New syntheses of the C,D-ring pyrromethenones of phytochrome and phycocyanin

Article abstract of DOI:10.1021/jo005531k

Pyrromethenone 7, the C,D-ring segment of phytochrome (Pr, 4), has been prepared in an efficient fashion employing three new strategies. Each of these has potential advantages for the synthesis of labeled material. Our first approach is related to the Gos

Full text of DOI:10.1021/jo005531k

8478
J . Org. Chem. 2000, 65, 8478-8489
New Syn th eses of th e C,D-Rin g P yr r om eth en on es of P h ytoch r om e
a n d P h ycocya n in
Peter A. J acobi,* Robert W. DeSimone,† Indranath Ghosh, J iasheng Guo,‡
Sam H. Leung,§ and Douglas Pippin
Hall-Atwater Laboratories, Wesleyan University, Middletown, Connecticut 06459-0180, and
Burke Chemical Laboratory, Dartmouth College, Hanover, New Hampshire 03755
peter.a.jacobi@dartmouth.edu
Received May 30, 2000
Pyrromethenone 7, the C,D-ring segment of phytochrome (P r , 4), has been prepared in an efficient
fashion employing three new strategies. Each of these has potential advantages for the synthesis
of labeled material. Our first approach is related to the Gossauer synthesis, with the difference
that strong alkali is avoided in the condensation of the C- and D-ring components 8 and 17. The
key silyloxypyrrole 17 was readily prepared on multigram scales beginning with inexpensive
butyrolactone (10). A second synthesis began with 2-acetylbutyrolactone (41). The key steps involved
conversion of 41 to the Z-enoltriflate 42, followed by Pd(0)-catalyzed coupling with trimethylsilyl-
acetylene, p-chlorophenylselenide ring opening, and finally, amidation to afford the ring-D synthon
45 having the proper geometry and oxidation state for conversion to 7. Sonogashira coupling of 45
with the iodopyrrole 22, followed by oxidative elimination, and F--induced 5-exo-dig cyclization of
the resultant pyrroloalkyne 47, then completed the synthesis. In similar fashion, we have also
prepared pyrromethenone 6, the C,D-ring segment of phycocyanin (2).
In tr od u ction
In green plants, two important phenomena are driven
by light. One of these is photosynthesis, the fundamental
source of nearly all biochemical energy, which utilizes
chlorophyll (1) as the primary chromophore (Figure 1).
Chlorin 1 absorbs light between 400 and 500 nm and
600-700 nm and initiates an electron-transfer sequence
that leads ultimately to oxidation of H2O to O2 and
reduction of NADP+ to NADPH.1 Enzyme-mediated dark
reactions then convert CO2 to glucose. In addition, most
plants utilize auxiliary chromophores to supplement 1
(so-called “light-harvesting” pigments). These include
conjugated polyenes, ranging in color from yellow to
purple (carotenoids), and linear tetrapyrrole derivatives
such as phycocyanin (2) and phycoerythrin (3). These last
two compounds are protein-bound chromophores found
in blue-green, eucaryotic, and cryptomonad algae.2
F igu r e 1. Chromophores of photosynthesis.
stem growth, and chlorophyll (1) production (red light is
known to “turn on” the genes for RUBISCO). The
photoreceptor in this case is the blue-green tetrapyrrole
phytochrome (4) (Figure 2),3 a protein-bound chromo-
phore that is present in plants in much smaller quantities
than chlorophyll (4 kg of etiolated oat seedlings provide
50-60 mg of protein complex).3h In comparison to pho-
tosynthesis, where some aspects of the mechanism are
known in considerable detail, relatively little is known
about photomorphogenesis at the molecular level.4 In
Photomorphogenesis is also dependent upon light and
is the process by which growth regulatory information
is transmitted to a plant’s genetic apparatus.3 Informa-
tion of this type is vital to the timing of seasonal events,
such as flowering and fruiting, chloroplast movement,
* To whom correspondence should be addressed. Current address:
Burke Chemical Laboratory, Dartmouth College, Hanover, NH 03755.
† Current address: Neurogen Corporation, Branford, CT 06405.
‡ Current address: Glaxo Wellcome Inc., Research Triangle Park,
NC 27709.
(3) (a) Phytochrome and Photoregulation in Plants; Furuya, M., Ed.;
Academic Press: New York, 1987. For reviews on phytochrome-
mediated responses in plants, see: (b) Statter, R. L.; Galston, A. W.
In Chemistry and Biochemistry of Plant Pigments; Goodwin, T. W.,
Ed.; Academic Press: New York, 1976; Vol. 1, p 680. (c) Ru¨diger, W.;
Thu¨mmler, F. Angew. Chem., Int. Ed. Engl. 1991, 30, 1216. (d) Ru¨diger,
W. Photochem. Photobiol. 1992, 56, 803. For reviews on phytochrome
biochemistry and chromophore chemistry, see: (e) Terry, M. J .;
Wahleithner, J . A.; Lagarias, J . C. Arch. Biochem. Biophys. 1993, 306,
1. (f) Pratt, L. H.;Photochem. Photobiol. 1978, 27, 81. (g) Kendrick, R.
E.; Spruit, C. J . P. Ibid. 1977, 26, 201. Isolation and structure of
phytochrome: (h) Lagarias, J . C.; Rapoport, H. J . Am. Chem. Soc. 1980,
102, 4821. (i) Hunt, R. E.; Pratt, L. H. Plant Physiol. 1979, 64, 332. (j)
J ung, J .; Song, P.-S. Photochem. Photobiol. 1979, 29, 419.
§ Current address: Department of Chemistry, Washburn University,
Topeka, KS 66621.
(1) Lehninger, A. L. Principles of Biochemistry; Worth Publishers:
New York, 1982; pp 645-79.
(2) (a) Schoenleber, R. W.; Kim, Y.; Rapoport, H. J . Am. Chem. Soc.
1984, 106, 2645 and references therein. (b) Glazer, A. N. In The
Biochemistry of Plants; Hatch, M. D., Boardman, N. K., Eds.; Academic
Press: New York, 1981; Vol. 8. For a review on biliproteins, see: (c)
Tetrahedron 1983, 39, 1839; Symposia-In-Print, Bonnett, R., Ed. (d)
Scheer, H. Angew. Chem. 1981, 93, 230; Angew. Chem., Int. Ed. Engl.
1981, 20, 241.
10.1021/jo005531k CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/10/2000

C,D-Ring Pyrromethenones of Phytochrome and Phycocyanin
J . Org. Chem., Vol. 65, No. 25, 2000 8479
Sch em e 1
ated lactams of type 9 (C + D f CD; Scheme 1). This
approach is appealing due to its highly convergent
nature, and in principle, it offers a wide range of
flexibility. For example, condensation of 8 with 9a (X, G
) H) affords dihydropyrromethenone 6 in good yield
following re-esterification.5o In some instances, however,
the strongly alkaline conditions of this reaction are
incompatible with sensitive functionality. This is par-
ticularly an issue with lactams 9 having X as a leaving
group (9b,c), which are logical precursors to ∆-21 deriva-
tives related to 7. In such cases activation is typically
delayed until after condensation, which can complicate
the synthetic route.5c,m Inomata et al. recently described
a modification of this approach,5c in which the lactam 9
was substituted with a strongly electron withdrawing
group at the R-position (9c, G ) p-toluenesulfonyl, X )
STol). In this case condensation of 8 with 9c was effected
using the weaker base DBU, which alleviated the prob-
lem of propionate ester hydrolysis (see above). Subse-
quent oxidation of the STol group to the corresponding
sulfoxide then provided the necessary activation for
elimination. This methodology has a number of advan-
tages over the original strategy, although the synthesis
of 9c is lengthy (nine steps from acrolein) and requires
several expensive and/or toxic reagents.3c As described
below, we have developed a variant of the C + D f CD
approach to pyrromethenones that is amenable to mul-
tigram synthesis, and can be carried out under very mild
conditions.
F igu r e 2. Chromophore of photomorphogenesis.
part this is due to the difficulty of isolating 4 and
derivatives from natural sources,3h,i which has spurred
synthetic activity in this area.5 Recently, we reported a
stereo- and enantiospecific synthesis of pyrromethenone
5, a potential A,B-ring precursor to tetrapyrroles 2-4
(Figure 2).5f In this paper, we describe new syntheses of
pyrromethenones 6 and 7, which constitute the C,D-ring
precursors of 2 and 4, respectively.5h,i
Resu lts a n d Discu ssion
Th e C + D f CD Rou te to P yr r om eth en on es.
Nearly all reported syntheses of 6 and 7 employ some
variant of the Gossauer strategy,5m typified by the KOH
promoted condensation of formylpyrrole 8 with unsatur-
(4) (a) Andel, F., III; Murphy, J . T.; Haas, J . A.; McDowell, M. T.;
van der Hoef, I.; Lugtenburg, J .; Lagarias, J . C.; Mathies, R. A.
Biochemistry 2000, 39, 2667 and references therein. (b) Bischoff, M.;
Hermann, G.; Rentsch, S.; Strehlow, D.; Winter, S.; Chosrowjan, H. J .
Phys. Chem. B 2000, 104, 1810. (c) Mizutani, Y.; Tokutomi, S.;
Kitagawa, T. Biochemistry 1994, 33, 153. (d) Micura, R.; Grubmayr,
K. Bioorg. Med. Chem. Lett. 1994, 4, 2517. (e) Hildebrandt, P.;
Hoffmann, A.; Lindemann, P.; Heibel, G.; Braslavsky, S. E.; Schaffner,
K.; Schrader, B. Biochemistry 1992, 31, 7957. (f) Fodor, S. P. A.;
Lagarias, J . C.; Mathies, R. A. Biochemistry 1990, 29, 11141. (g)
Farrens, D. L.; Holt, R. E.; Rospendowski, B. N.; Song, P.-S.; Cotton,
T. M. J . Am. Chem. Soc. 1989, 111, 9162. (h) Thu¨mmler, F.; Ru¨diger,
W. Tetrahedron 1983, 39, 1943. (i) Ru¨diger, W.; Thu¨mmler, F.; Cmiel,
E.; Schneider, S. Proc. Natl. Acad. Sci. U.S.A. 1983, 80, 6244. See also
ref 3h.
Our strategy built upon the ready availability of the
silyloxypyrrole 17, which was synthesized in efficient
fashion beginning with butyrolactone (10) (Scheme 2).
Lactone 10 proved to be a convenient (and inexpensive)
precursor to the carboxylic acid 11, which was obtained
in 75-85% yield upon SN2-ring opening with p-chlo-
rophenylselenide anion.5i,p Acid 11 was then converted
in two steps, and excellent overall yield, to the amide
derivative 14, by initial activation with (COCl)2 followed
by in situ amination with aminoacetone dimethylacetal
(13) (10-20 g scales). The remaining steps necessary in
order to prepare 17 required considerable experimenta-
tion but were eventually reduced to a very clean process.
Thus, reaction of 14 with (Boc)2O gave an essentially
quantitative yield of the carbamate ester 15, which
underwent smooth intramolecular aldol condensation
upon treatment with t-BuOK in THF at -10 °C.5q The
resultant lactam 16 then afforded an 80-90% yield of
(5) For leading references, see: (a) J ayasundera, K. P.; Kinoshita,
H.; Inomata, K. Bull. Chem. Soc. J pn. 2000, 73, 497. (b) J acobi, P. A.;
Coutts, L. D.; Guo, J .; Hauck, S. I.; Leung, S. J . Org. Chem. 2000, 65,
205. (c) Takashi, K.; Kinoshita, H.; Inomata, K. Synlett 1999, 901. (d)
Lindner, I.; Knipp, B.; Braslavsky, S. E.; Ga¨rtner, W.; Schaffer, K.
Angew. Chem., Int. Ed. Engl. 1998, 37, 1843. (e) J ayasundera, K. P.;
Kinoshita, H.; Inomata, K. Chem Lett. 1998, 1227. (f) J acobi, P. A.;
Guo, J .; Rajeswari, S.; Zheng, W. J . Org. Chem. 1997, 62, 2907. (g)
J acobi, P. A.; Buddhu, S. C.; Fry, D.; Rajeswari, S. J . Org. Chem. 1997,
62, 2894. (h) J acobi, P. A.; Guo, J .; Hauck, S. I.; Leung, S. H.
Tetrahedron Lett. 1996, 37, 6069. (i) J acobi, P. A.; DeSimone, R. W.;
Tetrahedron Lett. 1992, 33, 6239. (j) Bishop, J . E.; Nagy, J . O.;
O’Connell, J . F.; Rapoport, H. J . Am. Chem. Soc. 1991, 113, 8024. (k)
Schoenleber, R.; Kim, Y.; Rapoport, H. J . Am. Chem. Soc. 1984, 106,
2645. (l) Thu¨mmler, F.; Ru¨diger, W. Tetrahedron 1983, 39, 1943. (m)
Weller, J .-P.; Gossauer, A. Chem. Ber. 1980, 113, 1603. (n) Gossauer,
A.; Weller, J .-P. Ibid. 1978, 111, 486. (o) Gossauer, A.; Miehe, D. J ustus
Liebigs Ann. Chem. 1974, 352. (p) Sharpless, K. B.; Laver, R. J . J .
Am. Chem. Soc. 1973, 95, 2697. See also ref 11. (q) Dillard, R. D.;
Easton, N. R. J . Org. Chem. 1966, 31, 2580. (r) Casiraghi, G.; Rassu,
G.; Spanu, P.; Pinna, L. J . Org. Chem. 1992, 57, 3760. (s) Montforts,
F.-P.; Schwartz, U. M.; Maib, P.; Mai, G. Liebigs Ann. Chem. 1990,
1037. (t) Langlois, N.; Choudhury, P. K. Tetrahedron Lett 1999, 40,
2525 and references therein.

