Stereoselective total synthesis of natural (+)-streptazolin via a palladium-catalyzed enyne bicyclization approach

Article abstract of DOI:10.1021/ja9529910

The natural Z isomer of (+)-streptazolin (1), isolated from cultures of Streptomyces viridochromogenes, was synthesized in an optically pure form for the first time on the basis of a palladium-catalyzed enyne bicyclization approach in 12 steps and 4.3% ov

Full text of DOI:10.1021/ja9529910

1054
J. Am. Chem. Soc. 1996, 118, 1054-1059
Stereoselective Total Synthesis of Natural (+)-Streptazolin via a
Palladium-Catalyzed Enyne Bicyclization Approach
Hironari Yamada, Sakae Aoyagi, and Chihiro Kibayashi*
Contribution from the School of Pharmacy, Tokyo UniVersity of Pharmacy & Life Science
Horinouchi, Hachioji, Tokyo 192-03, Japan
ReceiVed August 30, 1995X
Abstract: The natural Z isomer of (+)-streptazolin (1), isolated from cultures of Streptomyces Viridochromogenes,
was synthesized in an optically pure form for the first time on the basis of a palladium-catalyzed enyne bicyclization
approach in 12 steps and 4.3% overall yield from (3R,4R)-3,4-bis(benzyloxy)succinimide (5). The requisite enyne
13 for palladium-catalyzed bicyclization was prepared from 5 via N-acyliminium ion cyclization of the acetoxy
lactam 9, partial reduction of 10 with DIBALH-BuLi, and conversion to the dibromo olefin 12. The best result in
the palladium-catalyzed bicyclization was obtained when treated with 30 mol % Pd(OAc)2 and N,N ′-bis(benzylidene)-
ethylenediamine (BBEDA) as the ligand in benzene at reflux, thus affording a 93:7 mixture of the 1,2,4a,7a,6,7-
hexahydro-5H-1-pyrindine (Z)-14 along with its isomerized product (Z)-15 in 84% total yield. The isomerization of
the 1,4-diene in (Z)-14 to the 1,3-diene was achieved by treatment with triiron dodecacarbonyl to generate the stable
tricarbonyl(η4-1,3-diene)iron complex 16, which was then converted to the glycol 17. Treatment of 17 with sodium
methoxide followed by ordinary chromatography on silica gel resulted in isolation of chemically and enantiomerically
pure (+)-streptazolin (1).
Streptazolin (1), isolated from cultures of Streptomyces
both syntheses, the lack of stereoselectivity in the introduction
of the ethylidene side chain by the Wittig reaction of the cyclic
ketone led to streptazolin as a 1:2 mixture of the ethylidene
stereoisomers with its incorrect E isomer predominating. Since
the E/Z 1,3-diene isomers of streptazolin thus formed were found
to be inseparable and to have the tendency to readily polymerize
due to the conjugated diene system, this mixture was, without
isolation, immediately hydrogenated to the stable dihydro or
tetrahydro derivatives for isolation and characterization.8,9
Viridochromogenes (strain Tu¨ 1678)1 for the first time in 1981
and later discovered by a chemical screening of Streptomyces
luteogriseus (strain FH-S 1307)2 or the high-producing strain
Streptomyces sp. (strain FH-S 2184),3 is a unique antibiotic
which possesses the structural feature of an unusual ring system
(hexahydro-1H-1-pyrindine) embodying an internal urethane unit
and an exocyclic ethylidene side chain.4 This antibiotic has
been claimed to be unstable and readily polymerizes during the
isolation and purification although it may be kept for some time
in diluted solutions at low temperatures. For this reason,
structural investigations based on X-ray5 and extensive NMR
analyses were carried out using its crystalline stable derivative
O-acetyldihydrostreptazolin (3) transformed from 1 by catalytic
hydrogenation followed by O-acetylation. To enhance the
stability and solubility, streptazolin (1) and dihydrostreptazolin
(2) have been converted to the glucopyranosides.6 While 1
exhibits limited antimicrobial activities, some Diels-Alder
adducts with naphthoquinones have been reported7 to have
striking bactericidal, fungicidal, protozoacidal, and antitumor
activity as effective as adriamycin on leukemia L1210 cells as
well as improvement of the chemical stability. In view of the
unique structural feature and promising pharmacological activity
profile, this antibiotic has posed an interesting challenge.
Indeed, the pioneering synthetic studies toward 1 have been
published by the two groups of Kozikowski8 and Overman.9 In
We initiated a synthetic program to overcome this problem
in these syntheses associated with preponderant formation of
the undesired (E)-ethylidene isomer of streptazolin under the
Wittig conditions. Preparation of stereodefined exocyclic
alkenes seems an important objective for development,10 since
various types of biologically active natural products containing
an exocyclic alkenyl moiety other than streptazolin are known.
However, the difficulties associated with controlling exocyclic
alkene geometry have been recognized even in a more general
sense. In our own involvement in this area, we have recently
reported11 a solution to this problem through utilizing intramo-
lecular chromium-nickel-mediated cyclization12 in the total
synthesis of the dendrobatid alkaloids allopumiliotoxins.
X Abstract published in AdVance ACS Abstracts, January 15, 1996.
(1) Drautz, H.; Za¨hner, H.; Kupfer, E.; Keller-Schierlein, W. HelV. Chim.
Acta 1981, 64, 1752.
(2) Grabley, S.; Hammann, P.; Kluge, H.; Wink, J.; Kricke, P.; Zeek,
A. J. Antibiot. 1991, 44, 797.
(3) Grabley, S.; Hammann, P.; Thiericke, R.; Wink, J.; Philipps, S.; Zeek,
A. J. Antibiot. 1993, 46, 343.
(4) For a biosynthetic study of streptazolin, see: Mayer, M.; Thiericke,
R. J. Org. Chem. 1993, 58, 3486.
(5) Karrer, A.; Dobler, M. HelV. Chim. Acta 1982, 65, 1432.
(6) Wiesner, M.; Thiem, J. J. Carbohydr. Chem. 1989, 8, 705.
(7) Grabley, S.; Kluge, H.; Hoppe, H.-U. Angew. Chem., Int. Ed. Engl.
1987, 26, 664.
