Asymmetric construction of the azaspiro[5.5]undec-8-ene system towards gymnodimine synthesis

Article abstract of DOI:10.1055/s-2002-20450

In the course of the synthetic studies on gymnodimine, a potent shellfish toxin, the asymmetric construction of the azaspirocyclic part was achieved by the (-)-siam·Cu(SbF₆)₂ complex catalyzed intermolecular Diels-Alder reaction in high exo- and enantioselectivities.

Full text of DOI:10.1055/s-2002-20450

LETTER
399
Asymmetric Construction of the Azaspiro[5.5]undec-8-ene System Towards
Gymnodimine Synthesis
A
symmetric Co
a
nstruction
k
of the
A
zasp
a
iro[5. 5]und
s
ec-8-ene
S
h
yste
m
i Tsujimoto, Jun Ishihara, Mariko Horie, Akio Murai*
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo, 060-0810, Japan
Fax +81(11)7062714; E-mail: amurai@sci.hokudai.ac.jp
Received 29 December 2001
Me
Abstract: In the course of the synthetic studies on gymnodimine, a
Me
OH
10
H
H
H
potent shellfish toxin, the asymmetric construction of the azaspiro-
cyclic part was achieved by the (–)-siam Cu(SbF6)2 complex cata-
lyzed intermolecular Diels–Alder reaction in high exo- and
enantioselectivities.
4
O
O
H
Me
O
22
Me
N
Me
Key words: asymmetric Diels–Alder reactions, gymnodimine
-methylene lactam, azaspirocyclic system
Gymnodimine (1)
Gymnodimine 1 is a potent marine toxin which was iso-
lated from New Zealand oysters Tiostrea chilensis as well
as the concurrent dinoflagellate Gymnodinium cf. mikim-
otoi.1 The toxin includes a characteristic spirocyclic imine
moiety which has been proposed to be biogenetically con-
structed by intramolecular Diels–Alder reaction of the
triene part with the , -unsaturated ketone as the precur-
sor of the cyclic imine part in an exo-cycloaddition.1 On
the other hand, the first total synthesis of pinnatoxin A2
and its enantiomer, structurally reminiscent of 1, has been
achieved by Kishi et al.3 according to the proposed bio-
genesis.2 We have studied aiming to the synthesis of 1,4,5
the pathway of which involves asymmetric intermolecular
exo-cyclic Diels–Alder reaction in the different manner
from the Kishi procedure (Scheme 1). In this paper we
present the efficient asymmetric construction of the 1-
oxo-2-azaspiro[5.5]undec-8-ene part, which could be a
key intermediate for the total synthesis of 1.
Me
OR
O
H
H
R
O
N
O
H
Me
O
+
Me
OR Me
Scheme 1 Our synthetic strategy for 1.
