The scope of the direct proline-catalyzed asymmetric addition of ketones to imines

Article abstract of DOI:10.1002/adsc.200404114

A full account of catalytic direct asymmetric Mannich-type reactions is presented describing the scope of amino acid-catalyzed additions of unmodified ketones to a large variety of imines. These reactions are performed under very mild, operationally simpl

Full text of DOI:10.1002/adsc.200404114

FULL PAPERS
The Scope of the Direct Proline-Catalyzed Asymmetric Addition
of Ketones to Imines
Wolfgang Notz, Shin-ichi Watanabe, Naidu S. Chowdari, Guofu Zhong,
Juan M. Betancort, Fujie Tanaka, Carlos F. Barbas III*
The Skaggs Institute for Chemical Biology and the Departments of Chemistry and Molecular Biology, The Scripps
Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Fax: (þ1)-858-784-2583, e-mail: carlos@scripps.edu
Received: April 21, 2004; Accepted: June 21, 2004
Abstract: A full account of catalytic direct asymmet- methodology developed was applied as a powerful ap-
ric Mannich-type reactions is presented describing proach toward the synthesis of enantiomerically pure
the scope of amino acid-catalyzed additions of un- functionalized a-amino acids, g-lactones, oxime-func-
modified ketones to a large variety of imines. These tionalized amino acids as well as pharmacologically
reactions are performed under very mild, operational- important targets such as (R)-cyclohexylglycine.
ly simple, and environmentally friendly and benign
conditions employing a one-pot, three-component
protocol as well as preformed imines. Typically, prod- Keywords: asymmetric catalysis; C C bond forma-
ucts were obtained with high regio- and diastereose- tion; imines; ionic liquids; Mannich-type reactions; or-
À
lectivities and excellent enantioselectivities. The ganic catalysis; g-oxo-a-amino acids
Introduction
ed as an inseparable ~5:2-mixture in favor of the syn-di-
astereomer. Both regioisomers were obtained with very
Over the past few years, we and others have developed high enantioselectivities (ees) and, in the case of 7a, with
direct organocatalytic asymmetric versions of several excellent diastereoselectivity. In the parent aldol reac-
important carbon-carbon bond-forming reactions.[1,2] tion, however, product formation involving the methyl-
Mechanistically, these reactions are based as the catalyt- ene moiety of the ketone donor was not observed. Inter-
ic activation of one reaction partner to an enamine or estingly, the reaction using 1-naphthaldehyde as accept-
iminium intermediate; the intermediate subsequently or gave 8 in 73% yield and 96% ee as the exclusive prod-
reacts in a highly stereospecific manner to form a new uct (Table 1, entry 8), and the same regioselectivity was
carbon-carbon bond and one or more stereocenters. observed with 5-hexen-2-one as donor (Table 1, en-
Herein, we disclose our findings on the catalytic asym- tries 11–16). The reactions with benzaldehyde, 1-naph-
metric Mannich-type reaction using ketones as donors thaldehyde, and p-nitrobenzaldehyde provided Man-
that reveal some interesting aspects distinctly different nich products 13–15 in good yields and in a completely
from those of the parent aldol reaction.
regioselective manner. Likewise, p-nitrobenzaldehyde
and 1-naphthaldehyde afforded products 14 and 15, re-
spectively, with high enantioselectivities (Table 1, en-
tries 14 and 15). Both branched and linear aliphatic alde-
hydes were effective acceptors as shown for isovaleral-
Results and Discussion
In order to define the scope of the catalytic asymmetric dehyde and hexanal, which yielded 82% 11 and 71%
Mannich reaction with ketonedonors, we used the previ- 12 with 76% ee and 48% ee, respectively (Table 1, en-
ously established one-pot, three-component protocol re- tries 11 and 12).[3] In the case of the more reactive benzyl-
acting acetone, an aldehyde, and p-anisidine in the pres- oxyacetaldehyde, however, the two regioisomers (16a
[1g]
ence of l-proline as catalyst (Table 1, entries 1–6).
and 16b) were formed in nearly equal amounts; 16b
Thus, a number of unsymmetrical ketones, which could was formed as the only detectable diastereomer with
give rise to the formation of regioisomers as well as dia- 90% ee. 3-Pentanone was also successfully used as a do-
stereoisomers, were evaluated as donors. For example, nor, and with isovaleraldehyde and benzaldehyde as al-
when 2-butanone was reacted under our standard condi- dehyde acceptor components, led to products 9 and 10
tions withp-anisidineandp-nitrobenzaldehyde(Table 1, in excellent diastereoselectivities with 73% and 62%
[4]
entry 7), the two regioisomers 7a and 7b could be isolat- ee, respectively (Table 1, entries 9 and 10).
Adv. Synth. Catal. 2004, 346, 1131–1140
DOI: 10.1002/adsc.200404114
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Table 1. One-pot, three-component Mannich-type reactions between various ketone donors and aldehyde acceptors and p-an-
isidine.
[a]
PMP¼p-methoxyphenyl.
[b]
Yields of isolated pure products after column chromatography; the ee values were determined by chiral-phase HPLC ana-
lysis; dr¼syn/anti as determined by NMR.
[c]
5,5-Dimethyl thiazolidinium-4-carboxylate was used as catalyst.
Next, we studied hydroxyacetone as donor in the one- tivities.[3] Furthermore, products 17, 18, and 21 represent
pot, three-component Mannich-type reaction. This do- the first examples of Mannich reactions that involved
nor afforded anti-diols with excellent regio-, diastereo-, linear and a-unbranched aliphatic aldehydes as accept-
and enantioselectivities in aldol reactions.[1a, c] When this or components in reactions with hydroxyacetone as do-
donor was reacted with p-anisidine and isovaleralde- nor.
hyde, the corresponding Mannich product 17 was
Further insight into which regioisomer of the assumed
formed as a single regioisomer in 74% yield, with excel- enamine intermediate was involved in the addition step
lent diastereoselectivity, and with an ee of 93% (Table 2, came from the reactions of N-PMP-protected a-imino
entry 1). Hexanal, 1-naphthaldehyde, benzaldehyde, ethyl glyoxylate as acceptor in these Mannich-type reac-
and benzyloxyacetaldehyde provided Mannich prod- tions (Table 3). In all cases studied, the Mannich prod-
ucts 18 – 21 (Table 2, entries 2–5) in clean reactions ucts were obtained as a single enantiomer in a smooth
with very high enantioselectivities (ee¼86–94%) and, and clean reaction. For example, the reaction with 2-bu-
with the exception of 1-naphthaldehyde adduct 19 (Ta- tanone afforded Mannich product 23 (Table 3, entry 2)
ble 2, entry 3), with excellent syn-diastereoselectivity.[5] in 72% yield with an ee>99%. In contrast to the reac-
In all of the cases studied, the formation of only a single tion of this donor with p-nitrobenzaldehyde and 1-naph-
regioisomeric product was observed. It is noteworthy thaldehyde (Table 1, entries 7 and 8), exclusive re-
that both isovaleraldehyde and hexanal gave products gioisomer formation occurred due to the regioselective
with excellent stereoselectivities with DMSO as solvent, attack of the more substituted a-carbon atom of the ke-
whereas the use of chloroform provided products with tone and reaction afforded predominantly the syn-dia-
lower yields and very poor diastereo- and enantioselec- stereomer. Very similar results were obtained from the
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Proline-Catalyzed Asymmetric Addition of Ketones to Imines
FULL PAPERS
Table 2. Formation of vicinal syn-amino alcohols via catalytic
Table 3. Formation of functionalized g-oxo-a-amino acids.
