Stereocontrolled synthesis of triazacyclopenta[cd]pentalenes by intramolecular 1,3-dipolar cycloaddition reactions of azomethine imines

Article abstract of DOI:10.1021/jo026282y

The construction of triazacyclopenta[cd]pentalene diesters 6 by the reaction of dihydropyrrole α-ketoesters 3 with acylated hydrazines was evaluated further as a potential central strategic step in the total syntheses of complex guanidine alkaloids such as palau'amine and styloguanidine. Successful cyclocondensations were realized with acid-stable 2,2,2-trichloroethyl carbazate and thiosemicarbazide, but not tert-butyl carbazate. The substituent on the pyrrolidine nitrogen can be alkoxycarbonyl, sulfonyl, or an N-alkyl-2-acylpyrrole group. Siloxy substitution at C1 of the α-ketoester side chain is also tolerated.

Full text of DOI:10.1021/jo026282y

SCHEME 1
Ster eocon tr olled Syn th esis of
Tr ia za cyclop en ta [cd ]p en ta len es by
In tr a m olecu la r 1,3-Dip ola r Cycloa d d ition
Rea ction s of Azom eth in e Im in es
Guillaume Be´langer,1a Fang-Tsao Hong,1b
Larry E. Overman,* Bruce N. Rogers,1c
J ohn E. Tellew,1d and William C. Trenkle1e
Department of Chemistry, 516 Rowland Hall,
University of California, Irvine, California 92697-2025
leoverma@uci.edu
Received August 2, 2002
Abstr a ct: The construction of triazacyclopenta[cd]penta-
lene diesters 6 by the reaction of dihydropyrrole R-ketoesters
3 with acylated hydrazines was evaluated further as a
potential central strategic step in the total syntheses of
complex guanidine alkaloids such as palau′amine and sty-
loguanidine. Successful cyclocondensations were realized
with acid-stable 2,2,2-trichloroethyl carbazate and thiosemi-
carbazide, but not tert-butyl carbazate. The substituent on
the pyrrolidine nitrogen can be alkoxycarbonyl, sulfonyl, or
an N-alkyl-2-acylpyrrole group. Siloxy substitution at C1 of
the R-ketoester side chain is also tolerated.
lecular azomethine imine cycloaddition reactions. In this
paper, we report our studies to further explore the scope
of this new construction of triazacyclopenta[cd]pentalenes
in the context of its potential use for the total synthesis
of complex guanidine alkaloids of the palau′amine and
styloguanidine families.
Cycloaddition of azomethine imines with suitable di-
polarophiles is a powerful method for constructing tet-
rahydropyrazole rings.2 Beginning with pioneering in-
vestigations by Oppolzer and co-workers in the 1970s,3
intramolecular variants of this class of 1,3-dipolar cy-
cloadditions have found wide utility for synthesis of
complex nitrogen heterocycles.2 Exemplified in Oppolzer’s
early studies3 and J acobi’s incisive synthesis of saxitoxin,4
the 1,3-dipole is often formed by condensation of a 1-acyl-
2-alkylhydrazine with an aldehyde. A second commonly
used procedure to generate azomethine imine dipoles is
tautomerization of acyl hydrazones.5 This latter approach
was employed in our recent construction of tetracyclic
nitrogen heterocycle 4 (R ) Cbz, X ) H) during our early
studies to uncover routes to complex guanidine alkaloids
such as palau′amine (1) and styloguanidine (2) (Scheme
1).6 To the best of our knowledge, hydrazones derived
from R-ketoesters or R,â-unsaturated R-amino esters had
not been described previously as components of intramo-
Syn th esis of th e Dih yd r op yr r ole R-Ketoester Cy-
cloa d d ition Com p on en ts. To explore how the nitrogen
substituent of the dipolarophile would influence the
cycloaddition, three dihydropyrrole R-ketoesters 12a -c
were prepared (Scheme 2). In two cases, the nitrogen
carried an acid-stable protecting group, Cbz or SES (SO2-
CH2CH2TMS).7 In the third, the nitrogen carried a
2-acylpyrrole group to investigate whether this fragment
of palau′amine and styloguanidine could be incorporated
early in a synthetic sequence. These syntheses began
with readily available amino diester 7,8 which was
acylated or sulfonylated in standard fashion to deliver
8a -c in high yield. Dieckmann cyclization9 of 8 using
potassium tert-butoxide followed by sodium borohydride
reduction10 of the resulting â-ketoesters generated â-hy-
droxyesters 9a -c as mixtures of stereoisomers.
