Total synthesis of (-)-4a,5-Dihydrostreptazolin

Article abstract of DOI:10.1002/1099-0690(200108)2001:15<2841::AID-EJOC2841>3.0.CO;2-W

(-)-4a,5-Dihydrostreptazolin has been synthesized in nine steps from D-glyceraldehyde acetonide. Key steps include a diastereoselective addition of a vinylic Grignard reagent to an imine derived from D-glyceraldehyde acetonide, a ring-closing metathesis, and a stereoselective radical-mediated enyne cyclization.

Full text of DOI:10.1002/1099-0690(200108)2001:15<2841::AID-EJOC2841>3.0.CO;2-W

FULL PAPER
Total Synthesis of (؊)-4a,5-Dihydrostreptazolin
[a]
[a]
[a]
´
Janine Cossy,* Isabelle Pevet, and Christophe Meyer*
Keywords: Cyclizations / Metathesis / Natural products / Radical reactions / Total synthesis
(−)-4a,5-Dihydrostreptazolin has been synthesized in nine
an imine derived from
D-glyceraldehyde acetonide, a ring-
steps from -glyceraldehyde acetonide. Key steps include a closing metathesis, and a stereoselective radical-mediated
D
diastereoselective addition of a vinylic Grignard reagent to
enyne cyclization.
Introduction
cemic form.[4b] In Kibayashi’s approach, a palladium-cata-
lyzed enyne cycloisomerization allowed direct stereoselec-
tive access to (ϩ)-streptazolin for the first time.[6] More
recently, Comins reported the first chiral-auxiliary-medi-
ated synthesis of (ϩ)-streptazolin, starting from an N-acyl-
pyridinium salt.[7]
(ϩ)-Streptazolin, first isolated from cultures of Strepto-
myces viridochromogenes in 1981, was found to exhibit anti-
biotic and antifungal properties.[1,2] The pure compound is
rather labile, due to the presence of the conjugated diene
part, which enhances its polymerization, although it may
be kept for some time in dilute solutions at low temperature.
Most structural investigations have therefore been carried
out on a derivative, (ϩ)-5,8-dihydrostreptazolin acetate, ob-
tained by catalytic hydrogenation and acetylation of strep-
tazolin. Although less active, this derivative also exhibits
antibacterial activity (Figure 1).[3]
Since streptazolin does not obviously meet the criteria for
an ideal antibiotic, owing to its marginal activity and its
low stability, attempts were made to synthesize derivatives
with improved properties.[8,9] Recently, 5-(alk-1-enyl)-
1,2,3,6-tetrahydropyridines, mimicking only the two sug-
gested pharmacophores of streptazolin (the diene and the
carbamate moieties), have been synthesized, but despite
their enhanced stability, no satisfactory improvement in the
antibiotic activity was observed.[10] These studies have high-
lighted the possible importance of the five-membered ring
and probably its alcohol functionality at C-3. We were par-
ticularly interested in another dihydro derivative of strepta-
zolin, (Ϫ)-4a,5-dihydrostreptazolin (Figure 1), which is
structurally closely related to streptazolin thanks to the
presence of the exocyclic alkene moiety, but which has not,
to the best of our knowledge, been evaluated for biological
activity. One synthesis of (Ϫ)-4a,5-dihydrostreptazolin has
already been described by Kibayashi, taking advantage of
the same enyne intermediate as involved in the synthesis of
streptazolin, and carrying out the palladium-catalyzed en-
yne cycloisomerization in the presence of a reducing
agent.[11] In order to assess the biological properties of this
structurally interesting compound, we have achieved its to-
tal synthesis[12] and prepared some related structures. Here
we would like to give a full account of this work.
Figure 1. (ϩ)-Streptazolin and derivatives
The unique structure of streptazolin has elicited some
synthetic interest, and four total syntheses have been
achieved. The first racemic one, by Kozikowski, features
an aza-Ferrier reaction and a [3 ϩ 2] nitrile oxide-alkene
cycloaddition to construct the azabicyclic core of streptazo-
lin.[4] The ethylidene side-chain was installed by means of a
Wittig reaction, which took place with low stereoselectivity
and afforded streptazolin as a mixture of geometrical iso-
mers. Two enantioselective syntheses were subsequently car-
ried out. Both started from an -tartaric acid derivative, the
absolute configuration of which translates directly to the
C-2a and C-3 stereocenters.[5,6] Both approaches rely on a
vinylsilaneϪiminium cyclization for the construction of the
tetrahydropyridine ring. In Overman’s approach,[5] the five-
membered ring was elaborated by an intramolecular acyl-
ation of a vinylic organolithium reagent, producing an aza-
bicyclic ketone that had previously been synthesized in ra-
Results and Discussion
In our retrosynthetic analysis of (Ϫ)-4a,5-dihydrostrepta-
zolin, we anticipated that a radical-mediated enyne cycliza-
tion induced by nBu3SnH[13] could be used in order to elab-
orate the five-membered ring. This reaction would produce
a vinylstannane as a reasonable precursor to the target, of-
fering potential control over the exocyclic double bond con-
figuration and the cis-fused ring junction. Two different ap-
proaches for the preparation of the enyne precursor were
considered. In the first approach (Path A), we envisaged
[a]
´
Laboratoire de Chimie Organique, associe au CNRS, ESPCI,
10 rue Vauquelin-75231 Paris Cedex 05, France
Fax: (internat.) ϩ33-1/4079-4660
E-mail: janine.cossy@espci.fr
christophe.meyer@espci.fr
Eur. J. Org. Chem. 2001, 2841Ϫ2850
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0815Ϫ2841 $ 17.50ϩ.50/0
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´
J. Cossy, I. Pevet, C. Meyer
FULL PAPER
introducing the triple bond by performing
a
controllable by variation of the experimental conditions,[16]
FuchsϪCorey[14a] or a SeyferthϪGilbert[14b,14c] reaction on thus also allowing easy access to both C-3 epimeric com-
the corresponding aldehyde. This strategy, as in the previ- pounds. The aldehyde would be produced from the corres-
ously reported total syntheses of streptazolin, would take ponding alcohol by oxidation and the tetrahydropyridine
advantage of the possibility of using -tartaric acid derivat- ring would be elaborated by a ring-closing metathesis,[15] in
ives to introduce the C-2a and C-3 stereocenters.[5,6] We en- an approach similar to that described above. In this case, -
visaged that the tetrahydropyridine ring could be formed by glyceraldehyde acetonide was selected as an optically active
ring-closing metathesis of the corresponding diene,[15] for starting material, while addition of the Grignard reagent to
which the homoallyl substituent would be introduced by the corresponding imine would dictate the absolute config-
alkylation of the nitrogen, and the vinyl group by addition uration at C-7b in both approaches (Scheme 1).
of a vinylic Grignard reagent to the corresponding imine
(Scheme 1).
The initial stages of Path A were examined first. The
known alcohol (Ϫ)-1, prepared in three steps from -di-
methyl tartrate (acetonide formation, LiAlH4 reduction,
and monosilylation with NaH/TBDPSCl, 64% overall
yield),[17] was oxidized to afford the unstable aldehyde 2,
which was converted directly into the imine 3 by treatment
with p-methoxybenzylamine (PMB-NH2) in the presence of
anhydrous MgSO4. Although Grignard reagents were re-
ported to be unreactive towards such imines in the absence
of additives,[18] treatment of 3 with vinylmagnesium brom-
ide afforded the allylic amine 4 in modest overall yield
(35%, dr Ն 95:5). Its relative configuration was not deter-
mined, but was assumed to be anti on the basis of literature
precedent for this series of compounds.[18Ϫ20] Although this
route would have unambiguously ensured the absolute con-
figurations at C-2a and C-3, it was abandoned because of
the low yields of the first steps and the greater number of
functional group manipulation steps required in compar-
ison with Path B (Scheme 2).
Scheme 2. Synthesis of allylic amine (Ϫ)-4 according to Path A
Following the second approach (Path B), -glyceral-
dehyde acetonide (ϩ)-5, readily prepared by oxidative cleav-
age of 1,2,5,6-diisopropylidene--mannitol,[21] was con-
verted into imine 6 by treatment with p-methoxybenzylam-
ine in the presence of anhydrous MgSO4 in ether. This was
then allowed to react directly with vinylmagnesium chlor-
ide, to afford the allylic amine (ϩ)-7 (84%) in a highly dia-
stereoselective fashion (dr Ն 98:2) (Scheme 3).