Mannich reactions of hydroxyacetone.
[a]
PMP¼p-methoxyphenyl.
[b]
Yields of isolated pure products after column chromato-
graphy.
[c]
dr¼syn/anti as determined by NMR.
[d]
The ee values were determined by chiral-phase HPLC
analysis.
ee of anti-isomer.
[e]
[a]
PMP¼p-methoxyphenyl.
[b]
Yields of isolated pure product after column chromatogra-
phy.
[c]
dr¼syn/anti as determined by NMR.
reactions employing 3-pentanone, cyclohexanone, 5-
hexen-2-one, hydroxyacetone, and two structurally in-
teresting donors, 1-hydroxy-2-butanone and 4-hy-
droxy-2-butanone. The corresponding Mannich prod-
ucts 24–29 were obtained with excellent enantioselec-
tivities (ee>99%). In the case of unsymmetrical donors,
only one regioisomer was formed, which, with the ex-
ception of Mannich product 28, exhibited very high dia-
[d]
The ee values of products were determined by chiral-phase
HPLC analysis.
Acetone was used as solvent.
ee of anti-isomer.
[e]
[f]
stereoselectivity (dr>19:1). On the other hand, aceto- knowledge, such allylated or hydroxymethylated b-ami-
phenone, 3-methyl-2-butanone, and cyclopentanone[6] no ketone subunits have not been reported until now.[7]
did not furnish detectable amounts of the corresponding We confirmed the anticipated (S)-stereochemistry of
Mannich products under these conditions. Amino acids the newly formed a-stereocenter by synthesis of known
26 and 29 (Table 3, entries 5 and 8) can also be consid- isopropyl ester 22b (Table 3, entry 1) and by comparison
ered products from the stereoselective allylation and hy- to data reported earlier.[8]
droxymethylation, respectively, of the corresponding
From these results, it is evident that N-PMP-protected
linear g-keto amino acid scaffold. To the best of our a-imino ethyl glyoxylate was always attacked by the
Adv. Synth. Catal. 2004, 346, 1131–1140
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Table 4. Synthesis of functionalized g-oxo-a-amino acids in
most substituted enamine intermediate regardless of the
donor. Additionally, a-substitution of the ketone donor
with electron-donating heteroatoms appeared to dictate
the regioselectivity of the enamine formation regardless
of the acceptor component (Table 2; Table 3, entries 6
and 7). In both cases, the syn-diastereomers were pre-
dominant.[9] Furthermore, the results of the reaction of
unsymmetrical ketone donors (e.g., 2-butanone or 5-
hexen-2-one) indicated that very reactive, electron-defi-
cient acceptor imines (e.g., glyoxylates, Table 3) were
preferentially attacked by the more substituted enamine
intermediate in the carbon-carbon bond-forming step
leading to the corresponding syn-diastereomer. On the
other hand, imines derived from aliphatic and aromatic
aldehydes were typically attacked by the less substituted
enamine intermediate with the methyl group of the ke-
tone donors as nucleophilic center (Table 1). Benzylox-
yacetaldehyde and p-nitrobenzaldehyde are more reac-
tive than unsubstituted aromatic and linear aliphatic al-
dehydes, but less reactive than glyoxylates; the forma-
various solvents.[a, b]
[a]
Reaction as per Table 3.
[b]
dr>19: 1 for all solvents.
tion of a mixture of regioisomers (Table 1, entries 7 to 50-fold using ionic liquids as solvents and the products
and 16) is in accord with this trend. were obtained in high yield with excellent enantioselec-
The Mannich reactions of ketones with N-PMP-pro- tivity with catalyst loadings as low as 1%.
tected a-imino ethyl glyoxylate were well behaved in a
We did note, however, a significant limitation in the
wide variety of organic solvents in addition to DMSO use of ionic liquid solvents in Mannich reactions involv-
(Table 4). We were pleased to find that in the reaction ing hydroxyacetone as a nucleophile in reactions. While
using acetone as donor, 22a was obtained in comparable the desired amino alcohol product was obtained with ex-
yields and enantioselectivities in all the solvents studied. cellent yield, the diastereo- and enantioselectivity of the
In the cases of dioxane and THFas solvents, the amounts reaction was severely compromised as compared to the
of proline or ketone donor can be reduced to 5 mol % same reaction in organic solvents. For example, the reac-
and 2 equivalents, respectively, furnishing 22a in essen- tion of hydroxyacetone with N-PMP-protected a-imino
tially the same yield. Reduction of catalyst loading and ethyl glyoxylate as an acceptor provided 27 in 97% yield
the amount of ketone donor led to a significantly re- albeit with a dr of 68:32 and ee of 3/24% (syn/anti). Oth-
duced reaction rate, which required inconveniently er acceptor imines, however, remain to be studied. To
long reaction times (>72 h) to achieve similar yields. determine if the poor performance of hydroxyacetone
These prolonged reaction times, however, did not affect in ionic liquids was a general phenomenon, we studied
the excellent stereoselectivities observed.[10]
the aldol reaction under similar conditions. Contrary
A significant improvement in this reaction came with to the results we obtained in the Mannich reaction, the
the introduction of ionic liquids as solvents. The Man- aldol reaction using hydroxyacetone afforded the de-
nich reaction of N-PMP protected a-imino ethyl glyox- sired product with excellent diastereo- and enantiose-
ylate with cyclohexanone using a catalytic amount of l- lectivity.[11]
proline (5 mol %) in [bmim]BF4 at room temperature
The Mannich products described herein are versatile
[11]
(Table 5) was studied. The reaction was complete building blocks for a large variety of valuable synthons,
within 30 min and provided the Mannich product 25 in and the functionalities present offer attractive sites for
quantitative yield with excellent ee (>99%) and diaster- further modifications. For example, it has been shown
eoselectivity (>19:1). In order to study catalyst and sol- that the products from the reaction of hydroxyacetone
vent recycling, the product was extracted with ether. The with imines (Table 2) can be readily converted into
recovered ionic liquid containing l-proline was then 1,2-amino alcohols by application of a four-step oxida-
used for another reaction. Again, the Mannich product tion/reduction protocol; the conversion was accompa-
was obtained with excellent yield and ees. After four nied by the loss of one of the newly generated stereogen-
consecutive reaction cycles (Table 5) there was no di- ic centers.[2n] We were particularly interested in exploit-
minution in ee and only a slight decrease in yield when ing the inherent access to functionalized non-proteino-
the 30 min reaction time was strictly maintained. The genic a-amino acids. We devised a scheme for synthesis
use of another ionic liquid, [bmim]PF6, as reaction sol- of N-Boc-cyclohexylglycine 34 (Scheme 1), which had
vent also afforded the Mannich products with identical been posted on “www.innocentive.com” as an interest-
yields and ees. In further studies, we found that our Man- ing and exemplary target. Cyclohexylglycine itself is a
nich-type reactions were generally accelerated from 4- constituent of effective inhibitors of the blood coagula-
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Proline-Catalyzed Asymmetric Addition of Ketones to Imines
FULL PAPERS
Table 5. Catalyst and ionic liquid solvent recycling.