To generate the dihydropyrrole R-ketoester cycloaddi-
tion components 12 from 9, the hydroxypyrrolidine ester
must be dehydrated and the allyl substituent converted
to a 4-carbon R-ketoester side chain. In the Cbz and SES
series, the hydroxyl groups of 9a and 9b were first
mesylated, followed by ozonolysis of the allyl side chain
and Horner-Emmons elaboration of the resulting side
chain aldehydes (Scheme 3).11,12 The use of excess DBU
in the condensation step promoted in situ elimination of
the mesylate to form the dihydropyrrole. After cleavage
(1) Current addresses: (a) Universite´ de Sherbrooke, De´partement
de Chimie, 2500 Boul. Universite´, Sherbrooke, Que´bec, J 1K 2R1,
Canada. (b) Amgen, Inc., One Amgen Center Drive, Thousand Oaks,
CA, 91320. (c) Pharmacia, 301 Henrietta Street, Kalamazoo, MI 49007-
4940. (d) Neurocrine Biosciences, Inc., 10555 Science Center Drive,
San Diego, CA 92121. (e) Department of Chemistry, Brown University,
Box H, Providence, RI 02912.
(2) Wade, P. A. “Intramolecular 1,3-Dipolar Cycloadditions” In
Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds.;
Pergamon: London, 1991; Vol. 4, pp 1144-49.
(3) (a) Oppolzer, W. Tetrahedron Lett. 1970, 11, 3091-3094. (b)
Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1977, 16, 10-23.
(4) (a) J acobi, P. A.; Martinelli, M. J .; Polanc, S. J . Am. Chem. Soc.
1984, 106, 5594-5598. (b) J acobi, P. A.; Brownstein, A.; Martinelli,
M.; Grozinger, K. J . Am. Chem. Soc. 1981, 103, 239-241. (c) Martinelli,
M. J .; Brownstein, A. D.; J acobi, P. A.; Polanc, S. Croat. Chem. Acta,
1986, 59, 267-295.
(7) Weinreb, S. M.; Demko, D. M.; Lessen, T. A.; Demers, J . P.
Tetrahedron Lett. 1986, 27, 2099-2102.
(8) Yu, L.-C.; Helquist, P. J . Org. Chem. 1981, 46, 4536-4541.
(9) Blake, J .; Willson, C. D.; Rapoport, H. J . Am. Chem. Soc. 1964,
86, 5293-5299 and references therein.
(5) Kanemasa, S. R.; Tomoshige, N.; Wada, E. J .; Tsuge, O. Bull.
Chem. Soc. J pn. 1989, 62, 3944-3949.
(6) Overman, L. E.; Rogers, B. N.; Tellew, J . E.; Trenkle, W. C. J .
Am. Chem. Soc. 1997, 119, 7159-7160.
(10) Rozing, G. P.; de Koning, H.; Huisman, H. O. Recl. Trav. Chim.
Pays-Bas, 1981, 100, 359-368.
10.1021/jo026282y CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/10/2002
7880
J . Org. Chem. 2002, 67, 7880-7883

SCHEME 2
SCHEME 3
of the TBDMS group, this sequence provided 12a and
12b in ∼45% overall yield. In the 2-acylpyrrole series,
the aldehyde intermediate was generated in the first step
by dihydroxylation of the allyl side chain of 9c, followed
by cleavage of the resulting vicinal diol with NaIO4.13
Mesylation of the hydroxy aldehyde, condensation of the
resulting product with 10, and desilylation delivered 12c
in 58% overall yield from acyclic amino diester 8c.
Epimeric cyclization precursors 23 and 24 bearing a
protected alcohol at C-1 of the R-ketoester side chain were
prepared to study the impact of substitution on the tether
joining the cycloaddends (Scheme 3). Oxidation of al-
lylpyrrolidine 9b14 with catalytic selenium dioxide using
t-BuO2H as the reoxidant provided an inseparable 3:1
mixture of two epimeric diols 14 in low yield, as well as
50-60% of recovered 9b.15,16 The mixture of diols 14 was
converted into the corresponding acetonides, which were
readily separable by column chromatography. The rela-
tive configuration of these epimers was determined by
the method of Rychnovsky and co-workers from the
diagnostic chemical shifts of the acetonide methyl carbons
in the 13C NMR spectra: 15 (25.5 and 24.4 ppm) and 16
(29.9 and 19.6 ppm).17 The epimeric acetonides were
independently cleaved with Dowex 50WX8 acidic resin
in methanol to provide the corresponding diols in good
yields.18 Selective silylation of the side chain allylic
alcohol of 17 and 18 delivered silyl ethers 19 and 20.19
These intermediates were processed identically to the
simpler SES analogue 9b to provide dihydropyrrole
R-ketoester epimers 23 and 24.
