Stereospecific construction of contiguous quaternary and tertiary stereocenters by rearrangement from indoline-2-methanol to 2,2,3-trisubstituted tetrahydroquinoline: Application to an efficient total synthesis of natural virantmycin

Article abstract of DOI:10.1002/anie.200351069

Only nine steps away: PPh₃/CCl₄-mediated stereospecific rearrangement of α,α-disubstituted indoline-2-methanol to 2,2,3-trisubstituted optically active tetrahydroquinoline (see scheme) has been developed. The reaction was applied to

Full text of DOI:10.1002/anie.200351069

Communications
Total Synthesis of Virantmycin
Stereospecific Construction of Contiguous
Quaternary and Tertiary Stereocenters by
Rearrangement from Indoline-2-methanol to
2,2,3-Trisubstituted Tetrahydroquinoline:
Application to an Efficient Total Synthesis of
Natural Virantmycin**
Mayuko Ori, Narihiro Toda, Kazuko Takami,
Keiko Tago, and Hiroshi Kogen*
The stereoselective construction of chiral quaternary stereo-
centers is one of the most challenging problems in synthetic
organic chemistry.[1] Substituted tetrahydroquinolines and
tetrahydroisoquinolines have attracted considerable attention
from organic and medicinal chemists, primarily because they
display a wide range of physiological activities.[1c,2] These ring
systems are present in various important natural products.[2]
Moreover, chiral quaternary centers are often essential for
these compounds. For example, chiral contiguous quaternary
and tertiary stereocenters are found in virantmycin (6a),[3]
a
potent antiviral agent (Scheme 1). Recently, Shibasaki et al.
reported an elegant synthesis of 1,1-disubstituted tetrahy-
[*] Dr. H. Kogen, M. Ori, N. Toda, K. Takami, Dr. K. Tago
Exploratory Chemistry Research Laboratories
Sankyo Co., Ltd.
1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710 (Japan)
Fax: (+81)3-5436-8570
E-mail: hkogen@shina.sankyo.co.jp
¯
[**] We thank Prof. Satoshi Omura (Kitasato Institute) for providing
copies of NMRspectra of natural virantmycin and Mr. Youji
Furukawa (Sankyo) for X-ray analysis.
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DOI: 10.1002/anie.200351069
Angew. Chem. Int. Ed. 2003, 42, 2540 – 2543

Angewandte
Chemie
OMe
H
N
R
H
N
H
N
R'
Cl
H
N
R'
OH
PPh3, CCl4
PPh3, CCl4
CH2Cl2
63%
OH
H
R
H
H
H
Cl
1
2
1a
1b
2a
2b
OMe
OMe
H
N
H
N
OMe
H
N
H
N
H
PPh3, CCl4
R'
R'
OH
+
CH2Cl2
74%
OH
Cl
R
-
R
Cl
3
4
+
PPh3
Scheme 2.
-
Cl
CCl3
with nBu3SnH and azobisisobutyronitrile afforded the dech-
lorinated derivative, which was identical with the dechlori-
nated compound derived from 2a except for the optical
rotation. On the basis of these results, the rearrangement is
considered to be stereospecific.[13] Table 1 presents the results
of the rearrangement of various chiral indoline-2-methanol
derivatives. All the reactions provide single isomers in
moderate to good yield.[14] The reaction of 1c (enantiomer
of 1a) provided the antipode of 2a (entry 1). Use of polymer-
supported triphenylphosphane gave the same result (entry 6).
Thus, this rearrangement provides a new method for the
synthesis of various optically active 2,2,3-trisubstituted tetra-
hydroquinolines.
The utility of this reaction was clearly demonstrated by an
efficient total synthesis of the potent antiviral agent virant-
mycin (6a)[3] in its natural form. Several total syntheses of
(ꢁ )- or ent-virantmycin are known.[15,16] However, the
naturally occurring form of virantmycin has not been
synthesized to date. The synthesis of (ꢀ)-virantmycin is
outlined in Scheme 3. Acylindoline 9,[7] which was prepared
from commercially available (S)-(ꢀ)-indoline-2-carboxylic
acid (8) in four steps (37%), was treated with iodine
monochloride to afford iodide 10 in 91% yield. Iodide 10
was subjected to diastereoselective Grignard addition[7] with
2,3-dimethyl-3-pentenylmagnesium bromide[17] to give tert-
alcohols as a 95/5 mixture of separable isomers, as determined
by HPLC analysis of the product mixture. The Boc protecting
group of the major isomer was removed by treatment with
HCO2H to afford 11.[18] The resulting amino alcohol 11 was
treated with tri-n-butylphosphane (20 equiv)[19] and CCl4
(30 equiv) to provide tetrahydroquinoline 12 as a single
isomer in 45% yield. The tetrahydroquinoline 12 was
carbonylated by reaction with 1 atm of CO in H2O/DMF
in the presence of catalytic Pd(OAc)2 and K2CO3 to give
OMe
Cl
H
N
H
N
OH
OMe
benzastatin E (5)
H2NOC
H
R"
R" = CO2H: virantmycin (6a)
R" = CONH2: benzastatin C (6b)
Scheme 1.
