Dihydropyrromethenones by Pd(0)-Mediated Coupling of Iodopyrroles and Acetylenic Amides. Synthesis of the A,B-Ring Segment of Phytochrome

Article abstract of DOI:10.1021/jo970289b

Dihydropyrromethenone derivative 32b, which constitutes the A,B-ring segment of phytochrome (6), has been prepared in enantiomerically pure form beginning with acetylenic amide 47b and iodopyrrole 27. The key steps involved the TBAF-catalyzed 5-exo-dig cyclization of the acetylenic pyrrole 48b, followed by thia-Mitsunobu inversion of the resulting alcohol derivative 31b.

Full text of DOI:10.1021/jo970289b

J . Org. Chem. 1997, 62, 2907-2916
2907
Dih yd r op yr r om eth en on es by P d (0)-Med ia ted Cou p lin g of
Iod op yr r oles a n d Acetylen ic Am id es. Syn th esis of th e A,B-Rin g
Segm en t of P h ytoch r om e
Peter A. J acobi,* J iasheng Guo, S. Rajeswari, and Wanjun Zheng
Hall-Atwater Laboratories, Wesleyan University, Middletown, Connecticut 06459-0180
Received February 14, 1997X
Dihydropyrromethenone derivative 32b, which constitutes the A,B-ring segment of phytochrome
(6), has been prepared in enantiomerically pure form beginning with acetylenic amide 47b and
iodopyrrole 27. The key steps involved the TBAF-catalyzed 5-exo-dig cyclization of the acetylenic
pyrrole 48b, followed by thia-Mitsunobu inversion of the resulting alcohol derivative 31b.
In tr od u ction
In comparison to photosynthesis, where some aspects
of the mechanism are known in considerable detail,
relatively little is known about photomorphogenesis at
the molecular level. In part this is due to a lack of
suitable model systems, as well as to the difficulty of
isolating and purifying the parent chromophore (6 is
present in much lower concentrations in plants than
chlorophyll). In order to address these issues we have
begun a synthetic program that we hope will serve two
purposes: (1) to provide ample quantities of material to
study the fundamental photochemistry of 6 and (2) to
prepare labeled phytochromobilin intermediates for re-
constitution with recombinant apophytochrome. This
last approach offers perhaps the best opportunity for
studying E,Z isomerization in the protein-bound chro-
mophore, a likely step in phytochrome activation.1a,4
Ultimately this work might lead to a better understand-
ing of the process of photomorphogenesis.
In the accompanying paper of this series we described
a novel synthesis of dihydropyrromethenone 5,1a a po-
tential synthetic precursor to the biologically important
plant pigment phytochrome (6) and related materials
(Scheme 1). Phytochrome is a biliprotein that plays a
Sch em e 1
Our previous studies took advantage of the ready
availability of N-aminopyrroles of type 15 and acetylenic
acids 2 (Scheme 1).1a,6 These compounds contain all of
the stereo- and regiochemical features necessary for
eventual conversion to dihydropyrromethenone 5. Thus,
EDCI-mediated coupling of 1 and 2 afforded an excellent
yield of the acetylenic hydrazide 3, which upon F--cata-
lyzed 5-exo-dig cyclization gave N-pyrroloenamide 4 in
enantiomerically pure form (TBAF ) n-Bu4NF). This last
step completes the formation of ring A, and it is signifi-
cant for the fact that hydrazide cyclization takes place
with an unactivated alkyne (vide infra).1 Finally, pho-
tochemical 3,5-sigmatropic rearrangement of 4 gave a
46% yield of the target compound 5 as a ∼1:1 mixture of
E and Z isomers (60% yield based on recovered 4). Also
produced were varying amounts of products derived from
1,3- and 1,5-rearrangements.
The utility of this approach stems partly from the ease
of preparation of its starting components,1a,5 which allows
key role in photomorphogenesis, the process by which
light governs the growth, development, and aging of
plants.1a,2 The same A,B-ring segment (5) is also found
in light-harvesting pigments such as phycocyanin (7a )
and phycoerythrin (7b), which serve as auxiliary chro-
mophores in photosynthesis.3
(4) (a) Thu¨mmler, F.; Ru¨diger, W. Tetrahedron 1983, 39, 1943. (b)
Ru¨diger, W.; Thu¨mmler, F.; Cmiel, E.; Schneider, S. Proc. Natl. Acad.
Sci., U.S.A. 1983, 80, 6244. (c) Farrens, D. L.; Holt, R. E.; Rospen-
dowski, B. N.; Song, P.-S.; Cotton, T. M. J . Am. Chem. Soc. 1989, 111,
9162. (d) Fodor, S. P. A.; Lagarias, J . C.; Mathies, R. A. Biochemistry
1990, 29, 11141. (e) Fodor, S. P. A.; Lagarias, J . C.; Mathies, R. A.
Photochem. Photobiol. 1988, 48, 129. (f) Cornejo, J .; Beale, S. I.; Terry,
M. J .; Lagarias, J . C. J . Biol. Chem. 1992, 267, 14790. (g) Wahleithner,
J . A.; Li, L.; Lagarias, J . C. Proc. Natl. Acad. Sci. U.S.A. 1991, 88,
10387. (h) Li, L.; Lagarias, J . C. J . Biol. Chem. 1992, 267, 19204
(5) J acobi, P. A.; Cai, G. Heterocycles 1993, 35, 1103.
(6) (a) Schreiber, S. L.; Klimas, M. T.; Sammakia, T. J . Am. Chem.
Soc. 1987, 109, 5749. (b) Schreiber, S. L.; Sammakia, T.; Crowe, W. E.
J . Am. Chem. Soc. 1986, 108, 3128. See also: (c) Lockwood, R. F.;
Nicholas, K. M. Tetrahedron Lett. 1977, 18, 4163. (d) Nicholas, K. M.;
Nestle, M. O.; Deyferth, D. Transition Metal Organometallics; Alper,
H., Ed.; Academic Press: New York, 1978; Vol. 2, p 1.
X Abstract published in Advance ACS Abstracts, April 15, 1997.
(1) (a) J acobi, P. A.; Buddhu, S. C.; Fry, D.; Rajeswari, S., J . Org.
Chem. 1997, 62, 2894. (b) J acobi, P. A.; Buddhu, S. C. Tetrahedron
Lett. 1988, 29, 4823. Preliminary communications: (c) J acobi, P. A.;
Rajeswari, S. Tetrahedron Lett. 1992, 33, 6235. (d) J acobi, P. A.; Guo,
J .; Zheng, W. Tetrahedron Lett. 1995, 36, 1197.
(2) Phytochrome and Photoregulation in Plants; Furuya, M. Ed.;
Academic Press: New York, 1987. See also footnote 6 in ref 1a.
(3) Scheer, H. Angew. Chem. 1981, 93, 230; Angew. Chem., Int. Ed.
Engl. 1981, 20, 241. See also footnotes 8 and 9 in ref 1a.
S0022-3263(97)00289-2 CCC: $14.00 © 1997 American Chemical Society

2908 J . Org. Chem., Vol. 62, No. 9, 1997
J acobi et al.
for considerable flexibility in introducing substituents on
the tetrapyrrole skeleton. However, a number of limita-
tions remain. First, photochemical rearrangement of 4
to 5 invariably leads to ∼1:1 mixtures of E and Z isomers
at C4-C5, while the natural stereochemistry at this
position is Z. Second, protecting groups must be chosen
with care to avoid complications arising from triplet-
sensitized hydrazide cleavage.1a Third, yields, although
moderate to good (40-60%), have been optimized and
there is probably little opportunity for improvement. In
this paper we describe an alternative synthesis of dihy-
dropyrromethenones of type 5 that remedies each of these
deficiencies, while still retaining the most positive fea-
tures of our original strategy. Also, we have prepared a
viable precursor to phytochrome (6) that incorporates the
natural substitution pattern.
At the time we began this work, only scattered reports
had appeared describing the coupling of acetylenes with
halopyrroles,9 and few provided experimental details.
Therefore, our initial studies were carried out with the
model iodopyrrole 17, which was readily prepared by
iodination of 2-carbomethoxy-3,4-butane-1,4-diylpyrrole
(16), itself derived in 75% yield from 1-nitrocyclohexene
(13) and methyl isocyanoacetate (14) using the methodol-
ogy of Zard et al. (Scheme 3).10 Iodopyrrole 17 afforded
Sch em e 3
Discu ssion a n d Resu lts
The cyclization of hydrazide 3 to enamide 4 took
advantage of the exceptional catalytic activity of TBAF,7a
which was discovered in a serendipitous fashion upon
attempted cleavage of certain (trimethylsilyl)acetylene
derivatives with F- (Scheme 9 in ref 1a).1a This discovery
was of interest since it demonstrated that even unacti-
vated alkynes could undergo ring-A cyclization (formerly
this transformation was successful only with acetylenic
esters1b). Consequently, we set out to explore a number
of modifications to our original strategy that previously
did not appear to be feasible. One such modification is
outlined in Scheme 2. As with alkyne 2, we expected that
a 21% yield of pyrroloacetylene 19 upon coupling with
phenylacetylene (18) using the reagent combination
PdCl2(Ph3P)2/CuI in NEt3 as a solvent.8 The major
byproduct in this case was the bis(acetylene) PhCtC-
CtCPh (20) arising from oxidative dimerization of 18.
Similar results were obtained using Pd(PPh3)4 and most
other Pd(0) catalysts, although modest improvements
were observed with Pd[P(o-tolyl)3]4.11 A number of varia-
tions in solvent (THF, MeCN, DMF) and molar ratio of
18:17 were also explored, all with the catalyst system
Pd(PPh3)4/CuI/NEt3. In general, DMF provided the
cleanest reactions,12 while ratios of 18:17 as high as 2:1
afforded slight increases in yields of coupling product 19,
together with much larger quantities of dimer 20. How-
ever, by far the most important factor influencing yields
in these reactions was the presence of oxygen. At least
three freeze-thaw cycles are necessary for optimum
yields of 19 and to minimize formation of 20.13 Thus,
our best results were obtained with a ratio of 18:17 )
1.1:1.0, using DMF as the solvent under rigorously
degassed conditions (cf. Experimental Section). This
protocol appeared to be general for the Sonogashira
coupling of 1H-2-iodopyrroles with acetylenes8,9e and
consistently afforded 19 in >85% yield with little or no
dimer formation.
Sch em e 2
ring-A synthons 9 could be prepared in enantiomerically
pure form from the acetylenic acids 8, themselves derived
with unequivocal control over stereochemistry using a
Nicholas-Scheiber reaction.1a,6 However, in this case
bond connectivity between C5 and C6 would be estab-
lished via Pd(0)-mediated coupling of halopyrroles 10
with acetylenic amides 9. Acetylenic pyrroles 11 would
then be converted directly to dihydropyrromethenones 12
by TBAF-catalyzed 5-exo-dig cyclization, in close analogy
to the cyclization of 3 to 4 (cf. Scheme 1). This sequence
represents a significant improvement over that outlined
in Scheme 1, since it eliminates the need for a subsequent
3,5-sigmatropic rearrangement. Finally, it seemed likely
that kinetic control in the amide addition to the alkyne
triple bond would lead directly to the naturally occurring
Z configuration at C4-C5.
(9) (a) Vasilevskii, S. F.; Sundukova, T. A.; Shvartsberg, M. S.;
Kotylarevskii, I. L. Bull. Acad. Sci. USSR Div. Chem. Sci. (Engl.