(9) Flann, C. J.; Overman, L. E. J. Am. Chem. Soc. 1987, 109, 6115.
(10) For a review of the effective metal-organic approach to stereose-
lective synthesis of exocyclic alkenes, see: Negishi, E. In AdVances in
Metal-Organic Chemistry; Liebeskind, L. Ed., JAI Press: Greenwich, CT,
1989; Vol. 1, pp 177-207.
(11) (a) Aoyagi, S.; Wang, T.-C.; Kibayashi, C. J. Am. Chem. Soc. 1992,
114, 10653. (b) Aoyagi, S.; Wang, T.-C.; Kibayashi, C. J. Am. Chem. Soc.
1993, 115, 11393. (c) Kibayashi, C. Pure Appl. Chem. 1994, 66, 2079.
(8) Kozikowski, A. P.; Park, P. J. Am. Chem. Soc. 1985, 107, 1763.
Kozikowski, A. P.; Park, P. J. Org. Chem. 1990, 55, 4668.
0002-7863/96/1518-1054$12.00/0 © 1996 American Chemical Society

Total Synthesis of Natural (+)-Streptazolin
J. Am. Chem. Soc., Vol. 118, No. 5, 1996 1055
Scheme 1
the method of Kakisawa.16 Mitsunobu coupling of 5 with (Z)-
4-(trimethylsilyl)-3-butenol (6)17 provided the N-butenylimide
7 (77% yield), which was converted to the acetoxy lactam 9
via reduction of the one of the carbonyl groups with NaBH4
followed by O-acetylation (Ac2O, DMAP) of 8 (obtained as an
essentially single diastereomer) in 93% overall yield. Treatment
of 9 with BF3‚Et2O at room temperature induced N-acyliminium
ion cyclization to produce the indolizidinone 10 as a single
diastereomer in 99% yield. The partial reduction of the tertiary
amide moiety in 11 was cleanly attained by using the aluminum
ate complex from DIBALH and butyllithium.18 The amino
aldehyde thus obtained via hemiaminal ring opening was
protected at nitrogen in situ with the ethoxycarbonyl group to
give the tetrahydropyridine 11 in 86% overall yield. Treatment
of 11 with carbon tetrabromide and triphenylphosphine afforded
the dibromo olefin 12 (88%), which was then transformed into
the requisite enyne 13 (80%) by treatment with 2 equiv of BuLi
and then iodomethane in the presence of HMPA.
Palladium-catalyzed bicyclization of 13 was carried out at a
0.02 M substrate concentration at reflux. Although with 5-10
mol % Pd(OAc)2 (in benzene) the reaction was slow, increasing
the quantity of the catalyst to 30 mol % allowed the reaction
rate to be enhanced and resulted in the bicyclic products in 85%
total yield as a mixture of the (Z)-ethylidene isomers ((Z)-14
and its isomerized product (Z)-15) and the (E)-ethylidene
isomers ((E)-14 and its isomerized product (E)-15) in a Z/E ratio
of 70:30 (Table 1, entry 1). In this case, the actual yield for
the required ene adduct (Z)-14 was very poor (38%), and more
seriously, the Z and E isomers were inseparable by ordinary
chromatography. The same reaction using Pd(OAc)2(PPh3)2 was
very sluggish; heating for 24 h resulted in no reaction, but
addition of AcOH (2 equiv) brought the reaction to completion
in 4 h (Table 1, entry 2). In the latter case, however, the product
was again a mixture of (Z)-14, (Z)-15, (E)-14, and (E)-15 in
88% total yield. Although the Z/E product ratio was slightly
improved to 78:22 by this process, these reaction conditions
greatly produced isomerization to the (Z)-enamide (Z)-15. The
actual yield for the desired (Z)-14 was thus only 8%.
Use of N,N ′-bis(benzylidene)ethylenediamine (BBEDA) as
the ligand dramatically improved the selectivity, leading to
formation of a 93:7 mixture of (Z)-14 and (Z)-15 in 84% yield
with no detection of the E isomers (Table 1, entry 4). These
isomers that were produced were easily separable by column
chromatography, and that both compounds (Z)-14 and (Z)-15
individually obtained indeed possess the Z geometry as well as
the cis ring junction was evidenced by NOESY (Figure 1). We
thus could obtain pure (Z)-14 in 73% yield from 13. When the
same reaction using Pd(OAc)2-BBEDA was performed in the
presence of a proton source such as acetic acid or water, the
reaction was completed in a shorter time compared with the
reaction without these proton sources (Table 1, entries 5 and
6). In each case, none of the E isomers was detected in the
product, but a somewhat lower selectivity for (Z)-14 due to its
isomerization to (Z)-15 was observed.
With these issues in mind, we envisioned that this problem
might be resolved by using the strategy based on the carbo-
cyclization by palladium-catalyzed ene type reaction of enyne
compounds via palladacycles (eq 1) broadly developed by
Trost.13 This approach would allow a direct, highly stereo-
selective incorporation of the E configuration (corresponds to
the Z configuration in 1) at the exocyclic alkylidene group. We
herein present our highly stereoselective total synthesis of the
natural Z isomer of (+)-streptazolin (1) in a chemically and
enantiomerically pure form for the first time based on a
palladium-catalyzed enyne bicyclization approach.
The synthesis began by preparation of an enyne compound
adequate for palladium-catalyzed bicyclization as outlined in
Scheme 1. Our initial plan for this centered on the construction
of an optically active indolizidinone (i.e., 10) based on the
N-acyliminium ion-vinylsilane cyclization protocol previously
developed by Overman's group.9,14 The dibenzyl ether 4,
prepared from diethyl L-tartrate by a modified Yamamoto
procedure15 (BnBr, NaH, Bu4NI, DMF, room temperature) in
92% yield, was converted to the cyclic imide 5 according to
(12) (a) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H.
Tetrahedron Lett. 1983, 24, 5281. (b) Takai, K.; Tagashira, M.; Kuroda,
T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108,
6048. (c) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc.
1986, 108, 5644.
