Synthetic studies towards (-)-lemonomycin, synthesis of fused tetracycles

Article abstract of DOI:10.1055/s-2006-944225

The asymmetric synthesis of 1,3-lactol-bridged tetrahydroisoquinoline 5 is developed. Subsequent cyclization of 5 under acidic conditions leads to the formation of a tricyclic enamide 22, which is in turn converted to a tetracyclic compound 23. Georg Thie

Full text of DOI:10.1055/s-2006-944225

LETTER
1691
Synthetic Studies towards (–)-Lemonomycin, Synthesis of Fused Tetracycles
S
ynthesis of Fuse
é
d
T
etracyc
d
les ric Couturier,a Thierry Schlama,b Jieping Zhu*a
a
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
b
Société Rhodia, Centre de Recherches de Lyon, 69192 Saint-Fons Cedex, France
Fax +33(1)69077247; E-mail: zhu@icsn.cnrs-gif.fr
Received 21 March 2006
Mannich reaction of 4 is shown in Scheme 1. The 1,3-lac-
tol-bridged tetrahydroisoquinoline 5, derived from the
corresponding lactone, was thought to be a suitable pre-
cursor of 4. Compound 5 could in turn be elaborated from
tetrahydroisoquinoline 6 and L-5,5¢-dimethyl-N-Cbz-4-
carboxy-glutamate (7).9 We report herein a successful
synthesis of lactol 5 and results of the subsequent cycliza-
tion studies.
Abstract: The asymmetric synthesis of 1,3-lactol-bridged tetrahy-
droisoquinoline 5 is developed. Subsequent cyclization of 5 under
acidic conditions leads to the formation of a tricyclic enamide 22,
which is in turn converted to a tetracyclic compound 23.
Key words: amino acid, lemonomycin, tetrahydroisoquinoline,
Mannich rection, intramolecular Pictet–Spengler reaction
The tetrahydroisoquinoline alkaloids represented by sa-
framycins, ecteinascidins, quinocarcins, tetrazomine and
lemonomycin have attracted multidisciplinary interests
because of their architectural complexity and potent bio-
activities (Figure 1).1 Lemonomycin (1)2 was isolated for
the first time from the fermentation broth of Streptomyces
(LL-AP191) in 1964, but its structure was elucidated only
in 2000 by He and co-workers at Wyeth–Ayerst.3
Lemonomycin displays interesting antibiotic activities
against methicillin-resistant S. aureus and vancomycin-
resistant Enterococcus faecium (VRE). It is also cytotoxic
against a human colon tumor cell line (HCT-116). The
broad spectra of antibiotic activities in conjunction with
its molecular complexity have made lemonomycin (1) an
attractive synthetic target. Indeed, Stoltz and co-workers
reported the first total synthesis of 1 in 2003,4 whereas
Fukuyama5 and Magnus6 reported syntheses of advanced
intermediates of 1 in 2005.
CO2Me
OMe
Cbz
N
1
N
MeO
OP
OH
O
OH
3
OMe
Cbz
CO2Me
N
N
MeO
CO2Me
OP
O
4
OH
OMe
OH
O
NHCbz
MeO
OP
CO2Me
CO2Me
N
O
5
OMe
O
+
O
CbzHN
HO
CO2Me
CO2Me
MeO
OP
N
OMe
O
H
HO
HO
Me
6
7
OH
O
O
H
OAc
H
Scheme 1 Retrosynthetic analysis of lemonomycin (1)
Me
N
Me
HN
N
N
O
MeO
O
S
Synthesis of L-(2,4-dimethoxy-3-methyl-5-tert-butyldi-
methylsiloxy)phenylalanine tert-butyl ester (12) is de-
tailed in Scheme 2. Substituted benzyl bromide 9 was
synthesized from 2,6-dimethoxytoluene (8) following
literature procedure.10 Enantioselective alkylation of N-
(diphenylmethylene) glycine tert-butyl ester 10 by 9 in the
presence of a catalytic amount of O-(9)-allyl-N-(9¢-an-
thracenylmethyl)cinchonidium bromide (11, 0.1 equiv)
afforded, after chemoselective hydrolysis of the imine
function (THF–H2O–AcOH), the amino ester 12 in 85%
overall yield.11,12 The S-configuration of aminoester 12
was assigned, taking for granted the Corey–Lygo empiri-
cal model. To confirm this assignment, both (S)-and (R)-
O-methylmandelic acid derivatives 13 and 14 were syn-
thesized (Scheme 2). The calculated chemical shift differ-
ences (DdArCH2(13–14)) = –0.05 ppm; DdCO2t-Bu(13–14)) = 0.10
ppm) are in accord with the S-configuration of the amino
OH
OH
O
OH
O
O
MeO
HO
O
NH
N
Lemonomycin (1)
Ecteinascidin 743 (2)
Figure 1 Structure of lemonomycin (1) and ecteinascidin 743 (2)
We have been interested in the total synthesis of this class
of natural products and have recently accomplished a total
synthesis of ecteinascidin 743 (2).7,8 Our planned syn-
thesis of lemonomycin (1) featuring a key intramolecular
SYNLETT 2006, No. 11, pp 1691–1694
1
2
.0
7
.2
0
0
6
Advanced online publication: 04.07.2006
DOI: 10.1055/s-2006-944225; Art ID: G10006ST
© Georg Thieme Verlag Stuttgart · New York

