Model study of the Hoppe reaction between racemic titanated crotyl carbamate and enantiopure aldehyde or γ-lactol

Article abstract of DOI:10.1055/s-1998-1872

In our strategy for the total synthesis of tylonolide 2, aglycon of tylosin 1, and for the construction of the eastern part C1-C9, we planned to carry out a Hoppe homoaldolisation. In a model study, reaction was performed between racemic titanated crotyl carbamate (±)-3b and optically active aldehydes 6a-c. The expected syn-anti adducts 7a-c were obtained in good isolated yield together with the anti-anti isomer 8a-c. Interestingly, the γ-lactol 6d was also tested and delivered the syn-anti 7d compound in 70% isolated yield.

Full text of DOI:10.1055/s-1998-1872

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Model Study of the Hoppe Reaction Between Racemic Titanated Crotyl Carbamate
and Enantiopure Aldehyde or γ-Lactol.
Isabelle Berque, Patrick Le Ménez, Patrick Razon, Claude Anies, Ange Pancrazi, Janick Ardisson, Alain Neuman, Thierry Prangé, Jean-
a
a
a
a
a*
a*
b
b*
a
Daniel Brion
a
Laboratoire de Chimie Thérapeutique, URA 1843 BIOCIS, Faculté de Pharmacie, 92296, Châtenay-Malabry, France.
b
Laboratoire de Chimie Structurale Biomoléculaire, Université Paris Nord, 74 rue Marcel Cachin, F-93017 Bobigny, France.
Received 27 July 1998
Abstract: In our strategy for the total synthesis of tylonolide 2, aglycon
of tylosin 1, and for the construction of the eastern part C1-C9, we
planned to carry out a Hoppe homoaldolisation. In a model study,
reaction was performed between racemic titanated crotyl carbamate
(±)-3b and optically active aldehydes 6a-c. The expected syn-anti
adducts 7a-c were obtained in good isolated yield together with the anti-
anti isomer 8a-c. Interestingly, the γ−lactol 6d was also tested and
delivered the syn-anti 7d compound in 70% isolated yield.
In this paper, we report the results obtained in a study of the Hoppe
homoaldolisation reaction using the racemic titanated (E)-crotyl
3
carbamate 3b and optically active butanals 6a-d with the desired C3
and C4 tylosin configurations.
7
The racemic Hoppe's reagent 3b was prepared in the usual manner and
8
the aldehydes 6a-d from the known lactone 5 (Scheme 3). Reaction
with aldehyde 6a resulted in the formation of an unseparable mixture of
syn-anti 7a and anti-anti 8a isomers in 75% yield and a 60:40 ratio
(Scheme 4, table 1, entry 1).
In our synthetic approach to tylonolide 2, aglycon of the macrocyclic
1
antibiotic tylosin 1 (scheme 1), the western fragment C10-C15 was
2
prepared earlier. Stereospecific control at centers C14 and C15 was
3
achieved using an extension of the Hoppe reaction.
Scheme 1
The Hoppe reaction is an allylation of achiral aldehydes with crotyl
N,N-diisopropyl carbamate 3, described as a "homoaldol reaction" by
the authors. It involved the preparation of an optically active titanated
crotyl carbamate 3b via the intermediate formation of an optically active
Scheme 3
lithio crotyl carbamate 3a by crystallization of its complex with
i
(-)-sparteine [n-BuLi/(-)-sparteine, Ti(O Pr) ] (Scheme 2). The
4
4
transition state was assumed to be a Zimmerman-Traxler cyclic model,
responsible for the formation of the Z-anti homoallylic alcohol 4. This
reaction was earlier performed between the optically active allyltitanate
3,4
3b and achiral aldehydes, and in a few cases between optically active
5
partners, or between an enantiopure aldehyde and racemic titanated
6
crotyl carbamate.
Scheme 4
When the same conditions were applied to the two silylated aldehydes
6b and 6c, reactions proceeded in better yields to deliver 7b,c and 8b,c
derivatives (Table 1, entries 2 and 4). For the bis(triethylsilyl) aldehyde
6b the diastereoselectivity was unchanged but increased for the bulkier
7
bis(triisopropylsilyl) aldehyde 6c (Table 1, entries 2 and 3).