Transl.) 1979, 1536 (p 1661 in Russian); cf. Chem. Abstr. 1979, 91,
157544g. (b) Vasilevskii, S. F.; Sundukova, T. A.; Shvartsberg, M. S.;
Kotylarevskii, I. L. Bull. Acad. Sci. USSR Div. Chem. Sci. (Engl.
Transl.) 1980, 1871; cf. Chem. Abstr. 1981, 94, 30464n. (c) Alvarez,
A.; Guzman, A.; Ruiz, A.; Velarde, E.; Muchowski, J . M. J . Org. Chem.
1992, 57, 1653. (d) Chen, W. Ph.D. Dissertation, Department of
Chemistry, University of Alabama, Tuscaloosa, 1990. (e) Coupling
appears to be much slower with 1-Boc-2-iodopyrroles.
(10) (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. (c) Baulder, C.; Ocampo, R.; Callot, H. J . Tetrahedron
1992, 48, 5135. (d) Tang, J .; Verkade, J . G. J . Org. Chem. 1994, 59,
7793. (e) J acobi, P. A.; DeSimone, R. W. Tetrahedron Lett. 1992, 33,
6231.
(7) (a) Clark, J . H. Chem. Rev. 1980, 80, 429. (b) Pless, J . J . Org.
Chem. 1974, 39, 2644. (c) Sharma, R. K.; Fry, J . L. J . Org. Chem. 1983,
48, 2112.
(8) 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) Farina, V.; Roth, G. P. Tetrahedron Lett. 1991, 32, 4243. (b)
Farina, V.; Krishnan, B. J . Am. Chem. Soc. 1991, 113, 9585.
(12) Robins, M. J .; Vinayak, R. S.; Wood, S. G. Tetrahedron Lett.
1990, 31, 3731.
(13) Magnus, P.; Carter, P.; Elliott, J .; Lewis, R.; Harling, J .;
Pitterna, T.; Bauta, W. E.; Fortt, S. J . Am. Chem. Soc. 1992, 114, 2544.

Dihydropyrromethenones by Pd(0)-Mediated Coupling
J . Org. Chem., Vol. 62, No. 9, 1997 2909
Sch em e 5
These experiments were readily extrapolated for use
with more complicated acetylenic amides of type 9
(Scheme 4). In every case, Pd(0)-mediated coupling of
Sch em e 4
was accomplished using either of the routes outlined in
Scheme 5. The first of these makes use of the methodol-
ogy of Zard et al.,10 which we had previously employed
in the synthesis of pyrrole 16 (cf. Scheme 3). In this case,
aldehyde 22 was first converted to the Henry adduct 24
by DBU-catalyzed condensation with nitroethane (23),
followed by acylation with acetic anhydride. In the
presence of base, 24 underwent rapid elimination of
HOAc, followed by Michael addition with tert-butyl
isocyanoacetate (25) and ring closure to afford the desired
pyrrole 26 in a single step.10e A wide range of base/
solvent combinations was explored in order to optimize
the transformation of 24 to 26. However, we eventually
found that the system tert-butyltetramethylguanidine/
isopropyl alcohol consistently gave the best yields.10
Iodination of 26 with NIS then gave a 47% yield of the
ring-C precursor 27 on a 0.5-1 g scale. As an alternative
route to 27, Rapoport et al. have recently described an
efficient procedure for the oxidative degradation of benzyl
ester 28, which ultimately affords 27 by decarboxylative
iodination.15a Although this sequence is somewhat longer,
it works quite well for preparing 27 on multigram scales
(>5 g).
iodopyrrole 17 with acetylenic amides 9a -e and ent-9b
was accomplished in yields of >88%. Significantly, there
was no need to protect either the amide or pyrrole
components. Furthermore, cyclization of pyrroloacetyl-
enes 20a -e and ent-20b occurred under conditions nearly
identical to those employed in the conversion of acetylenic
hydrazide 3 to cyclic enamide 4 (TBAF, THF, reflux),
affording Z dihydropyrromethenones 21b-e and ent-21b
in 73-83% yield. Little or no formation of the corre-
sponding E isomers was observed, except for the case of
21e (R ) Bn), where steric crowding causes partial Z,E
isomerization. The materials thus obtained were identi-
cal to, in both physical properties and optical rotation,
the corresponding Z isomers prepared using our photo-
chemical strategy.1a
Iodopyrrole 27 proved to be an excellent precursor for
dihydropyrromethenones related to tetrapyrroles 6-7b
(Scheme 6). Thus, in a very efficient two-step sequence,
Sch em e 6
Several characteristics of this cyclization warrant
special mention. First, for maximum yield it is essential
that cyclization be carried out under strictly anaerobic
conditions (g three freeze-thaw cycles). Second, cycliza-
tion occurs faster with more highly substituted substrates
(rate: A, B ) Me, S-CHORCH3 ≈ Me, Me > H, H; also
21e [R ) Bn] > 21a [R ) H]) and is very slow with simple
aliphatic acetylenic amides lacking a conjugated pyrrole
ring. Finally, all of these cyclizations exhibit a brief
induction period prior to the onset of reaction. This last
characteristic might indicate that the actual catalytic
species is the thermodynamically stable n-Bu4N+FHF-
complex (“tetra-n-butylammonium bifluoride”).14 This
material forms rapidly upon heating n-Bu4NF in solution
and upon attempted drying of n-Bu4NF‚3H2O at 40-70
°C.14a Indeed, it is likely that n-Bu4N+FHF- is also
involved in other F--catalyzed reactions which specify the
use of TBAF at T > 40 °C.14b,c
Pd(0)-catalyzed coupling of 27 with the enantiomerically
pure amide 9d gave a virtually quantitative yield of the
acetylenic pyrrole 29, which upon TBAF-induced cycliza-
tion as described above afforded the ring-A,B precursor
30 in 87% yield. In identical fashion, but beginning with
Before extending these studies to the synthesis of
dihydropyrromethenones of type 5, it was necessary to
devise an efficient preparation of the iodopyrrole 27. This
(15) (a) Bishop, J . E.; O’Connell, J . F.; Rapoport, H. J . Org. Chem.
1991, 56, 5079. See also: (b) J ackson, A. H.; Kenner, G. W.; Smith, K.
M. J . Chem. Soc. C 1971, 502. (c) Sessler, J . L.; Mozaffari, A.; J ohnson,
M. R. Org. Synth. 1991, 70, 68.
(14) (a) Sharma, R. K.; Fry, J . L. J . Org. Chem. 1983, 48, 2112. (b)
Pless, J . J . Org. Chem. 1974, 39, 2644. (c) Clark, J . H. Chem. Rev.
1980, 80, 429.

2910 J . Org. Chem., Vol. 62, No. 9, 1997
J acobi et al.
Sch em e 8
acetylenic amide ent-9d , enantiomer ent-30 was also
prepared as a single isomer, and with [R]25D of essentially
equal magnitude but opposite sign. The results sum-
marized in Schemes 4 and 6 are considerably better than
those obtained by following our original strategy (Scheme
1),1a and we believe that this methodology has significant
advantages over traditional approaches.
We initially planned that (3′R)-dihydropyrromethenone
32a might be derived via thia-Mitsunobu inversion of 3′-
(S)-hydroxy derivative 31a (R ) H),1a,16 followed by
decarboxylative formylation (Scheme 7).17 This trans-
Sch em e 7
2R,3R,3′R mercaptide 40. Once in hand, 40 was con-
verted in 49% overall yield to the acetylenic amide 43 by
a three-step sequence involving deprotection, oxidation,
and finally amidation with isobutyl chloroformate (i-BCF)
and NH3. Although circuitous, this route was suitable
for preparing gram quantities of 43 with excellent
stereocontrol. At this stage, however, we were disap-
pointed to find that 43 gave only modest yields of the
acetylenic pyrrole 44 upon Pd(0)-mediated coupling with
the iodopyrrole 27 (Scheme 9). Presumably sulfur in-
formation would give material having the 2R,3R,3′R
configuration found in tetrapyrroles 6-7b, in suitable
form for coupling with an appropriate C,D-ring frag-
ment.17 However, this approach failed, since 30 (R ) Bn)
suffered extensive decomposition upon attempted benzyl
ether cleavage to afford 31a . Reagents tested included
H2/Pd, BBr3, Me3SiI, and P4S10 (vide infra). We also
explored the possibility that 3′R mercaptide derivatives
of type 35 might be prepared directly using the Nicholas-
Schreiber methodology (Scheme 7).6 Surprisingly, how-
ever, all attempts at condensing boron enolates of type
33 with the cobalt complex 34 were unsuccessful. At low
temperatures little or no reaction occurred, while more
forcing conditions caused rapid decomposition. This
failure is most likely due to mercaptide complexation
with Bu2BOTf, which inhibits the requisite homolytic
cleavage in 34 to generate carbocation intermediates.6a
In any event, as described elsewhere,18 mismatched
condensations of this type typically proceed with anti
selectivity.
Sch em e 9
terferes in this case by poisoning the Pd catalyst. Even
more discouraging, all attempts at effecting cyclization
of 44 to the corresponding dihydropyrromethenone 45
gave only extensive decomposition.
On the basis of these results, we concluded that thia-
Mitsunobu inversion at C3′ could only be effected after
formation of the dihydropyrromethenone ring. Until
now, however, all attempts at cleaving protected hydroxyl
derivatives of type 30 had failed (cf. Scheme 7). Fortu-
nately, this problem was resolved with the finding that
lactone 37 underwent facile ring opening with a variety
of amines 46, affording acetylenic alcohols of type 47 in
90-95% yield (Scheme 10). Alkynes 47a ,b (R ) H, PMB)
then gave 80-95% yields of the corresponding pyrrolo-
acetylenes 48a ,b upon Pd(0)-catalyzed coupling with
iodopyrrole 27.
With ample quantities of both 48a (R ) H) and 48b
(R ) Bn) now in hand, we turned our attention to the
remaining steps necessary to complete the synthesis of
32 (Scheme 10). Unexpectedly, cyclization of 48a turned
out to be relatively slow, affording a 43% yield of 31a
These difficulties were partly circumvented with the
experiments outlined in Scheme 8. Thus, debenzylation
of acetylenic acid 36 with P4S10 led directly to the lactone
derivative 37 (95%),1a,19 which upon LAH reduction and
selective protection (TBDMSiCl) gave an 82% yield of the
secondary alcohol 39. This last material then underwent
thia-Mitsunobu inversion with the reagent system ZIRAM/
DEAD/Ph3P,20 affording a 39% yield of the desired
(16) Volante, R. P. Tetrahedron Lett. 1981, 22, 3119 and references
cited therein.
(17) (a) Bishop, J . E.; Nagy, J . O.; O’Connell, J . F.; Rapoport, H. J .
Am. Chem. Soc. 1991, 113, 8024. (b) Bishop, J . E.; Dagam, S. A.;
Rapoport, H. J . Org. Chem. 1989, 54, 1876. (c) Gossauer, A.; Hirsch,
W. Liebigs Ann. Chem. 1974, 1496. (d) Gossauer, A.; Hinze, R.-P. J .
Org. Chem. 1978, 43, 283. (e) Gossauer, A.; Weller, J .-P. Chem. Ber.
1980, 113, 1603.
(18) J acobi, P. A.; Murphree, S.; Rupprecht, F.; Zheng, W. J . Org.
Chem. 1996, 61, 2413.
(19) Cleavage of benzyl ethers with P4S10 does not appear to be a
general reaction, but this reagent works well with carboxylic acids
where intramolecular participation is possible.
(20) (a) Rollin, P. Tetrahedron Lett. 1986, 27, 4169. (b) Rollin, P.
Synth. Commun. 1986, 16, 611.

