Versatile 8-oxabicyclo[3.2.1]oct-6-en-3-one: stereoselective methodology for generating C-glycosides, delta-valerolactones, and polyacetate segments.

Article abstract of DOI:10.1021/ol006737a

[figure: see text] A new rearrangement of functionalized methoxy glycosides and a regioselective as well as stereoselective intramolecular Michael addition giving delta-valerolactones and C-glycosides are described. Applications to the synthesis of marine

Full text of DOI:10.1021/ol006737a

ORGANIC
LETTERS
2001
Vol. 3, No. 2
177-180
Versatile
8-Oxabicyclo[3.2.1]oct-6-en-3-one:
Stereoselective Methodology for
Generating C-Glycosides,
δ-Valerolactones, and Polyacetate
Segments
A. Vakalopoulos and H. M. R. Hoffmann*
Department of Organic Chemistry, UniVersity of HannoVer, Schneiderberg 1B,
D-30167 HannoVer, Germany
hoffmann@mbox.oci.uni-hannoVer.de
Received October 16, 2000
ABSTRACT
A new rearrangement of functionalized methoxy glycosides and a regioselective as well as stereoselective intramolecular Michael addition
giving δ-valerolactones and C-glycosides are described. Applications to the synthesis of marine natural products are reported. Chemoselective
deprotection of benzylated hydroxy groups is assumed to be facilitated by 6-endo-tet interaction with the 1,3-dithiane functionality.
Marine natural products are of much current interest because
of their challenging stereochemistry and their high bioac-
tivity. In preceding papers we have targeted prominent
polyoxygenated marine metabolites using our oxabicyclic
concept with the aim of developing a unified synthetic
strategy.1 We now exemplify our approach with the synthesis
of the C11-C17 segment of macrolactin A,2 the C3-C11
segment of the phorboxazoles,3 the C1-C9 segment of
leucascandrolide A,4 and the C2-C8 segment of hennoxazole
A5 from a single precursor (Scheme 1).
These various polyketide segments are of the simple
polyacetate type,6 the stereocontrolled synthesis of which is
generally more challenging than that of polypropionates. Our
strategy is outlined in Scheme 1. The segments are cyclic
and of the tetrahydropyran type (phorboxazoles, leucascan-
drolide A, and hennoxazole A) and also acyclic as in
macrolactin A.
As starting material we chose 8-oxabicylo[3.2.1]oct-6-en-
3-one 2, which has to be elaborated into a suitable six-
membered ring ether and also into a polyol chain. The key
intermediate is methoxy acetal 1,7 in which the oxygenation
pattern and stereochemistry are already placed correctly for
the task at hand. Methoxy acetal 1 is a multiple aldol addition
equivalent and available in high chemical yield and enantio-
(1) (a) Beck, H.; Stark, C. B. W.; Hoffmann, H. M. R. Org. Lett. 2000,
2, 883 and references therein. (b) Misske, A. M.; Hoffmann, H. M. R. Chem.
Eur. J. 2000, 6, 3313.
(2) (a) Isolation: Gustafson, K.; Roman, M.; Fenical, W. J. Am. Chem.
Soc. 1989, 111, 7519. (b) Stereochemical determination: Rychnovsky, S.
D.; Skalitzky, D. J.; Pathirana, C.; Jensen, P. R.; Fenical, W. J. Am. Chem.
Soc. 1992, 114, 671. (c) Total syntheses: Smith, A. B.; Ott, G. R. J. Am.
Chem. Soc. 1996, 118, 13095. (d) Kim, Y.; Singer, R. A.; Carreira, E. M.
Angew. Chem. 1998, 110, 1321; Angew. Chem., Int. Ed. 1998, 37, 1261.
10.1021/ol006737a CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/29/2000