1692
C. Couturier et al.
LETTER
OMe
OMe
O
OMe
OMe
CO2t-Bu
OH
NHCbz
Br
a, b
a, b
NH2
MeO
MeO
MeO
Ph
N
CO2t-Bu
10
MeO
OTBDMS
OTBDMS
OTBDMS
Ph
8
9
15
12
OMe
O
OMe
OMe
OMe
c
O
Br
CO2t-Bu
NH2
NHCbz
OMe
OMe
N
O
MeO
MeO
HO
OTBDMS
OMe
MeO
16
17
OTBDMS
N
O
O
h
12
11
d–f
N
H
PO
O
H
H
O
H
6a P = TBDMS
6b P = Bn
CO2t-Bu
OMe
CO2t-Bu
OMe
g
H
N
N
H
H
O
OMe
OMe
OMe
O
i
NHCbz
MeO
TBDMSO
CO2Me
TBDMSO
N
OMe
OMe
CO2Me
PO
O
13
14
18a P = TBDMS
18b P = Bn
OH
Scheme 2 Reagents and conditions: a) 10, 11 (10%), CsOH·H2O,
CH2Cl2, –78 °C; b) THF–H2O–AcOH, (1:1:1), 85%.
OMe
O
NHCbz
MeO
CO2Me
CO2Me
1
ester 12.13 In addition, analysis of H NMR spectra of
N
PO
compounds 13 and 14 indicated that the de of 13 and 14,
and hence the ee of their precursor 12, is higher than 90%.
O
5a P = TBDMS
5b P = Bn
The synthesis of amino lactol 5, a precursor of aminal 4,
is shown in Scheme 3. N-Protection (CbzOSu, NaHCO3)
Scheme 3 Reagents and conditions: a) CbzOSu, dioxane–NaHCO3
sat. H2O; b) TFA, Et3SiH, CH2Cl2; c) EDCI, DMAP, 16, CH2Cl2, 83%
followed by unmasking of tert-butyl ester of 12 under for three steps; d) BF3·OEt2, H2O, CH2Cl2, 0 °C; e) BF3·OEt2, 4 Å mo-
lecular sieves, CH2Cl2, 0 °C then r.t.; f) H2, Pd/C, EtOAc, 90% for
three steps; g) TBAF, THF, 0 °C, then BnBr, K2CO3, DMF, 87%; h)
7, HATU, i-Pr2NEt, DMF, 0 °C; i) LiAlH2(OEt)2, Et2O, –78 °C, 85%.
mild acidic conditions (TFA, Et3SiH) afforded the acid
15, which was coupled with 2,2-dimethoxy ethanol 16
(EDCI, DMAP) to furnish ester 17 in 83% overall yield
from 12. Chemoselective hydrolysis of the acetal function
With lactol 5 in hands, the key intramolecular Mannich re-
action for the formation of bridged bicyclic ring system
was next investigated (Scheme 4). Following literature
precedents dealing with the intramolecular amidoalkyl-
ation of malonate,17 a set of conditions varying the pro-
moters [TiCl4·Et3N, TiCl4·pyridine, TiCl4, SnCl4, AlCl3,
Yb(OTf)3, TFA, CF3SO3H], the solvents (CH2Cl2,
MeCN), and the temperature (–78 °C, 0 °C, r.t., heating)
were examined. Whereas most of these conditions led to
the degradation of the starting material, reaction of 5a
mediated by BF3·OEt2 in CH2Cl2 provided enamide 22a in
42% yield. The formation of compounds 22a could be
rationalized as follows. Conversion of lactol 5a to aminal
4a followed by dehydration under Lewis acidic conditions
would produce the acyliminium intermediate 19a. The
intramolecular nucleophilic addition of malonate onto this
electrophilic species would produce the expected product
20. However, this desired reaction did not take place most
probably for unfavorable steric interaction since the eno-
late of malonate had to attack the iminium from the same
face as that occupied by the adjacent C–C bond.18 There-
fore, an alternative iminium–enamine tautomerization
would take place to produce enamide 21a that was further
isomerized to afford the conjugated olefin 22a.19
of 17 (BF3·OEt2, CH2Cl2–H2O) afforded the correspond-
ing aldehyde. Without purification, crude aldehyde was
submitted to the optimized conditions for intramolecular
Pictet–Spengler reaction (10 equiv of BF3·OEt2, 4 Å MS,
CH2Cl2) to afford, after removal of the N-Cbz function
(H2, Pd/C, EtOAc), the desired tetrahydroisoquinoline 6a
in 90% overall yield. While acetal-deprotection and cy-
clization sequence can be performed in a one-pot fashion,
we found that the overall yield is superior when the two
steps were carried out separately. The presence of the
bridged lactone unit guaranteed the required 1,3-cis stere-
ochemistry.14 The TBDMS ether 6a was converted to the
benzyl ether 6b in 87% yield following a standard depro-
tection (TBAF, THF, 0 °C) and benzylation sequence
(NaH, BnBr, DMF). Coupling of 6a with L-5,5¢-dimethyl-
N-Cbz-4-carboxy-glutamate (7, HATU,15 i-Pr2NEt, DMF,
0 °C) afforded the amide 18a in 75–85% yield. Chemose-
lective reduction of lactone 18a with diisobutylaluminium
hydride (DIBAL-H) afforded the corresponding lactol 5a
in 80% yield. Alternatively, the same reduction can be
realized with lithium diethoxyaluminium hydride
[LiAlH2(OEt)2, prepared in situ from lithium aluminium
hydride and EtOAc] in diethyl ether at –78 °C to provide
5a in 85–95% yield.16 Lactol 5b was synthesized from 6b
following the same synthetic sequence.
Synlett 2006, No. 11, 1691–1694 © Thieme Stuttgart · New York

