A general, highly enantioselective method for the synthesis of D and L α-amino acids and allylic amines

Article abstract of DOI:10.1021/ja027271p

Catalytic and enantioselective synthesis of amino acids is a subject of intense interest in the field of asymmetric catalysis. Traditionally, researchers have concentrated their efforts largely on the design and discovery of enantiopure catalysts for the

Full text of DOI:10.1021/ja027271p

Published on Web 09/24/2002
A General, Highly Enantioselective Method for the Synthesis
of D and L r-Amino Acids and Allylic Amines
Young K. Chen, Alice E. Lurain, and Patrick J. Walsh*
Contribution from the P. Roy and Diane T. Vagelos Laboratories, Department of Chemistry,
UniVersity of PennsylVania, 231 South 34th Street, Philadelphia, PennsylVania 19104-6323
Received June 12, 2002
Abstract: Catalytic and enantioselective synthesis of amino acids is a subject of intense interest in the
field of asymmetric catalysis. Traditionally, researchers have concentrated their efforts largely on the design
and discovery of enantiopure catalysts for the Strecker reaction, alkylation of tert-butyl gylcinate-
benzophenone, electrophilic amination of carbonyl compounds, and hydrogenation of N-acyl-aminoacrylic
acid; however, the scope of these reactions is limited. In this paper, we report on a different approach to
amino acids based on an expeditious route to enantiopure allylic amines. A highly enantioselective and
catalytic vinylation of aldehydes leads to allylic alcohols that are then transformed to the allylic amines via
Overman’s [3,3]-sigmatropic rearrangement of imidates. Oxidative cleavage of the allylic amines furnishes
the amino acids in good yields and excellent ee’s. The scope and utility of this method are demonstrated
by the synthesis of challenging allylic amines and their subsequent transformation to valuable nonprotei-
nogenic amino acids, including both D and L configured (1-adamantyl)glycine.
N-acylaminoacrylic acids and related compounds.7,11-16 This
Introduction
methodology has been used very successfully in the synthesis
of R-amino acids that possess a primary alkyl group directly
bonded to the R-carbon.
The development of enantio- and regioselective syntheses of
nonproteinogenic amino acids and their derivatives remains an
important goal.1-5 In particular, processes that are catalytic and
highly enantioselective6,7 toward both enantiomers of substituted
R-amino acids remain scarce. One of the most popular methods
for the catalytic asymmetric synthesis of R-amino acids was
introduced by O’Donnell et al.8,9 This process involves the
alkylation of a tert-butyl glycinate-benzophenone Schiff base
under phase-transfer catalysis using N-benzylcinchoninium
cations. Modification of the phase-transfer catalyst by Corey
and Noe10 resulted in a highly enantioselective method for
alkylation of tert-butyl glycinate derivatives. This method relies
on an SN2 substitution reaction and is, therefore, most suitable
for the synthesis of unhindered R-amino acids. It is not
applicable to the synthesis of R-amino acids bearing bulky
substituents on the R-carbon.
The electrophilic amination of carbonyl compounds also
represents an efficient method to generate precursors to amino
acids.17 This method usually involves attack of a nucleophilic
R-carbon on a diazo compound.18-21 This method has been done
asymmetrically with chiral metal catalysts22-24 and with organic
catalysts.25
Another approach that holds great promise is the catalytic
asymmetric Strecker reaction.26-37 In this chemistry, N-alkyl
or N-aryl imines are treated with HCN, or another cyanide
(11) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New York,
1994.
(12) Kagan, H. B.; Phat, D.-T. J. Am. Chem. Soc. 1972, 94, 6429-6433.
(13) Knowles, W. S. Acc. Chem. Res. 1983, 16, 106-112.
(14) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40-73.
(15) Burk, M. J. Acc. Chem. Res. 2000, 33, 363-372.
(16) Wang, W.; Zhang, J.; Xiong, C.; Hruby, V. J. Tetrahedron Lett. 2002, 43,
2137-2140.
An excellent route that has been used to prepare R-amino
acids with high ee’s is catalytic asymmetric hydrogenation of
(17) Genet, J.-P.; Greck, C.; Lavergne, D. In Modern Amination Methods; Ricci,
A., Ed.; Wiley-VCH: New York, 2000; Chapter 3.
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* To whom correspondence should be addressed. E-mail: pwalsh@
sas.upenn.edu. Phone: (215) 573-2875. Fax: (215) 573-6743.
