RCM-mediated stereoselective synthesis of three novel tetrahydroisoquinoline tetracyclic core frameworks

Article abstract of DOI:10.1016/j.tetlet.2008.06.094

Three novel tetrahydroisoquinoline tetracyclic core frameworks were stereoselectively synthesized. The key steps included a ring-closing metathesis (RCM)-mediated cyclization and a subsequent intramolecular S_N2 N(O)-substituted reaction. This simple method for tetracyclic core synthesis facilitates the further exploration of the chemical space of tetrahydroisoquinoline alkaloids.

Full text of DOI:10.1016/j.tetlet.2008.06.094

Tetrahedron Letters 49 (2008) 5141–5143
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
RCM-mediated stereoselective synthesis of three novel
tetrahydroisoquinoline tetracyclic core frameworks
*
Qing-Qing Huang , Lin-Hai Chen , Fa-Jun Nan
Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences,
189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Three novel tetrahydroisoquinoline tetracyclic core frameworks were stereoselectively synthesized. The
key steps included a ring-closing metathesis (RCM)-mediated cyclization and a subsequent intramolec-
ular SN2 N(O)-substituted reaction. This simple method for tetracyclic core synthesis facilitates the fur-
ther exploration of the chemical space of tetrahydroisoquinoline alkaloids.
Received 27 May 2008
Revised 19 June 2008
Accepted 20 June 2008
Available online 25 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Tetrahydroisoquinoline
Ring-closing metathesis
The antitumor antibiotics belonging to the tetrahydroisoquino-
line family have been studied thoroughly over the past 33 years,
since the isolation of naphthyridinomycin (Fig. 1) in 1974.1 These
tetrahydroisoquinoline alkaloids contain multichiral stereogenic
centers, and display a range of antitumor activities and antimicro-
bial activity. Therefore, it is meaningful to design and optimize
simple tetrahydroisoquinoline alkaloid analogues as new lead
compounds. To date, several total synthesis of tetrahydroisoquino-
line alkaloids were reported.2 Here, we report a potentially general
and concise method of constructing three densely functionalized
tetracyclic tetrahydroisoquinoline core frameworks (Fig. 2): gen-
eral core 1, 2 (with an ‘anti-N-ring bridge’), and a unique ether-
containing tetracyclic core 3, via the ring-closing metathesis
O
H
N
H
COOH
NMe
O
O
N
H
N
NMe
MeO
OH
OMe
O
OH
Naphthyridinomycin
Quinocarcin
Figure 1. Natural tetrahydroisoquinoline alkaloids.
NH
H
N
H
N
H
MeO
MeO
MeO
MeO
MeO
MeO
O
NH
N
(RCM) reaction of
a-amino acylamide, that we reported previ-
ously,3 and the intramolecular SN2 reaction. This simple method
could be applied to the total synthesis of related natural products
and further exploration of their chemical space.
NHBoc
O
O
O
HO
HO
1
2
3
Figure 2. Tetrahydroisoquinoline tetracyclic core frameworks 1–3.
Two core structures of this family are the quinone a and the aro-
matic core b (Fig. 3). The quinone core a can be easily constructed
by the oxidation of aromatic core b. The goal of this study was to
construct highly strained tetrahydroisoquinoline core frameworks
containing several reactive groups, which could be useful key
intermediates for the further chemical modification.
The synthesis of the intermediate aldehyde 7 is outlined in
Scheme 1. We started from tetrahydroisoquinoline-3-carboxylic
acid ester 4, which was prepared from L-dopa methyl ester by
the Pictet–Splender reaction, as reported previously.4 Protection
of the nitrogen of 4 by the Boc group produced 5, which was trans-
formed into the methylated product 6 by treatment with CH3I/
K2CO3 in acetone at room temperature. The reduction of 6 with
LiAlH4 and its subsequent oxidation under Swern conditions pro-
duced the single product 7.
Treatment of 7 with allylic bromide with Zn mediation in aque-
ous NH4Cl medium generated the alcohol 8 with an R configuration
in quantitative yield (diastereomeric ratio >20:1 by 1H NMR)
(Scheme 2).5 However, the addition reaction of 7 with allylmagne-
sium bromide produced alcohol 8 with low diastereoselectivity
(69% yield, S/R = 1/3 by 1H NMR). With 8 in hand, the amine inter-
mediate 9 was readily produced by deprotection with TFA in
* Corresponding author. Tel./fax: +86 21 50800954.
E-mail address: fjnan@mail.shcnc.ac.cn (F.-J. Nan).
