Remarkable selectivity in addition of alcohols to epoxydienes of 5,7 bicyclic and 5,7,6 tricyclic systems

Article abstract of DOI:10.1021/jo0481295

(Chemical Equation Presented) Acid-catalyzed addition of alcohols to tricyclic dienyl epoxides such as 4 or bicyclic vinyl oxiranes such as 17 exclusively occurred at the vinyl terminus of unsaturated system through a typical S_N2′ process affording 1,6- and 1,4-dioxygenated derivatives, respectively.

Full text of DOI:10.1021/jo0481295

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
SCHEME 1
Remarkable Selectivity in Addition of
Alcohols to Epoxydienes of 5,7 Bicyclic and
5,7,6 Tricyclic Systems
Franc¸ois-Didier Boyer† and Issam Hanna*,‡
Unite´ de Phytopharmacie et Me´diateurs Chimiques, INRA,
Versailles, France, and Laboratoire de Synthe`se Organique
associe´ au CNRS, Ecole Polytechnique, Palaiseau, France
hanna@poly.polytechnique.fr
Received October 22, 2004
Acid-catalyzed addition of alcohols to tricyclic dienyl epoxides
such as 4 or bicyclic vinyl oxiranes such as 17 exclusively
occurred at the vinyl terminus of unsaturated system
through a typical SN2′ process affording 1,6- and 1,4-
dioxygenated derivatives, respectively.
Vinyl epoxides are versatile building blocks in organic
synthesis, and their behavior as electrophiles is well
documented.1 Nucleophilic addition to these substrates
may occur at the vinyl terminus through a typical
conjugated addition (1,4 or SN2′ process) and/or at the
allylic position through a direct 1,2-addition (SN2 pro-
cess).2 While transition-metal-catalyzed reactions prefer-
ably proceed via an SN2′ process affording 1,4-adducts,3,4
in the presence of Lewis acid, carbon and oxygen nucleo-
philes add in a 1,2-manner, presumably because of their
ability to coordinate to the oxirane oxygen to help deliver
the nucleophile to the adjacent carbon.5
Recently, we described a concise formal synthesis6 of
guanacastepene A (1), an antibacterial diterpenoid natu-
ral product with a novel carbon skeleton.7-9 Our approach
was based on the simultaneous construction of the seven-
and six-membered rings through a tandem ring-closing
metathesis (RCM), i.e., 2 f 3 (Scheme 1). Among the
issues that had to be addressed to complete the synthesis
of 1 was the stereoselective incorporation of oxygen
functionalities. In the course of this study, to our surprise,
we found that dienyl epoxide 4 underwent facile 1,6-
addition of alcohols through a SN2′ type process in the
presence of Lewis acid. In this reaction, palladium
catalyst is not required: simply stirring 4 in allyl alcohol
in the presence of catalytic ytterbium triflate [Yb(OTf)3]
† INRA.
‡ Ecole Polytechnique.
(1) Hudlicky, T.; Reed, J. W. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol.
5; p 931.
(6) Boyer, F.-D.; Hanna, I.; Ricard, L. Org. Lett. 2004, 6, 1817.
(7) Isolation and biological activity: (a) Brady, S. F.; Singh, M. P.;
Janso, J. E.; Clardy, J. J. Am. Chem. Soc. 2000, 122, 2116. (b) Brady,
S. F.; Bondi, S. M.; Clardy, J. J. Am. Chem. Soc. 2001, 123, 9900. (c)
Singh, M. P.; Janso, J. E.; Luckman, S. W.; Brady, S. F.; Clardy, J.;
Greenstein, M.; Maiese, W. M. J. Antibiot. 2000, 53, 256.
(8) Total and formal syntheses: (a) Tan, D. S.; Dudley, G. B.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2002, 41, 2185. (b) Lin, S.;
Dudley, G. B.; Tan, D. S.; Danishefsky, S. J. Angew. Chem., Int. Ed.
2002, 41, 2188. (c) Shi, B.; Hawryluk, N. A.; Snider, B. B.; J. Org.
