On the absolute stereochemistry of (-)-4-alkylnonan-2-ones

Article abstract of DOI:10.1016/S0957-4166(02)00574-8

The alcohols (S)-C₅H₁₁ⁿCH(R)CH₂OH (R=Me, Et) have been prepared by Evans' alkylation chemistry (>98% e.e.). For R=Me [α]_D=-15.5 (c 0.31, MeOH); for R=Et [α]_D=+6.8 (c 0.31, MeOH). Equivalent alcohols are obtained by Baeyer-Villiger oxidative cleavage of (S)-(-)-C₅H₁₁ⁿCH(R)CH₂COMe (R=Me, 85% e.e.; R=Et, 62% e.e.) derived from catalytic asymmetric conjugate addition. Thus, AlMe₃ or ZnEt₂ addition to the Si face of the enone generates a (-) antipode with a 4S stereocentre.

Full text of DOI:10.1016/S0957-4166(02)00574-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2177–2180
On the absolute stereochemistry of (−)-4-alkylnonan-2-ones
Victor Garcia-Ruiz and Simon Woodward*
School of Chemistry, University of Nottingham, Nottingham NG7 2RD, UK
Received 4 September 2002; accepted 11 September 2002
n
Abstract—The alcohols (S)-C H CH(R)CH OH (R=Me, Et) have been prepared by Evans’ alkylation chemistry (>98% e.e.).
5
11
2
For R=Me [h] =−15.5 (c 0.31, MeOH); for R=Et [h] =+6.8 (c 0.31, MeOH). Equivalent alcohols are obtained by
D
D
n
Baeyer–Villiger oxidative cleavage of (S)-(−)-C H CH(R)CH COMe (R=Me, 85% e.e.; R=Et, 62% e.e.) derived from catalytic
5
11
2
asymmetric conjugate addition. Thus, AlMe or ZnEt addition to the Si face of the enone generates a (−) antipode with a 4S
3
2
stereocentre. © 2002 Elsevier Science Ltd. All rights reserved.
1
. Introduction
Reaction of 1 with AlMe , utilising 5.5 mol% (S)-L
A
8
3
under our improved conditions, afforded a 53% iso-
lated yield of (−)-2 in 85% e.e. by chiral GC. Dramati-
cally improved conversion of (−)-2 to (−)-3 could be
attained by treatment with Na CO /CF CO H followed
Previously, we have presented copper(I)-catalysed addi-
tions of AlMe and ZnEt using chiral thioether ligands
and have often employed (E)-non-3-en-2-
one 1 as a standard test substrate (Scheme 1, in part).
We assigned the (−) antipode of the methyl addition
product to be (S)-2 based on its degradation to 2-
methylheptan-1-ol 4 and subsequent comparison of the4
chiroptical data to literature values for (S)-(−)-4.
Based on the GC elution order of the analogous ethyl
3
2
1
2,3
L and L
A
B
2
4
3
2
9
by hydrolysis of the trifluroacetate/acetate mixture.
1
The specific rotation of this catalyst derived (−)-4
[−14.8 (c 0.31 MeOH)] was comparable to the pub-
lished value for (S)-(−)-4 [−13.1 (c 1.15 in CHCl )] and
3
similar to that for the related compound (S)-(−)-6
addition product 3 on the same oktakis-(6-O-methyl-
5
2
,3-di-O-pentyl)-g-cyclodextrin column as 2 we tenta-
tively assigned (−)-3 to also have (S) stereochemistry.
This deduction is not satisfactory for a number of
reasons: Firstly, full experimental details on the purity
and preparation of literature (S)-(−)-4 are not avail-
4
able. Secondly, the Na S O -based Baeyer–Villiger oxi-
2
2
8
1
dation we used to obtain our sample of (S)-(−)-4 was
inefficient and could not be used in the degradation of
the equivalent ethyl compound. Thirdly, the assump-
tion that the chiral GC elution order predicts the
stereochemistry may not be correct. Finally, we
included a typographical error in the ligand-to-product
correlation in our original disclosure regarding ligand
6
L . Recently, Hoveyda used our (S)-(−)-3 correlation
B
in a communication using L attaining 3 in very high
C
7
enantiomeric excess. For all of these reasons we felt it
was appropriate to explicitly check the required correla-
tions again and this short note gives the outcome of this
study.
