Synthesis of (-)-β conhydrine and analogues using N-Boc-2-acyl oxazolidine methodology and ring closing metathesis

Article abstract of DOI:10.1016/S0040-4039(00)00580-3

Two key-steps involving: (i) a stereoselective reduction of an N-Boc-2- acyl oxazolidine; and (ii) an RCM performed on enantiopure trans-3,4,5- trisubstituted oxazolidin-2-ones account for the synthesis of unsaturated bicyclic oxazolidin-2-ones with various sizes of ring. One of these bicyclic compounds was transformed into (-)β-conhydrin. An unsaturated and a dihydroxylated analogue of this alcaloid were also prepared from the same starting material. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00580-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 4113–4116
Synthesis of (−)-β conhydrine and analogues using N-Boc-2-acyl
oxazolidine methodology and ring closing metathesis
Claude Agami, François Couty ∗ and Nicolas Rabasso
Laboratoire de Synthèse Asymétrique associé au CNRS, Université Pierre et Marie Curie, 4 place Jussieu, 75005 Paris,
France
Received 19 February 2000; accepted 5 April 2000
Abstract
Two key-steps involving: (i) a stereoselective reduction of an N-Boc-2-acyl oxazolidine; and (ii) an RCM
performed on enantiopure trans-3,4,5-trisubstituted oxazolidin-2-ones account for the synthesis of unsaturated
bicyclic oxazolidin-2-ones with various sizes of ring. One of these bicyclic compounds was transformed into (−)-
β-conhydrin. An unsaturated and a dihydroxylated analogue of this alcaloid were also prepared from the same
starting material. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: oxazolidines; asymmetric synthesis; ring closing metathesis.
N-Boc-2-acyl oxazolidines 1, prepared either from commercialy available (R) or (S)-phenylglycinol
are recognized as useful chiral protected forms of 1,2-dicarbonyl compounds and were recently used by
our group for the asymmetric synthesis of homochiral 1,2-diols,1 amino acids2 or piperidinic alkaloids.3
It was indeed observed that reduction of the keto moiety adjacent to the heterocyclic ring occurs with
high diastereoselectivity and that the direction of the hydride attack can be chosen depending on the
nature of the reducing agent.
We wish to describe in this letter that this methodology can be used, combined with ring closing
metathesis (RCM),4 in order to provide a new access to piperidinic alkaloids, as exemplified by the
synthesis of (−)-β-conhydrin 2 (n=1) and analogous compounds.5
To this end, Weinreb amide 33 prepared from (S)-phenylglycinol was treated with ethylmagnesium
bromide (Scheme 1), to provide ethyl ketone 4. This crude ketone was then reduced with sodium boro-
∗
Corresponding author. Fax: (33) 1 44 27 26 20; e-mail: couty@ccr.jussieu.fr (F. Couty)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00580-3
tetl 16859

4114
hydride at −78°C to give α-hydroxy oxazolidine 5 showing a 86:14 isomeric ratio on the newly created
stereogenic center. Although stereoselectivity was quite modest, pure isomer 5 could be conveniently
isolated with an overall yield of 49% from 3. The same stereochemical course of NaBH4-mediated
reductions on similar substrates was explained on the basis of a Felkin–Ahn control.3 Oxazolidine 5 was
then treated with sodium hydride in THF in order to induce a transcarbamation and to provide bicyclic
heterocycle 6. This compound was then reacted with allyltrimethylsilane in the presence of TiCl4 and
gave allylated oxazolidinone 7 with a high stereoselectivity (98% de).6 Finally, reductive debenzylation
with a controlled amount of sodium7 gave diastereoisomerically pure oxazolidinone 8 in good yield.
Scheme 1. Reagents and conditions. a. Ethylmagnesiumbromide, Et2O, rt; b. NaBH4, EtOH, −78°C, 49% overall; c. NaH, THF,
reflux, 98%; d. allyltrimethylsilane, TiCl4, −78°C, CH2Cl2, 71%; e. Na (3.5 equiv.), EtOH, THF, NH3, 93%
From a mechanistical point of view, it should be pointed out that an attempt to prepare ent-8 from the
same Weinreb amide 3 (Scheme 2) was unsuccessful: although reduction of 4 with sodium borohydride
in the presence of CeCl3 occurred with the anticipated opposite diastereoselectivity,8 the intramolecular
nucleophilic attack in 5a to give bicyclic oxazolidinone 6a was not operative, probably because of a
severe steric crowding between the ethyl and the phenyl groups during the cyclization step.
Scheme 2. Reagents and conditions. a. NaBH4/CeCl3, EtOH, −78°C, 45% overall from 3; b. NaH, THF, reflux
In order to synthesize substrates for the ring closing metathesis, oxazolidinone 8 was transformed
into unsaturated compounds 9–12, and oxazolidine 7 was transformed into 13 (Scheme 3). The modest
yield obtained in the case of the preparation of compound 10 (alkylation of the sodium amide derived
from 6 with 4-bromo-1-butene) can be explained by a competitive elimination of the unsaturated
bromoalkene.These unsaturated oxazolidinones were then subjected to ring closing metathesis using
Grubb’s catalyst (4% molar ratio added in two portions in refluxing CH2Cl2 during 8 h). Whereas
oxazolidinones 9–11 gave the expected bicyclic heterocycles 14–16 in good yields, compound 12
sluggishly yielded 17 along with unreacted starting material and substrate 13 only gave intermolecular
reactions under forcing conditions.