Chem. 2003, 68, 1030.
(9) For recent synthetic studies related to guanacastepene, see, inter
alia: (a) Magnus, P.; Ollivier, C. Tetrahedron Lett. 2002, 43, 9605. (b)
Shipe, W. D.; Sorensen, E. J. Org. Lett. 2002, 4, 2063 (c) Nguyen, T.
M.; Seifert, R. J.; Mowrey, D. R.; Lee, D. Org. Lett. 2002, 4, 3959. (d)
Nakazaki, A.; Sharma, U.; Tius, M. A. Org. Lett. 2002, 4, 3363. (e)
Mehta, G.; Umarye, J. D.; Srinivas, K. Tetrahedron Lett. 2003, 44,
4233. (f) Du, X.; Chu, H. V.; Kwon, O. Org. Lett. 2003, 5, 1923. (g)
Brummond K. M.; Gao, D. Org. Lett. 2003, 5, 3491. (h) Hughes, C. C.;
Kennedy-Smith, J. J.; Trauner, D. Org. Lett. 2003, 5, 4113. (i)
Srikrishna, A.; Dethe, D. H. Org. Lett. 2004, 6, 168. (j) Chiu, P.; Li, S.
Org. Lett. 2004, 6, 613.
(2) For a recent example on the SN2 versus SN2′ addition of dithiane
anions to vinyl epoxides, see: Smith, A. B.; Pitram, S. M.; Boldi, A.
M.; Gaunt, M. J.; Sfouggatakis, C.; Moser, W. H. J. Am. Chem. Soc.
2003, 125, 14435.
(3) For leading references on palladium(0)-catalyzed reactions, see:
(a) Trost, B. M.; Molander, G. A. J. Am. Chem. Soc. 1981, 103, 5969.
(b) Tsuji, J.; Kataoka, H.; Kobayashi, Y. Tetrahedron Lett. 1981, 22,
257. For a review on SN2′ addition of organocuprates to vinyl epoxides,
see: Marshall, J. A. Chem. Rev. 1989, 89, 1503.
(4) For SN2′ palladium-catalyzed addition of alkoxides, see: (a)
Deardorff, D. R.; Myles, D. C.; MacFerrin, K. D. Tetrahedron Lett. 1985,
26, 5615. (b) Deardorff, D. R.; Myles, D. C. Organic Synthesis; Wiley
& Sons: New York, 1993; Collect. Vol. 8, p 13. (c) Trost, B. M.; Ito, N.;
Greenspan, P. D. Tetrahedron Lett. 1993, 34, 1421. (d) Snider, B. B.;
Hawryluk, N. A. Org. Lett. 2001, 3, 569.
(5) (a) For Lewis acid promoted SN2 addition of alkyllithiums, see:
Alexakis, A.; Vranken, E.; Mangenay, P.; Chemla, F. J. Chem. Soc.,
Perkin Trans. 1 2000, 3352. (b) For 1,2-addition of alcohols, see:
Prestat, G.; Baylon, C.; Heck, M.-P.; Mioskowski, C. Tetrahedron Lett.
2000, 41, 3829. (c) For rhodium-catalyzed 1,2-ring opening of vinyl
epoxides, see: Fagnou, K.; Lautens, M. Org. Lett. 2000, 2, 2319.
10.1021/jo0481295 CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/06/2005
J. Org. Chem. 2005, 70, 1077-1080
1077

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
troscopic data,12 and assignment of the relative config-
uration at C5, C8, and C14 was unambiguously estab-
lished on the basis of the following transformations.
Alcohols 8a and 9a were separately oxidized with Dess-
Martin’s periodinane reagent13 to ketones 10 and 11,
respectively, and the protecting silyl group was cleaved
to afford hydroxyketones 12 and 13.14 These compounds
are crystalline, and their structures were confirmed by
X-ray crystallographic analysis. In the same way, triene
7 furnished allyl ethers 8b and 9b albeit in lower yield
(37%).15 Thus, replacing the methyl group by OSiEt3 at
C8 has no effect on the regio- and stereoselectivity of the
reaction. As for 4, the stereochemical outcome of this SN2′
process is governed by the substituent at C8.