Scheme 1. Methyl and ethyl addition products, from asym-
metric conjugate additions to (E)-1, and their Baeyer–Villiger
derived alcohols. All [h]D values were obtained in MeOH at c
0.31.
*
0
Corresponding author. Tel.: +44-115-951-3541; fax: +44-115-951-
564; e-mail: simon.woodward@nottingham.ac.uk
3
957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00574-8

2
178
V. Garcia-Ruiz, S. Woodward / Tetrahedron: Asymmetry 13 (2002) 2177–2180
1
0
[
−14.2 (c 0.31, MeOH)]. Treatment of 1 with ZnEt2
83% e.e. the major antipode eluting second on our GC
column. This sample when subjected to Baeyer–Villiger
degradation with Na CO /TFA yielded (R)-5 with a
negative optical rotation in agreement with our own
studies.
and (R)-L (20 mol%) under the literature conditions
B
yielded (−)-3 [−2.4 (c 0.31 MeOH)] with the chiral GC
elution properties expected for the (S) enantiomer.
However, Baeyer–Villiger degradation using percarbon-
ate/TFA yielded 5 with a positive rotation (Scheme 1).
This finding necessitates independent synthesis of (S)-5
to make sure this is the (+) antipode and that a
stereochemical misassignment has not occurred.
2
4
3
. Conclusion
We have demonstrated explicitly that all stereochemical
assignments made for the methyl and ethyl addition
products derived from (E)-1 are correct. However, it is
apparent that the optical rotations of the alkyl addition
2
. Independent synthesis
11
Ample literature precedent shows that alkylations of
the lithium enolate (S)-7 occur exclusively from the top
face, yielding, in our cases, the required (S) centre after
alkylation with methyl or ethyl iodide (Scheme 2).
1
2
1
2
products of (E)-R CHꢀCH(COR ) enone (R , R =
alkyl) and their Baeyer–Villiger oxidation products are
small and subject to reversal in an unpredictable man-
13
ner. Therefore, stereochemical assignments based only
on comparison of specific rotation data will be inappro-
priate in some cases.
4
. Experimental
The general experimental setup has been described
1–3
before. Optical rotations were measured on a JASCO
DIP-370 instrument. Key specific rotations in units of
−
1
2
−1
3
1
0
deg. cm
g
(c in g/100 cm ) are reported in
Schemes 1 and 2.
4
4
.1. Asymmetric conjugate additions
.1.1. (S)-(−)-4-Methylnonan-2-one, (S)-(−)-2. To a
stirred 0.028 M solution of (S)-L (35 mg, 0.098 mmol)
Scheme 2. Alternative preparations of (S)-4 and (S)-5 using
Evans’ auxiliary chemistry. Enolate (S)-7 was alkylated with
RI (R=Me, Et); [h]D values are under (c 0.31, MeOH)
conditions.
A
and [Cu(MeCN) ]BF (28 mg, 0.089 mmol) in absolute
4
4
THF at −45°C was simultaneously added (E)-3-nonen-
-one in THF (250 mg, 1.783 mmol, 0.72 ml) and a
2
solution of AlMe in THF (1.40 M, 0.72 ml) with a
3
In our hands, the yield of (S,S)-9 was unexpectedly low
syringe pump over a period of 20 min. After stirring for
(
21%) but the compound was isolated in a chemically
16 h at −45°C, the reaction solution was diluted with
and stereochemically pure form (the mass balance of
the reaction was accounted for by the proton quench
product of (S)-7). The yields of reactions of (S)-7 are
known to be dependent on the electrophile used and are
often below 40% for reactions of lithium enolates with
Et O and quenched with aqueous 1 M HCl. The
2
aqueous layer was extracted four times with Et
washed twice with brine, dried over MgSO and chro-
matographed on silica gel (Et O:petrol 1:9) to afford 2
(148 mg, 0.947 mmol) as a clear oil with the expected
O,
2
4
2
1
,7
EtI. Treatment of (S,S)-8 or (S,S)-9 with LiAlH leads
spectroscopic data
(e.e. 85%, oktakis-(6-O-methyl-
4
5
to clean formation of the required alcohols for com-
parison purposes and indicates the correctness of our
2,3-di-O-pentyl)-g-cyclodextrin ).
