The versatile conversion of lactams to the α-alkylated azacycles via cyclic N,O-acetal TMS ether

Article abstract of DOI:10.1016/S0040-4039(02)00459-8

The efficient preparation of the cyclic N,O-acetals from lactams by DIBAL reduction followed by direct trapping of the resulting N,O-hemiacetals using TMSOTf/pyridine system is described. In addition, the facile nucleophilic addition of various carbon nucleophiles at the carbonyl carbons of the lactams through the corresponding N,O-acetals is also reported.

Full text of DOI:10.1016/S0040-4039(02)00459-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3165–3167
The versatile conversion of lactams to the a-alkylated azacycles
via cyclic N,O-acetal TMS ether
Young-Ger Suh,* Seok-Ho Kim, Jae-Kyung Jung and Dong-Yun Shin
College of Pharmacy, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea
Received 14 February 2002; revised 5 March 2002; accepted 7 March 2002
Abstract—The efficient preparation of the cyclic N,O-acetals from lactams by DIBAL reduction followed by direct trapping of
the resulting N,O-hemiacetals using TMSOTf/pyridine system is described. In addition, the facile nucleophilic addition of various
carbon nucleophiles at the carbonyl carbons of the lactams through the corresponding N,O-acetals is also reported. © 2002
Published by Elsevier Science Ltd.
As a part of our continuing studies directed toward the
synthesis of the medium to macrolactam alkaloids, we
have been interested in the versatile functionalization of
the lactam carbonyl (Fig. 1).1
tam functionality and the instability of the reaction
intermediate (e.g. imine or enamine, which were readily
hydrolyzed to the corresponding amido aldehyde). In
light of the result4,5 that aluminum alkoxide of hemiac-
etal prepared by DIBAL reduction of esters is more
stable than the free hemiacetal, we were able to reduce
the medium-sized lactam without lactam ring-opening
and trap the resulting N,O-hemiacetal.
Synthetic routes involving cyclic N-acyliminium ions
are generally useful strategies that have been applied to
a wide variety of synthetic transformations.2 The use of
a-alkoxy azacycles as precursors to cyclic N-
acyliminium ions has been especially well reviewed.2
Despite significant progress made in the preparation of
these intermediates, most of these methods are limited
in that they are only applicable to the five- or six-mem-
bered azacycles, and are rarely applicable to the seven-
membered azacycle.3 In fact, unlike the five- and
six-membered a-alkoxy azacycles, which can be readily
prepared by sequential reduction of the corresponding
N-acyl lactam or imide and etherification, the synthesis
of the medium to large sized a-alkoxy azacycle from the
corresponding lactam has not been successful due to
the considerable difficulty in manipulation of their lac-
We herein report a novel and versatile method for the
preparation of the stable N,O-acetal TMS ether 26 as
an excellent precursor of cyclic acyliminium ions 3. To
the best of our knowledge, such a method in the
medium to large-sized lactam systems has not been
reported in spite of its significant synthetic utilities.
Moreover, the facile nucleophilic additions of various
carbon nucleophiles to the resulting N,O-acetal TMS
ether in the presence of the Lewis acid are also
reported.
Our initial studies were carried out by intensive exami-
nation of the reaction conditions for the transformation
of lactam to N,O-acetal alkyl ether. Surveying a num-
ber of trapping reagents commonly used, we have
found the TMSOTf/pyridine system4a,b which only
gives satisfactory results as shown in Table 1. Thus,
treatment of 1aa with DIBAL (1.2 equiv.) in CH2Cl2 at
−78°C followed by sequential addition of pyridine (3
equiv.) and TMSOTf (2.5 equiv.) afforded the N,O-ace-
tal 2aa7 in excellent yield along with a small amount
(<5%) of the remaining amido aldehyde 4.8
Figure 1.
The N,O-acetal TMS ethers are quite stable, and can be
stored for months at room temperature in 1% Et3N/
ether solution. When an MeOTf/pyridine or an Ac2O/
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00459-8

