Extending the scope of the [2+2] cycloaddition of dichloroketene to chiral enol ethers: Synthesis of (-)-detoxinine

Article abstract of DOI:10.1055/s-2005-868515

Allylic oxidation of a known lactam, obtained by asymmetric [2+2] cycloaddition of dichloroketene to a chiral enol ether, followed by Beckmann ring expansion and dechlorination, affords a potential intermediate for the synthesis of various natural product

Full text of DOI:10.1055/s-2005-868515

LETTER
1413
Extending the Scope of the [2+2] Cycloaddition of Dichloroketene to Chiral
Enol Ethers: Synthesis of (–)-Detoxinine
Total
S
ynt
u
hesis of (–)-D
l
etoxin
i
ine en Ceccon, Jean-François Poisson,* Andrew E. Greene
Université Joseph Fourier de Grenoble, Chimie Recherche (LEDSS), 38041 Grenoble, France
Fax +33(4)76514494; E-mail: jean-francois.poisson@ujf-grenoble.fr
Received 25 March 2005
The pivotal intermediate in our program was anticipated
Abstract: Allylic oxidation of a known lactam, obtained by asym-
metric [2+2] cycloaddition of dichloroketene to a chiral enol ether,
followed by Beckmann ring expansion and dechlorination, affords
a potential intermediate for the synthesis of various natural prod-
to be allylic alcohol III (Scheme 1). Since a preparation of
highly diastereomerically enriched lactam II from enan-
tiopure 1-(2,4,6-triisopropylphenyl)ethanol was already
ucts. The usefulness of this intermediate is first demonstrated by an available from previous work in our laboratory,1a its allyl-
asymmetric synthesis of (–)-detoxinine.
ic oxidation to access III seemed worth examining, partic-
ularly in view of the encouraging literature precedent with
Key words: allylic oxidation, asymmetric synthesis, cycloaddition,
lactam, natural product
SeO2 on related systems.5
O
NH
The [2+2] cycloaddition of dichloroketene to chiral enol
ethers has already proven highly effective for the synthe-
sis of several natural alkaloids,1 including the simple aza-
sugars (–)-2-epilentiginosine and (+)-lentiginosine.1b To
demonstrate that this chemistry can also provide access to
the more complex indolizidine and pyrrolizidine azasug-
ars, we have selected for synthesis (+)-castanospermine
(1), (–)-swainsonine (2), and (+)-australine (3), popular
synthetic targets that are potent inhibitors of glycosidases
and of potential use in cancer chemotherapy (Figure 1).2
A common intermediate in our synthetic strategy ap-
peared to offer also an approach to the unusual amino acid
(–)-detoxinine (4),3 the parent structure of the depsipep-
tide metabolites of the detoxin complex, which has been
isolated from various strains of streptomyces and displays
a unique detoxification effect in both plant and animal
cells.4 In this communication, we describe a non-chiral
pool, stereoselective synthesis of (–)-detoxinine.
1–4
R*OH
I
H
X
R*O
II X = H
III X = OH
Scheme 1
Thus, lactam 8b was synthesized as reported,1a with slight
modification: The S-enantiomer of 1-(2,4,6-triisopropyl-
phenyl)ethanol (5), chosen to gain access to the desired
antipodal series, was converted in high yield to the dichlo-
roenol ether 6, which in turn was treated with 2 equiva-
lents of n-BuLi, followed by allyl iodide, to yield ynol
ether 7a (Scheme 2). Partial reduction of the triple bond
was performed with DIBAL-H in toluene at 50 °C,6 in-
stead of by catalytic hydrogenation with the Lindlar cata-
lyst, to give enol ether 7b, now free of the 10–20% of
over-reduced material previously observed on hydrogena-
tion.1a Diastereoface-selective cycloaddition of dichloro-
ketene to 7b, followed by Beckmann ring expansion and
dechlorination, then afforded lactam 8b in 38% overall
yield for the five steps (82%/step). The diasteromeric
purity of 8b was found, as previously, to be excellent (ca.
OH
OH
N
N
N
H
HO
OH
OH
H
H
HO
HO
OH
HO
OH
OH
1
95%, H NMR); furthermore, the minor diastereomers,
conveniently, filtered out over the subsequent steps of the
synthesis.
