A new, general entry to 3,5-unsubstituted 4-O-alkyl tetramates

Article abstract of DOI:10.1055/s-2002-28522

A variety of 3,5-unsubstituted 4-O-benzyl tetramates 10 was prepared in good overall yield from methyl (E)-3-benzyloxy-4-oxobut-2-enoate 7 by a reductive amination-lactamization sequence. An efficient approach to this building block as well as to various 3-alkoxy analogues is presented.

Full text of DOI:10.1055/s-2002-28522

PAPER
869
A New, General Entry to 3,5-Unsubstituted 4-O-Alkyl Tetramates
A
N
ew
,
G
ene
r
r
al Entry
a
to 3,5-Unsu
n
bstitute
d
4-
O
z
-Alkyl Tetramat
F
es . Paintner,* Marcel Metz, Gerd Bauschke
Department Pharmazie – Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Butenandtstraße 5–13, Haus C,
81377 München, Germany
Fax +49(89)21807247; E-mail: ffpai@cup.uni-muenchen.de
Received 20 March 2002
Dedicated to Prof. Dr. Gotthard Wurm on the occasion of his 65th birthday
hyde 2; and (b), reductive amination of this building block
followed by lactamization (Scheme 1).
Abstract: A variety of 3,5-unsubstituted 4-O-benzyl tetramates 10
was prepared in good overall yield from methyl (E)-3-benzyloxy-4-
oxobut-2-enoate 7 by a reductive amination–lactamization se-
quence. An efficient approach to this building block as well as to
various 3-alkoxy analogues is presented.
Key words: tetramic acids, enols, conjugate additions, aminations,
lactams
Enol ethers of 3,5-unsubstituted tetramic acids [4-alkoxy-
pyrrol-2(5H)-ones] 1 are versatile building blocks for the
synthesis of a wide variety of natural products and ana-
logues thereof,1 a number of which exhibit interesting bi-
ological activities, including potent antibacterial and
immunosupressive properties. Unlike their oxygen ana-
logue, tetronic acid, 3,5-unsubstituted tetramic acids (pyr-
rolidine-2,4-diones) are generally unsuitable starting
materials for the preparation of the corresponding enol
ethers,2 since they are prone to self-condensations under
the requisite reaction conditions.3,4 Thus they are usually
prepared by reaction of alkyl (E)-4-bromo-3-alkoxybut-2-
enoates or the respective 4-chloro analogues with ammo-
nia or primary amines in moderate to good yields.5 The
former building blocks are readily available by bromina-
tion of alkyl acetoacetate derivative alkyl 3-alkoxybut-2-
enoates with N-bromosuccinimide or by acid-catalyzed
enol ether formation from alkyl 4-chloroacetoacetates.
These approaches, however, are essentially restricted to
the formation of 4-O-methyl and 4-O-ethyl derivatives.
Other 4-O-alkyl tetramates, e.g. 4-benzyloxypyrrol-
2(5H)-one have to be prepared indirectly.6 Thus heating
of commercially available 4-methoxypyrrol-2(5H)-one
with an excess of benzyl alcohol in the presence of strong
acid afforded the corresponding 4-O-benzyl tetramate in
satisfactory yield. Quite naturally, this method is incom-
patible with acid-sensitive alcohols and tetramates. We
now report a new, general entry to 3,5-unsubstituted 4-O-
alkyl tetramates, which offers high flexibility in the
choice of substituents both at O-4 and N-1.
Scheme 1
According to the method of Inanaga and co-workers,8 a
variety of alcohols was added to butynoate 3, using tri-
methylphosphine as a nucleophilic catalyst to give enol
ethers 4 and 5 in good overall yields (Scheme 2; Table 1).
To attain such high yields, however, the order of addition
of the reagents is quite critical, since 3 rapidly undergoes
self-condensation in the presence of the trialkylphosphine
catalyst. Accordingly, the best yields of enol ethers were
accomplished by slow addition of 3 to a mixture of the re-
spective alcohol (1.1–3.0 equiv) and trimethylphosphine
(10 mol%) in dichloromethane at 0 °C. In the case of pri-
mary alcohols, the desired E-configurated enol ethers 4
were obtained almost exclusively (E:Z 97:3) (Table 1,
entries 1–5). However, even with a secondary alcohol
bearing bulky substituents, only slightly higher amounts
of the respective Z-isomer 5 arose (Table 1, entry 7). The
double-bond geometry in E/Z-isomers 4 and 5 was deter-
mined on the basis of NOE experiments. Thus irradiation
of H-4, in the case of Z-isomers 5, gave rise to significant
NOE’s for H-2.
Tetramates 1 were envisioned to arise from two key trans-
formations: (a), the conjugate addition of alcohols to the
known butynoate 3,7 followed by deprotection and subse-
quent oxidation of the allylic hydroxyl group to give alde-
Scheme 2
In the course of our further studies we focused on the syn-
thesis of 4-O-benzyl tetramates 10. As depicted in
Scheme 3, the appropriate key intermediate 7 was readily
obtained from 4c in an efficient two-step sequence.
