Synthetic study of manzamine B: synthesis of the tricyclic central core by an asymmetric Diels-Alder and RCM strategy

Article abstract of DOI:10.1016/j.tetlet.2006.12.029

Tricyclic core of manzamine B was successfully synthesized through asymmetric Diels-Alder reaction and RCM strategy. Cr-salen-F complex was found to be the most effective catalyst in DA reaction of aminodienes with heterocyclic dienophiles to give up to 9

Full text of DOI:10.1016/j.tetlet.2006.12.029

Tetrahedron Letters 48 (2007) 1265–1268
Synthetic study of manzamine B: synthesis of the tricyclic
central core by an asymmetric Diels–Alder and RCM strategy
Tomoaki Matsumura,a Masakatsu Akiba,a Shigeru Arai,a
Masako Nakagawab and Atsushi Nishidaa,*
aGraduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-Cho, Inage-ku, Chiba 263-8522, Japan
bDepartment of Chemistry, Faculty of Science, Kanagawa University, Hiratsuka, Kanagawa 259-1273, Japan
Received 23 October 2006; revised 7 December 2006; accepted 8 December 2006
Available online 8 January 2007
Abstract—Tricyclic core of manzamine B was successfully synthesized through asymmetric Diels–Alder reaction and RCM strategy.
Cr–salen–F complex was found to be the most effective catalyst in DA reaction of aminodienes with heterocyclic dienophiles to give
up to 97% ee. In the construction of 11-membered ring by RCM, first-Grubbs cat. gave better stereoselectivity.
Ó 2006 Elsevier Ltd. All rights reserved.
Manzamine B (1) was isolated in 1987 by Higa and co-
workers from the marine sponge Haliclona sp., collected
at Okinawa (Fig. 1).1 Its unique structure, which con-
tains a b-carboline and tetracyclic ring system, such as
a hydroisoquinoline core and 11- and 13-membered aza-
cycles with (Z)-olefins, is a highly challenging target in
synthetic organic chemistry. While its biological activity,
such as cytotoxicity against P388 mouse leukaemia cells
(IC50 6 lg/mL), has been reported,1 a good supply of
this material is required for a complete survey of its bio-
logical activity.
of manzamine A (2) and (ꢀ)-nakadomarin A (4),6 we
have already studied the synthesis of chiral hydroiso-
quinoline derivatives using the DA reaction. This meth-
odology was quite efficient for access to a cyclic core
with a cis functional-group arrangement that is favor-
able for the total synthesis. In this synthetic study of
manzamine B (1), an asymmetric DA reaction could
be used to construct the chiral hydroisoquinoline core
(AB ring) while controlling three consecutive stereocen-
ters and introducing a key nitrogen functionality for
C-ring formation. An asymmetric DA reaction using
amino-siloxydienes catalyzed by chromium(III)–salen
complex7 developed by Rawal8 would be suitable for
this purpose. DA precursors of 9 and 10 are easily pre-
pared from commercially available compounds such as
11–13, respectively.
In contrast to manzamine A (2),2 the total synthesis of
which has been described by Winkler and Martin,3 there
has been no previous report on the synthesis of 1. We
describe here our model study focusing the asymmetric
synthesis of the ABC ring system of manzamine B (1).
The substrates for the asymmetric DA reaction were
prepared by the following procedure (Scheme 2).
Demethylation of 11 by 1-chloroethyl chloroformate,9
followed by N-protection with benzenesulfonyl (Bs)
chloride, gave dehydropiperidine ester (14). Subsequent
reduction by DIBAL followed by Swern oxidation of
the resulting alcohol gave dienophile (9) in 73% overall
yield in six steps from 11. N-Protected aminodienes such
as 10a,b were prepared by Rawal’s protocol,8c and the
synthesis of 10c,d was achieved by its modification.10
Our retrosynthetic analysis of 1 is outlined in Scheme 1.