In tr a m olecu la r Cycloa d d ition Rea ction s. Results
obtained from our initial survey of the reaction of
dihydropyrrole R-ketoester 12a with various acylhydra-
zines are summarized in Scheme 4. With 2,2,2-trichlo-
roethyl carbazate (25, Z ) Troc), cycloaddition took place
smoothly in refluxing xylenes to provide cycloadduct 26
in 86% yield. Only a trace of the analogous product was
formed from identical reaction with tert-butyl carbazate
(25, Z ) Boc), an outcome we ascribe to the instability of
the tert-butoxycarbonyl group under these conditions.20
Reaction of 12a with thiosemicarbazide in refluxing
(15) Umbreit, M. A.; Sharpless, K. B. J . Am. Chem. Soc. 1977, 99,
9, 5526-5528.
(11) (a) Nakamura, E. Tetrahedron Lett. 1981, 22, 663-666. (b)
Horne, D.; Gaudino, J .; Thompson, W. J . Tetrahedron Lett. 1984, 25,
3529-3532.
(16) Due to decomposition of 14 under the reaction conditions, the
yield of these allylic alcohol products was no higher if the allylic
(12) Blanchette, M. A.; Choy, W.; Davis, J . T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183-2186.
oxidation was carried out for a longer time to ensure complete
consumption of 9b.
(17) Rychnovsky, S. D.; Rogers, B. N.; Yang, G. J . Org. Chem. 1993,
58, 3511-3515.
(13) This procedure was employed as the acylpyrrole reacted slowly
with ozone.
(14) This sample was largely (∼90%) one stereoisomer. Although
not rigorously established, it is likely that this was the all-cis
stereoisomer that is depicted in Scheme 3.
(18) Rychnovsky, S. D.; Khire, U. R.; Yang, G. J . Am. Chem. Soc.
1997, 119, 2058-2059.
(19) Significantly lower yields of 19 were observed due to competitive
silylation of the hydroxyl on the pyrrolidine ring of 17.
J . Org. Chem, Vol. 67, No. 22, 2002 7881

SCHEME 4
tuted with SES or N-SEM-2-acylpyrrole functionality
behaved similarly to the corresponding Cbz-protected
substrate and gave tetracyclic adducts 27b and 27c in
high yield. The SES-protected substrates 23 and 24
having a tert-butyldimethylsiloxy group at C1 of the
R-ketoester side chain also readily provided the corre-
sponding tetracyclic cycloadducts 29 and 30 when con-
densed in acetic acid at 70 °C with thiosemicarbazide.
We had anticipated that the thiosemicarbazone derived
from 23 might be less prone to undergo cycloaddition as
the siloxy group would reside on the hindered concave
face of the triazacyclopenta[cd]pentalene cycloadduct.
However, both siloxy epimers provided their respective
cycloadducts with nearly equal efficiency.23
This study shows that dihydropyrrole R-ketoesters of
general structure 3 react with acid-stable alkyl carba-
zates and thiosemicarbazide, but not tert-butyl carbazate,
to efficiently provide cycloadducts containing the triaza-
cyclopenta[cd]pentalene ring system. The substituent on
the pyrrolidine nitrogen can be varied widely, as suc-
cessful cycloadditions were realized when this group was
alkoxycarbonyl, sulfonyl, or an N-alkyl-2-acylpyrrole
group. Moreover, silyloxy substitution at C1 of the
R-ketoester side chain is also tolerated. These results
encourage us to explore further the utility of the cyclo-
condensation outlined in Scheme 1 for the total synthesis
of complex guanidine alkaloids of the palau′amine (1) and
styloguanidine (2) families.