Scheme 1. Synthesis of N-Boc-cyclohexylglycine 34 and a-
amino-d-lactone 36. Reagents and conditions: (a) l-Selec-
tride, THF, À788C, 89%; (b) PhI(OAc)2, MeOH, 08C,
30 min; 1 N HCl, 08C, 30 min; (c) aqueous Na2CO3, Ac2O
(64%) or Boc2O (68%); (d) TsNHNH2, MeOH, D; then
tion factor Xa and of a doxorubicin conjugate with an
oligopeptide of aprostate-specific antigen.[12] Finally, cy-
clohexylglycinehas served as a building blocks for serine
protease inhibitors used as anti-inflammatory agents
and as inhibitors of hepatitis C virus.[13] The starting ma-
terial, ent-25, was readily available in gram quantities
from the d-proline-catalyzed Mannich reaction of N-
PMP protected a-imino ethyl glyoxylate with cyclohex-
anone. N-Boc-cyclohexylglycine 34 was synthesized in
three straightforward steps. First, the N-PMP group of
ent-25 was removed oxidatively by using PhI(OAc)2
and the resulting amine was protected in situ with Boc2O
and Ac2O in the presence of aqueous Na2CO3 affording
!
NaBH4, 08C D, 50% overall; (e) LiOH, dioxane/H2O, r.t.,
14 h, 78%.
Scheme 2. Synthesis of oxime-functionalized amino acids.
30 and 31 in 68% and 64% yield, respectively.[14] Second, tone donor derived amino acids was readily converted to
removal of the keto functionality present in 30 was ac- the corresponding oxime as shown for 37 (Scheme 2).
complished by its treatment with tosylhydrazine in re-
Oximes of this type were recently integrated into gly-
fluxing methanol and subsequent reduction of the inter- copeptide analogues containing unnatural sugar-pep-
mediate hydrazone with NaBH4 provided N-Boc-pro- tide linkages.[17] Acetone was used as donor and solvent,
tected ethyl cyclohexylglycinate 33 in 50% overall yield. the mixture was concentrated after complete consump-
Alternatively, the keto group could be removed prior to tion of the imino glyoxylate, the residue dissolved in di-
the oxidative cleavage ofthe p-methoxyphenylgroupaf- oxane/pyridine (10:1), and stirred together with O-ben-
fording 33 via N-PMP-protected cyclohexylglycine 32. zylhydroxylamine hydrochloride for 14 h at room tem-
Finally, saponification of the ethyl ester moiety of 33 perature. This afforded a ~2:1 mixture of oximes 37 in
by means of LiOH in aqueous dioxane afforded N- favor of the (E)-isomer.[18,19] Thus, reaction of these ke-
Boc-protected (R)-cyclohexylglycine 34 with 99% ee.
tone-containing amino acids with a variety of hydroxyl-
The keto functionality in ent-25 can be reduced to the amines can provide for the synthesis of a diverse family
secondary alcohol in a completely diastereoselective of d- or l-amino acids with oxime-containing side chains
manner by treatment with l-Selectride at very low tem- which can now be considered as building blocks in com-
peratures with concomitant in situ lactonization. Subse- binatorial syntheses.
quent oxidative removal of the N-PMP group in 35
yielded a-amino g-lactone hydrochloride 36 in 76%
yield without any detectable epimerization. NMR stud- Conclusion
ies (NOE experiments, J values) of both 35 and 36 con-
firmed the anticipated syn-stereochemistry.[1i,15]
In conclusion, we have successfully further extended our
Unnatural amino acids that contain carbonyl groups concept of proline-catalysis involving enamine inter-
have been shown to be useful as reactive handles that mediates to the direct asymmetric Mannich-type reac-
provide for the facile modification of proteins and pep- tion.[20] We have defined and broadened the scope of
tides,[16] and the ketone moiety provides for facile diver- the transformation by showing that a wide variety of
sification. For example, the carbonyl group of these ke- structurally different ketones were effective donors in
a catalytic Mannich-type reaction, which could be ac-
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HRMS (MALDI-FTMS): calcd. for C19H22N2O3 (MNaþ):
349.1523; found: 349.1516.
complished in a highly chemoselective, one-pot, three-
component protocol or by using preformed imines.
The Mannich products were typically formed in a
highly chemo-, regio-, diastereo-, and enantioselective
manner, and in many cases the Mannich products could
be obtained as single stereoisomers with syn/anti ratio
of>19:1 and ees>95%. In the cases where the forma-
tion of both diastereomers occurred, two adjacent ster-
eocenters were created with complete stereocontrol
upon carbon-carbon bond formation, affording the
syn-diastereomer with high preference. Furthermore,
we were able to identify factors that control the regio-
chemistry of the enamine key intermediate involved in
the carbon-carbon bond forming event. The use of an
a-imino glyoxylate as acceptor in the reaction with ke-
tones as donors provided a facile and stereoselective en-
try to functionalized amino acids, which were readily
converted into a-amino-g-lactones and oximes.
(4S)-4-(4-Methoxyphenylamino)-4-(1-naphthyl)-butan-
2-one (4): 1H NMR: d¼2.13 (s, 3H, COMe), 2.91 (dd, 1H, J¼
8.3 Hz, J¼16.3 Hz), 3.06 (dd, 1H, J¼4.0 Hz, J¼16.3 Hz), 3.64
(s, 3H, OMe), 4.27 (bs, 1H, NH), 5.58 (dd, 1H, J¼8.3 Hz, J¼
4.0 Hz), 6.44–6.48 (m, 2H), 6.62–6.65 (m, 2H), 7.37 (m, 1H),
7.51–7.60 (m, 3H), 7.74 (m, 1H), 7.90 (m, 1H), 8.15 (m,1H),
13C NMR: d¼30.6, 50.2, 50.9, 55.6, 122.1, 123.2, 125.5, 125.7,
126.4, 127.8, 129.3, 130.4, 134.1, 137.3, 140.8, 152.1, 207.3;
HPLC (Daicel Chiralpak AS, hexanes/i-PrOH¼90:10, flow
rate 1.0 mL/min, l¼254 nm): major isomer: tR ¼14.94 min; mi-
nor isomer: tR ¼19.59 min; [a]D: þ111.7 (c 1, CHCl3); HRMS
(MALDI-FTMS): calcd. for C21H21NO2 (Mþ): 319.1572; found:
319.1581
(4S)-4-Cyclohexyl-(4-methoxyphenylamino)-4-butan-2-
1
one (5): H NMR: d¼0.96–1.25 (m, 5H), 1.45–1.87 (m, 6H),
2.13 (s, 3H, COMe), 2.58 (m, 2H), 3.62 (m, 1H), 3.74 (s, 3H,
OMe), 6.56 (d, 2H, J¼8.8 Hz), 6.75 (d, 2H, J¼8.8 Hz);
13C NMR: d¼26.3, 26.4, 29.3, 29.5, 30.6, 41.7, 45.5, 55.7,
114.7, 114.9, 141.7, 151.9, 208.6; HPLC (Daicel Chiralpak AS,
hexanes/i-PrOH¼90:10, flow rate 1.0 mL/min, l¼254 nm):
major isomer: tR ¼8.23 min; minor isomer: tR ¼14.88 min;
[a]D: þ3.1 (c 1, CHCl3); HRMS (MALDI-FTMS): calcd. for
C17H26NO2 (MHþ): 276.1964; found 276.1970.