Authors contributed equally to this work.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.094

5142
Q.-Q. Huang et al. / Tetrahedron Letters 49 (2008) 5141–5143
O
O
OH
OMs
H
N
(CH2)n
N
H
Crabtree's Cat
H2, CH2Cl2
H
N
H
N
(CH2)n
N
O
O
O
O
MsCl, Et3N, CH2Cl2
0 ºC, 1 h, 71%
NHBoc
R1
R4
N
n = 1 or 2
0 ºC - r.t., 4 h
94%
R4
MeO
R3
NHBoc
R3
R2
O
O
O
16b
R2
a
BnO
BnO
BnO
NOE
OMs
14b
b
Pd(OH)2, H2, MeOH
0 ºC - r.t., 12 h, 80%
(1)
(2)
(3)
H
H
N
Figure 3. General structures of the tetrahydroisoquinolines.
O
O
O
O
, 0 ºC - r.t. 1 h
TFA, CH2Cl2
N
NH
AcONa, C2H5OH, 50 ºC,
16h, 65% two steps
NHBoc
O
HO
1
17
HO
HO
BnO
H
H
H
N
Scheme 3. Synthesis of the tetracyclic core framework 1.
HO
HO
COOCH3
Boc
COOCH3
NH
Boc2O, NaHCO3
Dioxane/H2O, 0 ºC - r.t.
H3
overnight
H1
NOE
The recyclable Hoveyda catalyst was better than the Grubbs II cat-
alyst. After the deprotection of the acetyl group, the product 14a
was conveniently transformed to its isomer 14b, when treated
with Dess–Martin periodinane (DMP), followed by its reduction
with NaBH(OAc)3 (83% in two steps, S/R = 19/1 by HPLC). The con-
figurations were confirmed by nuclear Overhauser effect (NOE)
analysis of their acetylates. The two epimers 14a and 14b were
easily separated by silica-gel column chromatography and were
OBn
4
5
(1)
LiAlH4, Et2O
0 ºC - r.t.
2h, 86%
H
N
H
N
CH3I, K2CO3
acetone, rt.
O
CHO
Boc
O
COOCH3
(2)
overnight
Swern, quant
O
O
Boc
91% two steps
OBn
6
7
OBn
Scheme 1. Synthesis of the segment 7.
used in the subsequent synthesis of compounds
respectively.
1 and 2,
CH2Cl2. The synthesis of the amide intermediate 11 was problem-
atic because of the very low reactivity of the NH at the 2-position.
When the hydroxyl at the 11-position was protected, the conden-
sation reaction did not proceed at all, regardless of the conven-
tional coupling reagent used. However, the reaction of free
hydroxyl intermediate 9 with the active pentafluorophenyl (PFP)
ester 103b and N,N-diisopropylethylamine (DIPEA) as the base in
t-BuOH at 50 °C had taken place smoothly, the product 11 was pro-
duced in an 80% yield based on 65% conversion. After the protec-
tion of the hydroxyl with an acetyl group, the key tricycle 13a
The alcohol 14b was transformed to methanesulfonate 16b
with a minor alkene byproduct formed simultaneously under these
reaction conditions, as a result of the elimination of the MsO group
(Scheme 3). Compound 16b was hydrogenated in the presence of
Crabtree’s catalyst,6 with hydrogen bubbled through a solution of
CH2Cl2, forming the anti product 17 in a yield of 94%. After the
deprotection of the benzyl group using Pd(OH)2 and the Boc group
in TFA/CH2Cl2, the resulting primary amine was instantly dissolved
in ethanol and heated to 50 °C in the presence of AcONa,7 forming
the tetracyclic quinone 1 in a 65% yield.8
Mesylate 16a was obtained under similar conditions, in quanti-
tative yield, because there was no elimination. Subsequent hydro-
genation with 20% Pd(OH)2 in methanol produced a mixture of 18
and its diastereomer in a ratio of 8:1, and they were separated by
silica-gel column chromatography (Scheme 4). Deprotection of the
Boc group, followed by treatment with AcONa in C2H5OH, as
shown in Scheme 3, produced the reverse N-substituted product
2 in a 68% yield.9
was produced by RCM of the
a-amino acrylamine, in a high yield.
OH
H
H
O
O
CHO
Boc
O
Br
TFA, CH2Cl2
(R)
, Zn
N
N
0 ºC - r.t., 4 h
quant
sat.NH4Cl/THF(5/3)
0 ºC - r.t. 24 h, quant
O
Boc
8
OBn
OBn
7
O
10
OPFP
NHBoc
Interestingly, when compound 18 was treated with NaH in
MeTHF, the intramolecular O-substituted SN2 reaction produced
the unique ether-containing tetracyclic product 3 in a 59% yield.10
Compound 3 represents a novel framework of tetrahydroisoquino-
line, which has never been reported before.
