Stereoselective total synthesis of (+)-streptazolin by using a temporary silicon-tethered RCM strategy

Article abstract of DOI:10.1021/jo060555y

A stereoselective total synthesis of (+)-streptazolin 1 was accomplished starting from readily available aminocyclopentenol (-)-7. The synthetic sequence highlights an intramolecular aldol condensation strategy to construct the piperidine core and a silic

Full text of DOI:10.1021/jo060555y

Stereoselective Total Synthesis of (+)-Streptazolin by Using a
Temporary Silicon-Tethered RCM Strategy
Fangzheng Li and Marvin J. Miller*
Department of Chemistry and Biochemistry, UniVersity of Notre Dame, Notre Dame, Indiana 46556
mmiller1@nd.edu
ReceiVed March 13, 2006
A stereoselective total synthesis of (+)-streptazolin 1 was accomplished starting from readily available
aminocyclopentenol (-)-7. The synthetic sequence highlights an intramolecular aldol condensation strategy
to construct the piperidine core and a silicon-tethered ring-closing metathesis strategy to install the Z
exocyclic ethylidene side chain of streptazolin. Separate protodesilylation and Tamao oxidation of a
common intermediate 32 afforded streptazolin and the precursor for 13-hydroxystreptazolin. The overall
yield for (+)-streptazolin 1 from aminocyclopentenol (-)-7 was 4.8% for a total of 16 steps.
Introduction:
Streptazolin (+)-1 (Figure 1) was isolated from cultures of
Streptomyces Viridochromogenes for the first time in 1981 by
Drautz and Zahner and later discovered by a chemical screening
of Streptomyces luteogriseus1 and a high-producing strain of
Streptomyces.2 This lipophilic neutral tricyclic compound, which
possesses the structural feature of an unusual ring system
embodying an internal urethane unit and an exocyclic ethylidene
side chain, has been shown to possess antibiotic and antifungal
activities.3 As reported, the isolation and purification of (+)-
streptazolin 1 were markedly complicated by its propensity to
polymerize upon concentration from organic solutions. For this
reason, hydrogenation of streptazolin affords a stable dihydro
product, whose crystalline acetate 2 was employed in much of
the structural investigations.4 Puder et al.5 recently reported the
isolation of some of co-secondary metabolites from Streptomyces
sp. with streptazolin including 13-hydroxystreptazolin 3 and
FIGURE 1. Structures of dihyrostreptazolin acetate, streptazolin, and
cosecondary metabolites.
5-O-(â-D-xylopyranosyl)streptazolin 4 which have shown sig-
nificant cytostatic activity against several human cancer cell
lines. The unique structural features of streptazolin as well as
its promising biological activity profile have prompted several
total syntheses.6-8
As part of a project directed at synthetic applications of
acylnitroso Diels-Alder cycloadducts in our group, we devel-
* To whom correspondence should be addressed. Tel: (574) 631 7571 Fax:
(574) 631-6652.
(1) (a) Drautz, H.; Za¨hner, H.; Kupfer, E.; Keller-Schierlein, W. Helv.
Chim. Acta 1981, 64, 1752. (b) Grabley, S.; Hammann, P.; Kluge, H.; Wink,
J.; Kricke, P.; Zeek, A. J. Antibiot. 1991, 44, 797.
(2) Grabley, S.; Hammann, P.; Thiericke, R.; Wink, J.; Philipps, S.; Zeek,
A. J. Antibiot. 1993, 46, 343.
(3) (a) For a biosynthetic study of streptazolin, see: Mayer, M.; Thiericke,
R. J. Org. Chem. 1993, 58, 3486. (b) Grabley, S.; Kluge, H.; Hoppe, H.-U.
Angew. Chem., Int. Ed. Engl. 1987, 26, 664.
(6) (a) Kozikowski, A. P.; Park, P. J. Am. Chem. Soc. 1985, 107, 1763.
(b) Kozikowski, A. P.; Park, P. J. Org. Chem. 1990, 55, 4668.
(7) Flann, C. J.; Overman, L. E. J. Am. Chem. Soc. 1987, 109, 6115.
(4) Karrer, A.; Dobler, M. Helv. Chim. Acta 1982, 65, 1432.
(5) Puder, C.; Loya, S.; Hizi, A.; Zeeck, A. J. Nat. Prod. 2001, 64, 42.
10.1021/jo060555y CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/13/2006
J. Org. Chem. 2006, 71, 5221-5227
5221

Li and Miller
SCHEME 1
been shown to be synthetically very effective in controlling the
geometry of di- and trisubstituted alkenes.12-14 We considered
that this methodology could be applied to introduction of the Z
ethylidene side chain of 13-hydroxystreptazolin and (+)-
streptazolin. In this paper, we detail our efforts toward a highly
stereoselective asymmetric synthesis of (+)-streptazolin based
on a ring-closing metathesis/silicon-assisted intramolecular
cross-coupling strategy and an intramolecular aldol condensation
strategy starting from aminocyclopentenols (-)-7.
Results and Discussion
In this event, the advanced intermediate, enone 18, was
synthesized in nine steps and 32% total yield from aminocy-
clopentenol (-)-7 by an improved synthetic sequence based on
our previous work (Scheme 3).11 Careful optimization of the
previous reductive amination step revealed that the use of
TBDPS- instead of TBS-protected aldehyde 10 and Na2SO4
instead of 4 Å molecular sieves as a drying agent improved
both the yield (from 69% to 76%) and, most importantly, the
reproducibility on large scale. An improved yield (86%) for the
preparation of enone 18 was also realized by treatment of aldol
product 16 with Et3N, DMAP, and MsCl to induce the desired
dehydration reaction.
