Ring-closing metathesis of diolefinic oxazolidinones: A new access to tropanes and aminocyclitols

Article abstract of DOI:10.1016/S0040-4039(01)00830-9

Ring-closing metathesis of diolefinic oxazolidinones prepared through N-Boc-2-acyl or α,β-epoxy oxazolidine methodology give stereodefined bicyclic oxazolidinones. The 5,6-membered bicyclic oxazolidinones are then converted into new aminocyclitols by diastereoselective dihydroxylation whereas their 5,7-membered bicyclic homologues are transformed into tropanic alkaloids through an aminocyclization step.

Full text of DOI:10.1016/S0040-4039(01)00830-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4633–4635
Ring-closing metathesis of diolefinic oxazolidinones: a new access
to tropanes and aminocyclitols
Claude Agami, Franc¸ois Couty* and Nicolas Rabasso
Laboratoire de Synthe`se Asyme´trique associe´ au CNRS, Universite´ Pierre et Marie Curie, 4 place Jussieu, 75005 Paris, France
Received 30 April 2001; accepted 14 May 2001
Abstract—Ring-closing metathesis of diolefinic oxazolidinones prepared through N-Boc-2-acyl or a,b-epoxy oxazolidine method-
ology give stereodefined bicyclic oxazolidinones. The 5,6-membered bicyclic oxazolidinones are then converted into new
aminocyclitols by diastereoselective dihydroxylation whereas their 5,7-membered bicyclic homologues are transformed into
tropanic alkaloids through an aminocyclization step. © 2001 Elsevier Science Ltd. All rights reserved.
Owing to the introduction of efficient and easy to
handle catalysts, ring-closing metathesis (RCM) has
emerged as a powerful tool in organic synthesis, and
this reaction is now recognized as the cornerstone of
new strategies for the preparation of diverse classes of
compounds.1 In this rapidly expending area, we
recently reported the use of RCM combined with the
chemistry of N-Boc-2-acyloxazolidines for the synthesis
of piperidinic alkaloids.2 This work was based on the
RCM of enantiopure diolefinic oxazolidinones of gen-
eral structure 1. We wish to report in this Letter new
developments in this field, i.e. the synthesis and RCM
of diolefinic oxazolidinones of type 3, leading ultimately
to tropanes 4 or aminocyclitols 5 after further transfor-
Scheme 1.
Scheme 2. Reagents and conditions: (a) allylmagnesium chloride (7), but-4-enylmagnesium bromide (8), pent-5-enylmagnesium
bromide (9); (b) NaBH4, EtOH, −78°C, 59% overall (10), 84% overall (11), 67% overall (12); (c) NaH, THF, reflux, 68% (13), 95%
(14), 85% (15).
* Corresponding author. Tel.: (33) 1 44 27 30 13; fax: (33) 1 44 27 26 20; e-mail: couty@ccr.jussieu.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00830-9

