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Chiral Lithium-1-oxyalkanides by Asymmetric Deprotonation; Enantioselective Synthesis of 2-Hydroxyalkanoic Acids and Secondary Alkanols.

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tionally stable. The required non-racemic stannanes (R)- or
obtained by optical resolution,[6a*b1 asymmetric
reduction of acylstannanes,‘6d3 or oxidation of a-trialkylstannyl boronates.[6‘1We now report on the hitherto simplest
entry to chiral synthetic building blocks of type 3; it comprises an enantiotopically differentiating deprotonation of the
precursor 3 in the presence of (-)sparteine[’’ and is made
possible by a protecting group R 2 of the carbamate typeL91,
which activates through chelate and dipole stabilization and
which is cleavable under mild conditions.[’] We obtained the
carbamates
from the spirocyclic oxazolidine[”] 6 by
acylation with the corresponding alkoxycarbonyl chlorides 7
(route A) or via the carbamoyl chloride (CIC=O for H in 6)
and reaction with sodium alkoxides 9 (route B) in yields of
87 to 95 %. Treatment of the esters 10 with sec-butyllithium
in ether/N,N,N’.N’-tetramethylethylenediamine(TMEDA)
at -78°C leads to the persistent lithium compounds
rac-11 . TMEDA, which were trapped as ~ i l a n e s [ ~roc-12
’
(Table 1).
[7] The overall yield OF 6a from Keinp’s tricarboxylic acid was 44%: m.p.
195-196”C, [a]” = 89.7” (c = 1.51, CH,CI,). For 6 b (43%) m.p. 107 109 C, IllD= - 252; (c = 1.04, CH,CI,). All the new compounds were
characterized by a full complement of high-resolution spectra.
[XI Further details of the crystal structure investigation are available on request from the Director of the Cambridge Crystallographic Data Centre.
University Chemical Laboratory, Lensfield Road, GB-Cambridge CB2
1EW (UK). on quoting the full journal citation.
[91 J. Rebek. Jr. Chemtrucfs 2 (1989) 337; J. Rebek, Jr. Angeu. Chem. I02
(1990) 261; Angeic. Chcm. Inf. Ed. Engl. 29 (1990) 245. The results reported
in these papers for protonation of 8 a are in error.
[lo] W. H. Pirkle, D. L. Sikkenga, M. S . Pavlin, J Org. Chem. 42(1977) 384.
Ill] W. H. Pirkle, T. C. Pochapsky, Chem. Rev. 89(1989) 347; J. Rebek, Jr.. B.
Askew, P. Ballester, M. Doa. J Am. Chcm. Soc. 109 (1987) 41 19.
[12] M. Farines. J. Soulier. BUN. Soc. Chim. Fr. (1970) 332.
Chiral Lithium-1-oxyalkanides by Asymmetric
Deprotonation; Enantioselective Synthesis of
2-Hydroxyalkanoic Acids and Secondary
Alkanols **
By Dieter Hoppe,* Folker Hintze, and Petra Trhben
(q-1were
Q
CI(C=O)OCH,R’ 7
7.
1. CI,CO(C=O)ClS
0
%
o$04H
sBuLilTMEDA
J
a-Lithiated ethers 4 a and acetals 4 b are of great preparative importance as umpoled synthetic building blocks[’] for
the nucleophilic introduction of 1-0xyalkyl groups. As long
as R’ is not a stabilizing group like aryl, 1-alkenyl or 1alkynyl, the lithium compounds 4 cannot be generated by
simple deprotonation of 3 at low temperature. The reagents
4 a or 4b are therefore prepared, in general, by transmetalationl3] of the stannanes 1 or by reductive cleavage of the
nionothioacetals 2.14] Some racemic a-lithioalkyl benzoates
with sterically shielded carbonyl groups, such as 4c, were
generated by deprotonation;[’] however, the subseqtient
cleavage of the aroyl group presents difficulties.