(13) For a review of palladium-catalyzed cycloisomerization of enynes
and related recent papers, see: (a) Trost, B. M. Acc. Chem. Res. 1990, 23,
34. (b) Trost, B. M.; Pedregal, C. J. Am. Chem. Soc. 1992, 114, 7292. (c)
Trost, B. M.; Tanoury, G. J.; Lautens, M.; Chan, C.; MacPherson, D. T. J.
Am. Chem. Soc. 1994, 116, 4255. (d) Trost, B. M.; Romero, D. L.; Rise, F.
J. Am. Chem. Soc. 1994, 116, 4268.
With correct (Z)-ethylidene stereochemistry and the config-
uration at all stereocenters in hand, the only remaining problem
was the isomerization of the 1,4-diene in (Z)-14 to the 1,3-diene.
Thus, (Z)-14 was treated with 2 equiv of triiron dodecacarbonyl,
freshly prepared from iron pentacarbonyl by treatment with Et3N
and then HCl,19 in 1,2-dichloroethane (reflux, 5 h) (Scheme 2).
(16) Ohwada, J.; Inouye, Y.; Kimura, M.; Kakisawa, H. Bull. Chem.
Soc. Jpn. 1990, 63, 287.
(17) Flann, C. J.; Malone, T. C.; Overman, L. E. Org. Synth. 1990, 68,
182.
(14) (a) Overman, L. E.; Malone, T. C.; Meier, G. P. J. Am. Chem. Soc.
1983, 105, 6993. (b) Flann, C.; Malone, T. C.; Overman, L. E. J. Am. Chem.
Soc. 1987, 109, 6097.
(15) Nemoto, H.; Takamatsu, S.; Yamamoto, Y. J. Org. Chem. 1991,
56, 1321.
(18) Kim, S.; Ahn, K. H. J. Org. Chem. 1984, 49, 1717.
(19) McFarlane, W.; Wilkinson, G. Inorg. Synth. 1966, 8, 181.

1056 J. Am. Chem. Soc., Vol. 118, No. 5, 1996
Table 1. Palladium-Catalyzed Bicyclization of Enyne 13
Yamada et al.
product ratiob
(Z)-14:(Z)-15:(E)-14:(E)-15
entrya
catalyst (mol %)
Pd(OAc)2 (30)
solvent
time (h)
yield (%)c
1
2
3
4
5
6
benzene
10
4
26
7
3
1.5
45:25:27:3
9:69:6:16
92:8:0:0
93:7:0:0
81:19:0:0
85:15:0:0
85
88
80
84
93
85
Pd(OAc)2(PPh3)2 (30)
benzene containing AcOH (2 equiv)
benzene
Pd(OAc)2-BBEDAd (10)
Pd(OAc)2-BBEDA (30)
Pd(OAc)2-BBEDA (30)
Pd(OAc)2-BBEDA (30)
benzene
benzene containing AcOH (2 equiv)
benzene saturated with water
a All reactions were run at a substrate concentration of 0.02 M at reflux. b HPLC determination. c HPLC determination using 2-naphthol as an
internal standard. d BBEDA ) N,N ′-bis(benzylidene)ethylenediamine.
Figure 1. Some selected NOEs for (Z)-ethylidene isomers (Z)-14 and
(Z)-15.
Scheme 2
Figure 2. ORTEP drawing of the X-ray crystal structure of the complex
16 (C30H31NO7Fe). Selected bond lengths (Å) and angles (deg): Fe-
C4 ) 2.076(6), Fe-C10 ) 2.209(6), Fe-C11 ) 2.067(5), Fe-C12 )
2.143(6), N-C7 ) 1.479(9), N-C8 ) 1.45(1), C4-C5 ) 1.512(9),
C4-C11 ) 1.404(8), C4-C12 ) 1.421(8), C5-C6 ) 1.562(9), C6-
C7 ) 1.516(9), C7-C11 ) 1.525(9), C8-C9 ) 1.54(1), C9-C10 )
1.506(9), C10-C11 ) 1.401(10), C12-C13 ) 1.504(9); C5-C4-
C11 ) 108.6(6), C5-C4-C12 ) 132.9(6), C11-C4-C12 ) 118.4(6),
Fe-C10-C9 ) 129.1(5), Fe-C10-C11 ) 65.5(3), C9-C10-C11 )
113.5(5), C4-C11-C7 ) 108.9(6), C4-C11-C10 ) 124.9(6), C7-
C11-C10 ) 126.0(5), Fe-C12-C4 ) 67.8(3), Fe-C12-C13 )
125.1(5), C4-C12-C13 ) 120.4(6).
After workup, chromatography and recrystallization from hexane
provided the stable tricarbonyl(η4-1,3-diene)iron complex 16
as a yellow crystalline compound having mp 68 °C in 41% yield.
This complexation is very advantageous not only because of
the stabilization of the conjugated diene system but also because
of the greater ease of structural identification by X-ray crystal-
lography (Figure 2).20 This served primarily to confirm the
absolute and relative stereochemistry of 16 but also to un-
ambiguously established the Z geometry of the exocyclic
ethylidene.
Exposure of 16 to BBr3 in CH2Cl2 at -90 °C led to removal
of the Fe(CO)3 fragment and the benzyl protecting groups,
affording the glycol 17 in 51% yield. On treatment with sodium
methoxide in methanol at reflux, 17 underwent oxazolidinone
formation. After usual workup, purification and isolation were
performed by conventional chromatographic techniques to
provide (+)-streptazolin (1) as a colorless clean oil in 65% yield.
The synthetic sample of (+)-streptazolin had spectroscopic data
(1H NMR, IR) identical to those reported1 for natural product.
The specific rotation, [R]27D +21.5° (c 0.65, CHCl3), was also
(20) Crystal data for 16: monoclinic space group P21, Z ) 2, a )
in agreement with the literature data1 ([R]25 +22° (c 2.8,
CHCl3)).
In summary, the highly stereoselective total synthesis of
chemically and enantiomerically pure (+)-streptazolin (1) was
8.255(4) Å, b ) 14.015(4) Å, c ) 12.230(4) Å, â ) 92.94(3)°, dcalcd
)
D
1.348 g cm-3, λ ) 1.541 78 Å. Of the 2324 reflections measured at 2θmax
) 120.2°, 2212 unique reflections were used in the structure solution by
direct methods. Refinement on F2 converged at R ) 3.8%, wRF ) 5.1%,
2
with GOF ) 1.19.