Although the addition of vinylmagnesium bromide to the
benzylimine of -glyceraldehyde has already been studied
and shown to afford the corresponding allylic amine (ϩ)-8
without racemization,[20] we nevertheless checked that the
same result was obtained in our hands during the alkylation
Scheme 1. Retrosynthetic analyses for (Ϫ)-4a,5-dihydrostreptazolin
A second shorter approach (Path B) involved the intro- of 6 with vinylmagnesium chloride. Thus, optically pure
duction of the triple bond by addition of an acetylenic (ϩ)-8 was prepared as described[20] and alkylated with p-
Grignard reagent to the corresponding aldehyde. We an- methoxybenzyl bromide to afford the tertiary amine (ϩ)-9
ticipated that the diastereoselectivity of this nucleophilic ad- (65%). At the same time, (ϩ)-7 was alkylated with benzyl
dition to the chiral α-oxygenated aldehyde would easily be bromide, which also afforded (ϩ)-9 (81%), exhibiting the
2842
Eur. J. Org. Chem. 2001, 2841Ϫ2850

Total Synthesis of (Ϫ)-4a,5-Dihydrostreptazolin
FULL PAPER
izing the high regioselectivity observed in this reaction, even
though the amine (ϩ)-10 is also allylic (Scheme 3).
The next steps included the formation of the tetrahy-
dropyridine ring, and functional group manipulation of the
isopropylidene ketal and carbamate in order to elaborate
the urethane five-membered ring of (Ϫ)-4a,5-dihydrostrep-
tazolin. Treatment of the carbamate (Ϫ)-11 with a catalytic
amount of Grubbs’ catalyst[23] in CH2Cl2 efficiently af-
forded the corresponding tetrahydropyridine (Ϫ)-12 (84%).
The acetonide was easily hydrolyzed with 80% aqueous
AcOH, and subsequent treatment of the crude intermediate
diol 13 with methanolic potassium hydroxide afforded the
alcohol (ϩ)-14; however, the latter was contaminated with
an unidentified impurity that could not be efficiently separ-
ated. No attempts were made to optimize this reaction,
since it was found advantageous to reverse the order of
these two steps, with the ring-closing metathesis occurring
preferentially later in the synthesis. Thus, hydrolysis of the
acetonide of (Ϫ)-11 afforded a crude diol 15, which was
quantitatively cyclized to urethane (ϩ)-16 (80%, two steps),
by treatment with a methanolic potassium hydroxide solu-
tion. At this stage, the ring-closing metathesis proceeded
efficiently and treatment of (ϩ)-16 with a catalytic amount
of Grubbs’ catalyst (3 mol %)[23] afforded (ϩ)-14 (90%),
highlighting the remarkable functional group tolerance of
this reaction, which does not require the protection of the
alcohol function (Scheme 5).
Scheme 3. Synthesis of carbamate (Ϫ)-11
same optical rotation and confirming that no racemization
had occurred during the addition of vinylmagnesium chlor-
ide to imine 6 (Scheme 4).
Scheme 4. Synthesis of allylic amine (ϩ)-9 from (ϩ)-7 and (ϩ)-8
The alkylation of (ϩ)-7 was carried out with 4-bromo-
but-1-ene in the presence of potassium carbonate and so-
dium iodide in DMF at 70Ϫ100 °C. In most initial at-
tempts, low and limited degrees of conversion into the de-
sired tertiary amine (ϩ)-10 were observed (30%). Slightly
improved results were obtained when one equivalent of the
soluble iodide source nBu4NI was used, but the isolated
yield of (ϩ)-10 remained quite low (38%), even though un-
changed (ϩ)-7 (50%) could easily be recovered and re-
cycled. However, we discovered that the concentration of
the reaction mixture had a significant effect on the yield:
performing the alkylation at a concentration of 2.7 mol·LϪ1
Scheme 5. Synthesis of tetrahydropyridine (ϩ)-14
The oxidation of (ϩ)-14 into the corresponding aldehyde
in 7 instead of 0.3 mol·LϪ1 raised the isolated yield of (ϩ)- 17 turned out to be problematic. Use of buffered PCC[24]
10 to 74%, despite the completely heterogeneous character gave
a
complex mixture of products, whereas
of the reaction mixture. The tertiary amine (ϩ)-10 was then DessϪMartin,[25] ParikhϪDoering,[26] and Swern[27] oxida-
debenzylated with methyl chloroformate[22] to afford the tions, followed by aqueous workup, afforded mixtures of
corresponding carbamate (Ϫ)-11 (91%). It is worth emphas- products in which the desired aldehyde 17 and variable
Eur. J. Org. Chem. 2001, 2841Ϫ2850
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´
J. Cossy, I. Pevet, C. Meyer
FULL PAPER
quantities of its inseparable, highly water-soluble hydrate 18
could be identified. Moreover, in the last case epimerization
at C-2a seemed to occur to a significant extent (ca. 15%)
(Scheme 6). Thus, aldehyde 17 could not be isolated by an
aqueous workup and its low solubility in nonpolar solvents
precluded their use to precipitate the ammonium salts after
completion of the Swern oxidation. Moreover, the temper-
ature had to be carefully controlled in order to avoid the
epimerization of the aldehyde, probably by triethylamine.
Figure 2. Differential NOE observed for diastereomers (ϩ)-20a and
(ϩ)-20b
Finally, completion of the synthesis required the ex-
change of the tributylstannyl group for a methyl one. To
this end, (ϩ)-20a was first iododestannylated to afford (ϩ)-
21a (93%). The latter was insoluble in most organic solvents
and so the organotin residues could easily be removed by
extensive washing with a pentane/ether mixture. For intro-
duction of the methyl group, we first investigated the use of
Me2CuLi in ether,[28] but the result was not satisfactory
since inseparable mixtures of reduced product and (Ϫ)-
4a,5-dihydrostreptazolin were formed even in the presence
of methyl iodide. Fortunately, (ϩ)-21a could be coupled
with MeZnBr in THF/DMF[29] to give (Ϫ)-4a,5-dihydro-
streptazolin (73%) {m.p. 161 °C, [α]2D0 ϭ Ϫ43 (c ϭ 0.67,
CHCl3)} (Scheme 7). Its structure was unambiguously con-
firmed by an X-ray crystallographic analysis (Figure 3), al-
though the previously reported optical rotation and melting
point for this compound were lower {m.p. 154Ϫ155 °C,
[α]2D3 ϭ Ϫ24.3 (c ϭ 0.54, CHCl3)}.[11]
Scheme 6. Oxidation of alcohol (ϩ)-14
Therefore, upon completion of the Swern oxidation, a
large excess of ethynylmagnesium bromide was added dir-
ectly to the reaction mixture. Under these conditions, no
efficient diastereocontrol could occur and a mixture of the
diastereomeric propargyl alcohols 19a and 19b was ob-
tained (63%, 60:40 ratio). They were not separated at this
stage but treated directly with tributyltin hydride in the
presence of AIBN in refluxing benzene. This radical-medi-
ated enyne cyclization afforded a 60:40 mixture of two dias-
tereomeric vinylstannanes (ϩ)-20a and (ϩ)-20b, which were
readily separated by flash chromatography (Scheme 7). In
these compounds, the relative configuration was unambigu-
ously assigned by differential NOE. Both vinylstannanes ex-
hibit a cis-fused ring junction and a Z olefinic configura-
tion, as suggested by the reciprocal intensity enhancement
caused by irradiation of the signals corresponding to H-
4a and H-7b, as well as H-8 and one proton (H-5) of the
tetrahydropyridine ring. Moreover, no NOE was observed
between H-2a and H-3 in (ϩ)-20a, in contrast to (ϩ)-20b,
indicating that the major diastereomer (ϩ)-20a has the re-
quired configuration at C-2a and C-3 for the synthesis of
(Ϫ)-4a,5-dihydrostreptazolin. (Figure 2).
Figure 3. ORTEP diagram for (Ϫ)-4a,5-dihydrostreptazolin
Thus (Ϫ)-4a,5-dihydrostreptazolin has been synthesized
in nine steps from -glyceraldehyde acetonide, in 9% overall
yield (Scheme 8).
The epimeric vinylstannane (ϩ)-20b was similarly con-
verted into the vinyl iodide (ϩ)-21b (88%) and the latter
was also coupled with methylzinc bromide to afford (ϩ)-
4a,5-dihydro-3-epistreptazolin 22 (50%). Finally, palladium-
catalyzed cross-coupling of (ϩ)-21a with PhZnBr and vinyl-
ZnBr afforded compounds (Ϫ)-23 (58%) and (Ϫ)-24 (62%)
respectively, illustrating the synthetic interest of inter-
mediate (ϩ)-21a for the synthesis of structures related to
(Ϫ)-4a,5-dihydrostreptazolin (Scheme 9).