LETTER
Synthesis of Fused Tetracycles
1693
OMe
OP
OH
NCbz
Compound 22b was obtained under identical conditions
from 5b in 40% yield.
5a
or
5b
a
CO2Me
CO2Me
N
Taking advantage of the ready availability of 22b, a tetra-
cyclic compound 23 is synthesized as shown in Scheme 5.
Krapcho decarbomethoxylation of 22b (LiCl in DMSO–
H2O, 160 °C) afforded monoester 24. Reduction of both
ester and amide function with lithium ethoxyaluminium
hydride [LiAlH3(OEt)] in diethyl ether at 0 °C provided
the aminal 25 in 44% yield. Simultaneous removal of N-
Cbz and O-Bn functions under hydrogenolysis conditions
(H2, Pd/C, MeOH) furnished the secondary amine, which,
upon purification (flash chromatograpy, SiO2), was air-
oxidized to provide the conjugated imine 23 in 36% yield.
The structure of 23 was fully determined by detailed spec-
troscopic studies.20 The observation of Ca–Hb correlation
in the HMBC spectrum indicated that a six-membered
rather than a five-membered aminal (oxazolidine) was
produced, while the coupling constant JHa–Hc = 2.0 Hz)
was indicative of the cis-orientation of protons Ha and Hc.
The preferred 6-exo- over 5-endo-addition of alcohol may
explain the preferred formation of observed compound
23.21
MeO
OMe
O
4a P = TBDMS
4b P = Bn
OH
NCbz
CO2Me
CO2Me
N
MeO
OP
O
OH
19a P = TBDMS
19b P = Bn
X
MeO2C
CO2Me
OMe
NCbz
N
MeO
OMe
OP
CO2Me
CO2Me
O
OH
NCbz
20
N
MeO
OP
O
OH
21a P = TBDMS
21b P = Bn
OMe
NCbz
Compound 23 was inactive against three cancer cell lines
CO2Me
N
(KB, MCF7, MCF7R) tested.
MeO
CO2Me
OP
O
In summary, we have developed an efficient synthesis of
highly functionalized 1,3-lactol-bridged tetrahydroiso-
quinoline 5 and its subsequent transformation to the tetra-
cyclic compound 23. We are pursuing the total synthesis
of lemonomycin by combining 6 with other type of suit-
ably functionalized amino acid building blocks.
OH
22a P = TBDMS
22b P = Bn
Scheme 4 Reagents and conditions: a) BF3·OEt2, CH2Cl2, r.t., 22a
(42%); 22b (40%).
Acknowledgment
OMe
We thank CNRS and this institute for financial support. A doctoral
fellowship from Rhodia to C. Couturier is gratefully acknowledged.
We thank Dr. Marie-Thérèse Martin for helpful discussion regar-
ding the structural determination of compound 23.
a
b
NCbz
22b
N
MeO
CO2Me
OBn
OMe
O
24
OH
NCbz
References and Notes
N
MeO
(1) (a) Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102,
1669. (b) Arai, T.; Kubo, A. The Alkaloids, Vol. 21; Brossi,
A., Ed.; Academic Press: New York, 1983, 55–100.
(c) Fukuyama, T. Adv. Heterocycl. Nat. Prod. Synth. 1992,
2, 189. (d) Ozturk, T. The Alkaloids, Vol. 53; Brossi, A., Ed.;
Academic Press: New York, 2000, 119–238.
(2) Whaley, H. A.; Patterson, E. L.; Dann, M.; Shay, A. J.;
Porter, J. N. Antimicrob. Agents Chemother. 1964, 8, 83.
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2003, 125, 15000.
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12476.
(7) Chen, J.; Chen, X.; Bois-Choussy, M.; Zhu, J. J. Am. Chem.
Soc. 2006, 128, 87.
OBn
O
OH
25
OMe
NH
c
N
MeO
OH
O
OH
26
OMe
N
b
c
a
N
MeO
OH
O
OH
23
Scheme 5 Reagents and conditions: a) LiCl, DMSO–H2O, 160 °C,
67%; b) LiAlH3(OEt), Et2O, 0 °C, 44%; c) H2, Pd/C, MeOH, 36%.
(8) For other total syntheses, see: (a) Corey, E. J.; Gin, D. Y.;
Kania, R. S. J. Am. Chem. Soc. 1996, 118, 9202. (b) Endo,
A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.;
Synlett 2006, No. 11, 1691–1694 © Thieme Stuttgart · New York