8480 J . Org. Chem., Vol. 65, No. 25, 2000
J acobi et al.
Sch em e 2
F igu r e 3. The alkyne amide route to pyrromethenones.
important limitation. It is not suitable for the synthesis
of saturated derivatives at C17, which might be useful
for studying the mode of action of phytochrome (4) (cf.
25, Figure 3).4 Therefore, we have developed a comple-
mentary strategy to synthesize pyrromethenones of type
6 and 7, and dihydropyrromethenones of type 25, that is
equally convergent and can accommodate a wide range
of functionality. The key steps in this approach involve
the Pd(0)-catalyzed coupling of iodopyrrole 22 with
terminal alkynes 23 (X ) H, leaving group) and subse-
quent 5-exo-dig cyclization of the resultant pyrroloalkyne
amides 24.5f
As previously reported,5f,i the requisite C-ring compo-
nent 22 was conveniently synthesized using the Barton-
Zard methodology,6a which has the advantage of permit-
ting maximum flexibility in the choice of ester group R.
We then made use of a Nicholas-Schreiber reaction for
preparing the alkyne amide 30,7 our projected D-ring
precursor to 6 (Scheme 3). In related studies we exploited
this methodology for the synthesis of homochiral amides
related to 30, which required the use of chiral oxazolidi-
nones.5f,g However, in the present case we employed the
achiral oxazolidinone 27, since control of absolute ster-
eochemistry at C17-C18 was unnecessary. Thus, dibutyl-
borontriflate/i-Pr2NEt-catalyzed condensation of 27 with
the cobalt complex 26 gave a 97% yield of the racemic
Nicholas adduct 28, which by NMR analysis had exclu-
sively syn-stereochemistry at C17-C18 (determined after
the silyloxypyrrole 17 when reacted with tert-butyldi-
methylsilyl triflate (TBSOTf).5r
Our choice of pyrrole 17 as the D-ring component was
influenced by a report of Montforts et al.,5s who described
the aldol-like condensation of 2-methoxypyrroles with
pyrroloaldehydes upon treatment with 48% HBr. Al-
though these conditions proved to be too harsh for our
purposes, there was precedent that the silyloxypyrrole
17 might react with aldehydes under much milder
conditions.5r,t This in fact turned out to be the case. Lewis
acid-catalyzed condensation of 17 with the pyrroloalde-
hyde 8 occurred rapidly at -78 °C and afforded a
virtually quantitative yield of the silyl ethers 18a ,b (R
) TBS) and alcohols 18c,d (R ) H). The composition of
this diastereomeric mixture varied with the reaction
conditions, and initially each isomer was isolated and
independently characterized (cf. Experimental Section).
However, in practice, it proved to be much more conve-
nient to simply treat the mixture directly with TFA,
which effected concomitant dehydration and decarboxy-
lation to give a 95-99% yield of the dihydropyrro-
methenone 19 (R ) H). Finally, this last material was
cleanly converted to the desired C,D-ring precursor 21
by initial formylation with TMOF (70-75%, not opti-
mized), followed by peracid induced selenoxide elimina-
tion (95-99%). The material thus obtained was identical
in all respects to an authentic sample of 21.5i,m,14
(6) (a) Barton, D. H. R.; Kervagoret, J .; Zard, S. Z. Tetrahedron 1990,
46, 7587. See also: (b) May, D. A.; Lash, T. D. J . Org. Chem. 1992, 57,
4820. Following our initial communication,5i Drinan and Lash reported
a synthesis of 17a employing essentially the same procedure: (c)
Drinan, M. A.; Lash, T. D. J . Het. Chem. 1994, 31, 255. For an
alternative synthesis of 22, see: (d) (Bishop, J . E.; O’Connell, J . F.;
Rapoport, H. J . Org. Chem. 1991, 56, 5079. (e) J ackson, A. H.; Kenner,
G. W.; Smith, K. M. J . Chem. Soc. C 1971, 502.
(7) (a) Schreiber, S. L.; Klimas, M. T.; Sammakia, T. J . Am. Chem.
Soc. 1987, 109, 5749. (b) Lockwood, R. F.; Nicholas, K. M. Tetrahedron
Lett. 1977, 18, 4163.
Th e Alk yn e Am id e Rou te to P yr r om eth en on es.
Although versatile, the C + D f CD strategy has one

C,D-Ring Pyrromethenones of Phytochrome and Phycocyanin
J . Org. Chem., Vol. 65, No. 25, 2000 8481
Sch em e 3
Sch em e 4
decomplexation). Adduct 28 then afforded a 60% overall
yield of the target amide 30 by a straightforward se-
quence involving imide hydrolysis with concomitant TMS
removal (67%)8 and amidation of the resultant carboxylic
acid 29 via the mixed isobutyl carbonate derivative
(90%).9 Interestingly, simple alkyl esters corresponding
to 27 gave much lower yields of Nicholas adducts and
exhibited little selectivity between syn and anti stereo-
chemistry. Syn vs anti stereocontrol is important since
only the syn isomers undergo facile 5-exo-dig cyclization.5f
In any event, alkyne amide 30 was cleanly converted to
the dihydropyrromethenone 25 by initial Pd(0)-catalyzed
coupling with the iodopyrrole 22 (30 f 31, 99%),10
followed by F--induced cyclization (Z-isomer only, 60%
overall yield from 22).5f Finally, oxidation of 25 with DDQ
gave a 72% yield of the pyrromethenone 6, which had
identical physical and spectral properties as reported in
the literature.5k,o
We explored two approaches for the synthesis of ∆-21
pyrromethenone 7, the C,D-ring precursor to phyto-
chrome (4) (cf. Figure 2). Our initial experiments were
carried out with the imide derivative 32 (Scheme 4), itself
derived by acylation of 2-oxazolidinone with 4-bromobu-
tyryl chloride. Imide 32 underwent clean condensation
with the cobalt complex 26,5f,7 affording an ∼80% overall
yield of adduct 33 following Co-decomplexation (syn
isomer exclusively). Adduct 33 contains all of the features
necessary for eventual conversion to alkyne amides of
general structure 23 (cf. Figure 3, X ) leaving group).
Interestingly, however, all attempts at the selective
hydrolysis of the imide group in 33 led directly to the
formation of the alkyne lactone 34, which was complete
in <5 min at 0 °C (68% overall yield of 35 after TMS
cleavage). Although not anticipated, this transformation
was readily put to advantage. Thus, alkyne lactone 35
was now cleanly converted to the ring-opened alkyne
amide 37 by initial SN2 displacement with sodium
p-chlorophenylselenide (72%),11 followed by amidation of
the resultant carboxylic acid 36 with isobutylchlorofor-
mate and NH3 (93%).9 Amide 37 then gave a 57% overall
yield of dihydropyrromethenone 39 upon Pd(0)-mediated
coupling with iodopyrrole 22 (93%), followed by 5-exo-
dig cyclization of the resultant pyrroloalkyne 38 (61%,
Z-isomer only).5f Finally, as described above for 6 (Scheme
3), oxidation of 39 with DDQ afforded a 78% yield of
pyrromethenone 40 as a stable, crystalline solid, which
had identical spectral and physical properties as those
reported in the literature.5m,14 Selenide 40 has previously
been converted to 7 by oxidative elimination with H2O2
(65%).5m
(8) Evans, D. A.; Britton, T. C.; Ellman, J . A. Tetrahedron Lett. 1987,
28, 6141.
(9) J acobi, P. A.; Brielmann, H. L.; Hauck, S. I. J . Org. Chem. 1996,
61, 5013.
(10) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467. For related methodology, see: (b) Cassar, L. J .
Organomet. Chem. 1975, 93, 253. (c) Dieck, H. A.; Heck, F. R. J .
Organomet. Chem. 1975, 93, 259. (d) Stephans, R. D.; Castro, C. E. J .
Org. Chem. 1963, 28, 3313.
(11) (a) Dowd, P.; Kennedy, P. Synth. Commun. 1981, 11, 935 and
references therein. See also: (b) Liotta, D.; Santiesteban, H. Tetrahe-
dron Lett. 1977, 18, 4369. (c) Scarborough, R. M., J r.; Smith, A. B.,
III. Tetrahedron Lett. 1977, 18, 4361.
(12) (a) Scheuplein, S. W.; Harms, K.; Bru¨ckner, R.; Suffert, J . Chem.
Ber. 1992, 125, 271. See also: (b) Nakatani, K. Arai, K.; Yamada, K.;
Terashima, S. Tetrahedron Lett. 1991, 32, 3405.

8482 J . Org. Chem., Vol. 65, No. 25, 2000
J acobi et al.
Sch em e 5
Sch em e 6
We also developed a modification of the alkyne amide
strategy, which for pyrromethenone 7 is more direct, and
avoids the use of cobalt alkynes. As noted above, the
Nicholas-Schreiber methodology is extremely useful for
preparing syn-alkyne amides of type 30 and 37 in
enantiomerically pure form.5f,g This was crucial for the
preparation of chiral A,B-ring precursors such as 5
(Figure 2).5f For the synthesis of 7, however, this strategy
incorporates an unnecessary level of complexity, since the
final pyrromethenone is devoid of stereochemical fea-
tures. The stereocenters which are introduced at C17 and
C18 in 33 are ultimately destroyed by oxidation.
Our third synthesis of 7 employs the unsaturated
alkyne amide 46, which has the proper oxidation state
for final cyclization (Scheme 5). In this case, however, it
was necessary to rigorously control the double bond
geometry at C17 (phytochrome numbering). After inves-
tigating a number of routes, we were eventually able to
prepare 46 in five steps from inexpensive starting
materials. The key step in this synthesis was a stereo-
selective enolization of 2-acetylbutyrolactone (41), which
at -78 °C afforded nearly exclusively the Z-lithioenolate.
This last material, upon quenching with triflic anhydride
(Tf2O), then gave a 60-80% yield of Z-enoltriflate 42 as
the only detectable isomer (yields represent a range from
many experiments). Selectivity in this case presumably
is due to Li+ coordination with the enolate anion derived
from 41, in close analogy to the work of Bru¨ckner, Suffert
et al. with 2-formylbutyrolactone.12 Sonogashira coupling
of 42 with trimethylsilylacetylene then gave a 90-95%
yield of the alkyne lactone 43,10 which correctly sets the
double bond geometry as Z. Next, alkyne lactone 43 was
directly converted to the alkyne amide 45 by initial SN2
ring opening with sodium p-chlorophenylselenide,11 fol-
lowed by in situ amidation of the resultant carboxylic acid
44 with (COCl)2/NH3 (45-70% overall yield).9 Amide 45
is a stable crystalline solid which we have routinely
prepared on multigram scales. Finally, oxidation of 45
with H2O2 led to smooth selenoxide elimination, produc-
ing the alkene derivative 46 as an unstable, easily
polymerized solid (80-90%).
Ta ble 1. Cycliza tion of P yr r oloa lk yn e 48
entry
reagent
Pd(II)
Mont. clay
CsF/silica gel
TBAF
TBAF/Al2O3
F-/polymer
CsF/Si(OMe)4
conditions
time (h)
yield of 7 (%)
1
2
3
4
5
6
7
MeCN/rt
CHCl3/∆
THF/∆
THF/∆
THF/∆
THF/∆
THF/∆
48
13
48
96
24
13
0
0
0
40
25
0
Both 45 and 46 proved to be excellent substrates for
Pd(0)-mediated coupling with the iodopyrrole 22 (Scheme
6). On relatively small scales (<1 g), Sonogashira cou-
pling of 22 with the unsaturated alkyne amide 46 gave
a 90-95% yield of the pyrroloalkyne 48. This pathway
has the advantage of being highly convergent. However,
the success of this reaction depends on employing only
freshly prepared 46, since this material polymerizes
rapidly even when stored at 0 °C. For larger scale
reactions (>1 g), it was generally more convenient to
delay oxidative elimination until a later step of the
synthesis. Following this route, Pd(0)-catalyzed coupling
of alkyne amide 45 with 22 gave an 85-90% yield of the
stable alkyne pyrrole 47, which upon treatment with
H2O2 was cleanly converted to the identical unsaturated
derivative 48.
Finally, we investigated numerous conditions to effect
the requisite 5-exo-dig cyclization leading from 48 to the
pyrromethenone 7 (Table 1). As in our previous studies,
no cyclization was observed using Pd(II) as a catalyst,5f
using Montmorillonite K-10 clay,13a or using CsF ab-
sorbed on silica gel (entries 1-3). Some measure of
success was achieved employing a large excess of TBAF
(>6 equiv),5f which afforded ∼40% of 7 after 96 h at reflux
in THF (entry 4). Under these conditions, however,
substantial decomposition also occurred. No improvement
was observed with various modified TBAF reagents,
including TBAF/Al2O3 (entry 5, 25%), and Amberlyst A-26
quaternary ammonium fluoride resin (entry 6, 0%). By
far the best results were obtained with the reagent
system CsF/Si(OMe)4 (entry 7), which was initially
introduced by Corriu and Perz as a catalyst for Michael
(13) (a) J ackson, A. H.; Pandey, R. K.; Rao, K. R. N.; Roberts, E.
Tetrahedron Lett. 1985, 26, 793. (b) Corriu, R. J . P.; Perz, R.
Tetrahedron Lett. 1985, 26, 1311. See also (b) Ahn, K. H.; Lee, S. J .
Tetrahedron Lett. 1994, 35, 1875.
(14) We are grateful to Professor Albert Gossauer, of the Universite´
de Fribourg Suisse, for providing us with NMR and IR spectra for 7.
We also thank Professor Franz-Peter Montforts, of the Universita¨t
Bremen, for bringing to our attention ref 5s.

