Regioselective and diastereoselective allylic amination using chlorosulfonyl isocyanate. A novel asymmetric synthesis of unsaturated aromatic 1,2-amino alcohols

Article abstract of DOI:10.1021/jo0267089

The diastereoselective synthesis of unsaturated aromatic 1,2-amino alcohols can be achieved on an epimeric mixture of optically active allylic ethers having a hydroxyl group attached to an allylic chiral center to the π-system using chlorosulfonyl isocyanate. These reactions produced the unsaturated anti-1,2-amino alcohols either exclusively or predominantly only for aromatic derivatives. The anti-selectivity may be explained by the Cieplak electronic model during the conversion from ethers to carbamates.

Full text of DOI:10.1021/jo0267089

of these procedures sometimes have one or more prob-
lems, for example, low stereoselectivity, limited applica-
tions, and the use of heavy metals.
Regioselective a n d Dia ster eoselective
Allylic Am in a tion Usin g Ch lor osu lfon yl
Isocya n a te. A Novel Asym m etr ic Syn th esis
of Un sa tu r a ted Ar om a tic 1,2-Am in o
Alcoh ols
These facts prompted us to find a milder and widely
applicable method for the synthesis of the 1,2-amino
alcohols, especially the unsaturated 1,2-amino alcohols,
which can be easily converted to â-hydroxy-R-amino
acids. Since we have developed the novel synthetic
methods for N-protected allylic amines from allyl ethers
using chlorosulfonyl isocyante (CSI),12 we found that the
reaction of 1,4-diphenylbut-2-enyl methyl ether (1) with
CSI gave only one product, methyl N-(1-benzylcinnamyl)-
carbamate (2), due to the electronical repulsion of the
phenyl ring and the formation of a stable conjugated
product (Scheme 1).12c
J i Duck Kim, Ok Pyo Zee, and Young Hoon J ung*
College of Pharmacy, Sungkyunkwan University,
Suwon 440-746, Korea
yhjung@skku.ac.kr
Received November 13, 2002
Abstr a ct: The diastereoselective synthesis of unsaturated
aromatic 1,2-amino alcohols can be achieved on an epimeric
mixture of optically active allylic ethers having a hydroxyl
group attached to an allylic chiral center to the π-system
using chlorosulfonyl isocyanate. These reactions produced
the unsaturated anti-1,2-amino alcohols either exclusively
or predominantly only for aromatic derivatives. The anti-
selectivity may be explained by the Cieplak electronic model
during the conversion from ethers to carbamates.
Herein, we now describe a new approach to a variety
of unsaturated 1,2-amino alcohols by the control of the
stereocenters by asymmetric induction as an extension
of the CSI reactions and how to control the diastereose-
lectivity in this reaction (Scheme 2).
Our initial studies examined the diastereoselective
effect of the protecting group of the hydroxyl moiety in
5-methoxy-5-phenylpent-3-en-2-ol 3 (R1, R3 ) Me, R2 )
Ph) as shown in Table 1. The treatment of 3a with CSI
at -78 °C furnished a 7:1 inseparable mixture of 4a and
5a in 55% chemical yield (entry 1). As the size of the silyl
moiety of the protecting groups increased, the formation
of the anti-isomer of the 1,2-amino alcohols decreased
(entries 2-4). However, for the acetyl- or methyl-
protected case (entries 5 and 6), a high diastereoselec-
tivity was obtained despite the small bulkiness.
The anti-stereochemistry as a major product was
confirmed by converting the inseparable mixture of
carbamates, 4b and 5b, upon treatment with Bu4NF and
NaH, into the oxazolidinones 6a and 6b which are
separable. The planar nature of the five-membered ring
induced an eclipsing interaction of C4-C5 substituents.
Thus, the trans-substitution provides a shielding envi-
The synthesis of chiral 1,2-amino alcohols has been an
area of intense study in the synthetic and industrial fields
because of their important roles in organic synthesis as
fundamental building blocks and their occurrence in a
number of natural products, drugs, and chiral auxiliaries
or ligands.1 General methods for the synthesis of these
compounds can be divided into two large categories:
functional group transformations and the C-C or the
C-N bond formations. Of these two methods, the former
has been used widely so far, including the reduction of
R-amino acids, R-amino ketones, or R-hydroxy imines;2
the nucleophilic substitution of 1,2-diols,3 epoxides,4
aziridines,5 cyclic carbonates, or cyclic sulfates;6 the
aminohydroxylation or oxymecuration of olefins;7 and the
hydroboration of enamines.8 The latter involves the
addition of an organometallic reagent to the N-protected
R-amino aldehydes9 or to the O-protected R-hydroxy
imines10 and coupling of carbanions with imines.11 Many
(7) (a) Li, G.; Chang, H.-T.; Sharpless, K. B. Angew. Chem., Int. Ed.