SCHEME 2
In an attempt to explore the effect of the ester group
at C4, triene 1411 was submitted to the above-described
conditions. As in preceding examples, oxidation of 14 with
m-CPBA at 0 °C in CH2Cl2 and saturated aqueous
NaHCO3 was chemo- and stereoselective producing a
mixture of two diastereomeric epoxides 15a and 15b as
deduced from NMR spectra. However, treatment of the
crude epoxide with allyl alcohol in the presence of
catalytic Yb(OTf)3 led to a mixture from which only one
isomer, alcohol 16, was isolated in low yield (19%).15
A
similar result was obtained with methanol as nucleophile.
Thus, removal of the electron-withdrawing ester group
presumably destabilizes the dienyl system and may
explain the low yield and the loss of the other isomer.
To gain insight into the effect of the cyclic structure,
we have designed vinyl epoxides allowing the selective
incorporation of alkoxy substituents into various bicyclic
frameworks. First epoxides derived from dienes 178c and
1816 were submitted to the conditions described above.
As shown in Scheme 3, while both substrates undergo
exclusively 1,4-addition, a reversal of stereoselectivity
was observed. In contrast to tricyclic epoxides, additions
occurred preferably anti to the leaving group producing
mainly trans 1,4-dioxygenated compounds. In the event,
addition of either methanol or allyl alcohol to the epoxide
derived from 17 in the presence of Yb(OTf)3 (1%) fur-
nished a 7:3 separable mixture of 19 (21) and 20 (22) in
68-76% overall yield. Roughly the same result was
obtained in the presence of catalytic cerium chloride.
Similarly, 18 gave diastereomers 23 (25) and 24 (26) in
for 1 h at room temperature produced a 3:2 separable
mixture of alcohols 5a and 6a in 56% overall yield from
3. Under these conditions none of the 1,2-adduct was
isolated. This reaction proceeded with high stereoselec-
tivity: the nucleophilic attack of alcohol took place
exclusively on the opposite face to the angular methyl
group at C8 (guanacastepene numbering). When metha-
nol was used instead allyl alcohol, 4 was converted to
5b and 6b (1:1.1 ratio) in 69% combined yield. To our
knowledge 1,6-addition of alcohols to epoxydiene such as
4 is hitherto unprecedented.10 This prompted us to
further investigate the scope of this reaction. We report
herein our finding.
(12) As for 5 and 6,6 diastereomers 8 and 9 exhibit strike differences
in their NMR spectra. In particular, while 9 showed sharp signals for
all carbon atoms, many of its diastereomer were broad or hardly
observed (see the Supporting Information).
(13) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. Meyer,
S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549.
(14) While cleavage of the silyl ether in 10 with TBAF in THF was
very easy (0 °C, 30 min, quantitative yield), complete conversion of 11
to 13 necessitated longer time and higher temperature (17 h, rt).
(15) The structure of 16 were deduced from its NMR spectra in
comparison with those 8 and 9 (see ref 12).
(16) 18 was prepared by the following sequence by analogy with 178c:
To assess the effect of substituents on the tricyclic
framework, trienes 7 and 14 were first studied. When
epoxide derived from 711 was treated with methanol in
the presence of CeCl3 or Yb(OTf)3 a similar transforma-
tion was observed providing 8a and 9a (Scheme 2). The
structure of these compounds was deduced from spec-
(10) For palladium-catalyzed alkylation of dienyl epoxides, see:
Trost, B. M.; Urch, C. J.; Hung, M.-H. Tetrahedron Lett. 1986, 27, 4949.
(11) Boyer, F.-D.; Hanna, I. Tetrahedron Lett. 2002, 43, 7469.
Details concerning the preparation of bicylic dienes 27 and 30 will be
reported shortly.
