Oxabicyclo[3.2.1]octenes in Organic Synthesis - Direct Ring Opening of Oxabicyclo[3.2.1] Systems Employing Silyl Ketene Acetals in Concentrated Solutions of Lithium Perchlorate-Diethyl Ether: Application to the Synthesis of the C(19)-C(27) Fragment of Rif

Article abstract of DOI:10.1021/ol0003836

(Matrix Presented) The direct opening at the bridgehead of oxabicyclo[3.2.1]octenes employing silyl ketene acetals in 4.0-5.0 M lithium perchlorate in diethyl ether has been realized, which gives rise to highly functionalized cycloheptadienes that can be

Full text of DOI:10.1021/ol0003836

ORGANIC
LETTERS
2001
Vol. 3, No. 3
481-484
Oxabicyclo[3.2.1]octenes in Organic
SynthesissDirect Ring Opening of
Oxabicyclo[3.2.1] Systems Employing
Silyl Ketene Acetals in Concentrated
Solutions of Lithium Perchlorate−Diethyl
Ether: Application to the Synthesis of
the C(19)−C(27) Fragment of
Rifamycin S
Kevin W. Hunt and Paul A. Grieco*
Department of Chemistry and Biochemistry, Montana State UniVersity,
Bozeman, Montana 59717
grieco@chemistry.montana.edu
Received December 15, 2000
ABSTRACT
The direct opening at the bridgehead of oxabicyclo[3.2.1]octenes employing silyl ketene acetals in 4.0−5.0 M lithium perchlorate in diethyl
ether has been realized, which gives rise to highly functionalized cycloheptadienes that can be further manipulated for use in natural product
synthesis. The bridgehead opening reaction has been employed in the construction of the C(19)−C(27) fragment of Rifamycin S.
The use of rigid oxabicyclo[3.2.1]octenes as stereochemical
control vehicles in organic synthesis has received only limited
attention despite the potential such ring systems hold for
those engaged in natural products synthesis. Despite the
reported successes employing 8-oxabicyclo[3.2.1]octenes,1,2
where stereochemical information built into the oxabicyclo-
[3.2.1] system was transformed into acyclic and cyclic
molecules rich in stereogenic centers, efforts to selectively
introduce substituents into the bridgehead positions have met
with no success. Lautens2,3 recognized the importance of
carrying out such transformations; however, he has shown
that the predominant mode of attack in such systems is SN2′
syn. We detail below a solution to this problem featuring
the direct bridgehead opening of oxabicyclo[3.2.1]octadienes
(cf. 1) with 1-methoxy-1-(tert-butyldimethylsiloxy)-ethylene
in 4.0-5.0 M lithium perchlorate-diethyl ether (LPDE).4,5
(3) Lautens, M. Pure Appl. Chem. 1992, 64, 1873. Woo, S.; Keay, B.
A. Synthesis 1996, 669.
(4) For the use of highly polar media to promote organic reactions, see:
Grieco, P. A.; Nunes, J. J.; Gaul, M. D. J. Am. Chem. Soc. 1990, 112,
4595. Grieco, P. A. Aldrichimica Acta 1991, 24, 59. Grieco, P. A. Organic
Chemistry in Lithium Perchlorate/Diethyl Ether. In Organic Chemistry: Its
Language and Its State of the Art; Kisaku¨rek, V., Ed.; VCH: Basel, 1993;
p 133.
(1) (a) White, J. D.; Fukuyama, Y. J. Am. Chem. Soc. 1979, 101, 226.
(b) Rama Rao, A. V.; Yadav, J. S.; Vidyasagar, V. J. Chem. Soc., Chem.
Commun. 1985, 55. (c) Lautens, M.; Belter, R. K. Tetrahedron Lett. 1992,
33, 2617.
(2) Lautens, M. Synlett 1993, 177.
10.1021/ol0003836 CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/17/2001