Deprotection of the hydroxy group was achieved under
mild conditions by treatment with HF–pyridine9 (Olah´s
Synthesis 2002, No. 7, 21 05 2002. Article Identifier:
1437-210X,E;2002,0,07,0869,0874,ftx,en;Z04902SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

870
F. F. Paintner et al.
PAPER
Table 2 Consecutive Reductive Amination–lactamization of Alde-
hyde 7 with Various Primary Amines
Table 1 Conjugate Additions of Various Alcohols to Butynoate 3
Entry R =
Product
Yield a
(%)
Ratio b 4:5
Entry
R =
Method a Product Yield b
(%)
1
2
3
4
5
6
7
Me
4a
4b
4c
4d
4e
4f
80
85
90
69
81
75
78
98:2
99:1
97:3
97:3
97:3
96:4
95:5
1
2
3
4
5
6
7
Me
Ac
A
10a
10b
10c
10d
10e
10f
84
48
73
74
65
66
53
TMSCH2CH2
Bn
HC CCH2
Bn
A
p-MeOC6H4CH2
CH2=CHCH2
i-Pr
(S)-PhCH(Me)
B
( )-CH(i-Pr)COOMe
Bc
B
t-Bu
(1R)-menthyl
4g
Ph
Bd
10g
a Yield of isolated, purified product 4.
a Method A: (i), amine (1.5 equiv), MS 3 Å, THF, r.t., 24–40 h; (ii),
NaBH4 (1.3 equiv), MeOH, 45 °C, 24 h. Method B: (i), amine (1.5
equiv), MS 3 Å, THF, r.t., 24–40 h; (ii), NaBH4 (1.3 equiv), MeOH,
45 °C, 24 h; (iii), toluene–HOAc = 10:1, , 1.5 h.
b Ratio 4:5 determined by 1H NMR (500 MHz) of the crude products.
b Yield of isolated, purified product 10.
reagent) in THF at 0 °C or alternatively with HF (1.0
equiv) in acetonitrile at the same temperature to give -hy-
droxy ester 6 in 84% and 80% yield, respectively. Under
the latter conditions, however, we also obtained small
amounts of 4-benzyloxyfuran-2(5H)-one, due to lacton-
ization of the -hydroxy ester. The subsequent oxidation
of alcohol 6 was accomplished with 2-iodoxybenzoic acid
(IBX)10 in DMSO at r.t. to afford aldehyde 7 in excellent
yield (99%).
c The respective hydrochlorimide (1.5 equiv) together with i-Pr2NEt
(2 equiv) was used instead of the free amine.
d HOAc (1.0 equiv) was added to catalyze the formation of the imine.
The reductive aminations were best accomplished in a
stepwise manner involving preformation of the intermedi-
ate imines 8 followed by reduction.12 Initially the imines
8 were generated almost quantitatively by reaction of al-
dehyde 7 with the respective amines (1.5 equiv) in the
presence of a dehydrating agent [molecular sieves (MS) 3
Å, THF, r.t., 24–40 h]. In the case of volatile or unstable
amines the respective hydrochlorides (1.5 equiv) were
used by adding N,N-diisopropylethylamine (2.0 equiv).
As determined by 1H NMR, the crude imines 8 were suf-
ficiently pure (> 95%) for the subsequent reactions and
employed as such. The reductions were carried out by
treatment of the imines 8 with sodium borohydride (1.3
equiv) in methanol at 45 °C for 24 hours.13 In case of un-
hindered aliphatic amino residues, spontaneous cyclisa-
tion of the intermediate -amino esters 9 occurred, to give
the corresponding 4-O-benzyl tetramates 10 directly in
satisfactory to good overall yields (Table 2, entries 1–3).
On the other hand, with aromatic or bulky aliphatic resi-
dues present, mainly the respective -amino esters 9 were
obtained, even after prolonged heating at 45 °C, in addi-
tion to minor amounts of the desired tetramates 10. Nev-
ertheless these lactamizations could be driven to
completion by heating the crude reduction products in a
10:1 mixture of toluene and glacial acetic acid for 1.5
hours (Table 2, entries 4–7).
Scheme 3
Finally key building block 7 was converted into a series of
4-O-benzyl tetramates 10 by a reductive amination–lac-
tamization sequence (Scheme 4, Table 2).11
In conclusion we have developed a general approach to
3,5-unsubstituted 4-O-alkyl tetramates starting from
readily available butynoate 3, which offers high flexibility
in the choice of substituents both at O-4 and N-1.
Unless otherwise noted, reactions were carried out in oven-dried
glassware under an atmosphere of dry N2. All reagents were used as
commercially available. CH2Cl2 was distilled from CaH2 and THF
from sodium metal immediately before use. Flash chromatography:
Scheme 4
Synthesis 2002, No. 7, 869–874 ISSN 0039-7881 © Thieme Stuttgart · New York

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A New, General Entry to 3,5-Unsubstituted 4-O-Alkyl Tetramates
871
silica gel (Merck 60, 0.040–0.063 mm). Mp (uncorrected values):
Electrothermal 9100 (Electrothermal). Optical rotations: Polarime-
ter 241 (Perkin Elmer). H NMR spectra: Eclipse 500 FTNMR
spectrometer (Jeol), 500 MHz, chemical shifts ( ) are reported in
ppm, TMS as internal standard. IR spectra: FT-IR spectrometer FT/
IR-410 (Jasco). Mass spectra: 5989 Mass spectrometer with 59980
B particle beam LC/MS interface (Hewlett Packard); API 2000
(Applied Biosystems). High resolution mass spectrometry: MSta-
tion 700 (Jeol). Elemental analysis: CHN Rapid (Heraeus).
chromatography (hexane–CH2Cl2–Et2O, 90:5:5) to give 4c (3.03 g,
90%) and 5c (106 mg, 3%) as colorless oils.
4c: IR (film): 3093, 3065, 3034, 1714, 1630 cm–1.