(1) Williams, R. M. Synthesis of Optically ActiVe R-Amino Acids; Pergamon
Press: Oxford, 1989.
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9
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A R T I C L E S
Chen et al.
Scheme 1. Enantioselective Synthesis of Allylic Alcohols
Table 1. Yields and ee’s of Allylic Alcohols (Scheme 1)
source, in the presence of an asymmetric catalyst to furnish
amino nitriles. Several Lewis acids and organic catalysts have
been developed that give excellent enantioselectivities with a
range of imine substrates.26,37 The resulting amino nitriles are
converted to R-amino acids by deprotection of the amino group
and hydrolysis of the nitrile to the acid. Two drawbacks to this
approach to amino acid synthesis are the harsh conditions
necessary to hydrolyze the nitrile and the extreme toxicity of
HCN.
In this report, we outline an efficient and highly enantiose-
lective synthesis of protected D and L R-amino acids from
terminal alkynes. The key steps in our synthesis are a catalytic
asymmetric vinylation of an aldehyde, followed by an Overman
imidate rearrangement to install the nitrogen.38,39 An attractive
feature of this methodology is that it provides entry into
sterically hindered allylic amines that are difficult to access using
conventional methods.40 The protected allylic amines are
versatile intermediates that can be transformed directly into a
series of functionalized building blocks such as R-amino acids,
aldehydes, esters, and alcohols through oxidative cleavage of
the double bond. To highlight this methodology, we have
synthesized a series of R-amino acids, including the synthetically
challenging (1-adamantyl)glycine (>99% ee).41-43
The transmetalation reactions were typically performed at
-78 °C;44,46-48 however, we found that this step could be
performed at 0 °C, as outlined below. To perform the asym-
metric addition reaction, we chose Nugent’s isoborneol-based
amino alcohol ligand, MIB.49-51 Both enantiomers of MIB can
be easily synthesized from commercially available (R)- and (S)-
camphor in only three steps and one purification.49,52-54 Addition
of Nugent’s (-)-MIB ligand (2 mol %) to the vinylzinc reagent,
followed by benzaldehyde, leads to asymmetric C-C bond
formation to afford the E-allylic alcohols with excellent ee’s
and in good yields (Table 1). The reactions were carried out on
a 1.0-20.0 mmol scale, and the operational simplicity of the
methodology makes it amenable to larger scale synthesis. It is
noteworthy that highly enantioselective catalytic vinylations of
aldehydes are rare, and only a few ligands have been shown to
successfully promote this addition.46-48,55-59 Furthermore, the
existing ligands require greater synthetic effort than MIB.
One of the strengths of this asymmetric vinylation reaction
is its compatibility with a wide range of terminal alkynes. We
found that the substituents on the propargylic position had very
little effect on the enantioselectivity of the reaction. For example,
1-hexyne gave the corresponding allylic alcohol 1 (Table 1) in
95% ee, and the bulky 1-adamantyl acetylene gave allylic
alcohol 5 in 97% ee. In fact, all substrates tested gave ee’s in
the mid-90’s, except for the commercially available diyne, which
gave the diol 7 in 88% ee. In this case, the allylic alkoxide
generated upon reaction of the first equivalent of aldehyde may
Results and Discussion
Synthesis of Allylic Alcohols. The synthesis begins with an
enantioselective one-pot preparation of an allylic alcohol using
a modified Oppolzer protocol (Scheme 1).44 Hydroboration of
a terminal alkyne with dicyclohexylborane proceeds regiose-
lectively to afford the vinylborane.45 Transmetalation of this
vinylborane with Me2Zn or Et2Zn generates the reactive
vinylzinc reagent in situ (Scheme 1).
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Hydroboration and Synthetic Utility of Organoboranes Thus Obtained;
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Synthesis of R-Amino Acids and Allylic Amines
A R T I C L E S
Figure 1. Possible transition state for the vinylation of benzaldehyde.
influence the vinylation of the second equivalent and lower the
ee. To our knowledge, catalytic asymmetric vinylation of
aldehydes to provide such C2-symmetric bis(allylic) alcohols
was previously unknown. Our initial attempts at generating the
bis(allylic) alcohol from 1,6-heptadiyne gave unsatisfying
results, largely due to the insolubility of the bis(vinylzinc)
species at low temperature. To solve this problem, we used an
inverse-addition procedure to keep the concentration of the bis-
(vinylzinc) intermediate low and to take advantage of the greater
reactivity of the vinylzinc group over Me2Zn. The bis(vinylbor-
ane) was added slowly to a solution of Me2Zn, MIB, and
benzaldehyde at 0 °C. At that temperature, the reaction of Me2-
Zn with benzaldehyde in the presence MIB is negligible, while
the vinylzinc species generated in situ reacts rapidly. By this
method, we were able to obtain the desired bis(allylic) alcohol
7 in 65% yield (Table 1, entry 7).
