Organic Letters
Letter
methanol (16 equiv) during the reaction (Scheme 4). Other O-
alkyl-N,O-acetals 4b−d were also easily made in moderate
Ti(OEt)4, we finally found that a treatment with Zn(OTf)2 led
to cyclic product 9 in a moderate yield. Final deprotection of
TBS from 9 successfully afforded O-turtschamide 10. The
stereochemical configuration of 10 could not be assigned by
NOESY spectra, and we are currently attempting to obtain an
X-ray structure.
a,b
Scheme 4. Preparation of N-Acyl-O-alkylacetal 4
In conclusion, we have discovered a novel concise method to
construct N-acyl-O-ethyl-N,O-acetals from both aliphatic and
aromatic aldehydes with a broad range of amides and
carbamates, mediated by Ti(OEt)4. Our method also offers
access to other O-alkyl-N-acyl-N,O-acetals, either by the use of
other titanium alkoxides or by incorporating other alcohols
during the reaction. In our further study, these special
functional groups can be converted into N-acyl-N,O-hemi-
acetals, another important motif present in some natural
products, such as zampanolide. Finally, the methods were
successfully applied to the synthesis of turtschamide analogue
10. Further investigation to synthesize enantiomeric O-alkyl-N-
acyl-N,O-acetals is underway.
a
Reaction conditions: p-nitrobenzaldehyde 2a (1.0 equiv), amide 1a
b
(1.5 equiv), Ti(OEt)4 (2.0 equiv). HPLC yields. Isolation yields given
in parentheses.
yields with Ti(OEt)4 by the addition of other alcohols as
cosolvents. It was noteworthy that steric hindrance of acohols
seemed to play an important role. The yield of O-propyl-N,O-
acetal (4b) was almost twice as that of O-isopropyl-N,O-acetal
4c. Meanwhile, N-acyl-N,O-hemiacetal can be obtained by
removing ethyl from 3k using Zn(OTf)2 in acetonitrile (Figure
S1, Supporting Information).
Having established a general concise method for the
formation of N-acyl-N,O-acetals from aldehydes and amides
catalyzed by Ti(OEt)4, we sought to employ our method for
target-oriented synthesis. A recently reported natural product
turtschamide is a cyclic putrescine bisamide with anticancer
activity.20 It has incorporated an unusual N,N-aminal motif
which we reasoned could be constructed from N,O-acetals. To
confirm the concept, we first investigated the synthesis of a
simpler analogue, compound 10 in which oxygen was installed
to replace nitrogen for the ease of synthesis (Scheme 5).
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures for all reactions and characterization
data for all new compounds. This material is available free of
AUTHOR INFORMATION
Corresponding Authors
■
Notes
Scheme 5. Synthesis of O-Turtschamide 10
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Doctoral Program of Higher
Education of China (grant 20110171120098) and the National
Basic Research Program of China (973 Program grant
2012CB967004).
REFERENCES
■
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Initially, an easily obtained L-tyrosine derivative protected
with Cbz and TBS was esterified using EDCI to give ester 5.
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acetal 7 was prepared in a moderate yield. Cleavage of Cbz with
Pd/C afforded a free amine in a quantitive yield. Then,
methods for the formation of a cyclic N,N-aminal were
studied.21 After extensive experimentation using a variety of
acids including BF3·Et2O, TMSCl, TFA, PPTS, Zn(OTf)2, and
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C
dx.doi.org/10.1021/ol4031155 | Org. Lett. XXXX, XXX, XXX−XXX