Total Synthesis of Natural (+)-Streptazolin
J. Am. Chem. Soc., Vol. 118, No. 5, 1996 1057
layer was extracted with CH2Cl2 (3 × 70 mL). The combined organic
phases were washed with saturated aqueous NH4Cl (100 mL) and then
brine (100 mL) and dried (MgSO4). Removal of the solvent in vacuo
followed by chromatography on silica gel (hexane-EtOAc, 8:1)
accomplished in an overall yield of 4.3% by a 12-step sequence
from (3R,4R)-3,4-bis(benzyloxy)succinimide (5). This synthesis
representing a new and efficient approach to the natural isomer
of streptazolin was devised in the stereoselective construction
of the (Z)-ethylidene group by utilizing a palladium-catalyzed
enyne cyclization as the key step.
afforded 9 (3.79 g, 95%) as a colorless oil: [R]26 +31.6° (c 1.0,
D
CHCl3); IR (neat) 2953, 2897, 1718, 1608, 1455, 1427, 1364, 1218,
1
1162, 1104, 1019, 839 cm-1; H NMR (400 MHz, CDCl3) δ 0.12 (9
H, s), 2.10 (3 H, s), 2.30-2.51 (2 H, m), 3.06 (1 H, ddd, J ) 14.0, 8.4,
5.9 Hz), 3.60 (1 H, ddd, J ) 14.2, 8.4, 7.0 Hz), 3.93 (1 H, dd, J ) 2.8,
1.4 Hz), 4.04 (1 H, d, J ) 2.8 Hz), 4.56 (1 H, 1/2 AB q, J ) 11.9 Hz),
4.62 (1 H, 1/2 AB q, J ) 11.9 Hz), 4.76 (1 H, 1/2 AB q, J ) 11.9 Hz),
4.96 (1 H, 1/2 AB q, J ) 11.9 Hz), 5.63 (1 H, d, J ) 14.1 Hz), 6.11 (1
H, d, J ) 1.4 Hz), 6.22 (1 H, dt, J ) 7.3, 14.1 Hz), 7.22-7.43 (10 H,
m); 13C NMR (100.6 MHz, CDCl3) δ 0.1 (3 carbons), 21.0, 31.5, 40.4,
72.0, 72.7, 79.3, 81.9, 85.4, 127.8 (2 carbons), 128.0, 128.1, 128.2 (2
carbons), 128.4 (2 carbons), 128.5 (2 carbons), 132.5, 137.0, 137.3,
143.7, 170.2, 171.3; EIMS m/z (relative intensity) 481 (M+, 1), 466
(2), 423 (1.4), 390 (0.3), 366 (0.4), 330 (2.3), 286 (0.9), 210 (100),
181 (0.7), 155 (0.5), 111 (0.9). Anal. Calcd for C27H35NO5Si: C,
67.33; H, 7.32; N, 2.91. Found: C, 67.29; H, 7.39; N, 2.96.
Experimental Section
General Procedures. All melting points were measured on Yanaco
MP-5000 micro melting point apparatus and are uncorrected. Optical
rotation were recorded on a JEOL DIP-4 instrument. IR spectra were
performed with a Perkin-Elmer FTIR spectrometer. Nuclear magnetic
resonance (1H and 13C NMR) spectra were taken with a Varian Gemini-
300, a Bruker AM-400, or a AM-500 spectrometer. Residual chloro-
form (7.26 ppm) was used as the internal reference for 1H NMR spectra
measured in CDCl3. 13C chemical shifts were reported on the δ scale
relative to CDCl3 as an internal reference (77.1 ppm), and the degree
of substitution of each carbon atom was determined by DEPT composed
90° and 135° pulsed sequence experiments. Mass spectra were
measured on a Hitachi M-80 or a VG Auto Spec spectrometer at 70
eV. Thin-layer chromatography (TLC) was performed on Merck silica
gel 60 F254 TLC plates, and Merck silica gel 60 (230-400 mesh) was
used for column chromatography. HPLC analysis was performed on
a 6.0 × 150 mm 5 µm Shim-pack CLC-SIL column with hexane-
EtOAc (7:1) as eluent at a flow rate of 1 mL/min and 254 nm detection
using a JASCO PU-980 pump equipped with a JASCO UV-970
detector.
(1S,2R,8aS)-1,2-Bis(benzyloxy)-1,2,3,5,6,8a-hexahydroindolidin-
3-one (10). To a stirred solution of 9 (3.79 g, 7.87 mmol) in CH2Cl2
(160 mL) was added dropwise BF3‚Et2O (2.23 g, 15.7 mmol), and the
mixture was stirred at room temperature for 2 h. After addition of
saturated aqueous NaHCO3 (80 mL), the mixture was stirred for 30
min, and the layers were separated. The aqueous layer was extracted
with CH2Cl2 (3 × 100 mL), and the combined organic layers were
washed with saturated aqueous NH4Cl (100 mL) and then brine (100
mL), dried (MgSO4), and concentrated in vacuo. The residue was
purified by chromatography on silica gel (hexane-EtOAc, 4:1) to give
10 (2.72 g, 99%) as a colorless oil: [R]26D +63.2° (c 1.15, CHCl3); IR
(3R,4R)-1-[(Z)-4-(Trimethylsilyl)-3-butenyl]-3,4-bis(benzyloxy)-
pyrrolidine-2,5-dione (7). To a stirred, cooled (0 °C) mixture of 5
(4.70 g, 15.1 mmol), (Z)-4-(trimethylsilyl)-3-butenol (6) (2.40 g, 16.6
mmol), PPh3 (5.15 g, 19.6 mmol), and THF (150 mL) was added DEAD
(3.68 g, 21.1 mmol), and the mixture was stirred under Ar at room
temperature for 30 min. Condensation in vacuo followed by chroma-
tography on silica gel (hexane-EtOAc, 15:1) gave 7 (5.10 g, 77%) as
1
(neat) 2871, 1708, 1455, 1437, 1358, 1302, 1110, 736, 698 cm-1; H
NMR (400 MHz, CDCl3) δ 2.01-2.10 (1 H, m), 2.17-2.30 (1 H, m),
2.80 (1 H, dt, J ) 4.9, 11.8 Hz), 3.83 (1 H, t, J ) 7.3 Hz), 3.88-3.96
(1 H, m), 4.25 (1 H, dd, J ) 13.1, 6.7 Hz), 4.35 (1H, dd, J ) 7.2, 1.4
Hz), 4.61 (1 H, 1/2 AB q, J ) 11.7 Hz), 4.71 (1 H, 1/2 AB q, J ) 11.7
Hz), 4.84 (1 H, 1/2 AB q, J ) 11.5 Hz), 5.18 (1 H, 1/2 AB q, J ) 11.5
Hz), 5.72-5.87 (2 H, m), 7.21-7.47 (10 H, m); 13C NMR (100.6 MHz,
CDCl3) δ 23.9, 35.3, 56.1, 72.6 (2 carbons), 82.1, 84.3, 125.2, 126.1,
127.8 (4 carbons), 127.8, 127.9, 128.4 (4 carbons), 137.6, 137.7, 168.9;
EIMS m/z (relative intensity) 351 (M+ + 2, 0.5), 243 (3.1), 172 (0.3),
153 (1.4), 137 (4.7). Anal. Calcd for C22H23NO3: C, 75.62; H, 6.63;
N, 4.01. Found: C, 75.51; H, 6.79; N, 3.90.