Figure 2. Nonlinear effects in the addition of vinyl ethyl zinc and
diethylzinc to benzaldehyde with (-)-MIB.
Scheme 2. Synthesis of Allylic Amine Derivatives
Table 2. Yields and ee’s of Allylic Amines (Scheme 2)
A transition state for the asymmetric vinylation of aldehydes
is illustrated in Figure 1 using the Noyori model.11 Other
transition states have also been proposed for this reaction.60
Nonlinear Effects in Vinyl Addition Reactions. Positive
nonlinear effects in asymmetric catalysis, or “asymmetric
amplification”, can provide important information about reaction
mechanisms.61-64 They can also be useful in synthesis because
ligands that are far from enantiopure can be employed to
generate product of high ee.65 We have previously demonstrated
the substrate dependence of nonlinear effects in the asymmetric
addition of alkyl groups to aldehydes.51 Examination of
nonlinear effects in the vinyl addition to benzaldehyde was
performed by variation of the ee of (-)-MIB and determination
of the ee of the allylic alcohol product (Scheme 1). As can be
seen in Figure 2, the vinylation reaction does exhibit a strong
positive nonlinear effect. Thus, use of MIB of 50% ee gives
product of 91% ee, whereas use of enantiopure (-)-MIB
generates product of 96% ee. A comparison with the diethylzinc
addition to benzaldehyde using MIB is also shown in Figure 2.
These results indicate that the vinylation of benzaldehyde does
not exhibit as strong a nonlinear effect as the addition of ethyl
groups to this substrate.59
a NHTAc ) NHCOCCl3. b %ee after one recrystallization listed in bold;
determined by HPLC Chiralcel OD-H. c The Boc derivative can be
recrystallized to 99% ee. d Combined yield; see Scheme 3.
Synthesis of Allylic Amines. By making use of the high ee’s
achieved in the vinylation step, we transformed the allylic
alcohols 1-7 into valuable allylic amines40 via Overman’s [3,3]-
sigmatropic rearrangement of trichloroacetimidates (Scheme
2).38,39 Chirality is conserved in the rearrangement, and, as a
result, the stereochemistry set in the initial vinylation is
transferred to the allylic amine. Following Overman’s proce-
dure,38,39 the allylic alcohols were treated with catalytic potas-
sium hydride and trichloroacetonitrile to afford the correspond-
ing allylic trichloroacetimidates (Scheme 2). In general, thermal
rearrangement of these imidates to the trichloroacetamides took
place smoothly in 1-2 h in refluxing toluene (Table 2, TAc )
COCCl3).
The ee’s were maintained in all cases except for that of the
cyclopropyl derivative 9, where a small decrease in ee (95% to
89%) was observed. The cyclopropyl substituent significantly
lowers the barrier for the [3,3]-sigmatropic rearrangement, and,
as a result, the [3,3]-sigmatropic shift occurs readily at ambient
temperature. The reactions to generate the allylic imidate from
2 with catalytic KH did not go to completion. We found,
(60) Norrby, P.-O.; Linde, C.; Åkermark, B. J. Am. Chem. Soc. 1995, 117,
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111, 4028-4036.
9
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A R T I C L E S
Chen et al.
Scheme 3. Conversion of 7 to 14
Scheme 5. Pd-Catalyzed Route to Allylic Amine Derivatives (Nu
Is Nitrogen-Based)
Scheme 6. Oxidative Cleavage of Protected Allylic Amines
Scheme 4. Synthesis of Boc and Cbz Derivatives of 9, 11, and 12
similar in size or electronic properties, most catalysts give
mixtures of regioisomers70 or low enantioselectivities71 due to
the formation of diastereomeric metal-allyl intermediates.40,67,68
Other catalytic routes to allylic amines, such as the asym-
metric hydroamination of dienes72,73 and the asymmetric addition
of alkyl groups to R,â-unsaturated imines,74 are in the early
stages of development.
however, that by switching to DBU (15 mol %),66 we could
successfully convert the allylic alcohol directly to the trichlo-
roacetamide 9 in one pot, at ambient temperature and in 93%
yield.