1H NMR (CDCl3): = 0.05 (s, 6 H, SiCH3), 0.88 [s, 9 H, (CH3)3C],
3.67 (s, 3 H, OCH3), 4.87 (s, 2 H, CH2OSi), 4.88 (s, 2 H, CH2Ph),
5.12 (s, 1 H, C=CH), 7.31–7.38 (m, 5 H, Harom).
13C NMR (CDCl3): = –5.28 (SiCH3), 18.39 [(CH3)3C], 25.88
[(CH3)3C], 50.99 (OCH3), 60.57 (C-4), 70.32 (CH2Ph), 91.99 (C-2),
127.61–128.23, 135.35 (C6H5), 167.36 (C-1), 171.97 (C-3).
1
Conjugate Addition of Alcohols to Butynoate 3; General Proce-
dure
MS (CI, CH4): m/z (%) = 337 (80) [M + H+] 279 (100).
Anal. Calcd for C18H28O4Si (336.5): C, 64.25; H, 8.39. Found: C,
64.38; H, 8.30.
5c: 1H NMR (CDCl3): = 0.06 (s, 6 H, SiCH3), 0.90 [s, 9 H,
(CH3)3C], 3.71 (s, 3 H, OCH3), 4.14 (d, 2 H, J = 1.1 Hz, CH2OSi),
5.25 (s, 2 H, CH2Ph), 5.38 (t, 1 H, J = 1.1 Hz, C=CH), 7.29–7.42 (m,
5 H, Harom).
A solution of butynoate 3 (228 mg, 1.0 mmol) in CH2Cl2 (5 mL)
was added dropwise to a solution of the alcohol (3.0 mmol) and
PMe3 (100 L, 1.0 M in THF, 0.1 mmol) in CH2Cl2 (5 mL) at 0 °C
by means of a syringe. Then the reaction mixture was allowed to
warm to r.t. and stirred overnight, before it was concentrated under
reduced pressure. The crude product (mixture of E/Z-isomers) was
purified by flash chromatography.
Methyl (E)-4-(tert-Butyldimethylsilanyloxy)-3-(4-methoxyben-
zyloxy)but-2-enoate (4d) and Methyl (Z)-4-(tert-Butyldimethyl-
silanyloxy)-3-(4-methoxybenzyloxy)but-2-enoate (5d)
Prepared according to the general procedure from 3 (183 mg, 0.8
mmol) and 4-methoxybenzyl alcohol (298 L, 2.4 mmol). Purified
by flash chromatography (hexane–CH2Cl2–Et2O, 8:1:1) to give 4d
(202 mg, 69%) and 5d (12 mg, 3%) as colorless oils.
Methyl (E)-4-(tert-Butyldimethylsilanyloxy)-3-methoxybut-2-
enoate (4a) and Methyl (Z)-4-(tert-Butyldimethylsilanyloxy)-3-
methoxybut-2-enoate (5a)
Prepared according to the general procedure from 3 (183 mg, 0.8
mmol) and MeOH (97 L, 2.4 mmol). Purified by flash chromatog-
raphy (hexane–CH2Cl2–Et2O, 90:5:5) to give 4a (167 mg, 80%) and
5a (4 mg, 2%) as colorless oils.
4d: IR (film): 2998, 1714, 1628 cm–1.
4a: IR (film): 3008, 1715, 1632 cm–1.
1H NMR (CDCl3): = 0.03 (s, 6 H, SiCH3), 0.87 [s, 9 H, (CH3)3C],
3.67 (s, 3 H, COOCH3), 3.81 (s, 3 H, OCH3), 4.80 (s, 2 H,
CH2C6H4OCH3), 4.85 (s, 2 H, CH2OSi), 5.12 (s, 1 H, C=CH), 6.87–
6.91 (m, 2 H, Harom), 7.28–7.32 (m, 2 H, Harom).
13C NMR (CDCl3): = –5.28 (SiCH3), 18.40 [(CH3)3C], 25.83
[(CH3)3C], 50.97 (COOCH3), 55.29 (OCH3), 60.63 (C-4), 70.21
(CH2C6H4OMe), 91.76 (C-2), 113.92, 127.40, 129.41, 159.65
(C6H4OCH3), 167.43 (C-1), 172.10 (C-3).
1H NMR (CDCl3): = 0.09 (s, 6 H, SiCH3), 0.91 [s, 9 H, (CH3)3C],
3.68 (2 s, 6 H, 2 OCH3), 4.83 (s, 2 H, CH2OSi), 5.02 (s, 1 H,
C=CH).
MS (CI, CH4): m/z (%) = 261 (58) [M + H+] 107 (100).
Anal. Calcd for C12H24O4Si (260.4): C, 55.35; H, 9.20. Found: C,
55.35; H, 9.29.
5a: 1H NMR (CDCl3): = 0.10 (s, 6 H, SiCH3), 0.92 [s, 9 H,
(CH3)3C], 3.68 (s, 3 H, OCH3), 3.94 (s, 3 H, OCH3), 4.19 (d, 2 H,
J = 0.9 Hz, CH2OSi), 5.24 (t, 1 H, J = 0.9 Hz, C=CH).
MS (CI, CH4): m/z (%) = 367 (48) [M + H+] 121 (100).
Anal. Calcd for C19H30O5Si (366.5): C, 62.26; H, 8.25. Found: C,
62.01; H, 8.53.