SCHEME 2. Second-Generation Retrosynthetic Analysis
With the advanced intermediate enone 18 in hand, the initial
plan was to install a methylidene unit instead of ethylidene by
a Wittig reaction. Hence, compound 18 was treated with an ylide
premade from sodium hydride and methyltriphenylphosphonium
bromide to provide diene 19 in 71% yield. Epoxide opening of
19 with 25% AcOH/NaOAc was followed by base (NaOMe/
MeOH)-induced cyclization and deprotection to give rise to
methylidene streptazolin 21 in 78% total yield for the two steps.
At this point, commercially available allylchlorodimethylsilane
was chosen as the silane tether for the ring-closing metathesis
substrate. Compound 22 was obtained in 88% yield by the
treatment of triethylamine, DMAP, and allylchlorodimethylsi-
lane in methylene chloride. Further ring-closing metathesis,
catalyzed by 5 mol % of Grubbs’ II catalyst 24, was found to
proceed smoothly to furnish six-five-six ring fused diene 25 in
quantitive yield. Further manipulation of 25 by treatment with
different fluoride reagents (TBAF, HF-pyridine) was found to
give rise to triene 26 via an elimination reaction, which was
similar to a recently reported example (Scheme 4).15
Attempts to convert compound 25 to 13-hydroxystreptazolin
3 using Tamao oxidation conditions16 (KF/KHCO3/H2O2) led
to decomposition. To explore alternatives, we used an allyoxy-
diphenylchlorosilane as a tethering reagent in the RCM reaction
(Scheme 5). The advantage of this approach was that instead
of incorporating a carbon silicon bond into the conjugated diene
system, an oxygen silicon bond was used, with the anticipation
that it would make the RCM product much more prone to further
manipulation. Meanwhile, we also envisioned that the RCM
oped a highly efficient and practical chemoenzymatic synthesis
of enantiopure aminocyclopentenols (Scheme 1).9,10 Starting
from enantiopure versatile intermediate aminocyclopentenol (-)-
7, we recently accomplished a total synthesis of (+)-strepta-
zolin11 by combining an intramolecular aldol condensation
strategy and a Wittig olefination late-stage strategy developed
earlier by Kozikowski and Overman.6,7
In both Kozikowski and Overman’s syntheses,6,7 however,
the ethylidene side chain was introduced by the Wittig reaction
of the cyclic ketone and led to streptazolin as a 1:2 mixture of
the ethylidene stereoisomers with the incorrect E isomer
predominating. The lack of stereoselectivity in the introduction
of the ethylidene side chain by the Wittig reaction prompted us
to propose a ring-closing metathesis/silicon-assisted intramo-
lecular cross-coupling strategy to overcome this problem
(Scheme 2). The use of tethered heteroatoms such as silicon,
boron, or esters in ring-closing metathesis (RCM) reactions has
(11) Li, F.; Warshakoon, N. C.; Miller, M. J. J. Org. Chem. 2004, 69,
8836.
(12) (a) Chang, S.; Grubbs, R. H. Tetrahedron Lett. 1997, 38, 4757. (b)
Meyer, C.; Cossy, J. Tetrahedron Lett. 1997, 38, 7861.
(13) Micalizio, G. C.; Schreiber, S. L. Angew. Chem., Int. Ed. 2002, 41,
152.
(14) Chen, W.; Taylor, R. E.; Dent, W. H., III. Progress toward the total
synthesis of the Cornexistins. Abstracts of Papers. 226th ACS National
Meeting, Sep 7-11, 2003, New York; American Chemical Society:
Washington, DC, 2003.
(8) (a) Trost, B. M.; Chung, C. K.; Pinkerton, A. B. Angew. Chem., Int.
Ed. 2004, 43, 4327. (b) Huang, S.; Comins, D. L. J. Chem. Soc., Chem.
Commun. 2000, 569. (c) Yamada, H.; Aoyagi, S.; Kibayashi, C. J. Am.
Chem. Soc. 1996, 118, 1054.
(9) (a) Jiang, M. X.; Warshakoon, N. C.; Miller, M. J J. Org. Chem.
2005, 70, 2824. (b) Li, F.; Brogan, J. B.; Gage, J. L.; Zhang, D.; Miller, M.
J. J. Org. Chem. 2004, 69, 4538. (c) Lee, W.; Miller, M. J. J. Org. Chem.
2004, 69, 4516.
(15) Ahmed, M.; Atkinson, C. E.; Barrett, A. G. M.; Malagu, K.;
Procopiou, P. A. Org. Lett. 2003, 5, 669.
(16) Tamao, K.; Ishida, N.; Kumada, M. Org. Synth. 1990, 69, 96.
(10) Mulvihill, M. J.; Gage, J. L.; Miller, M. J. J. Org. Chem. 1998, 63,
3357.
5222 J. Org. Chem., Vol. 71, No. 14, 2006

StereoselectiVe Total Synthesis of (+)-Streptazolin
SCHEME 3
SCHEME 4
product of the bis-alkoxysilane could be a potential precursor
for 13-hydroxystreptazolin. Toward this end, compound 21 was
converted to allyoxydiphenylsilane 27 in 80% yield. Unfortu-
nately, a series of attempts with different metathesis conditions
and different substitutions in the allyoxysilane tether (R) Me
or i-Pr in 27) gave a mixture of E/Z intermolecular dimerization
products (28, R ) Ph) as the major products based on mass
spectrometry and crude NMR data. None of the expected
intramolecular seven-membered ring RCM silane was detected
even when the reaction was performed at low concentration (2
mM) and with the use of less active Grubbs I catalyst 24. When
treated with TBAF, compound 28 was converted to methylidene
streptazolin 21 smoothly in ∼60% yield, which also was
consistent with the dimerization product as the major product.