2
original proposal. The only spectroscopic feature of
4.1.2. (S)-(−)-4-Ethylnonan-2-one, (S)-(−)-3. To
a
note is that the a-hydroxylic protons of (S)-5 are highly
0.0028 M solution of ligand (R)-LB (66 mg, 0.178
second order and appear as an apparent doublet in the
mmol, 10 mol%) and [Cu(MeCN) ]BF (28 mg, 0.098
4
4
1
H NMR spectrum at 400 MHz (CDCl ). As added
mmol, 5 mol%) in anhydrous anaerobic THF were
3
proof, Normant reported a positive rotation for (S)-10
added simultaneously a solution of ZnEt in THF (1.0
2
1
2
in carbometallation studies. In a final comparison we
M, 3.92 mL, 3.92 mmol, 2.2 eq.) and (E)-3-nonen-2-one
in THF (0.72 M solution, 250 mg (1.783 mmol) over a
period of 20 min to the chilled reaction solution
7
subjected (E)-1 to Hoveyda’s conditions and obtained,
under unoptimised conditions using ZnEt , (R)-(+)-3 in
2

V. Garcia-Ruiz, S. Woodward / Tetrahedron: Asymmetry 13 (2002) 2177–2180
2179
(
−20°C). After stirring for a further 20 min the reaction
NMR (CDCl , 400 MHz): l 7.33 (ddd, J=7.6, 7.2 and
3
mixture was treated as above to afford (S)-(−)-4-ethyl-
nonan-2-one 3 (259 mg, 1.52 mmol, 85%) as a pale
1.5 Hz, 2H), 7.28 (dt, J=7.2 and 1.5 Hz, 1H), 7.22 (dd,
J=7.6 and 1.5 Hz, 2H), 4.68 (ddt, J=7.3, 7.3 and 3.2
Hz, 1H), 4.17 (dd, J=9.0 and 7.4 Hz, 2H), 3.71 (br,
1H), 3.27 (dd, J=13.3 and 10.1 Hz, 1H), 2.77 (dd,
J=13.3 and 9.6 Hz, 1H), 1.43–1.36 (m, 1H), 1.35–1.25
3,7
yellow oil with the expected spectroscopic properties
62% e.e., oktakis-(6-O-methyl-2,3-di-O-pentyl)-g-
(
5
cyclodextrin ).
(
m, 6H), 1.22 (d, J=6.8 Hz, 3H), 0.88 (t, J=6.7 Hz,
13
3
1
3
1
H); C NMR (CDCl , 100 MHz): l 177.3, 153.0,
4.2. Baeyer–Villiger oxidations
3
35.3, 129.4, 128.85, 127.25, 65.9, 55.3, 37.8, 37.6, 33.3,
1.75, 26.85, 22.45, 17.3, 14.0; IR (neat): 1782, 1698,
4.2.1. (S)-2-Methylheptanol, (S)-(−)-4. To a stirred solu-
−
1
605, 1497, 1455, 1385, 1211, 1099, 702 cm ; HRMS
tion of (S)-(−)-4-methylnonan-2-one 2 (112 mg, 0.717
mmol) in TFA (1.0 mL) at 0°C were added sodium
percarbonate (225 mg, 1.434 mmol) in small portions.
After stirring for 16 h at room temperature, the reac-
+
(
EI): calcd for C H NO : 303.18344 (M ), found:
18 25 3
+
3
03.18324; MS (EI): 303 (M , 5%), 212 (14), 178 (7),
27 (57), 99 (21), 91 (14), 57 (100).
