Diastereocontrolled synthesis of an enantiopure 4,4-disubstituted cyclohex-2-en-ol: A new route to (+)-quebrachamine

Article abstract of DOI:10.1016/S0040-4039(01)02075-5

A diastereoselective route to an enantiopure 4,4-disubstituted cyclohex-2-en-1-ol has been developed using the synthetic equivalent of chiral 4-hydroxycyclohex-2-en-1-one. Its stereochemistry has been determined by its transformation into the Aspidosperma

Full text of DOI:10.1016/S0040-4039(01)02075-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 97–99
Diastereocontrolled synthesis of an enantiopure 4,4-disubstituted
cyclohex-2-en-ol: a new route to (+)-quebrachamine
Takashi Fujimura, Hiromi Nakashima, Hideki Sakagami, Takahiko Taniguchi and
Kunio Ogasawara*
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Received 16 October 2001; revised 30 October 2001; accepted 2 November 2001
Abstract—A diastereoselective route to an enantiopure 4,4-disubstituted cyclohex-2-en-1-ol has been developed using the synthetic
equivalent of chiral 4-hydroxycyclohex-2-en-1-one. Its stereochemistry has been determined by its transformation into the
Aspidosperma indole alkaloid (+)-quebrachamine. © 2001 Elsevier Science Ltd. All rights reserved.
We have developed an efficient method for the prepara-
tion of the enantiopure tricyclic ketone 2,1 which serves
as a synthetic equivalent of the chiral 4-ketocyclohex-2-
en-1-ol 3 in both enantiomeric forms from the meso
2-ene-1,4-diol bis-silyl ether 1 using the RhI-chiral
BINAP-mediated asymmetric 1,3-hydrogen transfer
reaction.2 Owing to its sterically biased framework
allowing convex-face selective modification and its ther-
mal lability to generate a cyclohexene double bond with
extrusion of a cyclopentadiene molecule, the ketol 2
was used as the synthetic equivalent of the chiral 4-
ketocyclohex-2-en-1-ol.3 Because of its chemical and
stereochemical nature, it has been utilized as a versatile
chiral building block for the enantioselective synthesis
of a variety of natural products by diastereocontrolled
modification at the C2 and/or C3 centers of the cyclo-
hexanol moiety.4 However, a modification of its C4
center, namely construction of a quaternary center sub-
stituted by two carbon functionalities, was found to be
very difficult and therefore prevented its utilization as a
more versatile chiral building block. We report here a
procedure for the diastereoselective construction of a
quaternary stereogenic center on the C4-carbonyl cen-
ter of the ketol (−)-2 leading to the 4,4-disubstituted
cyclohex-2-en-1-ol 3, and the conversion of the product
into (+)-quebrachamine,5 the Aspidosperma indole alka-
loid containing a quaternary stereogenic center. These
findings confirm the stereochemistry of the newly intro-
duced quaternary center as well as demonstrate its
synthetic utility (Scheme 1).
Since the ketone (−)-2 (>98% ee)6 was somewhat unre-
active toward organolithium or organomagnesium
reagents as well as toward Wittig type reagents, pre-
sumably due to its facile enolization,6 it was first treated
with N-bromosuccinimide (NBS) to form the bromo–
ether 4,1 mp 60–61°C, [h]D29 −224.2 (c 0.5, CHCl3),
which has a more rigid framework. Although com-
pound 4 was still not very reactive toward organometal-
lic reagents, it did react with vinylmagnesium chloride
in the presence of cerium(III) chloride7 to give the
tertiary allyl alcohol 5, mp 120–121°C, [h]2D9 −108.0 (c
0.3, CHCl3), diastereoselectively, in good yield. After
considerable experimentation, the isomerization of 5
into an E/Z-mixture of the primary allyl alcohol 8 was
carried out by employing
a
palladium-mediated
reaction8 of the tertiary allyl acetate 6 proceeding via an
E/Z-mixture of the primary allyl acetate 7. Thus, acetyl-
OH
OH
OTMS
ref.1
present
study
TMSO
O
R1 R2
1
(–)-2
3
Scheme 1.
* Corresponding author. E-mail: konol@mail.cc.tohoku.ac.jp
0040-4039/02/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02075-5