J. Org. Chem, Vol. 71, No. 14, 2006 5223

Li and Miller
SCHEME 5
In contrast to the RCM reaction of 22 which preceded very
smoothly, a possible explanation for the failure of the RCM
with 27 is that the required seven-membered ring transition state
for the reaction of 27 is less ordered relative to the rigid six-
membered ring transition state involved in the reaction of 22
(Figure 2).
FIGURE 2. Proposed six-membered and seven-membered ring transi-
tion states of RCM reactions.
the pivaloate group and cyclization of 32 were achieved by
refluxing it in 5% NaOMe in MeOH to provide Streptazolin 1
in ∼76% yield. Since we also found that these materials partially
decomposed upon isolation,6,7 the crude spectroscopic data were
compared to those reported in the literature8 to confirm the
structure of 1. To further prove the structure, our synthetic
streptazolin was converted to the stable crystalline dihydro
acetate 2 after hydrogenation and acetylation. Compound 2 was
confirmed by comparison of spectroscopic data and specific
rotation to those reported in the literature for this natural product
(Scheme 6).
At this point, we decided to focus on use of allylchlorodim-
ethylsilane as a temporary silane tether for the ring-closing
metathesis reaction and explore alternative synthetic sequences.
Because of the rather labile character of streptazolin, presumably
due to the fused ring system and the conjugated diene, we
decided to explore the possibility of conducting ring-closing
metathesis and protodesilylation before the formation of the
cyclic urethane unit of streptazolin. Accordingly, compound 20
was treated with trimethylacetic anhydride in the presence of a
catalytic amount of TMSOTf to furnish compound 29 in 80%
yield. Removal of the acyl group of 29 followed by silylation
with allylchlorodimethylsilane provided RCM substrate 30 in
a total of 74% yield for two steps. We were delighted to find
that the RCM reaction of 30 proceeded smoothly with 2 mol %
of Grubbs II catalyst in CH2Cl2 to give RCM product 31 cleanly.
With compound 31 in hand, we fortunately found that by
treatment with KF and KHCO3 compound 31 underwent a
protodesilylation process to give compound 32 in 50% yield.
To our knowledge, this is one of very few examples of
protodesilylation of a conjugated and fused allylic silane system.
On the other hand, diol 33 was obtained under Tamao oxidation
conditions in 55% yield. Attempts to convert diol 33 to 13-
hydroxystreptazolin 3 were unsuccessful.17 Further removal of
Conclusion
In conclusion, the total synthesis of (+)-streptazolin 1 was
accomplished using an intramolercular aldol condensation and
temporary silicon-tethered RCM strategy in 16 steps and 4.8%
total yield starting from readily available aminocyclopentenol
(-)-7. Our synthesis features a silicon-tethered RCM to set the
Z geometry of the ethylidene side chain and a novel protode-
silylation reaction of cyclic allylsilane. This synthesis also
highlights the versatile synthetic applications of aminocyclo-
pentenol building blocks developed in this laboratory.11 Mean-
while, a series of analogues of natural streptazolin were
SCHEME 6
5224 J. Org. Chem., Vol. 71, No. 14, 2006

StereoselectiVe Total Synthesis of (+)-Streptazolin
and filtered. The solvent was evaporated to provide the crude
product as a light yellow oil which was purified by flash
chromatography (EtOAc/hexanes 3: 1) to give enone 18 (474 mg,
2.14 mmol, 86%) as a colorless oil. All of the spectral data and
physical properties are identical to our previously reported data.11
prepared, and further synthetic investigations of novel strepta-
zolin Diels-Alder derivatives and the evaluations of their
biological activities are currently in progress.
Experimental Section:
(1S,8S,9S)-2-(Carbethoxy)-8,9-epoxy-2-azabicyclo[4.3.0]-5,7-
diene (19). A solution of methyltriphenylphosphonium bromide
(346 mg, 0.97 mmol)/NaH (60%, 38.6 mg, 0.97 mmol) in dry THF
(2 mL) in a flame-dried flask was stirred for 2 h at room
temperature. Epoxy ketone 18 (180 mg, 0.81 mmol) in dry THF (2
mL) was added at 0 °C. The reaction mixture was warmed to room
temperature over 1 h. After the mixture was stirred for another 0.5
h at room temperature, the reaction was quenched with saturated
NH4Cl aqueous solution (6 mL). The mixture was extracted with
ether (4 × 20 mL). The combined organic extracts were dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pres-
sure. Flash chromatography (hexanes/AcOEt 5:1) yielded 19 (128
(1R,4S)-4-[N-(tert-Butyldiphenylsilanyloxy)propylamino]-2-
cyclopenten-1-ol 1-O-Acetate (11). Modified reductive amination
procedure:11 To a solution of acetate 99b (5.0 g, 20.75 mmol) in
CH2Cl2 (10 mL) was added trifluoroacetic acid (5 mL) at room
temperature. The reaction mixture was stirred at room temperature,
until TLC showed that all starting material was consumed (∼2 h).
The reaction mixture was diluted with CH2Cl2 (40 mL) and was
washed with 10% Na2CO3 solution (40 mL). The aqueous layer
was extracted with CH2Cl2 (4 × 50 mL), and the combined organic
layers were dried over anhydrous Na2SO4. (It is important that pH
value of aqueous layer should be >10, if not, 1 NaOH aqueous
solution should be added to adjust the pH.) Filtration and
concentration under reduced pressure gave the crude amine product
(2.75 g) as a light yellow oil. The residue was dissolved in dry
CH2Cl2 (15 mL). To this solution was added anhydrous Na2SO4
(3.0 g, 21.12 mmol), followed by aldehyde 1018 (6.48 g, 20.75
mmol) in CH2Cl2 (10 mL) at -20 °C under Ar atmosphere, slowly.
