/z: 313 (M1).
HRMS C15H14F3NO3: 313.092 (M1). Found: 313.093.
4.1.13. Benzyl 4---S)-1-acetoxy-2,2,2-tri¯uoroethyl)-5-
methoxycarbonyl-3-methylpyrrole-2-carboxylate --S)-7).
In a stream of Ar, sulfuryl chloride (5.41 mL, 67.3 mmol)
was added to a solution of (S)-6 (5.99 g, 16.2 mmol) in
anhydrous CH2Cl2±Et2O (39.0 mL, 61.0 mL) at room
temperature, and the mixture was stirred for 1.5 h. The
mixture was concentrated under vacuum, and the residue
was dissolved in acetone (84 mL) and H2O (18 mL). A
similar workup of the mixture as in the case of (R)-7 gave
the carboxylic compound (6.43 g, 99%). Coloress crystals
(CH2Cl2±hexane). Mp 142±1448C. MS (EI) m/z: 399 (M1).
HRMS C18H16F3NO6: 399.093 (M1). Found: 399.092.
4.1.18. Dibenzyl -3R,40R)-4,30-dimethyl-3,40-bis-2,2,2-
tri¯uoro-1-hydroxyethyl)-2,20-dipyrrylmethane-5,50-di-
carboxylate --R,R)-12). In a stream of Ar, boron tri¯uoride
diethyl etherate (20 mL, 0.16 mmol) was added to a solution
of (R)-5 (62 mg, 0.16 mmol) and (R)-11 (51 mg,
0.16 mmol) in anhydrous CH2Cl2 (5.0 mL) under ice-cool-
ing, and the mixture was stirred for 1 h at room temperature.
The mixture was poured into ice-H2O and the whole was
extracted with CH2Cl2. The CH2Cl2 layer was washed with
H2O and dried over anhydrous MgSO4. After evaporation of
the solvent under vacuum, the residue was separated by
column chromatography (SiO2, Et2O±CH2Cl2, 5:95) to
give (R,R)-12 (91 mg, 88%, .95% ee from NMR analysis
of Mosher's ester). (R,R)-12: colorless crystals (CH2Cl2±
Treatment of the carboxylic acid (6.43 g, 16.1 mmol) with
CH2N2 and a similar workup as in the case of (R)-7 gave (S)-
20
20
7 (5.39 g, 81%) as a colorless syrup. (S)-7: [a]D ˆ17.488
hexane). Mp 80±828C. [a]D ˆ2152.48 (c 1.01, CH2Cl2).
(c 1.30, CH2Cl2). MS (EI) m/z: 413 (M1). HRMS
MS (EI) m/z: 638 (M1). HRMS C31H28F6N2O6: 638.185
C19H18F3NO6: 413.109 (M1). Found: 413.109.
(M1). Found: 638.186. H NMR (CDCl3) d: 9.62 (1H,
1
bs), 8.83 (1H, bs), 7.34 (5H, s), 7.33 (5H, s), 6.88 (1H, d,
Jˆ11.3 Hz), 5.27 (1H, d, Jˆ12.2 Hz), 5.25 (1H, d, Jˆ
12.2 Hz), 5.23 (1H, d, Jˆ12.2 Hz), 5.22 (1H, d, Jˆ
12.2 Hz), 5.11 (1H, q, Jˆ7.0 Hz), 5.03 (1H, dq, Jˆ11.3,
7.0 Hz), 4.10 (1H, d, Jˆ16.5 Hz), 3.83 (1H, d, Jˆ
16.5 Hz), 3.19 (1H, bs), 2.29 (3H, s), 2.03 (3H, s). 19F
NMR (CDCl3) d: 274.05 (3F, d, Jˆ7.0 Hz), 274.15 (3F,
d, Jˆ7.0 Hz).
4.1.14. 4---S)-1-Acetoxy-2,2,2-tri¯uoroethyl)-5-methoxy-
carbonyl-3-methylpyrrole-2-carboxylic acid --S)-8). A
solution of (S)-7 (622 mg, 1.51 mmol) in THF (13 mL)
was shaken in an atmosphere of H2 in the presence of 5%
Pd-C (53 mg), and the mixture was worked up as in the case
of (R)-8 to give (S)-8 (480 mg, 99%). (S)-8: colorless crystals
(CH2Cl2±hexane). Mp 188±1908C. MS (EI) m/z: 323 (M1).
