Enantioselective synthesis of a tetrasubstituted oxocane via a double diastereoselective hetero Diels-Alder reaction

Article abstract of DOI:10.1055/s-2001-9717

A procedure for the enantioselective preparation of tetra-substituted medium sized cyclic ethers is presented. An oxocane is prepared by a sequence which involves a double diastereoselective hetero Diels-Alder reaction between a chiral aldehyde and a diene bearing an allylic chiral centre. The cycloadduct is transformed into a linear ether which is then converted to the cyclic ether by a highly regioselective intramolecular alkylation of a lithiosulfone with an epoxide. The sense of induction of the chiral centre on the diene is discussed.

Full text of DOI:10.1055/s-2001-9717

LETTER
117
Enantioselective Synthesis of a Tetrasubstituted Oxocane via a Double
Diastereoselective Hetero Diels-Alder Reaction
Mercedes Martín, María M. Afonso, Antonio Galindo, J. Antonio Palenzuela*
Instituto Universitario de Bio-Orgánica “Antonio González”, Universidad de La Laguna, E-38206 La Laguna, Tenerife, Spain
Fax +34922630095; E-mail: jpalenz@ull.es
Received 23 October 2000
SO2pTol
SO2pTol
Abstract: A procedure for the enantioselective preparation of tetra-
substituted medium sized cyclic ethers is presented. An oxocane is
prepared by a sequence which involves a double diastereoselective
hetero Diels-Alder reaction between a chiral aldehyde and a diene
bearing an allylic chiral centre. The cycloadduct is transformed into
a linear ether which is then converted to the cyclic ether by a highly
regioselective intramolecular alkylation of a lithiosulfone with an
epoxide. The sense of induction of the chiral centre on the diene is
discussed.
R1O
R1O
OR2
O
O
O
R3
R4
R3
R4
R1O
SO2pTol
R1O
SO2pTol
Key words: hetero Diels-Alder reaction, double diastereoselectivi-
ty, intramolecular alkylation, cyclic ethers
H
O
O
+
H
O
L3SiO
L3SiO
O
O
Medium sized cyclic ethers, substituted at the positions
adjacent to the oxygen atom (a, a’,b, b’) have attracted
considerable interest because they constitute the basic
skeleton of many metabolites isolated mainly from marine
sources,1 and also because they are the basic units of the
important fused polyether marine toxins.2 In these latter
compounds, the most usual relative stereochemistry of the
substituents in each of the fused cyclic ethers is trans, syn,
trans (Figure 1).
O
2
Scheme 1
Since the introduction of the fourth substituent in the mol-
ecule requires its placement at the allylic position of the
diene, another important point to consider is the sense of
induction of both components in the key hetero Diels-Al-
der reaction. To obtain an acceptable yield and selectivity,
both fragments must work in the same direction, that is, it
must be a matched double diastereoselective reaction. The
sense of induction of the chosen (R)-(+)-2 aldehyde is
well known,4 following Cram’s rule with high endo selec-
tivity (endo:exo 7:1 in our previous work with non-chiral
dienes3b). The induction exerted by an allylic chiral centre
in a linear diene, however, is not that well understood,
giving rise, in the cases reported,5 to products coming
from the approach of the dienophile through either face of
the diene (like or unlike approaches6). The selectivity
seems to depend on several factors, such as the nature of
the dienophile and the substitution pattern on the diene.5
The number of examples of chiral dienes acting in a hetero
Diels-Alder reaction with aldehydes as dienophiles is
scarce, but in a system closely related to ours, Wu et al.7
observed a major product coming from the unlike ap-
proach of ethyl glyoxylate to the diene. The face selectiv-
ity due exclusively to the dienic chiral centre seems to be
low in the absence of other chiral partners such as chiral
Lewis acids or dienophiles.
( )n
OR2
R4
R1O
R3
O
1
Figure 1
We have recently reported on a methodology for the enan-
tioselective preparation of medium sized, bi- and trisubsti-
tuted cyclic ethers using an intramolecular alkylation of a
lithiosulfone with an epoxide.3 The control over the rela-
tive stereochemistry of the substituents is attained by the
use of a hetero Diels-Alder reaction between a monoacti-
vated diene and a chiral aldehyde.