Methyl (E)-4-(tert-Butyldimethylsilanyloxy)-3-(2-trimethylsi-
lanylethoxy)but-2-enoate (4b) and Methyl (Z)-4-(tert-Butyldim-
ethylsilanyloxy)-3-(2-trimethylsilanylethoxy)but-2-enoate (5b)
Prepared according to the general procedure from 3 (686 mg, 3.0
mmol) and 2-(trimethylsilyl)ethanol (1.29 mL, 9.0 mmol). Purified
by flash chromatography (hexane–CH2Cl2–Et2O, 95:2.5:2.5) to
give 4b (882 mg, 85%) and 5b (2.2 mg, 0.2%) as colorless oils.
5d: 1H NMR (CDCl3): = 0.06 (s, 6 H, SiCH3), 0.90 [s, 9 H,
(CH3)3C], 3.71 (s, 3 H, COOCH3), 3.81 (s, 3 H, OCH3), 4.12 (d, 2
H, J = 1.0 Hz, CH2OSi), 5.18 (s, 2 H, CH2C6H4OCH3), 5.38 (t, 1 H,
J = 1.0 Hz, C = CH), 6.87–6.91 (m, 2 H, Harom), 7.26–7.34 (m, 2 H,
Harom).
Methyl (E)-3-Allyloxy-4-(tert-butyldimethylsilanyloxy)but-2-
enoate (4e) and (Z)-3-Allyloxy-4-(tert-butyldimethylsilanyl-
oxy)but-2-enoate (5e)
Prepared according to the general procedure from 3 (183 mg, 0.8
mmol) and allyl alcohol (164 L, 2.4 mmol). Purified by flash chro-
matography (hexane–CH2Cl2–Et2O, 90:5:5) to give 4e (188 mg,
82%) and 5e (6 mg, 3%) as colorless oils.
4b: IR (film): 3010, 1716, 1628 cm–1.
1H NMR (CDCl3): = 0.06 (s, 9 H, SiCH3), 0.09 (s, 6 H, SiCH3),
0.91 [s, 9 H, (CH3)3C], 1.10 (m, 2 H, CH2CH2Si), 3.67 (s, 3 H,
OCH3), 3.88 (m, 2 H, CH2CH2Si), 4.80 (br d, 2 H, J 0.5 Hz,
CH2OSi), 4.97 (br t, 1 H, J 0.5 Hz, C=CH).
MS (CI, CH4): m/z (%) = 347 (20) [M + H+] 303 (100).
4e: IR (KBr): 3089, 3019, 1715, 1630 cm–1.
Anal. Calcd for C16H34O4Si2 (346.6): C, 55.44; H, 9.89. Found: C,
55.56; H, 9.71.
1H NMR (CDCl3): = 0.09 (s, 6 H, SiCH3), 0.90 [s, 9 H, (CH3)3C],
3.67 (s, 3 H, OCH3), 4.36 (dt, 2 H, J = 1.5, 5.5 Hz, CH2CH=CH2),
4.84 (s, 2 H, CH2OSi), 5.02 (s, 1 H, C=CH), 5.29 (ddd, 1 H, J = 1.5,
3.0, 10.6 Hz, CH2CH=CH2), 5.39 (ddd, 1 H, J = 1.5, 3.0, 17.3 Hz,
1
5b: H NMR (CDCl3): = 0.04 (s, 9 H, SiCH3), 0.09 (s, 6 H,
SiCH3), 0.91 [s, 9 H, (CH3)3C], 1.10 (m, 2 H, CH2CH2Si), 3.67 (s, 3
H, OCH3), 4.14 (d, 2 H, J = 1.0 Hz, CH2OSi), 4.26 (m, 2 H,
CH2CH2Si), 5.27 (t, 1 H, J = 1.0 Hz, C=CH).
CH2CH=CH2), 5.97 (ddt,
CH2CH=CH2).
1 H, J = 5.5, 10.6, 17.3 Hz,
13C NMR (CDCl3): = –5.25 (SiCH3), 18.42 [(CH3)3C], 25.85
[(CH3)3C], 50.95 (OCH3), 60.61 (C-4), 69.16 (CH2CH=CH2), 91.53
(C-2), 118.40 (CH2CH=CH2), 131.62 (CH2CH=CH2), 167.37 (C-1),
171.88 (C-3).
Methyl (E)-3-Benzyloxy-4-(tert-butyldimethylsilanyloxy)but-2-
enoate (4c) and Methyl (Z)-3-Benzyloxy-4-(tert-butyldimethyl-
silanyloxy)but-2-enoate (5c)
Prepared according to the general procedure from 3 (2.28 g, 10.0
mmol) and benzyl alcohol (1.14 mL, 11.0 mmol). Purified by flash
MS (CI, CH4): m/z (%) = 287 (85) [M + H+] 255 (100).
Synthesis 2002, No. 7, 869–874 ISSN 0039-7881 © Thieme Stuttgart · New York

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F. F. Paintner et al.
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HRMS: m/z Calcd for C14H26O4Si (M+): 286.1600. Found:
286.1600.
added, the pH value was adjusted to 8.0 with NaHCO3, and the mix-
ture was extracted with Et2O (4 300 mL). The combined organic
layers were washed with 10% aq KH2PO4 (3 100 mL) and H2O (2
100 mL), dried (MgSO4) and evaporated under reduced pressure.
The residue was purified by flash chromatography (pentane–ace-
tone, 9:1) to give 6 (1.56 g, 84%) as a colorless oil.