Engl. 1996, 35, 451-454. (b) Reddy, K. L.; Sharpless, K. B. J . Am.
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K. R.; Sharpless, K. B. Angew. Chem., Int. Ed. 1999, 38, 1080-1083.
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3455-3457.
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D. J . J . Org. Chem. 1996, 61, 2677-2685. (b) Fisher, G. B.; Goralski,
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Chem. 1995, 60, 2026-2034.
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(c) Andre´s, J . M.; Barrio, R.; Martinez, M. A.; Pedrosa, R.; Pe´rez-
Encabo, A. J . Org. Chem. 1996, 61, 4210-4213. (d) Ciapetti, P. C.;
Taddei, M.; Ulivi, P. Tetrahedron Lett. 1994, 35, 3183-3186.
(10) (a) Schwardt, O.; Veith, U.; Gaspard, C.; J a¨ger, V. Synthesis
1999, 1473-1496. (b) Friestad, G. K. Org. Lett. 1999, 1, 1499-1501.
(11) (a) Marshall, J . A.; Gill, K.; Seletsky, B. M. Angew. Chem., Int.
Ed. 2000, 39, 953-956. (b) Masson, G.; Py, S.; Valle´e, Y. Angew. Chem.,
Int. Ed. 2002, 41, 1772-1775.
(12) (a) Kim, J . D.; Han, G.; Zee, O. P.; J ung, Y. H. Tetrahedron
Lett. 2003, 44, 733-735. (b) Kim, J . D.; Han, G.; J eong, L. S.; Park,
H.-J .; Zee, O. P.; J ung, Y. H. Tetrahedron 2002, 58, 4395-4402. (c)
Kim, J . D.; Lee, M. H.; Han, G.; Park, H.; Zee, O. P.; J ung, Y. H.
Tetrahedron 2001, 57, 8257-8266. (d) Kim, J . D.; Lee, M. H.; Lee, M.
J .; J ung, Y. H. Tetrahedron Lett. 2000, 41, 5073-5076. (e) J ung, Y.
H.; Kim, J . D. Arch. Pharm. Res. 2001, 24, 371-376. (f) J ung, Y. H.;
Kim, J . D. Arch. Pharm. Res. 2000, 23, 574-578.
* To whom correspondence should be addressed. Fax: 8231-290-
5403. Tel: 8231-290-7711.
(1) (a) Bergmeier, S. C. Tetrahedron 2000, 56, 2561-2576. (b) Ager,
D. J .; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835-875. (c)
Paleo, M. R.; Cabeza, I.; Sardina, F. J . J . Org. Chem. 2000, 65, 2108-
2113.
(2) (a) Tramontini, M. Synthesis 1982, 605-644. (b) Hoffman, R.
V.; Maslouh, N.; Cervantes-Lee, F. J . Org. Chem. 2002, 67, 1045-
1056. (c) Abiko, A.; Masamune, S. Tetrahedron Lett. 1992, 33, 5517-
5518. (d) Petasis, N. A.; Zavialov, I. A. J . Am. Chem. Soc. 1998, 120,
11798-11799.
(3) (a) Nicolaou, K. C.; Huang, X.; Snyder, S. A.; Rao, P. B.; Bella,
M.; Reddy, M. V. Angew. Chem., Int. Ed. 2002, 41, 834-838. (b) Xu,
D.; Sharpless, K. B. Tetrahedron Lett. 1993, 34, 951-952. (c) Pyne, S.
G.; Dong, Z. Tetrahedron Lett. 2000, 41, 5387-5391.
(4) (a) Caron, M.; Sharpless. K. B. J . Org. Chem. 1985. 50, 1557-
1560. (b) Lindstro¨m, U. M.; Franckowiak, R.; Pinault, N.; Somfai, P.
Tetrahedron Lett. 1997, 38, 2027-2030.
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Yamamoto, Y. Tetrahedron 1996, 52, 11739-11752. (b) Xiong, C.;
Wang, W.; Cai, C.; Hruby, V. J . J . Org. Chem. 2002, 67, 1399-1402.
