A novel synthesis of chiral 1-allyl-1,2,3,4-tetrahydro-β-carboline employing allyltributyltin and chiral acyl chlorides

Article abstract of DOI:10.1055/s-1999-2952

β-Carboline was acylated at its 9-position by a chiral acyl chloride, followed by reaction with allyltributyltin and 2,2,2-trichloroethyl chloroformate to afford an 1-allyl-1, 2-dihydrocarboline derivative in a diastereoselective manner. The chiral acyl group at N-9 was readily eliminated by aqueous alkali to give carboxylic acid quantitatively without racemization on C-1 position. The formed 1-allyl-1,2-dihydro-β-carboline was transformed to 1-allyl-1,2,3,4-tetrahydro-β-carboline.

Full text of DOI:10.1055/s-1999-2952

LETTER
1799
A Novel Synthesis of Chiral 1-Allyl-1,2,3,4-tetrahydro-b-carboline Employing
Allyltributyltin and Chiral Acyl Chlorides
Takashi Itoh, Yûji Matsuya, Yasuko Enomoto, Kazuhiro Nagata, Michiko Miyazaki, Akio Ohsawa*
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
Fax +81-3-3784-5982; E-mail: ohsawa@pharm.showa-u.ac.jp
Received 6 August 1999
the N-2 position, and subsequent alkylation resulted in
Abstract: b-Carboline was acylated at its 9-position by a chiral acyl
high diastereo excess (de) of the reaction products.9
chloride, followed by reaction with allyltributyltin and 2,2,2-
trichloroethyl chloroformate to afford an 1-allyl-1, 2-dihydrocarbo-
line derivative in a diastereoselective manner. The chiral acyl group
at N-9 was readily eliminated by aqueous alkali to give carboxylic
acid quantitatively without racemization on C-1 position. The
formed 1-allyl-1,2-dihydro-b-carboline was transformed to 1-allyl-
1,2,3,4-tetrahydro-b-carboline.
In a previous paper, we reported that an acyl chloride de-
rived from simple amino acid afforded high de in the 1,2-
addition of silyl enol ethers to the isoquinoline nucleus.10
Thus, we investigated the application of the system to b-
carboline derivatives. Although the first application of
1,2-addition was simply carried out using 3,4-dihydro-b-
carboline, a chiral acyl chloride, and allyltributyltin
according to the reported procedures,5-7 there resulted
in almost no stereoselectivity in spite of moderate
chemical yields. One of the examples is shown in Scheme
1 (1Æ 2).11 An addition to the aromatic b-carboline 3 also
resulted in a low yield and low de of the product formation
shown. To our surprise, however, the exchange of two
acyl groups raised the de considerably (Scheme 1). In the
reaction, 9-[N-(phenylsulfonyl)prolinyl]-b-carboline was
treated with allyltributyltin and phenyl chloroformate to
give the adduct 4 in 53% yield and 74% de.
Key words: b-carboline, allyltributyltin, asymmetric addition,
chiral acyl chloride, 2,2,2-trichloroethyl chloroformate
Introduction of allyl group to organic compounds is one of
the major subjects of organic synthesis1 due to ready
transformation of allyl group into other functional groups.
In the course of our study on the reaction of N-acylated
azaaromatics, we found that allyltributyltin is a versatile
nucleophile toward a variety of azaaromatics without side
reactions with coexisting acyl chlorides.2 This result
prompted us to investigate an asymmetric allyl addition
toward azaaromatics, and it was found that b-carboline
having a chiral acyl group at N-9 position is a good sub-
strate for the asymmetric addition of allyltributyltin at C-
1, and the adduct thus formed is readily transformed to 1-
allyl-1,2,3,4-tetrahydrocarboline in good yields. This pa-
per describes the results.
Bu3Sn
N
N
N
H
COR*
N
H
R*COCl, CH2Cl2
H
1
2
y 75%, de 6% (rt., 1.5 h)
1-Substituted-1,2,3,4-tetrahydro-b-carboline moiety is
one of the most universal parent structures in alkaloids,
and there are a lot of reports concerning its synthesis.3
Most of these studies adopted 3-(2-aminoethyl)indole de-
rivatives as starting materials, and the subjection to Pictet-
Spengler reaction afforded the nucleus.4 In contrast, there
are few examples in which the 1,2-unsaturated b-carbo-
line moiety was directly derivatized by addition reaction
of nucleophiles to give tetrahydro-b-carboline deriva-
tives, and these limited examples treated almost exclu-
sively the introduction of allyl groups. Martin et al.,5 and
Yamaguchi et al.,6 reported that 3,4-dihydro-b-carboline
was subjected to addition reaction of nucleophiles in the
presence of acyl halides to give 1-substituted tetrahydro-
b-carboline derivatives. In these reactions, N-acylated
iminium salts formed in situ were trapped by silyl enol
ethers or organotin reagents.7 There has been, however,
only an asymmetric version of these reactions reported so
far.8 There has been only one type of general asymmetric
induction to the tetrahydro-b-carboline framework, that
is, Meyers et al. developed lithiation of tetrahydro-b-car-
boline having O-tert-butylvalinol formamidine moiety at
Bu3Sn
R2COCl, CH2Cl2
N
N
N
COR2
N
COR1
H
COR1
4
3
R1=OPh, R2=R*: y 18% (de 38%) (rt., 48 h)
R1=R*, R2=OPh: y 53% (de 74%) (-40°C, 4 h)
R *=
N
SO2Ph
Scheme 1
Consequently, it was found that the chiral auxiliary was
more effective at N-9 in spite of one atom farther than N-
2. The chiral auxiliary used was readily removed by the
treatment of 4 with aqueous NaOH/THF for 30 min at
room temperature.
Synlett 1999, No. 11, 1799–1801 ISSN 0936-5214 © Thieme Stuttgart · New York

