Highly stereoselective additions of cuprates to a polyfunctional enone

Article abstract of DOI:10.1016/S0957-4166(97)00148-1

The stereoselectivity of the addition of cuprates to a polyfunctional γ-alkoxy enone depended on the γ-hydroxyl protective group. Protection as a blocking silyl ether gave the best results (de=93-95%). An unexpected and original cleavage-oxidation reactio

Full text of DOI:10.1016/S0957-4166(97)00148-1

Tetrahedron: A,!wnmettT, Vol. 8, No. 10, pp. 1515-1518. 1997
(~) 1997 Elsevier Science Ltd. All rights reserved
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Highly stereoselective additions of cuprates to a polyfunctional enone
S. A m i g o n i , J. Schulz, L. Martin and Y. Le F l o c ' h *
Laboratoire de Synth6ses et Activations de Biomoldcules, ESA 6052, Avenue du G6n6ral Leclerc, 35700
Rennes, France
Abstract:
The stereoselectivity of the addition of cuprates to a polyfunctional y-
alkoxy enone depended on the y-hydroxyl protective group. Protection as a blocking silyl
ether gave the best results (de=93-95%). An unexpected and original cleavage-oxidation
reaction at ambient temperature transformed the addition products into well known lactones
well characterized in the literature. Comparison of the spectral data of these lactones
with those in the literature allowed the configuration of the new asymmetric centers to be
assigned. (~) 1997 Elsevier Science Ltd
The polyfunctional enone, (3E,5S)-l,l-diethoxy-5-t-butyldiphenylsilyloxy-hex-3-en-2-one 1, was
synthesizedI from (S)-ethyl lactate as a potential precursor of natural macrodiolides 3 and their
analogues. Indeed, the enone function should enable the introduction of many functions to the
appropriate positions in the desired analogues. One possible modification was the addition of alkyl or
aryl groups in position 4 of the enone by addition of cuprates (Scheme 1).
.... ]
5
"
~
O
OP
~
R
OH i
. . . . . . . .
......
. . . . . . . . . . .
.
.
R
0 \\.
OP
,."[x,~CH(OEt)2
O
l
Scheme I.
According to our experience, the reaction of the enone 1 with higher order cuprates2 provoked the
formation of 1-2 addition products only. In order to execute these !-4 addition reactions, we used
lower order cyano-cuprates (RCu(CN)Li)3,4 that we obtained under inert atmosphere in ether medium
with two equivalents of copper cyanide per equivalent of lithiated reagent. The cuprates used were of
three types: MeCu(CN)Li; nBuCu(CN)Li; PhCu(CN)Li; the stereoselectivity of the reaction depends
strongly on the protecting group on the y-hydroxyl function (Table 1).
It is interesting to note that such additions to ot,13-insaturated-y-alkoxy esters have been extensively
studied in the literature5-7 whereas few examples of addition to y-alkoxy enones are known. The best
des were obtained for the enone 1 having the hydroxyl function protected as a silyl ether. We therefore
chose to study more closely the corresponding addition products since for a total synthesis, only des
around 90% are acceptable at the first stages. The phenyl group was introduced with low efficiency
* Corresponding author. Email: Ylefloch@aol.com
|515