Oxidative Cleavage of Protected Allylic Amines. All of
the N-protected allylic amines prepared here were successfully
cleaved with catalytic RuCl3‚3H2O, using NaIO4 as the sto-
ichiometric oxidant,75 to afford the corresponding N-protected
amino acids in good yields (Table 3). This procedure worked
well with the trichloroacetamide, Boc, and Cbz protected amines.
In addition, the N-protected allylic amines were ozonized in
2.5 M methanolic NaOH, according to Marshall’s procedure,76
to give the orthogonally protected methyl esters 27-30 (Table
4). HPLC analysis of the Cbz-protected amino ester 30 indicated
that no racemization occurred under the ozonolysis conditions
(>99% ee).
We have also applied our methodology to the synthesis of
R,R′-diamino diacids. Certain R,R′-diamino diacids such as
(S,S)-diaminopimelic acid (DAP) play a crucial role in bacterial
biosynthesis of R-amino acids.77-79 (S,S)-DAP, epimerized by
L,L-DAP epimerase, forms meso-DAP, which confers structural
rigidity to Gram positive and many Gram negative bacteria by
cross-linking the polysaccharides of the peptidoglycan in their
cell walls.80 meso-DAP is also converted to L-lysine by meso-
DAP decarboxylase.77 There is a significant interest in the use
of R,R′-diamino diacids as potential antibiotics because pepti-
doglycans and lysine biosynthesis are foreign to mammalian
biochemistry.78 Additionally, several naturally occurring and
synthetic derivatives of DAP peptides such as RP 5612481 have
Under normal rearrangement conditions, the bis(allylic)
alcohol gave a mixture of two products. The major product
(40%) was the desired bis(allylic) trichloroacetamide protected
amine 14, and the minor product 15 (27%) was a result of the
rearrangement of only one allylic imidate and hydrolysis of the
other (Scheme 3).
Products 14 and 15 were easily separated by column
chromatography. The minor product 15 was subsequently
recycled to give the desired product 14 in 90% yield (Table 2)
by treatment under the same reaction conditions (Scheme 3).
It is noteworthy that, in most cases, the resultant trichloro-
acetamides are highly crystalline, and, upon a single recrystal-
lization, they are enriched to greater than 99% ee (Table 2).
Recrystallization of the cyclopropyl derivative 9 proved difficult.
Therefore, hydrolysis of the trichloroacetamide moiety was
performed in the presence of excess 2 M NaOH in ethanol. In
the same reaction flask, the free amine was converted directly
to the Boc derivative 16 in 82% yield and 99% ee after
recrystallization. Additionally, the tert-butyl and adamantyl
trichloroacetamides 11 and 12 were converted to the Cbz
protected 17a and 17b in 84% and 78% yield, respectively
(Scheme 4).
The two-step method for the asymmetric synthesis of allylic
amines outlined here features excellent control over regio- and
enantioselectivity. This is an advantage over the well-established
method of transition metal catalyzed allylic substitution reactions
with amine-based nucleophiles (Scheme 5).40,67,68 Substrates for
these reactions are typically allylic acetates, carbonates, and
phosphates, the most studied of which is the allylic alcohol
derivative where R ) R′ ) Ph (Scheme 5).69 Several catalysts
will promote the efficient and highly enantioselective amination
of this substrate; however, when R * R′, or when R and R′ are
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Synthesis of R-Amino Acids and Allylic Amines
A R T I C L E S
of the (S,S), (R,R), and meso forms.42,107-109 Others employ
diastereoselective syntheses based on chiral auxiliaries such as
Scho¨llkopf’s auxiliary.95,96,102,103,110,111 Application of Scho¨llko-
pf’s auxiliary, however, results in low diastereoselectivity (60%
de).
Table 3. Oxidative Cleavage Products from Scheme 6
Employing the methodology outlined above, we have syn-
thesized the N,N-protected DAP 26 (Table 3) in just three steps.
More importantly, this sequence of reactions can be applied to
structural variants of DAP, and we are currently pursuing this
objective.
Conclusions
We have successfully synthesized highly substituted nonpro-
teinogenic R-amino acids such as tert-leucine, (cyclopropyl)-
glycine, (cyclohexyl)glycine, and (1-adamantyl)glycine that are
important in peptidomimetics and are components in pharma-
ceutical agents. In the past, these amino acids have been
synthesized in enantiopure form by classical resolving agents,
use of chiral auxiliaries, and enzymatic kinetic resolutions;
however, there are few catalytic asymmetric methods for
generating this class of amino acids.36 Access into the unnatural
D-configured R-substituted amino acids using conventional
methods is even more challenging. Our approach constitutes
an efficient and general method toward both the L and the D
configuration of this class of R-substituted glycines, as dem-
onstrated by our synthesis of N-protected L and D (1-adamantyl)-
glycines.