Experimental Section
(4S)-4-(4-Methoxyphenylamino)-5-methylhexan-2-one
Typical Three-Component, One-Pot Procedure for the
Catalytic Asymmetric Mannich-Type Reaction of
Ketones, Aldehydes and p-Anisidine
1
(6): H NMR: d¼0.89 (d, 3H, J¼7.0 Hz), 0.96 (d, 3H, J¼
7.0 Hz), 1.91 (m, 1H), 2.14 (s, 3H, COMe), 2.55 (m, 2H), 3.64
(m, 1H), 3.73 (s, 3H, OMe), 6.57 (d, 2H, J¼9.2 Hz). 6.75 (d,
2H, J¼9.2 Hz); 13C NMR: d¼18.4, 18.8, 30.6, 31.3, 45.2, 55.7,
56.2, 115.0, 141.6, 152.1, 208.4; HPLC (Daicel Chiralpak AS,
hexanes/i-PrOH¼97:3, flow rate 1.0 mL/min, l¼254 nm):
major isomer: tR ¼15.35 min; minor isomer: tR ¼11.90 min;
[a]D: þ1.5 (c 1, CHCl3); ESI-MS: calcd. for C14H22NO2
(MHþ): 236.16; found: 236.
To a mixture of anhydrous DMSO (4 mL) and acetone (1 mL)
was added p-anisidine (0.5 mmol) and the corresponding alde-
hyde (0.5 mmol) followed byproline (20 mol %) and theresult-
ing homogeneous reaction mixture was stirred at room temper-
ature for 4–48 h. Then, half saturated NH4Cl solution and eth-
yl acetate were added with vigorous stirring, the layers were
separated and the aqueous phase was extracted thoroughly
with ethyl acetate. The combined organic phases were dried
(MgSO4), concentrated, and purified by flash column chroma-
tography (silica gel, mixtures of hexanes/ethyl acetate) to af-
ford the desired b-amino ketones. The enantiomeric excesses
of the products were determined by HPLC analysis using chiral
stationary phases.
(1S)-1-(4-Methoxyphenylamino)-1-phenylbutan-3-one
(1): 1H NMR: d¼2.06 (s, 3H, COMe), 2.86 (m, 2H), 3.65 (s, 3H,
OMe), 4.12 (bs, 1H, NH), 4.75 (m, 1H), 6.49 (d, 2H, J¼9.1 Hz),
6.67 (d, 2H, J¼9.1 Hz), 7.20–7.36 (m, 5H); 13C NMR: d¼30.5,
51.2, 55.1, 55.5, 114.6, 115.1, 126.2, 127.1, 128.6, 140.8, 142.6,
152.1, 207.2; HPLC (Daicel Chiralpak AD, hexanes/i-
PrOH¼97:3, flow rate 1.0 mL/min, l¼254 nm): major iso-
mer: tR ¼27.06 min; minor isomer: tR ¼21.46 min; HRMS
(MALDI-FTMS): calcd. for C17H19NNaO2 (MNaþ):
292.1313; found: 292.1319.
(1S)-1-(4-Acetamidophenyl)-1-(4-methoxyphenylami-
no)-butan-3-one (2): 1H NMR: d¼2.10 (s, 3H, COMe), 2.13 (s,
3H, COMe), 2.90 (d, 1H, J¼3.7 Hz), 2.95 (d, 1H, J¼3.7 Hz),
3.65 (s, 3H, OMe), 4.24 (m, 1H), 4.87 (m, 1H), 4.95 (bs, 1H),
6.56 (d, 2H, J¼8.8 Hz), 6.75 (d, 2H, J¼8.8 Hz), 7.21 (bs, 1H),
7.30 (d, 2H, J¼8.4 Hz), 7.43 (d, 2H, J¼8.4 Hz); 13C NMR:
d¼24.7, 30.5, 51.3, 55.6, 55.6, 114.6, 120.2, 126.9, 136.4, 136.9,
138.3. 146.9, 168.2, 207.2; HPLC (Daicel Chiralpak AD, hex-
anes/i-PrOH¼80:20, flow rate 1.0 mL/min, l¼254 nm): ma-
jor isomer: tR ¼23.54 min; minor isomer: tR ¼27.66 min;
(1S)-1-(4-Methoxyphenylamino)-1-(1-naphthyl)-pentan-
3-one (8): 1H NMR: d¼8.14 (1H, d, J¼8.4), 7.88 (1H, dd, J¼
8.4, 1.2 Hz), 7.71 (1H, d, J¼8.1 Hz), 7.52 (3H, m), 7.35 (1H,
t, J¼7.5 Hz), 6.61 (2H, d, J¼9.3 Hz), 6.44 (2H, d, J¼9.3 Hz),
5.56 (1H, m), 3.63 (3H, s), 3.02 (1H, dd, J¼15.9, 3.9 Hz), 2.89
(1H, dd, J¼15.9, 8.4 Hz), 2.36 (2H, m), 0.98 (3H, t, J¼
7.1 Hz); 13C NMR (CDCl3): d¼209.8, 151.9, 140.8, 137.3,
133.9, 130.3, 129.1, 127.7, 126.3, 125.6, 125.4, 123.1, 122.0,
114.8, 114.5, 55.6, 51.1, 48.9, 36.8, 7.5; HPLC (Daicel Chiralpak
AS, hexanes/i-PrOH¼93:7, flow rate 1.0 mL/min, l¼
254 nm): major isomer: tR ¼10.52 min; minor isomer: tR ¼
14.07 min; HRMS (MALDI-FTMS): calcd. for C22H23NO2
(MNaþ): 356.1626; found: 356.1625.
(4S,5S)-5-(4-Methoxyphenylamino)-4,7-dimethyloctan-
3-one (9): 1H NMR: d¼6.74 (2H, d, J 9.3 Hz), 6.53 (2H, d, J¼
9.3 Hz), 3.72 (3H, s), 3.61 (1H, m), 2.77 (1H, m), 2.43 (2H, qd,
J¼7.5, 2.4 Hz), 1.73 (1H, m), 1.31 (2H, m), 1.12 (3H, d, J¼
6.9 Hz), 0.98 (3H, t, J¼6.9 Hz), 0.92 (3H, d, J¼6.6 Hz), 0.86
(3H, d, J¼6.6 Hz); 13C NMR: d¼214.0, 151.7, 141.9, 114.9,
114.1, 55.8, 54.6, 49.6, 42.4, 35.6, 25.1, 23.4, 22.1, 12.7, 7.7.