droisoquinolines by a catalytic, enantioselective Reissert-type
reaction.[1c] However, efficient stereoselective synthesis of
2,2-disubstituted tetrahydroquinolines still remains to be
solved. Herein we describe an indoline-2-methanol to tetra-
hydroquinoline rearrangement in which contiguous quater-
nary and tertiary stereogenic centers are constructed in one
step. This reaction was successfully applied to an efficient
total synthesis of natural virantmycin (6a).
Kim et al. reported the isolation from Streptomyces
nitrosporeus 30643 of a novel class of indoline alkaloids, that
is benzastatins such as benzastatin E (5), and tetrahydroqui-
noline alkaloids, namely, benzastatin C (6b) and its conge-
ners, which are structurally related to virantmycin (6a).[4] The
structures of these alkaloids suggested that an aziridine
intermediate, such as 4, is involved in their biosyntheses.[5]
Based on this hypothesis, we designed the triphenylphos-
phane/CCl4-mediated rearrangement from a,a-disubstituted
indoline-2-methanol 1 to 2,2,3-trisubstituted tetrahydroqui-
noline 2 via the aziridine 4, followed by ring opening by attack
of chloride anion (Scheme 1).[6] This type of rearrangement is
a useful method of accessing various chiral 2,2,3-trisubstituted
tetrahydroquinoline derivatives in conjunction with our
previously developed, highly diastereoselective synthesis of
optically active a,a-disubstituted indoline-2-methanol com-
pounds 1 by Grignard addition to 2-acylindoline.[7]
We investigated the reaction by using optically active
alcohol 1a[7] as starting material (Scheme 2). Treatment of 1a
with PPh3 (3 equiv) and CCl4 (10 equiv) in CH2Cl2 under
reflux for 30 min afforded tetrahydroquinoline 2a as a single
isomer in 63% yield. The same treatment of diastereomer
1b[7] gave 2b as a sole isomer in 74% yield.[8,9] Relative
configurations of 2a and 2b were determined by comparison
with the corresponding authentic racemic samples, reported
by Shirahama et al.[10] The absolute configuration of 2a was
determined to be 2R,3R by X-ray analysis of (1S,2R,4R)-(ꢀ)-
camphorsultam[11] derivative
7
(Figure 1),[12] which was
Figure 1. X-ray structure of the (1S,2R,4R)-(ꢀ)-camphorsultam
derivative of 2a.
derived from 2a in a two-step sequence. Treatment of 2b
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Table 1: Rearrangement of indoline 1 to tetrahydroquinoline 2.
Entry[a] Indoline 1[b]
Tetrahydroquinoline 2[c] Yield[%][d] Entry[a] Indoline 1[b]
Tetrahydroquinoline 2[c]
Yield[%][d]
63
1
63
63
7
8
2
3
55
62
53
9
4
5
6
65
10
11
12
41
50
52
31
37 (44)[e]
[a] All the reactions conducted were with Ph3P (3 equiv) and CCl4 (10 equiv), except for entry 6. [b] For synthesis of indoline 1, see ref. [7]. [c] The
absolute stereochemistry was tentatively assigned by analogy with the reaction mechanism, except for 2c (enantiomer of 2a). [d] Yield of isolated
product after column chromatography. [e] Polymer-supported triphenylphosphane (5 equiv) was used.
virantmycin in only nine steps from commercially available
starting material. We believe that our rearrangement reaction
provides some support for the proposed biosynthetic pathway
of virantmycin and related tetrahydroquinoline alkaloids via
an aziridine intermediate. Further applications of this meth-
odology to complex polycyclic tetrahydroquinoline alkaloids
are underway.