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Y.-G. Suh et al. / Tetrahedron Letters 43 (2002) 3165–3167
Table 1. Synthesis of a-alkoxy azacycle
Entry
Conditions
R
Yieldsa (%)
87b
1
2
3
TMSOTf (2.5 equiv.)/pyridine (3 equiv.)
MeOTf (2.5 equiv.)/pyridine (3 equiv.)
TMS
Me
Ac
c
–
Ac2O (4 equiv.)/pyridine (3 equiv.)/DMAP (2 equiv.)d
–
c
a Isolated yields after chromatography.
b Compound 4 was isolated in about 5% yield.
c Trace amounts of the corresponding products were detected.
d Variation of the reagent equivalents gave similar results.
pyridine/4-DMAP system5 was employed, only a trace
amount of the corresponding product was formed.
Table 3. Nucleophilic additions of the carbon nucleophile
to the cyclic N,O-acetal TMS ethers
The DIBAL reduction of a variety of medium-sized
lactams (1a–c)9 and subsequent etherification of the
resulting N,O-hemiacetal with TMSOTf is illustrated in
Table 2. All reactions were completed in 1 h. After an
aqueous work-up, the N,O-acetal TMS ether was iso-
lated by flash column chromatography using 1% Et3N
eluents in excellent yield. The benzyl and tert-butyl
carbamate were superior to the methyl carbamate in
terms of yield due to the decomposition of the methyl
carbamate upon DIBAL reduction.
Table 2. Formation of the cyclic N,O-acetalsa
Entry
Lactams
Products
Yieldsb (%)
1
2
3
4
5
1aa
1ab
1ac
1ba
1ca
2aa
2ab
2ac
2ba
2ca
87
85
71
82
89
(0°C) for completion of the reaction (entries 6–10). It
was of interest to study the diastereoselectivity of this
addition reaction. To this end, the diastereoselective
addition of siloxyfurans to the cyclic N-acyliminium
ions prepared by a different route was investigated,
although the intermolecular nucleophilic addition of
2-trialkylsiloxyfurans to the five- to seven-membered
N-acyliminium ions has been reported.3 In the seven-
membered ring systems, the results were similar to that
reported by Pilli et al.3 to show good diastereoselectiv-
ity (entry 11). The addition of siloxyfurans to the eight
and nine-membered ring systems also afforded the cor-
responding a-alkylated products 7 in 89 and 91% yields,
respectively. However, the diastereoselectivities for the
eight- and nine-membered ring systems were lower than
that of seven-membered ring system (entries 12, 13).11
a Reaction conditions, see the representative procedure in text.
b Isolated yields after chromatography
With the desired N,O-acetal TMS ether 2 in hand, a
survey of the nucleophilic addition of the various car-
bon nucleophiles was carried out in the presence of
Lewis acid as shown in Table 3. Boron trifluoride
etherate turned out to be the most effective Lewis acid.
As expected, TMSCN underwent facile addition to
afford the a-cyano azacycle 5 in quantitative yield
(entries 1–5). In the case of allylsilane,10 the homoallylic
amine 6 was obtained in excellent yield although this
reaction generally required the higher temperature