When
1 equivalent of crotyl carbamate 3 was used in the
homoaldolisation of aldehyde 6c, yield decreased while the selectivity
Scheme 2
remained identical (Table 1, entry 4).

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SYNLETT
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Lactol 6d did not react with (±)-crotyltitanate 3b at -78°C but when
temperature was maintained at 0°C for 4 h, reaction took place and both
anti isomers 7d and 8d were isolated together with the syn adduct 9d
(Scheme 5, table 1, entry 5). The best result was obtained when 3
equivalents of base (n-BuLi/TMEDA) were used. In theory, two
equivalents of the carbamate and two equivalents of base are needed. An
additional equivalent of base for opening the lactol seems to be required
for a better yield (Table 1, entry 6)
Scheme 6
was crystallized. An X-ray analysis of 16 then established the absolute
11
configuration at C3, C4, C5 and C6.
Treatment of the syn compound 9d with Bu NF led to the corresponding
4
triol which was then transformed into the crystalline diester 18 for
11
which an X-ray analysis confirmed the proposed structure.
Scheme 5
In order to establish the structure of the homoallylic alcohols obtained
during this study, some chemical transformations were performed.
9
Starting from the minor anti-anti compounds 8b-d, triol 10 was first
prepared by treatment with Bu NF (Scheme 6). At this stage a selective
4
protection of the primary hydroxyl group led to the 1,3-diol derivative
11 which was transformed into the acetonide compound 12.
13
A
C NMR study was effected on 12 and chemical shifts of the
acetonide methyl groups were observed at 23.4 and 25.0 ppm which are
characteristic for a trans relationship between the two 1,3 oxygen
10
functions at C3 and C5. To determine the trans stereoselectivity at C5-
C6, starting from 8c, an ozonolysis was performed on the
vinylcarbamate function followed by reduction with NaBH , to yield the
4
corresponding diol derivative 13. This diol was then transformed into
the acetonide 14. The C5-C6 stereochemistry was proved by H NMR
Scheme 7
1
analysis which showed a diaxial coupling constant J H -H = 9.3 Hz.
5
6
The allylation reaction developed here, between racemic titanate 3b and
optically active aldehydes 6a-c, proceeded in good yield when the
reaction was performed with an excess of the racemic crotyl carbamate.
For the structural proof of the major adducts 7b-d, the corresponding
triol 15 was formed as before by treatment with Bu NF. Etherification of
4
the primary alcohol then gave access to the trityl derivative 16 which
The
best
diastereoselectivity
was
obtained
when
the

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bis(triisopropylsilyloxy) 6c was used. Interestingly lactol 6d could be
advantageously employed in the Hoppe reaction to deliver the expected
syn-anti 7d derivative in 70% isolated yield, along with small amounts
of the anti-anti 8d and the syn-syn 9d isomers.
vacuo. The residue was purified by flash chromatography on silica
gel (hexane/ethyl acetate, 90:10) to give compound 7c (660 mg,
70% yield) and 8c (208 mg, 22% yield).
1
7c : H NMR (400 MHz) δ 0.95 (d, 3H, J = 7.0 Hz, CH , CH -3),
3
3
0.97 (d, 3H, J = 7.0 Hz, CH , CH -5), 1.07 {s, 42H, 6CH +
As compounds 7c and 7d were obtained in good yield and present the
expected configurations at C3, C4, C5 and C6, this homoaldol reaction
was used in a synthetic approach to the eastern part of tylonolide 2 via a
modified carbamate derivative in order to introduce the side chain at C-
6.