Boc
N
O
H
N
H
N
CO2H
b
S
OH
OMe
H
H
X
I
H
11
OMe
9: X = H
10: X = I
8
a
OMe
OMe
H
N
H
N
c
d
I
Cl
HO2C
Cl
( )-virantmycin (6a)
12
Experimental Section
2a: Triphenylphosphane (135 mg, 0.420 mmol) was added to a
solution of 1a (31 mg, 0.14 mmol) and CCl4 (135 mL, 1.40 mmol) in
CH2Cl2 (3 mL) at 408C (bath temp.). The mixture was stirred under
reflux for 1 h, and then concentrated. Purification by column
chromatography on silica gel (n-hexane/AcOEt 10/1 to 2/1) gave
tetrahydroquinoline 2a as a colorless oil (21 mg, 63%): [a]2D4 = + 7.2
(c = 0.45 in CHCl3); 1H NMR (400 MHz, CDCl3): d = 7.01 (t, J =
8.1 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.63 (t, J = 8.1 Hz, 1H), 6.53
(d, J = 8.1 Hz, 1H), 4.33 (dd, J = 6.6, 5.2 Hz, 1H), 3.99 (brs, 1H), 3.53
(d, J = 9.2 Hz, 1H), 3.48 (d, J = 9.2 Hz, 1H), 3.35 (s, 3H), 3.30 (dd, J =
16.8, 5.2 Hz, 1H), 3.05 (dd, J = 16.8, 6.6 Hz, 1H), 1.76 (dq, J = 14.9,
7.3 Hz, 1H), 1.66 (dq, J = 14.9, 7.3 Hz, 1H), 0.92 ppm (t, J = 7.3 Hz,
3H); 13C NMR (100 MHz, CDCl3): d = 142.3, 129.4, 127.4, 117.6,
117.2, 114.7, 73.5, 59.4, 57.6, 57.0, 33.9, 27.2, 7.1 ppm; IR (CHCl3
solution): n˜ = 3422, 2972, 2935, 2896, 1607, 1588, 1482, 1312, 1260,
Scheme 3. Reagents and conditions: a) ICl, 2,6-di-tert-butyl-4-methyl-
¼
pyridine, CH2Cl2, 08C!RT, 91%; b) 1) Me2C C(Me)(CH2)2MgBr, THF,
ꢀ788C, 73%; 2) HCO2H, CH2Cl2, 508C, 59%; c) (nBu)3P, CCl4, CH2Cl2,
reflux, 45%; d) CO 1 atm, K2CO3, Pd(OAc)2, H2O/DMF, RT, 53% (80%
based on recovered starting material); Boc=1,1-dimethylethoxycar-
bonyl.
(ꢀ)-virantmycin (6a) in 53% yield (80% based on recovered
starting material). Synthetic 6a was identical in all respects to
natural virantmycin[3,16] [1H NMR, 13C NMR spectra, and
[a]2D4 = ꢀ15.0 (c = 0.84 in CHCl3) (ref.[16,20] [a]1D8 = ꢀ11.1
(c = 0.175 in CHCl3))]. This synthesis required only nine steps
from indoline 8.
In summary, we have developed a novel synthesis of chiral
trisubustituted tetrahydroquinolines in which contiguous
quaternary and tertiary stereogenic centers are constructed
in analogy to the hypothetical biosynthetic pathway. The
reaction was applied to the first total synthesis of natural
1112, 980, 960, 834 cmꢀ1
239.1077; found 239.1075.
;
HRMS calcd for C13H18NOCl [M+]:
2b: [a]2D4 = ꢀ30.2 (c = 0.67 in CHCl3); 1H NMR (500 MHz,
CDCl3): d = 7.01 (t, J = 8.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.67
(t, J = 8.0 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 4.44 (dd, J = 7.0, 5.0 Hz,
1H), 3.99 (brs, 1H), 3.42 (1H, d, J = 9.5 Hz), 3.40 (d, J = 9.5 Hz, 1H),
2542
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3.35 (s, 3H), 3.24 (dd, J = 16.5, 5.0 Hz, 1H), 3.09 (dd, J = 16.5, 6.5 Hz,
1H), 1.82 (dq, J = 14.5, 7.5 Hz, 1H), 1.72 (dq, J = 14.5, 7.5 Hz, 1H),
0.94 ppm (t, J = 7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3): d = 142.1,
129.3, 127.3, 117.8, 117.7, 115.0, 75.1, 59.3, 57.9, 57.5, 34.0, 25.4,
7.5 ppm; IR (CHCl3 solution): n˜ = 3424, 2972, 2935, 2883, 1607, 1588,
1498, 1481, 1307, 1156, 1111, 962 cmꢀ1; HRMS: calcd for C13H18NOCl
[M+]: 239.1077, found: 239.1081.