The introduction of a b-carboline core and epoxy ring
will be set at a late stage of the total synthesis.4,5 There-
fore, ircinal B (3) is regarded to be a precursor of 1. (Z)-
Selective formation of both the C and D rings should be
achieved by ring-closing metathesis (RCM) using the
corresponding a,x-dienes 5 and 7, respectively. There-
fore, we can consider hydroisoquinoline (8) as a key
intermediate, which should be synthesized by the
Diels–Alder (DA) method. Through a synthetic study
Only two cyclic dienophiles were tested in the asymmet-
ric DA reaction under Rawal’s conditions and they were
reported to have lower reactivities compared to acyclic
*
Corresponding author. E-mail: nishida@p.chiba-u.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.029

1266
T. Matsumura et al. / Tetrahedron Letters 48 (2007) 1265–1268
N
N
H
N
H
N
H
CHO
H
H
H
H
H
O
H
N
OH
A
B
O
OH
H
N
N
N
N
D
N
.
HN
HCl
HN
H
H
C
Manzamine B (1)
Manzamine A (2)
Ircinal B (3)
Nakadomarin A (4)
Figure 1. Structure of manzamine alkaloid.
PO
H
OP
CHO
H
H
H
X
RCM
X
RCM
OH
OP
N
H
N
N
H
N
N
N
Bs
H
Bs
O
O
HN
O
HN
HN
HN
A
B
O
N
D
HN
C
7
Ircinal B (3)
5
6
H
OTBS
OTBS
Manzamine B (1)
+
N
N
OHC
Bs
CHO
Bs
N
Bs = SO2Ph
9
N
P
P
10
Asymmetric Diels-Alder Reaction
8
Scheme 1. Retrosynthetic analysis of 1.
OTBS
Cl
O
1-4)
5,6)
7-9)
.
NH2
+
N
HBr
N
N
N
Bs
CHO
Bs
CO2Me
Me
CO2Me
9
OMe
O
14
11
10d
12
13
Scheme 2. Synthesis of dienophile (9) and aminodiene (10). Reagents and conditions: (1) satd NaHCO3, (2) ClCO2CH(Cl)CH3, DCE, (3) MeOH,
reflux, (4) BsCl, Et3N, DCM. 90% (4 steps), (5) DIBAL, PhCH3, (6) Swern oxidation, 81% (2 steps), (7) DCM, (8) ClCH2COCl, pyridine, DCM,
0–30 °C, (9) TBSOTf, Et3N, DCM, 79% (3 steps).
dienophiles.8a,d Since there have been no reports on the
use of a heterocyclic dienophile, we started to investigate
the reactivity of 9 in detail using four types of N-acyl-
aminodienes (10a–d) (Table 1, entries 1–4). When 9 was
stirred with 2 equiv of 10a for 72 h with 50 mol % of
(R,R)-Cr–salen–F complex7d in benzotrifluoride (PhCF3),
which was the best solvent of choice, cycloadduct (8a)
was obtained in 70% yield with 92% ee (entry 1).
Although the use of N-Boc aminodiene (10b) gave 8b
in 58% yield, the reaction had to proceed for 282 h,
probably because of bulkiness of its protecting group
(entry 2). The reaction of amide-type aminodienes
(10c,d) gave cycloadducts (8c,d) within a shorter reac-
tion time compared to 10a and 10b. In particular, the
DA reaction using N-chloroacetyl aminodiene (10d)
gave the best result (entry 4). Furthermore, we found
that the reactivity and enantiomeric excess each
depended on the counter anions in chiral Cr–salen
complexes. For example, the reaction using Cr–salen–
F complex7d (50 mol %) gave 8d11 in 77% yield with
93% ee within 20 h (entry 4). Other Cr–salen complexes
with Cl, BF4, N3, and SbF6 as counter anions gave a
slow reaction or a low ee compared to entry 4 (entries
5–8). Under reflux conditions, the reaction proceeded
faster and gave 8d in 52% yield with 79% ee within
2.5 h (entry 9). The reaction at 0 °C gave 8d in 58% yield
with the highest ee within 64 h (entry 10). Competitive
decomposition of aminodiene (10d) was always observed
under the reaction conditions because of the Lewis acid-
ity of Cr–salen complexes. Thus, the use of 1 equiv of
10d decreased the chemical yield to 41% (entry 11).