The mixture was stirred at -20 °C for 12 h. The reaction mixture
was warmed to room temperature and then stirred for another 0.5
h at room temperature. NaBH4 (1.15 g, 30.77 mmol) was added to
the reaction mixture, followed by MeOH (15 mL) immediately.
The reaction mixture was stirred for 20 min and quenched with
saturated NaHCO3 solution. The product was extracted with CH2-
Cl2 (3 × 50 mL). The CH2Cl2 extract was washed with saturated
aqueous NaCl and dried over MgSO4. The solvent was evaporated
to give the crude product as a nearly colorless oil which was purified
by flash chromatography (MeOH/CH2Cl2 ) 1:15) to provide amine
mg, 0.58 mmol, 71%) as a colorless oil: [R]20 ) -221.1 (c )
D
0.6, CHCl3); IR (thin film) 2982, 1698, 1412, 1244, 1117, 889 cm-1
;
1H NMR (500 MHz, CDCl3) δ 1.32 (t, J ) 7.2 Hz, 3 H), 2.08-
2.15 (m, 1 H), 2.24-2.30 (m, 1 H), 2.84 (dt, J ) 2.5, 10 Hz, 1H),
3.69 (d, J ) 3 Hz, 1 H), 4.06 (m, br, 1 H), 4.19-4.32 (m, 4 H),
5.26 (s, 1 H), 5.45 (s, 1 H), 6.38 (m, 1 H); 13C NMR (125 MHz,
CDCl3) δ 14.9, 25.1, 40.6, 55.2, 56.8, 57.1, 61.7, 109.2, 125.3,
134.1, 143.1, 156.2; HRMS [FAB, MH+] calcd for C12H16NO3
222.1130, found 222.1128.
(1S,8S,9S)-2-(Carbethoxy)-8-O-acetyl-9-hydroxy-2-azabicyclo-
[4.3.0]-5,7-diene (20). To a solution of epoxide 19 (53 mg, 0.24
mmol) and sodium acetate (99%, 250 mg, 3.06 mmol) was added
acetic acid (3 mL) at room temperature. The reaction mixture was
heated to 65 °C for 2 h in an oil bath and then cooled to room
temperature. Acetic acid was removed under reduced pressure.
Saturated aqueous NaHCO3 (10 mL) and CH2Cl2 (30 mL) were
poured into the white solid residue. The aqueous layer was extracted
with ether CH2Cl2 (2 × 20 mL). The combined organic extracts
were dried over anhydrous potassium carbonate, filtered and
concentrated under reduced pressure. Flash chromatography of the
residue on silica gel with 50% EtOAc-hexanes afforded 20 (60
11 (6.90 g, 15.77 mmol) as a colorless oil: yield 76%; [R]20
)
D
-96 (c ) 1.0, CH3OH); 1H NMR (300 MHz, CDCl3) δ 1.06 (s, 9
H), 1.53 (td, J ) 4.7,14.1 Hz, 1 H), 1.78 (m, 3 H), 2.03 (s, 3 H),
2.77 (m, 3 H), 3.73 (m, 3 H), 5.57 (m, 1 H), 5.90 (td, J ) 1.59,
5.52 Hz, 1 H), 5.90 (m, 1 H), 7.40 (m, 6 H), 7.68 (m, 4 H); 13C
NMR (75 MHz, CDCl3) δ 19.4, 21.4, 27.0, 33.1, 38.1, 44.9, 62.5,
62.6, 78.0, 127.8, 129.8, 131.1, 135.7, 133.9, 138.4, 170.9; HRMS
[FAB, MH+] calcd for C26H36NO3Si 438.2426, found 438.2425.
(1S,8S,9S)-2-(Carbethoxy)-8,9-epoxy-2-azabicyclo[4.3.0]non-
5-en-7-one (18). Modified procedure for dehydration of aldol
product 16: To a solution of aldol product 16 (600 mg, 2.49 mmol)
in CH2Cl2 (5 mL) were added DMAP (61 mg, 0.50 mmol) and
triethylamine (900 µL, 6.48 mmol) followed by MsCl (306 µL,
3.98 mmol) at room temperature. The resulting reaction mixture
was stirred at room temperature under Ar atmosphere for 2 h. TLC
analysis showed that all of the aldol product 16 was converted to
enone 18. Saturated NH4Cl solution (15 mL) was added to quench
the reaction. The aqueous layer was extracted with CH2Cl2 (3 ×
50 mL), and the combined organic layers were dried over Na2SO4
mg, 0.21 mmol, 89%): [R]20 ) -119.1 (c ) 0.6, CHCl3); IR
D
(thin film) 3401, 2919, 1736, 1678, 1420, 1370, 1227, 1112, 887
1
cm-1; H NMR (500 MHz, CDCl3) δ 1.30 (t, J ) 7.5 Hz, 3 H),
2.07 (s, 3 H), 2.14-2.22 (m, 1 H), 2.27-2.33 (m, 1 H), 2.61 (d, J
) 3 Hz, 1 H), 2.98 (s, br, 1 H), 4.07 (m, br, 1 H), 4.16-4.23 (m,
2 H), 4.40-4.43 (m, 2 H), 5.37 (s, 1 H), 5.38 (s, 1 H), 5.70 (s, 1
H), 6.44 (m, 1 H); 13C NMR (125 MHz, CDCl3) δ 14.8, 21.4, 24.9,
41.1, 58.8, 61.8, 74.1, 78.0, 112.7, 121.2, 136.3, 142.2, 156.2, 170.5;
HRMS [FAB, MH+] calcd for C14H20NO5 282.1341, found
282.1346.