C,D-Ring Pyrromethenones of Phytochrome and Phycocyanin
J . Org. Chem., Vol. 65, No. 25, 2000 8483
additions.13b In the present case, cyclization of 48 with 5
equiv of CsF/20 equiv of Si(OMe)4 gave a 60% yield of 7
after only 6 h heating in THF, in contrast to the 96 h
period required with TBAF (entry 4).14 The only byprod-
uct was a small amount of the corresponding dimethyl-
ester obtained by transesterification. As previously
suggested,13b the active catalyst in this reaction might
involve a pentacoordinated silicon species formed by
nucleophilic attack by F- on Si(OMe)4.
an additional 4 h and concentrated under reduced pressure
to give acid chloride 12, which was used without further
purification.
A solution of 7.13 g (45.8 mmol, 1.2 equiv) of 1-amino-2,2-
dimethoxypropane hydrochloride (13) in 50 mL of CH2Cl2 was
treated with 16 mL (114.2 mmol, 3.0 equiv) of freshly distilled
Et3N. The resulting mixture was stirred at room temperature
for 20 min and then cooled to 0 °C. A solution of the crude
acid chloride 12 from above in 25 mL of CH2Cl2 was then added
dropwise to the reaction mixture over a period of 30 min. After
addition was complete, the reaction was allowed to warm to
room temperature and stirred for an additional 3.5 h. The
reaction mixture was the diluted with 75 mL of 1 M HCl, and
stirring was continued for 1 h. The aqueous layer was
extracted with CH2Cl2, and the combined organic extracts were
dried over anhydrous Na2SO4, concentrated under reduced
pressure, and chromatographed (silica gel, 40% EtOAc/hex-
anes) to afford 10.17 g (80%) of amide 14 as a white solid: mp
73.4-3.6 °C; Rf 0.15 (silica gel, 50% EtOAc/hexanes); IR (film)
Con clu sion
The synthesis of 7 outlined in Scheme 6 is about half
the length of our earlier approach (Scheme 4), and it
should be readily adaptable to the preparation of specif-
ically labeled substrates. The utility of the alkyne amide
strategy for the synthesis of 6 and 7 derives partly from
the ready availability of the key intermediates 22, 30,
and 45. In addition, the transformations involved are
sufficiently mild for the introduction of labile functional-
ity of the type found in naturally occurring tetrapyrroles.
We believe that in certain cases this route will have
advantages over the traditional C + D f CD strategy,
especially when such an approach requires strongly
alkaline conditions.
The versatility of the C + D f CD strategy has been
significantly enhanced by employing silyloxypyrroles of
type 17 as the nucleophilic D-ring component. Not only
are such pyrroles relatively simple to prepare, but this
modification permits the key bond forming step to be
accomplished under very mild conditions.
1
3312, 3073, 2954, 2924, 1724, 1635 cm-1; H NMR (CDCl3) δ
1.95-2.05 (m, 2H), 2.19 (s, 3H), 2.36 (t, J ) 7.2 Hz, 2H), 2.93
(t, J ) 6.9 Hz, 2H), 4.13 (d, J ) 4.5 Hz, 2H), 6.21 (bs, 1H),
7.21 (d, J ) 8.4 Hz, 2H), 7.41 (d, J ) 8.4 Hz, 2H); 13C NMR
(CDCl3) δ 15.80, 27.54, 27.67, 35.67, 50.02, 18.24, 129.44,
133.34, 134.28, 172.07, 203.04. Anal. Calcd for C13H16ClNO2-
Se: C, 46.93; H, 4.85; N, 4.21. Found: C, 47.12; H, 4.90; N,
4.19.
[4-(4-Ch lor oph en ylselan yl)bu tyl](2-oxopr opyl)car bam -
ic Acid , ter t-Bu tyl Ester (15). A solution of 9.00 g (27.1
mmol, 1.0 equiv) of amide 14 in 80 mL of CH2Cl2 was treated
successively with 3.8 mL (27.1 mmol, 1.0 equiv) of Et3N, 11.83
g (54.2 mmol, 2.0 equiv) of (Boc)2O, and 3.36 g (27.1 mmol,
1.0 equiv) of DMAP. The reaction was then stirred at room
temperature for 1 h before being concentrated to dryness under
reduce pressure. The residue was chromatographed (silica gel,
10% EtOAc/hexanes) to afford 11.0 g (94%) of carbamic ester
15 as a white solid: mp 40.7-40.9 °C; Rf 0.37 (silica gel, 20%
Exp er im en ta l Section
EtOAc/hexanes); IR (film) 2972, 2939, 1739, 1689 cm-1 1H
;
All reactions were carried out in oven-dried glassware under
an inert atmosphere of nitrogen or argon. Air- and moisture-
sensitive compounds were introduced via syringe or cannula
and weighed in a drybox. Reactions involving light sensitive
compounds were carried out wrapped in foil. Melting points
are uncorrected and were measured on a Fisher-J ones melting
point apparatus. Proton magnetic resonance spectra (1H NMR)
were recorded at either 300 or 400 MHz as indicated.
NMR (CDCl3) δ 1.46 (s, 9H), 1.96-2.06 (m, 2H), 2.13 (s, 3H),
2.93 (t, J ) 6.9 Hz, 2H), 3.06 (t, J ) 7.2 Hz, 2H), 4.47 (s, 2H),
7.20 (d, J ) 8.4 Hz, 2H), 7.41 (d, J ) 8.4 Hz, 2H); 13C NMR
(CDCl3) δ 25.61, 27.00, 27.55, 28.05, 37.83, 53.39, 83.93, 128.55,
129.35, 133.1, 134.11, 152.29, 174.90, 201.84. Anal. Calcd for
C
18H24ClNO4Se: C, 49.95; H, 5.59; N, 3.24. Found: C, 49.95;
H, 5.53; N, 3.31.
3-[2-(4-Ch lor op h en ylsela n yl)eth yl]-4-m eth yl-2-oxo-2,5-
d ih yd r op yr r ole-1-ca r boxylic Acid , ter t-Bu tyl Ester (16).
A solution of 3.3 g (7.63 mmol, 1.0 equiv) of carbamic ester 15
in 150 mL of THF was cooled to -10 °C (NaCl/ice bath) and
was treated with 1.71 g (15.26 mmol, 2.0 equiv) of freshly
sublimed t-BuOK. The reaction mixture was stirred at -10
°C for an additional 20 min, poured into 100 mL of ice-cold
H2O, and extracted with CH2Cl2. The combined organic
extracts were dried over Na2SO4, concentrated under reduced
pressure, and chromatographed (silica gel, 20% EtOAc/hex-
anes) to afford 1.90 g (60%) of lactam 16 as a white solid: mp
114.5-14.8 °C; Rf 0.74 (silica gel, 50% EtOAc/hexanes); IR
1-[4-(4-Ch lor op h en ylsela n yl)]bu tyr ic Acid (11). A solu-
tion of 10.80 g (28.34 mmol, 1.0 equiv) of bis(4-chlorophenyl)-
diselenide in 150 mL of absolute EtOH was cooled to 0 °C and
treated portionwise with 2.18 g (57.54 mmol, 2.03 equiv) of
NaBH4. After the addition was complete the reaction mixture
was degassed under Ar and stirred at 0 °C for an additional
30 min. To the resulting pale yellow solution was added 4.36
mL (56.68 mmol, 2.0 equiv) of γ-butyrolactone (10) dissolved
in 20 mL of anhydrous THF at 0 °C. The reaction was then
heated at reflux overnight, cooled to room temperature and
diluted with 150 mL of H2O. The aqueous layer was separated,
washed with Et2O, and then acidified with 1 M HCl to pH 2.
The acidified solution was extracted with Et2O, and the
combined organic extracts were dried over anhydrous Na2SO4,
concentrated under reduced pressure and chromatographed
(silica gel, hexane forerun, followed by 30% EtOAc/hexanes)
to afford 12.43 g (79%) of acid 11 as a light pink solid: mp
102.3-2.5 °C; Rf 0.36 (silica gel, 50% EtOAc/hexanes); IR (film)
3100-2500, 3072, 2916, 1691 cm-1; 1H NMR (CDCl3) δ 1.95-
2.05 (m, 2H), 2.51 (t, J ) 6.9 Hz, 2H), 2.94 (t, J ) 7.2 Hz, 2H),
7.24 (d, J ) 8.7 Hz, 2H), 7.43 (d, J ) 8.7 Hz, 2H); 13C NMR
(CDCl3) δ 25.05, 27.31, 33.71, 128, 129.49, 133.52, 134.41,
179.14. Anal. Calcd for C10H11ClO2Se: C, 43.27; H, 3.99.
Found: C, 43.32; H, 4.01.
(film) 2971, 2928, 1769, 1721, 1708, 1669 cm-1 1H NMR
;
(CDCl3) δ 1.56 (s, 9H), 1.95 (s, 3H), 2.07 (t, J ) 6.9 Hz, 2H),
3.12 (t, J ) 7.2 Hz, 2H), 4.00 (s, 2H), 7.21 (d, J ) 8.7 Hz, 2H),
7.41 (d, J ) 8.7 Hz, 2H); 13C NMR (CDCl3) δ 13.71, 24.99,
25.41, 28.33, 53.18, 82.92, 128.47, 129.36, 131.57, 132.98,
133.36, 149.72, 151.26, 169.71. Anal. Calcd for C18H22ClNO3-
Se: C, 52.12; H, 5.35; N, 3.38. Found: C, 52.28; H, 5.52; N,
3.31.
2-(ter t-Bu tyldim eth ylsilan yloxy)-3-[2-(4-ch lor oph en ylse-
la n yl)eth yl]-4-m eth ylp yr r ole-1-ca r boxylic Acid , ter t-Bu -
tyl Ester (17). A solution of 2.05 g (4.95 mmol, 1.0 equiv) of
lactam 16 in 20 mL of CH2Cl2 was treated successively with
1.72 mL (14.9 mmol, 3.0 equiv) of 2,6-lutidine and 1.26 mL
(5.49 mmol, 1.11 equiv) of TBSOTf under N2. The reaction was
stirred at room temperature for 30 min, after which it was
concentrated under reduced pressure, and the residue chro-
matographed (silica gel, 50%EtOAc/hexanes) to afford 2.2 g
(84%) of siloxypyrrole 17 as a pale yellow solid: mp 34.1-
1-[4-(4-Ch lor op h e n ylse la n yl)b u t yla m in o]p r op a n -2-
on e (14). A solution of 10.6 g (38.2 mmol, 1.0 equiv) of acid
11 in 70 mL of CH2Cl2 was treated dropwise with vigorous
stirring with 3.5 mL (40.11 mmol, 1.05 equiv) of oxalyl chloride
under N2. The reaction was stirred at room temperature for