In this communication we present the extension of this
methodology to the preparation of cyclic ethers tetrasub-
stituted at the a, a’, b, and b’ positions. Scheme 1 shows
a retrosynthetic scheme for the preparation of a tetrasub-
stituted oxocane, based on the methodology previously
used for trisubstituted systems. For this scheme to be suc-
cessful, the intramolecular cyclization reaction has to be
highly regioselective, a result that can be expected based
on our previous experience with similar compounds.3b
According to our modelization of the reaction, in order to
obtain the required stereochemistry (Scheme 1), the ap-
proach of the dienophile to the diene must occur as shown
in Figure 2. The (R)-(+)-2 aldehyde approaches the diene
Synlett 2001 No. 1, 117–119 ISSN 0936-5214 © Thieme Stuttgart · New York

118
M. Martín et al.
LETTER
by reduction followed by protection of the hydroxyl as the
tert-butyldiphenylsilyl ether. Deprotection of the ace-
tonide and cleavage of the diol with NaIO4 gave aldehyde
7, which was transformed into an a, b-unsaturated ketone
via a Wittig-Horner reaction. Formation of the tert-bu-
tyldimethylsilyl enol ether afforded the desired diene 8.
(CH2)2SO2pTol
H
(CH2)2SO2pTol
H
RO
O
RO
H
TBDMSO
TBDMSO
O
H
LA
O
H
H
H
O
O
O
The hetero Diels-Alder reaction of diene 8 and (R)-(+)-2
was carried out under similar conditions to those em-
ployed in our previous work,3 using 1.5 equivalents of
BF3◊Et2O as Lewis acid and diethyl ether as solvent. The
control of the temperature was critical in achieving good
selectivity, since at low temperature the reaction was very
slow and part of the diene reverted with time to the corre-
sponding a, b-unsaturated ketone. At higher temperature,
the selectivity was lower although the reaction proceeded
in a few minutes. The best results were obtained at
-15 ºC, at which point only one cycloadduct, 9, was ob-
tained in 74% yield after 15 minutes (Scheme 3). Part of
the starting material was recovered in the form of the a, b-
unsaturated ketone.
R=TBDPS
Figure 2
through its less hindered face with the alkoxy group situ-
ated at the “inside” position and the alkyl group almost
perpendicular to the plane of the diene and away from the
incoming aldehyde8 (this makes the approach unlike). The
Lewis acid coordinated to the oxygen atom is located in
the exo position9 and trans to the acetonide, making the
approach endo-Cram to the carbonyl. In this transition
state, all steric repulsions are minimized, and the stere-
ochemical outcome of the reaction should provide the re-
quired trans, syn, trans relative dispositions of the groups
around the oxygen atom of the ether.
TBDPSO
SO2pTol
H
O
BF3.Et2O
TBDMSO
H
8 +
2
SO2pTol
CO2Et
SO2pTol
OH
SO2pTol
a
b, c
O
O
O
O
9
3
5
4
Scheme 3
d,e,b
TBDPSO
TBDMSO
SO2pTol
i, j
TBDPSO
SO2pTol
The high selectivity and good yield of the reaction seems
to indicate that the reactants used are the matched pair of
the double diastereoselective reaction. At this point, it was
difficult to establish the configuration of the newly creat-
ed chiral centres due to the unstable nature of the adduct,
but since our goal was to prepare a cyclic ether, we decid-
ed to continue the synthesis and verify the stereochemistry
in the final product. From our experience, the relative dis-
position of the substituents in the cyclic ether can be easily
assigned by using nOe experiments. The transformation
of the adduct 9 into the oxocane 13 was carried out as
shown in Scheme 4. The transformations depicted in
Scheme 4 are similar to those used in our previous work,3
except that in this synthesis, each hydroxyl was protected
with a different group to differentiate them and allow fur-
ther elaboration of the final product, for instance to pre-
pare a polycyclic compound. The cyclization step was
carried out in THF at -65 ºC using 4 equivalents of LDA,
yielding 71% of the desired compound 13 with an oxo-
cane skeleton, as a single isomer, as determined by a spec-
troscopic analysis.13
SO2pTol
f, g, h
HO
O
O
O
8
7
6
a) EtO2CCH2P(O)(OEt)2, HNa, THF, 0ºC (74%); b) DIBALH, Et2O,
-70ºC (90%); c) Ti(OPr-i)4, (-)-DIPT, BuOOH, CH2Cl2, Molecular
t
sieves 3Å (84%); d) Ti(OPr-i)4, PhCO2H, CH2Cl2, (73%); e) DMP,
DMSO, pTsOH, (e+b, 98%); f) TBDPSCl, Imidazole, CH2Cl2,
(92%); g) CSA, MeOH, 0ºC (78%); h) NaIO4, nBu4NIO4, MeOH,
H2O; i) CH3COCH2P(O)(OEt)2, NaH, THF, 0ºC (85%, 2 steps); j)
TBDMSOTf, Et3N, 0ºC to r. t. (84%).