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10.1021/jo0267089 CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/27/2003
J . Org. Chem. 2003, 68, 3721-3724
3721

SCHEME 1
SCHEME 3
SCHEME 2
TABLE 2. CSI Rea ction of 3b w ith Va r iou s Solven tsa
TABLE 1. CSI Rea ction of Allyl Eth er s by Va r yin g th e
P r otectin g Gr ou p s of th e Hyd r oxyl Moiety (R1, R3 ) Me,
R2 ) P h )
ratiob
yieldc (%)
yieldc (%)
solvent
(4b/5b)
(4b + 5b)
(7b)
1
2
3
4
CH2Cl2
CHCl3
Et2O
6.2:1
5.7:1
5.6:1
5.2:1
83
77
53
57
d
9
8
23
PG
ratioa (4/5)
yieldb (%)
hexane
a
1
2
3
4
5
6
TMS (3a )
TBS (3b)
TIPS (3c)
TBDPS (3d )
Ac (3e)
7.0:1
6.2:1
4.5:1
2.5:1
7.4:1
5.1:1
55c
83
All the reactions were carried out at -78 °C, except for entry
b
2 (-60 °C). Based on integrals of OCH3 signals in carbamates.
c Isolated yield of pure material. Not detected.
d
83
76c
77d
81e
83% chemical yield (entry 1). However, the reaction in
CHCl3 gave a 5.7:1 mixture of 1,2-amino alcohol in 77%
yield and 1,4-amino alcohol (7b) in 9% yield (entry 2).
As the polarity of solvent decreased, the proportion of
1,4-amino alcohol increased via tight ion pair, due to the
decrease of the ability to stabilize allyl carbocation by
solvation. However, the ratios of anti-isomer and syn-
isomer of the 1,2-amino alcohols were similar to that
obtained in CH2Cl2. Therefore, these results suggested
that a free allyl carbocation12b,14 may be involved in
formation of the 1,2-amino alcohol and solvent should not
affect the diastereoselectivity but regioselectivity of the
process.
Next, we investigated the substituent effect on the
diastereoselectivity by varying the R1 moiety (R1 ) Me,
Et, i-Pr, Ph, R2 ) Ph, R3 ) Me) and protecting groups
(TBS and TIPS) as shown in Table 3. The treatment of
3g with CSI at -78 °C furnished a 6.5:1 inseparable
mixture of 4g and 5g in 75% chemical yield (entry 3). As
the size of R1 increased, the formation of the anti-isomer
of the 1,2-amino alcohols increased (entries 4-8). When
R1 is phenyl and the protecting group is TBS (3k ), the
highest diastereoselectivity (>99) was obtained in an 83%
chemical yield (entry 7). In all cases, the formation of
Me (3f)
a
b
Based on integrals of OCH3 signals in carbamates. Isolated
yield of pure material. c Yield determined after deprotection of the
hydroxy group with TBAF in THF at 0 °C, due to the difficulty in
d
obtaining the pure material from column chromatography. Yield
determined after deprotection of the hydroxy group with K2CO3
in MeOH-H2O at 0 °C. e Yield determined after deprotection of
the hydroxy group with BBr3 in CH2Cl2 at 0 °C.
ronment for both C4 and C5 methine hydrogens. The
chemical shifts of H4 and H5 are substantially upfield
compared to their cis-substituted oxazolidinones. Ad-
ditionally, the coupling constants J ab for the trans-
substituted oxazolidinones are slightly smaller than those
observed for the cis-isomers.13 Therefore, the chemical
shift of Ha and J ab value between Ha and Hb of 6a after
decoupling of the methyl moiety indicated that the major
product is 4b, which has the anti-stereochemistry in the
CSI reaction (Scheme 3).
To find the role of the solvent in this reaction, we
investigated the CSI reaction of TBS-protected ether (3b)
with various solvents. The results are summarized in
Table 2. The treatment of 3b with CSI in CH2Cl2
furnished a 6.2:1 inseparable mixture of 4b and 5b in
(13) (a) Williams, D. R.; Osterhout, M. H.; Reddy, J . P. Tetrahedron
Lett. 1993, 34, 3271-3274. (b) Futagawa, S.; Inui, T.; Shiba, T. Bull.
Chem. Soc. J pn. 1973, 46, 3308-3310.
(14) (a) Hall, R. H.; J ordaan, A.; de Villiets, O. G. J . Chem. Soc.,
Perkin Trans. 1 1975, 626-629. (b) Daniel, J .; Shukla, D.; Dhar, D.
N. Chem. Lett. 1992, 1575-1578.
3722 J . Org. Chem., Vol. 68, No. 9, 2003

TABLE 3. CSI Rea ction of Allyl Eth er s by Va r yin g R 1
(R2 ) P h , R3 ) Me)
R1
PG
ratioa (4/5)
yieldb (%)
F IGURE 2. Felkin-Anh model (A) and Cieplak electronic
1
2
3
4
5
6
7
8
Me
TBS (3b)
TIPS (3c)
TBS (3g)
TIPS (3h )
TBS (3i)
TIPS (3j)
TBS (3k )
TIPS (3l)
6.2:1
4.5:1
6.5:1
5.6:1
11:1
9.4:1
>99
83
83
model (B) of nucleophilic attack on the allyl carbocation.