8484 J . Org. Chem., Vol. 65, No. 25, 2000
J acobi et al.
34.5 °C; Rf 0.91 (silica gel, 50% EtOAc/hexanes); IR (film) 2937,
278 (4.17); IR (film) 3418, 2973, 2929, 1757, 1728, 1680 cm-1
;
1
1
2859, 1751, 1717 cm-1; H NMR (CDCl3) δ 0.10 (s, 6H), 0.96
500 MHz H NMR (CDCl3) δ 1.51 (s, 9H), 1.56 (s, 9H), 1.84 (s,
3H), 2.02 (s, 3H), 2.31 (m, 1H), 2.40 (t, J ) 8.3 Hz, 2H), 2.48
(m, 2H), 2.74 (m, 1H), 2.85 (m, 1H), 2.93 (m, 1H), 3.67 (s, 3H),
4.32 (d, J ) 2.9 Hz, 1H), 4.68 (d, J ) 3.6 Hz, 1H), 5.59 (m,
1H), 7.23 (d, J ) 8.8 Hz, 2H), 7.36 (d, J ) 8.3 Hz, 2H); 125
MHz 13C NMR (CDCl3) δ 8.90, 14.67, 20.88, 24.49, 24.59, 28.28,
28.54, 35.23, 51.75, 67.36, 67.80, 81.60, 83.59, 117.73, 119.49,
128.19, 129.04, 129.42, 130.00, 133.01, 133.29, 133.51, 150.31,
153.79, 161.74, 168.38, 173.70. Anal. Calcd For C33H43ClN2O8-
Se: C, 55.82; H, 6.10; N, 3.94. Found: C, 56.05; H, 6. 09; N,
3.87, relative stereochemistry not assigned.
(s, 9H), 1.54 (s, 9H), 1.89 (d, J ) 1.2 Hz, 3H), 2.60-2.97 (dt,
4H), 6.41 (q, J ) 1.2 Hz, 1H), 7.22 (d, J ) 8.4 Hz, 2H), 7.44 (d,
J ) 8.4 Hz, 2H); 13C NMR (CDCl3) δ -4.04, 11.36, 18.41, 24.95,
25.91, 26.04, 28.23, 82.48, 106.83, 110.09, 118.60, 128.58,
129.28, 133.15, 134.36, 139.60, 148.11. Anal. Calcd for C24H36
-
ClNO3SeSi: C, 54.49; H, 6.86; N, 2.65. Found: C, 54.75; H,
6.92; N, 2.61.
Ald ol Ad d u cts 18a -d . A solution of 1.63 g (5.52 mmol, 1.00
equiv) of pyrroloaldehyde 85o in 40 mL of dry CH2Cl2 was
cooled to -78 °C under Ar and was treated dropwise with
vigorous stirring with 1.05 g (607 µL, 5.52 mmol, 1.00 equiv)
of TiCl4. The resulting orange/red suspension was stirred for
an additional 15 min at -78 °C to ensure thorough mixing,
and was then treated portionwise with a solution of 2.93 g (5.54
mmol, 1.00 equiv) of silyloxypyrrole 17 in 30 mL of dry CH2-
Cl2. The resulting dark red solution was stirred for an
additional 10 min and was then quenched with saturated
NaHCO3 at -78 °C. The resulting mixture was warmed to 0
°C and extracted with CH2Cl2. The combined extracts were
washed with H2O and saturated brine, dried over anhydrous
Na2SO4, concentrated under reduced pressure, and chromato-
graphed (silica gel, 9:1 EtOAc/petroleum ether) to afford 1.81
g of 18a , 170 mg of 18b, 1.93 g of 18c, and 160 mg of 18d
(combined yield 4.07 g, 97%), relative stereochemistry not
assigned.
5-[[1-ter t-Bu toxycar bon yl-4-[2-(4-ch lor oph en ylselan yl)-
eth yl]-3-m eth yl-5-oxo-2,5-dih ydr o-1H-pyr r ol-2-yl]h ydr oxy-
methyl]-3-(2-methoxycarbonylethyl)-4-methyl-1H-pyrrole-2-
ca r boxylic Acid , ter t-Bu tyl Ester 18d . Column chromatog-
raphy afforded 18d as a pale yellow solid: mp 76-8 °C; Rf )
0.35 (silica gel, 30% EtOAc/petroleum ether); UV-vis (MeOH)
λmaxnm (log ꢀ) 220 (4.32), 280 (4.32); IR (film) 3415, 2971, 2929,
1758, 1728, 1680, 1659 cm-1; 500 MHz 1H NMR (CDCl3) δ 1.39
(s, 3H), 1.56 (s, 9H), 1.58 (s, 9H), 2.05 (s, 3H), 2.51 (t, J ) 8.4
Hz, 2H), 2.56 (t, J ) 7.0 Hz, 2H), 2.88-3.08 (m, 4H), 3.66 (s,
3H), 4.63 (s, 1H), 4.72 (br s, 1H), 5.56 (s, 1H), 7.190 (d, J )
8.4 Hz, 2H), 7.36 (d, J ) 8.8 Hz, 2H), 9.35 (s, 1H); 125 MHz
13C NMR (CDCl3) δ 9.58, 13.31, 20.89, 24.78, 25.00, 28.45,
28.64, 35.33, 551.67, 66.60, 67.20, 81.43, 83.94, 114.92, 118.67,
128.27, 129.33, 129.82, 130.27, 132.97, 133.32, 133.40, 150.32,
152.96, 161.46, 169.40, 173.79. Anal. Calcd For C33H43ClN2O8-
Se; C, 55.82; H, 6.10; N, 3.94. Found: C, 55.95; H, 6.13; N,
3.98, relative stereochemistry not assigned.
5-[[1-ter t-Bu t oxyca r b on yl-4-[2-(4-ch lor op h en ylsela n -
yl)e t h yl]-3-m e t h yl-5-oxo-2,5d ih yd r o-1H -p yr r ol-2-yl]-
(ter t-bu tyld im eth ylsila n yloxy)m eth yl]-3-(2-m eth oxyca r -
bon yleth yl)-4-m eth yl-1H-p yr r ole-2-ca r boxylic Acid , ter t-
Bu tyl Ester 18a . Recrystallization from EtOAc/petroleum
ether afforded 18a as a white solid: mp 106-7 °C; Rf 0.90
3-[5-[4-[2-(4-Ch lor op h en ylsela n yl)et h yl]-3-m et h yl-5-
oxo-1,5-dih ydr opyr r ol-2-yliden em eth yl]-4-m eth yl-1H-pyr -
r ol-3-yl]p r op ion ic Acid , Meth yl Ester (19). A mixture
consisting of 1.00 g (1.21 mmol, 1.00 equiv) of silanyloxypyr-
romethanes 18a and 18b and 860 mg (1.21 mmol, 1.00 equiv)
of hydroxypyrromethanes 18c and 18d was treated with 27.6
g (18.6 mL, 242 mmol, 100 equiv) of neat TFA under Ar at 23
°C. The resulting deep red solution was kept at room temper-
ature for 8 h and was then partitioned between 50 mL of ice-
cold H2O and 50 mL of CH2Cl2. The aqueous layer was
extracted with CH2Cl2, and the combined organic extracts were
washed with 2 × 20 mL of H2O and saturated NaHCO3, dried
over anhydrous Na2SO4, concentrated under reduced pressure,
and chromatographed (silica gel, 30% EtOAc/petroleum ether)
to afford 1.15 g (96%) of pyrromethenone 19 as a yellow-green
solid. Recrystallization from EtOAc/petroleum ether afforded
19 as yellow/green needles: mp 168-69 °C; Rf 0.55 (silica gel,
50% EtOAc/petroleum ether); UV-vis (MeOH) λmaxnm (log ꢀ)
206 (4.16), 226 (4.02), 270 (3.85), 400 (4.44); IR (film) 3372,
2920, 1728, 1699, 1637, 1606 cm-1; 500 MHz 1H NMR (CDCl3)
δ 2.13 (s, 3H), 2.17 (s, 3H), 2.56 (t, J ) 7.3 Hz, 2H), 2.78 (t, J
) 7.3 Hz, 2H), 2.84 (t, J ) 7.3 Hz, 2H), 3.20 (t, J ) 7.3 Hz,
2H), 3.70 (s, 3H), 6.19 (s, 1H), 6.76 (d, J ) 2.7 Hz, 1H), 7.13
(d, J ) 8.6 Hz, 2H), 7.38 (d, J ) 8.5 Hz, 2H), 10.34 (s, 1H),
11.01 (s, 1H); 125 MHz 13C NMR (CDCl3) δ 9.65, 10.24, 20.94,
25.10, 26.78, 35.01, 51.83; 102.57, 121.32, 123.18, 124.44,
124.59, 126.63, 128.53, 129.32, 129.51, 133.11, 133.95, 143.04,
173.63, 173.88. Anal. Calcd for C23H25ClN2O3Se: C, 56.16; H,
5.12; N, 5.70. Found: C, 55.88; H, 5.11; N, 5.67.
3-[5-[4-[2-(4-Ch lor op h en ylsela n yl)et h yl]-3-m et h yl-5-
oxo-1,5-dih ydr opyr r ol-2-yliden em eth yl]-2-for m yl-4-m eth -
yl-1H-p yr r ol-3-yl]p r op ion ic Acid , Meth yl Ester (20). A
degassed solution consisting of 1.04 g (1.07 mL, 9.76 mmol,
40.0 equiv) of trimethylorthoformate (TMOF) in 30 mL of
freshly distilled CH2Cl2 was treated with 2.23 g (1.50 mL, 19.5
mmol, 80.0 equiv) of anhydrous TFA and was kept for 20 min
at 23 oC under an Ar atmosphere. The reaction was then
treated dropwise with vigorous stirring with a solution of 120
mg (0.244 mmol, 1.00 equiv) of pyrromethenone 19 in 10 mL
of CH2Cl2. The resulting yellow-green solution was stirred for
an additional 10 min following addition and was then parti-
tioned between 15 mL of 10% NaHCO3 and 15 mL of CH2Cl2.
The aqueous layer was extracted with CH2Cl2, and the
combined organic extracts were washed with 10 mL of H2O,
dried over anhydrous Na2SO4, concentrated under reduced
(silica gel, 30% EtOAc/petroleum ether); UV-vis (MeOH) λmax
-
nm (log ꢀ) 208 (4.24), 226 (4.23); 280 (4.13); IR (film) 3467,
1
2954, 2923, 2854, 1777, 1739, 1705 cm-1; 500 MHz H NMR
(CDCl3) δ 0.01 (s, 3H), 0.19 (s, 3H), 0.93 (s, 9H), 1.50 (s, 9H),
1.57 (s, 9H), 1.83 (s, 3H), 2.12 (s, 3H), 2.28 (m, 1H), 2.33-2.51
(m, 2H), 2.40 (t, J ) 8.8 Hz, 2H), 2.65 (m, 1H), 2.82 (m, 1H),
2.96 (m, 1H), 3.65 (s, 3H), 4.53 (d, J ) 3.9 Hz, 1H), 5.60 (d, J
) 3.9 Hz, 1H), 7.22 (d, J ) 8.6 Hz, 2H), 7.37 (d, J ) 8.6 Hz),
8.49 (s, 1H); 125 MHz 13C NMR (CDCl3) δ -5.19, -4.88, 8.76,
15.21, 18.22, 20.81, 24.17, 24.59, 25.93, 28.35, 28.58, 35.25,
51.67, 67.23, 68.30, 81.10, 83.26, 117.80, 119.46, 128.21,
128.49, 129.19, 129.38, 132.93, 133.49, 133.55, 150.06, 153.45,
160.90, 168.10, 173.67. Anal. Calcd for C39H57ClN2O8SeSi: C,
56.82; H, 6.97; N, 3.39. Found: C, 57.07; H, 6.84; N, 3.40,
relative stereochemistry not assigned.
5-[[1-ter t-Bu toxycar bon yl-4-[2-(4-ch lor oph en ylselan yl)-
e t h y l]-3-m e t h y l-5-o x o -2,5d i h y d r o -1H -p y r r o l-2-y l]-
(ter t-b u t yl-d im et h ylsila n yloxy)m et h yl]-3-(2-m et h oxy-
ca r bon yleth yl)-4-m eth yl-1H-p yr r ole-2-ca r boxylic Acid ,
ter t-Bu tyl Ester 18b. Column chromatography afforded 18b
as a clear gel: Rf 0.80 (silica gel 30% EtOAc/petroleum ether);
UV-vis (MeOH) λmaxnm (log ꢀ) 208 (4.24), 224 (4.23); 272
(4.13); IR (film): 3481, 3468, 2977, 2952, 2930, 2859, 1778,
1
1739, 1705, 1683 cm-1; 500 MHz H NMR (CDCl3) δ -0.02 (s,
3H), 0.03 (s, 3H), 0.87 (s, 9H), 1.31 (s, 3H), 1.56 (s, 9H), 1.61
(s, 9H), 2.14 (s, 3H), 2.52-2.65 (m, 2H), 2.56 (t, J ) 7.8 Hz,
2H), 2.93-3.03 (m, 2H), 3.06 (m, 1H), 3.13 (m, 1H), 3.66 (s,
3h), 4.54 (br s, 1H), 5.59 (d, J ) 1.9 Hz, 1H), 7.22 (d, J ) 8.9
Hz, 2H), 7.40 (d, J ) 8.5 Hz, 2H), 8.77 (s, 1H); 125 MHz 13C
NMR (CDCl3) δ -05.08, -5.00, 9.50, 13.32, 18.25, 20.75, 24.85,
25.42, 25.99, 28.53, 28.69, 35.22, 51.68, 66.99 (2), 80.93, 83.41,
114.79, 118.20, 128.39, 129.41, 130.36, 130.41, 133.03, 133.44,
133.47, 150.19, 153.12, 160.54, 169.22, 173.82. Anal. Calcd for
C39H57ClN2O8SeSi: C, 56.82; H, 6.97; N, 3.39. Found: C, 57.08;
H, 6.82; N, 3.28; relative stereochemistry not assigned.
5-[[1-ter t-Bu toxycar bon yl-4-[2-(4-ch lor oph en ylselan yl)-
eth yl]-3-m eth yl-5-oxo-2,5-dih ydr o-1H-pyr r ol-2-yl]h ydr oxy-
methyl]-3-(2-methoxycarbonylethyl)-4-methyl-1H-pyrrole-2-
ca r boxylic Acid , ter t-Bu tyl Ester 18c. Recrystallization
from EtOAc/petroleum ether afforded 18c as fine white
needles: mp 150-51 °C; Rf 0.40 (silica gel, 30% EtOAc/
petroleum ether); UV-vis (MeOH) λmaxnm (log ꢀ) 228 (4.27),