SCHEME 5
Exp er im en ta l Section 24,25
E t h yl 2-[[E t h oxyca r b on ylm et h yl-[2′-(t r im et h ylsilyl)-
eth a n esu lfon yl]a m in o]m eth yl]p en t-4-en oa te (8b). A stir-
ring solution of 7 (5.50 g, 22.6 mmol),8 triethylamine (9.5 mL,
68 mmol), and CH2Cl2 (35 mL) was cooled to -78 °C, and a cooled
(-78 °C) solution of 2-(trimethylsilyl)ethanesulfonyl chloride
(9.00 g, 45.2 mmol) and CH2Cl2 (10 mL) was added by cannula.
Upon completion of the addition, the reaction flask was placed
in a -45 °C bath and left overnight. The resulting solution was
allowed to warm to 23 °C, 1 M HCl was added (40 mL), and the
aqueous layer was extracted with CH2Cl2. The combined organic
layers were dried (Na2SO4) and concentrated, and the residue
was chromatographed (9:1-4:1 pentanes-EtOAc) to yield 8.90
g (97%) of 8b as a colorless oil: 1H NMR (500 MHz, CDCl3) δ
5.73 (1H, ddd, J ) 17.1, 10.1, 7.0 Hz), 5.10 (2H, m), 4.2-4.0 (6H,
m), 3.51 (2H, m), 3.85 (1H, m), 3.01 (2H, m), 2.40-2.21 (2H, m),
1.28 (3H, t, J ) 7.2 Hz), 1.26 (3H, t, J ) 7.2 Hz), 1.08 (2H, m),
0.05 (9H, s); 13C NMR (125 MHz, CDCl3) δ 173.9, 136.4, 134.0,
117.6, 61.3, 60.8, 49.6, 49.1, 45.1, 34.4, 14.1, 11.1, 10.0, -2.1;
IR (film) 1737 cm-1; MS (CI) m/z 408.1877 (408.1876 calcd for
xylenes produced a product mixture containing some of
the expected tricyclic cycloadduct as well as tetracycle
27a resulting from loss of ethanol from this intermedi-
ate.21 Further investigation showed that the cycloaddition
of 12a with thiosemicarbazide occurred most cleanly in
acetic acid at 70 °C over a 24 h period, in which case 27a
was formed in 87-95% yield.22 The structure of this
cycloadduct was secured by cleavage of its benzyloxycar-
bonyl group with HBr in acetic acid to give crystalline
28, which was amenable to single-crystal X-ray analysis.6
The reaction of thiosemicarbazide with dihydropyrrole
R-ketoesters 12b,c was surveyed under identical reaction
conditions in acetic acid (Scheme 5). Cycloaddends 12b
and 12c in which the dihydropyrrole nitrogen is substi-
C
17H34NO6SSi, MH). Anal. Calcd for C17H33NO6SSi: C, 50.10;
H, 8.16; N, 3.44; S, 7.87. Found: C, 50.19; H, 8.15; N, 3.40; S,
7.97.
(20) (a) Wasserman, H. H.; Berger, G. D.; Cho, K. R. Tetrahedron
Lett. 1982, 23, 465-468. (b) Rawal, V. H.; J ones, R. J .; Cava, M. P. J .
Org. Chem. 1987, 52, 19-28.
(23) Analysis of 1H NMR coupling constants of 29 and comparison
with the X-ray structure of 28 indicates that the siloxy group of 29
assumes a quasi-equatorial orientation.
(21) The inefficiency of the cycloaddition in xylenes could be due,
in part, to the poor solubility of thiosemicarbazide in this solvent.
(22) Product 27a forms slowly at room temperature over the course
of 10-14 days when the solvent is acetic acid. Although, the cyclocon-
densation of 12a with acylhydrazines in refluxing xylenes undoubtedly
proceeds as depicted in Scheme 1, an alternative mechanism is possible
when the solvent is acetic acid. Dehydroamino esters are well-known
to exhibit ambiphilic reactivity. Thus, the finding that the cyclocon-
densation of 12a with thiosemicarbazide occurs optimally in acetic acid,
and even at room temperature, suggests that this cyclocondensation
likely takes place by an asynchronous or stepwise mechanism. In the
stepwise limit, the cycloadduct would be the result of an intra-
molecular Mannich cyclization followed by subsequent cyclization of
the acylated hydrazine with an N-acyl- or N-sulfonyliminium ion
intermediate.
(24) General experimental details have been described: Ando, S.;
Minor, K. P.; Overman, L. E. J . Org. Chem. 1997, 62, 6379-6387.