5e: 1H NMR (CDCl3): = 0.09 (s, 6 H, SiCH3), 0.91 [s, 9 H,
(CH3)3C], 3.69 (s, 3 H, OCH3), 4.17 (d, 2 H, J = 1.0 Hz, CH2OSi),
4.70 (dt, 2 H, J = 1.5, 5.3 Hz, CH2CH=CH2), 5.24 (ddd, 1 H, J = 1.5,
3.1, 10.6 Hz, CH2CH=CH2), 5.33 (t, 1 H, J = 1.0 Hz, C=CH), 5.40
(ddd, 1 H, J = 1.5, 3.1, 17.2 Hz, CH2CH=CH2), 5.96 (ddt, 1 H,
J = 5.3, 10.6, 17.2 Hz, CH2CH=CH2).
IR (film): 3447, 1709, 1688 cm–1.
1H NMR (CDCl3): = 3.73 (s, 3 H, OCH3), 4.30 (t, 1 H, J = 7.4 Hz,
OH), 4.45 (d, 2 H, J = 7.4 Hz, CH2OH), 4.85 (s, 2 H, CH2Ph), 5.25
(s, 1 H, C = CH), 7.34–7.42 (m, 5 H, Harom).
Methyl (E)-4-(tert-Butyldimethylsilanyloxy)-3-isopropoxybut-
2-enoate (4f) and Methyl (Z)-4-(tert-Butyldimethylsilanyloxy)-
3-isopropoxybut-2-enoate (5f)
MS (CI, CH4): m/z (%) = 223 (20) [M + H+], 191 (100).
Prepared according to the general procedure from 3 (183 mg, 0.8
mmol) and i-PrOH (184 L, 2.4 mmol). Purified by flash chroma-
tography (hexane–CH2Cl2–Et2O, 90:5:5) to give 4f (173 mg, 75%)
and 5f (7 mg, 3%) as colorless oils.
Anal. Calcd for C12H14O4 (222.2): C, 64.85; H, 6.35. Found: C,
65.18; H, 6.24.
Methyl (E)-3-Benzyloxy-4-oxobut-2-enoate (7)
4f: IR (film): 1716, 1624 cm–1.
A solution of 2-iodoxybenzoic acid (924 mg, 3.3 mmol) in DMSO
(3.3 mL) was added to the alcohol 6 (490 mg, 2.2 mmol) and the
mixture was stirred for 2 h at r.t. The resulting suspension was di-
luted with Et2O (5 mL), applied on a silica gel column (ca. 500 mL)
and eluted with pentane–Et2O (70:30) to give 7.
1H NMR (CDCl3): = 0.08 (s, 6 H, SiCH3), 0.93 [s, 9 H, (CH3)3C],
1.31 [d, 6 H, J = 6.1 Hz, CH(CH3)2], 3.66 (s, 3 H, OCH3), 4.40 [sept,
1 H, J = 6.1 Hz, CH(CH3)2], 4.80 (br s, 2 H, CH2OSi), 4.98 (br s, 1
H, C=CH).
Yield: 481 mg (99%); colorless crystals; mp 83 °C.
IR (film): 3072, 3034, 1713, 1694, 1627 cm–1.
1H NMR (CDCl3): = 3.77 (s, 3 H, OCH3), 4.95 (s, 2 H, CH2Ph),
5.84 (s, 1 H, C=CH), 7.33–7.42 (m, 5 H, Harom), 10.50 (s, 1 H,
CHO).
MS (CI, CH4): m/z (%) = 289 (24) [M + H+] 257 (100).
Anal. Calcd for C14H28O4Si (288.5): C, 58.29; H, 9.78. Found: C,
58.39; H, 9.61.
5f: 1H NMR (CDCl3): = 0.09 (s, 6 H, SiCH3), 0.92 [s, 9 H,
(CH3)3C], 1.29 [d, 6 H, J = 6.1 Hz, CH(CH3)2], 3.68 (s, 3 H, OCH3),
4.11 (d, 2 H, J = 1.1 Hz, CH2OSi), 4.81 [sept, 1 H, J = 6.1 Hz,
CH(CH3)2], 5.39 (t, 1 H, J = 1.1 Hz, C=CH).
MS (CI, CH4): m/z (%) = 221 (100) [M + H+].
Anal. Calcd for C12H12O4 (220.2): C, 65.45; H, 5.49. Found: C,
65.76; H, 5.46.
Methyl (E)-4-(tert-Butyldimethylsilanyloxy)-3-[(1R,2S,5R)-2-
isopropyl-5-methylcyclohexyloxy]but-2-enoate (4g) and Methyl
(Z)-4-(tert-Butyldimethylsilanyloxy)-3-[(1R,2S,5R)-2-isopropyl-
5-methylcyclohexyloxy]but-2-enoate (5g)
Prepared according to the general procedure from 3 (228 mg, 1.0
mmol) and (–)-menthol (469 mg, 3.0 mmol). Purified by flash chro-
matography (hexane–CH2Cl2–Et2O, 90:5:5) to give 4g (299 mg,
78%) and 5g (11 mg, 3%) as colorless oils.
Preparation of 4-O-Benzyl Tetramates; General Procedures
Method A: The respective amine (1.5 mmol) was added to a mixture
of 7 (220 mg, 1.0 mmol) and molecular sieves (MS) 3 Å (ca. 1 g) in
THF (10 mL). After stirring for 24–40 h at r.t. the MS were filtered
off and the filtrate was evaporated under reduced pressure to give
the corresponding imine in almost quantitative yield. This crude
product was sufficiently pure for the subsequent reduction with
NaBH4. To a solution of the imine in MeOH (20 mL), NaBH4 (49
mg, 1.3 mmol) was added at r.t. Then the mixture was stirred for 24
h at 45 °C. After cooling to r.t., sat. aq NaHCO3 (20 mL) was added
and the mixture was extracted with CH2Cl2 (4 20 mL). The com-
bined organic layers were dried (MgSO4) and evaporated under re-
duced pressure. The residue was purified by flash chromatography.