1800
T. Itoh et al.
LETTER
Table 2 Reaction of 9-[N-[p-(t-amyl)phenylsulfonyl]prolinyl]-β-carboline
with Allyltributyltin in the Presence of Various Chloroformates
R*COCl, Et3N
N
N
step A
N
H
N
Entry
R
Temp(°C) Time (h) Yield of 7(%) Yield of 8 (%)(%ee)
COR*
5
6
1
2
3
4
5
6
Ph
Et
CH2CCl3
CH2CCl3
CH2CCl3
CH2CCl3
-40
-40
-40
-78
-78
-78
4
5
2
24
24
48
90
36
94
62
84
98
95 (80)
98 (59)
96 (81)
96 (84)
96 (86)
96 (86)
Bu3Sn
R* =
N
N
ClCO2R
N
H
COR*
CO2R
O2S
X
step B
7
a) R=Ph
b) R=CH2CCl3
aq. NaOH/THF
N
+ R*CO2H
rt., 0.5 h
N
H
CO2R
The obtained 8 (Scheme 3) was allowed to be reduced
with triethylsilane-trifluoroacetic acid (TFA) to give 3,4-
dihydro derivative 9, and the trichloroethyl group was
eliminated by Zn-CH3CO2H to give 1-allyl-1,2,3,4-tet-
rahydro-b-carboline (10) in 86% ee.15 The overall yield of
10 from the parent 5 was 55% (86% ee) via 5 steps.
H
step C
9
8
Scheme 2
Thus we investigated using various chiral acyl chlorides
and chloroformates to optimize the reaction conditions.
Acylation of the N-9 position by various acyl chlorides
derived from N-sulfonyl proline derivatives12 resulted in
almost quantitative yields of compound 6 in Scheme 2
(step A).13 Thus the addition of allyltributyltin was inves-
tigated using various acyl groups at N-9 in CH2Cl2,14
whose results are summarized in Table 1.
2 steps
N
5
N
CO2CH2CCl3
y 89% (86%ee)
H
COR*
R* =
N
O2S
t-Am
aq. NaOH/THF
rt., 0.5 h, y 96%
N
Table 1 Reaction of 9-Acyl-β-carboline 6 with Allyltributyltin in the
Presence of Phenyl Chloroformate
N
H
CO2CH2CCl3
H
8
Entry
X
Time (h) Yield of 7(%) Yield of 8 (%) % ee of 8a)
1
2
3
4
5
6
7
8
9
H
4-NO2
4-MeO
4-Cl
4-I
4-Me
4
16
5
5
5
6
5
3
4
53
99
95
99
90
99
90
95
90
99
92
73
97 (83)b)
96 (90)
86 (85)
91 (96)
99 (95)
99 (95)
99 (94)
88 (99)
95 (88)
98 (94)
96 (99)
99 (90)
74
67
69
72
68
75
77
78
80
64
60
51
Et3SiH-TFA
N
rt., 15 min, y 76%
N
H
CO2CH2CCl3
H
9
4-i-Pr
4-t-Bu
4-t-Am
3-NO2
2,3-benzo
3,4-benzo
10
11
12
24
4
5
Zn-CH3CO2H
NH
N
H
THF-H2O, rt., 0.5 h, y 85%
H
10
a) Determined by HPLC using Chiralcel OD column.
b) The recovery of 9 (%) was shown in the parenthesis.
overall yield 55% (86% ee)
Scheme 3
The results show that the adducts 7 were obtained quanti-
tatively, and the recovery of the chiral auxiliary also pro-
ceeded smoothly. It was suggested from these data that the The absolute configuration of 10 was determined as R by
substituent at the para position of the phenylsulfonyl the derivatization of 10 to 1,2,3,4-tetrahydro-9-meth-
group has a slight influence on the stereoselectivity, and a oxymethyl-2-(trans-2,4-pentadienoyl)-b-carboline,16
bulky t-amyl group gave a superior result (Table 1, entry which was reported as an intermediate for the total synthe-
9).
sis of (+)-pseudoyohimban.9b
Accordingly, the other reaction condition was investigat- In this paper, we described the synthesis of chiral 1-allyl
ed using N-[p-(t-amyl)phenylsulfonyl]-L-prolinyl group derivative of 1,2,3,4-tetrahydro-b-carboline using a readi-
as the chiral auxiliary, and the results are summarized in ly available amino acid as a chiral auxiliary. The allyl
Table 2.
group is thought to be a versatile synthetic tool for diverse
kinds of alkaloids, and the syntheses of some natural prod-
ucts are now in progress.
Among the activators, 2,2,2-trichloroethyl chloroformate
was most reactive, and the reaction could be carried out at