Dihydropyrromethenones by Pd(0)-Mediated Coupling
J . Org. Chem., Vol. 62, No. 9, 1997 2911
Solvents and reagents were purified as described in the
accompanying article.
Sch em e 10
4-P en tyn oic Acid Am id e (9a ). A solution of 2.0 g (20.4
mmol) of 4-pentynoic acid (8a )1a in 20 mL of dry benzene was
treated with 1.64 mL (22.4 mmol, 1.1 equiv) of SOCl2, and the
reaction mixture was stirred for 4 h at rt and then heated at
reflux for 1 h. At the end of this period, the excess SOCl2 and
benzene were removed under reduced pressure, and the
residue was taken up in 10 mL of anhydrous THF, cooled to
-78 °C, and treated with 1.0 mL of dry NH3 condensed from
a cylinder. The reaction mixture was then allowed to come
slowly to rt and was stirred for an additional 8 h. The THF
was then removed under reduced pressure, and the residue
was taken up in 10 mL of H2O and extracted with 3 × 10 mL
of EtOAc. The combined extracts were dried over Na2SO4 and
concentrated under reduced pressure, and the residue crystal-
lized from EtOAc to afford 1.90 g (94%) of 9a as a colorless
crystalline solid: mp 112-3 °C; Rf 0.45 (50% acetone/hexanes);
IR (KBr) 3379, 2235, 1663, 1424, 1136, 1078, 645 cm-1 1H
;
NMR (CDCl3) δ 2.04 (d, J ) 2.4 Hz, 1H), 2.45 (m, 2H), 2.55
(m, 2H), 5.65 (br s, 2H); MS (EIMS) m/z 97 (M+•). Anal. Calcd
for C5H7NO: C, 61.84; H, 7.27; N,14.42. Found: C, 61.80; H,
7.29; N, 14.38.
Gen er a l P r oced u r e for th e P r ep a r a tion of Acetylen ic
Am id es 9b-d a n d en t-9b,d . A solution of 1.5-10.0 mmol
(1.0 equiv) of the appropriate carboxylic acid 81a in 15-50 mL
of anhydrous THF was cooled to 0 °C under argon and was
treated with vigorous stirring with 1.0 equiv of NEt3, followed
by 1.0 equiv of isobutyl chloroformate. A white precipitate of
Et3N‚HCl formed immediately, and the reaction mixture was
stirred at 0 °C for an additional 30 min to form the mixed
anhydride. The resultant suspension was then filtered directly
via cannula into an excess of dry liquid NH3 (∼1 mL, inverse
addition) that had been cooled to -78 °C. After the addition
was complete, the reaction mixture was allowed to come to rt
over a period of 3 h and was then stirred for an additional 8
h at rt. The solvent was then removed under reduced pressure
and the residue was taken up in 10 mL of H2O and extracted
with 3 × 20 mL of EtOAc. The combined extracts were washed
with 10 mL of H2O, dried over Na2SO4, and concentrated to
afford the crude amide 9 as a gum, which was purified by
chromatography and/or crystallization.
after 48 h at reflux with 6 equiv of TBAF. In addition,
all attempts at carrying out the required thia-Mitsunobu
inversion with 31a failed. This failure appears to be due
to interference by the free lactam group in ring A, which
underwent competitive reaction with DEAD. In any
event, much more satisfactory results were obtained with
48b (R ) PMB), which gave an 80% yield of 3′(S)-
hydroxydihydropyrromethenone 31b upon brief warming
with 1 equiv of TBAF (Z isomer exclusively). This result
is in accord with our previous observations pertaining
to the rate-enhancing effect of N-substitution on amide
cyclizations (cf. also 21a vs 21e in Scheme 4).21 Under
identical conditions (6 equiv of TBAF/1 h or 1 equiv of
TBAF/21 h), 48a gave <10% of 31a . Finally, we were
pleased to find that 31b gave a 62% overall yield of the
desired ring-A,B precursor 32b upon thia-Mitsunobu
inversion,16 followed by acid-catalyzed decarboxylative
formylation.17 We believe that 32b represents a conve-
nient ring-A,B synthon for eventual elaboration to phy-
tochrome (6).
2(R),3(R)-Dim eth yl-4-p en tyn oic Acid Am id e (9b). This
material was prepared in 89% yield from 8.7 mmol of 2(R),3-
(R)-dimethyl-4-pentynoic acid (8b),1a 1.0 equiv of NEt3, and
1.0 equiv of isobutyl chloroformate by following the general
procedure described above. Chromatography (silica gel, 20%
EtOAc/hexanes) followed by crystallization (EtOAc) afforded
980 mg (89%) of 9b as a colorless microcrystalline solid: mp
64-5 °C; Rf 0.52 (50% acetone/hexanes); [R]25D ) 35.7° (c 16.75,
MeOH); IR (CH2Cl2) 2933, 1736, 1463, 1375, 1200, 1090, 985,
Su m m a r y
1
912, 854 cm-1; H NMR (CDCl3) δ 1.26 (d, J ) 7.16 Hz, 3H),
1.29 (d, J ) 7.16 Hz, 3H), 2.19 (d, J ) 2.44 Hz, 1H), 2.42 (m,
1H), 2.77 (m, 1H), 5.46 (br s, 1H), 5.82 (br s, 1H); 13C NMR
(CDCl3) δ 177.18, 86.58, 70.33, 45.68, 28.80, 17.70, 15.08.
Anal. Calcd for C7H11NO: C, 67.17; H, 8.86; N, 11.19.
Found: C, 66.91; H, 8.96; N, 11.08.
2(S),3(S)-Dim eth yl-4-p en tyn oic Acid Am id e (en t-9b).
This material was prepared in 92% yield from 10.3 mmol of
2(S),3(S)-dimethyl-4-pentynoic acid (ent-8b),1a 1.0 equiv of
NEt3, and 1.0 equiv of isobutyl chloroformate by following the
general procedure described above. Chromatography (silica
gel, 20% EtOAc/hexanes) followed by crystallization (EtOAc)
afforded 1.19 g (92%) of ent-9b as a colorless microcrystalline
solid: mp 64-5 °C; [R]25D ) -35.95° (c 14.13, MeOH); spectral
data identical to those in 9b.
Synthetic studies in this area are important, since at
present we have little understanding of how phytochrome
(6) governs the growth, development, and aging of plants
(photomorphogenesis). In part this is due to a lack of
suitable model systems, as well as to the difficulty of
isolating and purifying the parent chromophore. The
methodology described in this paper is highly flexible,
and it allows for excellent control over both relative and
absolute stereochemistry, as well as regiochemistry along
the backbone of the tetrapyrrole skeleton. Flexibility of
this type is important not only for the synthesis of 6 but
also for the preparation of specifically labeled phyto-
chrome analogs.
2(R)-Meth yl-3(R)-(1′(S)-m eth oxyeth yl)-4-pen tyn oic Acid
Am id e (9c). This material was prepared in 90% yield from
1.46 mmol of 2(R)-methyl-3(R)-(1′(S)-methoxyethyl)-4-pen-
tynoic acid (8c),1a 1.0 equiv of NEt3, and 1.0 equiv of isobutyl
chloroformate by following the general procedure described
above. Chromatography (silica gel, 20% EtOAc/hexanes) fol-
lowed by crystallization (EtOAc/hexanes) afforded 223 mg
(90%) of 9c as a colorless microcrystalline solid: mp 148-9
Exp er im en ta l Section
Melting points were determined in open capillaries and are
uncorrected. 1H NMR spectra were recorded at 400 MHz and
are expressed as ppm downfield from tetramethylsilane.
°C; Rf 0.71 (50% acetone/hexanes); [R]25 ) -14.62° (c 3.01,
D
(21) J acobi, P. A.; Brielmann, H. L.; Hauck, S. I. Tetrahedron Lett.
1995, 36, 1193.
MeOH); IR (CH2Cl2) 3520, 3403, 3302, 2983, 2986, 2348, 2687,

2912 J . Org. Chem., Vol. 62, No. 9, 1997
J acobi et al.
1
1592, 1461, 1391, 1188, 1145, 1085, 1007, 960, 647 cm-1; H
NMR (CDCl3) δ 1.25 (d, J ) 6.7 Hz, 3H), 1.32 (d, J ) 6.24 Hz,
3H), 2.25 (d, J ) 2.4 Hz, 1H), 2.64 (m, 2H), 3.37 (s, 3H), 3.50
(m, 1H), 5.38 (br s, 1H), 5.83 (br s, 1H); 13C NMR (CDCl3) δ
180.89, 83.25, 75.57, 73.54, 56.83, 43.40, 42.10, 17.29, 16.26.
Anal. Calcd for C9H15NO2: C, 63.88; H, 8.93; N, 8.28.
Found: C, 63.69; H, 8.85; N, 8.30.
1-Ca r b om et h oxy-3-iod o-4,5,6,7-t et r a h yd r o-2H -isoin -
d ole (17). A solution of 1.75 g (9.77 mmol) of isoindole 16 in
20 mL of anhydrous THF was treated at rt with 4.40 g (19.54
mmol, 2 equiv) of N-iodosuccinimide, and the resulting dark
solution was stirred at rt for 2.5 h. The reaction mixture was
then concentrated under reduced pressure, and the residue
was taken up in 25 mL of H2O and extracted with 3 × 20 mL
of CH2Cl2. The combined extracts were dried over Na2SO4,
concentrated under reduced pressure, and purified by flash
chromatography (silica gel, 10% EtOAc/hexanes) to give 2.65
g (89%) of 17 as an off-white crystalline solid: mp 186-9 °C
(EtOAc/hexanes); Rf 0.75 (30% EtOAc/hexanes); IR (KBr) 3266,
2940, 1671, 1554, 1435, 1394, 1320, 1233, 1133, 1033, 957, 814,
2(R )-Me t h y l-3(R )-(1′(S )-(b e n zy lo x y )e t h y l)-4-p e n -
tyn oic Acid Am id e (9d ). This material was prepared in 96%
yield from 5.6 mmol of 2(R)-methyl-3(R)-(1′(S)-(benzyloxy)-
ethyl)-4-pentynoic acid (8d ),1a 1.0 equiv of NEt3, and 1.0 equiv
of isobutyl chloroformate by following the general procedure
described above. Chromatography (silica gel, 30% acetone/
hexanes) followed by crystallization (EtOAc/hexanes) afforded
1.32 g (96%) of 9d as a colorless microcrystalline solid: mp
768, 723, 598 cm-1 13C NMR (CDCl3) δ 160.56, 129.50, 127.92,
;
122.79, 71.50, 51.37, 23.43, 23.17, 23.12, 23.07. Anal. Calcd
for C10H12NO2I: C, 39.37; H, 3.96; N, 4.59. Found: C, 39.43;
H, 4.01; N, 4.54.