Scheme 1
meric purity from σ-symmetric title compound 2 (Scheme
2).8
to facilitate simultaneous deprotection7a,10 of the masked
hydroxy function. We discovered that the deprotective
opening in solvents more polar than dichloromethane is
feasible with BF3‚Et2O and 1,3-propanedithiol. Loss of the
PMB group is thought to be facilitated by 1,6-intramolecular
nucleophilic interaction of 1,3-dithiane sulfur (6-endo-tet, see
Table 1, i). In a structurally related case we found that
debenzylation also occurred with ease. Acyclic diol 4 and
functionalized δ-valerolactone 5 are formed in one step in a
single-flask reaction (Table 1). The opening and deprotection
worked best in acetonitrile. The conditions chosen (entry 5)
favored formation of lactone 5. After aqueous workup,
cyclization to the desired lactone 5 was completed by
addition of PPTS in CH2Cl2 (Table 1, footnote b). BF3‚Et2O
(1.1 equiv) also promotes the equilibration of 4 to 5, without
destroying diol ester 4.
Scheme 2a
a Reagents and conditions: (i) L-Selectride, perfusor, THF, -78
°C, 1 h, 82%; (ii) NaH, PMBCl, Bu4NI, THF, reflux, 6 h, 85%;
(iii) (+)-Ipc2BH, THF, -10 °C, 1 week, 85%, 96% ee; (iv) PCC,
CH2Cl2, rt, 5 h, 92%; (v), m-CPBA, CH2Cl2, rt, overnight, 96%;
(vi) MeOH, concentrated H2SO4 (catal.), rt, overnight, 91%.
At first sight the cascade 1 f 5 would seem to correspond
to no less than five classical steps: (i) reduction at C1 to
aldehyde, (ii) protection as thioacetal, (iii) deprotection at
The opening of methoxy acetals related to 1 has been
described previously.9 We chose the PMB protecting group
(6) Other recent stereoselective approaches to parent polyacetate aldol
patterns: Hale, K. J.; Hummersone, M. G.; Bhatia, G. S. Org. Lett. 2000,
2, 2189. Kiyooka, S.; Hena, M. A.; Yabukami, T.; Murai, K.; Goto, F.
Tetrahedron Lett. 2000, 41, 7511. Kiegiel, J.; Jo´zwik, J.; Wozniak, K.;
Jurczak, J. Tetrahedron Lett. 2000, 41, 4959. Bhattacharjee, A.; De
Brabander, J. K. Tetrahedron Lett. 2000, 41, 8069. Schwenter, M.-E.; Vogel,
P. Chem. Eur. J. 2000, 6, 4091. See also refs 2c, 2d, and 3d.
(7) (a) Wolbers, P.; Hoffmann, H. M. R.Tetrahedron 1999, 55, 1905.
(b) Dunkel, R.; Mentzel, M.; Hoffmann, H. M. R. Tetrahedron 1997, 53,
14929.
(3) (a) Isolation and structure determination: Searle, P. A.; Molinski,
T. F. J. Am. Chem. Soc. 1995, 117, 8126. (b) Searle, P. A.; Molinski, T. F.;
Brzezinski, L. J.; Leahy, J. W. J. Am. Chem. Soc. 1996, 118, 9422. (c)
Molinski, T. F. Tetrahedron Lett. 1996, 37, 7879. (d) Total Syntheses of
phorboxazoles: Evans, D. A.; Cee, V. J.; Smith, T. E.; Fitch, D. M.; Cho,
P. S. Angew. Chem. 2000, 112, 2633; Angew. Chem., Int. Ed. 2000, 39,
2533. (e) Evans, D. A.; Fitch, D. M. Angew. Chem. 2000, 112, 2636; Angew.
Chem., Int. Ed. 2000, 39, 2536. (f) Forsyth, C. J.; Ahmed, F.; Cink, R. D.;
Lee, C. S. J. Am. Chem. Soc. 1998, 120, 5597.
(8) Kim, H.; Hoffmann, H. M. R. Eur. J. Org. Chem. 2000, 2195 and
references therein.
(4) (a) Isolation and structure determination: Ambrosio, M. D.; Guerriero,
A.; Debitus, C.; Pietra, F. HelV. Chim. Acta 1996, 79, 51. (b) Synthetic
effort: Crimmins, M. T.; Carroll, C. A.; King, B. W. Org. Lett. 2000, 2,
597.
(5) (a) Isolation and structure: Ichiba, T.; Yoshida, W. Y.; Scheuer, P.
J.; Higa, T.; Gravalos, D. G. J. Am. Chem. Soc. 1991, 113, 3173. (b) Higa,
T.; Tanaka, J.; Kitamura, A.; Koyama, T.; Takahashi, M.; Uchida, T. Pure
Appl. Chem. 1994, 66, 2227. (c) Total syntheses: Wipf, P.; Lim, S. Chimia
1996, 50, 157 (including stereochemical determination). (d) Williams, D.
R.; Brooks, D. A.; Berliner, M. A. J. Am. Chem. Soc. 1999, 121, 4924.
(9) For some examples, see: (a) Meng, D.; Bertinato, P.; Balog, A.; Su,
D.-S.; Kamenecka, T.; Sorensen, E. J.; Danishefsky, S. J. J. Am. Chem.
Soc. 1997, 119, 10073. (b) Lampe, T. F. J.; Hoffmann, H. M. R. J. Chem.
Soc., Chem. Commun. 1996, 1931. (c) Nakata, T.; Nagao, S.; Takao, S.;
Tanaka, T.; Oishi, T. Tetrahedron Lett. 1985, 26, 73. (d) Nakata, T.; Nagao,
S.; Oishi, T. Tetrahedron Lett. 1985, 26, 75. (e) Nakata, T.; Takao, S.;
Fukui, M.; Takana, T.; Oishi, T. Tetrahedron Lett. 1983, 24, 3873.
(10) Deprotection of the benzyl group: (a) BF3‚Et2O/EtSH: Fuji, K.;
Ichikawa, K.; Node, M.; Fujita, E. J. Org. Chem. 1979, 44, 1661. (b) BF3‚
Et2O/NaI: Vankar, Y. D.; Rao, C. T. J. Chem. Res., Synop. 1985, 232.
178
Org. Lett., Vol. 3, No. 2, 2001