C,D-Ring Pyrromethenones of Phytochrome and Phycocyanin
J . Org. Chem., Vol. 65, No. 25, 2000 8485
pressure, and chromatographed (silica gel, 30% EtOAc/
petroleum ether) to afford 91 mg (72%) of 20 as a yellow-green
solid. Recrystallization from EtOAc/petroleum ether afforded
20 as yellow-green needles: mp 180-80.5 °C; Rf 0.45 (silica
gel, 40% EtOAc/petroleum ether); UV-vis (MeOH) λmaxnm (log
ꢀ) 206 (4.16), 270 (4.25), 398 (4.35); IR (film) 3345, 2939, 2854,
1732, 1694, 1662 cm-1; 500 MHz 1H NMR (CDCl3) δ 2.08 (s,
3H), 2.15, (s, 3H), 2.62 (t, J ) 7.6 Hz, 2H), 2.88 (t, J ) 7.1 Hz,
2H), 3.10 (t, J ) 7.6 Hz, 2H), 3.15 (t, J ) 7.4 Hz, 2H), 3.67 (s,
3H), 5.97 (s, 3H), 7.14 (d, J ) 8.5 Hz, 2H), 7.38, (d, J ) 8.5
Hz, 2H), 9.74 (s, 1H), 10.74, (s, 1H), 10.96 (s, 1H); 125 MHz
13C NMR (CDCl3) δ 9.27, 10.28, 19.48, 24.88, 26.63, 35.51,
51.97, 97.23, 124.52, 128.73, 129.26, 130.67, 131.30, 132.83,
132.90, 133.59, 134.64, 136.31, 143.78, 172.99, 173.55, 177.87.
Anal. Calcd For C24H25ClN2O4Se: C, 55.45; H, 4.85; N, 5.39.
Found: C, 55.38; H, 4.85; N, 5.45.
3-[2-F or m yl-4-m eth yl-5-(3-m eth yl-5-oxo-4-vin yl-1,5-d i-
h yd r op yr r ol-2-ylid en em et h yl)-1H -p yr r ol-3-yl]p r op ion -
ic Acid , Meth yl Ester (21). A solution of 61 mg (0.12 mmol,
1.00 equiv) of pyrromethenone 20 in 4.0 mL of freshly distilled
CH2Cl2 was cooled to -78 °C under Ar and was treated
dropwise with vigorous stirring with a solution of 22.3 mg (0.13
mmol, 1.10 equiv) of recrystallized m-CPBA in 1.0 mL of CH2-
Cl2. After addition was complete, the reaction was stirred for
an additional 1 h at -78 °C and was then treated with 119
mg (49 µL, 1.17 mmol, 10.0 equiv) of freshly distilled triethy-
lamine. After addition was complete, the reaction was allowed
to warm slowly to room temperature, and stirring was
continued for an additional 2 h. The resulting solution was
then partitioned between 5 mL of H2O and 5 mL of CH2Cl2,
and the aqueous layer was extracted with CH2Cl2. The
combined organic extracts were washed with H2O and satu-
rated brine, dried over anhydrous Na2SO4, concentrated under
reduced pressure, and chromatographed (silica gel, 30%
EtOAc/petroleum ether) to afford 37 mg (96%) of 21 as a
yellow-brown solid. Recrystallization from MeOH afforded 21
as yellow-green needles, having identical spectral and physical
properties as an authentic sample:5m mp 192-92.5 °C; Rf 0.40
(silica gel, EtOAc/petroleum ether); UV-vis (MeOH) λmaxnm
(log ꢀ) 208 (4.12), 280 (4.22), 406 (4.31); IR (film) 3260, 2920,
2850, 1735, 1700, 1630 cm-1; 500 MHz 1H NMR (CDCl3) δ 2.16
(s, 3H), 2.21 (s, 3H), 2.62 (t, J ) 7.6 Hz, 2H), 3.10 (t, J ) 7.6
Hz, 2H), 3.69 (s, 3H), 5.52 (dd, J AX ) 11.7 Hz, J BX ) 1.5 Hz,
HX), 6.02 (s, 1H), 6.30 (dd, J AB ) 17.7 Hz, J BX ) 1.5 Hz, HB),
6.59 (dd, J AB ) 17.7 Hz, J AX ) 11.7 Hz, HA), 9.74 (s, CHO),
10.00 (br s, NH), 10.64 (br s, NH). Anal. Calcd for
to 0 °C under Ar and was treated dropwise, and with vigorous
stirring, with 26.0 mL (0.026 mol, 4.0 equiv) of 1.0 M
dibutylboron triflate/CH2Cl2 over a period of 5 min. After
addition was complete, the reaction was treated with 2.2 mL
(0.013 mol, 2.0 equiv) of N,N-diisopropylethylamine over a
period of 5 min. The resulting solution was stirred for an
additional 15 min at 0 °C, cooled to -78 °C, and treated with
2.77 g (6.27 mmol, 1.0 equiv) of 265f in 50 mL of CH2Cl2 over
a period of 5 min. The reaction mixture was then stirred for
an additional 10 min at -78 °C, warmed to 0 °C over 10 min,
and quenched with 140 mL of pH 7.0 buffer. The aqueous layer
was extracted with CH2Cl2, and the combined organic extracts
were dried over anhydrous Na2SO4, concentrated under re-
duced pressure, and chromatographed (silica gel, 200 mL of
hexane forerun, followed by10% EtOAc/hexanes), to afford 3.5
g (98%) of the cobalt complex of 28-cobalt complex as a
burgundy oil: Rf 0.58 (silica gel, 30% EtOAc/hexanes); IR
(CCl4) 3667, 3627, 2959, 2931, 2831, 2873, 1790, 1741, 1699
1
cm-1; H NMR (CDCl3) δ 0.35 (s, 9H), 0.79 (t, 3H),1.20-1.70
(m, 5H), 1.90-2.00 (m,1H), 3.60-4.00 (m, 3H), 4.40-4.50 (m,
2H).
A solution of 3.5 g (6.2 mmol) of 28-cobalt complex in 100
mL of acetone was treated portionwise, and with vigorous
stirring, with ceric ammonium nitrate (CAN) until all gas
evolution ceased. The resulting orange solution was diluted
with 100 mL of H2O and extracted with EtOAc. The combined
organic extracts were dried over anhydrous Na2SO4, concen-
trated under reduced pressure, and chromatographed (silica
gel, 30% EtOAc/hexanes) to afford 1.7 g (97%) of 28 as a
colorless oil: Rf 0.60 (silica gel, 30% EtOAc/hexanes); IR (CCl4)
2959, 2166, 1787, 1703 cm-1; 1H NMR (CDCl3) δ 0.10 (s, 9H),
0.89 (t, J ) 7.0 Hz, 3H), 1.20 (d, J ) 6.5 Hz, 3H), 1.35 (m,
1H), 1.69 (m, 1H), 2.71 (m, 1H), 3.90-4.12 (m, 3H), 4.37 (m,
2H); 13C NMR (CDCl3) δ 0.0, 11.4, 17.9, 22.6, 29.4, 42.6, 48.7,
61.5, 84.9, 108.8, 153.1, 175.1. Anal. Calcd for C14H23NO3Si:
C, 59.75; H, 8.24; N, 4.98. Found: C, 60.12; H, 8.57; N, 4.59.
(()-syn -2-Eth yl-3-m eth ylp en t-4-yn oic Acid (29). A solu-
tion of 1.43 g (5.08 mmol, 1.0 equiv) of 28 in 90 mL of 3:1 THF/
H2O, containing 4.6 mL (0.041 mol, 8.0 equiv) of 30% H2O2,
was treated dropwise at 0 °C, with vigorous stirring, with a
solution of 0.42 g (0.01 mol, 2.0 equiv) of LiOH‚H2O in 5 mL
of H2O over a period of 5 min. After addition was complete,
the reaction mixture was stirred at 0 °C for an additional 40
min, at which time no starting material was detectable by
TLC. The reaction was then treated with a solution of 5.74 g
(0.046 mol, 8.8 equiv) of Na2SO3 in 10 mL of H2O and
concentrated under reduced pressure. The remaining aqueous
solution was diluted with 30 mL of saturated NaHCO3 and
20 mL of H2O and extracted with CH2Cl2. The aqueous layer
was then acidified to pH 1.0 with concentrated HCl and
extracted with EtOAc. The combined EtOAc extracts were
dried over anhydrous Na2SO4, concentrated to dryness under
reduced pressure, and chromatographed (silica gel, 50%
EtOAc/hexanes) to afford 0.48 g (67%) of acid 29 as a colorless
oil: Rf 0.75 (silica gel, EtOAc); IR (CCl4) 3307, 2966, 2878,
C
18H20N2O4: C, 65.84; H, 6.14; N, 8.53. Found: C, 65.80; H,
6.17; N, 8.49.
3-Bu tyr yloxa zolid in -2-on e (27). A solution of 5.0 g (0.057
mol, 1.0 equiv) of 2-oxazolidone in 250 mL of THF was cooled
to -78 °C under N2 and was treated dropwise, and with
vigorous stirring, with 22.8 mL (0.057 mol, 1.0 equiv) of 2.5
M n-BuLi/hexanes over a period of 10 min. The resulting
solution was stirred at -78 °C for an additional 15 min and
was then treated dropwise with 5.9 mL (0.057 mol, 1.0 equiv)
of butyryl chloride over a period of 5 min. After addition was
complete, the reaction mixture was allowed to stir an ad-
ditional 15 min at -78 °C and was then warmed to 0 °C over
a period of 30 min. The reaction was then diluted with 50 mL
of 1 M aqueous K2CO3, and stirring was continued for 1 h to
hydrolyze residual acid chloride. The resulting solution was
concentrated under reduced pressure and extracted with CH2-
Cl2, and the combined organic extracts were dried over
anhydrous Na2SO4, concentrated under reduced pressure, and
chromatographed (silica gel, 30% EtOAc/hexanes) to afford 6.6
g (74%) of 27 as colorless needles: mp 39-40 °C (from EtOAc);
Rf 0.35 (silica gel, 30% EtOAc/hexanes); IR (CCl4) 2967, 1779,
1
1737, 1711 cm-1; H NMR (CDCl3) δ 1.0 (t, J ) 8.0 Hz, 3H),
1.25 (d, J ) 7.0 Hz, 3H), 1.73 (m, 2H), 2.11 (d, J ) 2.5 Hz,
1H), 2.32-2.45 (m, 1H), 2.75-2.86 (m, 1H); 13C NMR (CDCl3)
δ 11.7, 17.7, 22.0, 27.5, 51.9, 69.7, 85.7, 180.0; exact mass calcd
for C8H12O2 140.0837, found 140.0811.
(()-syn -2-Eth yl-3-m eth ylp en t-4-yn oic Acid Am id e (30).
A solution of 0.31 g (2.2 mmol, 1.1 equiv) of alkyne acid 29 in
35 mL of THF, and 0.28 mL (2.0 mmol, 1.0 equiv) of NEt3,
was cooled to 0 °C under N2, and was treated dropwise, with
vigorous stirring, with 0.26 mL (2.0 mmol, 1.0 equiv) of
isobutyl chloroformate over a period of 5 min. The resulting
solution was stirred at 0 °C for an additional 40 min. The
solution was then cooled to -78 °C, and NH3, generated from
NH4OH dried through a CaCl2 drying tube, was bubbled into
the solution for 1 h. The reaction was then allowed to warm
to room temperature and stirred overnight before concentrat-
ing to dryness under reduced pressure. The residue was taken
up in 50 mL of H2O and 50 mL of EtOAc, and the aqueous
layer was extracted with EtOAc. The combined organic
extracts were dried over anhydrous Na2SO4, concentrated
1
1715 cm-1; H NMR (CDCl3) δ 0.97 (t, J ) 8.0 Hz, 3H), 1.68
(m, 2H), 2.88 (t, J ) 8.0 Hz, 2H), 4.0 (t, J ) 9.0 Hz, 2H), 4.39
(t, J ) 9.0 Hz, 2H); 13C NMR (CDCl3) δ 13.5, 17.5, 36.8, 42.3,
61.9, 153.4, 173.1. Anal. Calcd for C7H11NO3: C, 53.49; H, 7.05;
N, 8.91. Found: C, 53.44; H, 7.01; N, 8.87.
(()-syn -3-[2-Eth yl-3-m eth yl-5-(tr im eth ylsila n yl)p en t-4-
yn oyl]oxa zolid in -2-on e (28). A solution of 1.97 g (0.013 mol,
2.0 equiv) of oxazolidinone 27 in 75 mL of CH2Cl2 was cooled