98
T. Fujimura et al. / Tetrahedron Letters 43 (2002) 97–99
ation of 5 followed by treatment of the resulting ter-
tiary acetate 6, mp 124–125°C, [h]2D8 −163.5 (c 1.1,
CHCl3), with sodium acetate in the presence of
dichlorobis(acetonitrile)palladium(II) in THF induced
facile isomerization to furnish the primary acetate 7 as
an inseparable E/Z mixture, from which the primary
alcohol mixture 8 was obtained after alkaline methanoly-
sis. Upon treatment with N,N-dimethylacetaminde
dimethyl acetal9 at 280°C in diphenyl ether, the primary
alcohol mixture 8 furnished diastereoselectively the
acetamide 9, [h]2D8 −83.2 (c 0.7, CHCl3), having a qua-
ternary stereogenic center as the only product.
Although the stereochemistry of the quaternary stereo-
genic center was not determined at this stage, it was
assumed, on the basis of accumulated precedents,4 that
the Eschenmoser reaction of 8 should occur diastereose-
lectively to install the newly introduced functionality
from the convex-face giving rise to the quaternary
product 9 with an endo-vinyl functionality. This
assumption was confirmed at a later stage (Scheme 2).
smoothly to give the expected cyclohexene 13, [h]D26
+81.4 (c 1.0, CHCl3), in 93% yield. Although the effect
of the sodium hydrogen carbonate is uncertain, when it
is not used the reaction proceeds with considerable
decomposition. This is particularly true when
a
hydroxyl functionality is present in the substrate
(Scheme 3).
In order to obtain (+)-quebrachamine 23, the amide 13
was first reduced with lithium triethylborohydride11 to
give the primary alcohol 14, [h]2D7 +60.0 (c 0.9, CHCl3),
from which the silyl protective group was removed to
give the diol 15, [h]2D7 +69.9 (c 0.4, CHCl3). Upon
sequential ozonolysis, reduction with sodium borohy-
dride, and glycol-cleavage with sodium periodate in the
same flask, the diol 15 furnished the lactol 16 in 67%
overall yield from the amide 13. Oxidation of the lactol
16 with tetrapropylammonium perruthenate12 (TPAP)
afforded the formyl-lactone 18, in one step as an
unstable oil, which could also be obtained in compara-
ble overall yield via the hydroxy–lactone 17, [h]2D7 +2.7
(c 0.7, CHCl3), by sequential Fetizon oxidation13 and
Swern oxidation.14
To unambiguously confirm its stereochemical pathway,
as well as to demonstrate its synthetic utility, com-
pound 9 was converted via the hydrogenated product
10 into (+)-quebrachamine 23, an Aspidosperma indole
alkaloid having a quaternary (R)-stereogenic center.5
Thus, the vinyl-amide 9 was first hydrogenated on
palladized charcoal to give the ethyl–amide 10, mp
95–96°C, [h]2D9 −69.5 (c 1.6, CHCl3). Upon exposure to
zinc in methanol containing acetic acid,4 compound 10
afforded the hydroxy–olefin 11, mp 136–137°C, [h]D31
−20.1 (c 1.0, CHCl3), by reductive cleavage of its
bromo–ether linkage with regeneration of the olefin and
the secondary hydroxyl functionalities. Direct thermol-
ysis of the secondary alcohol 11 in diphenyl ether at
280°C afforded the expected retro-Diels–Alder product
in low yield accompanied by a complex mixture of
by-products. However, thermolysis of its TBS ether 12,
[h]2D9 +9.6 (c 0.4, CHCl3), in diphenyl ether at 280°C in
the presence of sodium hydrogen carbonate10 proceeded
Condensation of the lactone 18 with tryptamine in
benzene containing trifluoroacetic acid at reflux fur-
nished the tetracyclic lactam 19 in one step as a mixture
of two epimers by consective imine formation,
intramolecular Pictet–Spengler reaction, and lactamiza-
tion under the reaction conditions. The mixture was
reduced with lithium aluminum hydride to give the
tertiary amine mixture 20 the racemic mixture of which
had been obtained15 and ultimately transformed15 into
racemic quebrachamine ( )-23. Using the same proce-
dure for the racemic synthesis, the mixture 20 was
converted to the mesylate 21 which was immediately
refluxed in chloroform to give the quaternary ammo-
nium mesylate mixture 22. Upon subjection to Birch
reduction,16 the mesylate mixture 22 furnished (+)-que-
Br
Br
Br
Br
i
ii
iv
vi
(–)-2
O
O
O
O
O
O
OR
RO
NMe2
5:R = H
6:R = Ac
7:R = Ac
8:R = H
4
iii
v
9
Scheme 2. Reagents and conditions: (i) NBS, CH2Cl2, rt (99%); (ii) vinyl-Mg-Br, CeCl3, THF, −78°C (87%); (iii) Ac2O, pyridine,
DMAP (cat.), rt (95%); (iv) PdCl2(MeCN)2 (cat.), THF, rt (100%); (v) K2CO3, MeOH, rt (98%); (vi) MeC(NMe2)(OMe)2, Ph2O,
reflux (96%).
OTBS
OR
Br
i
ii
iv
9
O
O
O
O
NMe2
NMe2
NMe2
13
11:R = H
12:R = TBS
10
iii
Scheme 3. Reagents and conditions: (i) H2, 10% Pd-C, AcOEt (92%); (ii) Zn, AcOH–MeOH (1:10), reflux (93%); (iii) TBS-Cl,
imidazole, DMF, rt (94%); (iv) Ph2O, NaHCO3, reflux (93%).