130-1 °C; Rf 0.74 (50% acetone/hexanes); [R]25 ) -52.26° (c
D
2.13, MeOH); IR (CH2Cl2) 3377, 3283, 3201, 2966, 2892, 2343,
1642, 1613, 1454, 1343, 1278, 1143, 1102, 1049, 743, 643 cm-1
;
1-Ca r bom eth oxy-3-(2′-p h en yleth yn yl)-4,5,6,7-tetr a h y-
d r o-2H-isoin d ole (19). A solution of 100 mg (0.33 mmol) of
iodoisoindole 17, 36.8 mg (0.36 mmol, 1.1 equiv) of acetylene
18, 38.0 mg (0.033 mmol, 0.1 equiv) of Pd(Ph3P)4, and 13.73
mg (0.072 mmol) of CuI in 3.0 mL of dry DMF was prepared
in a drybox, purged thoroughly with argon, and treated via
syringe with 137.8 µL (0.99 mmol, 3 equiv) of freshly distilled
Et3N. The reaction mixture was then cooled in liquid nitrogen,
and the frozen solid was subjected to five freeze-thaw cycles
before being warmed to rt under an atmosphere of argon and
being stirred for 21 h. At the end of this period, the dark
reaction mixture was concentrated under reduced pressure,
and the residue was taken up in 50 mL of CH2Cl2. The CH2-
Cl2 was filtered through a short pad of Celite to remove the
catalyst and was then stirred with 5 mL of saturated NaHCO3
for 15 min. The organic layer was separated, washed with 10
mL of H2O, dried over Na2SO4, and concentrated under
reduced pressure. Purification of the residue by flash chro-
matography (silica gel, 5-30% EtOAc/hexanes) afforded 74.5
mg (89%) of 19 as a colorless gum, which crystallized from
EtOAc/pentanes as a colorless microcrystalline solid: mp
193-4 °C; Rf 0.78 (30% EtOAc/hexanes); IR (KBr) 3283, 2939,
2203, 1675, 1599, 1580, 1491, 1403, 1293, 1217, 1197, 1151,
1082 cm-1; 1H NMR (CDCl3) δ 1.76 (m, 4H), 2.62 (m, 2H), 2.79
(m, 2H), 3.85 (s, 3H), 7.33-7.49 (m, 5H), 8.90 (br s, 1H); 13C
NMR (CDCl3) δ 161.28, 131.22, 128.32, 128.30, 127.72, 122.71,
118.19, 113.71, 94.35, 80.26, 51.26, 23.03, 22.97, 22.87, 21.80.
Anal. Calcd for C18H17NO2: C, 77.40; H, 6.13; N, 5.01.
Found: C, 77.32; H, 6.14; N, 4.95.
P yr r oloa lk yn e 20a . This material was prepared in a
fashion identical to that of pyrroloalkyne 19 described above,
using 1.0 mmol of iodopyrrole 17, 1.3 mmol (1.3 equiv) of
alkyne 9a , 0.1 equiv of Pd(Ph3P)4, 0.2 equiv of CuI, and 3 equiv
of NEt3 in 5 mL of freshly distilled DMF. After workup, flash
chromatography (silica gel, 50% acetone/hexanes) afforded 246
mg (88%) of 20a as a colorless microcrystalline solid: mp
282-3 °C; Rf 0.29 (50% acetone/hexanes); IR (CH2Cl2) 3435,
3074, 1727, 1680, 1551, 1409, 1298, 1150, 1084 cm-1; 1H NMR
(CDCl3) δ 1.73 (br m, 4H), 2.51 (br m, 2H), 2.54 (m, 2H), 2.76
(br m, 2H), 2.82 (m, 2H), 3.83 (s, 3H), 5.35 (br s, 1H), 5.56 (br
s, 1H), 8.69 (br s, 1H); 13C NMR (DMSO-d6) δ 173.36, 159.73,
128.31, 125.62, 124.83, 81.32, 72.85, 51.51, 34.82, 28.40, 21.31,
11.78. Anal. Calcd for C15H18N2O3: C, 65.68; H, 6.61; N,
10.21. Found: C, 65.07; H, 6.59; N, 10.07.
1H NMR (CDCl3) δ 1.09 (d, J ) 6.24 Hz, 3H), 1.37 (d, J ) 6.2
Hz, 3H), 2.25 (d, J ) 1.76 Hz, 1H), 2.64 (m, 2H), 3.70 (m, 1H),
4.56 (A,B-q, J ) 11.88 Hz, 2H), 5.40 (br s, 1H), 5.85 (br s, 1H),
7.33 (m, 5H); 13C NMR (CDCl3) δ 177.47, 138.11, 128.32 (2),
127.97 (2), 127.68, 82.35, 72.75, 72.24, 70.57, 42.37, 41.73,
17.55, 15.99. Anal. Calcd for C15H19NO2: C, 73.44; H, 7.81;
N, 5.71. Found: C, 73.20; H, 7.87; N, 5.63.
2(S )-Me t h y l-3(S )-(1′(R )-(b e n z y lo x y )e t h y l)-4-p e n -
tyn oic Acid Am id e (en t-9d ). This material was prepared
in 96% yield from 5.6 mmol of 2(S)-methyl-3(S)-(1′(R)-(benz-
yloxy)ethyl)-4-pentynoic acid (ent-8d ),1a 1.0 equiv of NEt3, and
1.0 equiv of isobutyl chloroformate by following the general
procedure described above. Chromatography (silica gel, 30%
acetone/hexanes) followed by crystallization (EtOAc/hexanes)
afforded 1.32 g (96%) of ent-9d as a colorless microcrystalline
solid: mp 130-1 °C; [R]25 ) 51.6° (c 2.19, MeOH); spectral
D
data identical to those in 9d .
N-Ben zyl-4-p en tyn oic Acid Am id e (9e). A solution of
536 mg (5.0 mmol) of benzylamine and 491 mg (5.0 mmol, 1.0
equiv) of 4-pentynoic acid (8a )1a in 15.0 mL of anhydrous THF
was treated with 1.92 g (10.0 mmol, 2.0 equiv) of EDCI, and
the resulting mixture was stirred vigorously at rt for 28 h. At
the end of this period the reaction mixture was concentrated
and partitioned between 10 mL of H2O and 25 mL of CH2Cl2,
and the aqueous layer was extracted with 3 × 25 mL of CH2-
Cl2. The combined extracts were dried over Na2SO4, filtered,
and concentrated under reduced pressure to afford 966 mg of
a light yellow gum. Flash chromatography (silica gel, 20%
EtOAc/hexanes) then gave 902 mg (96%) of 9e as a colorless
microcrystalline solid: mp 65-6 °C (pentane); Rf 0.48 (30%
EtOAc/hexanes); IR (KBr) 3276, 1652, 1560, 1455, 1431, 1265,
1
1182, 1082, 748, 696, 645, 609 cm-1; H NMR (CDCl3) δ 1.98
(t, J ) 2.76 Hz, 1H), 2.43 (m, 2H), 2.55 (m, 2H), 4.45 (d, J )
5.6 Hz, 2H), 5.85 (br s, 1H), 7.29 (m, 5H). Anal. Calcd for
C
12H13NO: C, 76.98; H, 7.00; N, 7.48. Found: C, 76.30; H,
6.89; N, 7.43.
1-Ca r bom eth oxy-4,5,6,7-tetr a h yd r o-2H-isoin d ole (16).
A solution of 6.41 g (54.4 mmol) of 1-nitrocyclohexene (13) and
5.0 g (54.4 mmol, 1 equiv) of methyl isocyanoacetate (14) in
60 mL of anhydrous THF was cooled to 0 °C with stirring and
was treated with 8.28 g (54.4 mmol, 1 equiv) of DBU. After
the addition was complete, the reaction mixture was allowed
to warm to rt and stirring was continued for 12 h. The
resulting solution was then poured over 100 g of crushed ice
containing 25 mL of 1 N HCl. After melting, the aqueous
solution was extracted with 3 × 20 mL of EtOAc, and the
combined extracts were dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure to afford 12.08 g of
crude 16 as a honey-colored solid. Purification by flash
chromatography (silica gel, 20% EtOAc/hexanes) then gave
7.30 g (75%) of 16 as a colorless crystalline solid: mp 94-5 °C
(EtOAc/hexanes); Rf 0.77 (30% EtOAc/hexanes); 1H NMR
(CDCl3) δ 1.73 (br m, 4H), 2.53 (t, 2H), 2.79 (t, 2H), 3.82 (s,
3H), 6.66 (d, 1H), 8.80 (br s, 1H); 13C NMR (CDCl3) δ 162.00,
128.22, 122.00, 118.99, 117.36, 50.98, 23.35, 23.28, 23.03,
21.86. Combustion analysis was performed on iodo derivative
17.
P yr r oloa lk yn e 20b. This material was prepared in a
fashion identical to that of pyrroloalkyne 19 described above,
using 1.37 mmol of iodopyrrole 17, 1.70 mmol (1.25 equiv) of
alkyne 9b, 0.1 equiv of Pd(Ph3P)4, 0.2 equiv of CuI, and 3 equiv
of NEt3 in 5 mL of freshly distilled DMF. After workup, flash
chromatography (50% acetone/hexanes) afforded 399 mg (96%)
of 20b as a colorless microcystalline solid: mp 272-3 °C; Rf
0.58 (50% acetone/hexanes); [R]25 ) 35.1° (c 2.9, MeOH); IR
D
(CH2Cl2) 3296, 2850, 1685, 1636, 1560, 1458, 1267, 773 cm-1
;
1H NMR (CDCl3) δ 1.28 (d, J ) 7.1 Hz, 3H), 1.29 (d, J ) 7.0
Hz, 3H), 1.72 (m, 4H), 2.45 (m, 1H), 2.49 (m, 2H), 2.74 (m,
2H), 2.98 (m, 1H), 3.82 (s, 3H), 5.40 (br s, 1H), 5.76 (br s, 1H),
8.80 (br s, 1H); 13C NMR (DMSO-d6) δ 175.39, 160.42, 127.15,
125.37, 116.78, 114.21, 97.89, 72.74, 50.76, 45.79, 44.25, 29.09,
22.80, 21.31, 16.94, 13.78, 8.71; MS (EIMS) m/z 302 (M+•).

Dihydropyrromethenones by Pd(0)-Mediated Coupling
J . Org. Chem., Vol. 62, No. 9, 1997 2913
P yr r oloa lk yn e en t-20b. This material was prepared in a
fashion identical to that of pyrroloalkyne 19 described above,
using 1.0 mmol of iodopyrrole 17, 1.33 mmol (1.33 equiv) of
alkyne ent-9b, 0.1 equiv of Pd(Ph3P)4, 0.2 equiv of CuI, and 3
equiv of NEt3 in 5 mL of freshly distilled DMF. After workup,
flash chromatography (50% acetone/hexanes) afforded 298 mg
(98%) of entt-20b as a colorlesss microcrystalline solid: mp
the THF was evaporated under reduced pressure and the
residue was taken up in 5 mL of H2O and extracted with 3 ×
10 mL of CH2Cl2. The combined extracts were dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure to give a dark gum. Preparative TLC (silica gel, 50%
acetone/hexanes) then afforded 8.5 mg (25%) of 21a as a
colorless solid: mp 272 °C (EtOAc); Rf 0.60 (50% EtOAc/
hexanes); IR (CH2Cl2) 3430, 3310, 2938, 2858, 1715, 1683,
1572, 1498, 1307, 1168, 1146, 1083, 1052, 1022 cm-1; 1H NMR
(CDCl3) δ 1.73 (br m, 4H), 2.40 (br m, 2H), 2.58 (t, J ) 8.28
Hz, 2H), 2.78 (br m, 2H), 2.91 (t, J ) 8.28 Hz, 2H), 3.80 (s,
3H), 5.28 (s, 1H), 8.46 (br s, 1H), 8.95 (br s, 1H); MS (EIMS)
m/z 274 (M+•), 242, 214, 185, 91, 78, 63; MS (CIMS) m/z 275
(M + 1)+; HRMS (EIMS) calcd for C15H18O3N2 274.1317, found
274.1336. Anal. Calcd for C15H18N2O3: C, 65.68; H, 6.61; N,
10.21. Found: C, 64.70; H, 6.70; N, 10.17.
272-3 °C; Rf 0.58 (50% acetone/hexanes); [R]25 ) -36.9° (c
D
5.2, MeOH); spectral data identical to those in 20b.