Scheme 2
In order to check the viability of our retrosynthetic analy-
sis, and whether the reaction proceeds with the required
sense of induction, we decided to carry out the synthesis
of an oxocane skeleton, and for this the diene needs to
have a three carbon chain (Scheme 1). The required diene
was prepared as shown in Scheme 2. Aldehyde 33b was
transformed into an allylic alcohol by the sequence: Wit-
tig-Horner reaction, yielding 4, and reduction with
DIBALH. The asymmetric induction was performed by a
Sharpless asymmetric epoxidation reaction10 which gave
5 in greater than 95% yield.11 Epoxide 5 was then opened
with benzoic acid and Ti(OPr-i)4.12 The resulting diol was
protected as the acetonide, and the benzoate was removed
The nOe data (ROESY and noediff experiments) showed
the correlations indicated in Scheme 4 for 13, clearly indi-
cating that the relative stereochemistry is the expected
trans, syn, trans, and that the cycloaddition step took
place as anticipated through the combination of endo-
Synlett 2001, No. 1, 117–119 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Enantioselective Synthesis of a Tetrasubstituted Oxocane
119
(4) (a) Danishefsky, S. J.; Kobayashi, S.; Kerwin, J. F., Jr. J. Org.
Chem. 1982, 47, 1981-1983. (b) Danishefsky, S. J.; Pearson,
W. H.; Harvey, D. F.; Maring, C. J.; Springer, J. P. J. Am.
Chem. Soc. 1985, 107, 1256-1268.
Cram approach to the aldehyde and unlike approach to the
diene. It was not possible, however, to determine the ste-
reochemistry at the carbon atom bearing the sulfone group
due probably to the conformational flexibility of that part
of the molecule.
(5) (a) McDougal, P. G.; Rico, J. G.; VanDerveer, D. J. Org.
Chem. 1986, 51, 4492-4494. (b) Kozikowski, A. P.; Nieduzak,
T. R.; Konoike, T.; Springer, J. P. J. Am. Chem. Soc. 1987,
109, 5167-5175. (c) Barluenga, J.; González, F. J.; Fustero, S.;
García-Granda, S.; Pérez-Carreño, E. J. Org. Chem. 1991, 56,
4459-4463. (d) Bloch, R.; Chaptal-Gradoz, N. J. Org. Chem.
1994, 59, 4162-4169. (e) Adam, W.; Gläser, J.; Peters, K.;
Prein, M. J. Am. Chem. Soc. 1995, 117, 9190-9193.
(6) We follow Franck’s lead in utilizing this nomenclature; see:
Tripathy, R.; Franck, R. W.; Onan, K. D. J. Am. Chem. Soc.
1988, 110, 3257-3262.
TBDPSO
TBDPSO
HO
SO2pTol
SO2pTol
d, e
H
O
H
O
MOMO
HO
a, b, c
9
H
H
MeO2C
O
O
11
O
10
O
(7) Hu, Y-J.; Huang, X-D.; Yao, Z-J.; Wu, Y-L. J. Org. Chem.
1998, 63, 2456-2461.
f, g, h, i
(8) (a) Houk, K. N.; Moses, S. R.; Wu, Y-D.; Rondan, N. G.;
Jäger, V.; Schohe, R.; Fronczek, F. R. J. Am. Chem. Soc. 1984,
106, 3880-3882. (b) Kahn, S. D.; Hehre, W. J. Tetrahedron
Lett. 1985, 26, 3647-3650. (c) Kaila, N.; Franck, R. W.;
Dannenberg, J. J. J. Org. Chem. 1989, 54, 4206-4212.
(9) McCarrick, M. A.; Wu, Y-D.; Houk, K. N. J. Org. Chem.
1993, 58, 3330-3343.
SO2pTol
5
TBDPSO
MOMO
SO2pTol
TBDPSO
H
OH
H
j
3
H
7
O
H
8
2
O
OPiv
MOMO
H
PivO
H
O
(10) Katsuki, T.; Martín, V. S. In Organic Reactions; Paquette, L.
A.; et al. Eds.; Wiley: New York, 1996; Vol. 48, pp 1-299.
(11) The optical purities were determined by NMR spectroscopy of
the Mosher’s ester.
(12) (a) Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 1557-
1560. (b) Palazón, J. M.; Añorbe, B.; Martín, V. S.
Tetrahedron Lett. 1986, 27, 4987-4990.