HPLC (Daicel Chiralpak AD, hexanes/i-PrOH¼92:8, flow
rate 1.0 mL/min, l¼254 nm): major isomer: tR ¼4.59 min; mi-
nor isomer: tR ¼5.25 min; [a]D: þ14.9 (c 1.5, CHCl3); HRMS
(MALDI-FTMS): calcd. for C17H27NO2 (MNaþ): 300.1934;
found: 300.1934.
(1S,2S)-1-(4-Methoxyphenylamino)-2-methyl-1-phenyl-
pentan-3-one (10): 1H NMR: d¼7.27 (5H, m), 6.64 (2H, d, J¼
1136
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Proline-Catalyzed Asymmetric Addition of Ketones to Imines
FULL PAPERS
9.0 Hz), 6.43 (2H, d, J¼9.0 Hz), 4.57 (1H, d, J¼5.7 Hz), 3.66
(3H, s), 2.97 (1H, m), 2.34 (2H, t, J¼7.5 Hz), 1.10 (3H, d, J¼
7.2 Hz), 0.93 (3H, t, J¼7.2); 13C NMR: d¼213.2, 152.0, 141.3,
141.1, 128.4, 127.1, 126.8, 114.8, 114.6, 60.0, 55.7, 52.3, 35.6,
11.6, 7.6; HPLC (Daicel Chiralpak AD, hexanes/i-PrOH¼
92:8, flow rate 1.0 mL/min, l¼254 nm): major isomer: tR ¼
7.69 min; minor isomer: tR ¼6.72 min; [a]D: þ35.9 (c 0.7,
CHCl3); HRMS (MALDI-FTMS): calcd. for C19H23NO2
(MHþ): 298.1801; found: 298.1798.
(3S)-3-(4-Methoxyphenylamino)-2-methylnon-8-en-5-
one (11): 1H NMR: d¼6.74 (2H, d, J¼9.0 Hz), 6.55 (2H, d, J¼
9.0 Hz), 5.75 (1H, ddt, J¼17.1, 10.2, 6.6 Hz), 4.98 (1H, dm, J¼
17.1 HZ), 4.94 (1H, dm, J¼10.2 Hz), 3.79 (1H, m), 3.72 (1H, s),
2.64 (1H, dd, J¼16.2, 5.1 Hz), 2.51 (1H, dd, J¼16.2, 6.3 Hz),
2.46 (2H, t, J¼7.2 Hz), 2.28 (2H, q-like), 1.74 (1H, m), 1.45
(1H, m), 1.31 (1H, m), 0.92 (3H, d, J¼6.6 Hz), 0.90 (3H, d,
J¼6.3 Hz); 13C NMR: d¼209.4, 152.0, 141.2, 136.9, 115.2,
115.0, 113.9, 55.8, 49.2, 47.4, 44.9, 42.9, 27.6, 25.1, 23.1, 22.4;
HPLC (Daicel Chiralpak AD, hexanes/i-PrOH¼92:8, flow
rate 1.0 mL/min, l¼254 nm): major isomer: tR ¼6.26 min; mi-
nor isomer: tR ¼6.99 min; [a]D: þ14.2 (c 2.4, CHCl3); HRMS
(MALDI-FTMS): calcd. for C18H27NO2 (MNaþ): 312.1934;
found: 312.1931.
(6S)-6-(4-Methoxyphenylamino)-dodec-11-en-8-one (12):
1H NMR: d¼6.74 (2H, d, J¼8.7 Hz), 6.55 (2H, d, J¼8.7 Hz),
5.75 (1H, ddt, J¼16.5, 10.8, 6.6 Hz), 4.98 (1H, dm, J¼
16.5 Hz), 4.94 (1H, dm, J¼10.8 Hz), 3.74 (1H, m), 3.73 (1H,
s), 2.64 (1H, dd, J¼16.2, 5.1 Hz), 2.53 (1H, dd, J¼16.2,
6.3 Hz), 2.48 (2H, t, J¼7.2 Hz), 2.28 (2H, q-like), 1.50 (2H,
m), 1.28 (6H, m), 0.87 (3H, t, J¼6.9 Hz); 13C NMR: d¼209.4,
152.1, 141.2, 136.9, 115.2, 114.9, 114.0, 55.8, 51.2, 47.2, 42.8,
35.3, 31.8, 27.6, 26.0, 22.7, 14.2; HPLC (Daicel Chiralpak AS,
hexanes/i-PrOH¼95:5, flow rate 1.0 mL/min, l¼254 nm):
major isomer: tR ¼5.13 min; minor isomer: tR ¼8.60 min;
[a]D: þ12.1 (c 1, CHCl3); HRMS (MALDI-FTMS): calcd.
for C19H29NO2 (MNaþ): 326.2096; found: 326.2083.
(1H, t, J¼8.1 Hz), 6.61 (2H, d, J¼9.0 Hz), 6.44 (2H, d, J¼
9.0 Hz), 5.70 (1H, m), 5.57 (1H, dd, J¼8.3, 4.1), 4.95 (1H, m),
4.91 (1H, m), 3.62 (3H, s), 3.02 (1H, dd, J¼16.1, 3.9 Hz), 2.90
(1H, dd, J¼16.1, 8.4 Hz), 2.44 (2H, t, J¼7.2 Hz), 2.26 (2H,
m); 13C NMR: d¼208.4, 152.1, 140.7, 137.4, 136.6, 134.0,
130.3, 129.2, 127.7, 126.3, 125.6, 125.5, 123.2, 122.0, 115.3,
114.9, 114.6, 55.7, 51.2, 49.4, 42.7, 27.5; HPLC (Daicel Chiral-
pak AS, hexanes/i-PrOH¼94:6, flow rate 1.0 mL/min, l¼
254 nm): major isomer: tR ¼7.64 min; minor isomer: tR ¼
9.56 min; [a]D: þ117 (c 2, CHCl3); HRMS (MALDI-FTMS):
calcd. for C24H25NO2 (Mþ ): 359.1885; found: 359.1870.
(2S)-1-Benzyloxy-2-(4-methoxyphenylamino)-oct-7-en-
4-one (16a): 1H NMR: d¼7.29 (5H, m), 6.74 (2H, d, J¼
9.3 Hz), 6.57 (2H, d, J¼9.3 Hz), 5.74 (1H, ddt, J¼17.1, 10.2,
6.6 Hz), 4.98 (1H, dm, J¼17.1 Hz), 4.93 (1H, dm, J¼
10.2 Hz), 4.47 (2H, m), 3.95 (1H, m), 3.72 (3H, s), 3.55 (2H,
m), 2.71 (2H,m), 2.47 (2H, tm, J¼7.2 Hz), 2.26 (2H, q-like);
13C NMR: d¼209.2, 152.4, 140.6, 137.9, 136.9, 128.2, 127.8,
127.6, 115.5, 115.1, 114.8, 73.3, 71.0, 55.7, 50.7, 43.9, 42.7, 27.6;
HPLC (Daicel Chiralpak AD, hexanes/i-PrOH¼92:8, flow
rate 1.0 mL/min, l¼254 nm): major isomer: tR ¼14.00 min; mi-
nor isomer: tR ¼11.67 min; [a]D: À4.9 (c 1.5, CHCl3); HRMS
(MALDI-FTMS): calcd. for C22H27NO3 (MNaþ): 376.1883;
found: 376.1887.