8486 J . Org. Chem., Vol. 65, No. 25, 2000
J acobi et al.
under reduced pressure, and chromatographed (silica gel,
EtOAc) to afford 0.25 g (90%) of 30. Recrystallization from
EtOAc/hexanes afforded colorless needles: mp 81-82 °C; Rf
0.61 (silica gel, EtOAc); IR (CCl4) 3514, 3398, 3309, 2968, 2360,
methanol afforded 6 as yellow plates: mp 207-208 °C (lit.5k,o
mp 206-08 °C); Rf 0.45 (silica gel, 30% acetone/hexanes); IR
(CCl4) 3453, 3331, 2968, 2930, 2874, 1740, 1688 cm-1; 1H NMR
(CDCl3) δ 1.08 (t, J ) 7.0 Hz, 3H), 1.56 (s, 9H), 2.06 (s, 3H),
2.10 (s, 3H), 2.40 (q J ) 7.0 Hz, 2H), 2.51 (t, J ) 8.0 Hz, 2H),
2.98 (t, J ) 8.0 Hz, 2H), 3.66 (s, 3H), 5.91 (s, 1H), 8.74 (s, 1H),
9.29 (s, 1H); 13C NMR (CDCl3) δ 9.1, 9.6, 13.5, 16.5, 20.8, 28.2,
35.0, 51.4, 80.8, 97.7, 123.0, 123.1, 127.6, 128.1, 133.1, 134.5,
141.5, 160.4, 173.5, 174.1.
1
1693, cm-1; H NMR (CDCl3) δ 1.06 (t, J ) 8.0 Hz, 3H), 1.35
(d, J ) 7.0 Hz, 3H), 1.70-1.85 (m, 2H), 2.23 (m, 1H), 2.28 (d,
J ) 2.5 Hz, 1H), 2.83 (dt, J ) 7.0, 3.0 Hz, 1H), 5.42 (br s, 1H),
5.99 (br s, 1H); 13C NMR (CDCl3) δ 11.9, 18.4, 23.8, 27.7, 53.7,
70.7, 86.3, 176.6. Anal. Calcd for C8H13NO: C, 69.03; H, 9.41.
Found: C, 68.90; H, 9.38.
3-(4-Br om obu tyr yl)oxa zolid in -2-on e (32). A solution of
3.76 g (0.043 mol, 1.0 equiv) of 2-oxazolidone in 150 mL of THF
was cooled to -78 °C under N2 and was treated dropwise, and
with vigorous stirring, with 17.2 mL (0.043 mol, 1.0 equiv) of
2.5 M n-BuLi/hexanes over a period of 10 min. The resulting
solution was stirred at -78 °C for an additional 15 min and
was then treated dropwise with 6.0 mL (0.050 mol, 1.2 equiv)
of 4-bromobutyryl chloride over a period of 5 min. After
addition was complete, the reaction was stirred for an ad-
ditional 15 min at -78 °C and then warmed to 0 °C for 30
min. The resulting solution was diluted with 100 mL of H2O
and extracted with Et2O. The combined organic extracts were
dried over anhydrous MgSO4, concentrated under reduced
pressure, and chromatographed (silica gel, 50% EtOAc/hex-
anes) to afford 6.91 g (68%) of 32 as a light yellow oil: Rf 0.43
(silica gel, 50% EtOAc/hexanes); IR (CCl4) 2968, 2921, 1792,
(()-5-(4-Ca r ba m oyl-3-m eth ylh ex-1-yn yl)-3-(2-m eth oxy-
ca r bon yleth yl)-4-m eth yl-1H-p yr r ole-2-ca r boxylic Acid ,
ter t-Bu tyl Ester (31). A flame-dried flask was cooled to room
temperature under an inert atmosphere and was charged with
39 mg (0.20 mmol, 0.2 equiv) of CuI, 0.12 g (0.102 mmol, 0.1
equiv) of Pd(PPh3)4, and a solution of 0.4 g (1.02 mmol, 1.0
equiv) of iodopyrrole 22 in 2 mL of DMF containing 0.43 mL
(3.06 mmol, 3 equiv) of NEt3. The resulting solution was then
treated with 0.16 g (1.1 mmol, 1.1 equiv) of 30 in 2 mL of DMF,
and the reaction was degassed thoroughly by five freeze-thaw
cycles employing Ar and stirred for 19 h at room temperature
under Ar. At the end of this period the reaction was filtered
through Celite, washed with 100 mL of EtOAc, and concen-
trated under reduced pressure. The residue was partitioned
between 30 mL of 5% NaHCO3 and 30 mL of CH2Cl2, and the
aqueous layer was extracted with CH2Cl2. The combined
organic extracts were washed with 20 mL of H2O, dried over
anhydrous Na2SO4, concentrated under reduced pressure, and
chromatographed (silica gel, 50% acetone/hexanes) to afford
0.41 g (99%) of 31. Recrystallization from EtOAc/hexanes
afforded 31 as yellow plates: mp 112-13 °C; Rf 0.58 (silica
gel, 50% acetone/hexanes); IR (CCl4) 3453, 2976, 2933, 2876,
1
1705 cm-1; H NMR (CDCl3) δ 2.21 (m, 2H), 3.10 (t, J ) 7.5
Hz, 2H), 3.49 (t, J ) 6.5 Hz, 2H), 4.01 (t, J ) 8.0 Hz, 2H), 4.42
(t, J ) 8.0 Hz, 2H); 13C NMR (CDCl3) δ 27.0, 33.0, 33.4, 42.4,
62.2, 153.5, 171.9; exact mass calcd for C7H10NO3Br 235.9922,
found 235.9940.
(()-syn -3-[2-(2-Br om oeth yl)-3-m eth yl-5-(tr im eth ylsila -
n yl)p en t-4-yn oyl]oxa zolid in -2-on e (33). A solution of 1.57
g (6.65 mmol, 2.0 equiv) of 3-(4-bromobutyryl)oxazolidin-2-one
(32) in 40 mL of CH2Cl2 was cooled to 0 °C under Ar and was
treated dropwise, with vigorous stirring, with 13.3 mL (0.013
mol, 4.0 equiv) of 1.0 M dibutylboron triflate/CH2Cl2 over a
period of 5 min. This was followed by dropwise addition of 1.15
mL (6.65 mmol, 2.0 equiv) of N,N-diisopropylethylamine over
a period of 5 min. The resulting solution was stirred for an
additional 15 min at 0 °C, cooled to -78 °C, and treated
dropwise with 1.50 g (3.33 mmol, 1.0 equiv) of cobalt complex
265f in 20 mL of CH2Cl2 over a period of 5 min. After addition
was complete, the reaction was stirred for 10 min at -78 °C
and then warmed to 0 °C for 10 min before quenching with 75
mL of pH 7.0 buffer. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2. The combined
organic extracts were dried over anhydrous Na2SO4, concen-
trated under reduced pressure, and chromatographed (silica
gel, 200 mL of hexane forerun, 10% EtOAc/hexanes) to afford
1.75 g (99%) of 33-cobalt complex as a burgundy oil: Rf 0.56
(silica gel, 30% EtOAc/hexanes); IR (CCl4) 3670, 3630, 2959,
1
2360, 1741, 1687, 1585 cm-1; H NMR (CDCl3) δ 1.02 (t, J )
8.0 Hz, 3H), 1.35 (d, J ) 7.0 Hz, 3H), 1.57 (s, 9H), 1.74 (m,
2H), 2.06 (s, 3H), 2.23 (m, 1H), 2.53 (t, J ) 8.0 Hz, 2H), 2.98
(t, J ) 8.0 Hz, 2H), 3.0 (m, 1H), 3.69 (s, 3H), 5.42 (s, 1H), 5.84
(s, 1H), 8.74 (s, 1H); 13C NMR (CDCl3) δ 9.5, 12.0, 18.7, 20.8,
23.9, 28.4, 28.9, 34.9, 51.5, 54.2, 74.0, 81.2, 96.4, 114.7, 120.2,
124.6, 127.8, 160.2, 173.5, 176.4; exact mass calcd for
C
22H32N2O5 404.2311, found 404.2340.
(()-5-(4-Eth yl-3-m eth yl-5-oxopyr r olidin -2-yliden em eth -
yl)-3-(2-m et h oxyca r b on ylet h yl)-4-m et h yl-1H -p yr r ole-2-
ca r boxyl-ic a cid , ter t-bu tyl ester (25). A solution of 0.25 g
(0.62 mmol) of alkyne amide 34 in 20 mL of degassed CH3CN
was treated dropwise at room temperature, with vigorous
stirring, with 3.7 mL (3.7 mmol, 6 equiv) of 1 M n-Bu4NF/
THF. After addition was complete, the reaction was heated at
refux for 3 h under Ar and then concentrated to dryness under
reduced pressure. The residue was partitioned between 10 mL
of H2O and 10 mL of EtOAc, and the aqueous layer was
extracted with EtOAc. The combined organic extracts were
dried over anhydrous Na2SO4, concentrated under reduced
pressure, and chromatographed (silica gel, 40% acetone/
hexanes) to afford 0.15 g (60%) of 25 as a yellow oil: Rf 0.42
(silica gel, 30% acetone/hexanes); IR (CCl4) 3453, 3338, 2965,
1
2931, 2873, 2087, 1791, 1742, 1697 cm-1; H NMR (CDCl3) δ
0.4 (s, 9H), 1.3 (d, 3H), 2.2 (m, 1H), 2.55 (m,1H), 3.2-3.5 (m,
3H), 3.6-3.9 (m, 3H), 4.45 (m, 2H).
A solution of 1.75 g (3.31 mmol) of 33-cobalt complex in
100 mL of acetone was treated portionwise, and with vigorous
stirring, with ceric ammonium nitrate (CAN) until all gas
evolution ceased. The resulting orange solution was diluted
with 50 mL of H2O and extracted with EtOAc. The combined
organic extracts were dried over anhydrous Na2SO4, concen-
trated under reduced pressure, and chromatographed (silica
gel, 40% EtOAc/hexanes) to afford 0.95 g (80%) of 33 as
colorless needles: mp 69-70 °C (EtOAc/hexanes); Rf 0.49
(silica gel, 30% EtOAc/hexanes); IR (CCl4) 2962.1, 2168.7,
1
2930, 2874, 1739, 1677 cm-1; H NMR (CDCl3) δ 1.00 (t, J )
7.0 Hz, 3H), 1.30 (d, J ) 8.0 Hz, 3H), 1.51 (s, 9H), 1.61 (m,
1H), 1.81 (m, 1H), 1.93 (s, 3H), 2.15 (m, 1H), 2.49 (t, J ) 8.0
Hz, 2H), 2.79 (m, 1H), 2.96 (t, J ) 8.0 Hz, 2H), 3.65 (s, 3H),
5.23 (d, J ) 3.0 Hz, 1H), 7.84 (s, 1H), 8.67 (s, 1H); 13C NMR
(CDCl3) δ 9.1, 11.0, 19.6, 20.7, 23.4, 28.3, 35.0, 38.9, 49.9, 51.4,
80.5, 90.4, 117.7, 119.8, 128.3, 128.7, 143.1, 160.8, 173.6, 179.8;
exact mass calcd for C22H32N2O5 404.2311, found 404.2341.
5-(4-Eth yl-3-m eth yl-5-oxo-1,5-d ih yd r op yr r ol-2-ylid en e-
m eth yl)-3-(2-m eth oxycar bon yleth yl)-4-m eth yl-1H-pyr r ole-
2-ca r boxylic Acid , ter t-Bu tyl Ester (6). A solution of 0.25
g (0.62 mmol, 1.0 equiv) of lactam 25 in 40 mL of benzene was
treated at room temperature, with vigorous stirring, with a
solution of 0.15 g (0.68 mmol, 1.1 equiv) of DDQ in 5 mL of
benzene under N2. The resulting solution was stirred for 10
min at room temperature, diluted with 40 mL of H2O, and
extracted with CH2Cl2. The combined organic extracts were
dried over anhydrous Na2SO4, concentrated under reduced
pressure, and chromatographed (silica gel, 40% acetone/
hexanes) to afford 0.18 g (72%) of 6. Recrystallization from
1
1793.2, 1741.6, 1698.7 cm-1; H NMR (CDCl3) δ 0.11 (s, 9H),
1.20 (d, J ) 7.5 Hz, 3H), 2.19 (m, 1H), 2.36 (m, 1H), 2.80 (m,
1H), 3.29-3.41 (m, 2H), 3.95-4.15 (m, 2H), 4.20 (m, 1H), 4.39
(m, 2H); 13C NMR (CDCl3) δ 0.0, 17.7, 29.5, 30.7, 32.0, 42.7,
46.2, 61.7, 86.1, 107.6, 152.9, 173.7. Anal. Calcd for C14H22
-
BrNO3Si: C, 46.67; H, 6.15; N, 3.89. Found: C, 46.81; H, 6.18;
N, 3.84.
(()-syn-3-[1-Met h yl-3-(t r im et h ylsila n yl)p r op -2-yn yl]-
tetr a h yd r ofu r a n -2-on e (34). A solution of 0.50 g (1.39 mmol,
1.0 equiv) of oxazolidinone 33 in 100 mL of 3:1 THF/H2O,
containing 1.25 mL (0.011 mol, 8.0 equiv) of 30% H2O2, was