(+)-australine (3)
(+)-castanospermine (1)
(–)-swainsonine (2)
NH
It was found that allylic oxidation of 8b under Sharpless
conditions (SeO2, t-BuOOH, ClCH2CH2Cl, reflux) did in-
deed lead to the formation of the desired product, but ini-
tially in only 35% yield.8 Optimization studies revealed
that the corresponding enone was also formed, from oxi-
dation of the allylic alcohol, and was unstable under the
reaction conditions. Thus, the reaction was stopped before
complete consumption of the starting lactam (3 h at 70 °C)
and, in this way, lactams 9a,b could be obtained in 56%
yield (75%, based on recovered starting material).9
CO2H
H
HO
OH
(–)-detoxinine (4)
Figure 1
SYNLETT 2005, No. 9, pp 1413–1416
0
1.
0
6.
2
0
0
5
Advanced online publication: 29.04.2005
DOI: 10.1055/s-2005-868515; Art ID: G10505ST
© Georg Thieme Verlag Stuttgart · New York

1414
J. Ceccon et al.
LETTER
Cl
In all cases, the cis-anti isomer 9b was the major product,
ranging from 12:1, obtained through controlled LiAlH4
reduction, to 2:1, secured by using the chiral reagent (+)-
DIPCl.10 The preference for the cis-anti isomer is consis-
tent with a Felkin–Anh like reactive conformation, al-
though chelation may also be involved (entries 3, 4). It is
worth noting that lactam 9b, although not the desired
isomer in the present context, does possess the relative
stereochemistry found in a large number of alkaloids (e.g.,
1–3) and, together with its enantiomer formed from (R)-1-
(2,4,6-triisopropylphenyl)ethanol, should be quite useful
for accessing several of these compounds.
a
b
R*O
7a, triple bond
(S)-R*OH
R*O
Cl
c
6
5
b, double bond
O
O
NH
H
NH
d, e
g
X
X
H
R*O
OH
R*O
8a, X = Cl
b, X = H
9a,b
dr = 1:1
f
Scheme 2 Reagents and conditions: a) KH, THF, 0 °C to 20 °C;
trichloroethylene, –50 °C to 20 °C, 85%; b) n-BuLi, THF, –78 °C to
Following this study, the synthesis of (–)-detoxinine was
–50 °C; allyl iodide, HMPA, –60 °C to 0 °C; c) DIBAL-H, THF, continued from the equimolar mixture of diastereomers
50 °C; d) Cl3CCOCl, Zn-Cu, Et2O, 20 °C; e) NH2OSO2C6H2(CH3)3,7
Na2SO4, CH2Cl2, 0 °C; Al2O3, MeOH; f) NH4Cl, Zn-Cu, MeOH,
formed with SeO2, in the hope that a separation might be
forthcoming. Fortunately, this turned out to be the case:
20 °C, 38% from 6 (82%/step); g) SeO2, TBHP, ClCH2CH2Cl, 70 °C,
the diastereomeric Cbz pyrrolidine derivatives 11a,b,
formed from 9a,b in 83% yield over two steps, allowed
easy separation of the stereoisomers on silica gel (DRf =
0.16), which made possible a stereoconvergent approach
to (–)-detoxinine (Scheme 4).
56% (75%, based on recovered starting material).9 (S)-R*OH = (S)-1-
(2,4,6-triisopropylphenyl)ethanol.
It was disappointing, however, to find that there was,
essentially, a complete absence of stereoselectivity in this
reaction. While the mixture could not readily be separated
at this stage, it could be smoothly transformed in the pres-
ence of the Dess–Martin periodinane into the correspond-
ing enone 10, which could then be reduced (Scheme 3).
The sensitive functionality in the enone limited, however,
the range of possible reagents; the reducing reagents that
were screened are listed in Table 1.
NCbz
NCbz
a, b
9a,b
+
H
H
R*O
OH
11b
R*O
OH
11a
c
c
NCbz
NCbz
X
H
R*O
OH
X
O
O
O
H
13a, X = CH2OH
b, X = CO2H
R*O
OH
d
NH
NH
H
NH
H
b
a
9a,b
+
12a, X = CH2OH
b, X = CO2H
g, h
O
d
H
R*O
R*O
R*O
O
OH
OH
10
9a (cis-syn)
9b (cis-anti)
N
H
e, f
Scheme 3 Reagents and conditions: a) Dess–Martin periodinane,
CH2Cl2; b) see Table 1.