[15] Syntheses of (ꢁ )-virantmycin: a) M. L. Hill, R. A. Raphael,
Tetrahedron Lett. 1986, 27, 1293; b) M. L. Hill, R. A. Raphael,
Tetrahedron 1990, 46, 4587; c) Y. Morimoto, F. Matsuda, H.
Shirahama, Synlett 1991, 202 and ref. [10]; d) H. Steinhagen, E. J.
Corey, Org.Lett. 1999, 1, 823.
[16] Synthesis of ent-virantmycin: Y. Morimoto, F. Matsuda, H.
Shirahama, Tetrahedron 1996, 52, 10631.
[17] A. N. De Silva, C. L. Francis, D. Ward, Aust.J.Chem. 1993, 46,
1657.
Received: January 30, 2003 [Z51069]
[18] The configurations of the newly created asymmetric centers in
the Grignard adduct were determined after NOE experiments
on the acetonide derivative of 11. See ref. [7].
[19] When we used triphenylphosphane in the reaction, an undesired
deiodinated product and an indole derivative (dehydration
followed by isomerization) were obtained. However, using tri-n-
butylphosphane instead of triphenylphosphane prevented these
side reactions.
[20] Initially, the optical rotation of (ꢀ)-virantmycin was reported as
ꢀ0.05 in ref. [3]. Later, the optical rotation of (ꢀ)-virantmycin
was reexamined and reported as ꢀ11.1 by Shirahama and co-
workers.[16]
Keywords: alkaloids · natural products · rearrangement ·
total synthesis
.
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[2] I. Gallou-Dagommer, P. Gastaud, T. V. Rajan Babu, Org.Lett.
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¯
[3] S. Omura, A. Nakagawa, Tetrahedron Lett. 1981, 22, 2199.
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[5] S. E. Yoo, J. H. Kim, K. Y. Yi, Bull.Korean Chem.Soc. 1999, 20,
139. Yoo et al. speculated on an alternative biosynthetic pathway
for these alkaloids. See ref. [4c].
[6] Cossy et al. reported a ring-expansion reaction of N-benzylpyr-
rolidine-2-methanol derivatives to N-3-chloropiperidine deriva-
tives using MsCl (Ms = methanesulfonyl). They reported that
the rearrangement does not proceed with a,a-disubstituted N-
benzylpyrrolidine-2-methanol derivatives. J. Cossy, C. Dumas, D.
Gomez Pardo, Eur.J.Org.Chem. 1999, 1693. Under the same
conditions, a,a-disubstituted indoline-2-methanols do not
undergo the rearrangement reaction, probably because of
steric hindrance.
[7] N. Toda, M. Ori, K. Takami, K. Tago, H. Kogen, Org.Lett. 2003,
5, 269.
[8] The same reactions of corresponding a-monosubstituted or
unsubstituted indoline-2-methanols gave complex mixtures.
[9] No racemization occurs during the rearrangement, this is
confirmed by the resulting tetrahydroquinoline 2a which is
optically pure by chiral HPLC analysis. Daicel Chiralcel OJ
(1 = 0.46 cm ” 25 cm), n-hexane/iPrOH (95/5), 1 mLminꢀ1
.
[10] Y. Morimoto, F. Matsuda, H. Shirahama, Tetrahedron 1996, 52,
10609.
[11] N. Harada, N. Koumura, M. Robillard, Enantiomer 1997, 2, 303.
[12] CCDC 202237 (7) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: (+ 44)1223-336-033; or deposit@
ccdc.cam.ac.uk).
[13] There is no direct evidence for the formation of an aziridine
intermediate such as 4. A stepwise sequence may be possible
(1. formation of tertiary chloride; 2. intermolecular cyclization
to an aziridine; 3. ring opening by the attack of chloride anion).
However, we could not obtain the tertiary chloride by treatment
of 1a with various chlorinating agents. Also, treatment of 1a
under Mitsunobu conditions gave no aziridine compound
(starting material was recovered). For the ring-opening reaction
of an aziridine, such as 4, with chloride anions to provide
tetrahydroquinoline 2, see ref. [10].
[14] All the other products were highly polar materials which were
not isolated.
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