4g: [ ]D20 –107° (c = 1.08, CH2Cl2).
IR (film): 3089, 3018, 1715, 1623 cm–1.
1H NMR (CDCl3): = 0.07 (s, 3 H, SiCH3), 0.08 (s, 3 H, SiCH3),
0.72 (d, 3 H, J = 6.8 Hz, CHCH3), 0.86–1.10 (m, 3 H, CH and CH2),
0.88 [d, 3 H, J = 7.1 Hz, CH(CH3)2], 0.90 [s, 9 H, (CH3)3C], 0.92 [d,
3 H, J = 6.6 Hz, CH(CH3)2], 1.37–1.50 [m, 2 H, CH and CH(CH3)2],
1.66–1.74 (m, 2 H, CH2), 2.09–2.19 (m, 2 H, CH2 and CHCH3), 3.67
(s, 3 H, OCH3), 3.92 [dt, 1 H, J = 4.1, 10.6 Hz, OCH], 4.60 (d, 1 H,
J = 13.7 Hz, CH2OSi), 4.99 (d, 1 H, J = 13.7 Hz, CH2OSi), 5.02 (br
s, 1 H, C=CH).
Method B: As described above with the exception of refluxing the
crude reduction product in a mixture of toluene (10 mL) and HOAc
(1 mL) for 1.5 h. After cooling to r.t., the solvents were evaporated
under reduced pressure and the residue was purified by flash chro-
matography.
MS (CI, CH4): m/z (%) = 385 (100) [M + H+].
4-Benzyloxy-1-methylpyrrol-2(5H)-one (10a)
Anal. Calcd for C21H40O4Si (384.6): C, 65.58; H, 10.48. Found: C,
65.53; H, 10.76.
Prepared according to Method A from 7 (110 mg, 0.5 mmol). How-
ever, instead of the free amine, methylamine hydrochloride (51 mg,
0.75 mmol) together with i-Pr2NEt (166 L, 1.0 mmol) was em-
ployed. Purified by flash chromatography (EtOAc–CH2Cl2–MeOH,
80:16:4) to give 10a.
5g: 1H NMR (CDCl3): = 0.10 (s, 6 H, SiCH3), 0.81 (d, 3 H, J = 7.0
Hz, CHCH3), 0.86–1.13 (m, 3 H, CH and CH2), 0.91 [d, 3 H, J = 6.4
Hz, CH(CH3)2], 0.92 [s, 9 H, (CH3)3C], 0.92 [d, 3 H, J = 6.9 Hz,
CH(CH3)2], 1.35–1.49 [m, 2 H, CH and CH(CH3)2], 1.63–1.71 (m,
2 H, CH2), 2.00–2.18 (m, 2 H, CH2 and CHCH3), 3.66 (s, 3 H,
OCH3), 4.10 (dd, 1 H, J = 0.8, 15.7 Hz, CH2OSi), 4.17 (dd, 1 H,
J = 0.8, 15.7 Hz, CH2OSi), 4.36 [dt, 1 H, J = 4.2, 10.4 Hz, OCH],
5.27 (t, 1 H, J = 0.8 Hz, C=CH).
Yield: 85 mg (84%); colorless crystals; mp 85 °C.
IR (film): 3091, 3034, 1682, 1621, 1585 cm–1.
1H NMR (CDCl3): = 2.95 (s, 3 H, NCH3), 3.87 (s, 2 H, CH2), 4.96
(s, 2 H, CH2Ph), 5.13 (s, 1 H, C=CH), 7.36–7.39 (m, 5 H, Harom).
MS (CI, CH4): m/z (%) = 204 (100) [M + H+].
Methyl (E)-3-Benzyloxy-4-hydroxybut-2-enoate (6)
HF–pyridine complex (Olah’s reagent) (10.0 mL, ca. 70% HF) was
added dropwise to a solution of 4c (2.82 g, 8.38 mmol) in THF (168
mL) at 0 °C and stirred for 3.5 h. Sat. aq NaHCO3 (300 mL) was
Anal. Calcd for C12H13NO2 (203.2): C, 70.92; H, 6.45; N, 6.89.
Found: C, 70.79; H, 6.49; N, 6.86.
Synthesis 2002, No. 7, 869–874 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A New, General Entry to 3,5-Unsubstituted 4-O-Alkyl Tetramates
873
4-Benzyloxy-1-prop-2-ynylpyrrol-2(5H)-one (10b)
Prepared according to Method A from 7 (110 mg, 0.5 mmol) and
propargylamine (51 L, 0.75 mmol). Purified by flash chromatog-
raphy (hexane–EtOAc, 40:60) to give 10b.
1H NMR (CDCl3): = 0.92 [d, 3 H, J = 6.7 Hz, CH(CH3)2], 0.98 [d,
3 H, J = 6.7 Hz, CH(CH3)2], 2.16 [m, 1 H, CH(CH3)2], 3.71 (s, 3 H,
OCH3), 3.93 (d, 1 H, J = 17.2 Hz, NCH2), 4.29 (d, 1 H, J = 17.2 Hz,
NCH2), 4.60 (d, 1 H, J = 9.6 Hz, CHCOOCH3), (4.98 (s, 2 H,
CH2Ph), 5.16 (s, 1 H, C=CH), 7.36–7.42 (m, 5 H, Harom).
