Enantioenriched acid, ester, and ketone β-phenyl homoenolate synthetic equivalents from N-Boc-N-(p-methoxyphenyl)cinnamylamine

Article abstract of DOI:10.1016/S0040-4039(00)01663-4

Oxidation of the β-substituted highly enantioenriched aldehydes obtained by hydrolysis of the 3,3-disubstituted enecarbamates affords enantioenriched β-substituted acids and esters. Lithiation of enantio-enriched 3,3-disubstituted enecarbamates and subsequent reaction with electrophiles provides vinylically substituted enecarbamates. The use of benzyl and alkyl halide electrophiles affords α-substituted enecarbamates, which can be hydrolyzed to provide enantioenriched β-substituted ketones. Reaction of the lithiated intermediate with ketones affords oxazolidinones, which can be reductively ring-opened with DIBAL and hydrolyzed to provide enantioenriched β-substituted, α'-hydroxy ketones. These transformations demonstrate that the enantioselective lithiation of N-Boc-N-(p-methoxyphenyl)cinnamylamine provides a reactive intermediate which can be a ketone, acid, or ester homoenolate synthon. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01663-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9527–9531
Enantioenriched acid, ester, and ketone b-phenyl
homoenolate synthetic equivalents from
N-Boc-N-(p-methoxyphenyl)cinnamylamine†
Marna C. Whisler, Eric D. Soli and Peter Beak*
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
Received 26 September 2000
Abstract
Oxidation of the b-substituted highly enantioenriched aldehydes obtained by hydrolysis of the 3,3-di-
substituted enecarbamates affords enantioenriched b-substituted acids and esters. Lithiation of enantio-
enriched 3,3-disubstituted enecarbamates and subsequent reaction with electrophiles provides vinylically
substituted enecarbamates. The use of benzyl and alkyl halide electrophiles affords a-substituted enecar-
bamates, which can be hydrolyzed to provide enantioenriched b-substituted ketones. Reaction of the
lithiated intermediate with ketones affords oxazolidinones, which can be reductively ring-opened with
DIBAL and hydrolyzed to provide enantioenriched b-substituted, a%-hydroxy ketones. These transforma-
tions demonstrate that the enantioselective lithiation of N-Boc-N-(p-methoxyphenyl)cinnamylamine
provides a reactive intermediate which can be a ketone, acid, or ester homoenolate synthon. © 2000
Published by Elsevier Science Ltd.
Homoenolate synthons (1) allow electrophilic substitution b to a carbonyl group and are of
increasing value as a synthetic tool in organic chemistry.1 Since homoenolates are umpoled
synthons, the carbonyl group is often masked as a heterovinyl group.2 Highly enantioenriched,
formally dipole stabilized carbanions,3 produced by enantioselective deprotonation of allylic
alcohol and amine derivatives, have been used primarily as aldehyde homoenolate synthetic
equivalents (1, R2=H).4–6 The reaction of N-Boc-N-(p-methoxyphenyl)cinnamylamine 2 with
n-BuLi/(−)-sparteine followed by electrophilic substitution to afford enecarbamates 3 and 4 with
high enantioenrichment is exemplary (Scheme 1).5 Treatment of 3 or 4 with 6 M HCl in CHCl3
provides b-substituted enantioenriched aldehydes 5 and 6.
* Corresponding author.
†
Dedicated to Harry H. Wasserman, an esteemed scientist and remarkable scholar, on the occasion of his 80th
birthday.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01663-4

9528
R
R
O
6 M HCl
CHCl3
1. n-BuLi/(–)-sparteine
2. RX
O
Ph
Ar
Boc
Ph
N
Ph
H
R1
R2
N
Ar
Boc
1
2
3, R = benzyl, 88 %, er = 98:2
4, R = allyl, 72 %, er = 97:3
5, R = benzyl, 98 %
6, R = allyl, 84 %
Scheme 1.
In this communication, we report that the aldehydes resulting from hydrolysis of enecarba-
mates 3 and 4 can undergo mild oxidation to acids followed by esterification to afford
enantioenriched esters in good yields. Previously, enantioenriched ester (1, R2=OR) homoenol-
ate equivalents have been prepared by treatment of b-iodoalanine with a zinc–copper couple,7 by
direct metallation of (S)-3-iodo isobutyrate with activated zinc, or by reductive cyclization of
(S)-3-bromo isobutyrate followed by ring opening with ZnCl2.8 We also describe the a-lithiation
and substitution of 3 and 4 to give enecarbamates which can be hydrolyzed to enantioenriched
ketones. In this methodology, the choice of electrophile allows for the incorporation of a variety
of R2 groups. Enantioenriched ketone (1, R2=alkyl or aryl) homoenolate equivalents have been
reported from chiral auxiliary-mediated lithiation of allylic amines6 and (−)-sparteine-mediated
lithiation of O-allyl carbamates4 for cases in which the R2 group is present in the starting
material.
Enantioenriched b-substituted acids and esters can be isolated in high yield upon derivatiza-
tion of aldehydes 5 and 6. Oxidation of 5 and 6 with sodium chlorite9 affords acids 7 and 8 in
high yield.10 Esterification of the carboxylic acids with 1 M HCl in diethyl ether and methanol
provides esters 9 and 10 in good yields (Scheme 2). Alternate approaches to esterification with
Cs2CO3 and iodomethane11 provide the desired ester in slightly lower yields.
R
O
R
O
1 M HCl in Et2O
MeOH
R
O
NaClO2/NaH2PO4
Ph
OH
Ph
OMe
Ph
H
Me2C=CHMe/t-BuOH
7, R = benzyl, 98 %
8, R = allyl, 96 %
9, R = benzyl, 93 %
10, R = allyl, 88 %
5, R = benzyl
6, R = allyl
Scheme 2.
Enantioenriched b-substituted ketones can be accessed by further elaboration of the enecarba-
mates 3 and 4. Directed a-lithiation/substitution sequences of 3 and 4 provide a-substituted
enecarbamates (Scheme 3).12 Treatment of 3 or 4 with t-BuLi/TMEDA at −78°C followed by
warming to −40°C provides the putative lithiated intermediate 11, which reacts with alkyl (Table
1, entries 1–4) or benzyl (Table 1, entry 5) halides to afford vinyl substituted products 12–16 in
moderate to good yields. Ketones (Table 1, entries 6 and 7) react with the lithiated intermediate
and cyclize with the Boc protecting group to provide oxazolidinones 17 and 18 in moderate
yields.
Ease of removal of the masking group to provide a b-substituted carbonyl compound is
important to the synthetic utility of a masked homoenolate methodology. In the cases of the
O-allyl carbamates, cleavage of the masking group is difficult.4 In the present work, removal of
the heterovinyl mask by treatment of the a-substituted enecarbamates with 6 M HCl in CHCl3
proceeds cleanly and quickly to afford b-substituted enantioenriched ketones in good yields. As