12-Dihydrostreptazolin (21). A solution of 20 (60 mg, 0.21
mmol) in 3 mL of 2.5% NaOMe/MeOH was heated to reflux for
1 h, and the methanol was removed under reduced pressure. The
mixture was diluted with water and extracted with ethyl acetate (4
× 5 mL). The organic extracts were dried over anhydrous potassium
carbonate, filtered, and concentrated. Flash chromatography of the
residue on silica gel with 50% EtOAc-hexanes afforded 21 (37
mg, 0.19 mmol, 90%) as a colorless oil: [R]20D ) +64.0 (c ) 0.4,
CHCl3); IR (thin film) 3425, 2919, 1723, 1385, 1201, 1030, 764
(17) Removal of the pivolayl group and cyclization of 33 by refluxing
in 5% NaOMe in MeOH was tried in an attempt to afford 13-hydrox-
ystreptazolin 3. Unfortunately, compound 3 was found to be unstable upon
concentration from organic solutions. This instability of 3 was also observed
by Puder et al.5 Further studies to solve this problem are currently in
progress.
1
cm-1; H NMR (500 MHz, CDCl3) δ 2.10 (d, J ) 7.5 Hz, 1 H),
2.19-2.30 (m, 1 H), 2.50-2.62 (m, 1 H), 3.37-3.59 (m, 2 H),
4.30 (overlap d, br, J ) 12.5, 1 H), 4.68 (s, br, 1 H), 4.75 (dd, J )
12.5, 0.5 Hz, 1 H), 5.31 (s, 1 H), 5.70 (s, 1 H), 6.19 (m, 1 H); 13
C
NMR (125 MHz, CDCl3) δ 23.0, 39.5, 58.5, 77.7, 81.7, 110.6,
122.6, 141.9, 147.2, 159.0; HRMS [FAB, MH+] calcd for C10H12-
NO3 194.0817, found 194.0813.
5-O-(o-Allyldimethylsilyl)-12-dihydrostreptazolin (22). To a
solution of 21 (21 mg, 0.11 mmol) in CH2Cl2 (4 mL) were added
a catalytic amount of DMAP (1-2 mg) and triethylamine (0.19
mL) at room temperature, followed by addition of allyldimethylsilyl
(18) Brimble, M. A.; Fares, F. A.; Turner, P. Aust. J. Org. Chem. 2000,
53, 845.
J. Org. Chem, Vol. 71, No. 14, 2006 5225

Li and Miller
chloride (0.08 mL, 0.55 mmol) at 0 °C. The mixture was allowed
to warm to room temperature and was stirred at room temperature
for 15 min. The solvent was removed under reduced pressure to
give a white solid residue. Et2O (30 mL) was added, and then the
mixture was filtered. Flash chromatography of the residue on silica
gel with hexanes/EtOAc (4: 1) afforded 22 (28 mg, 0.086 mmol,
1 H), 3.49 (td, J ) 7.63, 12.57 Hz, 1 H), 4.26 (app d, J ) 7.48 Hz,
1 H), 4.35 (td, J ) 1.74, 4.68 Hz, 2 H), 4.79 (app d, J ) 7.48 Hz,
1 H), 4.87 (s, 1 H), 5.14-5.17 (m, 1 H), 5.34-5.39 (m, 1 H), 5.49
(s, 1 H), 5.96 (tdd, J ) 4.68, 10.42, 17.10 Hz, 1 H), 6.12 (m, 1 H),
7.38-7.49 (m, 6 H), 7.67-7.73 (m, 4 H); 13C NMR (150 MHz,
CDCl3) δ 22.9, 39.5, 58.4, 64.4, 78.3, 81.9, 110.9, 115.2, 121.8,
128.2, 128.3, 130.7, 130.9, 131.0, 131.8, 131.9, 134.5, 135.1, 135.2,
136.3, 141.8, 146.0, 159.0; HRMS [FAB, MH+] calcd for C25H26-
NO4Si 432.1631, found 432.1636.
88%): [R]20 ) +161.3 (c ) 0.2, CHCl3); IR (thin film) 2924,
D
1763, 1630, 1380, 1255, 1038, 882, 765 cm-1; 1H NMR (500 MHz,
CDCl3) δ 0.23 (s, 6H), 1.71 (d, J ) 8 Hz, 2 H),2.20-2.27 (m, 1
H), 2.50-2.57 (m, 1 H), 3.39-3.55 (m, 2 H), 4.26 (d, br, J ) 8,
1 H), 4.68 (d, J ) 2, 1 H), 4.65 (dd, J ) 8, 1.5 Hz, 1 H), 4.94 (m,
1H), 4.97 (m, 1H), 5.15 (s, 1 H), 5.48 (s, 1 H), 5.76-5.85 (m,
1H), 6.12 (m, 1 H); 13C NMR (150 MHz, CDCl3) δ -1.85, -1.83,
23.0, 24.6, 39.4, 57.9, 78.8, 82.4, 110.0, 114.7, 121.9, 133.4, 141.4,
146.6, 158.7; HRMS [FAB, MH+] calcd for C15H22NO3Si 292.1369,
found 292.1370.
(1S,8S,9S)-2-(Carbethoxy)-8-O-acetyl-9-O-trimethylacetyl-2-
azabicyclo[4.3.0]-5,7-diene (29). To a solution of 20 (40 mg, 0.14
mmol) in CH2Cl2 (1.5 mL) was added trimethylacetic anhydride
(40 mg, 0.21 mmol) at 0 °C, followed by addition of TMSOTf (20
µL, 1 M in CH2Cl2) slowly. The reaction mixture was stirred at 0
°C for 30 min. TLC showed that all starting material was consumed.