1
tion mixture was diluted with MeOH/H O 9:1 solution
2
(
5 mL), cooled at 0°C, and treated with an excess of
4.3.2.
(S,S)-(+)-4-Benzyl-3-(-2-ethylheptanoyl)oxazo-
KOH. The reaction was complete in 15 min (TLC). The
lidin-2-one, (S,S)-9. Under the same conditions as
1
1
aqueous layer was diluted with Et O and water,
described above heptanoyl-Evans’ auxiliary
allowed to react with iodoethane to afford (S,S)-9 in
21% yield as a colourless oil. R (1:2 Et O:petrol) 0.32;
O); H NMR (CDCl , 400
was
2
extracted with Et O. The extract was washed with brine
2
and dried over MgSO , then evaporated. Chromatogra-
f
1
2
4
phy with Et O:petrol 1:10 afforded the alcohol (82 mg,
[h]
D
=+126.7 (c 0.30, Et
2
3
2
0
.63 mmol, 88%) as a pale yellow liquid. R (1:2
MHz): l 7.34 (dd, J=7.5 and 7.1 Hz, 2H), 7.28 (dt,
J=7.1 and 1.5 Hz, 1H), 7.24 (dd, J=7.5 and 1.5 Hz,
2H), 4.71(ddt, J=9.1, 9.1 and 6.1 Hz, 1H), 4.17 (dd,
J=9.1 and 6.1 Hz, 2H), 3.74 (dt, J=7.7 and 5.7 Hz,
1H), 3.35 (dd, J=13.3 and 10.0 Hz, 1H), 2.71 (dd,
J=13.2 and 10.0 Hz, 1H), 1.83–1.42 (m, 4H), 1.34–1.28
f
1
Et O:petrol) 0.21; H NMR (CDCl , 400 MHz): l 3.52
2
3
(
dd, J=10.4 and 5.7 Hz, 1H), 3.43 (dd, J=10.4 and 5.7
Hz, 1H), 1.61 (m, 1H), 1.44–1.20 (m, 8H), 0.92 (t,
13
J=6.7 Hz, 3H), 0.89 (t, J=7.1 Hz, 3H); C NMR
CDCl , 100 MHz): l 68.4, 35.8, 33.1, 32.1, 26.6, 22.6,
(
1
3
6.55, 14.05; IR (neat): 3332, 2925, 1465, 1378, 1033
(m-br, 6H), 0.97 (t, J=7.4 Hz, 3H), 0.88 (t, J=6.8 Hz,
−
1
+
13
cm , HRMS (EI): calcd for C H : 112.12520 (M −
3H); C NMR (CDCl , 100 MHz): l 176.8, 153.1,
3
8
16
+
H O), found: 112.12548; MS (EI): 112 (M −H O, 8%),
135.4, 129.4, 128.9, 127.3, 65.85, 55.5, 44.05, 38.1, 31.9,
31.4, 27.0, 25.4, 22.5, 14.0, 11.4; IR (neat): 1778, 1697,
2
2
9
8 (9), 70 (52), 57 (100).
−
1
1
(
3
1
605, 1497, 1455, 1388, 1235, 1098, 702 cm ; HRMS
+
EI): calcd for C H NO : 317.19910 (M ), found:
19 27 3
+
4
.2.2. (S)-(+)-2-Ethylheptanol, (S)-(+)-5. In the same
17.20003; MS (EI): 317 (M , 29%), 247 (8), 226 (15),
78 (13), 141 (100), 91 (18), 82 (30), 71 (43), 57 (51).