HRMS C12H12F3NO6: 323.062 (M1). Found: 323.062.
4.1.19. -3R,40R)-4,30-Dimethyl-3,40-bis-2,2,2-tri¯uoro-1-
hydroxyethyl)-2,20-dipyrrylmethane-5,50-dicarboxylic
acid --R,R)-13). A solution of (R,R)-12 (91 mg, 0.14 mmol)
in THF (5.0 mL) was shaken in an atmosphere of H2 in the
presence of 5% Pd-C (26 mg) until absorption of H2 was no
more observed. After ®ltration of the catalyst and evapo-
ration of the solvent, the residue was recrystallized from
hexane±CH2Cl2 to give (R,R)-13 (64 mg, 98%). (R,R)-13:
colorless crystals. Mp 121±1248C. MS (EI) m/z: 458 (M1).
1H NMR (CDCl3) d: 10.75 (1H, s), 10.07 (1H, s), 8.27 (4H,
bs), 5.13 (1H, q, Jˆ7.3 Hz), 5.07 (1H, q, Jˆ7.3 Hz), 4.22
(1H, d, Jˆ16.0 Hz), 3.82 (1H, d, Jˆ16.0 Hz), 2.29 (3H, s),
2.07 (3H, s). 19F NMR (CDCl3) d: 273.54 (3F, d, Jˆ
7.3 Hz), 273.96 (3F, d, Jˆ7.3 Hz).
4.1.15. Methyl 4---S)-1-acetoxy-2,2,2-tri¯uoroethyl)-2-
iodo-3-methylpyrrole-5-carboxylate --S)-9). A solution
of iodine (2.03 g, 8.00 mmol) and sodium iodide (2.20 g,
14.7 mmol) in H2O (11 mL) was added to a mixture of
(S)-8 (1.94 g, 6.00 mmol) and anhydrous sodium bicarbo-
nate (1.56 g, 18.6 mmol) in CH2ClCH2Cl±H2O (11 mL,
11 mL), and the mixture was re¯uxed for 40 min. After
the mixture was worked up as in the case of (R)-9, the
crude product was separated by column chromatography
(SiO2, CH2Cl2), and recrystallized from hexane±CH2Cl2 to
give (S)-9 (2.31 g, 95%). (S)-9: colorless crystals. Mp 109±
20
1118C. [a]D ˆ110.18 (c 2.35, CH2Cl2). MS (EI) m/z: 405
(M1). HRMS C11H11F3INO4: 404.969 (M1). Found:
404.969.
4.1.20. -3R,8R)-3,8-Bis-2,2,2-tri¯uoro-1-hydroxyethyl)-
deuteroporphyrin dimethyl ester --R,R)-HFHP-DME
-R,R)-16). In a stream of Ar, (R,R)-13 (64 mg, 0.14 mmol)
was dissolved in degassed ethanolamine (2.7 mL) and
stirred at 2008C for 30 min. The mixture was poured into
ice-H2O and the whole was extracted with CH2Cl2. The
CH2Cl2 layer was washed with H2O and dried over
anhydrous MgSO4. After evaporation of the solvent under
vacuum, the residue was used for the next step without
further puri®cation.
4.1.16. Methyl 3---S)-1-acetoxy-2,2,2-tri¯uoroethyl)-4-
methylpyrrole-2-carboxylate --S)-10). A solution of (S)-
9 (2.26 g, 5.58 mmol) in MeOH (28 mL) was stirred in an
atmosphere of H2 in the presence of PtO2 (37 mg) and
anhydrous NaOAc (1.40 g, 17.1 mmol), and the mixture
was worked up as in the case of (R)-10 to give (S)-10
20
(1.51 g, 97%). (S)-10: mp 139±1408C. [a]D ˆ128.28 (c
2.35, CH2Cl2). MS (EI) m/z: 279 (M1). HRMS
C11H12F3NO4: 279.072 (M1). Found: 279.072.