(2S)-1-Carbethoxy-2-[(1S,2S)-1,2-bis(benzyloxy)-4,4-dibromo-3-
butenyl]-1,2,5,6-tetrahydropyridine (12). DIBALH (0.9 M) in hexane
(4.2 mL, 3.78 mmol) was diluted with THF (10 mL), and to this solution
was added 1.6 M BuLi in hexane (2.4 mL, 3.78 mmol) at 0 °C. The
mixture was stirred under Ar at 0 °C for 30 min. The newly created
solution of LiAlHBu(i-Bu)2 reagent in hexane-THF (3.78 mmol) was
added dropwise to a solution of 10 (1.10 g, 3.15 mmol) in THF (30
mL), and the mixture was stirred under Ar at room temperature. After
5 min, 1 N NaOH (20 mL) and CH2Cl2 (50 mL) were added under
cooling, and the mixture was stirred for 5 min. A solution of ethyl
chloroformate (684 mg, 6.30 mmol) in CH2Cl2 (2 mL) was added, and
stirring was continued under Ar at room temperature. After 1 h, the
layers were separated, and the aqueous layer was extracted with CH2Cl2
(3 × 50 mL). The combined layers were washed with brine, dried
(MgSO4), concentrated, and passed through a short column of silica
gel (hexane-EtOAc, 8:1) to give (2S)-1-carbethoxy-2-[(1S,2R)-1,2-
bis(benzyloxy)-2-formylethyl]-1,2,5,6-tetrahydropyridine (11) (1.15 g,
86%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.14-1.34 (3
H, m), 1.92-2.34 (2 H, m), 2.95-3.08 (1 H, m), 3.83-3.97 (2 H, m),
3.98-4.27 (3 H, m), 4.45-4.93 (5 H, m), 5.80-6.03 (2 H, m), 7.20-
7.43 (10 H, m), 9.69 (1 H, br s).
a colorless oil: [R]27 +108.8° (c 1.0, CHCl3); IR (neat) 2953, 1718,
D
1398, 1348, 1249, 1118, 1070, 839 cm-1; 1H NMR (400 MHz, CDCl3)
δ 2.35-2.51 (2 H, m), 3.47-3.65 (2 H, m), 4.37 (2 H, s), 4.76 (2 H,
1/2 AB q, J ) 11.6 Hz), 5.00 (2 H, 1/2 AB q, J ) 11.6 Hz), 5.64 (1 H,
d, J ) 14.0 Hz), 6.19 (1 H, td, J ) 14.0, 7.3 Hz), 7.23-7.45 (10 H,
m); 13C NMR (100.6 MHz, CDCl3) δ 0.1 (3 carbons), 31.5, 38.1, 73.5
(2 carbons), 78.5 (2 carbons), 128.3 (6 carbons), 128.6 (4 carbons),
133.2, 136.6 (2 carbons), 143.0, 172.6 (2 carbons); EIMS m/z (relative
intensity) 438 (M+ + 1, 1), 421 (8), 346 (3.2), 318 (1), 294 (3), 250
(2), 225 (100), 182 (10.2), 157 (5.4), 134 (1.6), 111 (2.4). Anal. Calcd
for C25H31NO4Si: C, 68.62; H, 7.14; N, 3.20. Found: C, 68.70; H,
7.20; N, 3.35.
(3R,4R)-1-[(Z)-4-(Trimethylsilyl)-3-butenyl]-3,4-bis(benzyloxy)-
5-hydroxypyrrolidin-2-one (8). To a stirred, cooled (0 °C) solution
of 7 (3.70 g, 8.45 mmol) in MeOH (80 mL) was added NaBH4 (640
mg, 16.9 mmol) in small portions, and the mixture was stirred at 0 °C
for 30 min. After addition of H2O (20 mL), the mixture was
concentrated in vacuo to ca. one-third volume and extracted with CH2Cl2
(3 × 50 mL). The combined extracts were washed with brine (80 mL),
dried (MgSO4), and concentrated to dryness. The residue was purified
by chromatography on silica gel (hexane-EtOAc, 4:1) to give 8 (3.64
g, 98%) as a colorless oil: IR (neat) 3346, 2953, 1685, 1455, 1358,
1249, 1114, 1064, 839, 764, 737, 698 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 0.12 (9 H, s), 2.33-2.51 (2 H, m), 2.63 (1 H, dd, J ) 10.4,
1.6 Hz), 3.24-3.32 (1 H, m), 3.49-3.57 (1 H, m), 3.84 (1 H, dd, J )
1
4.0, 2.4 Hz), 4.03 (1 H, d, J ) 4.0 Hz), 4.60 (2 H, m), 4.76 (1 H, /2
AB q, J ) 11.7 Hz), 4.94 (1 H, dd, J ) 8.0, 2.4 Hz), 4.98 (1 H, 1/2 AB
q, J ) 11.7 Hz), 5.63 (1 H, d, J ) 14.3 Hz), 6.25 (1 H, td, J ) 14.3,
7.3 Hz), 7.26-7.40 (10 H, m).
The above material 11 is immediately used for the following reaction.
