Regioselective and diastereoselective amination with use of chlorosulfonyl isocyanate: A short and efficient synthesis of (-)-cytoxazone

Article abstract of DOI:10.1021/ol0515255

(Chemical Equation Presented) The total synthesis of (-)-cytoxazone 1 was achieved in six linear steps (34% overall yield) from p-anisaldehyde. The key steps in this route are the regioselective and stereoselective introduction of a N-protected amine grou

Full text of DOI:10.1021/ol0515255

ORGANIC
LETTERS
2005
Vol. 7, No. 18
4025-4028
Regioselective and Diastereoselective
Amination with Use of Chlorosulfonyl
Isocyanate: A Short and Efficient
Synthesis of (−)-Cytoxazone
Ji Duck Kim, In Su Kim, Cheng Hua Jin, Ok Pyo Zee, and Young Hoon Jung*
College of Pharmacy, Sungkyunkwan UniVersity, Suwon 440-746, Korea
yhjung@skku.ac.kr
Received June 29, 2005
ABSTRACT
The total synthesis of (
are the regioselective and stereoselective introduction of a N-protected amine group, using the CSI reaction of the anti-1,2-dimethyl ether 3,
and the subsequent regioselective cyclization of the N-protected amino diol 13 to give the 2-oxazolidinone unit of ( )-cytoxazone 1.
−)-cytoxazone 1 was achieved in six linear steps (34% overall yield) from p-anisaldehyde. The key steps in this route
−
Cytoxazone 1 is a novel cytokine modulator that was isolated
from Streptomyces sp., and interferes with cytokine IL4,
IL10, and IgG production via the selective inhibition of the
signaling pathway in Th2 cells. Its structure was determined
to be (4R,5R)-5-hydroxymethyl-4-p-methoxyphenyl-1,3-ox-
azolidin-2-one based on the NMR, CD, and X-ray data.1
Due to its potent bioactivity and relatively simple structure,
several methods of synthesizing (-)-cytoxazone and its trans-
diastereoisomer (4-epicytoxazone) have recently been re-
ported. These include Sharpless asymmetric dihydroxylation
and the introduction of amine,2 Sharpless asymmetric ami-
nohydroxylation,3 an asymmetric epoxidation and the regio-
selective introduction of azide,4 the Petasis reaction,5 an
asymmetric aldol reaction,6 an imino-1,2-Wittig rearrange-
ment,7 the addition of Grignard reagents to the protected
imines,8 and the conjugated addition of chiral lithium amide.9
This paper presents our synthetic approach to (-)-cytox-
azone, based on the regioselective and diastereoselective
chlorosulfonyl isocyanate (CSI) reaction.10
The retrosynthetic scheme is shown below (Scheme 1) and
the key steps are the regioselective and diastereoselective
introduction of a N-protected amine group into an anti-1,2-
dimethyl ether 3 to directly give the protected anti-1,2-amino
(4) Tosaki, S.-y.; Tsuji, R.; Ohshima, T.; Shibasaki, M. J. Am. Chem.
Soc. 2005, 127, 2147.
(5) Sugiyama, S.; Arai, S.; Ishii, K. Tetrahedron: Asymmetry 2004, 15,
3149.
(6) (a) Carda, M.; Gonzalez, F.; Sanchez, R.; Marco, J. A. Tetrahedron:
Asymmetry 2002, 13, 1005. (b) Carter, P. H.; LaPorte, J. R.; Scherle, P. A.;
Decicco, C. P. Bioorg. Med. Chem. Lett. 2003, 13, 1237. (c) Kumar, A. R.;
Bhaskar, G.; Madhan, A.; Rao, B. V. Synth. Commun. 2003, 33, 2907.
(7) Miyata, O.; Asai, H.; Naito, T. Synlett 1999, 12, 1915.
(8) Madham, A.; Kumar, A. R.; Rao, B. V. Tetrahedron: Asymmetry
2001, 12, 2009.
(9) Davies, S. G.; Hughes, D. G.; Nicholson, R. L.; Smith, A. D.; Wright,
A. J. Org. Biomol. Chem. 2004, 2, 1549.
(10) (a) Kim, J. D.; Lee, M. H.; Lee, M. J.; Jung, Y. H. Tetrahedron
Lett. 2000, 41, 5073. (b) Kim, J. D.; Lee, M. H.; Han, G.; Park, H.; Zee,
O. P.; Jung, Y. H. Tetrahedron 2001, 57, 8257. (c) Kim, J. D.; Zee, O. P.;
Jung, Y. H. J. Org. Chem. 2003, 68, 3721. (d) Kim, J. D.; Kim, I. S.; Jin,
C. H.; Zee, O. P.; Jung, Y. H. Tetrahedron Lett. 2005, 46, 1079.
* To whom correspondence should be addressed. Fax: 8231-290-5403.
(1) (a) Kakeya, H.; Morishita, M.; Kobinata, K.; Osono, M.; Osada, H.
J. Antibiot. 1998, 51, 1126. (b) Kakeya, H.; Morishita, M.; Koshino, H.;
Morita, T.; Kobayashi, K.; Osada, H. J. Org. Chem. 1999, 64, 1052.
(2) (a) Sakamoto, Y.; Shiraishi, A.; Jeong, S.; Nakata, T. Tetrahedron
Lett. 1999, 40, 4203. (b) Seki, M.; Mori, K. Eur. J. Org. Chem. 1999, 2965.
(c) Park, J. N.; Ko, S. Y.; Koh, H. Y. Tetrahedron Lett. 2000, 41, 5553. (d)
Boruwa, J.; Borah, J. C.; Kalita, B.; Barua, N. C. Tetrahedron Lett. 2004,
45, 7355.
(3) Milicevic, S.; Matovic, R.; Saicic, R. N. Tetrahedron Lett. 2004, 45,
955.
10.1021/ol0515255 CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/12/2005