R*O
OH
j
NH
H
14a, β-OH
b, α-OH
i
CO2H
Table 1 Reduction of Enone 10
HO
OH
(–)-detoxinine (4)
Entry Reagent
Conditions
dr (9a:9b)a Yield (%)b
1
2
NaBH4, CeCl3 EtOH, 0 °C
1:5
1:6
83
46
Scheme 4 Reagents and conditions: a) LiAlH4, THF, reflux; b)
BCN,11 THF, Et3N, 20 °C, 83% (2 steps); c) 9-BBN, THF, –20 °C to
20 °C; NaOH, H2O2, 84% for 12a, 85% for 13a; d) TEMPO, NCS,
NaClO2, isoprene, 88% for 12b, 91% for 13b (2 steps); e) H2,
Pd(OH)2, MeOH, HCl; f) TFA, CH2Cl2, 79% (2 steps); g) CH2N2,
Et2O, 92% (ester); h) H2, Pd(OH)2, EtOAc, AcOH, 40 °C, 82%;
i) PCC, CH2Cl2; NaBH4, EtOH, 0 °C, 51% (2 steps); j) HCl (3 N),
reflux, 85%.
Zn(BH4)2
Et20, –78 °C to
20 °C
3
4
5
6
Red-Al
Toluene, 0 °C
THF, –15 °C
THF, 0 °C
1:8
43
LiAlH4
1:12
1:2
89
(+)-DIPCl
(–)-DIPCl
<30
N.R.
THF, 20 °C
N.R.
The cis-syn isomer 11a, possessing the required configu-
ration, was first transformed into the natural product.
Hydroboration with 9-BBN, followed by oxidation of the
intermediate borane, furnish the 1,3-diol 12a in 84%
yield. Other hydroborating agents tested afforded
mixtures of the 1,2- and 1,3-diols. Oxidation to the
a Determined by 1H NMR.10
b Over two steps.
Synlett 2005, No. 9, 1413–1416 © Thieme Stuttgart · New York

LETTER
Total Synthesis of (–)-Detoxinine
1415
(3) (a) Ohfune, Y.; Nishio, H. Tetrahedron Lett. 1984, 25,
corresponding acid 12b proceeded smoothly by using
TEMPO, followed by sodium chlorite (88% yield). (–)-
Detoxinine was then secured in 79% yield by removal of
the Cbz protecting group through catalytic hydrogenation
and cleavage of the chiral auxiliary with TFA. The syn-
thetic material {[a]D20 –4.6 (c 0.50, H2O); lit.3b [a]D20 –4.4
4133. (b) Ewing, W. R.; Harris, B. D.; Bhat, K. L.; Joullié,
M. M. Tetrahedron 1986, 42, 2421. (c) Kogen, H.;
Kadokawa, H.; Kurabayashi, M. J. Chem. Soc., Chem.
Commun. 1990, 1240. (d) Denmark, S. E.; Hurd, A. R.;
Sacha, H. J. J. Org. Chem. 1997, 62, 1668. (e) Delle
Monache, G.; Misiti, D.; Zappia, G. Tetrahedron:
Asymmetry 1999, 10, 2961. (f) Flögel, O.; Okala Amombo,
M. G.; Reissig, H.-U.; Zahn, G.; Brüdgam, I.; Hartl, H.
Chem.–Eur. J. 2003, 9, 1405. (g) For (+)-detoxinine:
Mulzer, J.; Meier, A.; Buschmann, J.; Luger, P. J. Org.
Chem. 1996, 61, 566. (h) For a review, see: Li, W.-R.; Han,
S.-Y.; Joullié, M. M. Heterocycles 1993, 36, 359.
20
(c 0.50, H2O), lit.3d [a]D –4.6 (c 0.50, H2O)}, thus ob-
tained was indistinguishable from an independently pre-
pared sample of (–)-detoxinine (that had been shown to be
identical with the naturally derived material).