manner as described for the synthesis of 4, 347 mg (2.04
mmol) of 4-(S)-(−)-ethylnonan-2-one 3 reacted to yield
2
15 mg (1.49 mmol) of (S)-(+)-2-ethylheptanol 5 in 73%
yield as a pale yellow liquid. R (1:2 Et O:petrol) 0.23;
4.4. Reduction of Evans’ auxiliary products
f
2
1
H NMR (CDCl , 400 MHz): l 3.56 (apparent d,
3
J=5.2 Hz, 2H), 1.47–1.28 (m, 11H), 0.94–0.86 (m, 6H);
To a suspension of LiAlH (120 mg, 3.16 mmol) in
absolute THF (5 ml) at 0°C was added (S,S)-8 (240 mg,
0.79 mmol) in THF (1 mL). After stirring for 30 min,
4
1
3
C NMR (CDCl , 100 MHz): l 65.3, 42.0, 32.3, 30.4,
3
2
1
1
6.6, 23.4, 22.6, 14.1, 11.1; IR (neat): 3332, 2926, 1463,
−
1
379, 1040 cm ; HRMS (EI): calcd for C H :
the reaction mixture was diluted with Et O and care-
9
18
2
+
26.14085 (M −H O), found: 126.14057; MS (EI): 126
fully quenched with THF/H O and H O until a white
2
2
2
+
(
M −H O, 18%), 112 (14), 97 (52), 71 (90), 57 (100).
precipitate appears. The Et O/THF solution is then
2
2
decanted and the flask washed several times with Et O.
2
4.3. Alkylations of Evans’ auxiliary
Drying over MgSO and chromatography on silica gel
4
with Et O:petrol 1:2 as eluent gave (S)-(−)-2-methyl-
2
heptanol (S)-(−)-4 (86 mg, 0.66 mmol, 83%). In the
same manner, (S)-(+)-2-ethylheptanol (S)-(+)-5 was
obtained in 81% yield. The spectroscopic properties of
these materials were both identical to those derived by
the Baeyer–Villiger oxidation/hydrolysis procedure.
4
.3.1. (S,S)-(+)-4-Benzyl-3-(-2-methylheptanoyl)oxazo-
lidin-2-one, (S,S)-8. To a stirred solution of N,N-diiso-
propylamine (0.40 mL, 2.90 mmol) in absolute THF (7
mL) at −78°C was added a 2.5 M solution of n-BuLi in
hexanes (1.2 mL, 2.90 mmol). After stirring for 15 min
1
1
at −78°C, heptanoyl-Evans’ auxiliary (700 mg, 2.42
mmol) in absolute THF (3 mL) was added dropwise
followed, after 30 min, by MeI (0.18 mL, 2.90 mmol).
The reaction mixture was stirred overnight at room
temperature, quenched with 0.1 M aqueous HCl solu-
Acknowledgements
tion, extracted four times with Et O. The extract was
Support from EPSRC (GR/N37339), COST-D12
(0022/99) and COST-D24 (0003/01) is gratefully
acknowledged. We thank Professor Amir H. Hoveyda
and Sylvia J. Degrado for discussions and for supplying
a sample of Lc.
2
washed once with brine, and dried over MgSO . Flash
4
chromatography (Et O:petrol, 1:5) afforded (S,S)-8
2
(
472 mg, 1.56 mmol, 64%) as a colourless oil. R (1:2
f
1
Et O:petrol) 0.27; [h] =+140.0 (c 0.30, Et O);
H
2
D
2

2
180
V. Garcia-Ruiz, S. Woodward / Tetrahedron: Asymmetry 13 (2002) 2177–2180
7. Mizututani, H.; Degrado, S. J.; Hoveyda, A. H. J. Am.
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1
8. Fraser, P. K.; Woodward, S., unpublished results.
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. B o¨ rner, C.; K o¨ nig, W. A.; Woodward, S. Tetradedron
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2
059.
5
. K o¨ nig, W. A.; Icheln, D.; Runge, T.; Pforr, I.; Krebs,
13. For example, use of (S)-L gives (−)-2 similarly the (−)
A
A. J. High Resolut. Chromatogr. 1990, 13, 702–
antipode of CyCH(Me)CH
2
COMe is also isolated by use
7
07.
of (S)-L
A
and CyCHꢀCHCOMe. However, enone
i
6
. See footnote 17 in Ref. 3: (R)-L gives (S)-(−)-3; this was
Pr CHꢀCHCOMe gives the (+) isomer under the same
conditions. See: Fraser, P. K.; Woodward, S., unpub-
lished results.
B
accidentally inverted in Ref. 1 (Table 4, entries 18 and
1
9).