R‘
Path B
6
10
ruc-11-TMEDA
1, X = SnBu3
2, X = SAr
3,X=H
rac-12
a,R’=H
d, R’ = (CH2),CH3
b, R’ = CH,
C, R’ = (CH&CH,
e, R’ = CH(CH,),
4
xR,
Li H
Bu,Sn H
nBuLi
R20
R 2 0R
’1
(Sj-1
The deprotonation of the carbamate 10b under otherwise
the same conditions in the presence of (-)-sparteine[’], (-)13, instead of TMEDA leads to the uniformly configurated
complex (9-11 b . (-)-13 with high diastereomeric excess;
i.e. the reagent discriminates between the enantiotopic aprotons in 10. This is confirmed by carboxylationr’21to the
H H
R20);RI
(04
3
i
1. BIX
2. Deprotection
R’
El H
= Alkyl
a, R2 = Alkyl
C,
CbxOCH2R1
R2 = (2.4.6-iF~)~C~H,C(=0j(R)- or (S)-S
sBuLi, (-)-Sparteine 13
Ether, 5 h, -78°C
10
The lithiodestannylation of ( 9 - 1 and subsequent electrophilic substitutions to (R)- o r ( 9 - 5 proceed with retention of
configuration,[61 i.e. the intermediate ( 9 - 4 is configura-
CbxO
This work was supported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie.
1422
0 VCH
VErlugsgesellschaffmbH. W-6940 Wemheim. 1990
I
1. co2
2. HCLI120
C1SnMe3
Me3& H
[*] Prof. Dr. D. Hoppe, F. Hintze, Dipl. Chem. P. Tebben
lnstitut fur Organische Chemie der UniversitPt
Olhausenerstrd~e40, D-2300 Kiel 1
[**I
p7:
0
b, R2 = I-Alkoxyalkyl
HO,C
H
R’-+
(+)-(S)-lS
3 3.50+ .2S/O
0570-0833i9~il2I2-1422
TMEDA-Li H
(S)-lI-TMEDA
(-)-(&I4
A n p n Chem. Int. Ed. Engl. 29 (1990) No. 12
(!?)-lactic acid derivative (R)-14b,'1°. 13] which is formed
with > 95% ee.[l41Analogous results are achieved with the
long-chain or 8-branched carbamates 10c-e (Table 1).
Fable 1. Substitution products prepared from 10a-e.
Product
R'
rac-IZa[a]
rac-IZb[al
(S)-IZb' .
rur-l4b[a]
(R)-14b
rac-I4c[d]
(R )-14~
rac-l4d[a]
(R)-14d
(R1-14e
, ,
(S)-15b
( S ) -15c
(S)-ISd
(S)-15e
H
CH,
CH;
CH,
CH,
(CH,),CH,
iCHz)zCH,
(CH,),CH,
(CH,),CH,
CHICHI\,
CH,
(CH &CH3
(CH,),CH,
CH(CH,),
(CH,),CH,
(S)-16
..I
Electrophile
Yield [%]
Me,SiCI
MeSiCI
MeiSiCI
97
70
67
60
75
65
78
62
70
52
76
62
86
62
81
co,
co,
CO,
CO,
CO,
CO,
CO,
Me,SnCI
Me,SnCI
Me,SnCI
Me,SnCI
CH,I
[a] With TMEDA as ligand. [b] c
=
[or];'
ee [YO]
-23
-
-22.5[b]
-
-22.3[c]
sion for carboxylation and stannylation.['61As checked with
the complex 11 d . (-)-I3 (obtained from lOd), the methylation also proceeds highly stereoselectively; the (S)-Zoctylcarbamate (+)-(S)-16 is obtained with 96% ee."'] The Cbx
group is cleaved under mild conditions, as was demonstrated
on ( 9 - 1 6 . The methanolysis of the aminoketal 16 under acid
catalysis leads to the urethane 17, which, upon addition of
barium hydroxide, is hydrolyzed to the alcohol (+)-(S)-l8,
-
>95
10d
*
-
(+)-(S)-16
-
&
>
>9 5
>95
r
1
>95
Ba(OH)-JMeOH
>95
>95
295
96
1.4-2.8, CH,CI,. [c] c = 1.1-1.9. acetone.