Thus, a solution of 11 (1.15 g, 2.72 mmol), CBr4 (1.80 g, 5.44 mmol),
and triphenylphosphine (2.89 g, 10.9 mmol) in CH2Cl2 (60 mL) was
stirred at room temperature. After 15 min, the mixture was concentrated
in vacuo and subjected to chromatography on silica gel (hexane-
EtOAc, 10:1) to afford 12 (1.38 g, 88%) as a yellow oil: [R]24D -116.4°
(c 1.3, CHCl3); IR (neat) 2929, 1696, 1455, 1429, 1337, 1257, 1119,
(3R,4R)-1-[(Z)-4-(Trimethylsilyl)-3-butenyl]-5-acetoxy-3,4-bis-
(benzyloxy)pyrrolidin-2-one (9). To a stirred solution of 8 (3.64 g,
8.24 mmol) in CH2Cl2 (80 mL) were sequentially added acetic
anhydride (1.10 g, 10.8 mmol), triethylamine (1.10 g, 10.9 mmol), and
4-(dimethylamino)pyridine (800 mg, 6.55 mmol), and the mixture was
stirred at room temperature for 30 min. After addition of saturated
aqueous NaHCO3 (50 mL), the layers were separated and the aqueous
1
1110, 1072, 1029, 698 cm-1; H NMR (400 MHz, CDCl3) δ 1.21-

1058 J. Am. Chem. Soc., Vol. 118, No. 5, 1996
Yamada et al.
1.30 (3 H, m), 1.92-2.28 (2 H, m), 3.01-3.18 (1 H, m), 3.71-4.24 (4
H, m), 4.32 (1 H, dd, J ) 9.1, 6.7 Hz), 4.42-4.57 (2 H, m), 4.60-
4.66 (2 H, m), 4.79 (1 H, 1/2 AB q, J ) 11.3 Hz), 5.75-5.82 (1 H, m),
5.95-6.05 (1 H, m), 6.05-6.15 (1 H, m), 7.23-7.41 (10 H, m); 13C
NMR (100.6 MHz, CDCl3) δ 14.7, 24.5 (24.8), 38.4 (38.9), 53.1, 61.5,
71.6, 75.4, 81.3, 82.3 (83.4), 93.2, 124.2, 124.6, 127.7 (4 carbons),
127.9 (2 carbons), 128.3 (4 carbons), 136.6, 138.0 (2 carbons), 155.3;
EIMS m/z (relative intensity) 581 (M+ + 4, 21), 579 (M+ + 2, 31),
577 (M+, 21), 536 (13), 534 (17), 532 (13), 500 (24), 498 (24), 490
(55), 488 (100), 486 (55), 473 (27), 471 (28), 427 (20), 425 (29), 423
(200). Anal. Calcd for C22H23NO3: C, 53.90; H, 5.04; N, 2.42.
Found: C, 53.85; H, 5.00; N, 2.44.
ca 1:1 due to the carbamate rotamers), 5.80 (1 H, br qd, J ) 7.0, 2.1
Hz), 6.91 and 7.01 (total 1 H, br d, J ) 9.0 Hz, and br d, J ) 8.7 Hz,
respectively, in ca. 1:1 due to the carbamate rotamers), 7.20-7.39 (10
1
H, m); H NMR (400 MHz, pyridine-d5, 60 °C) δ 1.23 (3 H, br s),
1.81 (3 H, d, J ) 6.8 Hz), 2.29 (1 H, td, J ) 16.4, 6.8 Hz), 2.35-2.43
(1 H, m), 2.81 (1 H, td, J ) 9.1, 8.5 Hz), 4.27 (2 H, br s), 4.39 (2 H,
br s), 4.46-4.88 (5 H, m), 5.06 (1 H, br s), 5.88 (1 H, q, J ) 6.9 Hz),
7.10-7.45 (11 H, m); 13C NMR (100.6 MHz, CDCl3), a 1:1 mixture
of the carbamate rotamers, δ 14.4, 14.6, 14.8 (overlapping signals for
the rotamers), 28.2, 28.3, 36.9 (overlapping signals for the rotamers),
55.8, 56.0, 61.7, 61.8, 71.5, 71.8, 71.9, 72.3, 79.4, 79.5, 81.3
(overlapping signals for the rotamers), 82.1, 82.3, 104.3, 104.7, 124.5,
124.7, 125.3, 125.6, 127.2, 127.5 (2 carbons), 127.6, 127.8, 127.9, 128.2,
128.3, 128.4 (2 carbons), 137.9 (signals at δ 127.2 to 137.9 are all
overlapping due to the rotamers), 138.4, 138.7, 143.8, 144.1, 153.3,
153.8; EIMS m/z (relative intensity) 434 (M+ + 1, 89), 326 (28), 236
(28), 107 (100).
Data for (1S,6S,8S,9S)-8,9-bis(benzyloxy)-2-carbethoxy-7(E)-eth-
ylidene-2-azabicyclo[4.3.0]non-4-ene ((E)-14): 1H NMR (300 MHz,
CDCl3) δ 1.16-1.33 (3 H, m), 2.01 (3 H, d, J ) 9.5 Hz), 3.62-4.27
(6 H, m), 4.35-4.63 (5 H, m), 4.77-4.83 (1 H, m), 4.93-5.01 (1 H,
m), 5.18 (1 H, dd, J ) 10.2, 2.2 Hz), 5.38-5.31 (1 H, m), 7.28-7.41
(1 H, m).
Preparation of (Z)-14. Method A. A benzene (92.5 mL) solution
containing 13 (800 mg, 1.85 mmol), AcOH (222 mg, 3.70 mmol), and
the Pd(OAc)2-BBEDA complex (256 mg, 0.556 mmol) were treated
as described above for 3 h. After being passed through a short column
and concentrated as described above, the reaction product was subjected
to column chromatography on silica gel (hexane-EtOAc, 10:1). The
first fractions contained (Z)-15 (128 mg, 16%), and the second fractions
provided desired (Z)-14 (584 mg, 73%).