at -78 °C furnished a 7.0:1 ratio (entries 1 and 2). In
particular, in toluene at -78 °C (entry 6), the highest
diastereoselectivity (27:1) was obtained in 95% chemical
yield. Table 1 showed a tendency to increase the formation
of the anti-stereoisomer of the 1,2-amino alcohol as the
polarity of the solvent decreased.
Scheme 1. Retrosynthetic Strategy
From the reaction of the anti-1,2-dimethyl ethers with CSI,
it was found that the stereochemistry of the major product
was the same as that of the starting material, even though
the CSI reaction of p-methoxybenzylic methyl ether progresses
via a carbocation intermediate through a SN1 mechanism.
The results of these reactions can be explained as follows:
First, the regioselective substitution at the p-methoxyben-
zylic position is expected. This is because the regioselectivity
was controlled by the stability of the carbocation intermedi-
ate. Namely, the p-methoxybenzylic carbocation is more
stable than the allyl one.12
Second, the formation of the anti-1,2-amino alcohol 2 from
the anti-1,2-dimethyl ether 3 can be explained by the Cieplak
electronic model,9c,13 via a SN1 mechanism. In this model,
the vinyl group takes up an anti position to nucleophile attack
and the methoxy group orients inside (Figure 1).
alcohol 2, using the CSI reaction and the regioselective
intramolecular cyclization. Compound 3 could be easily
prepared from p-anisaldehyde by using the chiral reagent,
(-)-B-methoxydiisopinocampheyl-borane.11
First, the regioselectivity and the diastereoselectivity of
the CSI reaction was investigated with anti-1,2-dimethyl
ether 3 prior to the approach to the total synthesis of (-)-
cytoxazone.
The initial studies examined the diastereoselectivity of the
reaction of the anti-1,2-dimethyl ether 3 with CSI. The
treatment of anti-1,2-dimethyl ether with CSI afforded the
anti-1,2-amino alcohol 2 as the major product. The ratio of
anti-1,2-amino alcohol 2 and syn-1,2-amino alcohol 4
depended on the solvent and temperature, as shown in Table
1.
Figure 1. Cieplak electronic model of nucleophilic attack on the
p-methoxybenzylic carbocation.
Table 1. CSI Reactions of the anti-1,2-Dimethyl Ether 3 with
Various Solvents and Temperatures
Another plausible mechanism for the diastereoselectivity
is the neighboring group effect, as shown in Figure 2. This
neighboring group (OMe) can use its electron pair to interact
with the backside of the carbon atom undergoing substitution,
and then nucleophilic attack can take place only from the
front side, leading to the retention of the configuration.14
The initial attack by the oxygen of p-methoxybenzylic
methyl ether to CSI yields a p-methoxybenzylic carbocation,
which is following an internal attack by the vicinal OMe
that yields the oxiranium with an inversion of configuration
at the p-methoxybenzylic carbon. This p-methoxybenzylic
carbon atom, in turn, undergoes an ordinary SN2 attack by
ClSO2-N--CO2Me, with a second inversion of configuration.
In this result, the configuration of the product is the same as
that of the starting material. As the polarity of the solvent
decreases, the attack of the vicinal OMe (the neighboring
solvent
CH2Cl2
temp (°C)
ratio (2:4)a
yield (%)b
1
2
3
4
5
6
7
8
9
0
-78
0
0
0
-78
0
5.7:1
7.0:1
7.6:1
12:1
16:1
27:1
18:1
13:1
15:1
94
92
89
96
94
95
91
67
91
CHCl3
Et2O
toluene
CCl4
hexane
0
-78
1
a Isomer ratio determined from the H NMR spectrum. b Isolated yield
of pure material.
(12) Kim, J. D.; Han, G.; Jeong, L. S.; Park, H.-J.; Zee, O. P.; Jung, Y.
H. Tetrahedron 2002, 58, 4395.
(13) Cieplak, A. S. J. Am. Chem. Soc. 1981, 103, 4540.
(14) (a) Allred, E. L.; Winstein, S. J. Am. Chem. Soc. 1967, 89, 3991.
(b) Allred, E. L.; Winstein, S. J. Am. Chem. Soc. 1967, 89, 3998. (c) Krow,
G. R.; Yuan, J.; Lin, G.; Sonnet, P. E. Org. Lett. 2002, 4, 1259. (d) Roberts,
D. D. J. Org. Chem. 1997, 62, 1857.
The reaction in methylene chloride at 0 °C gave a 5.7:1
inseparable mixture of diastereoisomers in 94% yield, and
(11) Barrett, A. G. M.; Malecha, J. W. J. Org. Chem. 1991, 56, 5243.
4026
Org. Lett., Vol. 7, No. 18, 2005