MeSO,H/MeOH
CH3
>95
-12.4[c]
-17.31~1
+35.4[b]
+35.2[b]
+34.2[b]
+23.5[b]
+14.1[c]
OCbx
H
CH,(CH&
81% 96% ee
-
-
-12.6[c]
1. sB~Li/(-)-13
2.CH31
_____)
OH
CH,(CH&
77%
- -.
L
'^'
CH,
($18
J
17
The reaction of ( 8 - 1 1 b . (-)t3 with trimethyltin chloride
yields the stannane ( + ) - ( g - l S b , whose transmetalation to
( 9 - 1 1 b . TMEDA in ether and reaction with carbon dioxide
likewise leads to the carboxylic acid (R)-14b with > 95% ee
(yield 63 %). Restannylation of (S)-11 e . TMEDA again afforded (+)-(R)-15e (yield 83 %). The quoted (5)-configuration for 11 in the (-)-sparteine complex is based on the
well-founded assumption that here, as in all the other cases
investigated, the lithium a-oxyalkanide i s substituted by
electrophiles with retention.[6*1 2 , I s ] In contrast, in the case
of a similar benzyllithium derivative we observed an inver-
Table 2 Selected physical data of the compounds 10-18
lob:
Route A; yield 87%; colorless solid; m.p. 42°C; b.p. l O O T /
2.25 mbar; 'H N MR (CDCI,): b = 4.06 (q, '4H.H) = 7.1 Hz, 2 H ;
OCH,). 3.61 (s,2H;CH2),2.00-2.40(m, 2H;cyclohexyl), 1.40-1.70
1
(m, 8 H ; cyclohexyl), 1.30 (s, 6 H ; CH,), 1.21 (t. 'J(H.H) ~ 7 . Hz,
3H. CH,)
10d:
Route B; yield 95%; colorless oil; R, = 0.62 (etherjn-pentane 1:l);
'H NMR (CDCI,): b = 4.07 (t. 'J(H,H) = 6.6Hz. 2H; OCH,), 3.69
(s. 2H ; CH,), 2.00-2.50 (m, 2 H ; cyclohexyl), 1.70-1.48 (m; cyclohexyl, heptyl-CH,, CH,), 1.48-0.85 (m; cyclohexyl, heptyl-CH,)
12a:
colorless solid; m.p. 89°C; ' H N M R (CDCI,): 6 = 3.72 (s, 2 H ;
CH,). 3.69 (s, 2H; OCH,), 2.10-2.50 (m, 2H; cyclohexyl), 1.701.35 (m. 14H; cyclohexyl, CH,). 0.11 (s, 9 H ; Si(CH,),)
(Sf-IZb: colorless oil; R, = 0.64 (etherin-pentane 1: 1); ' H NMR (CDCI,).
Experimental
A solution of 2.8 mmol of sBuLi (in cyclohexane/isopentane) in 8 mL of ether
was cooled to -78°C and treated with 2.9 mmol of (-)-sparteine. (-)-13.
After 10 minutes' stirring and injection of a solutlon of 2.0 mmol of the carbamate 10 in 2 mL ether, the mixture was stirred for 5-6 h at -78 C. After
introduction of carbon dioxide (excess) into the solution of (S)-11 (-)-I3 (for
the synthesis of 14) or addition of 3.5 mmol of trimethyltin chloride or
methyl iodide (for the synthesis of 15 or 16), the reaction mixture was stirred for
16 h at - 78 "C. Work-up was carried out as usual with 10 mL of ether/lO mL
of 2h HCI, and the crude product was purified by flash chromatography on
silica gel with etherjpentane mixtures. The racemates roc-11 . TMEDA were
generated in the same way, hut with 2.9 mmol of TMEDA instead of ( - ) sparteine.
For cleavage of the Cbx group a solution of 2mmol of 16 In lOmL of
methanol was heated under reflux with 0.1 mL of methanesulfonic acid for
16 h. Finally, 1.O g of Ba(OH), . 8H,O was added to the mixture. which was
heated under reflux fora further 4 h before workup in the usual way in aqueous
medium and purification of the crude product on silica gel by flash chromatography.