9529
R
Ph
Ar
1. R'X
2. MeOH
N
R'
R
R
N
Boc
1. t-BuLi/TMEDA
THF, -78 °C
Ph
Ar
Ph
Ar
12-16
2. -40 °C
N
Li•L
Boc
R
O
O
3, R = benzyl, er = 98:2
4, R = allyl, er = 97:3
Ph
Ar
1. R'R"CO
2. MeOH
R'
R"
11
N
L = TMEDA
O
Ar = p-methoxyphenyl
Boc = t-butoxycarbonyl
O
17-18
Scheme 3.
Table 1
Lithiation/substitution sequences of 3 and 4
Entry
Substrate
Electrophile
R%
R%%
Product
Yield (%)
1
2
3
4
5
6
7
3
3
4
4
4
3
4
MeI
EtI
n-BuBr
CH2ꢀCHCH2Br
PhCH2Br
(CH2)5CO
(CH3)2CO
Me
Et
–
–
–
–
–
12
13
14
15
16
17
18
85
72
31
83
79
62
52
n-Bu
CH2CHꢀCH2
PhCH2
ꢁ(CH2)5ꢁ
Me
Me
Table 2
Hydrolysis of a-substituted enecarbamates
R
Ph
Ar
R
O
6 M HCl
N
R'
Ph
R'
CHCl3
1 hr
Boc
12-16
19-23
Entry
Substrate
R%
Product
Yield (%)
1
2
3
4
5
12
13
14
15
16
Me
Et
n-Bu
CH2CHꢀCH2
CH2Ph
19
20
21
22a
23
70
85
96
70
69
a Upon standing, the double bond isomerizes to the conjugated product, R%=ꢁCHꢀCHCH3.

9530
evidenced in Table 2, alkyl (entries 1–4) and benzyl (entry 5) groups can be incorporated into
the ketone.
a%-Hydroxy ketones are accessible in one pot from the oxazolidinones that were prepared by
reaction of the lithiated intermediate 11 with ketone electrophiles (vide supra). Treatment of the
oxazolidinone 17 or 18 with DIBAL at −78°C followed by warming to rt affords a ring-opened
enamine.13 The enamine is treated in situ with 6 M HCl to provide the enantioenriched
b-substituted, a%-hydroxy ketone 24 or 25 in good yield (Scheme 4).
R
R
R
O
DIBAL (4 eq)
Ph
Ar
6 M HCl
Ph
Ar
R'
R'
R"
R'
Ph
CH2Cl2
-78°C to rt
R"
N
N
HO
R"
O
OH
Me
O
17, R'=R"= –(CH2)5–
18, R'=R"= Me
24, R'=R"= –(CH2)5– , 82 %
25, R'=R"= Me, 81 %
Scheme 4.
In summary, the present work demonstrates that the (−)-sparteine complexed, lithiated
intermediate from N-Boc-N-(p-methoxyphenyl)cinnamylamine 2 can be developed as a b-phenyl
acid, ester, and ketone homoenolate equivalent. The approach should be easily extended to
other b-aryl systems and is being investigated for b-alkyl groups.
Acknowledgements
This work was supported by a grant from the National Institute of Health (GM-18874). We
are grateful for this support.
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9531
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12. Representative procedure: to a stirring solution of 4 (122 mg, 0.734 mmol) and TMEDA (68 mL, 0.321 mmol) in
dry THF (6 mL, 0.054 M) at −78°C under N2 was added t-BuLi (1.45 M, 0.24 mL, 0.385 mmol). The dark yellow
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product as a yellow oil. The oil was purified by column chromatography (90:10, petroleum ether:EtOAc) to give
pure 15 as a colorless oil (112 mg, 83%).
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.