As a further reaction mode of methoxy acetal 1, we
homologated the ester to R,â-unsaturated ester 8 by Wittig
methodology (Table 2). Alternatively, ester 8 was obtained
Table 1. Cascade Lactonization of Methoxy Acetal 1
Table 2. Two-Carbon Homologation to R,â-Unsaturated Esters
8 and 9. Cyclization to THP Building Blocks trans-10 and
cis-10
ratio 4:5 isolated
(TLC yield
analysis)a of 5 [%]
BF3‚Et2O
entry [equiv]
conditions
1
2
3
5
7
4.5
MeNO2, -20 °C f rt, 2 h
MeCN, -20 °C f rt, 4 h
MeCN, -20 °C f rt, 4 h;
then TFA (5 equiv), rt,
20 min
1:5
1:5
1:6
31
41
50
a
NaH
yield
entry [equiv]
conditions
[%] tr a n s-10:cis-10b
1
2
3
4
4.3
3.0
3.0
2.5
-60 °C, 1.5 h; -5 °C, 2 h
45
52:48
68:32
80:20
75:25
4
5
3
1.1
MeCN, -20 °C f 0 ° C, 1 h
MeCN 0 °C, 0.5 h
1:1
1:9
61b
80b
-78 °C, 1 h; -25 °C, 22 h 56
-78 °C f 0 °C, 3 h
-60 °C f -5 °C, 6 h;
-5 °C, 2 h
48
74
a Before aqueous workup. b Aqueous workup, then PPTS (0.5 equiv),
CH2Cl2, rt, 1 h, and column chromatography.
5
2.2
-78 °C f -5 °C, 1 h;
-5 °C, 15 h
50
57:43
C5, (iv) deprotection at C7, and (v) oxidation at C7. Owing
to the hidden C2 symmetry of acyclic intermediates, the
termini of 5 and 1 are simply interchanged and are fully
differentiated with umpolung of one terminus. Lactone 5,
more so than methoxy acetal 1, is a suitable precursor of
the C2-C8 segment of hennoxazole A.
To obtain the acyclic building block from 1, the cyclization
4 f 5 was stopped by simply reducing the ester terminus (1
f 6, Scheme 3). Ring opening of acetal 6 by our protocol
6
7
8
9
10
2.2
2.1
1.0
1.0
0.2
-78 °C f 0 °C, 2.5 h
-78 °C f rt, 3 h; rt, 3 h
-40 °C f rt, 1 h; rt, 15 h 25
-40 °C f r t, 1 h ; r t, 7 h
rt, 8 h
78
20
81:19
2:98
2:98
2:98
60:40
61
90
a (i) DIBAH, CH2Cl2, 0.5 h, -78 °C, then Ph3PCHCO2Me, 16 h, rt,
73%; (ii) 1. Dess-Martin periodinane, CH2Cl2, 1 h, 0 °C, 87%; 2.
Ph3PCHCO2Me, CH2Cl2, rt, 18 h, 98%; (iii) 1.5 equiv of HS(CH2)3SH, 1.3
equiv of BF3‚Et2O, MeCN, 0 °C f rt, 0.5 h, 70%. b The relative
configuration at the new stereocenter was confirmed by NOE experiments.
by the three-step sequence 1 f 6 f 8 (84% overall yield).
Ring opening dithioketalization of 8 was accompanied by
deprotection of the PMB group, giving diol 9 without
subsequent cyclization. Further investigations afforded C-
glycosidic tetrahydropyrans containing three individual ste-
reocenters. Either trans-10 (entry 6, Table 3) or predomi-
nantly cis-1011 (entry 9) was obtained under basic12 Michael-
type conditions.13 All-equatorial cis-10 is assumed to be the
stereoisomer of thermodynamic control.
Scheme 3. Polyol 7 from Methoxy Acetal 1a
a Reagents and conditions: (i) LiAlH4, THF, 0 °C to rt, 1 h,
99%; (ii) 1.3 equiv HS(CH2)3SH, 4.5 equiv of BF3‚Et2O, MeCN,
-20 °C to rt, 2.5 h, 71%.
Mitsunobu inversion14 of alcohol cis-10 usually occurred
with intervention of the dithioacetal group, giving bicyclic
O,S-acetal 12.15 The conditions of entry 5 provided the
afforded the acyclic polyketide 7 of macrolactin A, again
with umpolung of polarity of one terminus.
(11) Acid-induced cyclization appears to give poorer cis:trans ratios:
Paterson, I.; Keown, L. E. Tetrahedron Lett. 1997, 38, 5727.
Org. Lett., Vol. 3, No. 2, 2001
179