(2S,3S)-3-Acetyl-1-benzyloxy-2-(4-methoxyphenylami-
1
no)-hex-5-ene (16b): H NMR: d¼7.30 (5H, m), 6.74 (2H, d,
J¼8.7 Hz), 6.56 (2H, d, J¼8.7 Hz), 5.73 (1H, m), 5.03 (2H,
m), 4.42 (2H, s), 3.73 (1H, m), 3.72 (3H, s), 3.51 (1H, dd, J¼
9.6, 4.2 Hz), 3.44 (1H, dd, J¼9.6, 3.3 Hz), 3.00 (1H, td, J¼
8.6, 4.8 Hz), 2.45 (2H, m), 2.11 (3H, s); 13C NMR: d¼211.0,
152.3, 141.1, 137.7, 135.4, 128.3, 128.2, 127.7, 117.0, 115.2,
114.9, 73.4, 69.6, 55.8, 55.7, 53.8, 33.7, 31.9; HPLC (Daicel Chir-
alpak AD, hexanes/i-PrOH¼92:8, flow rate 1.0 mL/min, l¼
254 nm): major isomer: tR ¼8.28 min; minor isomer: tR ¼
9.63 min; [a]D: À31.5 (c 1.3, CHCl3); HRMS (MALDI-
FTMS): calcd. for C22H27NO3 (MNaþ): 376.1883; found:
376.1881.
(1S)-1-(4-Methoxyphenylamino)-1-phenylhept-6-en-3-
1
one (13): H NMR: d¼7.30 (5H, m), 6.66 (2H, d, J¼8.7 Hz),
(3S,4R)-3-Hydroxy-4-(4-methoxyphenylamino)-6-meth-
1
6.48 (2H, d, J¼8.7 Hz), 5.69 (1H, ddt, J¼17.1, 10.5, 6.6 Hz),
4.95 (1H, dm, J¼17.1 Hz), 4.91 (1H, dm, J¼10.5 Hz), 4.75
(1H, t, J¼6.3 Hz), 3.66 (3H, s), 2.86 (2H, m), 2.41 (2H, tm,
J¼6.9 Hz), 2.24 (2H, m); 13C NMR: d¼208.3, 152.2, 142.6,
140.8, 136.6, 128.6, 127.1, 126.2, 115.22, 115.18, 114.6, 55.6,
55.4, 50.5, 42.6, 27.4; HPLC (Daicel Chiralpak AD, hexanes/
i-PrOH¼92:8, flow rate 1.0 mL/min, l¼254 nm): major iso-
mer: tR ¼14.68 min; minor isomer: tR ¼12.31 min; [a]D: þ5.8
(c 4, CHCl3); HRMS (MALDI-FTMS): calcd. for C20H23NO2
(Mþ): 309.1729; found: 309.1732.
ylheptan-2-one (17): H NMR: d¼0.95 (d, J¼6.5 Hz, 3H),
1.01 (d, J¼6.6 Hz, 3H), 1.49 (m, 1H), 1.58 (m, 1H), 1.78 (m,
1H), 2.20 (s, 3H), 3.41 (bs, 1H), 3.74 (s, 3H), 3.81 (m, 1H),
3.88 (m, 1H), 4.26 (m, 1H), 6.55 (d, J¼8.8 Hz, 2H), 6.75 (d,
J¼8.8 Hz, 2H); 13C NMR: d¼22.1, 23.2, 24.9, 25.0, 40.2, 53.8,
55.7, 77.7, 114.9, 115.2, 140.7, 152.4, 208.6; HPLC (Daicel Chir-
alpak AS, hexane/i-PrOH¼94:6, flow rate 1.00 mL/min, l¼
254 nm): tR (major)¼8.30 min; tR (minor)¼27.46 min;
HRMS (MALDI-FTMS): calcd. for C15H23NO3 (MNaþ):
288.1570; found: 288.1559.
(1S)-1-(4-Methoxyphenylamino)-1-(4-nitrophenyl)-hept-
(3S,4R)-3-Hydroxy-4-(4-methoxyphenylamino)-nonan-
1
1
6-en-3-one (14): H NMR: d¼8.14 (2H, d, J¼9.0 Hz), 7.52
2-one (18): H NMR: d¼0.89 (m, 3H), 1.27–1.35 (m, 4H),
(2H, d, J¼9.0 Hz), 6.67 (2H, d, J¼9.0 Hz), 6.44 (2H, d, J¼
9.0 Hz), 5.72 (1H, m), 4.96 (2H, m), 4.85 (1H, t, J¼6.3 Hz),
4.27 (1H, s, br), 3.68 (3H, s), 2.92 (2H, m), 2.47 (2H, m), 2.27
(2H, m); 13C NMR: d¼207.3, 152.6, 150.6, 147.0, 140.0, 136.3,
127.3, 123.9, 115.5, 115.3, 114.7, 55.6, 54.8, 49.9, 42.6, 27.5;
HPLC (Daicel Chiralpak AS, hexanes/i-PrOH¼86:14, flow
rate 1.0 mL/min, l¼254 nm): major isomer: tR ¼30.70 min; mi-
nor isomer: tR ¼23.66 min; HRMS (MALDI-FTMS): calcd. for
C20H22N2O4 (Mþ): 354.1580; found: 354.1565.
1.38–1.48 (m, 2H), 1.61–1.71 (m, 2H), 3.45 (bs, 1H), 3.74 (s,
3H), 3.76 (m, 1H), 3.83 (bs, 1H), 4.28 (m, 1H), 6.54 (d, J¼
8.8 Hz, 2H), 6.75 (d, J¼8.8 Hz, 2H); 13C NMR: d¼14.0, 22.6,
24.9, 26.3, 31.3, 31.7, 55.7, 56.0, 77.6, 114.9, 115.2, 140.8, 152.4,
208.6; HPLC (Daicel Chiralpak AD, hexane/i-PrOH¼92:8,
flow rate 1.00 mL/min, l¼254 nm): tR (major)¼6.85 min; tR
(minor)¼8.10 min; HRMS (MALDI-FTMS): calcd. for
C16H25NO3 (MNaþ): 302.1727; found: 302.1737.