T. Fujimura et al. / Tetrahedron Letters 43 (2002) 97–99
99
O
OR
OH
O
N
O
O
iv
i
iii
vi
N
H
13
H
R
OH
OH
OH
17:R=CH2OH
18:R=CHO
14:R=TBS
15:R=H
19
16
v
ii
N
OMs—
vii
x
N+
ix
N
N
H
N
H
H
H
N
H
OR
20:R=H
(–)-quebrachamine 23
viii
22
21:R=Ms
Scheme 4. Reagents and conditions: (i) LiEt3BH, THF, rt (84%); (ii) TBAF, THF (99%); (iii) O3, MeOH, −78°C, then NaBH4,
then, NaIO4, H2O (67%); (iv) Ag2CO3–Celite, benzene, reflux (93%); (v) Swern oxidation; (vi) tryptamine, CF3CO2H, benzene,
reflux (62%, two steps); (vii) LiAlH4, dioxane, reflux (86%); (viii) Ms-Cl, pyridine, 0°C; (ix) CHCl3, reflux; (x) Na, liq. NH3, EtOH,
−78°C (69% from 20).
brachamine 23, mp 147–149°C, [h]D +106.1 (c 0.1,
acetone){lit.5a: mp 147–149°C, [h]D +108.9 (acetone)}, as
a single product. The stereochemistry of the quaternary
stereogenic center of the amide 9 as well as the stereo-
chemical pathway of the Eschenmoser reaction of the
allyl alcohol mixture 8 had thus been established unam-
biguously at this stage. The present synthesis implies
development of a new diastereo- and enantiocontrolled
route to both enantiomers of quebrachamine 23 since the
starting ketone 2 may be obtained in both enantiomeric
forms1 (Scheme 4).
2. For pertinent reviews, see: (a) Otsuka, S.; Tani, K. Syn-
thesis 1991, 665; (b) Noyori, R. Tetrahedron 1994, 50,
4259.
3. Ogasawara, K. Pure Appl. Chem. 1994, 66, 2119.
4. For a pertinent review, see: Ogasawara, K. J. Syn. Org.
Chem. Jpn. 1999, 57, 957.
5. For the first enantioselective synthesis, see: (a) (+)-enan-
tiomer: Takano, S.; Chiba, K.; Yonaga, M.; Ogasawara,
K. J. Chem. Soc., Chem. Commun. 1980, 616; (b) (−)-
enantiomer: Takano, S.; Yonaga, M.; Ogasawara, K. J.
Chem. Soc., Chem. Commun. 1981, 1153.
6. Konno, H.; Hiroya, K.; Ogasawara, K. Tetrahedron
Lett. 1997, 38, 6023.
7. Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima,
T.; Kamiya, Y. J. Am. Chem. Soc. 1989, 111,
4392.
In conclusion, a method for enantio- and diastereocon-
trolled preparation of a 4,4-disubstituted cyclohex-2-en-
1-ol using a synthetic equivalent of chiral 4-keto-
cyclohex-2-en-1-ol has been developed by employing the
Eschenmoser reaction as the key step. Moreover, its
stereochemical pathway has been verified by a new
synthesis of the Aspidosperma indole alkaloid (+)-que-
brachamine. Further research on the use of the enantio-
pure 4,4-disubstituted cyclohex-2-en-1-ols is in progress.
8. Overman, L. E.; Knoll, F. M. Tetrahedron Lett. 1979,
321.
9. Wick, A. E.; Felix, D.; Steen, K.; Eschenmoser, A. Helv.
Chim. Acta 1964, 47, 2425.
10. Kamikubo, T.; Ogasawara, K. J. Chem. Soc., Chem.
Commun. 1995, 1951.
11. Brown, H. C.; Kim, S. C.; Krishnamurthy, S. J. Org.
Chem. 1980, 45, 1.
Acknowledgements
12. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.
Synthesis 1994, 639.
13. Fetizon, M.; Golfier, M.; Louis, J.-M. Tetrahedron 1975,
31, 171.
14. Mancuso, A. J.; Swern, D. Synthesis 1978, 165.
15. Takano, S.; Hatakeyama, S.; Ogasawara, K. J. Am.
Chem. Soc. 1976, 98, 3022; 1979, 101, 6414.
16. For a pertinent review, see: Kutney, J. P. In The Total
Synthesis of Natural Products; ApSimon, J., Ed.;
Wiley–Interscience: New York, 1977; Vol. 3, pp. 273–
438.
We are grateful to the Ministry of Education, Culture,
Sports, Science and Technology, Japan for support of
this research. We also thank the Japan Society for the
Promotion of Science for a fellowship (to H.S.).
References
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