1516
S. AMIGONI et al.
Table 1. Influence of the protective groups on the stereoselectivity of the cuprate additions
OP
OP
RCu(CN)Li
Et20
~_ ...... * ~ " , ~ CH(OEt)2
0
R
O
enone 1
P
3-5
Compound
R
Temperature de*(+,- 3%) Yields
(°C)
3a
3b
3c
4a
4b
4c
5a
5b
5c
MEM
Me
n-Bu
Ph
Me
n-Bu
Ph
Me
n-Bu
Ph
-30
-50
-50
-30
-50
-50
-30
-50
-50
40 %
50 %
55 %
60 %
75 %
95 %
94 %
93 %
95 %
85 %
80 %
48 %
78 %
88 %
41%
88 %
82 %
65 %
Bn
SitBuPh2
because of its steric hindrance. This could be improved by running the reaction at - 3 0 ° C instead of
- 5 0 ° C , but at the cost of a loss of diastereoselection, which was not the pursued goal.
All the diastereomeric excesses could be calculated by the analysis of the I H NMR (400 MHz,
CDCI3) spectra thanks to the splitting of the acetal proton signals. In order to find the absolute
configuration of these addition products, we transformed them into molecules known in the literature.
In the case of 1-4 additions of cuprates to c~,13-insaturated ¥-alkoxy esters, the hydroxyl function of
the addition product is deprotected and cyclises directly on the ester function to give the corresponding
lactones (Scheme 2).5
~ P ~
' , , ~ _ _ ~ O
P
.....
~
O R '
R
O
R
Scheme 2.
In the case of the addition products of the enone, deprotection of the alcohol function did not give
a lactone directly but a cyclic hemiacetal.
An error of manipulation at the time of the cleavage of a para anisyl ether by the CAN in aqueous
acetonitrile medium, allowed us to observe that at ambient temperature, this reagent provoked an
oxidative cleavage. Indeed, the secondary protected alcohol function of compound 6 afforded in these
conditions an aldehyde 78 with a shorter skeleton (Scheme 3).
OSitBuPh2
~ , , . . , ~ C H { O E t )2 CAN, CH3CN/H20
OSkBuPh2
rt, 20 min
~
""J"'/~CHO
7
M e O ' ~O 6
(60 %)
Scheme 3.
Some reactions of this type had been already observed by Trahanosky et al.9 in the case of tertiary
alcohols. We thus had the idea to apply this method to the hemiacetals previously obtained. The
quaternary carbon had to be transformed into a carbonyl function in order to produce the iactones
known in the literature (Scheme 4). Table 2 summarizes the results obtained and it appears that the
new stereogenic carbons created had the R configuration.

Addilions of cuprates to a polyfunctional enone
1517
OSitBuPb2
' , . ~ O
, , " ~ ' ~ C H ( O E t ) 2
O
R
/ ~ b
R
\
,,
O- OH
8a-e
5a-c
a
" ~ ' ~ C H ( O E t ) 2
R
a) nBu~N*F, 4 eq, THF, rt, 4days : b) CAN. 3 eq, CH3CN/HzO (3/1), 20 rain, ft.
Scheme 4.
Table 2.
Cuprates
Addition product
Configuration
lactoncs
structureb
Product to
yieldsc
50 %
de (%)a
94 %
MeCu(CN)Li
C4(R)
'
~
O
OSiBuPh~
,
, " [ ~ OCH(OEt)2
8a
5a
nBuCu(CN)Li
PhCu(CN)Li
93%
95 %
40 %
40 %
C~(R)
C4(R)
OSitBuPh2
,,/~CH(OEI)2
~
o
5b
8b
8e
OSitBuPbz
, , " " ~ OCH(OEi)~-
5C
a- diastereomenc excesses were determined b'
NMR (400 MHz, CDCI3)
b- The lactone structures were determined by comparison with the analytical data of the literature and comfirmcd by
NOE studies
c- Global yields from the addition products (5a-c)
All these conclusions were in agreement with the hypotheses of Yamagushi5'6 and Morokuma.7
Indeed the modified Felkin-Ahn models they used anticipated an anti addition for some cx,13-
unsaturated esters with a trans configuration (Scheme 5).
NuI--'N
outside
inside
anti compound
Scheme 5.
These cuprate additions allowed us to obtain precursor compounds of macrodiolides with a high
diastereomeric purity. In order to prove the configuration of the new asymmetric centers, an unexpected
oxidative cleavage transformed the addition products into lactones fully characterized in the literature.
References
(1) Dumartin, H.; Le Floc'h, Y.; Gree, R. Tetrahedron Lett. 1994, 35, 6681-84.
(2) Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski, J. A. Tetrahedron 1984, 40, 5005-38.
(3) Acker, R. D. Tetrahedron Lett. 1977, 3407-10; 1978, 2399-402.
(4) Four, E; Le Tri, P.; Riviere, H. J. Organomet. Chem. 1977, 136, 103-10.