4.1.17. Benzyl 4-methyl-3---S)-2,2,2-tri¯uoro-1-hydroxy-
ethyl)pyrrole-2-carboxylate --S)-11). In a stream of Ar, a
solution of NaN(Si(CH3)3)2 (1.0 M in THF, 6.0 mL) was
In a stream of Ar, a solution of p-toluenesulfonic acid mono-
hydrate (86 mg, 0.45 mmol) in anhydrous MeOH (1.4 mL)
was added to a solution of the above residue (51 mg,
0.14 mmol) and 5,50-diformyl-3,30-bis(2-methoxycarbonyl-
ethyl)-4,40-dimethyl-2,20-dipyrrylmethane13 (15, 57 mg,
0.14 mmol) in anhydrous CH2Cl2±MeOH (14 mL,
1.4 mL) at room temperature, and the mixture was stirred
added dropwise to
a solution of (S)-10 (607 mg,
2.18 mmol) in anhydrous PhCH2OH (6.0 mL) at 808C, and
the mixture was re¯uxed for 5 min. The mixture was worked
up and separated as in the case of (R)-11 to give (S)-11

8092
M. Omote et al. / Tetrahedron 57 ,2001) 8085±8094
for 24 h. Further, a saturated solution of zinc acetate in
anhydrous MeOH (1.4 mL) was added and the mixture
was stirred for 24 h in air at room temperature. The mixture
was concentrated under vacuum, and the residue was stirred
with 5% sulfuric acid in MeOH at room temperature for
24 h. The mixture was poured into ice-H2O and the whole
was extracted with CH2Cl2. The CH2Cl2 layer was washed
with H2O and dried over anhydrous MgSO4. After evapo-
ration of the solvent under vacuum, the residue was sepa-
rated by column chromatography (SiO2, Et2O±CH2Cl2,
15:85) to give (R,R)-HFHP-DME ((R,R)-16, 37 mg, 37%,
89% ee from NMR analysis of Mosher's ester). (R,R)-16:
deep violet crystals (CH2Cl2±hexane). Mp 279±2818C. MS
(EI) m/z: 734 (M1). HRMS C36H36F6N4O6: 734.254 (M1).
Found: 734.253. IR (KBr) nmax 3472, 3315, 1738, 1725,
1268, 1163, 1129 cm21. UV (dichloromethane) l (1max):
439 (31510), 525 (21306), 557 (12490), 599 (10776),
was dissolved in degassed ethanolamine (4.1 mL) and
stirred at 2008C for 30 min. The mixture was poured into
ice-H2O and the whole was extracted with CH2Cl2. The
CH2Cl2 layer was washed with H2O and dried over anhy-
drous MgSO4. After evaporation of the solvent under
vacuum, the residue was used for the next step.
In a stream of Ar, a solution of p-toluenesulfonic acid mono-
hydrate (130 mg, 0.68 mmol) in anhydrous MeOH (2.2 mL)
was added to a solution of the above residue (77 mg,
0.21 mmol) and 15 (86 mg, 0.21 mmol) in anhydrous
CH2Cl2±MeOH (22 mL, 2.2 mL) at room temperature,
and the mixture was stirred for 24 h. The mixture was
treated with a saturated solution of zinc acetate in anhydrous
MeOH (2.2 mL) similarly as in the case of (R,R)-16. After
concentration under vacuum and treatment of the residue
with 5% sulfuric acid in MeOH (30 mL) for 24 h at room
temperature, the mixture was worked up as in the case of
(R,R)-16 to give (R,S)-HFHP-DME ((R,S)-16, 44 mg, 29%,
91% ee). (R,S)-16: deep violet crystals (CH2Cl2±hexane).