Received: July 5. 1990 [Z 4052 IE]
German version: Angew Chem. 1112 (1990) 1457
[I] Reviews: a) D. Seebach, Angew. Chem. 91 (1979) 259-278; Angcvr.. Chem.
Int. Ed. Engl. I8 (1979) 239-258; b) J. E. Saavedra in T. A. Haase (Ed.).
Umpoled Synthons. Wiley. New York 1987, p. 101.
[2] At high temperature Wittig rearrangements occur; review: T Nakai, K .
Mikami, Chem. Rev. 86 (1986) 885-902
6=465iq,'J(H.H)=7.4Hz,lH;CH),3.68(~,2H;CH,),2.50- 13) a) W. C. Still. A. Mitra, J. Am. Chem. SOL,./ 0 (1978) 1927- 1928; b) J. S.
Sawyer, A. Kucerovy, T. L. Macdonald, G. J. McGarvey. !bid. / I 0 (1988)
2.10(m.2H,cyclohexyl),1.70-1.35(m,14H.cyclohexyl,CH,), 1 2 6
842 -853.
(d. 'J(H,H) =7.4 Hz, 3H; CH,), 0.60 (s. 9 H ; Si(CH,),)
[4] a)Review: T. Cohen, M. Bhupathy. Ace. Chcm. Res. 22(1989) 152-161.
(R)-14b: colorless crystals; m.p. 112'C; ' HNMR (CDCI,): 6 = 8.90-8.00
b) T. Cohen, M. T. Lin, J. Am. Chem. Soc. 106 (1984) 1130- 1131 : c) A.
(br. s. 1 H; COOH), 5.0915.10 (4.,J(H.H) =7.1 Hz. 1 H; CH), 3.721
Fernandez-Mayoralas, A. Marra, M. Trumtel, A. Veyrieres, P Sinay, Tc,3.71 ( s , 2H ; CH,), 2.50-2.05 (m. 2 H ; cyclohexyl). 1.55 (d, 'J(H,H)
rruhedron LeI1.30 (1989) 2537-2540, d) S. D. Rychnovsky, D. E. Mickus.
=7.1 Hz, 3 H ; CH,), 1.85-1.00 (m. 14H; cyclohexyl, CH,)
!hid. 30 (1989) 301 1-3014
(R)-l4b-methyl ester: colorless oil; R, = 0 SO (etherin-pentane 1 :l); 'H NMR
151 a) P. Beak, B G. McKinnie,J. Am. Chem. SOC.99(1977) 5213; h) P. Beak,
(CDCI,): d = 5.09jS.10 (4.'J(H,H) =7.1 Hz, 1 H; CH). 3 75 ( s , 3 H ;
L. G. Carter. J. Urg. Chem. 46 (1981) 2363-2373; c) R. Schlecker. D.
OCH,). 3.72/3.71 (s, 2H; CH,), 2.50-2.00 (m, 2 H ; cyclohexyl),
Seebach, W. Lubosch, Hefv. Chim. Acra 61 (1978) 512-526.
1.66 -1.00 (m, 14H; cyclohexyl, CH,), 1.51 (d, 'J(H,H) =7.1 Hz,
[6] a) W. C. Still, C. Sreekumar. J Am. Chem. Soc. 102 (1980) 1201- 1202;
3H: CH,)
b) V. J. Jephcote, A. J. Pratt. E. J. Thomas, J. Chem. Sor. Chem. Commun
(S)-15b. colorless solid; m.p. 34°C; ' HNMR (CDCI,): b = 4.58 (q,
19x4, 800-802; J. Chem. Sor. Perkin Trans. 1 1989, 1529-1535; c) P .
'J(H,H) =7.6Hz, I H ; CHI, 3.68 (s, 2H, CH,). 2.20-2.40 (m, 2H;
Lesimple, J.-M. Beau. P. Sinay, J. Chem. Soc. Chem. Commun. IYK5. 894
cyclohexyl), 1.10-1.70 (m, 14H; cyclohexyl, CH,), 1.53 (d, 'J(H,H)
895; d) J A. Marshall, W. Y Gung, E~rrahedron45 (1989) 1043- 1052;
=7.6 Hz, 3 H ; CH,), 0.099 (s, 9 H ; Sn(CH,),)
e) J. M. Chong, E. K. Mar, ;bid. 45 (1989) 7709-7716; f ) D. S. Matteson.
