Claisen rearrangement of allylic alcohols prepared through N-Boc-2-acyloxazolidine methodology. Application to the synthesis of trisubstituted cyclopropanes

Article abstract of DOI:10.1016/S0040-4039(00)01465-9

Stereodefined allylic alcohols prepared from a (R)-phenylglycinol-derived Weinreb amide undergo a Claisen rearrangement with a high level of stereocontrol. The produced N-Boc-2-alcenyloxazolidines can be either hydrolyzed to afford enantiomerically enriched enals or further epoxidized using a two-step sequence. The resulting epoxyoxazolidines can then be transformed into trisubstituted cyclopropanes. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01465-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8301–8305
Claisen rearrangement of allylic alcohols prepared through
N-Boc-2-acyloxazolidine methodology. Application to the
synthesis of trisubstituted cyclopropanes
Claude Agami, Franc¸ois Couty* and Gwilherm Evano
Laboratoire de Synthe`se Asyme´trique associe´ au CNRS, Universite´ Pierre et Marie Curie, 4 place Jussieu,
75005 Paris, France
Received 18 July 2000; accepted 1 September 2000
Abstract
Stereodefined allylic alcohols prepared from a (R)-phenylglycinol-derived Weinreb amide undergo a
Claisen rearrangement with a high level of stereocontrol. The produced N-Boc-2-alcenyloxazolidines can
be either hydrolyzed to afford enantiomerically enriched enals or further epoxidized using a two-step
sequence. The resulting epoxyoxazolidines can then be transformed into trisubstituted cyclopropanes.
© 2000 Elsevier Science Ltd. All rights reserved.
Keywords: oxazolidines; asymmetric synthesis; Claisen rearrangement; epoxidation.
(R)- or (S)-Phenylglycinol-derived allylic alcohols such as 2, bearing a Z or E stereodefined
alkenyl moiety are easily prepared through a well established methodology, starting from
Weinreb amide 11 (Scheme 1). These allylic alcohols were previously shown to be useful chiral
substrates for the synthesis of piperidinic amino acids.2
Scheme 1.
* Corresponding author. Fax: (33) 1 44 27 26 20; e-mail: couty@ccr.jussieu.fr
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01465-9

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In order to extend the use of N-Boc-2-acyl oxazolidines in asymmetric synthesis,3 we began to
study 1,3-chirality transfers performed on these allylic alcohols 2 and producing alkenyl
oxazolidines 3.4 The double bond of these compounds can indeed be epoxidized in a highly
stereoselective way prior to other chemical transformations5 (Scheme 2), thus allowing the
preparation of valuable homochiral synthons such as trisubstituted cyclopropanes.
Scheme 2.
The aim of this letter is to present our preliminary results with regard to the Claisen
rearrangement performed on alkenols 2, and the epoxidation of the resulting alkenyl oxazoli-
dines. This methodology ultimately allows the preparation of densely functionalized
cyclopropanes.
(Z)- and (E)-Alkenyl substrates 5–12 were prepared from Weinreb amide 1 following a
previously reported three-step procedure4 including: (i) addition of a lithium acetylide; (ii)
Zn(BH4)2-mediated reduction of the produced ynone and (iii) stereoselective reduction (using
Red-Al or an hydrogenation with Lindlar catalyst) of the alkyne moiety. Through this sequence,
unreported compounds 8, 11 and 12 were, respectively, obtained in 38, 80 and 48% overall
yields. Claisen rearrangement was performed on these compounds giving alkenyl oxazolidines
13–20 in good yields and with a high level of stereocontrol since no minor stereoisomer could
be detected in the crude reaction product (Scheme 3):
Scheme 3. Reagents and conditions: (a) CH3C(OEt)3, propionic acid (cat.), reflux, 3 h6d
This efficient 1,3-chirality transfer is controlled by the classical Zimmerman–Traxler transition
state6 and the configuration of the double bond of the starting alkenol determines the
configuration of the newly formed stereocenter. Yet this was verified through the sequence
depicted in Scheme 4. Oxidative cleavage of the alkenyl moiety in compound 15, followed by
reduction of the resulting aldehyde ester, gave diol 21. Determination of the configuration of
this known diol7 by examination of its optical rotation then confirmed the course of the chirality
transfer.