P yr r oloa lk yn e 20c. This material was prepared in a
fashion identical to that of pyrroloalkyne 19 described above,
using 0.49 mmol of iodopyrrole 17, 0.59 mmol (1.2 equiv) of
alkyne 9c, 0.1 equiv of Pd(Ph3P)4, 0.2 equiv of CuI, and 3 equiv
of NEt3 in 5 mL of freshly distilled DMF. After workup, flash
chromatography (5-30% acetone/hexanes) afforded 151 mg
(89%) of 20c as a colorless microcrystalline solid: mp 188-9
°C (EtOAc/hexanes); Rf 0.54 (50% acetone/hexanes); [R]25
)
Dih yd r op yr r om eth en on e 21b. This material was pre-
pared in a fashion identical to that of 21a described above,
using 55.0 mg (0.18 mmol) of pyrroloalkyne 20b, 3.64 mL of
anhydrous THF, and 1.09 mL (1.09 mmol, 6 equiv) of 1 M
n-Bu4NF/THF in a 25 mL round bottom flask. After the
mixture was heated at reflux for 48 h under argon, workup
and chromatography (silica gel, 30% acetone/hexanes) afforded
44.6 mg (82%) of 21b as a colorless solid: mp 266-7 °C; Rf
D
-30.62° (c 2.32, MeOH); IR (CH2Cl2) 3050, 2936, 2858, 2253,
1689, 1530, 1460, 1376, 1343, 1247, 1180, 1150, 1094, 1030,
1
909, 548 cm-1; H NMR (CDCl3) δ 1.21 (d, J ) 6.88 Hz, 3H),
1.32 (d, J ) 6.08 Hz, 3H), 1.68 (m, 4H), 2.46 (m, 2H), 2.73 (m,
3H), 2.83 (m, 1H), 3.34 (s, 3H), 3.54 (m, 1H), 3.78 (s, 3H), 5.44
(br s, 1H), 5.89 (br s, 1H), 8.97 (br s, 1H); 13C NMR (CDCl3) δ
177.92, 162.40, 127.93, 126.51, 117.07, 114.16, 92.51, 76.05,
56.44, 50.91, 42.65, 42.60, 36.39, 22.95, 22.75, 21.54, 17.08,
15.77; MS (EIMS) m/z 346 (M+), 314, 270, 255, 244, 212, 170,
141, 115, 84; HRMS calcd for C19H26O4N2 346.1894, found
346.1898. Anal. Calcd for C19H26N2O4: C, 65.88; H, 7.56; N,
8.09. Found: C, 65.72; H, 7.62; N, 8.06.
0.80 (50% acetone/hexanes); [R]25 ) 41.55 (c 3.3, MeOH);
D
spectral data identical to those of an authentic sample.1a
Dih yd r op yr r om eth en on e en t-21b. This material was
prepared in a fashion identical to that of 21a described above,
using 102.0 mg (0.34 mmol) of pyrroloalkyne ent-20b, 6.75 mL
of anhydrous THF, and 2.03 mL (2.03 mmol, 6 equiv) of 1 M
n-Bu4NF/THF in a 25 mL round bottom flask. After the
mixture was heated at reflux for 48 h under argon, workup
and chromatography (silica gel, 30% acetone/hexanes) afforded
81.6 mg (81%) of ent-21b as a colorless solid: mp 266-7 °C;
Rf 0.80 (50% acetone/hexanes); [R]25D ) -41.08 (c 2.58, MeOH);
spectral data identical to those of an authentic sample.1a
Dih yd r op yr r om eth en on e 21c. This material was pre-
pared in a fashion identical to that of 21a described above,
using 50.0 mg (0.14 mmol) of pyrroloalkyne 20c, 3.5 mL of
anhydrous THF, and 0.87 mL (0.87 mmol, 6 equiv) of 1 M
n-Bu4NF/THF in a 25 mL round bottom flask. After the
mixture was heated at reflux for 48 h under argon, workup
and chromatography (silica gel, 30% acetone/hexanes) afforded
39.0 mg (78%) of 21c as a yellow foam: Rf 0.77 (50% acetone/
P yr r oloa lk yn e 20d . This material was prepared in a
fashion identical to that of pyrroloalkyne 19 described above,
using 0.91 mmol of iodopyrrole 17, 1.0 mmol (1.1 equiv) of
alkyne 9d , 0.1 equiv of Pd(Ph3P)4, 0.2 equiv of CuI, and 3 equiv
of NEt3 in 5 mL of freshly distilled DMF. After workup, flash
chromatography (5-40% acetone/hexanes) afforded 422 mg
(96%) of 20d as a colorless solid: mp 188-9 °C (EtOAc/
hexanes); Rf 0.33 (50% acetone/hexanes); [R]25 ) -91.38° (c
D
5.45, MeOH); IR (CH2Cl2) 3686, 3436, 3073, 2940, 2859, 2358,
1700, 1604, 1459, 1343, 1179, 1152, 1088, 1028, 958, 908 cm-1
;
1H NMR (CDCl3) δ 1.23 (d, J ) 6.9 Hz, 3H), 1.47 (d, J ) 6.2
Hz, 3H), 1.77 (m, 4H), 2.56 (m, 2H), 2.80 (m, 3H), 2.94 (m,
1H), 3.83 (m, 1H), 3.88 (s, 3H), 4.63 (A,B-q, J ) 11.72 Hz, 2H),
5.48 (br s, 1H), 5.93 (br s, 1H), 7.3-7.4 (m, 5H), 9.01 (br s,
1H); 13C NMR (CDCl3) δ 177.47, 161.31, 138.16, 128.34 (2),
127.95 (2), 127.72, 127.70, 127.01, 117.70, 114.01, 92.99, 75.99,
72.69, 70.59, 51.40, 42.98, 42.62, 23.06, 23.00, 22.90, 21.76,
17.84, 16.11; MS (EIMS) m/z 422 (M+), 378, 360, 332, 314, 305,
287, 255; MS (CIMS) m/z 423 (M + 1)+; HRMS calcd for
hexanes); [R]25 ) -20.46° (c 6.84, MeOH); IR (CH2Cl2) 3437,
D
2931, 2821, 1732, 1686, 1591, 1497, 1455, 1366, 1298, 1238,
1189, 1083, 1018, 956, 809 cm-1; 1H NMR (CDCl3) δ 1.18 (d, J
) 6.2 Hz, 3H), 1.34 (d, J ) 7.36 Hz, 3H), 1.75 (m, 4H), 2.41
(m, 2H), 2.62 (m, 1H), 2.78 (m, 2H), 2.98 (m, 1H), 3.39 (s, 3H),
3.82 (s, 3H), 3.58 (m, 1H), 5.33 (d, J ) 1.28 Hz, 1H), 8.26 (br
s, 1H), 8.97 (br s, 1H); MS (EIMS) m/z 346 (M+), 314, 270,
255, 244, 212, 170, 115, 84; MS (CIMS) m/z 347 (M + 1)+;
HRMS calcd for C19H26O4N2: 346.1892, found 346.1880. Anal.
Calcd for C19H26N2O4: C, 65.88; H, 7.56; N, 8.09. Found: C,
65.89; H, 7.60; N, 8.08.
C25H30O4N2 422.2207, found 422.2238. Anal. Calcd for C25
-
H30N2O4: C, 71.07; H, 7.16; N, 6.63. Found: C, 70.93; H, 7.14;
N, 6.50.
P yr r oloa lk yn e 20e. This material was prepared in a
fashion identical to that of pyrroloalkyne 19 described above,
using 0.91 mmol of iodopyrrole 17, 1.0 mmol (1.1 equiv) of
alkyne 9e, 0.1 equiv of Pd(Ph3P)4, 0.2 equiv of CuI, and 3 equiv
of NEt3 in 5 mL of freshly distilled DMF. After workup, flash
chromatography (30% acetone/hexanes) afforded 338 mg (92%)
of 20e as a colorless solid: mp 179-80 °C (EtOAc/hexanes);
Rf 0.60 (50% acetone/hexanes); IR (CH2Cl2) 3440, 3043, 2980,
2858, 2359, 1684, 1516, 1459, 1343, 1179, 1152, 1098, 1036
cm-1; 1H NMR (CDCl3) δ 1.71 (m, 4H), 2.45 (m, 2H), 2.51 (t, J
) 7.04 Hz, 2H), 2.76 (m, 2H), 2.83 (t, J ) 7.04 Hz, 2H), 3.84
(s, 3H), 4.49 (d, J ) 5.72 Hz, 2H), 5.87 (br s, 1H), 7.27 (m,
5H), 8.58 (br s, 1H); 13C NMR (CDCl3) δ 170.74, 161.00, 137.95,
128.61 (2), 128.19, 127.68 (2), 127.49, 126.85, 117.34, 113.69,
93.56, 72.55, 51.14, 43.68, 35.61, 22.98, 22.93, 22.86, 21.67,
16.21. Anal. Calcd for C22H24N2O3: C, 72.51; H, 6.64; N, 7.69.
Found: C, 72.47; H, 6.70; N, 7.67.
Dih yd r op yr r om eth en on e 21a . A solution of 34.0 mg
(0.12 mmol) of pyrroloalkyne 20a in 5 mL of anhydrous THF
was treated with 0.72 mL (0.72 mmol, 6 equiv) of 1.0 M n-Bu4-
NF/THF in a 25 mL round bottom flask. The reaction mixture
was then cooled in liquid nitrogen, and the frozen solution was
subjected to five freeze-thaw cycles before being warmed to
rt under an atmosphere of argon and, finally, being heated at
reflux in an oil bath at 90 °C for 48 h. At the end of this period,
Dih yd r op yr r om eth en on e 21d . This material was pre-
pared in a fashion identical to that of 21a described above,
using 90.0 mg (0.21 mmol) of pyrroloalkyne 20d , 4.24 mL of
anhydrous THF, and 1.3 mL (1.3 mmol, 6 equiv) of 1 M n-Bu4-
NF/THF in a 25 mL round bottom flask. After the mixture
was heated at reflux for 48 h under argon, workup and
chromatography (silica gel, 50% acetone/hexanes) afforded 67.5
mg (75%) of 21d as a yellow foam: Rf 0.72 (50% acetone/
hexanes); [R]25 ) 8.14° (c 5.28, MeOH); IR (CH2Cl2) 3437,
D
1727, 1679 cm-1; 1H NMR (CDCl3) δ 1.20 (d, J ) 6.3 Hz, 3H),
1.31 (d, J ) 7.3 Hz, 3H), 1.70 (m, 4H), 2.35 (m, 2H), 2.50-
2.70 (m, 2H), 2.75 (m, 2H), 2.97 (m, 1H), 3.73 (s, 3H), 4.56
(A,B-q, J ) 11 Hz, 2H), 5.29 (s, 1H), 7.32 (m, 5H), 9.68 (br s,
1H), 9.97 (br s, 1H); 13C NMR (CDCl3) δ 182.31, 175.01, 162.98,
148.57, 139.06, 138.04, 130.37, 129.37 (2), 128.35, 128.30 (2),
121.42, 118.14, 93.47, 77.61, 71.57, 51.95, 51.77, 38.16, 24.09,
24.03, 22.65, 18.44, 16.01; MS (EIMS) m/z 422 (M+), 314, 287,
244, 212, 184, 141, 105, 91; MS (CIMS) m/z 423 (M + 1)+;
HRMS calcd for C25H30O4N2 422.2207, found 422.2238. Anal.
Calcd for C25H30N2O4: C, 65.88; H, 7.56; N, 8.09. Found: C,
65.89; H, 7.60; N, 8.08.

2914 J . Org. Chem., Vol. 62, No. 9, 1997
J acobi et al.
