Synthetic studies toward haouamine B: Construction of indenotetrahydropyridone skeleton

Article abstract of DOI:10.1055/s-0030-1259096

Synthetic studies on haouamine B are described. The characteristic indenotetrahydropyridone skeleton was constructed by intramolecular Friedel-Crafts alkylation of mesyloxy β-lactam derivative and intramolecular McMurry coupling as key processes. Georg Th

Full text of DOI:10.1055/s-0030-1259096

LETTER
73
Synthetic Studies toward Haouamine B: Construction of Indenotetrahydro-
pyridone Skeleton
Synthetic Studies
e
T
oward
H
a
i
ouamin
-
e
B
ichiro Okuyama, Yuichi Momoi, Kenji Sugimoto,1 Kentaro Okano, Hidetoshi Tokuyama*
Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, 980-8578 Sendai, Japan
Fax +81(22)7956877; E-mail: tokuyama@mail.pharm.tohoku.ac.jp
Received 14 October 2010
has so far been reported due to its highly strained struc-
ture.4 Regarding haouamine B (2), there has been no re-
port on total synthesis and the absolute stereochemistry.
Abstract: Synthetic studies on haouamine B are described. The
characteristic indenotetrahydropyridone skeleton was constructed
by intramolecular Friedel–Crafts alkylation of mesyloxy b-lactam
derivative and intramolecular McMurry coupling as key processes.
We planned to construct tetrahydropyridine ring in the
Key words: Friedel–Crafts reaction, b-lactam, McMurry coupling, central part of these molecules by intramolecular Mc-
Murry coupling5 of the advanced intermediate such as 3
natural products
having indane segment and macrolactam ring (Scheme 1).
After formation of six-membered lactam, reduction of
amide function3d and oxidative conversion to biaryl struc-
Haouamines, a family of marine alkaloids, were isolated
ture would lead to haouamines. In this context, we chose
compound 5 as a model compound to examine the pro-
posed intramolecular McMurry coupling as well as a pos-
sible intermediate for the synthesis of haouamine B, and
carried out its synthetic investigations.
from a tunicate, Aplidium haouarianum, in the southern
coast of Spain by Zubía and co-workers.2 Among them,
haouamine A (1) exhibits highly specific and strong cyto-
toxicity against HT-29 human colon carcinoma cell line
(IC50 = 200 nM). In addition to the significant biological
activity, haouamines have the unique structural features
such as cis-fused indenotetrahydropyridine and highly
strained 3-aza[7]paracyclophane containing bent aromat-
ic ring. Therefore, many synthetic efforts have been di-
rected toward these compounds.3 However, only one total
synthesis of haouamine A (1) by Baran and co-workers
Scheme 2 illustrates our retrosynthetic analysis of the sub-
strate 6 for the key reaction. b-Amino aldehyde 6 possess-
ing cis stereochemistry would be derived from indane-
fused tetracyclic b-lactam 7. We planned to construct this
unusual b-lactam 7 by Friedel–Crafts alkylation of b-
lactam derivative 8, which would be accessible from
OH OH
HO
HO
HO
HO
N
OH
R
N
H
H
R
haouamine A (1): R = H
haouamine B (2): R = OH
HO
oxidative biaryl formation;
reduction of amide
OMe
OMe
OMe
OMe
intramolecular
McMurry
coupling
MeO
MeO
O
N
O
O
O
R'
R'
N
H
H
OMe
OMe
4
3; R' = H or OMe
Scheme 1 Haouamine A (1) and B (2), and synthetic strategy
SYNLETT 2011, No. 1, pp 0073–0076
x
x.
x
x.
2
0
1
1
Advanced online publication: 14.12.2010
DOI: 10.1055/s-0030-1259096; Art ID: U09210ST
© Georg Thieme Verlag Stuttgart · New York

74
K. Okuyama et al.
LETTER
OMe
OMe OMe
MeO
OMe
Br
MeO
CHO
O
Br
O
MeO
N
MeO
N
H
H
H
H
O
6
5
OMe
OMe
intramolecular
Friedel–Crafts
alkylation
MeO
MeO
O
R
O
R
R'O
N
N
MeO
MeO
H
7
8
OMe
β-lactam
MeO
MeO
9
formation;
oxidation
MgBr
O
O
R
HO
CO2Me
NH2
N
MeO
MeO
11
10
Scheme 2 Retrosynthetic analysis
a-hydroxy-b-amino ester 11 by b-lactam formation and tained in 74% yield from tertiary alcohol 21.13 This meth-
1,2-addition of anisyl Grignard 9 to azetidine-2,3-dione odology was effective to construct the b-lactam-fused
derivative 10.