Under reduced catalyst loading of Cr-complex
(25 mol %), 8d was obtained in 58% yield without any
loss of ee (entry 12). The absolute stereochemistry of
23
8d (>99% ee, ½aꢁD +97 (c, 0.5, CHCl3), mp 166–
169 °C) was determined by X-ray crystallographic analy-
sis, based on an anomalous dispersion effect (Fig. 2). All
three of the stereocenters were assigned to be S, in
accord with natural manzamine B (1).
With the key intermediate (8d) in hand, we next investi-
gated the construction of an 11-membered azacycle (ring
C) by RCM (Scheme 3).12 Olefination of a formyl group
in 8d was unsuccessful, since the formyl carbon was

T. Matsumura et al. / Tetrahedron Letters 48 (2007) 1265–1268
Table 1. Asymmetric Diels–Alder reactiona
1267
H
OTBS
OTBS
N
O
N
O
(R,R)-Cr-salen complex (50 mol %)
N
Cr
X
+
N
Bs
t-Bu
t-Bu
Bs
CHO
4A MS, PhCF3
OHC
P
N
N
P
t-Bu
(R,R)-Cr-salen complex
X = F, Cl, BF , N , SbF
6
t-Bu
9
10
8
4
3
10c: P = Ac
10d: P = C(O)CH2Cl
10a: P = CO2Me
10b: P = Boc
Entry
Substrate
Cr–salen–X
Temperature (°C)
Time (h)
Product
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
10a
10b
10c
10d
10d
10d
10d
10d
10d
10d
10d
10d
X = F
X = F
X = F
X = F
X = Cl
X = BF4
X = N3
X = SbF6
X = F
rt
rt
rt
rt
rt
rt
rt
rt
102
0
72
282
42
20
87
20
160
87
2.5
64
20
8a
8b
8c
8d
8d
8d
8d
8d
8d
8d
8d
8d
70
58
57
77
65
65
12
0
52
58
41
58
92
—
—
93
75
88
89
—
79
97
90
93
10
11
12b
X = F
X = F
X = F
rt
rt
38
a All reaction was carried out in the ratio of 9 and 10 (1:2) except entry 11 (1:1).
b 25 mol % of Cr–salen-complex was employed.
fore, the N-allyl group was first removed using the
Pd-catalyzed deallylation reported by Nagakura.13
A
modified Horner–Wadsworth–Emmons reaction14 was
successfully applied to give 15 in 88% yield. Silyl enol
ether was then converted to cyclic ketal (16) in 97% yield
(2 steps). Subsequent hydrogenation followed by reduc-
tion of ester carbonyl and chloroacetyl moieties using
LiBH4 gave a N-acetyl primary alcohol, which was con-
verted to 17 in excellent yield through protection of the
hydroxyl group to PMB ether followed by N-Boc imide
formation. After deprotection of the PMB group by
DDQ, the resulting primary alcohol was converted to
olefin by a standard method. The acetyl group was
removed by treatment with CsOH to give 18 in 65%
overall yield in five steps. Deprotection of the Boc
group followed by acylation with hexenoyl chloride gave
Si
S
Cl
Figure 2. X-ray structure of 8d.
located at a neopentyl position and suffered from steric
hindrance by the adjacent nitrogen functionality. There-
H
H
O
H
O
H
OTBS
Cl
OTBS
Cl
O
O
N
N
5-8)
N
3,4)
N
1,2)
Bs
Bs
Bs
Bs
OHC
N
N
N
Boc
N
H
H
Cl
EtO2C
EtO2C
O
O
PMBO
O
O
O
N
15
16
8d
17
H
H
O
O
PPTS, acetone
H2O, quant
H
O
O
7a
7b
N
N
O
Bs
Bs
9-12)
+
13,14)
Bs
O
HN
HN
7a + 7b
N
H
Boc
.