Dih yd r op yr r om eth en on e 21e. This material was pre-
pared in a fashion identical to that of 21a described above,
using 50 mg (0.14 mmol) of pyrroloalkyne 20e, 2.75 mL of
anhydrous THF, and 0.83 mL (0.83 mmol, 6 equiv) of 1 M
n-Bu4NF/THF in a 25 mL round bottom flask. After the
mixture was heated at reflux for 48 h under argon, workup
and chromatography (silica gel, 30% acetone/hexanes) afforded
36.9 mg (73%) of 21e as a colorless foam (1/1 mixture of E/ Z
isomers): Rf 0.77 (50% acetone/hexanes); IR (CH2Cl2) 3436,
3036, 2931, 2848, 1695, 1560,1490, 1443, 1401, 1337, 1237,
mixture was heated at reflux for 48 h under argon, workup
and chromatography (preparative TLC, 500 µm silica gel, 30%
acetone/hexanes) afforded 78.0 mg (78%) of ent-30 as a yellow
foam: Rf 0.81 (50% acetone/hexanes); [R]25 ) -7.54° (c 5.7,
D
MeOH); spectral data identical to those of 30.
2(R),4(S)-Dim eth yl-3(R)-eth yn yl-γ-bu tyr ola cton e (37).
A solution of 3.64 g (14.78 mmol, 1.0 equiv) of acetylenic acid
36 in 120 mL of CH2Cl2 was treated at rt, with vigorous
stirring, with 6.57 g (1.0 equiv) of P4S10 under an atmosphere
of nitrogen. The reaction mixture was then stirred at rt for a
total of 40 h and diluted with 250 mL of H2O, and the aqueous
layer was extracted with 6 × 80 mL of CH2Cl2. The combined
organic extracts were dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure to afford a yellow
gum. Chromatography (20% EtOAc/hexanes) then gave 1.95
g (95%) of lactone 37 as a pale yellow solid, which crystallized
from Et2O/hexanes in the form of colorless needles: mp 44.5-
1202, 1149, 1084, 1031, 902, 820, 649, 520 cm-1 1H NMR
;
(CDCl3) δ (combined 1:1 mixture of E and Z isomers) 1.70-
1.90 (m, 8H), 2.18 (m, 2H), 2.38 (m, 2H), 2.60 (m, 1H), 2.75
(m, 2H), 2.75-3.00 (m, 7H), 3.10 (m, 2H), 3.88 (s, 3H), 3.91 (s,
3H), 4.70 (s, 2H), 4.90 (s, 2H), 5.36 (s, 1H), 5.62 (s, 1H), 6.78
(m, 2H), 7.20-7.50 (m, 8H), 8.28 (br s, 1H), 8.52 (br s, 1H);
MS (EIMS) m/z 364 (M+•), 273, 241, 242, 91 (base peak); MS
(CIMS) m/z 365 (M + 1)+; HRMS (EIMS) calcd for C22H24O3N2
364.1818, found 364.1788. Anal. Calcd for C22H24N2O3: C,
72.51; H, 6.64; N, 7.69. Found: C, 72.37; H, 6.63; N, 7.65.
P yr r oloa lk yn e 29. This material was prepared in a
fashion identical to that of pyrroloalkyne 19 described above,
using 0.64 mmol of iodopyrrole 27, 0.95 mmol (1.5 equiv) of
alkyne 9d , 0.1 equiv of Pd(Ph3P)4, 0.2 equiv of CuI, and 3 equiv
of NEt3 in 5 mL of freshly distilled DMF. After workup, flash
chromatography (30% acetone/hexanes) afforded 317 mg (97%)
of 29 as a colorless microcrystalline solid: mp 156-7 °C (CH2-
Cl2/pentanes); Rf 0.57 (50% acetone/hexanes); [R]25D ) -91.76°
(c 1.82, MeOH); IR (KBr) 3343, 2977, 2933, 1736, 1675, 1617,
1454, 1368, 1345, 1273, 1167, 1135, 1057, 957, 846, 779, 745,
5.5 °C; [R]25 -95.7° (c 12.2, CH2Cl2); MS m/z 138 (M+), 123,
D
110, 94, 77. 66; IR (CH2Cl2) 3303, 2988, 2939, 1775, 1453,
1390, 1324, 1181, 1125, 1055, 1015, 948 cm-1; 1H NMR (CDCl3)
δ 1.37 (d, J ) 7.2 Hz, 3H), 1.53 (d, J ) 6.3 Hz, 3H), 2.34 (d, J
) 2.4 Hz, 1H), 2.84 (m, 1H), 3.35 (m, 1H), 4.50 (m, 1H). Anal.
Calcd for C8H10O2: C, 69.55; H, 7.30. Found: C, 69.60; H, 7.33.
1-((ter t-Bu t yld im et h ylsilyl)oxy)-2(R)-m et h yl-3(R )-(1′-
(S)-h yd r oxyeth yl)-4-p en tyn e (39). A suspension of 0.64 g
(16.8 mmol, 1.2 equiv) of LiAlH4 in 300 mL of anhydrous THF
was treated in a dropwise fashion, with vigorous stirring, with
a solution of 1.94 g (14.0 mmol, 1.0 equiv) of lactone 37 in 15
mL of THF under an atmosphere of argon. The reaction
mixture was stirred for an additional 11 h at rt, and the
reaction was then carefully quenched with 27.6 mL of 10%
aqueous NaOH. The organic layer was decanted into a
separatory funnel, and the remaining gel was extracted
repeatedly with Et2O. The combined organic extracts were
washed with 150 mL of brine, dried over anhydrous NaSO4,
filtered, and concentrated under reduced pressure to afford a
colorless gum. Chromatography (50% EtOAc/hexanes) then
1
700 cm-1; H NMR (CDCl3) δ 1.16 (d, J ) 6.84 Hz, 3H), 1.40
(d, J ) 6.08 Hz, 3H), 1.55 (s, 9H), 2.04 (s, 3H), 2.50 (t, J )
8.44 Hz, 2H), 2.72 (m, 1H), 2.87 (m, 1H), 2.96 (t, J ) 8.44 Hz,
2H), 3.67 (s, 3H), 3.79 (m, 1H), 4.44 (d, J ) 11.72 Hz, 1H),
4.70 (d, J ) 11.72 Hz, 1H), 5.32 (br s, 1H), 5.83 (br s, 1H),
7.30-7.40 (m, 5H), 8.88 (br s, 1H); 13C NMR (CDCl3) δ 177.87,
173.50, 160.14, 138.05, 128.25 (2), 128.00, 127.89 (2), 127.62,
124.63, 120.01, 114.93, 92.66, 80.96, 76.12, 72.54, 70.49, 51.42,
42.48, 42.40, 34.81, 28.30 (3), 20.32, 17.75, 15.87, 9.48; MS
(EIMS) m/z 510 (M+). Anal. Calcd for C29H38N2O6: C, 68.21;
H, 7.50; N, 5.49. Found: C, 68.03; H, 7.47; N, 5.44.
gave 1.88 g (94%) of diol 38 (not shown) as a colorless oil: [R]25
D
) 5.7° (c 4.0, CH2Cl2); MS m/z 127 (M+ - Me), 124, 123, 109,
97, 94, 83, 79; IR (CH2Cl2) 3608, 3400, 3302, 2972, 2933, 2879,
1
2112, 1456, 1379, 1062, 1039, 859 cm-1; H NMR (CDCl3) δ
P yr r oloa lk yn e en t-29. This material was prepared in a
fashion identical to that of pyrroloalkyne 19 described above,
using 0.37 mmol of iodopyrrole 27, 0.41 mmol (1.1 equiv) of
alkyne ent-9d , 0.1 equiv of Pd(Ph3P)4, 0.2 equiv of CuI, and 3
equiv of NEt3 in 5 mL of freshly distilled DMF. After workup,
flash chromatography (5-30% acetone/hexanes) afforded 197
mg (94%) of ent-29 as a colorless crystalline solid: mp 156-7
1.01 (d, J ) 6.6 Hz, 3H), 1.35 (d, J ) 6.2 Hz, 3H), 1.98 (m,
1H), 2.24 (d, J ) 2.4 Hz, 1H), 2.48 (m, 1H), 2.73 (bs, 2H), 3.53
(dd, J ) 3.5, 11.2 Hz, 1H), 3.79 (dd, J ) 8.3, 11.2 Hz, 1H),
3.94 (dq, J ) 2.0, 6.3 Hz, 1H); 13C NMR (CDCl3) δ 17.1, 22.6,
38.9, 45.7, 65.0, 68.4, 74.1, 80.5; HRMS (CIMS) calcd for
(C8H14O2 + H) (M + H+): 143.1072, found 143.1069.
A solution of 1.83 g (12.9 mmol, 1.0 equiv) of diol 38 in 100
mL of dry CH2Cl2 was treated sequentially with 2.15 mL (1.2
equiv) of NEt3, 1.63 g (1.2 equiv) of TBDMSiCl, and 62.9 mg
(0.04 equiv) of DMAP. The reaction mixture was then stirred
under nitrogen for 18 h, washed with 50 mL of saturated NH4-
Cl, followed by 50 mL of brine, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure to afford a
pale yellow oil. Chromatography (5% EtOAc/hexanes) then
°C (EtOAc/hexanes); Rf 0.57 (50% acetone/hexanes); [R]25
)
D
91.34° (c 2.78, MeOH); spectral data identical to those of 29.
Dih yd r op yr r om eth en on e 30. This material was pre-
pared in a fashion identical to that of 21a described above,
using 160.0 mg (0.31 mmol) of pyrroloalkyne 29, 6.25 mL of
anhydrous THF, and 1.88 mL (1.88 mmol, 6 equiv) of 1 M
n-Bu4NF/THF in a 25 mL round bottom flask. After the
mixture was heated at reflux for 48 h under argon, workup
and chromatography (preparative TLC, 500 µm silica gel, 30%
acetone/hexanes) afforded 139.5 mg (87%) of 30 as a yellow
gave 2.72 g (82%) of 39 as a colorless oil: [R]25 5.7° (c 24.8,
D
CH2Cl2); MS m/z 241 (M+ - Me), 223, 199, 183, 155, 139, 105,
75; IR (CH2Cl2) 3381, 3303, 2958, 2931, 2859, 2111, 1472, 1390,
foam: Rf 0.81 (50% acetone/hexanes); [R]25 ) 7.46° (c 13.94,
1365, 1258, 1074, 838 cm-1; H NMR (CDCl3) δ 0.07 (s, 6H),
1
D
MeOH); IR (CH2Cl2) 3060, 2983, 2835, 2322, 1733, 1676, 1550,
1418, 1371, 1248, 1157, 906 cm-1; 1H NMR (CDCl3) δ 1.23 (d,
J ) 6.24 Hz, 3H), 1.32 (d, J ) 7.38 Hz, 3H), 1.55 (s, 9H), 1.92
(s, 3H), 2.51 (m, 2H), 2.65 (m, 1H), 2.99 (m, 3H), 3.69 (s, 3H),
3.80 (m, 1H), 4.55 (d, J ) 11.77 Hz, 1H), 4.63 (d, J ) 11.77
Hz, 1H), 5.31 (d, J ) 1.25 Hz, 1H), 7.38 (m, 5H), 8.11 (br s,
1H), 8.85 (br s, 1H); 13C NMR (CDCl3) δ 179.76, 172.07, 160.07,
138.96, 138.21, 129.05 (2), 128.49, 128.41, 128.18 (2), 119.99,
117.91, 92.42, 80.93, 76.00, 71.88, 70.78, 51.48, 50.86, 37.39,
35.01, 28.50 (3), 20.91, 17.85, 15.23, 9.27; MS (EIMS) m/z 510
(M+), 454, 402, 346, 319, 313, 301; (CIMS) m/z 511 (M + 1);
HRMS calcd for C29H38N2O6 510.2760, found 510.2731.