indane skeleton having a quaternary carbon.14
Our research commenced with the asymmetric prepara- We next turned our attention to examine the McMurry
tion of a-hydroxy-b-amino acid derivative 11 by applica- coupling strategy for the construction of indenotetra-
tion of Ellman’s diastereoselective Mannich reaction hydropyridone ring. After removal of benzyl group under
using chiral sulfinamide.6 Commercially available phenyl- Birch conditions, indane-fused b-lactam 23 was activated
acetaldehyde derivative 12 was condensed with chiral sul- with the Boc group to give 24. LiAlH4 reduction gave
finamide 13 to give the corresponding sulfinyl imine 14,
Table 1 Diastereoselective Mannich Reaction
which was subjected to Mannich reaction conditions with
glycolates 15. The diastereoselectivity was strongly de-
pendent on the choice of R group on the glycolates oxy-
O
S
H2N
13
gen. Thus, reaction of benzyl ether 15a provided an
MeO
MeO
PPTS
(3 mol%)
MgSO4
inseparable mixture of four diastereomers (Table 1, entry
1). In contrast, Qin’s modification7 utilizing Boc-protect-
ed compound 15b gave the desired 16b as a single product
(entry 2).8
O
S
CHO
CH2Cl2, r.t.
81%
MeO
RO
N
MeO
14
12
CO2Me
Having prepared a-hydroxy-b-amino acid derivative 16b
as a single diastereomer, we focused our efforts on con-
struction of the b-lactam-fused indane skeleton
(Scheme 3). Acidic removal of tert-butylsulfinyl and Boc
groups7 provided the corresponding aminoalcohol hydro-
chloride 17. Construction of b-lactam was carried out ac-
cording to the conventional method9 to give the N-TES-b-
lactam, which was then treated with KF to provide 18 in
96% ee.10 After N-benzylation and conversion to azeti-
dine 2,3-dione in two steps, m-anisyl group was intro-
duced by Grignard addition to give the tertiary alcohol 21
as a single isomer.11 The stage was set for the construction
of indane ring by Friedel–Crafts-type cyclization. We
found that conversion to the corresponding mesylate 22
and acidic treatment were crucial to promote smooth cy-
clization.12 Thus, upon treatment of 22 with triflic acid in
acetonitrile, the desired indane-fused b-lactam 23 was ob-
RO
MeO
15a R = Bn
15b R = Boc
LHMDS
CO2Me
O
S
THF
–78 °C, 25 min
MeO
N
H
16a R = Bn
16b R = Boc
Entry
R
Yield (%)a
drb
1
2
Bn
Boc
82
80
6:2:2:1c
d
–
a Isolated yields.
b Determined by 1H NMR of the crude material.
c The stereoselectivity of the diastereomers was not determined.
d Single diastereomer.
Synlett 2011, No. 1, 73–76 © Thieme Stuttgart · New York

LETTER
Synthetic Studies Toward Haouamine B
75
amino alcohol 25, which was condensed with acyl chlo-
ride 26. O-Acylation, followed by intramolecular acyl mi-
gration gave amide 27 after deprotection of Boc group.
Finally, TPAP oxidation gave aldehyde 6, a substrate for
the McMurry coupling reaction. To our delight, upon sub-
jection of aldehyde 6 to reductive conditions using a com-
bination of titanium tetrachloride and zinc–copper couple
in DME, the expected intramolecular McMurry coupling
took place to give the desired lactam derivative,15–17 al-
though the yield was unsatisfactory (Scheme 4).
OMe
OMe
MeO
MeO
1) Na, liq. NH3
O
O
THF, –78 °C
2) Boc2O
N
Bn
N
cat. DMAP
MeO
MeO
Boc
H
H
CH2Cl2, r.t.
23
24
61% (2 steps)
OMe
O
OMe
Cl
MeO
26
Br
O
Et3N
DMAP (10 mol%)
MeO
MeO
OH
LiAlH4
BocO
CO2Me
O
HO
CO2Me
THF
0 °C to r.t.
CH2Cl2
0 °C to r.t.
MeO
NH
H
HCl
S
N
MeO
Boc
25
MeOH–
1,4-dioxane
r.t.