Method B. A solution of 13 (1.18 g, 2.72 mmol) in benzene (136
mL) saturated with water and the Pd(OAc)2-BBEDA complex (376
mg, 0.816 mmol) was treated for 1.5 h and worked up as described
above in method A to afford (Z)-15 (142 mg, 12%) and (Z)-14 (814
mg, 69%).
(2S)-1-Carbethoxy-2-[(1S,2S)-1,2-bis(benzyloxy)-3-pentynyl]-1,2,5,6-
tetrahydropyridine (13). To a stirred, cooled (-78 °C) solution of
12 (1.13 g, 1.95 mmol) in THF (20 mL) was added 1.66 M BuLi in
hexane (0.235 mL, 3.90 mmol) via syringe, and the mixture was stirred
at the same temperature. After 1 h, HMPA (700 mg, 3.91 mmol) and
iodomethane (1.38 g, 9.72 mmol) were added, and the mixture was
stirred at -78 °C for 2 h and allowed to cool to room temperature.
After stirring was further continued at room temperature for 24 h, the
mixture was diluted with Et2O (40 mL) and aqueous saturated NH4Cl
(5 mL) was added. The mixture was stirred for 30 min and the layers
were separated. The aqueous layer was extracted with Et2O (3 × 50
mL), and combined organic layers were washed with brine, dried
(MgSO4), and concentrated. The residue was purified by chromatog-
raphy on silica gel (hexane-EtOAc, 10:1) to give 13 (675 mg, 80%)
as a colorless oil: [R]23D -94.9° (c 0.7, CHCl3); IR (neat) 2920, 1696,
1
1455, 1429, 1280, 1246, 1200, 1110, 739, 699 cm-1; H NMR (400
MHz, CDCl3) δ 1.17-1.31 (3 H, m), 1.91 (3 H, br s), 1.92-2.24 (2 H,
m), 3.10-3.27 (1 H, m), 3.85-4.30 (5 H, m), 4.51-4.90 (5 H, m),
5.70-6.03 (2 H, m), 7.23-7.41 (10 H, m); 13C NMR (100.6 MHz,
CDCl3) δ 3.7, 14.6, 24.7, 38.4 (39.1), 53.1 (53.3), 61.2, 71.1, 71.2,
72.0, 75.2, 83.1 (83.9), 84.5, 123.6, 124.1, 127.6 (2 carbons), 127.7 (2
carbons), 128.0 (2 carbons), 128.3 (4 carbons), 138.2 (2 carbons), 155.4;
EIMS m/z (relative intensity) 433 (M+, 0.1), 403 (0.1), 373 (0.1), 342
(1.1), 312 (0.3), 274 (100), 252 (0.2), 234 (1.1), 206 (0.5), 181 (0.1),
155 (100), 126 (0.2); HRMS calcd for C27H31NO4 (M+) 433.2253, found
433.2251.
General Procedure for Palladium-Catalyzed Bicyclization of
Enyne 13. To a 0.02 M solution of 13 in benzene, benzene containing
AcOH, or benzene saturated with water was added the catalyst (30
mol % or 10 mol %) as shown in Table 1, and the mixture was stirred
at reflux. After the amount of time indicated in Table 1, the mixture
was passed through a short column of silica gel and eluted with EtOAc.
The combined solutions were concentrated in vacuo, and a solution of
â-naphthol (1.00 mg) in hexane-EtOAc (7:1) was added to the residue.
The resulting solution was used for determinations of the product ratio
and the yield by HPLC analysis. The results are summarized in Table
1.
(1S,8S,9S)-Tricarbonyl[(η4-5,6,7,1′)-8,9-bis(benzyloxy)-2-carb-
ethoxy-7(Z)-ethylidene-2-azabicyclo[4.3.0]non-5-ene]iron (16). To
a solution of Fe3(CO)12 (1.78 g, 3.54 mmol) in 1,2-dichloroethane (5
mL) was added a solution of (Z)-14 (767 mg, 1.77 mmol), and the
mixture was stirred at reflux under Ar. During this reaction the initial
dark green color changed to dark brown. After 5 h, the mixture was
filtered through Celite with EtOAc (90 mL), and the filtrate was
concentrated in vacuo, dried (MgSO4), and purified by chromatography
on silica gel (hexane-EtOAc, 15:1) to provide 16 (417 mg, 41%) as
yellow crystals which were recrystallized from hexane to yield yellow
plates: mp 68 °C; [R]30D -28.3° (c 1.05, CHCl3); IR (KBr) 2923, 2871,
2035, 1981, 1953, 1687, 1456, 1420, 1385, 1349, 1246, 1212, 1123,
1
1089, 1073, 1036, 1016 cm-1; H NMR (400 MHz, CDCl3) δ 0.80-
Data for (1S,6S,8S,9S)-8,9-bis(benzyloxy)-2-carbethoxy-7(Z)-eth-
ylidene-2-azabicyclo[4.3.0]non-4-ene ((Z)-14): [R]26D -163.2° (c 0.75,
CHCl3); IR (neat) 2927, 2862, 1695, 1455, 1417, 1374, 1328, 1093,
1028, 698 cm-1; 1H NMR (400 MHz, pyridine-d5, 60 °C) δ 1.22 (3 H,
t, J ) 7.0 Hz), 1.74 (3 H, dd, J ) 6.9, 1.6 Hz), 3.43 (1 H, br d, J )
8.9 Hz), 4.05 (1 H, dd, J ) 17.8, 2.4 Hz), 4.25 (2 H, q, J ) 7.0 Hz),
4.12-4.72 (7 H, m), 5.25 (1 H, br s), 5.68 (1 H, dd, J ) 10.2, 3.2 Hz),
5.80-5.88 (2 H, m), 7.24-7.49 (10 H, m); 13C NMR (100.6 MHz,
CDCl3) δ 14.7, 14.8, 38.5, 42.5, 53.9, 61.3, 71.0, 72.2, 79.0, 82.1, 121.2
and 121.6 (due to the carbamate rotamers), 125.9, 127.0, 127.5 (2
carbons), 127.6 (2 carbons), 127.7, 127.9, 128.4 (4 carbons), 138.2,
138.4, 141.8, 156.0; EIMS m/z (relative intensity) 433 (M+, 0.1), 403
(0.1), 373 (0.1), 342 (1.1), 312 (0.3), 274 (100), 252 (0.2), 234 (1.1),
206 (0.5), 181 (0.1), 155 (100), 126 (0.2); HRMS calcd for C27H31-
NO4 (M+) 433.2253, found 43.2264.