as three fully differentiated nine-carbon polyacetate segments,
trans-10, cis-10,16 and 11, have been synthesized by efficient
chemistry and in high enantiomeric purity. All building
blocks can be used in the synthesis of marine natural
products.
Table 3. Mitsunobu Reaction of Alcohol cis-10 in the
Presence of a Dithiane Moiety
Acknowledgment. We thank the Deutsche Forschungs-
gemeinschaft, Volkswagen Foundation, and Fonds der Che-
mischen Industrie for their support and Ulrike Eggert for
her help.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data of the compounds 5-11. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL006737A
PPh3
entry [equiv]
conditions
yield 11 + 12 [%]
(12) Basic conditions in the cyclization to afford C-glycosides: (a)
Edmunds, A. J. F.; Trueb, W. Tetrahedron Lett. 1997, 38, 1009. (b)
Betancort, J. M.; Mart´ın, V. S.; Padro´n, J. M.; Palazo´n, J. M.; Ram´ırez, M.
A.; Soler, M. A. J. Org. Chem. 1997, 62, 4570. (c) Alvarez, E.; Candenas,
M.-L.; Pe´rez, R.; Ravelo, J. L.; Mart´ın, J. D. Chem. ReV. 1995, 95, 1953.
(d) Palazo´n, J. M.; Soler, M. A.; Ram´ırez, M. A.; Mart´ın, V. S. Tetrahedron
Lett. 1993, 34, 5467. (e) Evans, D. A.; Carreira, E. M. Tetrahedron Lett.
1990, 31, 4703. (f) Maurer, B.; Grieder, A.; Thommen, W. HelV. Chim.
Acta 1979, 62, 44.
1
2
3
4
5
1.6
5
10
10
14
1.6 equiv of DIAD, rt, 4 h
1.6 equiv of DIAD, rt, 3 h
2.0 equiv of DEAD, rt, 3 h
1.6 equiv of DBAD, rt, 5 h
2.0 equiv of DEAD, rt, 1 h
42 + 31
51 + 23
80 + 9
64 + n.d.a
85 + 0
a Not determined.
(13) The role of double bond geometry in controlling the diastereose-
lectivity in this type of Michael addition: Banwell, M. G.; Bui, C. T.; Pham,
H. T. T.; Simpson, G. W. J. Chem. Soc., Perkin Trans. 1 1996, 967.
(14) Modification of the Mitsunobu protocol for inversion of sterically
hindered secondary alcohols using p-nitrobenzoic acid: Martin, S. F.; Dodge,
J. A. Tetrahedron Lett. 1991, 32, 3017.
(15) The excess of PPh3 is assumed to suppress nucleophilic attack of
dithiane on DEAD and subsequent ring opening of 1,3-dithiane.
(16) (a) C11-C19 segment of 17-deoxyroflamycoin: Rychnovsky, S.
D.; Yang, G.; Hu, Y.; Khire, U. R. J. Org. Chem. 1997, 62, 3022. (b)
C-Glycoside unit of the hydrangenosides A-G: Uesato, S.; Takeda, Y.;
Hashimoto, T.; Uobe, K.; Inouye, H.; Taguchi, H.; Endo, T. HelV. Chim.
Acta 1984, 67, 2111 and references therein.
desired ester 11 in good yield (85%). Steric encumbrance
of azoester (DEAD, DIAD, DBAD) did not improve the
formation of 11. Tetrahydropyrans trans-10 and 11 serve as
the C3-C11 segment of the phorboxazoles and as the C1-
C9 segment of leucascandrolide A, respectively.
In summary, oxabicyclic precursor 2 and anomeric meth-
oxy acetal 1 are universal polyacetate building blocks. Two
deceptively simple seven-carbon segments, 5 and 7, as well
180
Org. Lett., Vol. 3, No. 2, 2001