Mp 236±2388C. MS (EI) m/z: 734 (M1). HRMS
C36H36F6N4O6: 734.254 (M1). Found: 734.254. IR (KBr)
nmax 3487, 3318, 1745, 1721, 1262, 1168, 1129 cm21. UV
(dichloromethane) l (1max): 435 (27959), 525 (12776), 560
1
649 nm (5143). H NMR (CDCl3) d: 10.56 (1H, s), 10.44
(1H, s), 9.91 (1H, s), 9.87 (1H, s), 6.99 (2H, m), 6.56 (1H, q,
Jˆ7.3 Hz), 6.50 (1H, q, Jˆ7.3 Hz), 4.26 (2H, t, Jˆ7.3 Hz),
4.24 (2H, t, Jˆ7.3 Hz), 3.64 (3H, s), 3.60 (3H, s), 3.58 (3H,
s), 3.56 (3H, s), 3.51 (3H, s), 3.46 (3H, s), 3.18 (2H, t,
Jˆ7.3 Hz), 3.16 (2H, t, Jˆ7.3 Hz), 23.96 (2H, bs). 19F
NMR (CDCl3) d: 271.56 (6F, d, Jˆ7.3 Hz).
1
(8000), 599 (7755), 648 nm (3918). H NMR (CDCl3) d:
4.1.21. Dibenzyl -3R,40S)-4,30-dimethyl-3,40-bis-2,2,2-
tri¯uoro-1-hydroxyethyl)-2,20-dipyrrylmethane-5,50-
dicarboxylate --R,S)-12). In a stream of Ar, boron tri-
¯uoride diethyl etherate (32 mL, 0.26 mmol) was added to
a solution of (R)-5 (98 mg, 0.26 mmol) and (S)-11 (80 mg,
0.26 mmol) in anhydrous CH2Cl2 (8.0 mL) under ice-cool-
ing, and then the mixture was stirred for 1 h at room
temperature. Workup of the mixture similarly as in the
case of (R,R)-12 gave (R,S)-12 (150 mg, 92%, 95% ee).
(R,S)-12: colorless crystals (CH2Cl2±hexane). Mp 86±
10.51 (1H, s), 10.40 (1H, s), 9.89 (1H, s), 9.87 (1H, s), 6.48
(2H, q, Jˆ7.3 Hz), 6.40 (2H, bs), 4.30 (2H, t, Jˆ7.8 Hz),
4.27 (2H, t, Jˆ7.8 Hz), 3.66 (3H, s), 3.64 (3H, s), 3.63 (3H,
s), 3.60 (3H, s), 3.54 (3H, s), 3.49 (3H, s), 3.23 (2H, t, Jˆ
7.8 Hz), 3.21 (2H, t, Jˆ7.8 Hz), 24.01 (2H, bs). 19F NMR
(CDCl3) d: 271.78 (3F, d, Jˆ7.3 Hz), 271.95 (3F, d, Jˆ
7.3 Hz).
4.1.24. Dibenzyl -3S,40R)-4,30-dimethyl-3,40-bis-2,2,2-
tri¯uoro-1-hydroxyethyl)-2,20-dipyrrylmethane-5,50-di-
carboxylate --S,R)-12). In a stream of Ar, boron tri¯uoride
diethyl etherate (20 mL, 0.16 mmol) was added to a solution
of (S)-5 (98 mg, 0.25 mmol) and (R)-11 (80 mg, 0.26 mmol)
in anhydrous CH2Cl2 (5.0 mL) under ice-cooling, and then
the mixture was stirred for 1 h at room temperature. Workup
of the mixture as in the case of (R,R)-12 gave (S,R)-12
(130 mg, 80%, .95% ee). (S,R)-12: colorless crystals
20
888C. [a]D ˆ2165.58 (c 0.989, CH2Cl2). MS (EI) m/z:
638 (M1). HRMS C31H28F6N2O6: 638.185 (M1). Found:
638.184. H NMR (CDCl3) d: 9.64 (1H, bs), 8.87 (1H,
1
bs), 7.32 (5H, s), 7.30 (5H, s), 6.90 (1H, bd, Jˆ11.3 Hz),
5.26 (1H, d, Jˆ12.2 Hz), 5.24 (1H, d, Jˆ12.2 Hz), 5.22 (1H,
d, Jˆ12.2 Hz), 5.19 (1H, d, Jˆ12.2 Hz), 5.10 (1H, qd,
Jˆ7.3, 4.0 Hz), 4.97 (1H, dq, Jˆ11.3, 7.3 Hz), 4.10 (1H,
d, Jˆ16.5 Hz), 3.84 (1H, d, Jˆ16.5 Hz), 3.27 (1H, bd,
Jˆ4.0 Hz), 2.29 (3H, s), 2.01 (3H, s). 19F NMR (CDCl3)
d: 274.07 (3F, d, Jˆ7.3 Hz), 274.27 (3F, d, Jˆ7.3 Hz).