Conclusion
We report a short and efficient synthesis of (Ϫ)-4a,5-di-
hydrostreptazolin, in nine steps from -glyceraldehyde ace-
Scheme 7. Total synthesis of (Ϫ)-4a,5-dihydrostreptazolin
2844
Eur. J. Org. Chem. 2001, 2841Ϫ2850

Total Synthesis of (Ϫ)-4a,5-Dihydrostreptazolin
FULL PAPER
Scheme 8. Total synthesis of (Ϫ)-4a,5-dihydrostreptazolin
ware under argon. Ϫ Analytical thin layer chromatography was
performed on Merck precoated silica gel (60 F254). Ϫ Flash chro-
matography was performed with Merck Kieselgel 60 (230Ϫ400
mesh). Ϫ Melting points were measured on a Kofler apparatus. Ϫ
IR: PerkinϪElmer 298 spectrometer.
Ϫ Optical rotations:
PerkinϪElmer 241MC polarimeter. Ϫ Elemental analyses: Service
´
´
Regional de Microanalyses de lЈUniversite P. et M. Curie (Paris
VI). Ϫ HRMS: Laboratoire de Spectrochimie de lЈEcole Normale
´
Superieure Ulm. Ϫ NMR: Bruker AC 300 spectrometer (300 MHz
1
and 75 MHz for H and 13C, respectively). Chemical shifts (δ) are
expressed in ppm relative to TMS. Ϫ MS: Mass spectra were ob-
tained by GC/MS with electron impact ionization using a 5971
Hewlett Packard instrument at 70 eV.
N-[(1S)-1-{(4S,5S)-5-[(tert-Butyldiphenylsiloxy)methyl]-2,2-
dimethyl-1,3-(dioxolan-4-yl)prop-2-enyl}]-4-methoxybenzylamine
[(؊)-4]: A solution of DMSO (2.60 mL, 36.6 mmol, 3.7 equiv.) in
CH2Cl2 (6 mL) was added dropwise at Ϫ78 °C to a solution of
oxalyl dichloride (1.46 mL, 16.7 mmol, 1.7 equiv.) in CH2Cl2
(40 mL). After 25 min, a solution of (Ϫ)-1 (4.0 g, 10 mmol) in
CH2Cl2 (13 mL) was added dropwise at Ϫ78 °C. After a further 15
min, Et3N (7.0 mL, 50 mmol, 5.0 equiv.) was added over 5 min,
Scheme 9. Synthesis of structural analogues of 4a,5-dihydrostrepta-
zolin
tonide, and in 9% overall yield. The stereoselective con-
struction of the tetrahydropyridine ring was performed us-
ing a vinylic Grignard reagent addition to an imine derived and the reaction was then allowed to warm slowly to room temp.
After 1 h, water (20 mL) was added to the reaction mixture, and
the organic layer was separated and concentrated under reduced
pressure. The residue was diluted with water and extracted with
ether. The combined extracts were washed with brine, dried over
Na2SO4, filtered, and evaporated under reduced pressure. The
crude aldehyde 2 (3.9 g) was dissolved in ether (50 mL). 4-Methox-
ybenzylamine (1.15 mL, 8.80 mmol, 0.90 equiv.) and anhydrous
MgSO4 (3 g) were then added and, after 3 h, the reaction mixture
was filtered through Celite and concentrated under reduced pres-
sure. The crude imine 3 (4.9 g) was dissolved in ether (35 mL) and
added dropwise to a solution of vinylmagnesium bromide (22 mL,
1  in THF, 22 mmol, 2.5 equiv.) at 0 °C. After 18 h at room temp.,
the reaction mixture was quenched with a mixture of 32% aqueous
NH4OH/saturated aqueous NH4Cl (1:2), and extracted with Ac-
OEt. The combined extracts were washed with brine, dried over
Na2CO3, and concentrated under reduced pressure. The crude mat-
from -glyceraldehyde acetonide and a ring-closing meta-
thesis reaction. Elaboration of the five-membered ring was
carried out by a highly stereoselective radical-mediated en-
yne cyclization. Furthermore, this strategy permits the
formation of derivatives of dihydrostreptazolin by cross-
coupling reactions with various organometallic reagents.
The biological properties of these compounds are currently
being evaluated.
Experimental Section
General: Unless otherwise specified, materials were purchased from
commercial suppliers and used without further purification. Ϫ
THF and ether were distilled from sodium/benzophenone ketyl im-
mediately before use. Ϫ Dichloromethane, DMF, DMSO, toluene, erial was purified by flash chromatography (cyclohexane/AcOEt,
benzene, acetonitrile, and triethylamine were distilled from calcium
hydride. Ϫ Zinc bromide was melted and cooled under argon. Ϫ
Moisture-sensitive reactions were conducted in oven-dried glass-
90:10) on silica gel previously impregnated with the eluent con-
taining 1% of 32% aqueous NH4OH solution. Compound (Ϫ)-4
(1.9 g, 35%) was obtained as an orange oil. Ϫ [α]2D0 ϭ Ϫ13 (c ϭ
Eur. J. Org. Chem. 2001, 2841Ϫ2850
2845

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J. Cossy, I. Pevet, C. Meyer
FULL PAPER
1.05, CHCl3). Ϫ IR (neat): ν˜ϭ 3330, 1610, 1585, 1510, 1245, 1170, as a colorless oil. Ϫ [α]2D0 ϭ ϩ12.9 (c ϭ 1.99, CHCl3). Ϫ IR (neat):
1
1110, 1000 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 0.97 (s, 9 H), 1.32 (s,
ν ϭ 3060, 1610, 1580, 1510, 1170, 1060 cmϪ1. Ϫ 1H NMR
˜
6 H), 1.62 (br. s, 1 H), 3.24 (dd, J ϭ 8.5, 4.1 Hz, 1 H), 3.58 (d, J ϭ (CDCl3): δ ϭ 1.23 (s, 3 H), 1.30 (s, 3 H), 2.97 (dd, J ϭ 9.0, 7.7 Hz,
13.2 Hz, 1 H), 3.58Ϫ3.81 (3 H), 3.71 (s, 3 H), 4.04 (m, 1 H), 4.14 1 H), 3.28 (d, J ϭ 13.2 Hz, 1 H), 3.32 (d, J ϭ 13.8 Hz, 1 H), 3.59
(dd, J ϭ 8.1, 4.1 Hz, 1 H), 5.17 (dd, J ϭ 17.3, 1.8 Hz, 1 H), 5.31 (dd, J ϭ 8.3, 7.4 Hz, 1 H), 3.76 (s, 3 H), 3.76 (d, J ϭ 13.2 Hz, 1
(dd, J ϭ 10.3, 1.8 Hz, 1 H), 5.74 (ddd, J ϭ 17.3, 10.3, 8.5 Hz, 1 H), 3.84 (d, J ϭ 13.8 Hz, 1 H), 4.11 (dd, J ϭ 8.3, 6.3 Hz, 1 H),
H), 6.85 (m, 2 H), 7.23 (m, 2 H), 7.35Ϫ7.46 (6 H), 7.66Ϫ7.72 (4 4.30 (ddd, J ϭ 7.7, 7.4, 6.3 Hz, 1 H), 5.17 (ddd, J ϭ 17.2, 2.2,
H). Ϫ13C NMR (CDCl3): δ ϭ 19.2 (s), 26.8 (q), 27.1 (q), 50.2 (t), 0.7 Hz, 1 H), 5.46 (ddd, J ϭ 10.3, 2.2, 0.4 Hz, 1 H), 5.95 (ddd, J ϭ
55.2 (q), 61.7 (d), 64.7 (t), 78.4 (d), 81.4 (d), 108.8 (s), 113.7 (d), 17.2, 10.3, 9.0 Hz, 1 H), 6.84 (m, 2 H), 7.20Ϫ7.26 (3 H), 7.29Ϫ7.31
118.6 (t), 127.6 (d), 129.3 (d), 129.7 (d), 132.5 (s), 133.2 (s), 135.6 (4 H). Ϫ 13C NMR (CDCl3): δ ϭ 25.6 (q), 26.4 (q), 54.0 (t), 54.5
(d), 136.3 (d), 158.5 (s). Ϫ MS (EI): m/z (%) ϭ 545 (0.1) [Mϩ], 176
(33), 136 (13), 121 (100).
(t), 55.1 (q), 63.9 (d), 68.5 (t), 76.8 (d), 109.2 (s), 113.6 (d), 120.6
(t), 126.9 (d), 128.2 (d), 128.7 (d), 129.8 (d), 131.6 (s), 132.2 (d),
139.8 (s), 158.6 (s). Ϫ MS (EI): m/z (%) ϭ 367 (0.5) [Mϩ], 266 (47),
121 (100), 91 (11).