(1R,2S)-2-Hydroxy-1-(4-methoxyphenylamino)-1-naph-
thylbutan-3-one (19): Major diastereomer: 1H NMR: d¼2.46
(s, 3H), 3.62 (d, J¼3.0 Hz, 1H), 3.64 (s, 3H), 4.52 (bs, 1H),
4.56 (m, 1H), 5.76 (bs, 1H), 6.45 (d, J¼8.8 Hz, 2H), 6.62 (d,
(1S)-1-(4-Methoxyphenylamino)-1-naphthylhept-6-en-3-
1
one (15): H NMR: d¼8.13 (1H, d, J¼8.4 Hz), 7.87 (1H, dd,
J¼8.3, 1.2 Hz), 7.71 (1H, d, J¼8.1 Hz), 7.51 (3H, m), 7.35
Adv. Synth. Catal. 2004, 346, 1131–1140
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Wolfgang Notz et al.
FULL PAPERS
J¼8.8 Hz, 2H), 7.41 (t, J¼7.9 Hz, 1H), 7.46 (d, J¼7.0 Hz, 1H),
7.55 (t, J¼7.9 Hz, 1H), 7.64 (t, J¼7.9 Hz, 1H), 7.78 (d, J¼
8.3 Hz, 1H), 7.94 (d, J¼8.3 Hz, 1H), 8.18 (d, J¼8.3 Hz, 1H);
13C NMR: d¼14.1, 25.5, 54.6, 55.6, 60.4, 79.0, 114.8, 114.9,
121.2, 124.7, 125.5, 125.6, 126.5, 128.2, 129.7, 130.7, 133.4,
208.9; HPLC (Daicel Chiralpak AS, hexane/i-PrOH¼89:11,
flow rate 1.00 mL/min, l¼254 nm): syn-isomer: tR (major)¼
9.06 min; tR (minor)¼15.54 min; anti-isomer: tR (major)¼
12.30 min; tR (minor)¼18.46 min; [a]D: þ23.6 (c 0.4, CHCl3);
HRMS (MALDI-FTMS): calcd. for; C15H21NO5 (MNaþ):
318.1312; found: 318.1319.
1
134.1, 139.8, 152.3, 207.5. Minor diastereomer: H NMR: d¼
2.35 (s, 3H), 3.67 (s, 3H), 3.78 (m, 1H), 4.29 (bs, 1H), 4.89 (m,
1H), 5.56 (d, J¼3.9 Hz, 1H), 6.54 (d, J¼8.8 Hz, 2H), 6.67 (d,
J¼8.8 Hz, 2H), 7.39–7.66 (m, 4H), 7.81 (d, J¼8.3 Hz,1H),
7.92 (d, J¼8.3 Hz, 1H), 8.25 (d, J¼8.3 Hz, 1H); 13C NMR:
14.2, 28.2, 55.6, 57.4, 60.4, 78.4, 114.7, 114.8, 115.2, 115.6,
122.3, 125.0, 125.5, 125.8, 126.6, 126.7, 128.7, 129.4, 130.9,
133.0, 134.1, 140.6, 152.7, 209.1; HPLC (Daicel Chiralpak
AD, hexane/i-PrOH¼92:8, flow rate 1.00 mL/min, l¼
254 nm): major diastereomer: tR (major)¼28.58 min; tR (mi-
nor)¼15.90 min; minor diastereomer: tR (major)¼41.47 min;
tR (minor)¼22.35 min; HRMS (MALDI-FTMS): calcd. for
C21H21NO3 (MNaþ): 358.1419; found: 358.1416.
Ethyl (2S,3R)-3-hydroxymethyl-2-(p-methoxyphenylami-
no)-4-oxo-pentanoate (29): 1H NMR (600 MHz, CDCl3): d¼
1.22 (t, 3H, J¼7.0 Hz), 2.39 (s, 3H), 3.09 (bs, 1H), 3.15 (m,
1H), 3.74 (s, 3H, OMe), 3.94 (dd, 1H, J¼4.4, 11.8 Hz), 4.07
(dd, 1H, J¼5.3, 11.8 Hz), 4.17 (q, 2H, J¼7.0 Hz), 4.29 (bs,
1H), 4.50 (d, 1H, J¼6.1 Hz), 6.68 (d, 2H, J¼8.8 Hz), 6.77 (d,
2H, J¼8.8 Hz); 13C NMR: d¼14.0, 29.2, 55.6, 56.0, 58.4, 60.9,
61.6, 114.8, 116.1, 140.4, 153.3, 172.7, 208.1; HPLC (Daicel
Chiralpak AD, hexane/i-PrOH¼98:2, flow rate 1.00 mL/
min, l¼254 nm): tR (major)¼24.86 min; tR (minor)¼
22.49 min; HRMS (MALDI-FTMS): calcd. for C15H21NO5
(MNaþ): 318.1312; found: 318.1309.
(1R,2S)-2-Hydroxy-1-(4-methoxyphenylamino)-1-phe-
Ethyl (R)-N-(p-methoxyphenyl)-cyclohexylglycinate (32):
To a solution of ent-25 (500 mg, 1.637 mmol) in MeOH
(32 mL, 0.05M) was added tosylhydrazine (427 mg, 1.4
equivs.), and the mixture was heated to reflux for 2 h. After
cooling to 08C, NaBH4 (620 mg) was added in small portions
over 45 min. After stirring for 30 min at 08C, the mixture was
heated to reflux for 2 h. Then brine was added and the mixture
was extracted with EtOAc. The combined organic layers were
dried (MgSO4) and concentrated, and the residue was purified
by flash column chromatography (hexanes/ethyl acetate¼
1
nylbutan-3-one (20): H NMR: d¼2.24 (s, 3H), 3.62 (s, 3H),
3.84 (m, 1H), 4.33 (m, 1H), 4.40 (bs, 1H), 4.85 (m, 1H), 6.46
(d, J¼8.8 Hz, 2H), 6.64 (d, J¼8.8 Hz, 2H), 7.17–7.33 (m,
5H); 13C NMR: d¼25.1, 55.4, 58.9, 80.6, 114.6, 115.0, 126.9,
127.4, 128.4, 139.2, 140.0, 152.1, 207.5; HPLC (Daicel Chiral-
pak AD, hexane/i-PrOH¼92:8, flow rate 1.00 mL/min, l¼
254 nm): tR (major)¼23.98 min; tR (minor)¼16.96 min; [a]D:
þ50.2 (c 0.6, CHCl3); HRMS (MALDI-FTMS): calcd. for
C17H19NO3 (MNaþ): 308.1257; found: 308.1269.
1
(2R,3S)-1-Benzyloxy-3-hydroxy-1-(4-methoxyphenyla-
mino)-pentan-4-one (21): 1H NMR: d¼2.19 (s, 3H), 3.60 (dd,
J¼8.34, 9.2 Hz, 1H), 3.68 (dd, J¼4.0, 9.2 Hz, 1H), 3.73 (s, 3H),
3.86 (m, 1H), 3.98 (m, 1H), 4.50–4.56 (m, 3H), 6.56 (d, J¼
8.8 Hz, 2H), 6.75 (d, J¼8.8 Hz, 2H), 7.28–7.37 (m, 5H);
13C NMR: d¼25.4, 53.4, 55.4, 55.7, 68.4, 73.6, 76.1, 115.0,
127.8, 127.9, 128.5, 137.8, 140.1, 152.6, 208.9; HPLC (Daicel
Chiralpak AD, hexane/i-PrOH¼92:8, flow rate 1.00 mL/
min, l¼254 nm): tR (major)¼16.67 min; tR (minor)¼
15.42 min; HRMS (MALDI-FTMS): calcd. for C19H23NO4
(MNaþ): 352.1525; found: 352.1527.