The cis-anti isomer 11b was next considered. Since nei-
ther a Mitsunobu reaction (low yield) nor an oxidation–re-
duction approach (mostly 1,4-reduction) proved useful for
inverting the carbinol center, lactam 14a was prepared for
this purpose. It was reasoned that in the derived ketone the
large chiral auxiliary and the folded nature of the bicycle
would combine to generate predominantly, if not exclu-
sively, the a-hydroxyl group on hydride reduction. Acid
13b was thus prepared as was acid 12b (77% yield) and
esterified, and the ester was cyclized to lactam 14a by
carbamate cleavage (75% yield, two steps). As hoped,
oxidation of 14a with PCC, followed by reduction of the
resultant ketone with NaBH4, afforded the inverted
epimer 14b as the major product (12:1 ratio), isolated as a
single isomer in 51% yield for the two steps. Acid
treatment of 14b then gave in 85% yield (–)-detoxinine,
identical with that obtained above.
(4) For the isolation and biological properties of the detoxin
complex, see: (a) Yonehara, H.; Seto, H.; Aizawa, S.;
Hidaka, T.; Shimazu, A.; Otake, N. J. Antibiot. 1968, 369.
(b) Yonehara, H.; Seto, H.; Shimazu, A.; Aizawa, S.;
Hidaka, T.; Kakinuma, K.; Otake, N. Agric. Biol. Chem.
1973, 37, 2771. (c) Ogita, T.; Seto, H.; Otake, N.; Yonehara,
H. Agric. Biol. Chem. 1981, 45, 2605.
(5) (a) Bateson, J. H.; Quinn, A. M.; Southgate, R. Tetrahedron
Lett. 1987, 28, 1561. (b) Ohfune, Y.; Nishio, H.
Tetrahedron Lett. 1984, 25, 4133.
(6) Denmark, S. E.; Dixon, J. A. J. Org. Chem. 1998, 63, 6178.
(7) Tamaru, Y.; Minamikawa, J.; Ikeda, M. Synthesis 1977, 1.
(8) (a) Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977,
99, 5526. (b) Warpehoski, M. A.; Chabaud, B.; Sharpless,
K. B. J. Org. Chem. 1982, 47, 2897. The allylic oxidation of
terminal olefins can be challenging (see ref. 5).
(9) (4R,5R)-5-(1-Hydroxyallyl)-4-[(S)-1-(2,4,6-triiso-
propylphenyl)ethoxy]pyrrolidin-2-one (9a,b).
TBHP (tert-butylhydroperoxide, 5 M in decane, 1.8 mL, 9.0
mmol) was added to SeO2 (254 mg, 2.27 mmol) in 1,2-
dichloroethane (10 mL). The mixture was vigorously stirred
at 20 °C for 1.5 h and lactam 8b (1.70 g, 4.58 mmol) in 1,2-
dichloroethane (20 mL) was then added rapidly. The
resulting mixture was warmed to 70 °C and stirred for 3.3 h.
After being allowed to cool to 20 °C, the reaction mixture
was treated with an aq solution of NaHCO3 (50 mL), diluted
with H2O (30 mL), and extracted with EtOAc (3 ꢀ 120 mL).
The combined organic extracts were washed with aq Na2SO3
(120 mL), H2O (120 mL), and brine (120 mL), dried over
MgSO4, filtered, and concentrated. The resulting oil in 7 mL
of EtOH at 0 °C was treated with 171 mg (0.46 mmol) of
CeCl3·7H2O, followed by 17.3 mg (0.46 mmol) of NaBH4
(to reduce the 5–10% of enone). After 1 h, the reaction
mixture was processed with EtOAc in the usual way and the
crude product was purified by flash chromatography on
silica gel with EtOAc in CH2Cl2 (40–100%) to afford 440
mg of recovered 8b, followed by 988 mg (56%; 75% based
on recovered starting material) of 9a,b as a white solid.
Extensive purification of this material over silica gel
provided enriched samples of 9a and 9b for spectral data.