4115
Scheme 3. Reagents and conditions. From 8; 9: NaH, DMF, C3H7Br, 74%; 10: NaH, DMF, C4H9Br, 42%; 11: NaH, DMF,
C5H10Br, 72%; 12: EtMgBr, THF, ClCH2CH2COCl, then Et3N, CH2Cl2 67%. From 7; 13: (i) SOCl2, THF (ii) DBU, CH2Cl2,
79%
Compared to oxazolidinones 9–11, the lower reactivity of substrate 12 towards RCM can be explained
on the basis of a conformational analysis. In fact, AM1 calculations show that conformer A of 12 is ca. 5
kcal mol−1 more stable than the reactive conformer B, probably because of a dipolar repulsion between
C_O moieties, thus lowering the population of the reactive conformer (Scheme 4). Notwithstanding,
attempts to use a Lewis acid (Ti(Oi-Pr)4, 20% molar ratio)9 in order to increase the population of
conformer by chelation with the C_O moieties only led to degradation products.
Scheme 4.
The reactivity of bicyclic urethane 14 was then briefly examinated (Scheme 5).10 It was observed
that its hydrogenation gave quantitatively 18 which was hydrolyzed to give (−)-β-conhydrine 2. On the
other hand, basic hydrolysis of 14 furnished the conhydrine unsaturated analogue 19. Dihydroxylation
of 14 was highly stereoselective yielding, albeit in modest isolated yield, compound 20 as a unique
stereoisomer, whose structure was secured by an X-ray radiocrystallography. The stereoselectivity of
this dihydroxylation can be easily understood by considering the spatial structure of 12, which shows a
less crowded exo diastereoface (Fig. 1).
Scheme 5. Reagents and conditions. a. Pd/C, EtOH, 92%; b. LiOH, EtOH, THF, reflux, 45% (2), 54% (19); c. OsO4, NMO,
acetone/water, 45%

4116
Fig. 1. Chem3D view of compound 14 showing the preferred exo dihydroxylation
Compound 20 belongs to the class of azasugars, intensively studied because of the biological activities
displayed by some of its members. Interestingly, recently reported hydroxylated 2-oxaindolizidines
related to 20 were found to be highly selective inhibitors of glycosidases.11
In summary, the strategy reported above provides a new entry for the synthesis of hydroxylated
piperidinic alkaloids and efforts are ongoing in our laboratory in order to synthesize other representative
targets belonging to this class of compounds.
Acknowledgements
The authors thank Dr. Jacqueline Vaisserman (Université P. et M. Curie) for the X-ray radiocrystallo-
graphic analysis performed on compound 20.
References
1. Agami, C.; Couty, F.; Lequesne, C. Tetrahedron 1995, 51, 4043–4056.
2. Agami, C.; Couty, F.; Mathieu, H. Tetrahedron Lett. 1996, 37, 4000–4002.
3. Agami, C. Couty, F.; Lam, H.; Mathieu, H. Tetrahedron 1998, 54, 8783–8796.
4. For some exemples of RCM applied to the synthesis of nitrogen heterocycles, see: (a) Martin, S. F.; Yusheng, L.; Chen, H.
J.; Pätzel, M.; Ramser, M. Tetrahedron Lett. 1994, 35, 6005–6008 (b) Huwe, C. M.; Blechert, S. Tetrahedron Lett. 1995, 36,
1621–1624 (c) Rutjes, F. P. J. T.; Schoemaker, H. E. Tetrahedron Lett. 1997, 38, 677–680 (d) Sauriat-Dorizon, H.; Guibé,
F. Tetrahedron Lett. 1998, 39, 6711–6714.
5. For an asymmetric synthesis of (+)-β-conhydrine see: Ratovelomanana, V.; Royer, J.; Husson, H. P. Tetrahedron Lett. 1985,
32, 3803–3806.
6. Agami, C.; Amiot, F.; Couty, F.; Dechoux, L.; Kaminsky, C.; Venier, O. Tetrahedron: Asymmetry, 1998, 9, 3955–3958.
7. The use of an excess of sodium (10 equiv.) surprisingly led to a partial reduction of the alkene moiety.
8. The same configuration was assigned to similar substrates on the basis of a chelated model (see Ref. 3).
9. Dirat, O.; Vidal, T.; Langlois, Y. Tetrahedron Lett. 1999, 40, 4801–4802.
10. All new compounds gave satisfactory analytical data. Selected data for 14: Rf: 0.39 (ether/petroleum ether: 70/30); GC
(OV17, rate 10°C/mn, 100 to 220°C): tr 6.73 mn (98%); [α]D20+3 (c 0.5, CHCl3); 1H NMR: 0.96 (t, J=7, 3H), 1.65–1.78
(m, 2H), .14–2.23 (m, 2H), 3.34 (quint, J=7, 1H), 3.56–3.65 (m, 1H), 3.98–4.08 (m, 2H), 5.69–5.78 (m, 2H); 13C NMR:
9.4, 27.7, 30.4, 41.2, 55.5, 83.1, 125.5, 124.2, 157.4. Anal. calcd For C9H13O2N, C, 64.65; H, 7.84; N, 8.33. Found. C,
65.04; H, 7.72; N, 8.02.
11. Diaz Pérez, V. M.; Garcia Moreno, M. I.; Ortiz Mellet, C.; Fuentes, J.; Diaz Arribas, J. C.; Cañada, F. J.; Garcia Fernandez,
J. M. J. Org. Chem. 2000, 65, 136–143.