The ready availability6 of strained bicyclic molecules such
as 8-oxabicyclo-[3.2.1]octene 3 makes them useful templates
for organic synthesis. In this regard, we set out to effect ring
opening at the bridgehead of oxabicyclic compounds such
as 3 in hopes of further exploiting these highly functionalized
systems for use in natural products synthesis. Whereas it has
been previously shown the treatment of 3 with n-butyllithium
in ether/pentane (1:1) at 0 °C gives rise to the SN2′ syn
product 4 exclusively,7 exposure of 3 to a silyl ketene acetal
in 5.0 M LPDE provided only recovered starting material.
Employment of traditional Lewis acids (boron trifluoride
etherate, titanium tetrachloride, magnesium bromide) returned
only 3 or resulted in loss of the silyl protecting group.
Examination of molecular models reveals that overlap of the
σ* orbital of the carbon-oxygen bond of the oxa bridge with
the π system of the olefin is minimal. It appeared that
introduction of an additional π system (cf. 1) would give
rise to enhanced overlap with the σ* orbital and thus render
the process more favorable.
The selectivity of the bridgehead addition proved to be
substrate-dependent. As illustrated in Table 1, the facial bias
ranges from exclusive R attack to being completely non-
selective. In three of the five examples cited in Table 1, 5.0
M LPDE was employed because the reaction rates in 4.0 M
LPDE were sluggish. In view of the stereochemical outcome
of the reactions depicted in Table 1, it is unclear what type
of mechanism is operational. The observation that the tert-
butyldimethyl silyl ether 3 fails to react may well suggest
the intermediacy of an extended oxocarbenium ion such as
6.
Whereas substrate 3 proved to be unreactive in 5.0 M
LPDE, exposure of silyl enol ether 7, lacking the ∆6,7 olefin,
to 1-methoxy-1-(tert-butyldimethylsiloxy)ethylene in 4.0 M
LPDE afforded, after 1 h at ambient temperature, a 98% yield
of 8 and 9 in a ratio of 10:1.
Thus, treatment of silyl enol ether 1, generated [LDA,
THF, HMPA, TBSCl] in near quantitative yield from ketone
5,8 with 2.0 equiv of 1-methoxy-1-(tert-butyldimethylsiloxy)-
ethylene in 5.0 M LPDE at ambient temperature provided
substituted cycloheptadienes 2a and 2b in a ratio of 4:1 in
quantitative yield.9 This ratio could be improved to 4.8:1 by
performing the reaction in 4.0 M LPDE at 0 °C. Further
attempts to improve the selectivity by attenuating the solvent
polarity by using 3.0 M LPDE and 3.0 M lithium perchlo-
rate-ethyl acetate were unsuccessful and led to incomplete
conversion. Traditional Lewis acids gave rise to recovered
starting material or ketone 5.
The operational simplicity of the bridgehead opening
reactions, coupled with the ready availability of oxabicyclo-
[3.2.1]octenones, prompted us to demonstrate the utility of
this methodology by transformation of cycloheptadienyl ester
2a into the C(19)-C(27) fragment 10 of Rifamycin S (11).
(5) For the direct bridgehead opening of a 2-methylthio-7-oxabicyclo-
[2.2.1]hept-2-ene derivative with a silyl ketene acetal in the presence of
TBSOTf and 4 Å MS, see: Yamamoto, I.; Narasaka, K. Chem. Lett. 1995,
1129.
(6) Herter, R.; Fo¨hlisch, B. Synthesis 1982, 976. Takaya, H.; Makino,
S.; Hayakawa, Y.; Noyori, R. J. Am. Chem. Soc. 1978, 100, 1765. Hoffmann,
H. M. R. Angew. Chem., Int. Ed. Engl. 1984, 23, 1.
(7) Lautens, M.; Belter, R. K. Tetrahedron Lett. 1992, 33, 2617.
(8) Ashcroft, M. R.; Hoffmann, H. M. R. Org. Synth. 1978, 58, 17.
482
Org. Lett., Vol. 3, No. 3, 2001