–78°C. The ee of 8 was up to 86%.
Synlett 1999, No. 11, 1799–1801 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Novel Synthesis of Chiral 1-Allyl-1,2,3,4-tetrahydro-b-carboline
1801
(9) a) Meyers, A. I.; Miller, D. B.; White, F. H. J. Am. Chem. Soc.,
1988, 110, 4778. b) Meyers, A. I.; Highsmith, T. K.; Buonora,
P. T. J. Org. Chem., 1991, 56, 2960, and references cited
therein.
(10) Itoh, T.; Nagata, K.; Miyazaki, M.; Ohsawa, A. Synlett, 1999,
1154.
(11) Compound 1 could not be acylated at N-9 under usual
conditions, thus the experiment parallel to 3 Æ 4 could not be
carried out.
(12) Other amino acids such as alanine, phenylalanine, valine, etc.,
were used for the reaction, but the de at step B was lower than
that of proline derivatives.
References and Notes
(1) Yamamoto,Y.; Asao. N. Chem. Rev. 1993, 93, 2207, and
references cited therein.
(2) a) Itoh, T.; Hasegawa, H.; Nagata, K.; Ohsawa, A. J. Org.
Chem., 1994, 59, 1319. b) Itoh, T.; Matsuya, Y.; Hasegawa,
H.; Nagata, K.; Okada, M.; Ohsawa, A. J. Chem. Soc., Perkin
Trans. 1, 1996, 2511. c) Itoh, T.; Miyazaki, M.; Nagata, K.;
Hasegawa, H.; Ohsawa, A.; Nakamura, K. T. Heterocycles,
1998, 47, 125.
(3) The Chemistry of Heterocyclic Compounds, Saxton, J. E. Ed.;
John Wiley & Sons: Chichester, 1994, Part 4, suppl. of Vol.
25.
(13) Step A of Scheme 2 proceeded by the use of one eq. of acyl
chloride and two eq. of triethylamine in THF at room
temperature for 2-4 h. All the isolated yields were above 80%,
and the details will be reported in a near future.
(14) The other solvents such as 1,2-dichloroethane, acetonitrile,
toluene, and DMF were used for the reaction, and
dichloromethane was found to afford the best results.
(15) The ee was monitored on a chiral HPLC, and it was found that
no racemization occurred in the transformation of 8 to 10.
(16) Compound 10 was treated with trans-2,4-pentadienoic acid
and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide in
CH2Cl2 to give 1-allyl-1,2,3,4-tetrahydro-2-(trans-2,4-
pentadienoyl)-b-carboline in 75% yield. The compound was
allowed to react with methoxymethyl chloride in the presence
of potassium hydride to give the product without
racemization.
(4) Yamada, H.; Kawate, T.; Matsumizu, M.; Nishida, A.;
Yamaguchi, K. Nakagawa, M. J. Org. Chem., 1998, 63, 6348,
and references cited therein.
(5) a) Martin, S. F.; Benage, B.; Hunter, J. E. J. Am. Chem. Soc.,
1988, 110, 5925. b) Martin, S. F.; Benage, B.; Geraci, L. S.;
Hunter, J. E.; Mortimore, M. J. Am. Chem. Soc., 1991, 113,
6161.
(6) a) Yamaguchi, R.; Otsuji, A.; Utimoto, K.; Kozima, S. Bull.
Chem. Soc. Jpn., 1992, 65, 298. b) Yamaguchi, R.; Hamasaki,
T.; Sasaki, T.; Ohta, T.; Utimoto, K.; Kozima, S.; Takaya, H.
J. Org. Chem., 1993, 58, 1136.
(7) For the recent applications for the achiral 1,2-additions, see, a)
Birman, V. B.; Rawal, V. H. Tetrahedron Lett., 1998, 39,
7219. b) Birman, V. B.; Rawal, V. H. J. Org. Chem., 1998, 63,
9146.
(8) Yamaguchi et al. reported in a review that benzyl 3,4-dihydro-
b-carboline-3-(S)-carboxylate underwent the addition
reaction with acryloyl chloride and tributyl(2,4-
pentadienyl)tin to give yohimban derivatives in 83% yield
(86% de). Yamaguchi,R. Yuki Gosei Kagaku Kyokaishi, 1991,
49, 128.
Article Identifier:
1437-2096,E;1999,0,11,1799,1801,ftx,en;Y16699ST.pdf
Synlett 1999, No. 11, 1799–1801 ISSN 0936-5214 © Thieme Stuttgart · New York