C,D-Ring Pyrromethenones of Phytochrome and Phycocyanin
J . Org. Chem., Vol. 65, No. 25, 2000 8487
treated dropwise at 0 °C, with vigorous stirring, with a solution
of 0.19 g (4.53 mmol, 3.3 equiv) of LiOH‚H2O in 5 mL of H2O
over a period of 1 min. After addition was complete, the
reaction mixture was stirred at 0 °C for an additional 5 min,
at which time no starting material was detectable by TLC.
The reaction was then treated with a solution of 1.55 g (0.012
mol, 8.8 equiv) of Na2SO3 in 10 mL of H2O at 0 °C, and acidified
to pH 1 with concentrated HCl (Caution: the reduction and
acidification sequence should take no longer than 2 min or the
yield of lactone 34 will be reduced). The reaction was then
extracted with CH2Cl2, and the combined organic extracts were
dried over anhydrous Na2SO4, concentrated under reduced
pressure, and chromatographed (silica gel, 30% EtOAc/hex-
anes) to afford 0.23 g (79%) of silyl lactone 34 as a colorless
oil: Rf 0.49 (silica gel, 30% EtOAc/hexanes); IR (CCl4) 2962.5,
extracted with EtOAc. The combined organic extracts were
dried over anhydrous Na2SO4, concentrated under reduced
pressure, and chromatographed (silica gel, 50% acetone/
hexanes) to afford 0.11 g (93%) of 37 as a light yellow oil: Rf
0.73 (silica gel, 50% acetone/hexane); IR (CCl4) 3507, 3310,
1
2960, 2360, 1698, 1583 cm-1; H NMR (CDCl3) δ 1.21 (d, J )
6.0 Hz, 3H), 1.82-1.95 (m, 1H), 2.00-2.15 (m, 1H), 2.09 (d, J
) 2.5 Hz, 1H), 2.35-2.49 (m, 1H), 2.69-2.86 (m, 2H), 2.95-
3.09 (m, 1H), 5.80 (s, 1H), 5.99 (s, 1H), 7.21 (d, J ) 8.0 Hz,
2H), 7.41 (d, J ) 8.0 Hz, 2H); 13C NMR (CDCl3) δ 18.1, 19.0,
25.5, 27.8, 30.3, 70.6, 85.8, 127.6, 129.1, 133.0, 133.9, 175.3;
exact mass calcd for C14H16ClNOSe (MSCI M + 1) 330.0165,
found 330.0117.
(()-syn -5-[4-Ca r b a m oyl-6-(4-ch lor op h en ylsela n yl)-3-
m eth ylh ex-1-yn yl]-3-(2-m eth oxyca r bon yleth yl)-4-m eth -
yl-1H-p yr r ole-2-ca r boxylic Acid , ter t-Bu tyl Ester (38). A
flame-dried flask was cooled to room temperature under an
inert atmosphere and was charged with 19 mg (0.098 mmol,
0.2 equiv) of CuI, 56 mg (0.049 mmol, 0.1 equiv) of Pd(PPh3)4,
a solution of 0.19 g (0.49 mmol, 1.0 equiv) of iodopyrrole 22 in
2 mL of DMF containing 0.20 mL (1.46 mmol, 3.0 equiv) of
NEt3, and a solution of 0.16 g (0.49 mmol, 1.0 equiv) of alkyne
amide 37 in 2 mL of DMF. The reaction was degassed
thoroughly by five freeze-thaw cycles employing Ar and
stirred for 20 h at room temperature under Ar. At the end of
this period, the reaction was filtered through Celite, washed
with 100 mL of EtOAc, and concentrated under reduced
pressure. The residue was partitioned between 15 mL of 10%
aqueous NaHCO3 and 15 mL of CH2Cl2 and stirred for 10 min.
The mixture was then extracted with CH2Cl2, and the organic
extracts were washed with 20 mL of H2O, dried over anhy-
drous Na2SO4, concentrated under reduced pressure, and
chromatographed (silica gel, 50% acetone/hexanes) to afford
0.27 g (93%) of 38 as a yellow oil: Rf 0.67 (silica gel, 50%
1
2168.4, 1779.1 cm-1; H NMR (CDCl3) δ 0.11 (s, 9H), 1.21 (d,
J ) 6.5 Hz, 3H), 2.19-2.25 (m, 1H), 2.32-2.41 (m, 1H), 2.80
(dt, J ) 10.0, 4.5 Hz, 1H), 3.00-3.06 (m, 1H), 4.21 (q, J ) 8.0
Hz, 1H), 4.36 (dt, J ) 10.0, 5.0 Hz, 1H); 13C NMR (CDCl3) δ
0.0, 16.6, 24.8, 27.0, 43.7, 66.6, 85.9, 107.7, 176.0; exact mass
calcd for C11H18O2Si 210.1076, found 210.1067.
(()-syn-3-(1-Me t h ylp r op -2-yn yl)t e t r a h yd r ofu r a n -2-
on e (35). A solution of 0.16 g (0.76 mmol, 1.0 equiv) of 34 in
15 mL of THF was cooled to 0 °C under N2, and was treated
with vigorous stirring over a period of 10 min with 0.84 mL
(0.84 mmol, 1.1 equiv) of 1 M n-Bu4NF/THF. The reaction
mixture was then diluted with 10 mL of H2O and extracted
with CH2Cl2. The combined organic extracts were dried over
anhydrous Na2SO4, concentrated under reduced pressure, and
chromatographed (silica gel, 30% EtOAc/hexanes) to afford 90
mg (86%) of 35 as a colorless oil: Rf 0.51 (silica gel, 30% EtOAc/
hexanes); IR (CCl4) 3311.8, 2983.3, 2908.3, 1789.3, 1462.8,
1
1374.2, 1166.4 cm-1; H NMR (CDCl3) δ 1.29 (d, J ) 7.5 Hz,
3H), 2.11 (d, J ) 2.5 Hz, 1H), 2.22-2.31 (m, 1H), 2.36-2.45
(m, 1H), 2.84 (dt, J ) 10.0, 4.0 Hz, 1H), 3.05 (m, 1H), 4.25 (m,
1H), 4.40 (dt, J ) 9.0, 3.0 Hz, 1H); 13C NMR (CDCl3) δ 16.6,
24.8, 25.8, 43.6, 66.5, 69.8, 85.2, 176.6. Anal. Calcd for
C8H10O2: C, 69.53; H, 7.30. Found: C, 69.65; H, 7.27.
acetone/hexane); IR (CCl4) 3450, 2975, 1741, 1691, 1580 cm-1
;
1H NMR (CDCl3) δ 1.25 (d, J ) 7.0 Hz, 3H), 1.53 (s, 9H), 1.85-
1.95 (m, 2H), 2.00 (s, 3H), 2.10 (m, 1H), 2.49 (t, J ) 8.0 Hz,
2H), 2.80 (m, 1H), 2.95 (t, J ) 8.0 Hz, 2H), 2.95-3.03 (m, 2H),
3.65 (s, 3H), 5.88 (s,1H), 5.98 (s, 1H), 7.17 (d, J ) 8.5 Hz, 2H),
7.39 (d, J ) 8.5 Hz, 2H0, 9.1 (s, 1H); 13C NMR (CDCl3) δ 9.6,
18.4, 19.0, 20.8, 27.9, 28.4, 29.0, 34.8, 51.5, 71.3, 74.3, 81.3,
96.0, 114.3, 120.3, 124.9, 127.5, 127.8, 129.2, 133.3, 134.0,
157.3, 160.1, 173.5; exact mass calcd for C28H35ClN2O5Se
594.1400, found 594.1393.
(()-syn -2-[2-(4-Ch lor op h en ylsela n yl)et h yl]-3-m et h yl-
p en t-4-yn oic Acid (36). A solution of 0.26 g (0.69 mmol, 0.6
equiv) of bis(4-chlorophenyl)diselenide and 33 mg (1.38 mmol
1.2 equiv) of NaH in 2.0 mL of dry THF was thoroughly
degassed under Ar, heated at reflux for a period of 1.5 h, cooled
to room temperature, and treated with a degassed solution of
0.16 g (1.15 mmol, 1.0 equiv) of 35 in 0.1 mL of HMPA. The
reaction was then heated at reflux for 3 h, cooled to room
temperature, treated with 1.0 mL of MeOH, and concentrated
under reduced pressure. The residue was taken up in 4 mL of
H2O and extracted with Et2O to remove HMPA. The aqueous
layer was then acidified to pH 1.0 with 10% HCl, and
re-extracted with Et2O. The latter Et2O extracts were com-
bined, dried over anhydrous MgSO4, concentrated under
reduced pressure, and filtered through a short column (silica
gel, 50% EtOAc/hexanes) to afford 0.27 g (72%) of alkyne acid
36 as a light yellow oil: Rf 0.37 (silica gel, 50% acetone/
(()-tr a n s-5-[4-[2-(4-Ch lor oph en ylselan yl)eth yl]-3-m eth -
yl-5-oxopyr r olidin -2-yliden em eth yl]-3-(2-m eth oxycar bon -
ylet h yl)-4-m et h yl-1H -p yr r ole-2-ca r b oxylic Acid , ter t-
Bu tyl Ester (39). A solution of 38 mg (0.007 mmol, 1.0 equiv)
of 38 in 4 mL of degassed CH3CN was treated at room
temperature, with vigorous stirring, with 0.38 mL (0.04 mmol,
6 equiv) of 1 M n-Bu4NF/THF and was then heated at refux
for 3.5 h under Ar. The reaction was then concentrated under
reduced pressure, and the residue was partitioned between
10 mL of H2O and 10 mL of EtOAc. The aqueous layer was
extracted with EtOAc, and the combined organic extracts were
dried over anhydrous Na2SO4, concentrated under reduced
pressure, and chromatographed (silica gel, 50% acetone/
hexanes) to afford 23 mg (61%) of 39 as a yellow oil: Rf 0.79
(silica gel, 50% acetone/hexane); IR (CCl4) 3449, 2958, 2929,
hexane); IR (CCl4) 3311.0, 2927.3, 1708.1, 1548.7 cm-1 1H
;
NMR (CDCl3) δ 1.21 (d, J ) 6.0 Hz, 3H), 1.90-2.00 (m, 1H),
2.10 (d, J ) 2.5 Hz, 1H), 2.10-2.20 (m, 1H), 2.70-2.75 (m,
1H), 2.82-2.90(m, 2H), 2.98-3.05 (m, 1H), 7.20 (d, J ) 8.0
Hz, 2H), 7.43 (d, J ) 8.0 Hz, 2H); 13C NMR (CDCl3) δ 17.5,
25.6, 27.7, 28.6, 49.4, 70.3, 85.1, 129.1, 133.9, 179.3; exact mass
calcd for C14H15ClO2Se 329.9926, found 329.9932.
(()-syn -2-[2-(4-Ch lor op h en ylsela n yl)et h yl]-3-m et h yl-
p en t-4-yn oic Acid Am id e (37). A solution of 0.13 g (0.395
mmol, 1.1 equiv) of 36 in 5 mL of THF and 0.05 mL (0.358
mmol, 1.0 equiv) of NEt3 was cooled to 0 °C under N2 and was
treated dropwise, with vigorous stirring, with 0.05 mL (0.358
mmol, 1.0 equiv) of isobutylchloroformate over a period of 5
min. The resulting solution was stirred at 0 °C for 40 min,
cooled to - 78 °C, and treated with an excess of dry NH3 (from
NH4OH dried through a CaCl2 drying tube) over a period of 1
h. The reaction solution was then allowed to warm to room
temperature and stirred overnight before being concentrated
to dryness under reduced pressure. The residue was parti-
tioned between 25 mL of H2O and 25 mL of EtOAc and
1
2872, 1739, 1717, 1685 cm-1; H NMR (CDCl3) δ 1.29 (d, J )
7.5 Hz, 3H), 1.52 (s, 9H), 1.80-2.12 (m, 2H), 1.91 (s, 3H), 2.38
(q, J ) 7.0 Hz, 1H), 2.49 (t, J ) 8.5 Hz, 2H), 2.71 (m, 1H),
2.90-3.12 (m, 4H), 3.65 (s, 3H), 5.25 (s, 1H), 7.20 (d, J ) 8.5
Hz, 2H), 7.40 (d, J ) 8.5 Hz, 2H), 7.99 (s, 1H), 8.78 (s, 1H);
13C NMR (CDCl3) δ 9.2, 14.1, 19.1, 20.7, 25.0, 28.4, 31.1, 35.0,
39.6, 48.2, 51.5, 80.8, 90.8, 118.0, 120.0, 127.8, 128.1, 129.2,
133.1, 133.9, 142.5, 158.5, 160.9, 173.6; exact mass calcd for
C
28H35lN2O5Se 594.1400, found 594.1289.
5-[4-[2-(4-C h lo r o p h e n y ls e la n y l)e t h y l]-3-m e t h y l-5-
oxo-1,5-dih ydr opyr r ol-2-yliden em eth yl]-3-(2-m eth oxycar -
bon yleth yl)-4-m eth yl-1H-p yr r ole-2-ca r boxylic Acid , ter t-
Bu tyl Ester (40). A solution of 64 mg (0.11 mmol, 1.0 equiv)
of 39 in 20 mL of benzene was treated at room temperature,
with vigorous stirring, with a solution of 27 mg (0.12 mmol,
1.1 equiv) of DDQ in 5 mL of benzene under N2. The reaction