N-{(1S)-1-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]prop-2-enyl}-4-
methoxybenzylamine [(؉)-7]: Anhydrous MgSO4 (30 g) was added
to
a solution of -glyceraldehyde acetonide (ϩ)-5 (19.8 g,
N-(But-3-enyl)-N-{(1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]prop-
2-enyl}-4-methoxybenzylamine [(؉)-10]: Anhydrous K2CO3 (11.2 g,
81.2 mmol, 3.0 equiv.), NaI (8.10 g, 54.0 mmol, 2.0 equiv.), and
nBu4NI (9.97 g, 27.1 mmol, 1.0 equiv.) were added successively to
a solution of (ϩ)-7 (7.50 g, 27.1 mmol) in DMF (10 mL). After
15 h at 70 °C, the reaction mixture was diluted with Et2O and fil-
tered through Celite. The insoluble salts were thoroughly washed
with ether and the filtrate was washed with water and brine, and
dried over Na2CO3. After filtration and concentration under re-
duced pressure, the crude material was purified by flash chromato-
graphy (petroleum ether/AcOEt, 95:5 to 90:10) to give 6.6 g (74%)
153 mmol) and 4-methoxybenzylamine (20.4 mL, 156 mmol, 1.02
equiv.) in ether (300 mL) at 0 °C. After 3 h at 0 °C, the reaction
mixture was filtered and concentrated under reduced pressure to
give 38.1 g (100%) of imine 6 as a slightly yellow liquid, which was
used directly in the next step. A solution of 6 (36.6 g, 147 mmol)
in ether (350 mL) was added dropwise at 0 °C to a solution of
vinylmagnesium chloride (218 mL, 1.68  in THF, 366 mmol, 2.5
equiv.). After stirring overnight at room temp., the reaction was
quenched with a mixture of 32% aqueous NH4OH/saturated aque-
ous NH4Cl: 1:2, and extracted with AcOEt. The combined extracts
were washed with brine, dried over Na2CO3, filtered, and concen-
trated under reduced pressure. The crude material was purified by
flash chromatography (cyclohexane/AcOEt/NH4OH, 90:10:0.1) to
give 34.0 g (84%) of (ϩ)-7 as a yellow liquid. Ϫ [α]2D0 ϭ ϩ21 (c ϭ
of (ϩ)-10 as a yellow liquid. Ϫ [α]2D0 ϭ ϩ 60 (c ϭ 1.10, CHCl3). Ϫ
Ϫ1
˜
IR (neat): ν ϭ 3070, 1640, 1610, 1585, 1510, 1250, 1060, 1035 cm
.
1
Ϫ H NMR (CDCl3): δ ϭ 1.32 (s, 3 H), 1.35 (s, 3 H), 2.17Ϫ2.25
(2 H), 2.45 (ddd, J ϭ 12.9, 7.0, 5.4 Hz, 1 H), 2.67 (dt, J ϭ 12.9,
8.1 Hz, 1 H), 2.97 (dd, J ϭ 8.8, 8.5 Hz, 1 H), 3.31 (d, J ϭ 13.6 Hz,
1 H), 3.72 (dd, J ϭ 8.5, 6.8 Hz, 1 H), 3.77 (d, J ϭ 13.6 Hz, 1 H),
3.81 (s, 3 H), 4.10 (dd, J ϭ 8.5, 6.2 Hz, 1 H), 4.21 (m, 1 H),
4.98Ϫ5.09 (2 H), 5.19 (m, 1 H), 5.42 (dd, J ϭ 10.3, 2.2 Hz, 1 H),
5.76 (ddt, J ϭ 16.9, 10.1, 6.8 Hz, 1 H), 5.89 (ddd, J ϭ 16.9, 10.3,
8.8 Hz, 1 H), 6.86 (m, 2 H), 7.21 (m, 2 H). Ϫ 13C NMR (CDCl3):
δ ϭ 25.6 (q), 26.6 (q), 33.1 (t), 50.0 (t), 54.3 (t), 55.1 (q), 65.1 (d),
68.6 (t), 76.5 (d), 109.2 (s), 113.5 (d), 115.5 (t), 120.0 (t), 129.7 (d),
131.8 (s), 132.6 (d), 136.8 (d), 158.5 (s). Ϫ MS (EI): m/z (%) ϭ 331
(0.02) [Mϩ], 316 (1.5) [M Ϫ CH3ϩ], 231 (8), 230 (44), 122 (9), 121
(100). Ϫ C20H29NO3 (331.45): calcd. C 72.47, H 8.81, N 4.22;
found C 72.52, H 8.87, N 4.13.
˜
1.14, CHCl3). Ϫ IR (neat): ν ϭ 3320, 3060, 1640, 1610, 1785, 1510,
1240, 1170, 1140 cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 1.35 (s, 3 H),
1.41 (s, 3 H), 1.65 (br. s, 1 H), 3.17 (dd, J ϭ 8.1, 4.8 Hz, 1 H), 3.58
(d, J ϭ 12.9 Hz, 1 H), 3.80 (s, 3 H), 3.81 (d, J ϭ 12.9 Hz, 1 H),
3.89 (dd, J ϭ 8.1, 7.0 Hz, 1 H), 4.00 (dd, J ϭ 8.1, 6.6 Hz, 1 H),
4.13 (ddd, J ϭ 7.0, 6.6, 4.8 Hz, 1 H), 5.22 (ddd, J ϭ 17.3, 1.8,
0.7 Hz, 1 H), 5.30 (ddd, J ϭ 10.3, 1.8, 0.7 Hz, 1 H), 5.68 (ddd, J ϭ
17.3, 10.3, 8.1 Hz, 1 H), 6.86 (m, 2 H), 7.24 (m, 2 H). Ϫ 13C NMR
(CDCl3): δ ϭ 25.0 (q), 26.3 (q), 50.1 (t), 55.1 (q), 61.8 (d), 66.0 (t),
78.2 (d), 108.9 (s), 113.6 (d), 118.3 (t), 129.1 (d), 132.4 (s), 136.4
(d), 158.4 (s). Ϫ MS (EI): m/z (%) ϭ 278 (0.05) [Mϩ], 176 (21), 121
(100). Ϫ C16H23NO3 (277.36): calcd. C 69.29, H 8.36, N 5.05;
found C 69.30, H 8.45, N 4.96.
N-Benzyl-N-{(1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]prop-2- Methyl N-(But-3-enyl)-N-{(1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-
enyl}-4-methoxybenzylamine [(؉)-9]
yl]prop-2-enyl}carbamate [(؊)-11]: Anhydrous Na2CO3 (20.0 g,
Synthesis from (؉)-8: Anhydrous K2CO3 (780 mg, 5.66 mmol, 2.0
189 mmol, 7.0 equiv.) and ClCO2CH3 (14.5 mL, 189 mmol, 7.0
equiv.), nBu4NI (100 mg, 0.28 mmol, 0.1 equiv.), and p-methoxyb- equiv.) were added to a solution of (ϩ)-10 (8.90 g, 26.9 mmol) in
enzyl bromide (630 mg, 3.11 mmol, 1.1 equiv.) were added success- benzene (160 mL). After 15 h at 75 °C, additional ClCO2CH3
ively to a solution of (ϩ)-8[21] (700 mg, 2.83 mmol) in CH3CN (5.0 mL, 65 mmol, 2.4 equiv.) was added and the reaction mixture
(6 mL). After 1 h at 40 °C and overnight at room temp., the reac-
tion mixture was diluted with ether, filtered, and concentrated un-
der reduced pressure. The crude material was purified by flash
chromatography (cyclohexane/AcOEt, 95:5 to 90:10) to give 0.68 g
(65%) of (ϩ)-9 as a colorless oil. Ϫ [α]2D0 ϭ ϩ12.5 (c ϭ 2.02,
CHCl3).