having (2S)-5-oxotetrahydrofuran-2-yl group gave satis-
factorily the desired cycloadduct 10 (89% yield) in 88%
diastereomeric excess (entry 4). The respective structures
of the cycloadducts 8 and 10 were determined by the
NMR spectroscopic analysis of their derivatives accord-
ing to the Kusumi procedure.10 On the other hand, the at-
tempted treatment of 9 (1.0 equiv) and 2 (1.0 equiv) under
the modified conditions of the chiral reagents developed
by Evans {Cu++[(S,S)-t-Bu-BOX](SbF6 )2 (0.2 equiv) in
-
In order to construct the requisite azaspirocyclic system,
we developed asymmetric intermolecular Diels–Alder re-
action reported by Ellman.6 Asymmetric addition of vari-
ous dienes to dienophilic -methylene lactam 2, prepared
from -valerolactam,7 in the presence of (–)-siam and
Cu(SbF6)26 was investigated (Table). The reaction of iso-
prene 3 (1.0 equiv) with 2 (2.0 equiv) and (–)-
siam·Cu(SbF6)2 (0.4 equiv) in the dark proceeded smooth-
ly to afford a cycloadduct 4 (98% yield) with >99% ee
(entry 1). In the case of cyclopentadiene 5, cycloadduct 6
was produced (99% yield) with >99% ee, and the ratio of
exo/endo isomers amounted to 87:13 (entry 2). The reac-
tion of further functionalized diene 7 afforded cycload-
duct 8 (33% yield) with high exo/endo selectivity (~95/5)
and high enantiomeric excess (94%), along with the regio-
isomer of 8 (29% yield) (entry 3).8 The reaction with 99
CH2Cl2 at 24 °C, 214 h}11 led to no reaction, in contrast
with the satisfactory results of 9 and -methylene -capro-
lactam.12 Ellman described that the Cu(II) ligand complex
exists as a unique M2L4 helicate in solid state, while the
complex coordinates predominantly through the sulfinyl
oxygen in solution.6 However, the transition structure of
the reaction seems to be still ambiguous. We presumed
that this high exo- and enantioselectivity of the reaction
could be provided due to the steric repulsion between the
siam ligand and the dienes in endo transition state. Fur-
thermore, as Roush has proposed,13 in the case of the con-
formationally restricted (S)-cis-enone, both dipole
moments of diene and dienophile-Lewis acid complex
might be cancelled in the exo-transition state in contrast to
the endo-transtion state. It is interesting that there were the
differences of the reactivity between Ellman’s and Evans’
chiral Lewis acids depending upon the ring size of the di-
enophilic -methylene lactams, though the reason is in-
trinsically unclear so far.
Synlett 2002, No. 3, 04 03 2002. Article Identifier:
1437-2096,E;2002,0,03,0399,0402,ftx,en;Y24701ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

400
T. Tsujimoto et al.
LETTER
Table The Model Experiments for Asymmetric Diels–Alder Reaction.
O
O
(-)-siam·Cu(SbF6)2 complex (0.4 eq)
diene (1.0 eq), MS3A
N
OBn
(2.0 eq)
CH2Cl2, in the dark, 25 °C, time
2
Entry
1
Diene
Product
Time (h)
2
Yield (%) ee (%)
Exo/endo
98
99
33
>99
–
Me
O
Me
NCBZ
3
4
2
3
0.4
99
87:13
95:5
O
NCBZ
Me
5
6
24
94
H
MPMO
OTBS
O
Me
MPMO
OTBS
NCBZ
7
8
4
36
89
–
94:6
Me
H
O
OTBS
O
O
Me
H
O
OTBS
O
H
NCBZ
9
10
Next, we applied these results to the gymnodimine syn- (5.0 equiv) in the presence of (–)-siam·Cu(SbF6)2 com-
thesis (Scheme 2). Reduction of 114 with DIBAL-H gave plex (1.0 equiv) at 25 °C for 35 h gave the desired adduct
allyl alcohol 12 (97% yield), which was converted to silyl 21 (58%)18 as a single product along with the recovered
ether 13 (99% yield). Hydroboration of 13 with 9-BBN starting materials [20 (31%), 2 (83%)]. The product 21
and the subsequent treatment with alkaline H2O2 afforded could be also obtained from the configurationally estab-
primary alcohol 14 (94% yield), followed by oxidation lished compound 10 in a 5-step sequence [i) detachment
with Dess–Martin periodinane14 to aldehyde 15 (98%), of the TBS group, ii) oxidation with Dess–Martin period-
which, on treatment of the lithium anion of inane,14 iii) HWE reaction with 16, iv) CBS reduction,16
(EtO)2P(O)CH2Me and then with Dess–Martin periodi- and v) protection of the alcohol with TBDPS]. According-
nane,14 furnished -ketophosphonate 16 (90% yield for 2 ly, the adduct 21 was found to have the desired stereo-
steps). The Horner-Wadsworth-Emmons (HWE) reaction chemistry.