8488 J . Org. Chem., Vol. 65, No. 25, 2000
J acobi et al.
was stirred for an additional 10 min at room temperature,
diluted with 20 mL of H2O, and extracted with CH2Cl2. The
combined organic extracts were dried over anhydrous Na2SO4,
concentrated under reduced pressure, and chromatographed
(silica gel, 50% acetone/hexanes) to afford 50 mg (78%) of 40
as a yellow solid. Recrystallization from CH2Cl2/Et2O/hexanes
afforded 7 as yellow plates: mp 194-95 °C (lit.5m mp 195 °C);
Rf 0.84 (silica gel, 50% acetone/hexane); IR (CCl4) 3353, 2975,
2929, 1738, 1688, 1648 cm-1; 1H NMR (CDCl3) δ 1.55 (s, 9H),
2.04 (s,3H), 2.09 (s, 3H), 2.51 (t, J ) 9.0 Hz, 2H), 2.81 (t, J )
7.0 Hz, 2H), 2.99 (t, J ) 9.0 Hz, 2H), 3.11 (t, J ) 7.0 Hz, 2H),
3.67 (s, 3H), 5.97 (s, 1H), 7.12 (d, J ) 8.0 Hz, 2H), 7.39 (d, J
) 8.0 Hz, 2H), 9.20 (s, 1H), 9.45 (s, 1H).
Z-1-(2-o x o -4,5-d ih y d r o fu r a n -3-y lid e n e )t r iflu o r o -
m eth a n esu lfon ic Acid Eth yl Ester (42). A solution of 7.26
g (6.1 mL, 0.057 mol) of 2-acetylbutyrolactone (41) in 250 mL
of freshly distilled anhydrous THF was cooled to -78 °C under
Ar using a dry ice/acetone bath. This solution was then treated
dropwise, with efficient stirring, with 22.6 mL (0.057 mol, 1.0
equiv) of a 2.5 M solution of n-BuLi in hexanes over a period
of 10 min. After addition was complete, the resulting white
slurry was stirred at -78 °C for an additional 30 min, and
then treated with 15.9 g (9.50 mL, 0.057 mol, 1.0 equiv) of
trifluoromethanesulfonic anhydride added over a period of 5
min. The resulting yellow solution was stirred at -78 °C for
an additional 20 min, quenched by careful addition of 200 mL
of ice-cold 1:1 saturated NaHCO3/brine, and extracted with
Et2O. The combined organic extracts were dried over MgSO4,
concentrated under reduced pressure, and the residue crystal-
lized from Et2O to give 7.4 g (50%) of 42 as a colorless
crystalline solid: mp 65-66 °C; Rf 0.19 (silica gel, 30% EtOAc/
hexanes); IR (CH2Cl2) 2964, 1753, 1695 cm-1; 1H NMR (CDCl3)
δ 2.19 (s, 3H), 3.03-3.08 (m, 2H), 4.37-4.42 (m, 2H); 13C NMR
(CDCl3) δ 20.0, 27.2, 65.1, 118.4, 118.9 (q, J ) 318 Hz, CF3),
150.2, 166.2. Anal. Calcd for C7H7F3O5S: C, 32.31; H, 2.71.
Found: C, 32.27; H, 2.74.
gel, 20% EtOAc/hexanes, increasing to 100% EtOAc) afforded
39 as an unstable tan solid: 1H NMR (CDCl3) δ 2.28 (s, 3H),
2.92-3.12 (m, 4H), 3.45 (s, 1H), 7.20-7.60 (m, 4H).
Z-2-[2-(4-Ch lor op h en ylsela n yl)eth yl]-3-m eth ylp en t-2-
en -4-yn oic Am id e (45). The crude acid 44 from above was
taken up in 5.0 mL of (COCl)2, and the resulting solution was
stirred overnight at room temperature. The excess (COCl)2 was
then removed under reduced pressure, and the residue was
dissolved in 15 mL of freshly distilled anhydrous THF. The
resulting solution was added dropwise, with vigorous stirring,
to 120 mL of ice-cold 30% aqueous NH4OH. The resulting
suspension was stirred at 0 °C for 15 min and then extracted
with EtOAc. The combined organic layers were washed with
H2O and brine, dried over MgSO4, concentrated under reduced
pressure, and chromatographed (silica gel, 5:1 CH2Cl2/EtOAc)
to afford 2.3 g (49%) of amide 45 as a yellow solid. Recrystal-
lization from CH2Cl2 afforded 45 as a colorless crystalline
solid: mp 128-130 °C; Rf 0.17 (silica gel, 40% EtOAc/hexanes);
IR (CH2Cl2) 3371, 3295, 3180, 1643, 1600 cm-1 1H NMR
;
(CDCl3) δ 2.01 (s, 3H), 2.90 (t, J ) 7.7 Hz, 2H), 3.06, (t, J )
7.7 Hz, 2H), 3.18 (s, 1H), 5.60 (br s, 1H), 6.00, (br s, 1H), 7.20-
7.50 (m, 4H); 13C NMR (CDCl3) δ 20.97, 26.24, 34.13, 82.83,
84.73, 84.78, 120.55, 128.42, 129.73, 134.70, 142.79, 171.54.
Anal. Calcd for C14H14ClNOSe: C, 51.47; H, 4.32; N, 4.29.
Found: C, 51.36; H, 4.31; N, 4.20.
Z-3-Meth yl-2-vin ylp en t-2-en -4-yn oic Acid Am id e (46).
A solution of 500 mg (1.53 mmol, 1.0 equiv) of alkyne amide
45 in 20 mL of THF was diluted with 2 mL of H2O and 0.4
mL of HOAc. The resulting solution was then treated dropwise,
and with efficient stirring, with 1.74 mL (15.30 mmol, 10.0
equiv) of 30% aqueous H2O2. After being stirred for a total of
50 min at room temperature, the initial brown solution had
turned to bright yellow. The reaction was then poured into 50
mL of saturated aqueous NaHCO3 and extracted with Et2O.
The combined Et2O extracts were washed with brine, dried
over MgSO4, and concentrated under reduced pressure to
afford 204 mg (98%) of 46 as an unstable yellow oil (Caution:
do not concentrate completely to dryness or the residue may
decompose exothermically). Amide 46 is labile to polymeriza-
tion and is best used immediately without further purifica-
tion: Rf 0.34 (silica gel, 40% acetone/hexanes); 1H NMR
(CDCl3) δ 2.03 (s, 3H), 3.39 (s, 1H) 5.33 (d, J ) 11 Hz, 1H),
5.44 (d, J ) 17 Hz, 1H), 5.85 (br s, 1H), 6.60 (br s, 1H), 6.92
(dd, J ) 11 Hz, 17 Hz, 1H).
Z-3-[1-Met h yl-3-(t r im et h ylsila n yl)p r op -2-yn ylid en e]-
tetr a h yd r ofu r a n -2-on e (43). A flame dried flask was cooled
to room temperature under an inert atmosphere (glovebox),
and was charged with 163 mg (0.86 mmol, 0.1 equiv) of CuI,
301 mg (0.43 mmol, 0.05 equiv) of Pd(Ph3P)2Cl2, a solution 2.23
g (8.57 mmol, 1.0 equiv) of triflate 42 in 56 mL of THF
containing 3.6 mL (25.71 mmol, 3.0 equiv) of NEt3, and 1.70
mL (12.0 mmol, 1.4 equiv) of trimethylsilylacetylene. The
resulting black solution was degassed thoroughly (freeze-
thaw) employing Ar and stirred for 2.5 h at room temperature
under Ar. At the end of this period, the reaction was diluted
with 100 mL of brine and extracted with Et2O. The combined
organic extracts were washed with 10% w/w aqueous NH4Cl
and brine, dried over MgSO4, concentrated under reduced
pressure, and chromatographed (silica gel, 20% EtOAc/hex-
anes) to afford 1.67 g (94%) of 43 as an off-white solid: mp
82-83 °C; Rf 0.38 (silica gel, 30% EtOAc/hexanes); IR (CH2-
Z-5-[4-Ca r ba m oyl-6-(4-ch lor op h en ylsela n yl)-3-m eth yl-
h ex-3-en -1-yn yl]-3-(2-m et h oxyca r b on ylet h yl)-4-m et h yl-
1H-p yr r ole-2-ca r boxylic Acid , ter t-Bu tyl Ester (47). This
material was prepared following an identical procedure to that
described above for ester 38, utilizing 1.00 g (2.54 mmol)
pyrrole 22, 1.25 g (3.82 mmol) amide 45 in 10 mL of DMF/1.0
mL of Et3N, 293.9 mg (0.254 mmol) Pd(Ph3P)4, and 96.9 mg
(0.509 mmol) CuI. The reaction mixture was thoroughly
degassed and stirred at room temperature under argon for 24
h. After this period, the reaction was quenched with saturated
NH4Cl and extracted with EtOAc. The combined extracts were
washed with H2O and brine, dried over anhydrous MgSO4,
concentrated under reduced pressure, and chromatographed
(silica gel, 2:1 hexanes/acetone) to afford 1.37 g (91%) of amide
47 as a yellow solid: mp 149-50 °C; Rf 0.42 (silica gel, 50%
acetone/hexanes); IR (CH2Cl2) 3427, 3341, 3179, 2978, 2930,
1
Cl2) 2951, 2143, 1752 cm-1; H NMR (CDCl3) δ 0.23 (s, 9H),
2.01 (s, 3H), 2.91-2.96 (m, 2H), 4.26-4.31 (m, 2H); 13C NMR
(CDCl3) δ 0.2, 23.4, 28.4, 64.6, 103.2, 107.2, 128.4, 130.4, 168.6.
Anal. Calcd for C11H16O2Si: C, 63.41; H, 7.74. Found: C, 63.17;
H, 7.75.
Z-2-[2-(4-Ch lor op h en ylsela n yl)eth yl]-3-m eth ylp en t-2-
en -4-yn oic Acid (44). A degassed solution of 2.74 g (7.20
mmol, 0.50 equiv) of bis(4-chlorophenyl)diselenide and 576 mg
(14.4 mmol, 1.0 equiv) of 60% NaH/mineral oil in 30 mL of
anhydrous THF was heated at reflux under Ar for a period of
1.5 h, cooled to room temperature, and treated portionwise
with 3.00 g (14.40 mmol, 1.0 equiv) of lactone 43. The resulting
black solution was then heated at reflux for 4 h, cooled to room
temperature, and quenched by careful dropwise addition of 1
mL of MeOH, resulting in effervescence. The solution was then
concentrated under reduced pressure, and the resulting black
oil was dissolved in H2O and extracted with Et2O to remove
selenide byproducts. The aqueous layer was acidified to pH 1
using 10% HCl and re-extracted with Et2O. The combined Et2O
extracts were dried over MgSO4 and concentrated under
reduced pressure to afford an orange oil that was used directly
for the synthesis of amide 45 (below). Chromatography (silica
1
2854, 2194, 1738, 1724, 1662 cm-1; H NMR (CDCl3) δ 1.58
(s, 9H), 2.04 (s, 3H), 2.10 (s, 3H), 2.55 (t, J ) 8.0 Hz, 2H),
2.93-3.03 (m 4H), 3.11 (t, J ) 7.7 Hz, 2H), 3.68 (s, 3H), 5.64
(br s, 1H), 5.92 (br s, 1H), 7.11 (d, J ) 8.4 Hz, 2H), 7.41 (d, J
) 8.4 Hz, 2H), 8.86 (br s, 1H); 13C NMR (CDCl3) δ 10.3, 21.1,
21.3, 26.5, 28.9, 34.4, 35.4, 52.0, 82.1, 88.3, 94.0, 114.5, 121.7,
122.2, 126.8, 128.5, 128.6, 129.7, 133.7, 134.4, 140.5, 160.5,
171.4, 174.0. Anal. Calcd for C28H33ClN2O5Se: C, 56.81; H,
5.62; N, 4.73. Found: C, 56.99; H, 5.69; N, 4.66.
Z-5-(4-Ca r ba m oyl-3-m eth ylh exa -3,5-d ien -1-yn yl)-3-(2-
m eth oxyca r bon yleth yl)-4-m eth yl-1H-p yr r ole-2-ca r boxy-
lic Acid , ter t-Bu tyl Ester (48). Meth od A. This material
was prepared following an identical procedure to that de-
scribed above for ester 38, utilizing iodopyrrole 22 and alkyne
amide 46. On small scales amide 48 was obtained in 90-95%

C,D-Ring Pyrromethenones of Phytochrome and Phycocyanin
J . Org. Chem., Vol. 65, No. 25, 2000 8489
yield as a yellow solid: mp 155-56 °C dec; Rf 0.29 (silica gel,
layer (containing suspended material) was filtered through
Hyflo-Super Cel, dried over anhydrous MgSO4, concentrated
under reduced pressure, and chromatographed (silica gel,
hexanes/acetone 3:1) to afford 60.6 mg (60%) of dihydropyr-
romethenone 7 as a yellow solid, having identical spectral data
as an authentic sample:5m 1H NMR (CDCl3) δ 1.56 (s, 9H), 2.10
(s, 3H), 2.19 (s, 3H), 2,53 (t, J ) 9.0 Hz, 2 H), 3.01 (t, J ) 9.0
Hz, 2H), 3.68 (s, 3H), 5.46 (d, J ) 11 Hz,1H), 6.03 (s, 1H),
6.29 (d, J ) 17 Hz 1H), 6.57 (dd, J ) 11,17 Hz 1H), 8.67 (br s,
1H), 9.20 (br s, 1H); 13C NMR (CDCl3) δ 9.8, 10.4, 21.3, 28.9,
35.5, 52.0, 81.9, 100.0, 120.7, 124.1, 124.4, 126.5, 126.7, 128.2,
129.4, 134.9, 142.3, 161.0, 173.4, 174.1. This material was
identical to 7 obtained by oxidative elimination of selenide
40.5m
40% acetone/hexanes); IR (CDCl3) 3439, 3323, 3187, 2983,
1
2185, 1733, 1670 cm-1; H NMR (CDCl3) δ 1.57 (s, 9H), 2.11
(s, 6H), 2.53 (t, J ) 8.0 Hz, 2H), 3.00 (t, J ) 8.0 Hz, 2H), 3.68
(s, 3H), 5.34 (d, J ) 11 Hz, 1H), 5.46 (d, J ) 17 Hz, !H), 5.62
(br s, 1H), 5.79 (br s, 1H), 6.95 (dd, J ) 11,17 Hz, 1H), 8.80
(br s, 1H). Anal. Calcd for C22H28N2O5: C, 65.98; H, 7.05; N,
7.00. Found: C, 65.86; H, 7.01; N, 6.92.
Meth od B. A solution of 1.30 g (2.20 mmol) of amide 47 in
20 mL of THF was diluted with 2.0 mL of H2O and 0.4 mL of
HOAc and was treated dropwise, with vigorous stirring, with
2.5 mL of 30% aqueous H2O2. After being stirred for a total of
1 h at room temperature, the reaction was poured into
saturated aqueous NaHCO3 and extracted with Et2O. The
combined extracts were washed with brine, dried over anhy-
drous MgSO4, concentrated under reduced pressure, and
chromatographed (silica gel, 3:2 hexanes/acetone) to afford 792
mg (90%) of amide 48 as a yellow solid, identical in all respects
to the material prepared following method A above.
Ack n ow led gm en t. Financial support of this work
by the National Institutes of Health, NIGMS Grant No.
GM38913, is gratefully acknowledged.
3-(2-Met h oxyca r b on ylet h yl)-4-m et h yl-5-(3-m et h yl-5-
oxo-4-vin yl-1,5-d ih yd r op yr r ol-2-ylid en em eth yl)-1H-p yr -
r ole-2-ca r boxylic Acid , ter t-Bu tyl Ester (7). A mixture of
100.0 mg (0.250 mmol) of alkyne amide 48 and 189.6 mg (1.25
mmol) of CsF in 5.0 mL of dry THF was treated with 0.74 mL
(4.99 mmol) of Si(OMe)4, and the resulting mixture was heated
at reflux under Ar for a period of 6 h. The reaction was then
cooled, diluted with CH2Cl2, and washed with H2O. The organic
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H- and
13C NMR spectra for compounds 6, 7, 11, 14, 15, 16, 17,
18a -d , 19, 20, 21, 28-cobalt complex, 33-cobalt complex, 33,
36, 40, 45, and 46. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O005531K