was refluxed. After 2 h, the reaction mixture was cooled to room
temp., filtered, and concentrated under reduced pressure, and the
crude material was purified by flash chromatography (cyclohexane/
AcOEt, 95:5) to give 6.6 g (91%) of (Ϫ)-11 as a yellow liquid. Ϫ
[α]2D0 ϭ Ϫ15 (c ϭ 2.08, CHCl3). Ϫ IR (neat): ν ϭ 3070, 1710, 1640,
˜
1
1150, 1060 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 1.35 (s, 3 H), 1.43 (s,
Synthesis from (؉)-7: Anhydrous K2CO3 (500 mg, 3.62 mmol, 2.0
3 H), 2.21Ϫ2.40 (2 H), 3.18Ϫ3.35 (2 H), 3.71 (s, 3 H), 3.75 (dd,
equiv.), nBu4NI (66 mg, 0.18 mmol, 0.1 equiv.), and benzyl bromide J ϭ 8.5, 6.2 Hz, 1 H), 4.04 (dd, J ϭ 8.5, 6.2 Hz, 1 H), 4.27Ϫ4.45
(0.24 mL, 1.98 mmol, 1.1 equiv.) were added successively to a solu-
tion of (ϩ)-7 (500 mg, 1.81 mmol) in CH3CN (5 mL). After 2 h at
(2 H), 5.01Ϫ5.10 (2 H), 5.20Ϫ5.33 (2 H), 5.75 (ddt, J ϭ 16.9, 10.3,
7.0 Hz, 1 H), 6.01 (m, 1 H). Ϫ 13C NMR (CDCl3): δ ϭ 25.2 (q),
35Ϫ40 °C and overnight at room temp., the reaction mixture was 26.6 (q), 34.0 (t), 45.3 (t), 52.5 (q), 61.4 (d), 67.1 (t), 76.5 (d), 109.8
diluted with ether, filtered, and concentrated under reduced pres- (s), 116.4 (t), 119.0 (t), 132.9 (d), 135.1 (d), 156.7 (s). Ϫ MS (EI):
sure. The crude material was purified by flash chromatography m/z (%) ϭ 254 (16) [M Ϫ CH3ϩ], 228 (12), 170 (14), 169 (14), 168
(cyclohexane/AcOEt, 95:5 to 90:10) to give 0.54 g (81%) of (ϩ)-9
(100), 140 (11), 128 (12), 127 (23), 101 (71), 88 (20), 81 (14), 55
2846
Eur. J. Org. Chem. 2001, 2841Ϫ2850

Total Synthesis of (Ϫ)-4a,5-Dihydrostreptazolin
(11). Ϫ C14H23NO4 (269.34): calcd. C 62.43, H 8.61, N 5.20; found (4S,5S)-4-(Hydroxymethyl)-3-oxa-1-azabicyclo[4.3.0]non-6-en-2-one
FULL PAPER
C 62.33, H 8.77, N 5.14.
[(؉)-14]
Synthesis from (؉)-16: A degassed solution of (ϩ)-16 (1.20 g,
6.09 mmol) in benzene (150 mL) was warmed to 55 °C and 1 mL
of a solution of Cl2(PCy3)2RuϭCHPh [150 mg, 0.18 mmol, 0.03
equiv., in benzene (7 mL)] was added every 20 min. After 1 h at 60
°C and overnight at room temp., the reaction mixture was exposed
to air. After 2 h, the resulting mixture was concentrated under re-
duced pressure and the crude material was purified by chromato-
graphy (CH2Cl2/AcOEt, 80:20 to 0:100) to give 930 mg (90%) of
(ϩ)-14 as a gray solid. Ϫ m.p. 67Ϫ70 °C. Ϫ [α]2D0 ϭ ϩ153 (c ϭ
Methyl 6-(2,2-Dimethyl-1,3-dioxolan-4-yl)-1,2,3,6-tetrahydropyrid-
ine-1-carboxylate [(؊)-12]: A solution of Cl2(PCy3)2RuϭCHPh
(93 mg, 0.11 mmol, 0.05 equiv.) in CH2Cl2 (5 mL) was added in
four portions at 20 min intervals to a refluxing degassed solution
of (Ϫ)-11 (610 mg, 2.27 mmol) in CH2Cl2 (20 mL). After 18 h at
reflux, the reaction mixture was cooled to room temp., exposed to
air and, after 2 h, concentrated under reduced pressure. The crude
material was purified by chromatography (cyclohexane/AcOEt,
80:20) to give 450 mg (84%) of (Ϫ)-12, as a slightly green oil. Ϫ
˜
1.67, CHCl3). Ϫ IR (KBr): ν ϭ 3400, 3030, 1740, 1645, 1445, 1430,
[α]2D0 ϭ Ϫ266 (c ϭ 1.50, CHCl3). Ϫ IR (neat): ν ϭ 3030, 1700,
˜
1
1230, 1055, 1035 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 2.05 (m, 1 H),
1655, 1255, 1200, 1150, 1105, 1055 cmϪ1. Ϫ 1H NMR (CDCl3) All
signals are broad, due to the presence of rotamers: δ ϭ 1.34 (s, 3 H),
1.44 (s, 3 H), 1.97 (m, 1 H), 2.20 (m, 1 H), 3.01 (m, 1 H), 3.72 (s,
3 H), 4.60Ϫ4.85 (5 H), 5.82 (m, 1 H), 5.97 (m, 1 H). Ϫ 13C NMR
(CDCl3): δ ϭ 24.3 and 24.7 (t, 2 rotamers), 25.3 (q), 26.6 and 26.8
(q, 2 rotamers), 38.1 and 38.7 (t, 2 rotamers), 52.6 (q), 54.2 (d),
67.2 (t), 77.9 (d), 109.6 (s), 125.1 (d), 126.8 and 127.2 (d, 2 rota-
mers), 156.0 (s). Ϫ MS (EI): m/z (%) ϭ 241 (2) [Mϩ], 140 (100),
101 (92), 73 (11).
2.22 (m, 1 H, OH), 2.36 (m, 1 H), 3.04 (ddd, J ϭ 13.4, 11.4, 4.6 Hz,
1 H), 3.72Ϫ3.75 (2 H), 3.94 (dd, J ϭ 13.6, 6.8 Hz, 1 H), 4.52 (m,
1 H), 4.70 (dt, J ϭ 8.8, 5.5 Hz, 1 H), 5.70 (m, 1 H), 6.03 (m, 1 H).
Ϫ
13C NMR (CDCl3): δ ϭ 23.3 (t), 38.0 (t), 54.2 (d), 61.1 (t), 77.1
(d), 122.0 (d), 128.7 (d), 157.0 (s). Ϫ MS (EI): m/z (%) ϭ 169 (48)
[Mϩ], 139 (18), 138 (100) [M Ϫ CH2OHϩ], 82 (16), 81 (48), 80 (26),
67 (20), 56 (16), 54 (15).
(3S,4S)-4-[(1S)-1-Hydroxyprop-2-ynyl]-3-oxa-1-azabicyclo-
[4.3.0]non-6-en-2-one (19a) and (3S,4S)-4-[(1R)-1-Hydroxyprop-
(4S,5S)-4-(Hydroxymethyl)-3-oxa-1-azabicyclo[4.3.0]non-6-en-2-one
[(؉)-14]:
2-ynyl]-3-oxa-1-azabicyclo[4.3.0]non-6-en-2-one
(19b):
DMSO
(3.10 mL, 43.4 mmol, 3.5 equiv.) was added dropwise at Ϫ78 °C to
a solution of oxalyl dichloride (1.81 mL, 21.1 mmol, 1.7 equiv.) in
CH2Cl2 (40 mL). After 10 min, a solution of (ϩ)-14 (2.10 g,
12.4 mmol) in CH2Cl2 (10 mL) was added dropwise at Ϫ78 °C.
After 20 min, Et3N (5.20 mL, 37.3 mmol, 3.0 equiv.) was added
and the reaction was gradually warmed to Ϫ40 °C. After 1 h, ethy-
nylmagnesium bromide (200 mL, 0.5  in THF, 100 mmol, 8.1
equiv.) was introduced slowly at Ϫ78 °C. The reaction mixture was
warmed to 0 °C, poured into a saturated aqueous solution of
NH4Cl, and extracted with AcOEt. The combined extracts were
dried over MgSO4 and concentrated under reduced pressure, and
the crude material was purified by flash chromatography (petro-
leum ether/AcOEt, 40:60 to 0:100) to give 1.50 g (63%) of a 60:40
Synthesis from (؊)-12: Compound (Ϫ)-12 (509 mg, 2.11 mmol) was
added to an 80% aqueous solution of acetic acid (40 mL). After
1 h at 80 °C, the reaction mixture was diluted with toluene and
concentrated under reduced pressure. The residue was diluted with
toluene and evaporated again. The crude material was dissolved in
a 10% KOH solution in methanol (15 mL). After 3 h at room temp.
the reaction mixture was concentrated under reduced pressure. The
residue was neutralized at 0 °C by addition of a 3  aqueous solu-
tion of hydrochloric acid and extracted several times with AcOEt.
The combined extracts were dried over Na2SO4, filtered, and con-
centrated under reduced pressure. The crude material was purified
by flash chromatography (CH2Cl2/EtOH, 95:5) to give 300 mg of
(ϩ)-14 as an oil, which was contaminated with an unidentified in-
separable impurity [spectroscopic data of (ϩ)-14 are listed under
the synthesis of this compound from (ϩ)-16].
diastereomeric mixture of 19a and 19b as a white solid. Ϫ IR
Ϫ1
˜
(KBr): ν ϭ 3396, 3237, 2112, 1720, 1445, 1120, 1056 cm
.