The CSI reaction of compound 5 in toluene and hexane
afforded a ratio similar to the case of methylene chloride
(entries 2 and 3). The results shown in Table 2 reveal that
the reaction of the â-methyl homoallyl ether with CSI is not
affected by the solvent, and progresses through a free
carbocation intermediate.
Therefore, it is clear that the diastereoselectivity of the
CSI reaction of the 1,2-dimethyl ether 3 can be explained
by the neighboring group effect and a partial SN1 mechanism.
On the basis of the above results, the total synthesis of
(-)-cytoxazone 1 was achieved from p-anisaldehyde as a
starting material (Scheme 3).
Scheme 3. Total Sythesis of (-)-Cytoxazone
Figure 2. Neighboring group effect of nucleophilic attack on the
p-methoxybenzylic carbocation.
group effect) becomes faster than the nucleophile attack and
the diastereoselectivity of 1,2-amino alcohol increases.
Therefore, this reaction is more efficient in nonpolar solvents.
A methyl moiety instead of a methoxy group was
introduced at the allylic position to confirm the neighboring
group effect. (Scheme 2).
Scheme 2. CSI Reactions of â-Methyl Homoallyl Ether 5 with
Various Solvents
p-Anisaldehyde was treated at -78 °C with B-[3-((diiso-
propylamino)dimethylsilyl)allyl]diisopinocampheyl-borane
(8), prepared from (-)-B-methoxydiisopinocampheyl-borane
and allyl(diisopropylamino)dimethylsilane,10 using n-butyl-
lithium in N,N,N′,N′-tetramethylethylenediamine (TMEDA)
in ether (Et2O) at 0 °C, to provide an optically pure (1R,2S)-
anti-diol 9 with a high enantioselectivity (95% ee via the
Mosher ester) and diastereoselectivity (> 99%) in 52%
chemical yield after recrystallization (toluene). The di-
methylation of compound 9 with sodium hydride and
iodomethane in tetrahydrofuran at 0 °C furnished the anti-
1,2-dimethyl ether 3 in 96% yield.
The treatment of threo-ether 5 with CSI in methylene
chloride at -78 °C furnished a 1:1.8 mixture of the threo-
stereoisomer 6 and the erythro-stereoisomer 7 in 91%
chemical yield (entry 1). The other results are summarized
in Table 2.
The key reaction is the regioselective and diastereoselec-
tive introduction of a N-protected amine group of compound
3 with CSI. The treatment of compound 3 with CSI in the
presence of sodium carbonate in anhydrous toluene at -78
°C, followed by the reduction of the N-chlorosulfonyl group
with an aqueous potassium hydroxide and sodium thiosulfate
solution furnished the desired anti-1,2-amino alcohol 4 with
a high diastereoselectivity (27:1) in 95% yield. The conver-
sion of compound 2 into the terminal primary alcohol 10
Table 2. CSI Reactions of â-Methyl Homoallyl Ether 5 with
Various Solvents (at - 78 °C)
solvent
ratio (6:7)a
yield (%)b
1
2
3
CH2Cl2
toluene
hexane
1:1.8
1:1.7
1:1.6
91
83
81
1
a Isomer ratio determined from the H NMR spectrum. b Isolated yield
of pure material
Org. Lett., Vol. 7, No. 18, 2005
4027