Saturated aqueous NaHCO3 (10 mL) and CH2Cl2 (20 mL) were
poured into the reaction mixture. The aqueous layer was extracted
with CH2Cl2 (2 × 20 mL). The combined organic extracts were
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. Flash chromatography of the residue on silica
gel with hexanes/EtOAc (6:1) afforded 29 (40 mg, 0.11 mmol, 80%)
as a colorless oil: [R]20D ) -65.9 (c ) 1.0, CHCl3); IR (thin film)
Silylstreptazolin (25). To a solution of 22 (25 mg, 0.086 mmol)
in CH2Cl2 (6 mL) was added Grubbs II catalyst 23 (4 mg, ∼5 mol
%), and the reaction mixture was heated to reflux under Ar. After
1 h, the reaction mixture was cooled to room temperature and
concentrated to dryness under vacuum. Examination of the crude
1
reaction mixture by H NMR indicated complete consumption of
1
22 with clean and quantitative formation of the tethered diene. The
crude reaction mixture was filtered through a pad of silica gel
quickly (compound 25 was found to decompose on silica TLC over
10 min at room temperature) with hexanes/EtOAc (1:1) to afford
25 (22.6 mg, 0.086 mmol) as light yellow oil: [R]20D ) +282.0 (c
) 0.3, CHCl3); IR (thin film) 3351, 2924, 2853, 1760, 1644, 1380,
2925, 2853, 1733, 1704, 1423, 1150, 771 cm-1; H NMR (300
MHz, CD3OD) δ 1.12 (1.19 rotamer) (s, 9H), 1.28 (t, J ) 7.10 Hz,
3 H), 2.09 (s, 3 H), 2.14-2.39 (m, 2 H), 2.77 (br, m, 1 H), 4.12-
4.17 (m, 4H), 4.56 (app q, J ) 3.78, 3.83 Hz, 1 H), 5.34 (br, s, 2
H), 5.39 (d, J ) 4.40 Hz, 1 H), 5.70 (s, 1 H), 6.53 (m, 1 H); 13C
NMR (125 MHz, CD3OD, 50 °C) δ 15.0, 21.0, 25.7, 27.6, 27.8,
40.0, 41.8, 57.7, 63.1, 77.1, 112.7, 122.3, 137.2, 143.8, 157.5, 171.6,
178.8; HRMS [FAB, MH+] calcd for C19H28NO6 366.1917, found
366.1920.
1
1252, 1043, 835, 768 cm-1; H NMR (500 MHz, CDCl3) δ 0.12
(s, 3H), 0.25 (s, 3H), 1.38 (d, overlap, J ) 17 Hz, 1 H), 1.58 (dd,
J ) 17 Hz, 8.5 Hz, 1 H), 2.18-2.24 (m, 1 H), 2.46-2.53 (m, 1
H), 3.36-3.41 (m, 1 H), 3.53 (dt, J ) 12.5, 7.5 Hz, 1 H), 4.24 (d,
br, J ) 8.5 Hz, 1 H), 4.59 (s, 1 H), 4.79 (dd, J ) 8, 1 Hz, 1 H),
5.90 (m, 1H), 6.18 (m, 1 H); 13C NMR (125 MHz, CDCl3) δ -0.38,
-0.34, 14.2, 22.8, 39.2, 57.8, 78.6, 82.4, 119.3, 121.7, 140.7, 141.2,
158.6; HRMS [FAB, MH+] calcd for C13H8NO3Si 264.1056, found
264.1037.
(1S,8S,9S)-2-(Carbethoxy)-8-O-allyldimethylsilyl-9-O-trime-
thylacetyl-2-azabicyclo[4.3.0]-5,7-diene (30). To a solution of
alcohol 29 (40 mg, 0.11 mmol) in methanol (3 mL) was added
K2CO3 (15 mg, 0.11 mmol) at room temperature. The resulting
reaction mixture was stirred at room temperature for 1 h. TLC
analysis showed that starting material was consumed. MeOH was
removed under reduced pressure, and then CH2Cl2 (20 mL) was
added to redissolve the residue, followed by saturated aqueous NH4-
Cl solution (10 mL). The aqueous layer was extracted with CH2-
Cl2 (3 × 20 mL), and the combined organic layers were dried over
Na2SO4 and filtered. The solvent was evaporated to provide a light
yellow oil residue. To a solution of this crude residue (∼36 mg) in
CH2Cl2 (4 mL) was added a catalytic amount of DMAP (1-2 mg)
and triethylamine (0.07 mL) at room temperature, followed by
addition of allyldimethylsilyl chloride (25 mg, 0.34 mmol) at 0
°C. The mixture warmed to room temperature and was stirred at
room temperature for 0.5 h. The solvent was removed under reduced
pressure to give a white solid residue. Et2O (30 mL) was added,
and then the mixture was filtered. The filtrate was concentrated.