1
Compound 19a: H NMR (CD3OD): δ ϭ 2.24 (m, 1 H), 2.52 (m,
1 H), 3.22 (d, J ϭ 2.6 Hz, 1 H), 3.27 (m, 1 H), 4.02 (dd, J ϭ 13.6,
6.6 Hz, 1 H), 4.60 (dd, J ϭ 6.2, 2.2 Hz, 1 H), 4.78Ϫ4.86 (2 H),
6.09Ϫ6.25 (2 H). Ϫ 13C NMR (CDCl3): δ ϭ 23.1 (t), 38.5 (t), 54.5
(d), 61.6 (d), 75.9 (d), 78.6 (d), 79.8 (s), 121.9 (d), 129.7 (d), 156.6
(s). Ϫ MS (EI): m/z (%) ϭ 164 (4), 139 (13), 138 (100) [M Ϫ
C3H3Oϩ], 132 (15), 94 (21), 93 (18), 81 (14), 80 (19), 67 (17), 56
(15), 55 (14), 53 (12).
(4S,5S)-3-(But-3-enyl)-4-ethenyl-5-(hydroxymethyl)oxazolidin-2-one
[(؉)-16]: Compound (Ϫ)-11 (3.50 g, 13.0 mmol) was added to an
80% aqueous solution of acetic acid (200 mL). After 4 h at 80 °C,
the reaction mixture was diluted with toluene and concentrated
under reduced pressure. The residue was diluted with toluene and
evaporated again. The crude material was dissolved in a 10% solu-
tion of KOH in methanol (50 mL). After 2 h at room temp., the
reaction mixture was concentrated under reduced pressure. The res-
idue was neutralized at 0 °C with a 3  aqueous solution of hydro-
chloric acid, and extracted with AcOEt. The combined extracts
were dried over Na2SO4, filtered, concentrated under reduced pres-
sure, and the crude material was purified by flash chromatography
(CH2Cl2/AcOEt, 75:25) to give 2.04 g (80%) of (ϩ)-16 as a yellow
oil. Ϫ [α]2D0 ϭ ϩ26 (c ϭ 1.00, CHCl3). Ϫ IR (neat): ν˜ ϭ 3400, 3070,
1
Compound 19b: H NMR (CD3OD): δ ϭ 2.24 (m, 1 H), 2.52 (m,
1 H), 3.12 (d, J ϭ 2.2 Hz, 1 H), 3.27 (m, 1 H), 4.03 (dd, J ϭ 13.2,
6.6 Hz, 1 H), 4.57 (dd, J ϭ 5.2, 2.2 Hz, 1 H), 4.78Ϫ4.86 (2 H),
6.09Ϫ6.25 (2 H). Ϫ 13C NMR (CDCl3): δ ϭ 23.4 (t), 38.0 (t), 54.1
(d), 61.9 (d), 75.9 (d), 78.3 (d), 80.2 (s), 121.9 (d), 129.2 (d), 156.4
(s). Ϫ MS (EI): m/z (%) ϭ 149 (7) [M Ϫ CO2ϩ], 139 (12), 138 (100)
[M Ϫ C3H3Oϩ], 132 (15), 94 (25), 93 (17), 81 (18), 80 (21), 67 (20),
56 (17), 53 (18). Ϫ C10H11NO3 (193.20): calcd. C 62.17, H 5.74, N
7.25; found C 62.10, H 5.75, N 7.12.
1
1740, 1640, 1420, 1220, 835, 760 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ
2.21Ϫ2.35 (2 H), 2.53 (t, J ϭ 6.3 Hz, 1 H, OH), 3.03 (ddd, J ϭ
14.0, 7.4, 5.9 Hz, 1 H), 3.51 (dt, J ϭ 14.0, 7.4 Hz, 1 H), 3.74Ϫ3.78
(2 H), 4.34 (dd, J ϭ 9.2, 8.8 Hz, 1 H), 4.61 (dt, J ϭ 8.8, 5.0 Hz, 1
H), 5.04Ϫ5.15 (2 H), 5.38Ϫ5.45 (2 H), 5.69Ϫ5.92 (2 H). Ϫ 13C Radical-Mediated Cyclisation of 19a and 19b: Bu3SnH (910 µL,
NMR (CDCl3): δ ϭ 31.7 (t), 41.2 (t), 61.0 (d), 61.3 (t), 76.7 (d), 3.37 mmol, 1.3 equiv.) was added to a solution of 19a and 19b
117.3 (t), 122.4 (t), 131.8 (d), 134.7 (d), 157.3 (s). Ϫ MS (EI): m/z (500 mg, 60:40 diastereomeric mixture, 2.59 mmol) and AIBN
(%) ϭ 197 (0.3) [Mϩ], 156 (100) [M Ϫ C3H5ϩ], 82 (11), 68 (67), 67 (17 mg, 0.10 mmol, 0.04 equiv.) in refluxing benzene (130 mL).
(22), 55 (35), 53 (10). Ϫ C10H15NO3 (197.24): calcd. C 60.90, H After 1 h and 2 h, the same quantities of AIBN and Bu3SnH were
7.66, N 7.10; found C 60.73, H 7.88, N 7.04.
added again to the reaction mixture. After a further 3 h reflux, the
Eur. J. Org. Chem. 2001, 2841Ϫ2850
2847

´
J. Cossy, I. Pevet, C. Meyer
FULL PAPER
reaction mixture was concentrated under reduced pressure and the
crude material purified by filtration through silica gel (cyclohexane/
CH2Cl2, 20:80, then CH2Cl2, then CH2Cl2/AcOEt, 95:5) to give
drostreptazolin as colorless crystals. Ϫ m.p. 161 °C. Ϫ [α]2D0 ϭ Ϫ43
˜
(c ϭ 0.67, CHCl3). Ϫ IR (KBr): ν ϭ 3360, 1710, 1665, 1025,
1
1000 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 1.35Ϫ1.59 (2 H), 1.80 (dd,
380 mg (30%) of (ϩ)-20b and 640 mg (52%) of (ϩ)-20a as white J ϭ 6.9, 2.7 Hz, 3 H), 1.83 (m, 1 H), 2.12 (m, 1 H), 2.31 (d, J ϭ
solids.
2.2 Hz, 1 H, OH), 2.78 (m, 1 H), 2.94 (m, 1 H), 3.79 (m, 1 H), 4.21
(dd, J ϭ 7.0, 5.5 Hz, 1 H), 4.72 (d, J ϭ 7.0 Hz, 1 H), 4.74 (br. s, 1
H), 5.54 (qdd, J ϭ 6.9, 2.7, 1.1 Hz, 1 H). Ϫ 13C NMR (CDCl3):
δ ϭ 14.2 (q), 18.5 (t), 20.6 (t), 38.5 (d), 40.6 (t), 59.0 (d), 74.7 (d),
81.2 (d), 123.8 (d), 138.9 (s), 156.0 (s). Ϫ MS (EI): m/z (%) ϭ 209
(17) [Mϩ], 194 (43) [Mϩ Ϫ CH3], 165 (63), 164 (87), 150 (100), 148
(29), 136 (23), 122 (28), 95 (34), 79 (23), 67 (22), 55 (24). Ϫ
C11H15NO3 (209.24): calcd. C 63.14, H 7.23, N 6.69; found C
63.11, H 7.26, N 6.63.
(5S,6Z,7S,8S,11S)-6-(Tri-n-butylstannylmethylidene)-7-hydroxy-9-
oxa-1-azatricyclo[6.2.1.05,11]undecan-10-one [(؉)-20a]:
Ϫ
˜
m.p.
71Ϫ72 °C. Ϫ [α]2D0 ϭ ϩ9 (c ϭ 1.25, CHCl3). Ϫ IR (KBr): ν ϭ 3336,
2853, 1722, 1456, 1425, 1245, 1035 cmϪ1. Ϫ 1H NMR (C6D6): δ ϭ
0.82 (m, 1 H), 0.98Ϫ1.09 (17 H), 1.36Ϫ1.46 (7 H), 1.58Ϫ1.67 (6
H), 1.90 (m, 1 H, OH), 2.21 (ddd, J ϭ 15.1, 12.1, 2.9 Hz, 1 H),
2.61 (m, 1 H), 3.52 (m, 1 H), 3.75 (m, 1 H), 4.23 (br. d, J ϭ 2.6 Hz,
1 H), 4.36 (d, J ϭ 7.4 Hz, 1 H), 6.00 (d, J ϭ 2.6 Hz, 1 H). Ϫ 13C
NMR (CDCl3): δ ϭ 10.6 (t), 13.6 (q), 18.9 (t), 21.1 (t), 27.2 (t),
28.9 (t), 40.2 (d), 40.8 (t), 59.1 (d), 79.6 (d), 81.2 (d), 129.1 (d),
155.9 (s), 156.5 (s). Ϫ C22H39NO3Sn (484.27): calcd. C 54.57, H
8.12, N 2.89; found C 54.90, H 8.13, N 2.72.