1078 J. Org. Chem., Vol. 70, No. 3, 2005

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
SCHEME 3
membered ring was replaced with a six membered-ring
as in diene 30. In this case, both 1,4- and 1,2-addition
products 31 and 32, respectively, were obtained in a 2.5:1
ratio. The structure of the major regioisomer was deduced
from its spectroscopic data and confirmed by its oxidation
to the corresponding R,â-unsaturated ketone 33 (νmax
1685 cm-1).
Lewis acid catalyzed addition of alcohols to simple
vinyloxiranes such as isoprene monooxide 34 and cyclo-
hexadiene monooxide 35 proceeded mainly via an SN2
process. While 34 led exclusively to 1,2-addition product
36,18 cyclic epoxide 35 gave a mixture of 3,4- and 3,6-
dioxygenated cyclohexenes 37 and 38 (3:1), respectively,
in a 2.5:1 ratio (Scheme 3).19 These results are best in
accord with the known behavior of vinyl epoxides in the
presence of acids.
In summary, we have shown that, unlike simple
vinyloxiranes, Lewis acid catalyzed addition of alcohols
to tricyclic dienyl epoxides such as 4 or bicyclic vinyl
oxiranes such as 17 exclusively occurred at the vinyl
terminus of unsaturated system through a typical SN2′
process. This regioselectivity is the result of the domina-
tion of steric factors at the cyclopentene part which direct
the attack at the most remote end of the unsaturated
system. These findings bear directly on synthetic efforts
toward guanacastepene and highlight the variability of
region- and stereoselectivity of oxygen nucleophiles in
various triene monoepoxides.
Experimental Section
Representative Procedure for the Preparation
and the Ring Opening of Epoxides.
Allyl Ethers 5a and 6a. m-CPBA (80%, 80 mg) was
added to a biphasic mixture of 3 (116 mg, 0.369 mmol),
CH2Cl2 (1.5 mL), and saturated aqueous sodium bicar-
bonate (1.5 mL) at 0 °C. The heterogeneous mixture was
stirred vigorously for 30 min and then quenched with
saturated sodium sulfite (0.2 mL). The mixture was
stirred for 15 min while slowly warming to room tem-
perature. The CH2Cl2 layer was separated, and the
aqueous layer was extracted three times with CH2Cl2.
The combined organic layers were washed with saturated
NaHCO3 and brine, dried (MgSO4), and evaporated under
reduced pressure to give 132 mg of crude epoxide 4, which
was used without further purification in the next reac-
tion.
good overall yield. None of the 1,2-adducts were isolated
(Scheme 3). It is noteworthy that palladium-catalyzed
addition of oxygen nucleophiles to vinyl epoxide prepared
from 17 proceeded with the opposite stereoselectivity.17
Subjecting the vinyl epoxide derived from 27 to the
ring-opening conditions with methanol afforded 28 as a
mixture of stereoisomers, which upon oxidation led to R,â-
unsaturated ketone 29 as a mixture of two diastereomers
in a 1:1 ratio (Scheme 3). As with precedent examples,
a complete regioselectivity was observed: nucleophilic
attack occurred exclusively at the vinyl epoxide terminus.
However, lack of methyl and isopropyl groups in the
starting diene led to a complete loss of stereoselectivity.
In contrast to the above epoxides, the nucleophilic
addition regioselectivity was marginal when the five-
To a solution of the above crude in allyl alcohol (1.0
mL) was added at room temperature ytterbium triflate
hydrate [Yb(OTf)3] (3 mg, 4.8 µmol, 0.013 equiv). After
being stirred at room temperature for 1 h, allyl alcohol
was removed under reduced pressure and the residue
was purified by flash chromatography on silica gel
(EtOAc/PE 1:4). Concentration of the appropriate frac-
tions afforded 32 mg (22%) of 5a as colorless oils and 48
mg (34%) of 6a (major, more polar isomer). Allyl Ether
1
5a. Colorless oil. Rf: 0.35 (EtOAc/PE 1:4). H NMR: δ
(18) For 1,2-asymmetric additions of alcohols to isoprene mono-
epoxide, see: Trost, B. M.; McEachern, E. J.; Toste, F. D. J. Am. Chem.