Yield: 55 mg (48%); colorless crystals; mp 58 °C.
IR (film): 3286, 3099, 3035, 2119, 1682, 1620, 1453 cm–1.
MS (CI, CH4): m/z (%) = 304 (100) [M + H+].
Anal. Calcd for C17H21NO4 (303.4): C, 67.31; H, 6.98; N, 4.62.
Found: C, 67.21; H, 6.87; N, 4.53.
1H NMR (CDCl3): = 2.24 (t, 1 H, J = 2.5 Hz, HC C), 4.01 (s, 2 H,
CH2), 4.23 (d, 2 H, J = 2.5 Hz, CH2C CH), 4.99 (s, 2 H, CH2Ph),
5.14 (s, 1 H, C=CH), 7.35–7.45 (m, 5 H, Harom).
13C NMR (CDCl3): = 30.88 (CH2C CH), 49.90 (C-5), 72.25
(CH2C CH), 73.20 (CH2Ph), 77.34 (CH2C CH), 95.08 (C-3),
127.99, 128.79, 128.84, 134.56, (C6H5), 171.59 (C-2), 172.42 (C-4).
4-Benzyloxy-1-tert-butylpyrrol-2(5H)-one (10f)
Prepared according to Method B from 7 (110 mg, 0.5 mmol) and
tert-butylamine (80 L, 0.75 mmol). Purified by flash chromatogra-
phy (hexane–EtOAc, 70:30 + 3% Me2NEt) to give 10f.
MS (CI, CH4): m/z (%) = 228 (100) [M + H+].
Yield: 81 mg (66%); colorless crystals; mp 51 °C.
IR (film): 3033, 1677, 1633 cm–1.
1H NMR (CDCl3): = 1.42 [s, 9 H, C(CH3)3], 3.92 (s, 2 H, CH2),
4.92 (s, 2 H, CH2Ph), 5.07 (s, 1 H, C=CH), 7.33–7.41 (m, 5 H,
Anal. Calcd for C14H13NO2 (227.3): C, 73.99; H, 5.77; N, 6.16.
Found: C, 73.71; H, 5.77; N, 6.14.
1-Benzyl-4-benzyloxypyrrol-2(5H)-one (10c)
Harom).
Prepared according to Method A from 7 (44 mg, 0.2 mmol) and ben-
zylamine (33 L, 0.3 mmol). Purified by flash chromatography
(hexane–EtOAc, 50:50) to give 10c.
MS (CI, CH4): m/z (%) = 246 (100) [M + H+].
Anal. Calcd for C15H19NO2 (245.3): C, 73.44; H, 7.81; N, 5.71.
Found: C, 73.20; H, 7.55; N, 5.59.
Yield: 38 mg (73%); colorless crystals; mp 97 °C.
IR (film): 3031, 1666, 1623 cm–1.
1H NMR (CDCl3): = 3.78 (s, 2 H, CH2), 4.58 (s, 2 H, NCH2Ph),
4.95 (s, 2 H, OCH2Ph), 5.18 (s, 1 H, C=CH), 7.24–7.37 (m, 10 H,
Harom).
13C NMR (CDCl3): = 45.41 (NCH2Ph), 50.17 (C-5), 73.07
(OCH2Ph), 95.32 (C-3), 127.48, 127.94, 128.75, 134.70, 137.42
(C6H5), 172.00 (C-2 and C-4).
4-Benzyloxy-1-phenylpyrrol-2(5H)-one (10g)
Prepared according to Method B from 7 (110 mg, 0.5 mmol) and
aniline (68 L, 0.75 mmol). HOAc (43 L, 0.75 mmol) was added
to the aromatic amine. Purified by flash chromatography (hexane–
EtOAc, 80:20 + 3% Me2NEt) to give 10g.
Yield: 72 mg (69%); colorless crystals; mp 58 °C.
IR (film): 3109, 3063, 3033, 1676, 1629, 1600, 1503, 1451 cm–1.
1H NMR (CDCl3): = 4.34 (s, 2 H, CH2), 5.05 (s, 2 H, CH2Ph), 5.27
(s, 1 H, C=CH), 7.06–7.65 (m, 10 H, Harom).
MS (CI, CH4): m/z (%) = 266 (100) [M + H+].
MS (CI, CH4): m/z (%) = 280 (100) [M + H+].
Anal. Calcd for C18H17NO2 (279.3): C, 77.40; H, 6.13; N, 5.01.
Found: C, 77.12; H, 6.11; N, 4.94.
(S)-4-Benzyloxy-1-(1-phenylethyl)pyrrol-2(5H)-one (10d)
Prepared according to Method B from 7 (220 mg, 1.0 mmol) and
(S)-(–)-1-phenylethylamine (192 L, 1.5 mmol). Purified by flash
chromatography (hexane–EtOAc, 80:20 + 3% Me2NEt) to give
10d.
Anal. Calcd for C17H15NO2 (265.3): C, 76.96; H, 5.70; N, 5.28.
Found: C, 76.65; H, 5.66; N, 5.17.
Acknowledgement
20
Yield: 217 mg (74%); colorless crystals; mp 84 °C; [ ]D – 40.3
(c 1.17, CH2Cl2).
IR (film): 3061, 3032, 1678, 1626 cm–1.