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Scheme 4. Reagents and conditions: (a) OsO4 (cat.), NaIO4, THF/H2O. (b) NaBH4, EtOH, 53% overall yield
The aldehydic moiety masked as an oxazolidine ring could be recovered starting from alkenyl
oxazolidines 14 and 18. To this end, N-Boc deprotection and mild hydrolysis gave the
corresponding enals that were reduced into allylic alcohols (−)-22 and (+)-ent-22 (Scheme 5).
Enantiomeric excesses of these alcohols were determined by chiral GC analysis (Chirasil-DEX-
CB, 160°C, tr of 9.6 and 10.7 mn, respectively, for (−)-22 and (+)-22) and found to be 98 and
93%, respectively. This demonstrates that little or no racemization occurs during these steps.
Scheme 5. Reagents and conditions: (a) CF3COOH, DCE. (b) THF, H2O. (c) NaBH4, CeCl3, 7H2O, EtOH, 0°C. 22:
72%; ent-22: 52%
We next examined the epoxidation of alkenyl oxazolidines 13, 14, 17 and 18 following our
previously described procedure5 that consists of bromocarbamation of the alkene, followed by
treatment of the resulting cyclic urethane with sodium ethoxide, as depicted in Scheme 6. As
previously reported with similar substrates,4 the configuration of the stereocenter set by the
Claisen rearrangement does not influence the stereochemical course of the bromocarbamation
process: urethanes 23–26 were in all cases obtained as unique stereoisomers. Relative configura-
1
tions of these urethanes were deduced from their H NMR data and were in accordance with
previous results.5,8 Epoxides 27–29 were then prepared in high yields from the corresponding
urethanes.
Scheme 6. Reagents and conditions: (a) NBS, DME/H2O. (b) EtONa/EtOH

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A further chemical transformation was then studied on these highly functionalized epoxides.
The epoxy esters 27–29 were transformed into their respective enolates by treatment with
LiHMDS; subsequent cyclization of these intermediates gave cyclopropanes 30–32 in good
yields and in a totally stereoselective way (Scheme 7). The stererochemistry of diastereoisomeric
cyclopropanes 30 and 32 was assigned on the basis of the values of the vicinal coupling
constants, as depicted in Scheme 8.9 Clearly, the configuration of the stereocenter created during
the Claisen rearrangement governs the stereochemical outcome of this intramolecular cyclo-
propanation: indeed, the carboethoxy moiety and the R group always show a trans relationship
in the product, and this is in accordance with previous results.10
Scheme 7. Reagents and conditions: (a) LiHMDS, THF, −50°C
Scheme 8.
Finally, treatment of the bicyclic urethane 23 with LiHMDS was examined: it led to
oxazoloazepinone 33 through an intramolecular opening of the urethane ring by the enolate,
instead of the expected intramolecular displacement of the bromine atom by the enolate (Scheme
9). In compound 33, the cis relationship between the released alkoxide and the halogen atom
prohibits its nucleophilic displacement to give the corresponding epoxide.
Scheme 9. Reagents and conditions: (a) LiHMDS, THF, −50°C, 61%
It should be noted that 33 is produced as a single diastereomer in which the configuration of
the newly created stereogenic center was not determined.
In conclusion, we have shown that Claisen rearrangements of allylic alcohols linked to a
N-Boc-oxazolidine ring provide a new access to enantiopure original chirons. Combined with a
diastereoselective epoxidation, this methodology allows the synthesis of trisubstituted cyclo-

8305
propanes. This work extends the scope of the use of N-Boc-acyloxazolidines in asymmetric
synthesis, and further applications of this methodology are under study in our group.
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9. All new compounds gave satisfactory analytical data. Selected data for 30: Rf: 0.45 (ether/petroleum ether: 60/40);
1
[h]2D0 +32 (c 1.3, CHCl3); IR (NaCl, film): 3420, 2955, 1680; H NMR: 0.00 (s, 6H), 0.83 (s, 9H), 1.07 (t, J=6.9,
3H), 1.12 (t, J=6.9, 3H), 1.47 (td, J=9 and 6, 1H), 1.75 (dd, J=9 and 5.2, 1H), 1.86 (broad quint, J=5.2, 1H),
3.53 (dd, J=10.7 and 5.2, 1H), 3.80 (dd, J=10.7 and 4.9, 1H), 3.85–4.09 (m, 6H), 4.21 (dd, J=8.7 and 7.2, 1H),
4.93 (t, J=6.6, 1H), 5.23 (d, J=7.2, 1H), 7.18–7.33 (m, 5H); 13C NMR: −5.2, 14.3, 14.4, 18.4, 22.4, 26.0, 27.0,
28.1, 60.5, 61.0, 62.4, 62.7, 70.7, 73.7, 93.1, 126.6, 127.7, 128.7, 139.7, 156.7, 173; anal. calcd for C26H41NO7Si,
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.