of tetrahydrofuran 16 and diene 17, derived from 9, was
In conclusion, we achieved the synthesis of the key inter-
mediate 21 for gymnodimine synthesis via highly exo-se-
lective asymmetric Diels–Alder reaction by utilizing (–)-
performed under the Masamune-Roush conditions15 to
give trienone 18 (91% yield) as a single diastereomer,
which, by Corey–Bakshi–Shibata (CBS) asymmetric re-
siam·Cu(SbF6)2. Further studies toward the total synthesis
duction,16 afforded (S)-alcohol 19 in >95% diastereomeric
of gymnodimine 1 are in progress in our laboratory.
excess.17 The alcohol part was protected by TBDPS group
to 20.
Acknowledgement
The Diels–Alder reaction of triene 20 was then examined
We thank Professor J. A. Ellman and Mr. T. D. Owens in California
University for their kind suggestion.
(Scheme 3). Treatment of 20 (1.0 equiv) with lactam 2
Synlett 2002, No. 3, 399–402 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Asymmetric Construction of the Azaspiro[5.5]undec-8-ene System
401
O
OR
O
H
MeO2C
O
O
O
O
Me
H
NCBZ
O
a
c
H
Me
H
a
H
H
Me
+
Me
Me
2
Me
11
N
H
Me
H
12: R = H
CBZ
O
O
Me
OTIPS
b
OTIPS
OTIPS
O
P
EtO
13: R = TIPS
OTBDPS
Me
O
OTBDPS
OTIPS
EtO
O
O
Me
R
Me
Me
H
e, f
H
H
H
H
O
Me
Me
H
Me
Me
d
O
O
20
21
H
14: R = CH2OH
15: R = CHO
O
Me
16
b, c, d, e, f
O
H
g
Me
O
H
Me
H
+
H
O
O
N
Me
H
O
OTBS
CBZ
Me
10
10
OTIPS
17
R1
R
Scheme 3 Asymmetric Diels–Alder reaction of 2 and 20.
a) (–)-siam·Cu(SbF6)2 (1.0 equiv), 2 (5.0 equiv), MS3A, CH2Cl2, 25
°C, 35 h (58%); b) PTS H2O, THF, H2O, 25 °C, 30 min (78%); c)
Dess–Martin periodinane, CH2Cl2, NaHCO3, 25 °C, 4 h (90%); d) 16,
LiCl, MeCN, i-Pr2NEt, 0 °C, 2 h (55%); e) (R)-B-Me-CBS, BMS, to-
luene, –10 °C, 10 min (85%); f) TBDPSCl, imidazole, CH2Cl2, 25 °C,
12 h (90%).
18: R = R1 = O
O
h
i
Me
H
H
19: R = OH, R1 = H
Me
20: R = OTBDPS
R1 = H
Scheme 2 Preparation of the diene 20.
a) DIBAL-H, CH2Cl2, –78 °C, 1 h (97%); b) TIPSCl, imidazole,
CH2Cl2, 0 to 25 °C, 5 h (99%); c) 9-BBN, THF, 25 °C, 12 h, then 3 M
NaOH aq, 30% H2O2 aq, 0 °C, 2 h (94%); d) Dess–Martin periodin-
ane, NaHCO3, CH2Cl2, 25 °C, 2 h (98%); e) (EtO)2P(O)CH2Me, t-Bu-
Li, THF, –78 °C, 30 min, then 15, 20 min; f) Dess–Martin
periodinane, NaHCO3, CH2Cl2, 25 °C, 2 h (90% from 15); g) 17, LiCl,
MeCN, i-Pr2NEt, 0 °C, 2 h (90%); h) (R)-B-Me-CBS, BMS, toluene,
–10 °C, 10 min (98%); i) TBDPSCl, imidazole, CH2Cl2, 25 °C, 12 h
(98%).
(6) Owens, T. D.; Hollander, F. J.; Oliver, A. G.; Ellman, J. A.