Dih yd r op yr r om eth en on e en t-30. This material was
prepared in a fashion identical to that of 21a described above,
using 100.0 mg (0.20 mmol) of pyrroloalkyne ent-29, 3.92 mL
of anhydrous THF, and 1.20 mL (1.20 mmol, 6 equiv) of 1 M
n-Bu4NF/THF in a 25 mL round bottom flask. After the
0.89 (s, 9H), 0.97 (d, J ) 6.9 Hz, 3H), 1.29 (d, J ) 6.3 Hz, 3H),
1.89 (m, 1H), 2.15 (d, J ) 2.4 Hz, 1H), 2.42 (m, 1H), 3.51 (dd,
J ) 4.2, 10.5 Hz, 1H), 3.79 (dd, J ) 7.8, 10.5 Hz, 1H), 3.88
(dq, J ) 2.3, 6.2 Hz, 1H); 13C NMR (CDCl3) δ -5.5 (2), 16.9,
18.3, 22.0, 25.9 (3), 38.6, 45.6, 65.7, 67.8, 73.2, 81.2. Anal.
Calcd for C14H28O2Si: C, 65.57; H, 11.00. Found: C, 65.35;
H, 11.08.
1-((ter t-Bu t yld im et h ylsilyl)oxy)-2(R)-m et h yl-3(R )-[1′-
(R)-(((N,N-d im et h yla m in o)t h ioca r b on yl)t h io)et h yl]-4-
pen tyn e (40). A solution of 2.90 g (2.0 equiv) of triphenylphos-
phine in 30 mL of of anhydrous toluene was cooled to 0 °C
under nitrogen and was treated in a dropwise fashion, with
vigorous stirring, with 2.0 equiv of DEAD to give a yellow
solution. After the mixture was stirred for an additional 30
min at 0 °C, the resulting light yellow suspension was treated
with a solution of 1.42 g (5.54 mmol, 1.0 equiv) of alcohol 39
and 1.70 g of Ziram in 8.0 mL of dry toluene. After being

Dihydropyrromethenones by Pd(0)-Mediated Coupling
J . Org. Chem., Vol. 62, No. 9, 1997 2915
stirred an additional 6 h at rt, the reaction mixture was treated
with an additional 0.84 g (0.5 equiv) of Ziram and stirring at
rt was continued for 16 h. The reaction mixture was then
concentrated under reduced pressure and chromatographed
(silica gel, 5-10% EtOAc/hexanes) to afford 772 mg (39%) of
J ) 7.2 Hz, 3H), 2.23 (d, J ) 1.8 Hz, 1H), 2.55 (m, 1H), 3.25
(m, 1H), 3.36 (s, 3H), 3.53 (s, 3H), 4.33 (m, 1H), 5.55 (br s,
1H), 5.77 (br s, 1H). Anal. Calcd for C11H18N2OS2: C, 51.13;
H, 7.02; N, 10.84; S, 24.81. Found: C, 51.25; H, 7.01; N, 10.88;
S, 24.71.
40 as a nearly colorless oil: [R]25 104.8° (c 6.3, CH2Cl2); MS
2(R)-Meth yl-3(R)-[1′(S)-h ydr oxyeth yl]-4-pen tyn oic Acid
Am id e (47a ). A solution of 60.0 mg (0.43 mmol, 1.0 equiv) of
lactone 37 in 1.0 mL of saturated NH3/MeOH was stirred at
rt under an atmosphere of argon for 24 h. At the end of this
period, the reaction was concentrated under reduced pressure
and the residue was crystallized from CH2Cl2 to afford 64.2
D
m/z 359 (M+), 244, 326, 302, 259, 239, 187, 178, 139, 121, 88;
IR (CH2Cl2) 3303, 2957, 2931, 2858, 1479, 1472, 1376, 1256,
1
1146, 1095, 1057, 982, 838 cm-1; H NMR (CDCl3) δ 0.05 (s,
6H), 0.89 (s, 9H), 1.12 (d, J ) 6.6 Hz, 3H), 1.45 (d, J ) 7.2 Hz,
3H), 1.78 (M, 1H), 2.13 (d, J ) 2.4 Hz, 1H), 2.86 (m, 1H), 3.36
(s, 3H), 3.53 (s, 3H), 3.60 (dd, J ) 6.6, 9.8 Hz, 1H), 3.84 (dd, J
) 3.3, 9.8 Hz, 1H), 4.33 (m, 1H); 13C NMR (CDCl3) δ -5.3 (2),
14.9, 15.3, 18.4, 26.0 (3), 38.4, 39.6, 41.5, 45.1, 48.3, 66.6, 71.8,
84.0, 196.5; HRMS (CIMS) calcd for (C17H33NOS2Si + H) (M
+ H+) 360.1851, found 360.1858.
mg (95%) of 47a as colorless needles: mp 140-2 °C; [R]25
D
-38.8° (c 1.04, MeOH); IR (KBr) 3349, 2976, 2360, 2341, 1667
cm-1; 1H NMR (CDCl3) δ 1.30 (d, J ) 6.6 Hz, 3H), 1.36 (d, J )
6.3 Hz, 3H), 2.23 (d, J ) 7.2 Hz, 1H), 2.29 (s, 1H), 2.57-2.69
(m, 2H), 3.99 (m, 1H), 5.47 (br s, 1H), 5.78 (br s, 1H); 13C NMR
(CD3OD) δ 16.65, 22.71, 43.99, 44.22, 66.34, 74.42, 83.51,
181.64. Anal. Calcd for C8H13NO2: C, 61.91; H, 8.44; N, 9.03.
Found: C, 61.94; H, 8.48; N, 8.95.
2(R)-Meth yl-3(R)-[1′(R)-(((N,N-d im eth yla m in o)th ioca r -
bon yl)th io)eth yl]-4-p en tyn oic Acid Am id e (43). A solu-
tion of 739 mg (2.05 mmol, 1.0 equiv) of silylated alcohol 40
in 12.5 mL of 1% HCl in 95% EtOH was stirred at rt for a
period of 12 h. The reaction was then neutralized by careful
addition of solid NaHCO3 until gas evolution ceased, dried over
anhydrous Na2SO4, filtered with the aid of EtOAc, and
concentrated under reduced pressure. Chromatography (20%
EtOAc/hexanes) then afforded 504 mg (100%) of alcohol 41 as
2(R)-Meth yl-3(R)-[1′(S)-h ydr oxyeth yl]-4-pen tyn oic Acid
N-(4′-Meth oxyben zyl)a m id e (47b). A solution of 45.0 mg
(0.32 mmol, 1.0 equiv) of lactone 37 in 0.5 mL of anhydrous
THF was treated with 0.26 mL (1.95mmol, 6.0 equiv) of
p-methoxybenzylamine, and the resulting solution was stirred
at rt under argon for 6 days. At the end of this period, the
reaction was concentrated under reduced pressure and the
residue was purified by flash chromatography (25% EtOAc/
hexanes) to afford 80.5 mg (90%) of 47b as a colorless
a colorless oil: [R]25 147.4° (c 7.6, CH2Cl2); MS m/z 245 (M+),
D
228, 212, 187, 157, 139, 121, 88; IR (CH2Cl2) 3618, 3458, 3301,
3046, 2970, 2932, 2877, 2111, 1498, 1452, 1377, 1256, 1147,
1
1036, 981 cm-1; H NMR (CDCl3) δ 1.15 (d, J ) 6.6 Hz, 3H),
crystalline solid: mp 113-4 °C; [R]25 19.1° (c 1.59, CH2Cl2);
D
1.48 (d, J ) 7.2 Hz, 3H), 1.88 (m, 2H), 2.20 (d, J ) 2.4 Hz,
1H), 2.91 (m, 1H), 3.37 (s, 3H), 3.54 (s, 3H), 3.68 (dd, J ) 5.4,
1H NMR (CDCl3) δ 1.25 (d, J ) 6.0 Hz, 3H), 1.34 (d, J ) 6.3
Hz, 3H), 2.17 (s, 1H), 2.29 (br s, 1H), 2.61 (m, 2H), 3.80 (s,
3H), 3.98 (m, 1H), 4.41 (m, 2H), 5.99 (br s, 1H), 6.86 (d, J )
9.0 Hz, 2H), 7.24 (d, J ) 9.0 Hz, 2H); 13C NMR (CDCl3) δ 16.57,
22.72, 43.49, 43.80, 43.83, 55.80, 66.56, 74.08, 82.34, 114.46
11.1 Hz, 1H), 3.85 (dd, J ) 4.8, 11.1 Hz, 1H), 4.34 (m, 1H); 13
C
NMR (CDCl3) δ 15.1, 15.6, 38.3, 40.4, 41.6, 45.2, 48.2, 66.8,
72.4, 83.8, 196.3; HRMS (CIMS) calcd for (C11H19NOS2 + H)
(M + H+) 246.0986, found 246.0985.
(2), 129.66 (2), 131.01, 159.44, 175.42. Anal. Calcd for C16
-
H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.62; H, 7.63;
N, 5.14.
A stirring solution of 324 mg (1.32 mmol, 1.0 equiv) of
alcohol 41 in 9.0 mL of dry DMF was treated at rt with 1.74
g (3.5 equiv) of pyridinium dichromate, and the resulting
mixture was stirred at rt for 48 h. The reaction mixture was
then poured carefully into 40 mL of H2O in a separatory funnel
with the aid of 40 mL of EtOAc. The separated aqueous layer,
which had pH ) 5, was acidified to pH ) 3.5 by the addition
of 0.5 mL of 5 N HCl and was then extracted with 5 × 40 mL
of EtOAc. The combined extracts were dried (Na2SO4), filtered,
concentrated under reduced pressure, and chromatographed
(75:25:0.3 hexanes/EtOAc/AcOH) to afford 280 mg (82%) of
carboxylic acid 42 as a pale yellow solid. Crystallization from
P yr r oloa lk yn e 48a . This material was prepared in a
fashion identical to that of pyrroloalkyne 19 described above,
using 135.9 mg (0.88 mmol, 1.0 equiv) of acetylenic amide 47a ,
516.5 mg (1.31 mmol, 1.5 equiv) of iodopyrrole 27, 4.0 mL of
freshly distilled DMF, 0.4 mL (3.0 equiv) of NEt3, 106.0 mg
(0.09 mmol, 0.1 equiv) of Pd(Ph3P)4, and 33.0 mg (0.17 mmol,
0.2 equiv) of CuI. After workup, flash chromatography (silica
gel, 50% acetone/hexanes) afforded 351.2 mg (95%) of 48a as
an off-white foam: [R]25 -43.1° (c 2.2, CH2Cl2); 1H NMR
D
(CDCl3) δ 1.29 (d, J ) 6.3 Hz, 3H), 1.37 (d, J ) 6.3 Hz, 3H),
1.53 (s, 9H), 2.00 (s, 3H), 2.44-2.49 (m, 2H), 2.71-2.85 (m,
2H), 2.90-2.96 (m, 2H), 3.37 (d, J ) 7.5 Hz, OH), 3.66 (s, 3H),
4.06 (m, 1H), 6.35 (br s, 1H), 6.40 (br s, 1H), 10.01 (br s, 1H);
13C NMR (CDCl3) δ 9.92, 16.59, 21.45, 22.84, 28.85 (3), 35.52,
43.55, 45.01, 51.90, 67.04, 77.63, 81.68, 92.34, 115.94, 120.83,
124.95, 128.16, 161.29, 174.03, 179.35; HRMS (FAB) calcd for
(C22H32N2O6 + H) 421.2339, found 421.2346 (M + H+).