Y.-G. Suh et al. / Tetrahedron Letters 43 (2002) 3165–3167
3167
Scheme 1. Reagents and conditions: (a) H2, Pd/C, MeOH; (b) n-BuLi, Boc anhydride, THF, −78°C, 91% from 8; (c) DIBAL,
CH2Cl2, −78°C, then, TMSOTf, pyridine, 87%; (d) BF3–OEt2, TMSCN, CH2Cl2, −78°C, 95%; (e) BF3–OEt2, allyltrimethylsilane,
CH2Cl2, −78°C to 0°C, 88%.
Based on the above results, we next attempted to
and in part by the Research Institute of Pharmaceutical
expand the same reaction on the 10-membered lactam
Science, Seoul National University.
as shown in Scheme 1. DIBAL reduction of Boc-pro-
tected lactam 9, derived from the lactam 8,12 followed
by TMSOTf/pyridine treatment afforded the desired
10-membered N,O-acetal TMS ether 10 in 87% yield.
Finally, on treatment with TMSCN or allyltrimethylsi-
References
1. Suh, Y.-G.; Kim, S.-A.; Jung, J.-K.; Shin, D.-Y.; Min,
lane in the presence of BF3·OEt2, the N,O-acetal 10
K.-H.; Koo, B.-A.; Kim, H.-S. Angew. Chem., Int. Ed.
gave the a-cyano azacycle 11 or a-allyl azacycle 12 in
Engl. 1999, 38, 3545–3547.
good yields, respectively.
2. For excellent reviews on the chemistry of N-acyliminium
ions and related intermediates, see: (a) Speckamp, W. N.;
Representative procedure: The lactam 1aa (213 mg, 1.0
Moolenaar, M. J. Tetrahedron 2000, 56, 3817–3856; (b)
mmol) was dissolved in CH2Cl2 (5 mL). Upon cooling
Hiernstra, H.; Speckamp, W. N. In Comprehensive
to −78°C, DIBAL (1.0 M solution in CH2Cl2, 1.2 mL,
Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Perga-
1.2 mmol, 1.2 equiv.) was added dropwise via syringe.
mon Press: Oxford, 1991; Vol. 2, pp. 1047–1082.
After 15 min, the reaction mixture was treated with
3. For an example of seven-membered azacyclic system, see:
pyridine (243 mL, 3.0 mmol, 3.0 equiv.) and then
de Oliveira, M. C. F.; Santos, L. S.; Pilli, R. A. Tetra-
hedron Lett. 2001, 42, 6995–6997.
4. (a) Kiyooka, S.; Shirouchi, M.; Kaneko, Y. Tetraheron
TMSOTf (452 mL, 2.5 mmol, 2.5 equiv.). The mixture
was stirred at −78°C for 30 min, quenched with 15%
aqueous sodium potassium tartrate (5 mL), and diluted
Lett. 1993, 34, 1491–1494; (b) Kiyooka, S.; Shirouchi, M.
J. Org. Chem. 1992, 57, 1–2; (c) Polt, R.; Peterson, M. A.;
Deyoung, L. J. Org. Chem. 1992, 57, 5469–5480.
with Et2O (20 mL). The resultant mixture was warmed
to room temperature and stirred vigorously until two
layers were completely separated. The mixture was
extracted with Et2O and the combined organic layers
were washed with brine, dried over Na2SO4 and con-
centrated in vacuo. The residue was purified by flash
column chromatography (20% EtOAc/hexanes with 1%
5. (a) Dahanukar, V.; Rychnovsky, S. D. J. Org. Chem.
1996, 61, 8317–8320; (b) Kopecky, D. J.; Rychnovsky, S.
D. J. Org. Chem. 2000, 65, 191–198.
6. For examples on the preparation of the acyclic N,O-ace-
tal TMS ether, see; (a) Ferraris, D.; Young, B.; Cox, C.;
Dudding, T.; Drury, W. J., III; Ryzhkov, L.; Taggi, A.
E.; Lectka, T. J. Am. Chem. Soc. 2002, 124, 67–77; (b)
Blond, G.; Billard, T.; Langlois, B. R. J. Org. Chem.
2001, 66, 4826–4830; (c) Johnson, A. P.; Luke, R. W. A.;
Boa, A. N. J. Chem. Soc., Perkin Trans. 1 1996, 895–
905.
Et3N) to afford 250 mg (87%) of the N,O-acetal TMS
ether 2aa as a colorless oil.
In summary, an unprecedented simple preparation of
the cyclic N,O-acetal silyl ether from the medium to
large-sized lactams as an important precursor for the
corresponding N-acyliminium ions has been devel-
oped. Particularly, these useful intermediates undergo a
facile nucleophilic addition reaction by a variety of
nucleophiles in the presence of Lewis acid. We are
currently evaluating the extension of this methodology
to the acyclic system as well as the asymmetric variants.
Moreover, this methodology will be extended to the
second-generation synthesis of the macrolactam antibi-
otic alkaloids such as fluvirucins.
7. Satisfactory spectral and analytical data were obtained
for all new compounds.
8. These compounds always remained irrespective of
amount of reagent, reaction time and reaction tempera-
ture.
9. Compounds 1a–c were synthesized by simple protection
of the commercially available lactams.
10. The use of allyltributyltin gave a similar result.
11. The relative stereochemistry of 7 was not determined
since 7 was obtained as an inseparable mixture, see Ref.
3.
Acknowledgements
12. Suh, Y.-G.; Lee, J.-Y.; Kim, S.-A.; Jung, J.-K. Synth.
Commun. 1996, 26, 1675–1680.
This work was supported by grant CHMP-00-CH-15-
0014 from the Korean Ministry of Health & Welfare