J. Am. Chem. Soc. 2001, 123, 1539.
(7) i) NaH, THF, CBZ-Cl, 25 °C, 5 h (89%); ii) TMSOTf,
i-Pr2NEt, CH2Cl2, 25°C, 2 h; iii) Me2N+=CH2I-, CH2Cl2,
25 °C, 12 h; iv) MeI, THF, 25 °C, 2 h (68% for 3 steps).
(8) The stereochemistry for the regioisomer of 8 has not been
fully assigned yet.
(9) 9 was prepared from L-glutamic acid in a 5-step process:
(i) NaNO2, aq HCl, 25 °C, 20 h (77%); (ii) SOCl2, 80 °C,
12 h (98%); (iii) (E)-1-t-Butyldimethylsilyloxy-3-tributyl-
stannylbut-2-ene, Pd(PPh3)4, ClCH2CH2Cl, 65 °C, 20 h
(82%); (iv) Ph3P=CH2, THF, –10 °C, 2 min (96%).
(10) Nagai, Y.; Kusumi, T. Tetrahedron Lett. 1995, 36, 1853;
PGME is the abbreviation of phenylglycine methyl ester
(Scheme 4).
(11) (a) Evans, D. A.; Miller, S. J.; Lectka, T. J. Am. Chem. Soc.
1993, 115, 6460. (b) Evans, D. A.; Murry, J. A.; von Matt,
P.; Norcross, R. D.; Miller, S. J. Angew. Chem. Int. Ed. Engl.
1995, 34, 798. (c) Evans, D. A.; Miller, S. J.; Lectka, T.; von
Matt, P. J. Am. Chem. Soc. 1999, 121, 7559. (d) Evans, D.
A.; Barnes, D. M.; Johnson, J. S.; Lectka, T.; von Matt, P.;
Miller, S. J.; Murry, J. A.; Norcross, R. D.; Shaughnessy, E.
A.; Campos, K. R. J. Am. Chem. Soc. 1999, 121, 7582.
(e) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33,
325.
References
(1) (a) Seki, T.; Satake, M.; Mackenzie, L.; Kaspar, H. F.;
Yasumoto, T. Tetrahedron Lett. 1995, 36, 7093.
(b) Stewart, M.; Blunt, J. W.; Munro, M. H. G.; Robinson,
W. T.; Hannah, D. J. Tetrahedron Lett. 1997, 38, 4889.
(c) Miles, C. O.; Wilkins, A. L.; Stirling, D. J.; MacKenzie,
A. L. J. Agric. Food Chem. 2000, 48, 1373.
(2) (a) Uemura, D.; Chou, T.; Haino, T.; Nagatsu, A.;
Fukuzawa, S.; Zheng, S.-z.; Chen, H.-s. J. Am. Chem. Soc.
1995, 117, 1155. (b) Chou, T.; Kamo, O.; Uemura, D.
Tetrahedron Lett. 1996, 37, 4023.
(3) (a) McCauley, J. A.; Nagasawa, K.; Lander, P. A.; Mischke,
S. G.; Semones, M. A.; Kishi, Y. J. Am. Chem. Soc. 1998,
120, 7647. (b) Review: Nagasawa, K. J. Synth. Org. Chem.
Jpn. 2000, 58, 877.
(4) Ishihara, J.; Miyakawa, J.; Tsujimoto, T.; Murai, A. Synlett
1997, 1417.
(12) Ishihara, J.; Horie, M.; Shimada, Y.; Tojo, S.; Murai, A.
Synlett; 2002, 403. The reactions of 2 with Cu2+[(S,S)-t-Bu-
BOX](OTf-)2 with isoprene 3 (23 °C, 60 h) and
cyclopentadiene 5 (25 °C, 1 h) afforded the adducts 4 (37%
yield, 93%ee) and 6 (82% yield, exo/endo 5:3, exo 93%ee),
respectively.