Ether, THF, dichloromethane and toluene were dried by passage
through a bed of activated alumina.25 For reactions requiring anhy-
drous conditions, substrates were dried by azeotropic evaporation with
benzene, the reaction flask was flame-dried under vacuum, and the
reaction was conducted under an atmosphere of anhydrous nitrogen.
High-resolution mass spectra were obtained by CI, ES or FAB methods.
IR spectra were recorded by applying substrates as thin films onto a
KBr plate. Details of the preparation and characterization of com-
pounds 8a , 9a , 11a , 12a , 27a , and 28 have been reported previously
in Supporting Information.6
(25) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J . Organometallics 1996, 15, 1518-1520.
7882 J . Org. Chem., Vol. 67, No. 22, 2002

Eth yl N-[2′-(Tr im eth ylsilyl)eth a n esu lfon yl]-3-h yd r oxy-
4-a llylp yr r olid in e-2-ca r boxyla te (9b). A stirring solution of
8b (1.10 g, 2.70 mmol) and THF (35 mL) was cooled to -78 °C,
and a solution of potassium tert-butoxide (340 mg, 3.0 mmol)
and THF (30 mL) was added dropwise by cannula. The reaction
was maintained at -78 °C for 5 min, quenched at this temper-
ature by adding 1 M HCl (20 mL), allowed to warm to 23 °C,
and extracted with EtOAc. The combined organic extracts were
washed with brine, dried (Na2SO4), and concentrated to yield
1.0 g of the crude â-ketoester product as a slightly yellow oil,
which was used in the next step without further purification. A
small sample was chromatographed (4:1-1:1 hexanes-EtOAc)
to yield a pure specimen as a colorless oil, diagnostic data: 1H
NMR (500 MHz, CDCl3, ∼1:1 mixture of diastereomers) δ 5.72
(1H, m), 5.08 (2H, m), 4.29-4.20 (4H, m), 3.48 (1H, m), 3.09 (2H,
m), 2.87 (1H, m), 2.50-2.10 (2H, m), 1.30 (3H, m), 1.27 (2H, m),
(9H, s), 0.12 (6H, s), 0.05 (9H, s); 13C NMR (125 MHz, CDCl3, of
the major diastereomer only) δ 164.8, 161.2, 142.0, 137.1, 128.2,
120.3, 117.8, 61.3, 55.6, 51.3, 42.6, 30.0, 25.5, 14.1, 10.2, -2.0,
-4.9; IR (film) 1728 cm-1; MS (CI) m/z 534.2373 (534.2376 calcd
for C23H44NO7SSi2 MH).
Gen er a l P r oced u r e for Gen er a tion of Dih yd r op yr r ole
R-Ketoester s fr om Silyl P r ecu r sor s a n d Con d en sa tion
w ith Th iosem ica r ba zid e. P r ep a r a tion of 12b a n d Cyclo-
a d d u ct 27b. Acetic acid (160 µL, 2.8 mmol) and CsF (230 mg,
1.5 mmol) were added to a solution of 11b (250 mg, 0.47 mmol)
and dry MeCN (4 mL) at 0 °C. The resulting mixture was stirred
at 0 °C for 30 min and at 23 °C for 4 h. The reaction mixture
was diluted with hexanes and EtOAc (50 mL each) and washed
with saturated aqueous NaHCO3. The organic layer was dried
(Na2SO4) and concentrated to give 200 mg of crude 12b (judged
>95% pure by 1H NMR analysis) as an unstable colorless oil,
which was used immediately: 1H NMR (500 MHz, CDCl3) δ 6.15
(1H, d, J ) 3.0 Hz), 4.25 (2H, dd, J ) 7.2, 7.1 Hz), 4.07 (1H, dd,
J ) 11.4, 9.1 Hz), 3.87 (3H, s), 3.79 (1H, dd, J ) 11.4, 5.6 Hz),
3.35 (2H, m), 2.99 (1H, m), 2.92 (2H, m), 1.83 (2H, m), 1.32 (3H,
t, J ) 7.1 Hz), 1.06 (1H, m), 0.06 (9H, s); 13C NMR (125 MHz,
CDCl3,) δ 193.1, 161.1, 161.0, 137.4, 127.5, 61.5, 55.8, 53.1, 51.5,
0.07 (9H, s); IR (film) 1770, 1739, 1642 cm-1
.