20
(CH2Cl2±hexane). Mp 81±838C. [a]D ˆ1128.088 (c
1.01, CH2Cl2). MS (EI) m/z: 638 (M1). HRMS
1
C31H28F6N2O6: 638.185 (M1). Found: 638.185. H NMR
(CDCl3) d: 9.65 (1H, bs), 8.84 (1H, bs), 7.34 (5H, s), 7.32
(5H, s), 6.91 (1H, bd, Jˆ11.0 Hz), 5.27 (1H, d, Jˆ12.2 Hz),
5.26 (1H, d, Jˆ12.2 Hz), 5.23 (1H, d, Jˆ12.2 Hz), 5.20 (1H,
d, Jˆ12.2 Hz), 5.11 (1H, q, Jˆ7.3 Hz), 4.98 (1H, dq, Jˆ
11.0, 7.3 Hz), 4.11 (1H, d, Jˆ16.5 Hz), 3.84 (1H, d, Jˆ
16.5 Hz), 3.21 (1H, bs), 2.29 (3H, s), 2.02 (3H, s). 19F
NMR (CDCl3) d: 274.02 (3F, d, Jˆ7.3 Hz), 274.24 (3F,
d, Jˆ7.3 Hz).
4.1.22. -3R,40S)-4,30-Dimethyl-3,40-bis-2,2,2-tri¯uoro-1-
hydroxyethyl)-2,20-dipyrrylmethane-5,50-dicarboxylic
acid --R,S)-13). A solution of (R,S)-12 (137 mg, 0.22 mmol)
in THF (7.3 mL) was shaken in an atmosphere of H2 in the
presence of 5% Pd-C (38 mg) until absorption of H2 was no
more observed. The mixture was worked up as in the case of
(R,R)-13 to give (R,S)-13 (98 mg, 99%). (R,S)-13: colorless
crystals (CH2Cl2±hexane). Mp 121±1258C. MS (EI) m/z:
1
458 (M1). H NMR (CDCl3) d: 10.87 (1H, s), 10.10 (1H,
4.1.25. -3S,40R)-4,30-Dimethyl-3,40-bis-2,2,2-tri¯uoro-1-
hydroxyethyl)-2,20-dipyrrylmethane-5,50-dicarboxylic
s), 6.39 (4H, bs), 5.14 (1H, q, Jˆ7.3 Hz), 4.97 (1H, q,
Jˆ7.3 Hz), 4.25 (1H, d, Jˆ16.0 Hz), 3.85 (1H, d, Jˆ
16.0 Hz), 2.31 (3H, s), 2.07 (3H, s). 19F NMR (CDCl3) d:
273.49 (3F, d, Jˆ7.3 Hz), 274.13 (3F, d, Jˆ7.3 Hz).
acid --S,R)-13).
A
solution of (S,R)-12 (130 mg,
0.20 mmol) in THF (7.0 mL) was shaken in an atmosphere
of H2 in the presence of 5% Pd-C (36 mg) until absorption of
H2 was no more observed. The mixture was worked up as in
the case of (R,R)-13 to give (S,R)-13 (92 mg, 98%). (S,R)-
13: colorless crystals (CH2Cl2±hexane). Mp 120±1248C.