P yr r oloa lk yn e 48b. This material was prepared in a
fashion identical to that of pyrroloalkyne 19 described above,
using 53.1 mg (0.14 mmol, 1.5 equiv) of iodopyrrole 27, 24.8
mg (0.09 mmol, 1.0 equiv) of acetylenic amide 47b, 1.0 mL of
freshly distilled DMF, 0.04 mL (3.0 equiv) of NEt3, 12.0 mg
(0.01 mmol, 0.11 equiv) of Pd(Ph3P)4, and 3.4 mg (0.018 mmol,
0.2 equiv) of CuI. After workup, flash chromatography (silica
gel, 25% hexanes/EtOAc) afforded 39.8 mg (82%) of 48b as an
off-white foam: [R]25D -17.4° (c 3.3, CH2Cl2); 1H NMR (CDCl3)
δ 1.26 (d, J ) 6.9 Hz, 3H), 1.37 (d, J ) 6.3 Hz, 3H), 1.54 (s,
9H), 1.99 (s, 3H), 2.50 (m, 2H), 2.68 (m, 1H), 2.82 (dd, J ) 7.8,
2.1 Hz, 1H), 2.97 (m, 2H), 3.18 (br, OH), 3.66 (s, 3H), 3.70 (s,
3H), 4.09 (m, 1H), 4.33 (m, 2H), 6.23 (t, J ) 5.4 Hz, 1H), 6.63
MeOH then gave 42 as colorless crystals: mp 167-71 °C; [R]25
D
171.7° (c 4.1, CH2Cl2); MS m/z 259 (M+), 226, 212, 182, 162,
139, 121, 88; IR (CH2Cl2) 3490-2500, 3302, 3072, 2975, 2934,
1749, 1714, 1498, 1454, 1378, 1254, 1146, 981 cm-1; 1H NMR
(CDCl3) δ 1.39 (d, J ) 7.2 Hz, 3H), 1.45 (d, J ) 7.2 Hz, 3H),
2.17 (d, J ) 2.4 Hz, 1H), 2.71 (m, 1H), 3.30 (m, 1H), 3.36 (s,
3H), 3.53 (s, 3H), 4.34 (m, 1H). Anal. Calcd for C11H17NO2S2:
C, 50.95; H, 6.61; N, 5.41. Found: C, 51.03; H, 6.64; N, 5.44.
A solution of 280 mg (1.08 mmol, 1.0 equiv) of carboxylic
acid 42 in 15 mL of anhydrous THF was cooled to 0 °C under
nitrogen and was treated with vigorous stirring with 0.15 mL
(1.0 equiv) of NEt3 and 0.14 mL of isobutylchlorofomate. The
resulting white suspension was stirred at 0 °C for an additional
30 min, then cooled to -78 °C, and treated with ∼2 mL of
liquid NH3 which had been condensed in a graduated cylinder
at -78 °C by being passed through a tube filled with NaOH
pellets. After the addition was complete, the reaction mixture
was allowed to warm slowly to rt and was then stirred at rt
for 3.5 h. The reaction mixture was then diluted with 25 mL
of H2O and EtOAc, and the separated aqueous layer was
extracted with 5 × 25 mL of EtOAc. The combined extracts
were dried (Na2SO4), filtered, concentrated under reduced
pressure, and chromatographed (33% EtOAc/hexanes) to afford
169 mg (60%) of amide 43 as a colorless solid. Crystallization
from Et2O/CH2Cl2 then gave 43 as colorless crystals: mp
(d, J ) 8.4 Hz, 2H), 7.08 (d, J ) 8.4 Hz, 2H), 9.38 (s, 1H); 13
C
NMR (CDCl3) δ 10.14, 16.71, 21.37, 22.98, 28.91 (3), 35.43,
43.57, 44.34, 45.15, 51.98, 55.68, 67.22, 77.45, 81.61, 92.45,
114.41 (2), 115.35, 120.89, 125.37, 128.28, 129.42 (2), 130.56,
159.45, 160.67, 174.09, 175.57; HRMS (FAB) Calcd for
(C30H40N2O7 + H) 541.2914, found 541.2912 (M + H+).
Dih yd r op yr r om eth en on e 31a . This material was pre-
pared in a fashion identical to that of 21a described above,
using 72.9 mg (0.17 mmol, 1 equiv) of pyrroloalkyne 48a , 4.0
167.5-8.0 °C; [R]25 230.6° (c 8.1, CH2Cl2); MS m/z 138 (M+
-
D
SCSNMe2), 122, 88, 76, 49, 44; IR (CH2Cl2) 3519, 3402, 3301,
2976, 2933, 1691, 1592, 1498, 1454, 1378, 1255, 1147, 1052,
981 cm-1; 1H NMR (CDCl3) δ 1.35 (d, J ) 6.9 Hz, 3H), 1.47 (d,

2916 J . Org. Chem., Vol. 62, No. 9, 1997
J acobi et al.
mL of anhydrous THF, and 1.04 mL (1.04 mmol, 6.0 equiv) of
1.0 M n-Bu4NF solution in THF. After the mixture was heated
at reflux under argon for 48 h, workup and purification by
flash chromatography (25% hexanes/EtOAc) afforded 31.5 mg
being poured into cold saturated NaHCO3 and being extracted
with EtOAc. The combined extracts were washed with H2O,
dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The unstable Mitsunobu product thus obtained was
partly purified by flash chromatography (silica gel, 90% CH2-
Cl2/EtOAc) and was then dissolved in a solution consisting of
1.0 mL of CH2Cl2 and 1.0 mL of CF3CO2H. This solution was
stirred under argon at rt for 3 h to effect tert-butyl ester
hydrolysis. The reaction mixture was then treated with 1.0
mL of CH(OCH3)3 and stirred for an additional 10 min at rt,
after which the resulting solution was poured over ice and
extracted with CH2Cl2. The combined extracts were washed
with saturated NaHCO3, followed by brine, dried over anhy-
drous Na2SO4, and concentrated under reduced pressure.
Flash chromatography (33% hexanes/EtOAC) afforded 44.1 mg
(43%) of 31a as a yellow foam: [R]25 -43.3° (c 1.05, CH2Cl2);
D
1H NMR (CDCl3) δ 1.26 (d, J ) 6.3 Hz, 3H), 1.28 (d, J ) 6.9
Hz, 3H), 1.51 (s, 9H), 1.94 (s, 3H), 2.46-2.60 (m, 3H), 2.65 (m
1H), 2.98 (m, 2H), 3.68 (s, 3H), 3.97 (m, 1H), 5.40 (s, 1H), 8.01
(br s, 1H), 8.93 (br s, 1H); 13C NMR (CDCl3) δ 9.69, 17.97,
20.14, 21.52, 28.91 (3), 35.60, 39.81, 51.95, 54.76, 70.20, 81.53,
94.49, 118.63, 120.52, 129.01, 129.72, 138.94, 161.96, 174.14,
181.68; HRMS (FAB) calcd for (C22H32N2O6 + H) 421.2339,
found 421.2346 (M + H+).
Dih yd r op yr r om eth en on e 31b. This material was pre-
pared in a fashion identical to that of 21a described above,
using 55.4 mg (0.10 mmol, 1.0 equiv) of pyrroloalkyne 48b in
2.0 mL of anhydrous THF and 28.6 mg (0.10 mmol, 1.0 equiv)
of n-Bu4NF‚3H2O. After the mixture was heated at reflux
under argon for 19 h, workup and purification by flash
chromatography (33% hexanes/EtOAc) afforded 44.4 mg (80%)
(62%) of 32b as a pale yellow gum: [R]25 -54.4° (c 2.5, CH2-
D
Cl2); IR (KBr) 3256, 2954, 1720, 1696, 1618, 1514, 1440, 1347,
1248, 1175 cm-1; 1H NMR (CDCl3) δ 1.25 (d, J ) 7.2 Hz, 3H),
1.37 (d, J ) 7.5 Hz, 3H), 1.82 (s, 3H), 2.09 (s, 3H), 2.52 (m,
1H), 2.58 (t, J ) 8.1 Hz, 2H), 3.02 (t, J ) 8.1 Hz, 2H), 3.05 (m,
1H), 3.61 (m, 1H), 3.67 (s, 3H), 3.79 (s, 3H), 4.49 (d, J ) 15.0
Hz, 1H), 4.89 (d, J ) 15.0 Hz, 1H), 5.55 (s, 1H), 6.85 (d, J )
8.7 Hz, 2H), 7.22 (d, J ) 8.7 Hz, 2H), 9.13 (br s, 1H), 9.56 (s,
1H); 13C NMR (CDCl3) δ 9.43, 19.29, 19.90, 21.05, 31.05, 35.99,
40.21, 42.42, 44.11, 48.74, 52.14, 55.80, 94.48, 114.57 (2),
120.38, 128.02, 129.25, 129.50 (5), 133.65, 134.49, 145.29,
159.62, 173.36, 176.89, 177.88, 194.07; HRMS (FAB) calcd for
(C28H34N2O6S + H) 527.2216, found 527.2218 (M + H+).
of 31b as a pale yellow gum: [R]25 -54.4° (c 2.5, CH2Cl2); IR
D
(KBr) 3267, 2975, 2932, 1688, 1650, 1613, 1514, 1439, 1250,
1175, 1137 cm-1; 1H NMR (CDCl3) δ 1.19 (d, J ) 6.0 Hz, 3H),
1.39 (d, J ) 7.2 Hz, 3H), 1.60 (s, 9H), 1.83 (s, 3H), 2.55 (m,
2H), 2.61 (t, J ) 8.4 Hz, 2H), 3.04 (t, J ) 8.4 Hz, 2H), 3.69 (s,
3H), 3.76 (s, 3H), 4.21 (d, J ) 15.0 Hz, 1H), 4.77 (d, J ) 15.0
Hz, 1H), 5.33 (s, 1H), 6.55 (d, J ) 8.7 Hz, 2H), 6.69 (d, J ) 8.7
Hz, 2H), 8.21 (br s, 1H); 13C NMR (CDCl3) δ 9.23, 17.73, 21.24,
21.61, 29.07 (3), 35.50, 41.43, 44.00, 51.98, 52.89, 55.79, 69.84,
80.84, 99.55, 114.77 (2), 119.13, 119.58, 128.62, 128.73, 128.94
(2), 129.75, 140.29, 159.57, 161.32, 174.36, 178.03; HRMS
(FAB) calcd for (C30H40N2O7 + H) 541.2914, found 541.2912
(M + H+).
Ack n ow led gm en t. Financial support of this work
by the National Institutes of Health, Grant No.
GM38913, is gratefully acknowledged.
Dih yd r op yr r om eth en on e 32b. A solution of 178.5 mg
(0.67 mmol, 5.0 equiv) of Ph3P in 2.0 mL of anhydrous THF
was cooled to 0 °C under argon and was treated with 0.14 mL
(0.67 mmol, 5.0 equiv) of diisopropyl azodicarboxylate. After
the mixture was stirred for an additional 30 min at 0 °C, the
resulting white suspension was treated sequentially with 76.9
mg (0.13 mmol, 1.0 equiv) of alcohol 31b and 0.05 mL (0.67
mmol, 5.0 equiv) of AcSH in 3.0 mL of dry THF. The reaction
mixture was then stirred for 1 h at 0 °C, and 1 h at rt, before
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 31a ,b-32b, 37-43, and 47a ,b-48a ,b
(19 pages). This material is contained in libraries on micro-
fiche, immediately follows this article in the microfilm version
of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
J O970289B