(S)-16: colorless oil. R, = 0.69 (etherin-pentane 1 :l); 'H NMR (CDCI,):
P. B. Tripathy, A. Sarkur. K. N. Sadhu, J. Am. Chem. SOC.1 i 1 (1989)
6 = 4.84 (t. 'J(H,H) = 6.2 Hz, 1 H; CH), 3.68 (s, 2 H , CH,), 2.554399-4402; g) R. J. Linderman, A. Ghannam, ibid. 112 (1990) 2392 -2398.
2.00 (m. 2H ; cyclohexyl), 1.75-1.00 (m. 24H; cyclohexyl, heptyl"71 For earlier attempts at the chiral modification of orgdnolithium comCH,. CH3). 1.12 (d, 'J(H,H) = 6.2, 3 H ; CH,), 0.88 (t, 'J(H,H) =
pounds by (-)-sparteine: a) H. Nozaki, 7. Aratani, T. Tordya, R. Noyori.
6 7 Hz, 3 H; heptyl-CH,)
Terrahedron 27 (1971) 905-913; b) L. M. Engelhardt, W.-P. Leung. C. L.
Angew. Chem. In!. Ed. Engl. 29 (ISYO) No. 12
8 VCH
VerlugsgesellschaffmbH. W-6940 Weinheim, 1990
0570-0833/90/I212-1423S3.511-t 2510
1423
Raston, G. Salem, P. Twiss, A. H. White, J Chem. Soc. Dulton Trans. 1588,
2403-2409. Asymmetric deprotonations of 2-alkenyl carbamates: c) D.
Hoppe. 0. Zschage, Angew. Chem. 101 (1989) 67 -69; Angew. Chem. Int.
Ed. Engl. 28 (1989) 65-67; d) 0 Zschage, JLR. Schwark, D. Hoppe, h i d .
102 (1990) 336-337 and 29 (1990) 296-297.
[S] N. G Rondan. K. N. Houk. P. Beak, W J. Zajdel, J.Chandrasekhar, P.
von R. Schleyer, J Org. Chem. 46 (1981) 4108-4110; cf. also D. SeebdCh,
J. Hansen, P. Seiler, J. M. Gromek, J. Orgunomrt. Chrm. 285 (1985) 1 - 13.
[9] Review: D. Hoppe, Angew. Chem. 96 (1984) 930-946; Angew. Chem. i n (
Ed Engl. 23 (1984) 932-948.
[lo] AII the new compounds gave correct elemental analyses (C,H i- 0.3%)
[ l l ] P. Mickon, A. Rassat, BUN. Soc. Chim. Fr. 1571, 3561-3567.
[12] During the preparation of the manuscript a paper concerning the carboxylation of enantiomerically enriched a-(henzyloxymethy1)alkanides of the
type 4b appeared in the literature: P. C.-M. Chan, J. M. Chong, Terruhedron Lett. 31 (1990) 1985-1988.
[13] Correlated as 14b-methyl ester with a sample obtained from (R)-lactic
acid.
1141 For the determination of the ee value the acids 14 were first converted with
diazomethane into their methyl esters and subsequently measured with
5 -8 mol-% tris-[(heptafluoropropylhydroxymethylene)-~-campherato]
europium(rii), Eu(hfpc),, on a 300 MHz spectrometer on the basis of the
2-H signal. The absorption bands are in each case doubled, due to amideEiZ isomerism. The enantiomeric(S)-14 methyl esters were not detectable
in any of the samples.
[15] Theoretical studies on the carboxylation: E. Kaufmann, S. Sieber, P. von
R. Schleyer, J Am. Cbem. Soc. / I / (1989) 4005-4008.
1161 D. Hoppe, A. Carstens,T. KrPmer, Angrw. Chem. /02(1990) 1455; Angew.
Chem. I n t . Ed. Engl. 29 (1990) 1424.