Table 1. Ring Opening of Oxabicyclo[3.2.1] Systems Employing Silyl Ketene Acetalsa
a All reactions were performed 0.2 M in substrate in 4.0 or 5.0 M LPDE at ambient temperature employing 2.0 equiv of silyl ketene acetal. b Method A:
4.0 M LPDE. Method B: 5.0 M LPDE. c Isolated yields.
Exposure of cycloheptadienyl ester 2 to tetra-n-butyl-
ammonium fluoride (HOAc, THF, 60 h) provided (98%)
cycloheptenone 12 (Scheme 1), which upon reduction,
iodolactonization, and deiodination afforded bicyclic lactone
13 in 80% overall yield. Selective silylation of the C(25)
hydroxyl, followed by dianion formation and alkylation with
methyl iodide, gave rise to 14 as the sole product. Benzy-
lation of the hindered C(23) hydroxyl and subsequent
reduction of the lactone carbonyl provided diol 15, which
upon silylation of the primary hydroxyl, Ley oxidation,10 and
desilylation generated hemiketal 16. Direct subjection of
hemiketal 16 to Baeyer-Villiger oxidation conditions11,12
followed by exposure of the resulting lactones to potassium
(10) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem.
Soc., Chem. Commun. 1987, 1625. Griffith, W. P.; Ley, S. V. Aldrichimica
Acta 1990, 23, 13.
(9) The structure of 2a was confirmed by conversion of 2a into the
crystalline p-bromobenzoate i, whose structure was confirmed by single-
crystal X-ray analysis.
(11) Hunt, K. W.; Grieco, P. A. Org. Lett. 2000, 2, 1717.
(12) Attempts to perform the Baeyer-Villiger oxidation on ketone ii or
similar substrates met with no success (see ref 11).
Org. Lett., Vol. 3, No. 3, 2001
483

Scheme 1a
a Conditions: (a) LiAl(O-t-Bu)3H, THF, -20 °C, 20 h; (b) NaOH, THF, MeOH, H2O; CO2; KI/I2, 0 °C; (c) Bu3SnH, THF, AlBN, 60
°C, 2 h; (d) TBSOTf, 2,6-lutidine, CH2Cl2; (e) LDA, THF, MeI, 0 °C; (f) KH, 18-C-6, BnBr, Bu4NI, DMF, -10 °C, 1 h; (g) LiBH4, THF,
36 h; (h) TESCl, 2,4,6-collidine, CH2Cl2, -78 °C, 30 min; (i) TPAP, NMO, CH2Cl2, 4 h; (j) TBAF, HOAc, THF; 0 °C, 12 h; (k) MCPBA,
CH2Cl2, 4 h; (l) K2CO3, MeOH, 0 °C, 1 h; (m) 2,2-DMP, PPTS, DMF, 4 h; (n) LDA, THF, MeI, -78 f -5 °C, 1 h; (o) H2, 10% Pd/C,
absolute EtOH, 6 h; (p) 2,2-DMP, PPTS, CH2Cl2, 12 h; (q) LiAlH4, Et2O, 1 h.
carbonate in methanol gave rise to ester 17. Acetonide
formation and subsequent installation of the C(20) methyl
group employing the Fra´ter-Seebach protocol13 provided 18
as a single diastereomer. This remarkably selective alkylation
can be rationalized by chelation of the benzyloxy group to
form the rigid bicyclic structure 19.14 Cleavage of the benzyl
ether, followed by acetonide formation and reduction of the
ester afforded the C(19)-C(27) fragment of Rifamycin S.
The spectra of 10 were identical in all respects with those
reported in the literature.15
Acknowledgment. This investigation was supported by
a Public Health Service research grant from the National
Institute of General Medical Sciences (GM 33605).
Supporting Information Available: 1H and 13C NMR
spectra for 1, 2a, 2b, 7, 8, 10, 12-15, 17, 18, i, ii and ring-
opened products from Table 1. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL0003836
(13) Fra´ter, G. HelV. Chim. Acta 1979, 62, 2825. Seebach, D.; Wasmuth,
D. HelV. Chim. Acta 1980, 63, 197.
(14) A similar substrate capable of forming this type of rigid structure
also provided a single alkylation product; see: Williams, D. R.; Rojas, C.
M.; Bogen, S. L. J. Org. Chem. 1999, 64, 736.
(15) Nagaoka, H.; Rutsch, W.; Schmid, G.; Iio, H.; Johnson, M. R.; Kishi,
Y. J. Am. Chem. Soc. 1980, 102, 7962. Iio, H.; Nagaoka, H.; Kishi, Y. J.
Am. Chem. Soc. 1980, 102, 7965. Nagaoka, H.; Kishi, Y. Tetrahedron 1981,
37, 3873. Harada, T.; Kagamihara, Y.; Tanaka, S.; Sakamoto, K.; Oku, A.
J. Org. Chem. 1992, 57, 1637.
484
Org. Lett., Vol. 3, No. 3, 2001