was achieved by ozonolysis of the double bond followed by
sodium borohydride reduction15 in 94% chemical yield.
The regioselective deprotection of the methyl ether of
compound 10 with boron tribromide16 in methylene chloride
at 0 °C gave the desired diol 11 in 80% yield without
affecting the methoxy group of the phenyl ring.
p-anisaldehyde. The optimum reaction conditions for the
diastereoselective CSI reaction of anti-1,2-dimethyl ether
were also identified. The retention of the configuration can
be explained by the neighboring group effect and a partial
SN1 mechanism.
This synthetic method with use of CSI can be applied to
the formation of various natural products with a more
complex amine.
Finally, the regioselective intramolecular cyclization of
compound 11, using sodium hydride7 in tetrahydrofuran at
0 °C, led to the (-)-cytoxazone 1 {mp 118-120 °C; [R]24
D
-70.9 (c 0.1, MeOH); lit.1 mp 118-120 °C; [R]25 -71 (c
D
Acknowledgment. This work was supported by a Korea
Research Foundation Grant (KRF-2003-015-E00232).
0.1, MeOH)} in 95% yield.
In conclusion, the total synthesis of (-)-cytoxazone 1 was
achieved in six linear steps (34% overall yield) from
Supporting Information Available: Experimental pro-
cedure and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Yudina, O. N.; Sherman, A. A.; Nifantiev, N. E. Carbohydr. Res.
2001, 332, 363.
(16) (a) Demuynck, M.; De Clercq, P.; Vandewalle, M. J. Org. Chem.
1979, 44, 4863. (b) Grieco, P. A.; Nishizawa, M.; Oguri, T.; Burke, S. D.;
Marinovic, N. J. Am. Chem. Soc. 1977, 99, 5773.
OL0515255
4028
Org. Lett., Vol. 7, No. 18, 2005