0.87 (1 H, m), 1.13-1.38 (5 H, m), 1.46-1.70 (2 H, m), 2.19-2.28 (1
H, m), 3.95-4.30 (3 H, m), 4.46-4.73 (5 H, m), 4.99 (1 H, br s),
7.21-7.48 (10 H, m); 13C NMR (100.6 MHz, CDCl3) δ 14.7, 15.7,
27.0, 44.9, 47.6, 51.1, 52.0, 59.3, 61.4, 72.5, 73.4, 81.4,, 86.6, 106.6,
107.0, 127.9, 128.0, 128.4, 128.5, 137.5, 138.2, 155.8, 211.4; EIMS
m/z (relative intensity) 489 (M+ - (CO)3, 39), 433 (2), 398 (14), 342
(5), 307 (5), 278 (7), 221 (7), 118 (30), 83 (100), 70 (6). Anal. Calcd
for C30H31NO7Fe: C, 62.84; H, 5.45; N, 2.44. Found: C, 62.88; H,
5.06; N, 2.40.
(1S,8S,9S)-2-Carbethoxy-7(Z)-ethylidene-8,9-dihydroxy-2-
azabicyclo[4.3.0]non-5-ene (17). To a stirred, cooled (-90 °C)
solution of 16 (130 mg, 0.226 mmol) in CH2Cl2 (6 mL) was added a
solution of BBr3 (283 mg, 1.13 mmol) in CH2Cl2 (2 mL), and the
mixture was stirred at -90 °C. After 30 min, the mixture was diluted
with CHCl3 (5 mL), the reaction was quenched by addition of a solution
of 29% aqueous ammonia (2 mL) in MeOH (6 mL), and the mixture
was stirred at -90 °C for 1 h and then at room temperature for 1 h.
The mixture was concentrated in vacuo, diluted with EtOAc (10 mL),
washed with brine (2 mL), and dried (MgSO4). Evaporation of the
solvent followed by chromatography on silica gel (EtOAc-hexane, 2:1)
gave 17 (29.0 mg, 51%) as a colorless oil: IR (neat) 3407, 2930, 1680,
1432, 1384, 1350, 1289, 1210, 1117 cm-1; 1H NMR (300 MHz, CDCl3)
δ 1.30 (3 H, t, J ) 7.2 Hz), 1.90 (3 H, d, J ) 7.2 Hz), 2.12-2.33 (2
Data for (1S,6S,8S,9S)-8,9-bis(benzyloxy)-2-carbethoxy-7(Z)-eth-
ylidene-2-azabicyclo[4.3.0]non-3-ene ((Z)-15): [R]24D -127.2° (c 0.75,
CHCl3); IR (neat) 2980, 2915, 2858, 1708, 1662, 1445, 1411, 1375,
1
1333, 1318, 1279, 1110, 1072 cm-1; H NMR (400 MHz, CDCl3) δ
1.14 and 1.32 (total 3 H, t, J ) 7.1 Hz, and t, J ) 6.9 Hz, respectively,
in ca 1:1 due to the carbamate rotamers), 1.69 (3 H, dd, J ) 6.6, 14.3
Hz), 2.02-2.23 (2 H, m), 2.61-2.74 (1 H, m), 4.00-4.24 (3 H, m),
4.25-4.62 (6 H, m), 4.83-4.87 and 4.87-5.01 (total 1 H, each m, in

Total Synthesis of Natural (+)-Streptazolin
J. Am. Chem. Soc., Vol. 118, No. 5, 1996 1059
H, m), 2.95-3.10 (1 H, m), 3.97-4.13 (1 H, m), 4.13-4.27 (3 H, m),
4.45 (2 H, br s), 4.60 (1 H, br d, J ) 2.4 Hz), 4.71 (1 H, br d, J ) 5.3
Hz), 6.20 (1 H, q, J ) 7.2 Hz), 6.23-6.30 (1 H, m); EIMS m/z (relative
intensity) 253 (M+, 100), 234 (31), 206 (31), 180 (11), 162 (24), 134
(31), 110 (24).
provided 1 (13.0 mg, 65%) as a colorless oil: [R]27 +21.5° (c 0.65,
D
CHCl3); IR (neat) 3418, 2955, 2924, 2854, 1734, 1655, 1446, 1380,
1219, 1202, 1097, 1039 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.83 (1
H, br s), 1.91 (3 H, d, J ) 7.3 Hz), 2.13-2.25 (1 H, m), 2.51 (1 H,
dtd, J ) 16.7, 7.2, 3.3 Hz), 3.36-3.51 (2 H, m), 4.26-4.31 (1 H, m),
4.73 (1 H, d, J ) 6.8 Hz), 4.88 (1 H, br s), 6.02-6.07 (1 H, m), 6.15
(1 H, q, J ) 7.3 Hz); 13C NMR (100.6 MHz, CDCl3) δ 14.9, 22.8,
39.9, 59.1, 74.5, 81.5, 118.9, 123.7, 139.1, 142.8, 159.3; EIMS m/z
(relative intensity) 207 (M+, 100), 192 (7), 178 (11), 162 (14), 149
(21), 134 (30), 119 (23), 111 (7), 105 (16), 97 (10), 91 (28.5), 56 (87.5);
HRMS calcd for C11H13NO3 (M+) 207.0895, found 207.0896.
Being unstable on standing, this material was immediately used for
the next reaction.
(+)-Streptazolin (1). The above diol 17 (24.2 mg, 0.0963 mmol)
was added to a 2.5% solution of NaOMe in MeOH (1 mL), and the
mixture was refluxed for 30 min. The mixture was diluted with EtOAc
(20 mL), washed with water (10 mL) and then brine (10 mL), and
dried (MgSO4). Evaporation of the solvent in vacuo followed by
purification by chromatography on silica gel (EtOAc-hexane, 1:1)
JA9529910