Flash chromatography of the residue on silica gel with hexanes/
EtOAc (7:1) afforded 30 (34 mg, 0.082 mmol, 74% for two steps):
[R]20D ) -128.6 (c ) 0.7, CHCl3); IR (thin film) 2924, 1734, 1706,
1678, 1636, 1152, 771 cm-1; 1H NMR (600 MHz, CDCl3) δ 0.22
(0.15, rotamer) (br s, 6 H), 1.11 (s, 9 H), 1.25-1.28 (m, 3 H), 1.71
(d, J ) 7.95 Hz, 2 H), 2.17-2.28 (m, 2 H), 2.73 (br, m, 1 H),
4.15-4.22 (m, 4 H), 4.65 (br, s, 1 H), 4.89 (dd, J ) 13.50, 24.11
Hz, 2 H), 5.11 (s, 1 H), 5.15 (br, s, 1 H), (5.58 (br, s, 1 H), 5.81
(dt, J ) 8.48, 17.48, 17.30 Hz, 1 H), 6.40 (m, 1 H); 13C NMR
(150 MHz, CDCl3) δ -1.7, -1.6, 14.8, 24.8, 27.3, 29.9, 39.0, 40.3,
56.1, 61.7, 75.7, 77.9, 109.7, 114.1, 120.4, 133.9, 136.?2, 145.5,
156.0, 178.0; HRMS [FAB, MH+] C22H36NO5Si 422.2363, found
422.2366.
Triene (26). To a solution of 25 (11.3 mg, 0.043 mmol) in THF
(1 mL) was added TBAF (1.0 M in THF, 45 µL, 0.045 mmol)
slowly at 0 °C under Ar atmosphere. The resulting reaction mixture
was stirred at 0 °C for 15 min. TLC showed that all starting material
was consumed. The solvent was removed under reduced pressure.
Flash chromatography with hexanes/EtOAc (2:1) provided triene
26 (6 mg, 0.031 mmol, 72%) as a colorless oil: [R]20D ) +20.0 (c
) 0.03, CHCl3); IR (thin film) 2924, 2852, 1753, 1389, 1216, 1039,
765 cm-1; 1H NMR (500 MHz, CDCl3) δ 2.36 (m, 1 H), 2.49 (dtd,
J ) 2.52, 6.88, 16.27 Hz, 1 H), 3.47 (m, 1H), 3.57 (m, 1 H), 4.40
(d, J ) 7.18 Hz, 1 H), 5.22 (dd, J ) 2.47, 7.38 Hz, 1 H), 5.46 (dd,
J ) 1.16, 11.10 Hz, 1 H), 5.75 (dd, J ) 0.87, 17.71 Hz, 1 H), 6.16
(m, 1 H), 6.07 (d, J ) 1.98 Hz, 1 H), 6.47 (dd, J ) 11.09, 17.83
Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 23.6, 42.6, 59.0, 77.4,
120.2, 121.1, 129.0, 129.2, 145.1, 146.9, 156.6; HRMS [FAB,
MH+] calcd for C11H12NO2 190.0868, found 190.0870.
5-O-(o-Allyloxydiphenylylsilyl)-12-dihydrostreptazolin (27).
To a solution of dichlorodiphenylsilane (0.163 mL, 0.78 mmol) in
CH2Cl2 (2 mL) was added a catalytic amount of DMAP (1-2 mg)
and triethylamine (0.22 mL), followed by the syringe-pump addition
of the allylic alcohol (68 mg, 1.17 mmol) in CH2Cl2 (1 mL) over
1 h at 0 °C under an atmosphere of argon. The mixture was allowed
to warm to room temperature and was stirred at room temperature
for 3 h. This mixture was cooled to 0 °C, and then compound 21
(15 mg, 0.078 mmol) in CH2Cl2 (1 mL) was added dropwise. The
mixture was allowed to warm to room temperature and was stirred
at room temperature for 15 min. The solvent was removed under
reduced pressure to give a white solid residue. Et2O (30 mL) was
added, and then the mixture was filtered. Flash chromatography of
the residue on silica gel with hexanes/EtOAc (15:1 to 9:1) afforded
27 (26.8 mg, 0.062 mmol, 80%): 1H NMR (500 MHz, CDCl3) δ
2.21 (m, 1 H), 2.51 (m, 1 H), 3.38 (ddd, J ) 4.08, 8.49, 12.46 Hz,
(1S,8S,9S)-2-(Carbethoxy)-7-cyclo-8-O-allyldimethylsilyl-9-O-
trimethylacetyl-2-azabicyclo[4.3.0]-5,7-diene (31). To a solution
of 30 (34 mg, 0.081 mmol) in CH2Cl2 (6 mL) was added Grubbs
II catalyst 23 (1.5 mg, ∼2 mol %), and the reaction mixture was
heated to reflux under Argon. After 1 h, the reaction was cooled to
room temperature and concentrated to dryness under vacuum.
5226 J. Org. Chem., Vol. 71, No. 14, 2006

StereoselectiVe Total Synthesis of (+)-Streptazolin
1
Examination of the crude reaction mixture by H NMR indicated
[R]20D ) +21.8 (c ) 0.5, CHCl3); IR (thin film) 3420, 2956, 2924,
1734, 1380, 1201, 1038 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.91
(d, J ) 7.5 Hz, 3 H), 2.15-2.24 (m, 1 H), 2.51 (dtd, J ) 17.5, 7.0,
3.5 2 Hz, 1 H) 3.37-3.45 (m, 2 H), 4.28-4.30 (overlap d, br, J )
7.5, 1 H), 4.74 (d, J ) 7 Hz, 1 H), 4.88 (s, br, 1 H), 6.04 (m, 1 H),
6.16 (q, J ) 7.5 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 15.1,
23.0, 40.1, 59.3, 74.6, 81.7, 119.0, 123.9, 139.1, 143.0, 159.1;
HRMS [FAB, MH+] calcd for C11H14NO3 208.0974, found
208.0972.