1694
C. Couturier et al.
LETTER
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Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 2545. (c) For a
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system, see ref. 6 and 17a.
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(20) Compound 23: [a]D25 +37.1 (c 0.04, CHCl3). IR (CHCl3):
3623, 3025, 3017, 2975, 2928, 1727, 1455, 1391, 1260,
1201, 1046 cm–1. 1H NMR (600 MHz, CDCl3): d = 8.01 (d,
J = 2.2 Hz, 1 H), 5.87 (s, 1 H), 4.75 (dd, 1 H, J = 2.2, 8.5 Hz),
4.46 (d, 1 H, J = 2.0 Hz), 3.95 (br d, 1 H, J = 11.5 Hz), 3.70
(s, 3 H), 3.68 (m, 1 H), 3.65 (m, 1 H), 3.64 (s, 3 H), 3.45 (m,
1 H), 3.11 (dd, 1 H, J = 1.7, 12.1 Hz), 2.41 (br d, 1 H,
J = 12.1 Hz), 2.14 (s, 3 H), 1.87 (dt, 1 H, J = 3.7, 13.1 Hz),
1.82 (m, 1 H), 1.41 (br d, 1 H, J = 13.9 Hz) ppm. 13C NMR
(300 MHz, CDCl3): d = 159.0, 145.4, 141.0, 130.7, 123.4,
121.8, 100.3, 83.8, 67.3, 62.6, 61.6, 61.1, 57.4, 30.4, 20.5,
9.6 ppm. HRMS (ESI): m/z cacld for C19H24N2O5 + H+:
361.1763; found: 361.1756.
(21) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
Synlett 2006, No. 11, 1691–1694 © Thieme Stuttgart · New York