4.1.23. -3R,8S)-3,8-Bis-2,2,2-tri¯uoro-1-hydroxyethyl)-
deuteroporphyrin dimethyl ester --R,S)-HFHP-DME
-R,S)-16). In a stream of Ar, (R,S)-13 (98 mg, 0.21 mmol)
1
MS (EI) m/z: 458 (M1). H NMR (CDCl3) d: 10.81 (1H,

M. Omote et al. / Tetrahedron 57 ,2001) 8085±8094
8093
s), 10.08 (1H, s), 8.29 (4H, bs), 5.15 (1H, q, Jˆ7.3 Hz),
4.97 (1H, q, Jˆ7.3 Hz), 4.26 (1H, d, Jˆ16.7 Hz), (1H, d,
Jˆ16.7 Hz), 2.28 (3H, s), 2.06 (3H, s). 19F NMR
(CDCl3) d: 273.51 (3F, d, Jˆ7.3 Hz), 274.16 (3F, d,
Jˆ7.3 Hz).
hydroxyethyl)-2,20-dipyrrylmethane-5,50-dicarboxylic
acid --S,S)-13). A solution of (S,S)-12 (191 mg, 0.30 mmol)
in THF (10 mL) was shaken in an atmosphere of H2 in the
presence of 5% Pd-C (53 mg) until absorption of H2 was no
more observed. The mixture was worked up as in the case of
(R,R)-13 to give (S,S)-13 (134 mg, 98%). (S,S)-13: colorless
crystals (CH2Cl2±hexane). Mp 124±1278C. MS (EI) m/z:
4.1.26. -3S,8R)-3,8-Bis-2,2,2-tri¯uoro-1-hydroxyethyl)-
deuteroporphyrin dimethyl ester --S,R)-HFHP-DME
-S,R)-16). In a stream of Ar, (S,R)-13 (92 mg, 0.20 mmol)
was dissolved in degassed ethanolamine (3.9 mL) and
stirred at 2008C for 30 min. The mixture was poured into
ice-H2O and the whole was extracted with CH2Cl2. The
CH2Cl2 layer was washed with H2O and dried over
anhydrous MgSO4. After evaporation of the solvent under
vacuum, the residue was used for the next step.
1
458 (M1). H NMR (CDCl3) d: 10.78 (1H, s), 10.15 (1H,
s), 8.77 (4H, bs), 5.10 (1H, q, Jˆ7.3 Hz), 4.93 (1H, q,
Jˆ7.3 Hz), 4.15 (1H, d, Jˆ16.0 Hz), 3.78 (1H, d, Jˆ
16.0 Hz), 2.21 (3H, s), 1.99 (3H, s). 19F NMR (CDCl3) d:
273.49 (3F, d, Jˆ7.3 Hz), 273.95 (3F, d, Jˆ7.3 Hz).
4.1.29. -3S,8S)-3,8-Bis-2,2,2-tri¯uoro-1-hydroxyethyl)-
deuteroporphyrin dimethyl ester --S,S)-HFHP-DME
-S,S)-16). In a stream of Ar, (S,S)-13 (134 mg, 0.29
mmol) was dissolved in degassed ethanolamine (5.7 mL)
and stirred at 2008C for 30 min. The mixture was poured
into ice-H2O and the whole was extracted with CH2Cl2. The
CH2Cl2 layer was washed with H2O and dried over
anhydrous MgSO4. After evaporation of the solvent under
vacuum, the residue was used for the next step.
In a stream of Ar, a solution of p-toluenesulfonic acid mono-
hydrate (123 mg, 0.65 mmol) in anhydrous MeOH (2.0 mL)
was added to a solution of the above residue (73 mg,
0.20 mmol) and 15 (82 mg, 0.20 mmol) in anhydrous
CH2Cl2±MeOH (20 mL, 2.0 mL) at room temperature,
and the mixture was stirred for 24 h. Further, a saturated
solution of zinc acetate in anhydrous MeOH (2.0 mL) was
added and the mixture was stirred for 24 h in air at room
temperature. The whole mixture was concentrated under
vacuum, and the residue was stirred with 5% sulfuric acid
in MeOH (20 mL) for 24 h at room temperature. A similar
workup of the mixture as in the case of (R,R)-16 gave (S,R)-
HFHP-DME ((S,R)-16, 59 mg, 41%, 89% ee). (S,R)-16:
deep violet crystals (CH2Cl2±hexane). Mp 238±2408C.