We are greatly indebted to Prof. Dr. Klaus Th. Wanner for his ge-
nerous support. We also thank Florian Plößl and Luzie Schmiz for
laboratory assistance.
1H NMR (CDCl3): = 1.57 (d, 3 H, J = 7.3 Hz, CHCH3), 3.53 (d, 1
H, J = 17.6 Hz, CH2), 3.83 (d, 1 H, J = 17.6 Hz, CH2), 4.93 (s, 2 H,
OCH2Ph), 5.15 (s, 1 H, C=CH), 5.59 (q, 1 H, J = 7.3 Hz, CHCH3),
7.24–7.40 (m, 10 H, Harom).
13C NMR (CDCl3): = 17.51 (CH3), 46.59 (C-5) 48.14 (CHCH3),
73.11 (CH2Ph), 95.41 (C-3), 127.06–128.81, 134.78, 141.12 (2
C6H5), 171.68 (C-2), 172.15 (C-4).
References and Notes
(1) (a) For a review covering tetramic acid based natural
products, see: Royles, B. J. L. Chem. Rev. 1995, 95, 1981.
(b) Jones, R. C. F.; Bates, A. D. Tetrahedron Lett. 1986, 27,
5285. (c) James, G. D.; Mills, S. D.; Pattenden, G. J. Chem.
Soc., Perkin Trans. 1 1993, 2581. (d) D´Allesio, R.;
Bargiotti, A.; Carlini, O.; Colotta, F.; Ferrari, M.; Gnocchi,
P.; Isetta, A.; Mongelli, N.; Motta, P.; Rossi, A.; Tibolla, M.;
Vanotti, E. J. Med. Chem. 2000, 43, 2557. (e) Zarantonello,
P.; Leslie, C. P.; Ferritto, R.; Kazmierski, W. M. Bioorg.
Med. Chem. Lett. 2002, 12, 561.
(2) 4-Methoxypyrrol-2(5H)-one was prepared from pyrrolidine-
2,4-dione3a in moderate yield by methylation with
diazomethane: Inami, K.; Shiba, T. Bull. Chem. Soc. Jpn.
1985, 58, 352.
(3) (a) Mulholland, T. P. C.; Foster, R.; Haydock, D. B. J. Chem.
Soc., Perkin Trans. 1 1972, 2121. (b) Van der Baan, J. L.;
Barnick, J. W. F. K.; Bickelhaupt, F. Tetrahedron 1978, 34,
223.
MS (CI, CH4): m/z (%) = 294 (100) [M + H+].
Anal. Calcd for C19H19NO2 (293.4): C, 77.79; H, 6.53; N, 4.77.
Found: C, 77.69; H, 6.51; N, 4.75.
(RS)-Methyl 2-(4-Benzyloxypyrrol-2(5H)-on-1-yl)-3-methylbu-
tanoate (10e)
Prepared according to Method B from 7 (110 mg, 0.5 mmol). How-
ever, instead of the free amine, DL-valine methyl ester hydrochlo-
ride (126 mg, 0.75 mmol) together with i-Pr2NEt (166 l, 1.0 mmol)
was employed. Purified by flash chromatography (hexane–EtOAc,
70:30 + 3% Me2NEt) to give 10e.
Yield: 96 mg (65%); colorless crystals; mp 75–78 °C.
IR (film): 3096, 1733, 1666, 1614 cm–1.
Synthesis 2002, No. 7, 869–874 ISSN 0039-7881 © Thieme Stuttgart · New York

874
F. F. Paintner et al.
PAPER
(4) For the synthesis of 4-O-alkyl tetronates starting from
tetronic acids, see: Schobert, R.; Siegfried, S. Synlett 2000,
686; and references cited therein.
(5) (a) Kochhar, K. S.; Carson, H. J.; Clouser, K. A.; Elling, J.
W.; Gramens, L. A.; Parry, J. L.; Sherman, H. L.; Braat, K.;
Pinnick, H. W. Tetrahedron Lett. 1984, 25, 1871. (b) Duc,
L.; McGarrity, J. F.; Meul, T.; Warm, A. Synthesis 1992,
391.
(10) Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J.
Org. Chem. 1995, 60, 7272.
(11) For tandem reductive amination-lactamizations, see: Abdel-
Magid, A. F.; Harris, B. D.; Maryanoff, C. A. Synlett 1994,
81; and references cited therein.
(12) Direct reductive aminations of aldehyde 7 with sodium
cyanoborohydride according to Borch and co-workers
involving in situ generated imines gave only small amounts
(< 20%) of the desired tetramates 10 in addition to 4-
benzyloxyfuran-2(5H)-one and a series of unidentified side-
products, see: Borch, R. F.; Bernstein, M. D.; Durst, H. D. J.
Am. Chem. Soc. 1971, 93, 2897.
(6) Meul, T. Eur. Pat. Appl. EP 252363, 1988; Chem. Abstr.
1988, 108, 186563.
(7) (a) Schlessinger, R. H.; Iwanowicz, E. J.; Springer, J. P.
Tetrahedron Lett. 1988, 29, 1489. (b) Schlessinger, R. H.;
Pettus, T. R. R. J. Org. Chem. 1994, 59, 3246.
(8) Inanaga, J.; Baba, Y.; Hanamoto, T. Chem. Lett. 1993, 241.
(9) Nicolaou, K. C.; Webber, S. E. Synthesis 1986, 453.
(13) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;
Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849.
Synthesis 2002, No. 7, 869–874 ISSN 0039-7881 © Thieme Stuttgart · New York