(5) Studies towards gymnodimine of other groups: (a) Rainier,
J. D.; Xu, Q. Org. Lett. 1999, 1, 27. (b) Yang, J.; Cohn, S.
T.; Romo, D. Org. Lett. 2000, 2, 763. (c) Ahn, Y.;
Cardenas, G. I.; Yang, J.; Romo, D. Org. Lett. 2001, 3, 751.
(13) Roush, W. R.; Brown, B. B. J. Org. Chem. 1992, 57, 3380.
(14) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
Synlett 2002, No. 3, 399–402 ISSN 0936-5214 © Thieme Stuttgart · New York

402
T. Tsujimoto et al.
LETTER
(15) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett.
1984, 25, 2183.
(16) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.;
Singh, V. K. J. Am. Chem. Soc. 1987, 109, 7925. (b)
Review: Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed.
1998, 37, 1986.
(17) The stereochemistry at the C10 hydroxyl group of 19 was
determined by modified Mosher’s method: Ohtani, I.;
Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc.
1991, 113, 4092.
: NOESY
correlation
Me
Me
Me
H
H
H
R
R
R
H
OTBS
O
OH
O
O
+
PTS·H2O
THF, H2O
25 °C, 6 h
H
O
NCBZ
NCBZ
(~50% yield)
H
8 or 10
H
NH
CBZ
(~40% yield)
R1
Me
H
(18) 21: A colorless oil; [ ]D24 -13.0 (c 0.24, CHCl3); 1H NMR
(300 MHz, C6D6), 7.85–7.69 (m, 4 H), 7.52 (2 H, d, J = 7.3
Hz), 7.26–7.17 (8 H, m), 7.13 (1 H, t, J = 7.3 Hz), 5.78 (1 H,
t, J = 5.5 Hz), 5.56 (1 H, d, J = 6.1 Hz), 5.28 (2 H, s), 4.84 (1
H, t, J = 6.6 Hz), 4.34 (2 H, d, J = 5.5 Hz), 3.79 (1 H, qui, J
= 6.6 Hz), 3.65 (1 H, d, J = 8.0 Hz), 3.58–3.50 (1 H, m),
3.44–3.34 (1 H, m), 2.93 (1 H, brd, J = 17.1 Hz), 2.38 (1 H,
brd, J = 17.1 Hz), 2.32 (1 H, dd, J = 11.5, 13.0 Hz), 2.18–
2.05 (1 H, m), 1.86 (1 H, ddd, J = 2.7, 5.9, 13.2 Hz), 1.95–
1.35 (12 H, m), 1.75, 1.74, 1.65, 1.60 (each 3 H, s), 1.11 (21
H, s), 1.08 (9 H, s), 0.80 (3 H, d, J = 6.6 Hz); IR(neat), 3071,
3048, 2951, 2930, 2891, 2863, 1782, 1771, 1714, 1612,
1471, 1461, 1428, 1389, 1297, 1252, 1180, 1111, 1060, 882,
837, 821, 777, 740, 701, 689, 658 cm–1; FAB-HR-MS, calcd.
for C63H89NO8Si2 (M+) 1043.6127, found 1043.6149.
Me
H
R
(1)Dess-Martin
periodinane
R
OH
O
O
O
(2) NaClO2
NCBZ
(93%, 2 steps)
NCBZ
R1 = OH
PGME·HCl
BOPCl
DMAP
(~100%)
R1 = (S) or (R)-PGME
∆(δ) = δ(S) - δ(R)
-0.006
-0.016
-0.107
-0.018
H
Me
O
N
Me
O
-0.055
H
H
O
MPMO
PGME
PGME
O
O
O
N
O
O
0.016
0.022
0.014
O
O
0.046
Scheme 4
Synlett 2002, No. 3, 399–402 ISSN 0936-5214 © Thieme Stuttgart · New York