OH
OH
H
N
H
O
O
O
O
NH
OBn
DIPEA, t-BuOH
50 ºC, 24 h, 52%
(80%, BORSM )
NHBoc
O
BnO
9
11
OAc
AcO
H
H
H
N
Hoveyda cat
O
O
O
Ac2O, Py
rt. 16 h
91%
toluene
OMs
OH
N
70 ºC 24 h
96%
H
N
H
N
Pd(OH)2, H2
O
O
O
O
O
MsCl, Et3N, CH2Cl2
0 ºC, 1 h, quant
NHBoc
NHBoc
NHBoc
MeOH, 0 ºC - r.t.
O
O
13a
BnO
BnO
12 h, 79%
NHBoc
12
NOE
O
16a
O
O
OH
(R)
BnO
BnO
H
N
K2CO3
H
DMP
14a
O
O
O
CH2Cl2, 1 h
MeOH/H2O
0 ºC - r.t. 3 h
94%
NH
H
N
N
88%
NHBoc
NOE
OMs
O
O
O
(1)TFA, CH2Cl
2, 0 ºC - r.t. 1 h
NHBoc
O
O
BnO
NOE
(2)
15
AcONa, C2H5OH, 50 ºC,
16h, 68% two steps
BnO
H
N
14a
O
O
O
OH
(S)
H
HO
OAc
2
H
H
NaBH(OAc)3
DCE, 2 h.
Ac2O, Py
rt. 16 h
quant
H
O
O
H
HMBC
H
NHBoc
O
O
HO
N
N
NaH, MeTHF, 80 ºC, 2 h
50 ºC, 12 h, 59%
94%
O
O
O
O
18
S/R=19/1
NHBoc
N
NHBoc
O
14b
O
13b
O
by HPLC
BnO
BnO
NHBoc
3
Scheme 2. Synthesis of the key intermediates 14a and 14b.
Scheme 4. Synthesis of the tetracyclic core frameworks 2 and 3.

Q.-Q. Huang et al. / Tetrahedron Letters 49 (2008) 5141–5143
5143
Chandrasekhar, S.; Reddy, N. R.; Rao, Y. S. Tetrahedron 2006, 62, 12098; (o)
Chen, J.; Chen, X.; Bois-Choussy, M.; Zhu, J. J. Am. Chem. Soc. 2006, 128, 87; (p)
Fishlock, D.; Williams, R. M. Org. Lett. 2006, 8, 3299; (q) Liu, Z.; Wang, Y.; Tang,
Y.; Chen, S.; Chen, X.; Li, H. Bioorg. Med. Chem. Lett. 2006, 16, 1282.
In summary, we have developed a simple and efficient synthesis
of the tetracyclic core frameworks 1, 2 of the tetrahydroisoquino-
line alkaloids containing the highly strained bicyclo[3.2.1]octane
framework, and a unique ether-containing tetracyclic core 3. This
synthesis uses the powerful RCM reaction for ready access to the
3. In a previous work, we reported the construction methodology for the RCM
reaction of
a-amino acrylamide with substituted amino caprolactams, and
extended the scope of this methodology to diverse substitutions at the amide
nitrogen. (a) Chen, Y.; Zhang, H.; Nan, F. J. Comb. Chem. 2004, 6, 684; (b) Liu, G.;
Tai, W.; Li, Y.; Nan, F. Tetrahedron Lett. 2006, 47, 3295; (c) Liu, G.; Ma, Y.; Tai,
W.; Xie, C.; Li, Y.; Li, J.; Nan, F. ChemMedChem 2008, 3, 74.
4. (a) Wang, Y.; Liu, Z.; Chen, S.; Liang, X. Chin. Chem. Lett. 2004, 15, 505; (b) Liu, Z.;
Wang, Y.; Tang, Y.; Chen, S.; Chen, X.; Li, H. Bioorg. Med. Chem. Lett. 2006, 16,
1282.
5. Tan, K.; Chng, S.; Cheng, H.; Loh, T. J. Am. Chem. Soc. 2003, 125, 2958.
6. Suggs, J. W.; Cox, S. D.; Crabtree, R. H.; Quirk, J. M. Tetrahedron Lett. 1981, 22,
303.
a-amino a,b-unsaturated caprolactam 13a, and the intramolecular
SN2 reaction of the lactams 17 and 18 to produce the highly
strained tetracycles. Further structural modifications to com-
pounds 1, 2, and 3 to explore their chemical space are in progress
in our laboratory.