(5S,6Z,7R,8S,11S)-7-Hydroxy-6-iodomethylidene-9-oxa-1-azatri-
cyclo[6.2.1.05,11]undecan-10-one [(؉)-21b]: Vinylstannane (ϩ)-20b
(1.20 g, 2.48 mmol) was converted into (ϩ)-21b as described for the
preparation of (ϩ)-21a from (ϩ)-20a, using iodine (1.90 g,
7.49 mmol, 3.0 equiv.) in CH2Cl2 (25 mL). The crude solid material
was washed several times with pentane/ether (3:1), to give 700 mg
(5S,6Z,7R,8S,11S)-6-(Tri-n-butylstannylmethylidene)-7-hydroxy-9-
oxa-1-azatricyclo[6.2.1.05,11]undecan-10-one [(؉)-20b]:
Ϫ
m.p.
(88%) of (ϩ)-21b as a white solid. Ϫ m.p. 200Ϫ204 °C. Ϫ [α]2D0
ϩ111 (c ϭ 1.20, DMSO). Ϫ IR (KBr): nu (tilde) ϭ 3340, 1710,
1650, 1640, 1260, 1230, 1060, 1010 cmϪ1 1H NMR
ϭ
45Ϫ46 °C. Ϫ [α]2D0 ϭ ϩ84 (c ϭ 1.32, CHCl3). Ϫ IR (KBr): ν˜ ϭ
3410, 2363, 1724, 1637, 1458, 1156, 1068, 1012 cmϪ1. Ϫ H NMR
1
.
Ϫ
(C6D6): δ ϭ 0.78 (m, 1 H), 0.98Ϫ1.14 (15 H), 1.38Ϫ1.50 (7 H),
1.64Ϫ1.81 (9 H), 2.17 (m, 1 H), 2.97 (d, J ϭ 9.6 Hz, 1 H, OH),
3.21 (dd, J ϭ 7.0, 5.5 Hz, 1 H), 3.65 (br. dd, J ϭ 13.6, 4.4 Hz, 1
H), 4.01 (m, 1 H), 4.16 (dd, J ϭ 7.0, 6.6 Hz, 1 H), 5.92 (apparent
t, J ϭ 2.4 Hz, 1 H). Ϫ 13C NMR (CDCl3): δ ϭ 11.6 (t), 13.7 (q),
19.1 (t), 20.8 (t), 27.3 (t), 29.2 (t), 38.5 (d), 41.2 (t), 57.2 (d), 73.8
(d), 74.8 (d), 123.8 (d), 153.2 (s), 155.7 (s). Ϫ C22H39NO3Sn
(484.27): calcd. C 54.57, H 8.12, N 2.89; found C 54.93, H 8.19,
N 2.76.
([D6]DMSO): δ ϭ 1.26Ϫ1.39 (2 H), 1.73 (m, 1 H), 2.04 (m, 1 H),
2.68 (m, 1 H), 2.82 (m, 1 H), 3.54 (m, 1 H), 4.41 (dd, J ϭ 6.6,
6.3 Hz, 1 H), 4.48 (ddd, J ϭ 6.6, 6.3, 1.8 Hz, 1 H), 4.81 (dd, J ϭ
6.6, 6.3 Hz, 1 H), 5.42 (d, J ϭ 6.6 Hz, 1 H), 6.43 (br. t, J ϭ 2.0 Hz
1 H). Ϫ 13C NMR ([D6]DMSO): δ ϭ 19.6 (t), 22.6 (t), 40.0 (t),
41.1 (d), 58.0 (d), 74.0 (d), 74.9 (d), 76.1 (d), 151.4 (s), 156.2 (s).
(؉)-4a,5-Dihydro-3-epistreptazoline [(؉)-22]:
Methyllithium
(2.7 mL, 1.6  in ether, 4.4 mmol, 7.0 equiv.) was added at 0 °C to
a solution of anhydrous ZnBr2 (1.12 g, 4.98 mmol, 8.0 equiv.) in
THF (5 mL). After 15 min at room temp., a solution of (ϩ)-21b
(0.20 g, 0.62 mmol) in DMF (10 mL) was added dropwise; 10 min
later Pd(PPh3)4 (22 mg, 19 µmol, 0.03 equiv.) was added, and the
reaction mixture was heated at 45 °C. After 1 h, the reaction mix-
ture was cooled to room temp. and poured into a cold saturated
aqueous solution of NH4Cl and extracted with AcOEt. The com-
bined extracts were dried over MgSO4, filtered, and concentrated
under reduced pressure. The crude material was purified by flash
chromatography (CH2Cl2/EtOH: 95:5) to give 65 mg (50%) of (ϩ)-
22 as a slightly yellow solid. Ϫ m.p. 149 °C. Ϫ [α]2D0 ϭ ϩ78 (c ϭ
0.33, CHCl3). Ϫ IR (KBr): ν˜ ϭ 3374, 1708, 1671, 1300, 1254, 1158,
1067, 1013 cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 1.40 (m, 1 H), 1.60
(m, 1 H), 1.80 (m, 1 H), 1.93 (m, 3 H), 2.08 (m, 1 H), 2.46 (m, 1
H), 2.52 (br. s, 1 H, OH), 2.81 (ddd, J ϭ 15.3, 12.0, 3.5 Hz, 1 H),
3.80 (m, 1 H), 4.10 (dd, J ϭ 7.0, 5.5 Hz, 1 H), 4.67 (br. s, 1 H),
4.77 (dd t, J ϭ 7.0, 6.6 Hz, 1 H), 5.52 (tdd, J ϭ 7.0, 2.5, 2.2 Hz, 1
H). Ϫ 13C NMR (CDCl3): δ ϭ 13.0 (q), 19.1 (t), 21.5 (t), 37.7 (d),
41.0 (t), 57.4 (d), 74.6 (d), 75.3 (d), 123.4 (d), 136.3 (s), 156.3 (s).
Ϫ MS (EI): m/z (%) ϭ 209 (100) [Mϩ], 194 (83), 164 (64), 150
(100), 122 (27), 95 (41), 79 (29), 67 (26), 55 (28). Ϫ HRMS (CIϩ,
CH4); C11H16NO3 [MHϩ]: calcd. 210.1130; found 210.1129.
(5S,6Z,7S,8S,11S)-7-Hydroxy-6-iodomethylidene-9-oxa-1-azatri-
cyclo[6.2.1.05,11]undecan-10-one
[(؉)-21a]:
Iodine
(580 mg,
2.29 mmol, 3.0 equiv.) was added to a solution of (ϩ)-20a (370 mg,
0.76 mmol) in CH2Cl2 (10 mL) at 0 °C. After 1 h at 0 °C, the reac-
tion mixture was quenched by addition of a saturated aqueous so-
lution of Na2S2O3 (4 mL) and extracted several times with AcOEt.
The combined extracts were dried over Na2SO4 and concentrated
under reduced pressure to give a solid material, which was washed
twice with pentane/ether (2:1) and filtered. Analytically pure (ϩ)-
21a (230 mg, 93%) was obtained as a white solid. Ϫ m.p. 200Ϫ201
°C. Ϫ [α]2D0 ϭ ϩ64 (c ϭ 0.70, DMSO). Ϫ IR (KBr): ν ϭ 3318,
˜
3062, 1718, 1235, 1078, 1029 cmϪ1. Ϫ 1H NMR ([D6]DMSO): δ ϭ
1.16Ϫ1.37 (2 H), 1.77 (m, 1 H), 2.12 (m, 1 H), 2.77 (m, 1 H), 2.89
(m, 1 H), 3.52 (m, 1 H), 4.30 (d, J ϭ 4.4 Hz, 1 H), 4.35 (m, 1 H),
4.61 (d, J ϭ 7.4 Hz, 1 H), 5.70 (d, J ϭ 4.4 Hz, 1 H, OH), 6.49 (d,
J ϭ 2.2 Hz, 1 H). Ϫ 13C NMR ([D6]DMSO): δ ϭ 18.7 (t), 20.0 (t),
40.1 (t), 40.2 (d), 58.7 (d), 78.5 (d), 79.9 (d), 81.2 (d), 151.2 (s),
155.0 (s).
(؊)-4a, 5-Dihydrostreptazoline: Methyllithium (12.2 mL, 1.6  in
ether, 19.6 mmol, 7.0 equiv.) was added at 0 °C to a solution of
anhydrous ZnBr2 (5.0 g, 22 mmol, 8.0 equiv.) in THF (25 mL).