Et
75c
72c
68c
77c
83
and a more bulkier group (OPG)15 takes up an anti
position to the nucleophile attack.16 However, from our
results shown in Tables 1 and 3, the predominant
formation of the anti-isomer in the CSI reactions was
observed. Thus, our results cannot be explained by the
steric factors of substituents such as model A. Instead,
these results can be accounted for by the Cieplak
electronic model (model B).17 In intermediates of these
CSI reactions, the π bond becomes electron deficient.
Therefore, σ-donor substitutions stabilize the transition
state. When the σ-donating group (R1) is in the anti
position and CO is inside, overlap of σ-donating σCH and
σCR orbitals with the π orbital is maximized and overlap
of σ/CO with π is minimized. So, the transition state is
stabilized. Therefore, the alkyl moiety becomes anti, the
OPG group orients inside, and the nucleophile attacks
the less hindered outside position, as shown in Figure 2.
This kind of model has been used for explanation of the
diastereoselectivity during nitrile oxide cyclization to
chiral allyl ethers (the “inside alkoxy” effect)17b,18 and
conjugate addition of nucleophiles to γ-alkoxy R,â-
unsaturated carbonyl derivatives.17c It is clear from these
models that an increase in the steric bulk at the OPG
group produced a low anti-diastereoselectivity and an
increase in the steric bulk at the alkyl moiety enhanced
the anti/syn isomer ratio.
i-Pr
Ph
98:2
85
a
b
Based on integrals of OCH3 signals in carbamates. Isolated
yield of pure material. c Yield determined after deprotection of the
hydroxy group with TBAF in THF at 0 °C, due to the difficulty in
obtaining the pure material from column chromatography.
F IGURE 1. Possible model of regioselective nucleophilic
attack on the allyl carbocation.
Another substituent effect on the diastereoselectivity
by varying the R2 moiety was examined as shown in
Table 4. The treatment of 3m with CSI at 20 °C furnished
a 9.2:1 inseparable mixture of 4m and 5m in 29% chem-
ical yield and the 1,4-amino alcohol (7m ) (45%) (entry
the anti-isomer in TBS protected compounds was slightly
increased as compared to the case of the TIPS-protected
ones. A similar method was used for the structural
determination of 4k through the formation of oxazolidi-
none (6c).
One plausible mechanism for these regioselective al-
lylic aminations is shown in Figure 1. The stable allyl
carbocation is formed by the cleavage of the C-O bond
of the ether followed by nitrogen anion attack to produce
the unsaturated 1,2-amino alcohol or 1,4-amino alcohol
according to the steric hindrance of R2. When R2 is
phenyl, the unsaturated 1,2-amino alcohol 4 is a major
product due to the steric hindrance and the formation of
a stable conjugated product.
(15) (a) Hoffman, R. W.; Ruhland, T.; Bewersdorf, M. J . Chem. Soc.,
Chem. Commun. 1991, 195-196. (b) Overman, L. E.; McCready, R. J .
Tetrahedron Lett. 1982, 23, 2355-2358. (c) Nakata, T.; Tanaka, T.;
Oishi, T. Tetrahedron Lett. 1983, 24, 2653-2656.
(16) (a) Paddon-Row, M. N.; Rondan, N. G.; Houk, K. N. J . Am.
Chem. Soc. 1982, 104, 7162-7166. (b) Anh, N. T.; Eisenestein, O. Nouv.
J . Chim. 1977, 1, 61-70. (c) Che´rest, M.; Felkin, H.; Prudent, N.
Tetrahedron Lett. 1968, 9, 2199-2204. (d) Che´rest, M.; Felkin, H.
Tetrahedron Lett. 1968, 9, 2205-2208. (e) Anh, N. T. Top. Curr. Chem.
1980, 88, 145. (f) Che´rest, M.; Felkin, H.; Frajerman, C. Tetrahedron
Lett. 1971, 12, 379-382.
The diastereoselectivity of 4 may be explained by the
Felkin-Anh model or the Cieplak model. These models
for a kind of Michael acceptor are based on the steric or
electronic factors of the substituents around the site
where the nucleophile attacks (Figure 2). From these
models, a syn-isomer should be the major product through
model A, in which a less bulkier group (R1) orients inside
(17) (a) Cieplak, A. S. J . Am. Chem. Soc. 1981, 103, 4540-4552. (b)
Houk, K. N.; Moses, S. R.; Wu, Y.-D.; Rondan, N. G.; J a¨ger, V.; Schohe,
R.; Fronczek, F. R. J . Am. Chem. Soc. 1984, 106, 3880-3882. (c)
Yamamoto, Y.; Chounan, Y.; Nishii, S.; Ibuka, T.; Kitahara, H. J . Am.