Acknowledgments
7. Gurjar, M. K.; Patil, V. J.; Pawar, S. M. Indian J. Chem. Sect. B 1987, 26, 1115.
8. Characterization data of compound 1: ½a D22
ꢀ
ꢁ65 (c 0.1450, CHCl3). 1H NMR
This work was supported financially by the National Natural
Science Foundation of China (Grants 30572242, 30725049) and
863 Hi-Tech Program Grant 2006AA09Z442.
(CDCl3, 300 MHz): d 6.70 (s, 1H), 6.63 (s, 1H), 5.19 (dd, J = 3.6, 6.3 Hz, 1H), 3.80–
3.90 (m, 7H), 3.71–3.76 (m, 1H), 3.58–3.67 (m, 3H), 2.79 (t, J = 13.5 Hz, 1H),
2.51 (dd, J = 1.8, 14.7 Hz, 1H), 2.14–2.21 (m, 1H), 2.01–2.11 (m, 2H), 1.90–1.97
(m, 1H). 13C NMR (CDCl3, 75 MHz): d 173.6, 148.4, 148.3, 127.8, 125.5, 111.0,
110.8, 70.1, 62.3, 61.0, 58.2, 57.7, 56.3, 56.2, 33.1, 32.0, 22.6. HRMS (EI) calcd for
References and notes
C
17H22N2O4 (M+) 318.1580, found 318.1579, error: ꢁ0.3 ppm.
9. Characterization data of compound 2: ½a D22
ꢀ
ꢁ145 (c 0.3900, CHCl3). 1H NMR
1. For a comprehensive account of the chemistry and biology of these compounds,
see: Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669.
(CDCl3, 300 MHz): d 6.69 (s, 1H), 6.62 (s, 1H), 4.94 (t, J = 3.3 Hz, 1H), 4.00 (dd,
J = 3.0, 11.7 Hz, 1H), 3.80–3.90 (m, 7H), 3.65 (dd, J = 4.5, 12.0 Hz, 1H), 3.59 (t,
J = 2.7 Hz, 1H), 2.95–3.10 (m, 2H), 2.55 (d, J = 13.2 Hz, 1H), 1.90–2.05 (m, 3H),
1.58–1.69 (m, 1H). 13C NMR (CDCl3, 75 MHz): d 177.3, 148.3, 148.0, 129.1,
126.4, 111.1, 110.4, 68.8, 61.5, 61.1, 60.3, 57.7, 56.3, 56.1, 36.7, 31.7, 28.9.
HRMS (EI) calcd for C17H22N2O4 (M+) 318.1580, found 318.1590, error: 3.1 ppm.
2. Recent synthesis papers: (a) Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan,
T.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 6552; (b) Zhou, B.; Guo, J.;
Danishefsky, S. J. Org. Lett. 2002, 4, 43; (c) Ashley, E. R.; Cruz, E. G.; Stoltz, B. M. J.
Am. Chem. Soc. 2003, 125, 15000; (d) Jin, W.; Williams, R. M. Tetrahedron Lett.
2003, 44, 4635; (e) Jin, W.; Metobo, S.; Williams, R. M. Org. Lett. 2003, 5, 2095;
(f) Magnus, P.; Matthews, K. S.; Lynch, V. Org. Lett. 2003, 5, 2181; (g) Menchaca,
R.; Martínez, V.; Rodríguez, A.; Rodríguez, N.; Flores, M.; Gallego, P.;
Manzanares, I.; Cuevas, C. J. Org. Chem. 2003, 68, 8859; (h) Tang, Y.; Liu, Z.;
Chen, S. Tetrahedron Lett. 2003, 44, 7091; (i) Mori, K.; Rikimaru, K.; Kan, T.;
Fukuyama, T. Org. Lett. 2004, 6, 3095; (j) Chen, X.; Chen, J.; De Paolis, M.; Zhu, J.
J. Org. Chem. 2005, 70, 4397; (k) Kwon, S.; Myers, A. G. J. Am. Chem. Soc. 2005,
127, 16796; (l) Lane, J. W.; Chen, Y.; Williams, R. M. J. Am. Chem. Soc. 2005, 127,
12684; (m) Magnus, P.; Matthews, K. S. J. Am. Chem. Soc. 2005, 127, 12476; (n)
10. Characterization data of compound 3: ½a D22
ꢀ
ꢁ46 (c 0.4200, CHCl3). 1H NMR
(CDCl3, 300 MHz): d 6.67 (s, 1H), 6.61 (s, 1H), 5.91 (d, J = 6.6 Hz, 1H), 5.32 (s,
1H), 4.90–4.98 (m, 1H), 4.24 (d, J = 8.1 Hz, 1H), 4.17 (dd, J = 3.3, 11.4 Hz, 1H),
3.87 (s, 3H), 3.86 (s, 3H), 3.32–3.43 (m, 2H), 2.93 (d, J = 17.7 Hz, 1H), 2.02–2.27
(m, 3H), 1.75–1.87 (m, 1H), 1.45 (s, 9H). 13C NMR (CDCl3, 150 MHz): d 175.1,
155.2, 148.7, 147.8, 125.4, 125.3, 110.5, 109.0, 79.7, 74.3, 66.7, 56.0, 55.9, 53.2,
51.3, 50.2, 32.3, 31.2, 31.0, 29.7, 28.4. HRMS (EI) calcd for C22H30N2O6 (M+)
418.2104, found 418.2101, error: ꢁ0.7 ppm.