MeO
NH2⋅HCl
H
84%
OMe
16b
17
MeO
OMe
TFA
MeO
1) BnBr, K2CO3
TBAI, MeCN
reflux
1) TESCl, Et3N
OH
O
TESO
O
CH2Cl2, r.t.;
NaHCO3 aq
0 °C to r.t.
Et2O, 0 °C to r.t.;
MeO
N
t-BuMgCl
0 °C to r.t.
2) KF, EtOAc–EtOH
–10 °C
69% (3 steps)
NH
96% ee
H
H
2) TBAF, THF, r.t.
79% (2 steps)
MeO
O
Br
65% (2 steps)
27
18
OMe
MeO
HO
MeO
OMe
MeO
(COCl)2
DMSO
O
cat. TPAP
NMO
CHO
O
O
O
N
CH2Cl2
Bn –78 to –45 °C;
Et3N, –45 °C
CH2Cl2–MeCN
r.t.
N
MeO
MeO
N
H
MeO
Bn
H
19
OMe
9
20
O
Br
72%
6
OMe OMe
OMe
O
MeO
TiCl4 (10 equiv)
Zn(Cu) (25 equiv)
MeO
HO
MsCl
Et3N
MgBr
DME
0 °C to r.t.;
reflux
22%
Br
O
CH2Cl2
0 °C to r.t.
N
THF, –40 °C
70% (2 steps)
MeO
N
MeO
Bn
H
H
21
5
Scheme
McMurry coupling
4
Synthesis of indenotetrahydropyridone 5 utilizing
OMe
OMe
O
MeO
MsO
MeO
O
TfOH
MeCN
segment consisting 3-aza[7]paracyclophane are currently
under investigation.
N
N
H
MeO
–40 °C to r.t. MeO
74% (2 steps)
Bn
Bn
22
23
Acknowledgment
Scheme 3 Construction of indane-fused b-lactam skeleton
This work was financially supported by the Ministry of Education,
Culture, Sports, Science, and Technology, Japan, the KAKENHI,
Grant-in-Aids for Scientific Research (B) (20390003) and for
Young Scientists (B) (19790004), Tohoku University Global COE
program ‘International Center of Research and Education for Mole-
cular Complex Chemistry’, and the Takeda Science Foundation.
In conclusion, synthetic studies on haouamine B were car-
ried out. Indenotetrahydropyridone derivative 5, which
would also be a potential intermediate of haouamine B
based on the Baran’s synthesis, was stereoselectively con-
structed through the quite unique indane-fused b-lactam
23, by highly diastereoselective Mannich reaction of sul-
finyl imine derivative, unprecedented Friedel–Crafts
cyclization on the b-lactam ring, and intramolecular Mc-
Murry coupling. Further extensive optimization of the
McMurry coupling and construction of the right-hand
References and Notes
(1) Current address: Graduate School of Medicine and
Pharmaceutical Sciences, University of Toyama, 2630
Sugitani, Toyama 930-0194, Japan.
(2) Garrido, L.; Zubía, E.; Ortega, M. J.; Salvá, J. J. Org. Chem.
2003, 68, 293.
Synlett 2011, No. 1, 73–76 © Thieme Stuttgart · New York

76
K. Okuyama et al.
LETTER
(3) (a) Smith, N. D.; Hayashida, J.; Rawal, V. H. Org. Lett.
2005, 7, 4309. (b) Grundl, M. A.; Trauner, D. Org. Lett.
2006, 8, 23. (c) Wipf, P.; Furegati, M. Org. Lett. 2006, 8,
1901. (d) Jeong, J. H.; Weinreb, S. M. Org. Lett. 2006, 8,
2309. (e) Fürstner, A.; Ackerstaff, J. Chem. Commun. 2008,
2870. (f) Taniguchi, T.; Zaimoku, H.; Ishibashi, H. J. Org.
Chem. 2009, 74, 2624.
(4) (a) Baran, P. S.; Burns, N. Z. J. Am. Chem. Soc. 2006, 128,
3908. (b) Burns, N. Z.; Baran, P. S. Angew. Chem. Int. Ed.
2008, 47, 205. (c) Burns, N. Z.; Krylova, I. N.; Hannoush,
R. N.; Baran, P. S. J. Am. Chem. Soc. 2009, 131, 9172.
(d) Burns, N. Z.; Jessing, M.; Baran, P. S. Tetrahedron 2009,
65, 6600.