MS (EI) m/z: 734 (M1). HRMS C36H36F6N4O6: 734.254
(M1). Found: 734.254. IR (KBr) nmax 3479, 3319, 1741,
1721, 1262, 1162, 1129 cm21. UV (dichloromethane) l
(1max): 435 (27102), 525 (15347), 559 (9184), 599 (8041),
In a stream of Ar, a solution of p-toluenesulfonic acid mono-
hydrate (180 mg, 0.95 mmol) in anhydrous MeOH (3.0 mL)
was added to a solution of the above residue (107 mg,
0.29 mmol) and 15 (120 mg, 0.30 mmol) in anhydrous
CH2Cl2±MeOH (30 mL, 3.0 mL) at room temperature,
and the mixture was stirred for 24 h. Further, a saturated
solution of zinc acetate in anhydrous MeOH (3.0 mL) was
added and the mixture was stirred for 24 h in air at room
temperature. The whole mixture was concentrated under
vacuum, and the residue was stirred with 5% sulfuric acid
in MeOH (20 mL) at room temperature for 24 h. A similar
workup of the mixture as in the case of (R,R)-HFHP-DME
gave (S,S)-HFHP-DME ((S,S)-16, 53 mg, 25%, 86% ee).
(S,S)-16: deep violet crystals (CH2Cl2±hexane). Mp 275±
2778C. MS (EI) m/z: 734 (M1). HRMS C36H36F6N4O6:
734.254 (M1). Found: 734.253. IR (KBr) nmax 3480,
3350, 1745, 1726, 1268, 1164, 1130 cm21. UV (dichloro-
methane) l (1max): 439 (31224), 525 (18286), 559 (10898),
599 (9796), 649 nm (5020). 1H NMR (CDCl3) d: 10.43 (2H,
s), 9.93 (1H, s), 9.92 (1H, s), 6.57 (1H, bs), 5.54 (1H, q,
Jˆ7.3 Hz), 6.42 (1H, q, Jˆ7.3 Hz), 6.33 (1H, bs), 4.33 (2H,
t, Jˆ7.3 Hz), 4.31 (2H, t, Jˆ7.3 Hz), 3.67 (3H, s), 3.65 (3H,
s), 3.60 (6H, s), 3.57 (3H, s), 3.51 (3H, s), 3.26 (2H, t, Jˆ
7.3 Hz), 3.24 (2H, t, Jˆ7.3 Hz), 23.98 (2H, bs). 19F NMR
(CDCl3) d: 271.67 (3F, d, Jˆ7.3 Hz), 271.75 (3F, d, Jˆ
7.3 Hz).
1
648 nm (3265). H NMR (CDCl3) d: 10.38 (1H, s), 10.23
(1H, s), 9.83 (2H, s), 6.35 (2H, q, Jˆ7.3 Hz), 5.98 (1H, bs),
5.91 (1H, bs), 4.28 (2H, t, Jˆ7.8 Hz), 4.24 (2H, t,
Jˆ7.8 Hz), 3.66 (3H, s), 3.64 (3H, s), 3.54 (3H, s), 3.53
(3H, s), 3.50 (3H, s), 3.46 (3H, s), 3.22 (2H, t, Jˆ7.8 Hz),
3.20 (2H, t, Jˆ7.8 Hz), 24.08 (2H, bs). 19F NMR (CDCl3)
d: 271.77 (6F, d, Jˆ7.3 Hz).
4.1.27. Dibenzyl -3S,40S)-4,30-dimethyl-3,40-bis-2,2,2-
tri¯uoro-1-hydroxyethyl)-2,20-dipyrrylmethane-5,50-di-
carboxylate --S,S)-12). In a stream of Ar, boron tri¯uoride
diethyl etherate (24 mL, 0.20 mmol) was added to a solution
of (S)-5 (74 mg, 0.190 mmol) and (S)-11 (60 mg,
0.190 mmol) in anhydrous CH2Cl2 (6.0 mL) under ice-
cooling, and then the mixture was stirred for 1 h at room
temperature. Workup of the mixture as in the case of (R,R)-
12 gave (S,S)-12 (106 mg, 87%, 93% ee). (S,S)-12: colorless
20
crystals (CH2Cl2±hexane). Mp 88±908C. [a]D ˆ1122.78
References
(c 1.20, CH2Cl2). MS (EI) m/z: 638 (M1). HRMS
1
C31H28F6N2O6: 638.185 (M1). Found: 638.185. H NMR
1. (a) Lipson, R. I.; Baldes, E. J.; Olsen, A. M. J. Natl Cancer
Inst. 1961, 26, 1. (b) Diamond, I.; Granelli, S.; McDonagh,
A. F.; Nielsen, S.; Wilson, C. B.; Jaenicke, R. Lancet 1972,
1175. (c) Dougherty, T. J.; Grinsley, G.; Fiel, B. R. J. Natl
Cancer Inst. 1975, 55, 115.