A suspension of sodium borohydride (200 mg, 5.4 mmol) in
MeOH (4 mL) was added dropwise to a solution of this unpurified
Dieckman product (1.0 g) and MeOH (50 mL) at -78 °C. The
cooling bath was removed after 10 min and the solution was
maintained at 23 °C for 1 h. Acetone (10 mL) was added and
the solution was concentrated. Saturated aqueous NaHCO3 (40
mL) was added to the residue and the resulting mixture was
extracted with 1:1 hexanes-EtOAc. The combined organic
extracts were dried (Na2SO4), concentrated and the residue was
chromatographed (2:1-1:1 hexanes-EtOAc) to yield 350 mg of
recovered 8b and 498 mg (51%, 75% overall based on consumed
8b) of 9b, a mixture of stereoisomers, as a nearly colorless oil:
1H NMR (500 MHz, CDCl3, major diastereomer only) δ 5.82 (1H,
m), 5.09 (2H, ddd, J ) 17.1, 10.2, 1.5 Hz), 4.73 (1H, d, J ) 4.7
Hz), 4.61 (1H, m), 4.24 (2H, m), 3.92 (1H, m), 3.20-3.10 (2H,
m), 3.00 (1H, m), 2.45 (1H, d, J ) 5.6 Hz), 2.40-2.20 (2H, m),
1.30 (3H, t, J ) 7.1 Hz), 1.09 (2H, m), 0.06 (9H, s); 13C NMR
(125 MHz, CDCl3, of the major diastereomer only) δ 169.8, 135.6,
117.2, 74.2, 67.9, 61.9, 52.0, 51.0, 44.9, 30.7, 14.6, 10.3, -1.4;
IR (film) 1738, 1642 cm-1; MS (CI) m/z 364.1612 (364.1614 calcd
for C15H30NO5SSi, MH).
41.0, 36.4, 26.2, 14.1, 10.2, -2.0; IR (film) 1732, 1622, cm-1
.
A solution of this sample of crude 12b, glacial acetic acid (50
mL) and thiosemicarbazide (128 mg, 1.4 mmol) was maintained
at 70 °C for 48 h. After cooling to 23 °C, the reaction mixture
was concentrated and the residue was azeotropically dried with
heptane (2×) to remove residual acetic acid. The residue was
chromatographed (1:19 MeOH-CH2Cl2) to give 187 mg of 27b
(89%) as a colorless amorphous solid: 1H NMR (500 MHz,
CDCl3) δ 8.95 (1H, br s), 5.40 (1H, s), 4.06 (1H, d, J ) 9.5 Hz),
3.92 (1H, dd, J ) 9.7, 6.4 Hz), 3.73 (3H, s), 3.62 (1H, d, J ) 9.7
Hz), 3.09 (2H, m), 2.95 (1H, m), 2.19 (1H, m), 2.07 (1H, m), 2.05
(1H, m), 1.07 (2H, m), 0.04 (9H, s); 13C NMR (125 MHz, CDCl3,)
δ 186.2, 171.8, 169.6, 92.4, 81.5, 63.6, 55.5, 53.3, 49.8, 40.5, 34.1,
31.2, 9.6, -2.0; IR (KBr) 3225, 1766 cm-1; MS (EI) m/z 446.1109
(446.1114 calcd for C16H26N4O5S2Si, M).
Cycloa d d ition of 12a w ith 2,2,2-Tr ich lor oeth yl Ca r ba -
za te To F or m Cycloa d d u ct 26. A solution of 12a (110 mg,
0.28 mmol), 2,2,2-trichloroethyl carbazate (280 mg, 1.3 mmol)
and xylenes (4 mL) was degassed (by gentle nitrogen bubbling
into the solution for 10 min) and heated at reflux for 30 h. After
cooling to 23 °C, the mixture was concentrated and the residue
was chromatographed (2:1 hexanes-EtOAc) to give 140 mg
(86%) of 26 as a colorless oil: 1H NMR (500 MHz, CDCl3, mixture
of rotamers) δ 7.32 (5H, br s), 6.36 (1H, br s), 5.32-5.27 (2H, br
s), 4.75-3.84 (6H, multiplets), 3.77 (3H, br s), 3.48 (1H, br d, J
) 8.5 Hz), 2.88 (1H, br s), 2.31-1.80 (4H, multiplets), 1.25-
1.10 (3H, multiplets); 13C NMR (125 MHz, CDCl3, mixture of
rotamers) δ 172.4, 166.3, 151.0, 136.1, 128.5, 128.3, 128.0, 95.5,
88.1, 75.4, 74.5, 73.2, 71.4, 67.5, 62.6, 53.4, 52.9, 40.9, 34.8, 31.3,
13.7; IR (film) 3352, 1732, 1408 cm-1; HRMS (FAB) 577.0782
(577.0785 calcd for C23H26Cl3N3O8, M).