(5) (a) Fürstner, A.; Jumbam, D. N. Tetrahedron 1992, 48,
5991. (b) Fürstner, A. Angew. Chem., Int. Ed. Engl. 1993,
32, 164. (c) Fürstner, A.; Bogdanović, B. Angew. Chem., Int.
Ed. Engl. 1996, 35, 2442.
(6) (a) Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J.; Ellman,
J. A. J. Am Chem. Soc. 1998, 120, 8011. (b) Weix, D. J.;
Ellman, J. A. Org. Lett. 2003, 5, 1317. (c) Ellman, J. A.;
Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984.
(7) Wang, Y.; He, Q.-F.; Wang, H.-W.; Zhou, X.; Huang, Z.-Y.;
Qin, Y. J. Org. Chem. 2006, 71, 1588.
(8) The relative stereochemistry was determined after
derivatization to b-lactam 18. The absolute stereochemistry
was tentatively assigned according to the Qin’s proposed
transition state (ref. 7).
(9) (a) Wentrup, C.; Winter, H.-W. J. Am. Chem. Soc. 1980,
102, 6161. (b) DeMattei, J. A.; Leanna, M. R.; Li, W.;
Nichols, P. J.; Rasmussen, M. W.; Morton, H. E. J. Org.
Chem. 2001, 66, 3330.
(10) The ee was determined by HPLC (Daicel CHIRALCEL
OD-H, flow rate: 0.50 mL/min, hexane-i-PrOH = 80:20, tR =
10.0, 13.1 min).
(11) The stereochemistry was tentatively assigned as described
based on the general reactivity of 4-substituted azetidine 2,3-
dione. For a typical example, see: Kant, J.; Schwartz, W. S.;
Fairchild, C.; Gao, Q.; Huang, S.; Long, B. H.; Kadow, J. F.;
Langley, D. R.; Farina, V.; Vyas, D. Tetrahedron Lett. 1996,
37, 6495.
evacuated and backfilled with argon gas. To the flask was
added anhyd MeCN (20 mL), and the resulting solution was
cooled to –40 °C. To the solution was added TfOH (0.70 mL,
7.9 mmol) at –40 °C. The reaction mixture was warmed to
r.t. and stirred for 3 h, after which time TLC (hexanes–
EtOAc, 3:2) indicated complete consumption of the starting
mesylate. After cooling to 0 °C, the reaction mixture was
treated with sat. aq NaHCO3, and the mixture was extracted
with EtOAc (3 ×). The combined organic extracts were
concentrated under reduced pressure to give the crude
material, which was purified by column chromatography on
silica gel to provide the title compound 23 (495 mg, 1.19
mmol, 74% over 2 steps) as a pale yellow amorphous solid;
[a]D23 –67.8 (c = 1.15, CHCl3). IR (neat): 2939, 2835, 1747,
1601, 1489, 1456, 1339, 1151, 1078, 1047, 910, 733, 698
cm–1. 1H NMR (400 MHz, CDCl3): d = 7.20–7.37 (m, 6 H),
6.88–6.95 (m, 2 H), 6.76–6.81 (m, 1 H), 6.31–6.35 (m, 2 H),
4.66 (d, 1 H, J = 15.2 Hz), 4.23 (d, 1 H, J = 15.2 Hz), 4.02
(d, 1 H, J = 6.4 Hz), 3.79 (s, 3 H), 3.76 (s, 3 H), 3.63 (s, 3 H),
2.99 (dd, 1 H, J = 17.6, 6.4 Hz), 2.87 (d, 1 H, J = 17.6 Hz).
13C NMR (100 MHz, CDCl3): d = 169.8, 161.9, 159.5, 158.3,
144.9, 139.0, 136.0, 129.2, 128.7, 128.1, 127.6, 120.8,
119.1, 112.5, 112.4, 102.0, 98.1, 75.4, 65.3, 55.7, 55.5, 55.1,
43.7, 32.8. HRMS (ESI+): m/z [M + Na+] calcd for
C26H25NO4Na: 438.1681; found: 438.1674.
(14) (a) D’Annibale, A.; Pesce, A.; Resta, S.; Trogolo, C.
Tetrahedron 1997, 53, 13129. (b) Bhalla, A.; Madan, S.;
Venugopalan, P.; Bari, S. S. Tetrahedron 2006, 62, 5054.