(+)-Dihydrostreptazolin Acetate (2). To a solution of 1 (6 mg,
0.030 mmol) in ethanol (1.5 mL) was added 10 wt % Pd on
activated carbon (6 mg) at room temperature. The resultant reaction
mixture was purged with H2 three times and then stirred at room
temperature under H2 for 1.2 h. TLC was used to monitor the
reaction carefully. The reaction mixture was filtered through a pad
of Celite and washed with MeOH (15 mL). The solvent was
removed under reduced pressure. Flash chromatography (EtOAc/
hexanes 2:3) gave 5 mg of chromatographically pure dihydros-
treptazolin. To a solution of this material in CH2Cl2 (1 mL) was
added Ac2O (0.012 mL, 0.30 mmol) and pyridine (0.05 mL, 0.60
mmol) at room temperature. The resulting reaction mixture was
stirred for 15 h at room temperature. The solvent was removed
under reduced pressure, and the crude product was purified by silica
gel flash chromatography (hexanes/EtOAc 2:3) to provide (86%
for two steps) of dihydrostreptazolin acetate 2 (6.8 mg, 0.27 mmol,
90% for two steps) as a white crystalline solid. All of the spectral
data and physical properties are identical to our previous reported
data11 and the original literature.4
complete consumption of 30 with clean and quantitative formation
of the tethered diene 31. The crude reaction mixture was filtered
through a pad of silica gel quickly (compound 31 was found to
decompose on silica TLC over 5 min at room temperature) with
hexanes/EtOAc (1:1) to afford 31 (30 mg, 0.076 mmol, 94%) as a
light yellow oil: [R]20D ) -36.2 (c ) 0.5, CHCl3); IR (thin film)
2925, 2653, 1733, 1705, 1463, 1283, 1151, 1056, 834 cm-1; H
1
NMR (300 MHz, CDCl3) δ 0.10 (s, 3 H), 0.25 (s, 3 H), 1.16 (s, 9
H), 1.27 (app dd, J ) 5.31, 8.55 Hz, 3 H), 1.37-1.43 (br, m, 1H),
1.60 (app dd, J ) 8.82, 15.97 Hz, 1 H), 2.19 (br, m, 2 H), 2.77 (m,
1 H), 4.12-4.25 (m, 4 H), 4.40 (m, 1 H), 5.37 (d, J ) 5.37 Hz, 1
H), 6.10 (m, 1 H), 6.20 (m, 1 H); 13C NMR (125 MHz, CD3OD)
δ 177.660, 156.254, 136.785, 134.863, 122.606, 115.510, 78.113,
71.681, 61.462, 55.968, 40.471, 38.428, 29.356, 26.173, 24.000,
19.391, 13.586, -3.852, -3.895; HRMS [FAB, MH+] calcd for
C20H32NO5Si 394.2050, found 394.2041.
(1S,8S,9S)-2-(Carbethoxy)-7-(Z)-8-O-hydroxy-9-O-trimethy-
lacetyl-2-azabicyclo[4.3.0]-5,7-diene (32). To a solution of com-
pound 31 (30 mg, 0.076 mmol) in MeOH/THF (1.5 mL/1.5 mL)
at 0 °C were added KHCO3 (33 mg, 0.33 mmol) and KF (19 mg,
0.33 mmol). The resulting reaction mixture was allowed to warm
to room temperature over 0.5 h and then stirred at room temperature
for 2 h. TLC indicated complete consumption of the starting
material, and the reaction mixture was poured into water and
extracted with EtOAc (3 × 20 mL). The combined organic extracts
were dried over anhydrous Na2SO4 and evaporated. Flash chro-
matography of the residue on silica gel with hexanes/EtOAc (1:1)
afforded compound 32 (12.8 mg, 0.038 mmol, 50%) as a colorless
oil: [R]20 ) -132.7 (c ) 0.06, CH2Cl2); IR (thin film) 2960,
D
Acknowledgment. We gratefully acknowledge the NIH for
support of this research and the Lizzadro Magnetic Resonance
Research Center (UND) for NMR facilities, as well as N. Sevova
for mass spectroscopic studies. We also would like to acknowl-
edge Dr. Wengsheng Chen and Professor Richard E. Taylor
for useful discussions about the silicon-tethered ring-closing
metathesis strategy. F.Z.L. acknowledges a Reilly Graduate
Fellowship (2005-2006, UND) and a University Endowed
Graduate Fellowship (2004-2005, UND).
2926, 2854, 1734, 1706, 1426, 1283, 1153, 1055, 771 cm-1; H
1
NMR (300 MHz, CDCl3) δ 1.13 (s, 9H), 1.28 (t, J ) 7.0 Hz, 3 H),
1.87 (d, J ) 7.0 Hz, 3 H), 2.20 (s, br, 2H), 2.22 (s, br, OH), 4.15-
4.23 (m, 4 H), 4.50-4.64 (m, 2H), 5.26 (s, 1 H), 6.14-6.23 (m, 2
H); HRMS [FAB, MH+] calcd for C18H28NO5 338.1967, found
338.1965.
(+)-Steptazolin (1). A solution of 32 (12.8 mg, 0.038 mmol) in
1.5 mL of 5% NaOMe/MeOH was heated to reflux for 1 h, and
the methanol was removed under reduced pressure. The mixture
was diluted with water and extracted with EtOAc (4 × 5 mL). The
combined organic extracts were dried over anhydrous Na2SO4,
filtered, and concentrated to provide (+)-steptazolin 1 (6 mg, 0.030
mmol, ∼76%) as a colorless oil (since we also found that
streptazolin partially decomposed when concentrated and purified
by chromatography on silica gel, the mixture was immediately
diluted with deuterated chloroform to provide crude NMR data):
1
Supporting Information Available: Copies of H NMR and
13C NMR spectra of new compounds 11, 19-27, 29-31, 1, and 2.
1H NMR of compound 32. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO060555Y
J. Org. Chem, Vol. 71, No. 14, 2006 5227