E t h yl N-[2′-(t r im et h ylsilyl)et h a n esu lfon yl]-4-[(3"-ter t-
bu tyldim eth ylsiloxy)-3"-m eth oxycar bon ylallyl]-4,5-dih ydr o-
1H-p yr r ole-2-ca r boxyla te (11b). Methanesulfonyl chloride
(320 µL, 4.8 mmol) was added to a solution of 9b (580 mg, 1.6
mmol), triethylamine (1.1 mL, 4.8 mmol), DMAP (48 mg, 0.40
mmol) and benzene (45 mL) at 0 °C. The resulting mixture was
allowed to warm to 23 ×a1C over 1 h and then was cooled to 0
°C. Saturated aqueous NaH2PO4 (40 mL), Et2O (60 mL) and
water (20 mL) were added and the resulting mixture was stirred
as it warmed to 23 °C. The organic layer was separated, washed
with saturated aqueous NaH2PO4 (2 × 20 mL), dried (Na2SO4)
and concentrated to yield ∼600 mg of a slightly yellow oil. A
ozone/oxygen gas mixture was bubbled through a solution of this
crude mesylate and CH2Cl2 (10 mL) at -78 °C until a blue color
persisted. The solution was then purged with N2 until the blue
color disappeared. Triphenylphosphine (500 mg, 1.9 mmol) was
added and the resulting solution was allowed to warm to 23 °C.
This solution was concentrated and the residual crude aldehyde
was dried azeotropically with benzene (3 × 25 mL).
Ackn owledgm en t. Support from the National Heart,
Lung, and Blood Institute (HL-25854), NIH NRSA
postdoctoral fellowship support to B.N.R. (CA-73122)
and J .E.T. (GM-16617), F.C.A.R.-Que´bec postdoctoral
fellowship to G.B., and graduate fellowship support to
W.C.T. from the Department of Education and Abbott
Laboratories are gratefully acknowledged. NMR and
mass spectra were determined at UC Irvine using
instruments acquired with the assistance of NSF and
NIH shared instrumentation grants.
A solution of methyl 2-(tert-butyldimethylsiloxy)-2-(dimeth-
ylphosphono)acetate11 (750 mg, 2.4 mmol), LiCl (120 mg, 2.8
mmol), DBU (1.2 mL, 8.0 mmol) and dry MeCN (25 mL) was
prepared and maintained for 1 h at 0 °C.12 A solution of the crude
aldehyde and acetonitrile (9.5 mL) was added and the resulting
solution was maintained at 0 °C for 2 h. Hexanes (25 mL), EtOAc
(25 mL) and saturated aqueous NaH2PO4 (40 mL) were added
and the layers were separated. The organic layer was washed
sequentially with water and brine, dried (Na2SO4), and concen-
trated. The residue was chromatographed (4:1 hexanes-EtOAc)
to yield 389 mg (46%) of 11b, a colorless oil that was a 4.5:1
mixture of E and Z alkene stereoisomers (by NMR analysis):
1H NMR (500 MHz, CDCl3) δ 6.13 (1H, d, J ) 6.1 Hz), 5.42 (1H,
t, J ) 8.1 Hz), 4.24 (2H, dd, J ) 7.2, 7.1 Hz), 4.10 (1H, dd, J )
11.3, 9.2 Hz), 3.75 (3H, s), 3.74 (1H, m), 3.35 (2H, m), 3.09 (1H,
m), 2.61 (2H, m), 1.30 (3H, t, J ) 7.1 Hz), 1.07 (2H, m), 0.94
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization for the preparation of 8c, 11c,
15-20, 27c, 29, and 30; copies of 1H NMR spectra for new
isolated and fully purified compounds: 8bc, 9b, 11bc, 12bc,
15-20, 26, 27bc, 29, and 30. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O026282Y
J . Org. Chem, Vol. 67, No. 22, 2002 7883