[I71 Determined gas-chromatographically on the alcohol I8 as (-)-(S)phenylethylurethane, 98:2; W. H. Pirkle, M. S . Hoekstra, J Org. Chem. 39
(1 974) 3904- 3906.
Although non-racemic, heterosubstituted benzyllithium
derivatives, e.g. carbanions derived from tetrahydroisoquinoIines,16, 1' play an important role in enantioselective
synthesis, knowledge of the stereochemical course of their
electrophilic substitution is very limited. The reason for this
is that the extent to which the chiral auxiliary influences the
properties of the carbanionic center is unknown."] We now
report on the generation of an enantiomerically enriched
benzyllithium derivative which is practically configurationally stable at low temperatures, and which, like some
allyllithium derivatives synthesized by us,[91is free of such
complications. Furthermore, we have investigated the stereochemistry of some important substitution reactions.
The N,N-diisopropyl carbamate ['O, ''I (R)-2, obtained
from (R)-l-phenylethanol"21 (97% ee['']),was deprotonated with sec-butyllithium/N,N,N',N'-tetramethyIethylenediamine (TMEDA) in hexane below -70"C,"41 and after
30 min the intermediary lithium alkanide (R)-3["3 1 6 ] was
trapped with chlorotrimethylsilane. The silane ( -)-4[17] of
unknown absolute configuration was obtained with 96 %
ee.[lS1This means that maximally 1 % racemization occurs
over the two reaction steps. Protonation of (R)-3with methanol leads to the initial carbamate (R)-2again, whereas with
acetic acid inversion takes place with formation of ( 9 - 2 .
CISiMe,
\/OCb
H3C
L
H3C
Generation of a Configurationally Stable Chiral
Benzyllithium Derivative, and the Capricious
Stereochemistry of Its Electrophilic Substitution **
Ph
OCb
1
H
(+)-(R)-2
(97%ee)
sBuLi
TMEDA
hexane
-78°C
NiPr,
___)
c-MeOH
(XO%, 80%ee)
-N
N-
1-1
yOCb
H3C
By Dieter Hoppe,* Axel Carstens, and Thomas Kramev
Dedicated to Professor Jiirgen Bestrnann
on the occasion of his 65th birthday
Cb = C(=O)NiPr,
Chiral benzyl alkali metal derivatives 1 A undergo rapid
racemization in solution via an ion pair 1B with planar configurated carbanion; hence, the chiral information of the
optically active precursor is generally lost during its generation."' Some cL-sulfonylbenzyl anions constitute an exception.[']
M@
n
r-
L
1A
The alkylation of (R)-3 with n-propyl bromide proceeds
with retention of the configuration; the tertiary carbamaterx7' (-)-(fl-S was correlated stereochemically with
the known carbinol ( -)-(S)-6.1'91
1B
J
V
M@
enf-1A
Short-lived benzyl anions have been trapped in situ with
high enantiomeric excesses by deprotonation/reprotonation
of optically active phenyl alkanes"] as well as in the HallerBauer cleavage of tertiary benzyl phenyl ketones.f31 Chiral
a-oxybenzyl anions are trapped as short-lived intermediates
in the Brookf4]and reverse Brook rearrangement.[51
(R)-3 reacts with dimethyl carbonate with retention of
configuration, but with methoxycarbonyl chloride with inversion, to give the methyl ester['7*'] (-)-(R)-7["' and
( +)-(S)-7, respectively. Surprisingly, carbon dioxide like-
H3C
Ph
OCb
(MeO),CO
(-)-(R)-7
W%ee)
[*] Prof. Dr. D. Hoppe, A. Carstens, Dr. T. KrZmer
lnstitut fur Organische Chemie der UniversitZt
Olshausenstrasse 40, D-2300 Kiel 1 (FRG)
[**I This work was supported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie.
1424
$1
VCH Verlugsgerellschuft mbH, W-6940 Weinheim. 1990
C1C02Me
t-- (R)-3
C02Me (8595,
(97%ee)
0570-0833l90j1212-1424$3.50+.25/0
!
H3C
OCb
(%%,85%ee)
(+)-(S)-7
Angew. Chem. Inr. Ed. Engl. 29 (1990) No 12
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