3
3
12CH ,
2Si[CH(CH ) ] },
1.24
{(m,
12H,
4CH ,
3
3
3 2 3
N[(CH(CH ) ] }, 2.11 (m, 1H, H-3), 2.86 (qt, 1H, J = 6.0, 10.0
3 2 2
Hz, H-5), 3.67 (dd, 1H, J = 8.0, 2.0 Hz, H-4), 3.67 (dd, 1H, J =
9.1, 8.4 Hz, Ha-1), 3.75 (dd, 1H, J = 9.1, 4.8 Hz, Hb-1), 3.78 {m,
1H, N[(CH(CH ) ] }, 4.05 (ddd, 1H, J = 8.5, 5.0, 3.0 Hz, H-2),
3 2 2
4.12 {m, 1H, N[(CH(CH ) ] }, 4.79 (dd, 1H, J = 10.0, 6.5 Hz, H-
6), 7.10 (d, 1H, J = 6.5 Hz, H-7). C NMR (100.6 MHz) δ 5.7
3 2 2
References and Notes
13
1
Tatsuta, K.; Amemiya, Y.; Kanemura, Y.; Takahashi, H.;
Kinoshita, M. Tetrahedron Lett. 1982, 23, 3375. Nicolaou, K. C.;
Seitz, S. P.; Pavia, M. R. J. Am Chem. Soc. 1982, 104, 2030.
Masamune, S.; Lu, L. D-L.; Jackson, W. P.; Kaiho, T.; Toyoda, T.
J. Am. Chem. Soc. 1982, 104, 5523. Grieco, P. A.; Inanaga, J.; Lin,
N-H.; Yanami, T. J. Am. Chem. Soc. 1982 104, 5781. Tanaka, T.;
Oikawa, Y.; Hamada, T.; Yonemitsu, O. Chem. Pharm. Bull. 1987,
35, 2219. Omura, S. Ed. Macrolides Antibiotics Ed. Academic
Press, 1984. Kirst, H. A. in Recent progress in the Chemical
Synthesis of Antibiotics Lukacs, G.; Ohno, M. ED, Springer
Verlag 1990, 39.
(CH , CH -3), 11.1 {3CH, Si[CH(CH ) ] }, 12.3 {3CH,
3
3
3 2 3
Si[CH(CH ) ] }, 17.1 {12CH , 2Si[CH(CH ) ] }, 17.3 (CH ,
3 2 3
3
3 2 3
3
CH -5), 19.6, 20.6 {4CH , N[(CH(CH ) ] }, 33.6 (CH, C-5), 37.3
3
3
3 2 2
(CH, C-3), 44.8, 45.9 {2CH, N[(CH(CH ) ] }, 64.0 (CH , C-1),
3 2 2
2
77.0 (CH, C-4), 77.9 (CH, C-2), 113.4 (CH, C-6), 134.5 (CH, C-
7), 152.2 (C, CO).
1
8c : H NMR (400 MHz) δ 0.81 (d, 3H, J = 7.0 Hz, CH , CH -3),
3
3
1.07 {s, 42H, 6CH + 12CH , 2Si[CH(CH ) ] }, 1.18 (d, 3H, J =
3
3 2 3
7.0 Hz, CH , CH -5), 1.21 {(m, 12H, 4CH , N[(CH(CH ) ] },
3
3
3
3 2 2
1.92 (m, 1H, H-3), 2.79 (m, 1H, H-5), 3.57 (dd, 1H, J = 9.0, 1.0
Hz, H-4), 3.66-4.20 (m, 6H, H -1 + N[(CH(CH ) ] + OH + H-2},
2
3 2 2
2
3
Le Ménez, P.; Fargeas, V.; Berque, I.; Poisson, J.; Ardisson, J.;
Lallemand, J.-Y.; Pancrazi, A. J. Org. Chem. 1995, 60, 3592.
4.91 (dd, 1H, J = 10.0, 6.5 Hz, H-6), 7.0 (d, 1H, J = 6.5 Hz, H-7).
13
C NMR (100.6 MHz) δ 12.1 {3CH, Si[CH(CH ) ] }, 12.5
3 2 3
{3CH, Si[CH(CH ) ] }, 13.7 (CH , CH -3), 18.1 {12CH ,
Hoppe, D. Angew. Chem., Int. Ed. Engl. 1984, 23, 932. Hoppe, D.;
Zschage, O. Angew. Chem., Int. Ed. Engl. 1989, 28, 69. Zschage,
O.; Hoppe, D. Tetrahedron 1992, 48, 5657 and references cited
therein.