12
13
a) O3, CH2Cl2, MeOH; b) NaBH4; c) CH2N2, Et2O (87% three steps);
d) MOMCl, Pr2NEt, 0ºC to r.t. (98%); e) DIBALH, Et2O, -60ºC
(94%); f) (CH3)3COCl, Py, 0ºC to r.t. (98%); g) CSA, MeOH, 0ºC to
r.t. (84%); h) TsCl, DMAP, Et3N, CH2Cl2; i) NaH, THF (85%, two
steps); j) LDA, THF, -65ºC (71%).
i
Scheme 4
(13) Procedure for the cyclization reaction: To a solution of 22 mg
(0.03 mmol) of 12 in 6 mL of THF at -65 ºC, were added
0.5 ml of a solution of LDA (0.24 M, 4 equiv.) in THF. When
no further progress was observed by TLC (15 min), 1 mL of
saturated aqueous solution of NH4Cl was added and the
reaction was allowed to reach room temperature. After
extraction with ether, concentration and flash column
chromatography (25% EtOAc in hexanes), 15.6 mg of 13 were
obtained as a clear oil (71% yield). Data for 13: 1H NMR
(400 MHz, CDCl3) d 1.06 (s, 9H, tBu), 1.17 (s, 9H, tBu), 1.65-
1.72 (m, 1H, -CH2-CH2OPiv), 1.82-1.94 (m, 2H, -CH2-
CH2OPiv, H6), 2.12 (dd, 1H, J = 8.4, 14.6 Hz, H4), 2.39-2.52
(m, 2H, H4’, H6’), 2.44 (s, 3H, CH3-ArSO2-), 2.95 (dd, 1H,
J = 6.7, 10.3 Hz, -CH2-OMOM), 3.01 (dd, 1H, J = 4.3, 10.3
Hz, -CH2-OMOM), 3.10 (s, 3H, CH3-O-), 3.52-3.55 (m, 1H,
H8), 3.68-3.72 (m, 1H, H2), 3.76-3.81 (m, 1H, H5), 3.88 (t,
1H, J = 5.9 Hz, H3), 4.02 (dd, 1H, J = 2.7, 2.7 Hz, H7), 4.08-
4.12 (m, 2H, -CH2OPiv), 4.28 (s, 2H, O-CH2-O), 7.28-7.70
(m, 14H, Ar). 13C NMR (100 MHz, CDCl3) d 19.1 (s), 21.5 (q,
CH3Ar), 26.9 (q, tBu), 27.1 (q, tBu), 29.9 (t, C6), 32.2 (t, C4),
33.2 (t, CH2CH2OPiv), 38.6 (s), 55.0 (q, CH3-O), 55.3 (d, C5),
61.1 (t, -CH2OPiv), 68.6 (t, CH2-OMOM), 72.3 (d, C3), 72.5
(d, C7), 80.7 (d, C2), 82.7 (d, C8), 96.2 (t, O-CH2-O), 127.8
(d, Ar), 129.7 (d, Ar), 130.0 (d, Ar), 130.1 (d, Ar), 132.1 (s,
Ar), 132.5 (s, Ar), 134.6 (s, Ar), 135.8 (d, Ar), 144.4 (s Ar),
178.5 (s, C=O).
The work reported herein demonstrates that medium sized
tetrasubstituted cyclic ethers can be prepared in enantio-
merically pure form through the synthetic scheme pro-
posed, making use of the double diastereoselective Diels-
Alder reaction. The opposite absolute stereochemistry can
be achieved by the use of the easily obtained enantiomers
of the aldehyde and diene. This work also presents new
evidence on the tendency of dienes bearing an allylic
chiral centre to react with aldehydes in an unlike manner.
Acknowledgement
Financial support of this work by the Ministerio de Educación y
Cultura (grant PB96-1041) and FEDER (1FD97-0747-C04-01) is
gratefully acknowledged.
References and Notes
(1) Faulkner, D. J. Nat. Prod. Rep. 1999, 16, 155-198. Faulkner,
D. J. Nat. Prod. Rep. 1998, 15, 113-158. Faulkner, D. J. Nat.
Prod. Rep. 1997, 14, 259-302. Faulkner, D. J. Nat. Prod. Rep.
1996, 13, 75-125 and previous reviews in this series.
(2) Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93, 1897-1909.
(3) (a) Mujica, M. T.; Afonso, M. M.; Galindo, A.; Palenzuela, J.
A. Synlett 1996, 983-984. (b) Mujica, M. T.; Afonso, M. M.;
Galindo, A.; Palenzuela, J. A. J. Org. Chem. 1998, 63, 9728-
9738.
Article Identifier:
1437-2096,E;2001,0,01,0117,0119,ftx,en;L16200ST.pdf
Synlett 2001, No. 1, 117–119 ISSN 0936-5214 © Thieme Stuttgart · New York