1518
(5)
S. A~,I]GONI et aL
Yamamoto, Y.; Nishii, S.; Ibuka, T. J. Chem. Soc., Chem. Commun. 1987, 464-6.
(6) Yamamoto, Y.; Chouan, Y.; Nishii, S. Ibuka, T.; Kitahara, H. J. Ant. Chem. Soc. 1992, 114,
7652-60.
(7) Dorigo, A. E.; Morokuma, K. J. Am. Chem. Soc. 1989. l 11, 6524-36.
(8) Analytical data of compound 7: Colorless oil, Rf=0.80 E/PE (50/50), MS (CI, NH3) m/z 356.5,
339.3, 281.0. 1H NMR (400 MHz, CDC13) 6 (multiplicity, J in Hz): 9.51 (d, J=7.6, IH), 7.38
(m, 10H), 6.73 (dd, J=15.8, 4.6, 1H), 6.25 (ddd, J=15.3, 7.6, 1.5, 1H), 4.56 (m, IH), 1.19 (d,
J=6.1, 3H), 1.08 (s, 9H). 13C NMR (100 MHz, CDCI3) 6: 19.2, 23.1, 26.9, 68.7, 127.7, 129.9,
133.2, 133.7, 135.7, 135.8, 160.5, 193.8.
Trahanovsky, W. S.; Macaulay, D. B. J. Org. Chem. 1973, 38, 1497-99.
(9)
(10) Analytical data of compounds 5a-c: 5a: Colorless oil, Calcd anal for C27H4004Si: C: 71.01%, H:
8.83%; Found: C: 71.24%, H: 8.92%. [O~]25D=+2.8 (c 1.07 CH2C12). Rf=0.60 E/PE (50/50). IR
(film): 1728 cm I. 1H NMR (400 MHz, CDCI3) 6 (multiplicity, J in Hz): 7.80-7.30 (m, 10H),
4.49 (s, 1H), 3.75-3.40 (m, 5H), 2.72 (dd, J=17.8, 4.1, 1H), 2.39 (dd, J=17.8, 9.2, IH), 2.19 (m,
1H), 1.23, 1.20 (2t, J=7.1,6H), 1.04 (s, 9H), 0.94 (d, J=6.1, 3H), 0.90 (d, J=7.1, 3H). 13C NMR
(100 MHz, CDCI3) 8: 15.1, 15.4, 19.4, 19.6, 27.0, 35.4, 39.9, 63.1, 63.2, 72.7, 102.7, 127.4,
127.5, 129.4, 129.5, 134.0, 134.9, 135.9, 205.6.5b: Colorless oil, Calcd anal for C30H4604Si:
C: 72.24%, H: 9.30%; Found: C: 72.06%, H: 9.16%. [¢x]25D=-3.3 (c 2.77 CH2CI2). Rf=0.70
E/PE (20/80). IR (film): 1729 cm-1. 1H NMR (400 MHz, CDC13) 6 (multiplicity, J in Hz):
7.80-7.30 (m, 10H), 4.51 (s, IH), 3.86 (m, 1H). 3.70-3.40 (m, 4H), 2.73 (dd, J=18.3, 5.6, IH),
2.51 (dd, J=18.3, 7.1, 1H), 2.01 (m, 1H), 1.50-1.10 (m, 6H), 1.24, 1.21 (2t, J=7.1, 6H), 1.04 (s,
9H), 0.94 (d, J=6.1, 3H), 0.83 (t, J=7.1.3H). 13C NMR (100 MHz, CDCI3) 8: 14.0, 15.1, 19.4,
20.4, 22.9, 27.1,29.6, 30.5, 37.7, 40.1,63.2, 63.3, 70.6, 102.8, 127.3, 127.5, 129.4, 129.5, 133.9,
134.9, 135.9,206.1.5c: Colorless oil, Calcd anal for C32H4204Si: C: 74.09%, H: 8.17%; Found:
C: 74.32%, H: 8.11%. [~x]25D=+l 1.5 (c 1.91 CH2C12). Rf=0.60 E/PE (20/80). IR (film): 1731
cm-1. IH NMR (400 MHz, CDCI3) 6 (multiplicity, J in Hz): 7.70-7.30 (m, 10H), 7.25-7.05
(m, 5H), 4.35 (s, 1H), 3.96 (m, IH), 3.60-3.05 (m, 7H), 1.17 and 1.11 (2t, J=7.1, 6H), 1.03 (s,
9H), 0.80 (d, J=6.1, 3H). 13C NMR (100 MHz. CDC13) 8: 15.0, 15.1, 19.4, 21.5, 27.0, 39.4,
48.3, 62.9, 73.1, 102.6, 126.4-141.9, 205.2.
(Received in UK 27 February 1997; accepted 2 April 1997)