3 2 3
3
3
3
2Si[CH(CH ) ] }, 18.4 (CH , CH -5), 20.5, 21.6 {4CH ,
3 2 3
3
3
3
N[(CH(CH ) ] }, 33.3 (CH, C-5), 40.7 (CH, C-3), 45.9, 46.7
3 2 2
{2CH, N[(CH(CH ) ] }, 64.9 (CH , C-1), 77.0 (CH, C-4), 78.8
3 2 2
2
(CH, C-2), 110.8 (CH, C-6), 134.5 (CH, C-7), 152.7 (C, CO).
4
5
Hoppe, D.; Hense, T. Angew. Chem., Int. Ed Engl. 1997, 36, 2282.
8
9
Henrot, S.; Larchevêque, M.; Petit, Y. Synth. Commun. 1986, 16,
183. Hamada, Y.; Yokokawa, F.; Kabeya, M.; Hatano, K.; Kurono,
Y.; Shiori, T. Tetrahedron Lett. 1996, 52, 8297.
Smith, N. D.; Kocienski, P. J.; Street, S. D. A. Synthesis 1996,
652. Férézou, J.-P.; Julia, M.; Li, Y.; Liu, L. W.; Pancrazi, A. Bull.
Soc. Chim. Fr. 1995, 132, 428. Férézou, J.-P.; Julia, M.;
Khourzom, R.; Li, Y.; Liu, L. W.; Pancrazi, A.; Robert, P. Synlett
1991, 611.
The mixture of 7a and 8a was treated in acidic conditions
(Amberlyst 15, MeOH, 20°C, 12 h, 82% yield) to deliver triols 15
and 10.
6
7
Hoffmann, R. W.; Lanz, J.; Metternich, R.; Tarara, G.; Hoppe, D.
Angew. Chem., Int. Ed Engl. 1987, 26, 1145. Hoppe, D.; Tarara,
G.; Wilckens, M. Synthesis 1989, 83.
10 Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31,
945.
To a solution of N,N,N',N'-tetramethylethylenediamine (TMEDA,
0.5 mL, 3.3 mmol, 2.2 equiv) in dry diethyl ether (1 mL) at -78°C,
under argon atmosphere, was added n-BuLi (1.6M in hexane, 2
mL, 3.3 mmol, 2.2 equiv). After stirring for 30 min at -78°C, a
11 The data of X-ray structure analyses were deposited as CIF
archive files with the Cambridge Crystallographic Data Center
(CCDC), 12 Union Road, Cambridge CB2 IEZ, UK. They are also
available by e-mail from one of us at prange@sgi1sb.univ-
paris13.fr.
3
solution of the crotyl carbamate 3b (597 mg, 3 mmol, 2 equiv),
in dry diethyl ether (2 mL), was slowly added. After stirring for 30
Compound 16: Space Group: P2 monoclinic, Z=2. Parameters:
1
i
min at -78°C, titanum tetraisopropoxide (Ti(O Pr) , 2.7 mL, 9
a=17.206(8) Å, b=8.739(2) Å, c=12.605(3) Å, β=109.99(8)°,
4
3
mmol, 6 equiv) was slowly added, and the mixture became limpid
and turned orange. After 30 min at -78°C, the aldehyde 6c (645
mg, 1.5 mmol), in dry diethyl ether (1 mL) was slowly added and
the reaction mixture was stirred for 2 h at -78°C and quenched at
-78°C by addition of methanol (5 mL). The solution was then
poured into a mixture of diethyl ether/aqueous HCl solution (2N).
After extraction with diethyl ether, the organic layer was washed
with brine, dried over sodium sulfate, filtered and concentrated in
V=1781(2) Å , crystal size=0.5x0.2x0.2 mm, d =1.092, abs. coef.
x
-1
0.59 mm , F
= 634. Anisotropic refinement R=5.4 % (obs.
000
data: 1139 F's).
Compound 17: Space Group: P2 2 2 orthorhombic, Z=4.
1
1 1
Parameters: a=27.310(4) Å, b=18.793(4) Å, c=9.350(1) Å,
3
V=4799(1) Å , crystal size = 0.4x0.3x0.03 mm, d = 1.312, abs.
x
-1
coef. 0.82 mm , F
= 1992. Anisotropic refinement : R=5.5%
000
(obs. data : 2516 F's).