Compound 9a: 1H NMR (300 MHz, CDCl3): d = 7.07 (s, 1
H), 6.99 (s, 1 H), 5.80 (ddd, J = 17.3, 10.7, 4.4 Hz, 1 H), 5.42
(dt, J = 17.3, 1.7 Hz, 1 H), 5.27 (dt, J = 10.7, 1.7 Hz, 1 H),
5.18 (q, J = 6.9 Hz, 1 H), 4.61 (m, 1 H), 4.35 (q, J = 7.5 Hz,
1 H), 3.82 (sept, J = 6.7 Hz, 1 H), 3.65 (dd, J = 7.6, 1.4, 1 H),
3.16 (sept, J = 6.7 Hz, 1 H), 2.87 (sept, J = 6.9 Hz, 1 H), 2.61
(dd, J = 16.7, 6.7 Hz, 1 H), 2.54 (dd, J = 16.6, 7.9 Hz, 1 H),
1.61 (d, J = 6.8 Hz, 3 H), 1.31–1.18 (m, 1 H). 13C NMR (75
MHz, CDCl3): d = 175.4, 149.0, 148.5, 146.8, 136.7, 123.8,
121.3, 117.0, 72.7, 72.1, 70.8, 60.9, 37.7, 34.4, 29.6, 28.6,
25.6, 25.5, 25.4, 24.6, 24.3, 23.6.
In summary, (–)-detoxinine has been synthesized in a
stereocontrolled approach in 8.3% overall yield starting
from (S)-1-(2,4,6-triisopropylphenyl)ethanol (5). Over
the course of this work, an effective preparation of allylic
alcohol 9b has also been realized, which, together with its
enantiomer, should allow access to several indolizidine
and pyrrolizidine azasugars.
Acknowledgment
We warmly thank Prof. S. E. Denmark for providing a sample of
(–)-detoxinine for comparison. We are also grateful to the Research
Ministry (MRT grant to J.C.) and the Université Joseph Fourier and
the CNRS (UMR 5616, FR2607) for financial support.
References
(1) (a) Roche, C.; Delair, P.; Greene, A. E. Org. Lett. 2003, 5,
1741. (b) Rasmussen, M. O.; Delair, P.; Greene, A. E. J.
Org. Chem. 2001, 66, 5438. (c) Pourashraf, M.; Delair, P.;
Rasmussen, M. O.; Greene, A. E. J. Org. Chem. 2000, 65,
6966. (d) Delair, P.; Brot, E.; Kanazawa, A.; Greene, A. E.
J. Org. Chem. 1999, 64, 1383. (e) Kanazawa, A.; Gillet, S.;
Delair, P.; Greene, A. E. J. Org. Chem. 1998, 63, 4660.
(2) For reviews on polyhydroxylated alkaloids, see:
(a) Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R.
J.; Nash, R. J. Phytochemistry 2001, 56, 265. (b) Asano, N.;
Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron:
Asymmetry 2000, 11, 1645.
Compound 9b: 1H NMR (300 MHz, CDCl3): d = 7.09 (s, 1
Synlett 2005, No. 9, 1413–1416 © Thieme Stuttgart · New York

1416
J. Ceccon et al.
LETTER
H), 7.00 (s, 1 H), 5.86 (ddd, J = 17.3, 10.5, 6.8 Hz, 1 H), 5.39
(dt, J = 17.3, 1.2 Hz, 1 H), 5.32 (dt, J = 10.4, 1.1 Hz, 1 H),
5.20 (q, J = 6.7 Hz, 1 H), 4.45–4.35 (m, 2 H), 3.72 (sept,
J = 6.9 Hz, 1 H), 3.56 (td, J = 7.7, 1.1 Hz, 1 H), 3.38 (d,
J = 2.3 Hz, 1 H), 3.17 (sept, J = 6.8 Hz, 1 H), 2.88 (sept,
J = 6.9 Hz, 1 H), 2.56 (d, J = 8.0 Hz, 1 H), 1.63 (d, J = 6.8
Hz, 3 H), 1.34–1.18 (m, 18 H). 13C NMR (75 MHz, CDCl3):
d = 174.6, 149.1, 148.7, 146.6, 137.0, 123.8, 121.4, 118.9,
73.6, 73.0, 60.3, 36.6, 34.4, 29.6, 29.0, 25.6, 25.5, 25.3, 24.5,
24.3, 23.5.
(10) The relative stereochemistry in 9a and 9b was assigned from
the NMR of derivatives prepared in a concomitant project (to
be published); these assignments were confirmed by the
successful synthesis of (–)-detoxinine.
(11) Henklein, P.; Heyne, H.-U.; Halatsch, W.-R.; Niedrich, H.
Synthesis 1987, 166.
Synlett 2005, No. 9, 1413–1416 © Thieme Stuttgart · New York