(CDCl3) d: 9.63 (1H, bs), 8.90 (1H, bs), 7.32 (5H, s), 7.29
(5H, s), 6.88 (1H, bd, Jˆ11.3 Hz), 5.25 (1H, d, Jˆ12.2 Hz),
5.22 (1H, d, Jˆ12.2 Hz), 5.21 (2H, s), 5.11 (1H, qd, Jˆ7.3,
3.4 Hz), 5.03 (1H, dq, Jˆ11.3, 7.3 Hz), 4.08 (1H, d, Jˆ
16.5 Hz), 3.81 (1H, d, Jˆ16.5 Hz), 3.25 (1H, bd, Jˆ
3.4 Hz), 2.29 (3H, s), 2.02 (3H, s). 19F NMR (CDCl3) d:
274.03 (3F, d, Jˆ7.3 Hz), 274.14 (3F, d, Jˆ7.3 Hz).
2. Bonnet, R. Chem. Soc. Rev. 1995, 19.
3. (a) Becker, E.; Bradley, R.; Watson, C. J. Am. Chem. Soc.
1961, 83, 3743. (b) Dougherty, T. J. Photochem. Photobiol.
1987, 45, 879. (c) Mironov, A. F.; Nizhnik, A. N.; Nockel,
A. Y. J. Photochem. Photobiol. B 1990, 4, 297.
4.1.28. -3S,40S)-4,30-Dimethyl-3,40-bis-2,2,2-tri¯uoro-1-

8094
M. Omote et al. / Tetrahedron 57 ,2001) 8085±8094
4. (a) Ando, A.; Kumadaki, I. Heterocycles 1996, 42, 885.
Tetrahedron Lett. 1991, 32, 6835. (b) Corey, E. J.; Link,
J . O.Tetrahedron Lett. 1992, 33, 3431.
(b) Ando, A.; Kumadaki, I. J. Fluorine Chem. 1999, 100, 135.
5. Ando, A.; Kitamura, T.; Aono, S.; Sato, H.; Omote, M.;
Koyama, M.; Takagi, T.; Miki, T.; Kumadaki, I.; Sato, H.
Heterocycles 1993, 35, 1309.
11. (a) Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990, 31, 611.
(b) Corey, E. J.; Azimioara, M.; Sarshar, S. Tetrahedron Lett.
1992, 33, 3429. (c) Corey, E. J.; Link, J. O. Tetrahedron Lett.
1992, 33, 4141. (d) Wallbaum, S.; Martens, J. Tetrahedron:
Asymmetry 1992, 3, 1475.
6. Sato, H.; Ido, K.; Kimura, K. Clin. Chem. 1994, 40, 1239.
7. Omote, M.; Ando, A.; Takagi, T.; Koyama, M.; Kumadaki, I.
Tetrahedron 1996, 52, 13961.
12. Arsenault, G. P.; Bullock, E.; MacDonald, S. F. J. Am. Chem.
Soc. 1960, 82, 4384.
8. Omote, M.; Ando, A.; Takagi, T.; Koyama, M.; Kumadaki, I.;
Shiro, M. Heterocycles 1997, 47, 65.
13. Robinson, J. A.; McDonald, E.; Battersby, A. R. J. Chem.
Soc., Perkin Trans. 1 1985, 1699.
9. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
10. (a) Corey, E. J.; Cheng, X.; Cimprich, K. A.; Sarshar, S.