3:1) to afford 32; yield: 241 mg (50%); H NMR (600 MHz,
CDCl3): d¼1.11–1.32 (m, 8H), 1.65–1.89 (m, 6H), 3.73 (s,
3H), 3.75 (d, 1H, J¼7.5 Hz), 3.86 (bs, 1H), 4.15 (m, 2H), 6.60
(d, 2H, J¼8.7 Hz), 6.75 (d, 2H, J¼8.7 Hz); 13C NMR: 14.3,
26.0. 26.1, 26.2, 29.5, 30.0, 41.6, 56.0, 61.0, 63.6, 115.1, 115.4,
141.9, 152.9, 174.3; [a]D: þ42.3 (c 0.7, CH2Cl2); HRMS (MAL-
DI-FTMS): calcd. for C17H25NO3 (MNaþ) 314.1727; found:
314.1724.
Ethyl (R)-N-(tert-butoxycarbonyl)-cyclohexylglycinate
(33): A solution of 32 (500 mg, 1.717 mmol) in MeOH (2 mL)
was added via syringe over 30 min to a solution of iodobenzene
diacetate (2.2 g, 6.7 mmol, 4 equivs.) in MeOH (20 mL). Fol-
lowing exactly the protocol described by Hoveyda and Snap-
per,[14] using (Boc)2O (1.9 g, 8.8 mmol) instead of acetic anhy-
dride, afforded 33 after column chromatography (hexanes/eth-
yl acetate, 4:1); yield: 330 mg (67%) 1H NMR (600 MHz,
CDCl3): d¼1.04–1.30 (m, 9H), 1.44 (s, 9H), 1.56–1.77 (m,
5H), 4.16–4.22 (m, 3H), 5.01 (m, 1H); 13C NMR: d¼14.2,
26.0, 28.1, 28.3, 29.4, 41.1, 58.3, 61.0, 79.6, 155.6, 172.4; [a]D:
À13.5 (c 2, CH2Cl2); HRMS (MALDI-FTMS): calcd. for
C15H27NO4 (MNaþ): 308.1832; found: 308.1836.
(R)-N-(tert-Butoyxcarbonyl)-cyclohexylglycine (34): T o a
solution of 33 (200 mg, 0.7 mmol) in dioxane/water (10 mL,
1:1) was added LiOH (250 mg) and the mixture was stirred
at room temperature for 14 h. Then, the mixture was acidified
with 1 N HCl and extracted with EtOAc. The combined organ-
ic layers were dried (MgSO4), filtered, and concentrated. Puri-
fication of the residue by flash column chromatography (hex-
anes/ethyl acetate¼1:5) afforded known N-Boc-protected cy-
clohexylglycine 34; yield: 141 mg (78%).
Ethyl (E)-(2S)-4-benzyloxyimino-2-(p-methoxyphenyla-
mino)-pentanoate (37): N-PMP-Protected a-imino ethyl
glyoxylate (0.5 mmol) was dissolved in anhydrous acetone
(5 mL) and l-proline (20 mol %) was added. After stirring
General Procedure for the Catalytic Asymmetric
Reaction between N-PMP-Protected a-Imino Ethyl
Glyoxylate and Ketone Donors
In a typical experiment, N-PMP-protected a-imino ethyl
glyoxylate (0.5 mmol) was dissolved in anhydrous DMSO
(4 mL), the corresponding ketone donor (1 mL) was added fol-
lowed by l-proline (20 mol %) and the mixture was stirred for
2–24 h at room temperature. Following aqueous work-up with
half-saturated ammonium chloride solution and extraction
with ethyl acetate, the organic layer was dried (MgSO4), fil-
tered, concentrated and the residue purified by column chro-
matography (silica, hexanes/ethyl acetate mixtures) to afford
the corresponding Mannich addition product.
Ethyl (2S,3S)-3-hydroxy-2-(p-methoxyphenylamino)-4-
1
oxohexanoate (28): H NMR (500 MHz, CDCl3): d¼1.12 (t,
¼
3H, J
7.4 Hz), 1.24 (t, 3H, J¼7.4 Hz), 2.61 (q, 2H, J¼
7.3 Hz), 3.73 (s, 3H, OMe), 3.92 (d, 1H, J¼3.7 Hz), 4.08 (m,
1H), 4.23 (m, 2H), 4.45 (m, 1H), 4.63 (m, 1H), 6.60 (d, 2H,
J¼8.8 Hz), 6.76 (d, 2H, J¼8.8 Hz); 13C NMR: d¼7.4, 14.1,
30.7, 55.6, 59.5, 61.8, 76.9, 114.8, 115.9, 140.2, 153.4, 170.9,
1138
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Proline-Catalyzed Asymmetric Addition of Ketones to Imines
FULL PAPERS
overnight at room temperature, the acetone was evaporated
and anhydrous dioxane (5 mL), O-benzylhydroxylamine hy-
drochloride (0.7 mmol) and pyridine (0.5 mL) were added to
the residue. After stirring for 14 h at room temperature, the
mixture was filtered through Celite, concentrated and the res-
idue purified by column chromatography (silica, hexanes/ethyl
acetate¼3/1) to afford oxime 37; yield: 102 mg (55%);
1H NMR (400 MHz): d ¼1.17 (t, 3H, OCHCH3), 1.88 (s,
3H), 2.64 (d, 2H), 3.69 (s, 3H, OCH3), 3.99 (bs, 1H, ArNHCH),
4.07 (q, 2H, OCH2CH3), 5.07 (s, 2H, PhCH2), 6.45 (d, 2H, J¼
8.8 Hz, ArH), 6.72 (d, 2H, J¼8.8 Hz, ArH), 7.25–7.40 (m,
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6H, ArH and HC N); 13C NMR (125 MHz): d¼173.0, 154.0,
¼
152.6, 140.5, 138.2, 128.2, 127.8, 127.5, 115.1, 114.6, 75.3, 60.9,
55.4, 55.2, 38.4, 14.6, 14.0; HPLC (Daicel Chiralpak AD, hex-
ane/i-PrOH¼98:2, flow rate 1.0 mL/min, l¼254 nm); tR
(major)¼26.30 min; tR (minor)¼33.10 min; HRMS (MAL-
DI-FTMS): calcd. for C21H26N2O4 (MNaþ): 393.1785; found:
393.1792.
Acknowledgements
This study was supported in part by the NIH (CA27489) and
The Skaggs Institute forChemical Biology.
References and Notes
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Adv. Synth. Catal. 2004, 346, 1131–1140
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Wolfgang Notz et al.
FULL PAPERS
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[19] Analogous attempts to prepare the corresponding hydra-
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phenylhydrazine, or methylhydrazine failed. In these cas-
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used were obtained or the corresponding hydrazones
were contaminated with by-products that could not be
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1140
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