Soc. 1998, 120, 12702.
(19) NMR spectra of 31 are identical to those described in ref 4c.
The regio- and stereochemistry of 33 was determined as follows:
oxidation of the inseparable mixture of diastereomers afforded a single
enone whose structure was deduced from spectroscopic data.
(17) In their study on the synthesis of guanacastepene, Snider and
co-workers reported preparation of an analogue to 20 (R ) OAc) using
palladium-catalyzed (Pd2dba3 and dppb) opening of the epoxide ring.8c
J. Org. Chem, Vol. 70, No. 3, 2005 1079

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
6.07 (br s, 1 H), 5.95-5.85 (m, 1 H), 5.23 (d, J ) 17.2 Hz,
1 H), 5.13 (d, J ) 10.3 Hz, 1 H), 4.55 (d, J ) 9.6 Hz, 1 H),
4.30 (t, J ) 5.9 Hz, 1 H), 4.09 (dd, J ) 12, 5.6 Hz, 1 H),
3.96 (dd, J ) 12, 5.6 Hz, 1 H), 3.72 (s, 3 H), 2.15-1.50
(m, 8 H), 1.43 (t, J ) 7.8 Hz, 1 H), 1.35-1.15 (m, 3 H),
1.14 (s, 3 H), 1.10-1.00 (m, 1 H), 0.98 (s, 3 H), 0.92 (d, J
) 6.6 Hz, 3 H), 0.85 (d, J ) 6.6 Hz, 3 H). 13C NMR: δ
169.0 (C), 155.6 (C), 149.6 (C), 135.4 (CH), 129.0 (C),
117.9 (CH2), 116.5 (CH), 73.6 (CH), 71.3 (CH2), 70.3 (CH),
53.3 (CH), 51.3(CH3), 48.8 (C), 41.0 (C), 38.0 (CH2), 36.3
(CH2), 36.2 (CH2), 35.9 (CH2), 30.6, 29.2, 24.1 (CH2), 23.3
H), 1.45-1.15 (m, 3 H), 1.04 (s, 3 H), 0.97 (d, J ) 6.6 Hz,
3 H), 0.94 (s, 3 H), 0.91 (d, J ) 6.6 Hz, 3 H). 13C NMR:
δ 135.5 (CH), 116.5 (CH2), 74.8 (br), 72.7 (br), 70.2 (CH2),
51.3 (CH3), 39.3, 37.5, 37.0, 36.6, 34.8, 29.7, 28.1, 23.7,
22.4. The remains of the carbons gave signals that were
too broad to be observed. IR (CCl4): 3612, 1720 cm-1
.
Acknowledgment. We gratefully thank Dr. Louis
Ricard (Ecole Polytechnique) for the X-ray structure
determination of compounds 12 and 13.
(CH3), 22.1 (CH3), 15.9 (CH3). IR (CCl4): 3612, 1720 cm-1
.
Supporting Information Available: Experimental pro-
cedure, characterization data of compounds 5, 6, 8-13, 16, 19-
23, 25, 29, and 33, X-ray analysis of 12 and 13, and copies of
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
Allyl Ether 6a. Colorless oil. Rf: 0.45 (EtOAc/PE 1:4).
1H NMR: δ 6.04 (br s, 1 H), 5.95-5.84 (m, 1 H), 5.23 (d,
J ) 17.2 Hz, 1 H), 5.13 (d, J ) 10.3 Hz, 1 H), 4.41 (br s,
1 H), 4.32 (br s, 1 H), 4.07 (dd, J ) 12, 5.6 Hz, 1 H), 3.99
(dd, J ) 12, 5.6 Hz, 1 H), 3.70 (s, 3 H), 2.15-1.50 (m, 10
JO0481295
1080 J. Org. Chem., Vol. 70, No. 3, 2005