7a
7b
ethylene glycol, TsOH H2O
benzene, 59%
18
inseparable mixture
Scheme 3. Conversion of DA adduct to a,x-dienes (7a,b). Reagents and conditions: (1) TolSO2H, Pd(PPh3)4, DCM, 91% (2 cycles), (2)
(EtO)2P(O)CH2CO2Et, LiCl, DBU, MeCN, 88%, (3) HF–pyridine MeCN, 99%, (4) ethylene glycol, TsOH, benzene, 98%, (5) H2, 5% Pd/C, MeOH,
99%, (6) LiBH4, THF, quant, (7) NaH, PMBCl, THF, 90%, (8) Boc2O, DMAP, Et3N, THF, (9) DDQ, DCM–acetone (18:1), (10) Swern oxidation,
(11) Ph3PCH3Br, t-BuOK, THF, (12) 50% CsOH, THF, 65% (5 steps), (13) TFA, DCM, (14) 5-hexenoyl chloride, Et3N, DCM, 86% (2 steps,
7a:7b = 4.7:1).

1268
T. Matsumura et al. / Tetrahedron Letters 48 (2007) 1265–1268
Table 2. C-ring formation using RCM
ward the total synthesis of manzamine B are currently
underway.
H
H
X
X
Ru cat.
N
N
( 30 mol %)
Bs
Bs
Acknowledgement
O
DCM, (0.5 mM)
reflux
O
HN
HN
This research was supported by a Grant-in-Aid for
Scientific Research on Priority Areas (17035014) from
the Ministry of Education, Culture, Sports, Science,
and Technology, Japan.
7a: X = O
6a: X = O
6b: X = -O(CH2)2O-
7b: X = -O(CH2)2O-
Entry
Substrate
Ru cat.
Time (h)
Yield of 6a (%)
(Z)-6
(E)-6
References and notes
1
2
3
4
5
6
7a
7a
7a
7b
7b
7b
19
20
21
19
20
21
5
7
7
4
6
6
39
23
32
64
9
11
43
28
23
22
14
1. Sakai, R.; Kohmoto, S.; Higa, T.; Jefford, C. W.;
Bernardinelli, G. Tetrahedron Lett. 1987, 28, 5493.
2. Sakai, R.; Higa, T.; Jefford, C. W.; Bernardinelli, G. J.
Am. Chem. Soc. 1986, 108, 6404.
23
3. (a) Winkler, J. D.; Axten, J. M. J. Am. Chem. Soc. 1998,
120, 6425; (b) Martin, S. F.; Humphrey, J. M.; Ali, A.;
Hillier, M. C. J. Am. Chem. Soc. 1999, 121, 866; (c)
Humphrey, J. M.; Liao, Y.; Ali, A.; Rein, T.; Wong,
Y.-L.; Chen, H.-J.; Courtney, A. K.; Martin, S. F. J. Am.
Chem. Soc. 2002, 124, 8584.
4. Kondo, K.; Shigemori, H.; Kikuchi, Y.; Ishibashi, M.;
Sasaki, T.; Kobayashi, J. J. Org. Chem. 1992, 57, 2480.
5. The conversion of ircinal B to 1 has not been reported and
this remains another challenge for the total synthesis of 1.
6. (a) Nakagawa, M.; Uchida, H.; Ono, K.; Kimura, Y.;
Yamabe, M.; Watanabe, T.; Tsuji, R.; Akiba, M.; Terada,
Y.; Nagaki, D.; Ban, S.; Miyashita, N.; Kano, T.;
Theeraladanon, C.; Hatakeyama, M.; Arisawa, M.; Nish-
ida, A. Heterocycles 2003, 59, 721; (b) Uchida, H.;
Nishida, A.; Nakagawa, M. Tetrahedron Lett. 1999, 40,
113; (c) Ono, K.; Nakagawa, M.; Nishida, A. Angew.
