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