After 20 min at room temp., a solution of (ϩ)-21a (900 mg,
2.80 mmol) in DMF (15 mL) was added dropwise. Ten min later,
Pd(PPh3)4 (100 mg, 0.08 mmol, 0.03 equiv.) was added and the re-
(5S,6Z,7S,8S,11S)-6-Benzylidene-7-hydroxy-9-oxa-1-azatri-
action mixture was heated at 60 °C. After 2 h, the reaction mixture cyclo[6.2.1.05,11]undecan-10-one [(؊)-(23)]: This compound was pre-
was cooled to 0 °C, poured into a saturated aqueous solution of
pared by cross-coupling of (ϩ)-21a (150 mg, 0.467 mmol) with
NH4Cl, and extracted with AcOEt. The combined extracts were phenylzinc bromide [prepared from phenyllithium (1.65 mL, 2  in
dried over MgSO4, filtered, and concentrated under reduced pres-
sure. The crude material was purified by flash chromatography (Ac-
cyclohexane/ether: 70:30, 3.28 mmol, 7.0 equiv.) and ZnBr2 (0.85 g,
3.77 mmol, 8.1 equiv.) in THF (3.5 mL)], catalyzed by Pd(PPh3)4
OEt). A slightly yellow, impure solid (550 mg) was obtained and (16 mg, 14 µmol, 0.03 equiv.) in DMF (7.5 mL) as described above.
recrystallized from benzene to give 430 mg (73%) of (Ϫ)-4a,5-dihy-
Flash chromatography (CH2Cl2/EtOH: 95:5) afforded 95 mg of a
2848
Eur. J. Org. Chem. 2001, 2841Ϫ2850

Total Synthesis of (Ϫ)-4a,5-Dihydrostreptazolin
FULL PAPER
yellow solid, which was washed with benzene to give 74 mg (58%)
of (Ϫ)-23 as a white solid. Ϫ m.p. 222 °C. Ϫ [α]2D0 ϭ Ϫ118 (c ϭ
[1]
[2]
H. Drautz, H. Zähner, E. Kupfer, W. Keller-Schierlein, Helv.
Chim. Acta 1981, 64, 1752Ϫ1765.
The Chemical Abstracts numbering system for streptazolin and
its dihydro derivatives is employed throughout the introduc-
tion, as well as in the results and discussion sections of this pa-
per.
˜
0.47, CH3CN). Ϫ IR (KBr): ν ϭ 3530, 1730, 1260, 1020,
1
1000 cmϪ1. Ϫ H NMR (CD3CN): δ ϭ 1.19Ϫ1.43 (2 H), 1.74 (m,
1 H), 2.05 (m, 1 H), 2.62 (ddd, J ϭ 15.8, 12.1, 3.7 Hz, 1 H), 2.83
(m, 1 H), 3.43 (m, 1 H), 3.44 (d, J ϭ 3.9 Hz, 1 H, OH), 4.07 (dd,
J ϭ 7.3, 5.7 Hz, 1 H), 4.26 (d, J ϭ 3.9 Hz, 1 H), 4.47 (d, J ϭ 7.3 Hz,
1 H), 6.34 (m, 1 H), 7.05Ϫ7.25 (5 H). Ϫ 13C NMR (CD3CN): δ ϭ
19.7 (t), 21.2 (t), 40.9 (d), 41.4 (t), 58.6 (d), 76.4 (d), 82.4 (d), 126.3
(d), 128.5 (d), 128.9 (d), 129.4 (d), 129.5 (d), 129.6 (d), 137.6 (s),
141.9 (s), 156.7 (s). Ϫ MS (EI): m/z (%) ϭ 271 (32) [Mϩ], 227 (90),
226 (100), 184 (33), 129 (34), 128 (36), 115 (44), 91 (53). Ϫ HRMS
(CIϩ, CH4); C16H18NO3 [MHϩ]: calcd. 272.1287; found 272.1283.
[3]
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[5]
[6]
(5S,6Z,7S,8S,11S)-7-Hydroxy-6-(prop-2-enylidene)-9-oxa-1-azatri-
cyclo[6.2.1.05,11]undecan-10-one [(؊)-(24)]: This compound was pre-
pared by cross-coupling of (ϩ)-21a (164 mg, 0.511 mmol) with vi-
nylzinc bromide [prepared from vinylmagnesium chloride (2.60 mL,
1.68  in THF, 4.37 mmol, 8.5 equiv.) and ZnBr2 (1.20 g,
5.33 mmol, 10.4 equiv.) in THF (4 mL)], catalyzed by Pd(PPh3)4
(22 mg, 19 µmol, 0.04 equiv.) in DMF (8 mL) as described above.
Flash chromatography (CH2Cl2/EtOH, 95:5) afforded 91 mg of a
yellow solid, which was recrystallized from n-hexane/AcOEt to give
70 mg (62%) of (Ϫ)-24 as a white solid. Ϫ m.p. 144Ϫ146 °C. Ϫ
[α]2D0 ϭ Ϫ67 (c ϭ 0.4, CHCl3). Ϫ IR (KBr): ν˜ ϭ 3420, 1710, 1270,
1240, 1060, 1025, 1000 cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 1.41Ϫ1.59
(2 H), 1.88 (m, 1 H), 2.16 (m, 1 H), 2.79 (ddd, J ϭ 15.6, 11.6,
4.2 Hz, 1 H), 3.02 (d, J ϭ 3.3 Hz, 1 H, OH), 3.05 (br. s, 1 H), 3.78
(m, 1 H), 4.23 (dd, J ϭ 7.4, 5.7 Hz, 1 H), 4.74 (d, J ϭ 7.4 Hz, 1
H), 4.82 (br. s, 1 H), 5.20 (d, J ϭ 9.9 Hz, 1 H), 5.28 (d, J ϭ 16.9 Hz,
1 H), 6.02 (dd, J ϭ 11.0, 1.8 Hz, 1 H), 6.61 (m, 1 H). Ϫ 13C NMR
(CDCl3): δ ϭ 18.9 (t), 20.9 (t), 39.2 (d), 40.7 (t), 59.1 (d), 75.4 (d),
81.4 (d), 119.6 (t), 128.5 (d), 132.1 (d), 141.2 (s), 155.7 (s). Ϫ MS
(EI): m/z (%) ϭ 221 (80) [Mϩ], 149 (79), 148 (99), 134 (88), 118
(83), 117 (100), 91 (78), 79 (93), 77 (72). Ϫ HRMS (CIϩ, CH4);
C12H16NO3 [MHϩ]: calcd. 222.1130; found 222.1129.
[7]
[8]
[9]
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J. Cossy, I. Pevet, C. Meyer, Synlett 2000, 122Ϫ124.
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X-ray Crystallographic Study of (؊)-4a,5-Dihydrostreptazolin: Col-
orless single crystals were grown from benzene; crystal shape: par-
allelepiped; crystal data: molecular formula C11H15O3N; molecular
mass: 209.25; temperature 295 K; crystal system: orthorhombic;
P. Evans, R. Grigg, M. I. Ramzan, V. Sridharan, M. York,
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space group: P212121; unit cell dimensions: a ϭ 6.140(2) A, b ϭ
˚
˚
11.347(3) A, c ϭ 14.714(3) A, α ϭ 90°, β ϭ 90°, γ ϭ 90°; volume
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[15k] L. A. Paquette, S. M. Leit, J. Am. Chem. Soc. 1999, 121,
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3
˚
8126Ϫ8127. Ϫ [15l] C. E. Grossmith, F. Senia, J. Wagner, Synlett
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.
Diffractometer: CAD4
[15m]
1999, 1660Ϫ1662. Ϫ
M. Lennartz, E. Steckhan, Synlett
K. C. M. F. Tjen, S. S. Kinderman, H.
˚
EnrafϪNonius; radiation used Mo-Kα (λ ϭ 0.71069 A); scan mode
ω/2θ; scan range 0.8ϩ0.345 tg θ; θ range for data collection 1° to
28°; number of data collected: 1463; number of unique data used
for refinement: 957 (F0)2 Ͼ 1.5σ(F0)2; final R indices: R ϭ 0.0561,
Rw ϭ 0.0648; absorption correction: none; secondary extinction
coefficient: 333.02; goodness of fit: S ϭ 1.10; number of variables:
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[17b]
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G. Chelucci, M. A.
Crystallographic data for the structure reported in this paper have
been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication no. CCDC-136167. Copies of the
data can be obtained free of charge on application to The Director,
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax: (internat.)
ϩ44-1223/336-033; E-mail: deposit@ccdc.cam.ac.uk.
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´
We thank Prof. Claude Agami (Universite Paris VI) for kindly wel-
[20]
coming us in his laboratory during the remodelling of ESPCI, while
this work was completed.
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Eur. J. Org. Chem. 2001, 2841Ϫ2850
2849

´
J. Cossy, I. Pevet, C. Meyer
FULL PAPER
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Received November 6, 2000
[O00564]
2850
Eur. J. Org. Chem. 2001, 2841Ϫ2850