Chem., Int. Ed. 2004, 43, 2020.
7. (a) Larrow, J. F.; Jacobsen, E. N. J. Org. Chem. 1994, 59,
1939; (b) Martinez, L. E.; Leighton, J. L.; Carsten, D. H.;
Jacobsen, E. N. J. Am. Chem. Soc. 1995, 117, 5897; (c)
Leighton, J. L.; Jacobsen, E. N. J. Org. Chem. 1996, 61,
389; (d) Schaus, S. E.; Branalt, J.; Jacobsen, E. N. J. Org.
Chem. 1998, 63, 403.
8. (a) Huang, Y.; Iwama, T.; Rawal, V. H. J. Am. Chem. Soc.
2000, 122, 7843; (b) Huang, Y.; Iwama, T.; Rawal, V. H.
Org. Lett. 2002, 4, 1163; (c) Kozmin, S. A.; Iwama, T.;
Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124,
4628; (d) Huang, Y.; Iwata, T.; Rawal, V. H. J. Am. Chem.
Soc. 2002, 124, 5950; (e) McGilvra, J. D.; Rawal, V. H.
Synlett 2004, 2440.
a Yields were determined by 1H NMR (entries 1–3) or isolated yield of
6b (entries 4–6).
PCy3
Ru
PCy3
Cl
Cl
N
N
Ph
N
Mes
Mes
Cl
Cl
Ru
19
iPrO
N
21
Mes
Mes
Ph
Cl
Cl
Ru
PCy3
Ru cat.
20
the desired a,x-diene 7a with 7b as an inseparable
mixture. Therefore, the mixture was treated with PPTS
or ethylene glycol in the presence of TsOHÆH2O to give
pure 7a and 7b, respectively.
The obtained dienes 7a,b were exposed to RCM condi-
tions (Table 2). The RCM reaction using 7a with
30 mol % of first-generation Grubbs catalyst (19) gave
6a as a separable mixture of (E)- and (Z)-isomers, and
the desired (Z)-6a was obtained in 39% yield (entry 1).
The cyclizations using second-generation Grubbs cata-
lyst (20) and Hoveyda–Grubbs catalyst (21) showed no
obvious improvement (entries 2 and 3). The reaction
of 7b in the presence of 19 gave 6b in 87% yield and
the desired (Z)-isomer was observed as a major product
9. Olofson, R. A.; Martz, J. T.; Senet, J.-P.; Piteau, M.;
Malfroot, T. J. Org. Chem. 1984, 49, 2081.
1
by H NMR15 (entry 4), while (E)- and (Z)-6b were
10. Because the reaction of N-acylallylamine with 13 was
unsuccessful, the modified preparation of 10c,d was estab-
lished via condensation, acylation, and silyl etherification.
11. Optically pure 8d [>99.9% ee, determined by HPLC using
DAICEL CHIRALCEL OD (hexane/iPrOH = 95:5, flow
rate: 1.0 mL/min, retention time: 23.8 and 28.6 min)]
could be obtained by recrystallization from MeOH.
12. Racemic 8d was used for further transformations.
13. Honda, M.; Morita, H.; Nagakura, I. J. Org. Chem. 1997,
62, 8932.
14. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A.
P.; Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron
Lett. 1984, 25, 2183.
15. Both (Z)- and (E)-6b were identified by deprotection and
separation to pure (Z)- and (E)-6a, respectively.
inseparable. The reactions using 20 or 21 were less
effective compared to entry 4 (entries 5 and 6). Interest-
ingly, remote functional groups (the carbonyl or ketal
group in B-ring) can influence the selectivity of the
RCM reaction.
In conclusion, we have constructed the tricyclic core of
manzamine B (1) through DA and RCM strategies.
The key asymmetric DA reaction proceeded efficiently
in a highly enantioselective fashion (up to 97% ee) with
complete stereocontrol using a Cr–salen–F complex. In
the RCM reaction, the desired (Z)-11-membered ring
was selectively formed in high yield. Further studies to-