Chem. Soc. 1992, 114, 7652-7660. (d) Lodge, E. P.; Heathcock, C. H.
J . Am. Chem. Soc. 1987, 109, 3353-3361. (e) Panek, J . S.; Cirillo, P.
F. J . Am. Chem. Soc. 1990, 112, 4873-4878.
(18) Lessard, J .; Saunders: J . K.; Viet, M. T. P. Tetrahedron Lett.
1982, 23, 2059-2062.
J . Org. Chem, Vol. 68, No. 9, 2003 3723

TABLE 4. CSI Rea ction of Allyl Eth er s by Va r yin g R 2 a
F IGURE 3. Modified Felkin-Anh model of nucleophilic
attack on the allyl carbocation.
In conclusion, we have developed a novel regioselective
and diastereoselective synthetic approach to the unsatur-
ated aromatic 1,2-amino alcohols from the epimeric
mixture of optically active allylic ethers having a hy-
droxyl group attached to an allylic chiral center to the
π-system using the CSI reaction. The diastereoselectivity
of this approach was investigated by varying the protect-
ing group of the hydroxyl moiety and alkyl substituents.
In all cases, an anti-stereoselectivity has been either
exclusively or predominantly observed. An increase in the
steric bulk at the OPG group produced a low anti-
diastereoselectivity and an increase in the steric bulk at
the alkyl moiety (R1) produced a high excess of the anti-
isomer. Treatment of 3k with CSI furnished the anti-
stereoisomer 4k in 83% chemical yield. The anti-
selectivity can be explained by the Cieplak electronic
model B. For 3s, the anti-stereoisomer 4s was obtained
as the sole product, which can be explained by the
modified Felkin-Anh Model C.
ratioa
(4/5)
yieldb (%)
(4 + 5)
yieldb (%)
R2
H (3m )
Me (3n )
Et (3o)
i-Pr (3p )
Bn (3q)
Ph (3c)
(7)
1
2
3
4
5
6
7
8
9.2:1
9.2:1
9.4:1
7.7:1
7.5:1
4.5:1
5.6:1
98:2
29
13
12
14
12
83
22
82
45
76
74
69
76
c
t-Bu (3r )
2-mesityl (3s)
63
c
a
All the reactions were carried out at 20 °C, except for entries
b
6 and 8 (-78 °C). Based on integrals of OCH3 signals in
carbamates. c Isolated yield of pure material. Not detected.
d
1). For the 3n and 3o cases, a similar formation of the
anti-isomer was obtained as compared to the 3m case
(entries 2 and 3). As the size of R2 increased, the forma-
tion of the anti-isomer of the 1,2-amino alcohols decreased
but not much due to the negligible steric repulsion
between OTIPS and R2 itself (entries 3-7).19 However,
for 3s, a very high diastereoselectivity (anti/syn ) 98:2)
was observed unexpectedly in 82% chemical yield. From
the data in Table 4, it appears that the factor controlling
the site of the substitution (1,2-amino alcohol or 1,4-
amino alcohol) depends more on the formation of a stable
conjugated product than on any steric effect.
Ack n ow led gm en t. This work was supported by a
grant (No. R01-2002-000-00005-0) from the Basic Re-
search Program of the Korea Science & Engineering
Foundation.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedure, characterization data, and spectra for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The diastereoselectivity in entry 8 can be explained by
the modified Felkin-Anh model C,20 in which the steric
repulsion between OTIPS and the mesityl group, and Me
and the mesityl group is minimized even though they are
far from each other (Figure 3).
J O0267089
(19) One of reviewers suggested that steric interaction between R2
and CHR1OTIPS in allyl cations cannot be responsible for anything
by geometry optimization with the PM3 Methodol. We deeply appreci-
ated this comment.
(20) Asao, N.; Shimada, T.; Sudo, T.; Tsukada, N.; Yazawa, K.;
Gyoung, Y. S.; Uyehara, T.; Yamamoto, Y. J . Org. Chem. 1997, 62,
6274-6282.
Finally, we changed the R3 from Me to benzyl group
(3t) in order to understand how the variation exerts an
influence upon the diastereoselectivity. This result (4t/
5t ) 4.0:1, 87% yield) is similar to the Me case.
3724 J . Org. Chem., Vol. 68, No. 9, 2003