(15) Procedure for the Intramolecular McMurry Coupling
Reaction: A 10-mL test tube equipped with a magnetic
stirrer bar and an inlet adapter with three-way stopcock was
charged with Zn/Cu (6.2 mg, 95 mmol). The flask was flame-
dried and backfilled with argon gas. To the flask was added
degassed anyhd 1,2-dimethoxyethane (0.18 mL), and the
resulting suspension was cooled to 0 °C. To the suspension
was added TiCl4 (4.0 mL, 36 mmol), and the mixture was
heated at 90 °C for 1.5 h. After the flask was cooled to 0 °C,
substrate 6 (2.0 mg, 3.5 mmol) in 1,2-dimethoxyethane (50
mL) was added to the flask. The reaction mixture was
warmed to r.t. over 30 min and then heated at 90 °C for 2 h,
after which time TLC (hexanes–EtOAc, 1:1) indicated
complete consumption of the starting material. After cooling
to r.t., the mixture was diluted with EtOAc and filtered
through a celite pad. The filtrate was concentrated under
reduced pressure to give the crude material, which was
purified by preparative TLC providing the title compound 5
(0.42 mg, 0.78 mmol, 22%) as a colorless film. IR (neat):
3302, 2934, 1674, 1599, 1470, 1337, 1290, 1207, 1150, 754
cm–1. 1H NMR (400 MHz, CDCl3): d = 7.45 (d, 1 H, J = 8.8
Hz), 7.21–7.26 (m, 1 H), 6.91 (d, 1 H, J = 2.4 Hz), 6.78–6.86
(m, 3 H), 6.75 (dd, 1 H, J = 8.8, 3.2 Hz), 6.66 (s, 1 H), 6.48
(d, 1 H, J = 2.0 Hz), 6.36 (d, 1 H, J = 2.0 Hz), 5.66 (s, 1 H),
4.14–4.21 (m, 1 H), 3.83 (s, 3 H), 3.79 (s, 3 H), 3.76 (s, 3 H),
3.59 (s, 3 H), 3.33 (dd, 1 H, J = 16.0, 7.6 Hz), 3.08–3.16 (m,
1 H). 13C NMR (125 MHz, CDCl3): d = 163.4, 161.7, 159.8,
158.8, 157.2, 145.1, 143.9, 141.1, 138.9, 134.0, 133.0,
129.3, 122.3, 119.1, 117.2, 115.0, 114.4, 112.9, 112.0,
101.2, 98.3, 77.2, 64.6, 55.6, 55.5, 55.2, 55.1, 41.2. HRMS
(ESI+): m/z [M + Na+] calcd for C28H2679BrNO5Na:
(12) We found that the hydroxyl group should be activated as a
mesylate for the smooth and high-yielding process. The O-
methylated substrate has a low reactivity, and degradation of
the starting material was observed. On the contrary, The O-
triflated substrate was found to be unstable.
(13) Procedure for the Intramolecular Friedel–Crafts
Alkylation: A 30-mL round-bottomed flask equipped with a
magnetic stirrer bar and an inlet adapter with three-way
stopcock was charged with tertiary alcohol 21 (740 mg, 1.62
mmol). The flask was evacuated and backfilled with argon
gas. To the flask was added anhyd CH2Cl2 (6.0 mL), and the
resulting solution was cooled to 0 °C. To the solution were
added Et3N (0.70 mL, 5.0 mmol) and methanesulfonyl
chloride (0.25 mL, 3.2 mmol) at 0 °C, respectively. The
reaction mixture was then warmed to r.t. and stirred for 8 h,
after which time TLC (hexanes–EtOAc, 1:1) indicated
complete consumption of the starting alcohol. The reaction
was quenched with sat. aq NH4Cl, and the mixture was
extracted with CH2Cl2 (3 ×). The combined organic extracts
were washed with brine, dried over MgSO4, and filtered. The
filtrate was concentrated under reduced pressure to give a
crude mesylate (1.1 g), which was used for the next reaction.
A 30-mL round-bottomed flask equipped with a magnetic
stirrer bar and an inlet adapter with three-way stopcock was
charged with the crude mesylate (1.1 g). The flask was
558.0892; found: 558.0873.
(16) Reduction of the amide is reported using a similar compound
by Weinreb (ref. 3d).
(17) Chemical shifts of 1H NMR and 13C NMR of 5 were in
excellent agreement with those of the analogous compound
reported by Weinreb (ref. 3d).
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