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C. Agami et al. / Tetrahedron Letters 42 (2001) 4633–4635
mations of the resulting bicyclic adducts. These
molecules both belong to intensively studied families of
molecules, because of the biological activity frequently
displayed by their members (Scheme 1).
This last result is not surprising owing to the well-
known difficulty to build 8-membered rings by RCM.5
(Scheme 3).
An alternative strategy was fruitful for the preparation
of 5,6-membered bicyclic oxazolidinones. To this end,
N-Boc alkenyloxazolidine 22 was epoxidized following
our reported6 two-step sequence, and the resulting
epoxide 23 was treated with vinylmagnesium cuprate to
give a-hydroxy oxazolidine 24 with high yield and total
regioselectivity. This compound was then transformed
into bicyclic oxazolidinone 25 upon treatment with
NaH. The next allylation step was induced in this case
by BF3(OEt2) and smoothly provided trans bis-allylic
oxazolidinone 26 with >90% de. Finally, RCM of 26
gave trisubstituted cyclohexene 27 (Scheme 4).
The synthesis of diolefinic oxazolidinones 3 started with
Weinreb amide 6, derived from (S)-phenylglycinol.3
Treatment of this amide with the appropriate unsatu-
rated Grignard reagent gave acyloxazolidines 7–9 in
good yields. These ketones were then reduced with high
(>90%) d.e.s using sodium borohydride at −78°C to
afford a-hydroxy oxazolidines 10–12. Transcarbama-
tion of these compounds (NaH in THF) then gave
bicyclic oxazolidinones 13–15. This synthetic sequence
was already reported for ent-14,4 and shows similar
yields and selectivities for the synthesis of nor and homo
analogues 13 and 16. However, the allyl-substituted
oxazolidinone 13 was sensitive to basic medium and
required optimized conditions (NaH, THF, 0.017 M
solution, reflux, 0.5 h) to be produced efficiently in the
last transcarbamation step (Scheme 2).
The chemistry of bicyclic oxazolidinones 20 and 27 was
next investigated. First, base-catalyzed hydrolysis of 20
gave amino alcohol 28, which was cyclized to tropane
derivatives 29 and 30. To this end, 28 was subjected to
an aminomercuration followed by reduction of the
intermediate organomercurial7 or to a treatment with
NIS,8 respectively. It should be noted that no competi-
tive nucleophilic opening of the transient mercuronium
or iodonium ion by the hydroxyl moiety could be
observed in these reactions. N-Debenzylation followed
by N-Boc protection then gave 31 from 29, whereas
intramolecular etherification of 30 gave 32. Since we
have recently shown that the starting b-aminoalcohol
used in these syntheses can be different from phenylgly-
The nature of the Lewis acid used during the next
allylation step was important to reach a good yield:
treatment of olefinic oxazolidinones with TiCl4 (14, 15)
or with BF3(OEt2) (13) in the presence of allyltrimethyl-
silane gave trans diolefinic oxazolidinones 16–18 with
high stereoselectivity,4 and the latter were subjected to
RCM in the presence of Grubbs’ catalyst, in refluxing
dichloromethane. Under these conditions, 5,6- and 5,7-
membered bicyclic compounds 19 and 20 were obtained
with good yields, whereas 5,8-membered 21 was not.
Scheme 3. Reagents and conditions: (a) TiCl4 or BF3(OEt2), allyltrimethylsilane, CH2Cl2, 66% (16), 80%(17), 77%(18); (b) Grubbs’
catalyst, 3% molar ratio, CH2Cl2, 73% (19), 88% (20), 17% (21).
Scheme 4. Reagents and conditions: (a) i. NBS, DME/H2O, ii. EtONa/EtOH, 72% overall; (b) (vinyl)2CuMgBr, THF, −60°C,
87%; (c) NaH, THF, reflux, 76%; (d) BF3(OEt2), allyltrimethylsilane, CH2Cl2, −78°C, 76%; (e) Grubbs’ catalyst, 3% molar ratio,
CH2Cl2, reflux, 91%.

C. Agami et al. / Tetrahedron Letters 42 (2001) 4633–4635
4635
Scheme 5. Reagents and conditions: (a) KOH, EtOH/H2O, reflux, 76%; (b) i. Hg(OAc)2, THF/H2O, rt. ii. NaBH4, NaOH, rt, 64%;
(c) NIS, CH2Cl2, −78°C–rt, 48%; (d) H2, Pd/C, AcOEt, Boc2O, 78%; (e) NaH, THF, reflux, 50%.
Scheme 6. Reagents and conditions: (a) OsO4 (cat.), NMO, acetone/H2O, 50%; (b) TFAA, H2O2, CH2Cl2, 0°C, 61%.
In conclusion, preliminary investigations of this syn-
thetic strategy successfully gave new entries to impor-
tant classes of bioactive compounds. Further work is in
progress in our group in order to delineate its scope.
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1
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3
tion) of N-debenzylated 33. The observed J couplings,
show unambiguously an axial orientation for the H5
proton, therefore a trans relationship between hydroxyl
substituent and phenyl ring is established.
Compound 33 is an aminocyclitol, and new synthetic
routes for the preparation of members of this family are
of high interest since they can provide potent glycosi-
dase inhibitors.10
.