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9
J. AM. CHEM. SOC. VOL. 124, NO. 41, 2002 12229

A R T I C L E S
Chen et al.
added 1.14 mL (5.0 mmol) of 1,7-heptadiyne dropwise at ambient
temperature. In a separate flask (B) charged with 48 mg (2.0 mol %,
0.2 mmol) of (-)-MIB was added Me2Zn (7 mL, 14.0 mmol, 2.0 M in
toluene), and it was all diluted with 20 mL of toluene. The reaction
was cooled to 0 °C, and 1.01 mL (10 mmol) of benzaldehyde was
added. The contents of the flask (A) were taken up in a syringe and
added to the flask (B), with the aid of a syringe pump, over 1 h. The
reaction was stirred at 0 °C for 2 h and quenched with 2.0 mL of H2O.
After the reaction was stirred for 1 h, MgSO4 was added, and the content
of the flask was filtered and thoroughly rinsed with ether. The filtrate
was concentrated in vacuo, and the residue was chromatographed on
silica (10-20% ethyl acetate in hexanes) to afford 7 as a viscous oil
We are currently applying the methodology outlined here to
the synthesis of other amino acids and their derivatives.
Experimental Section
General Methods. All reactions, except oxidative cleavage, were
carried out under a nitrogen atmosphere with oven-dried glassware.
The progress of all reactions was monitored by thin-layer chromatog-
raphy to ensure the reactions had reached completion. All manipulations
involving dicyclohexylborane and dimethylzinc were carried out using
an inert atmosphere in a Vacuum Atmosphere drybox with an attached
MO-40 Dritrain or by using standard Schlenk or vacuum line
techniques. Dichloromethane, diethyl ether, toluene, THF, and hexanes
were dried through alumina columns. Benzaldehyde and trichloroac-
etonitrile were distilled prior to use and stored under N2 in glass vessels
sealed with Teflon stoppers. Unless otherwise specified, all chemicals
were obtained from Acros, Aldrich, or GFS Chemicals, and all solvents
were purchased from Fischer Scientific. All terminal alkynes are
commercially available, except for (1-adamantyl)acetylene112 and (1-
cyclohexyl)acetylene,113 which were prepared by literature methods.
in 65% yield (1.02 g, 3.25 mmol). [R]25 ) -90 (c ) 0.48, CHCl3,
D
1
88% ee). H NMR (CDCl3, 500 MHz): δ 1.53-1.56 (m, 2H), 2.0 (s,
2H), 2.10 (m, 4H), 5.19 (d, 2H, J ) 6.6 Hz), 5.66-5.78 (m, 4H,
overlapping vinyl H’s), 7.29-7.39 (m, 10H) ppm. 13C{1H} NMR
(CDCl3, 125 MHz): δ 28.72, 32.08, 75.55, 126.57, 127.95, 128.91,
132.53, 133.11, 143.75 ppm. IR (neat): 3392, 1704, 1666, 1614, 1492,
1450 cm-1. HRMS-ESI m/z 331.1665 [(M + Na)+; calcd for C21H24O2-
Na: 331.1675].
1
The H NMR and 13C{1H} NMR spectra were obtained on a Bru¨ker
(S)-N-(1-Cyclopropyl-3-phenyl-allyl)-2,2,2-trichloro-acetamide (9).
A 25 mL round-bottom flask under N2 atmosphere was charged with
(S)-3-cyclopropyl-1-phenyl-2-en-1-ol, 2 (174 mg, 1.0 mmol), and Cl3-
CCN (120 µL, 1.2 mmol) followed by 10 mL of dry CH2Cl2. The
reaction mixture was cooled to 0 °C with an ice bath. DBU (22.4 µL,
0.15 mmol) was added dropwise to the reaction mixture via a
microsyringe. The reaction was allowed to stir at this temperature for
30 min, then warmed to room temperature and stirred for an additional
3.5 h. The solvent was removed in vacuo, and the residue was
chromatographed on silica (5% ethyl acetate in hexanes) to afford 296
mg (93% yield) of 9 as a viscous oil that solidified on standing over
AM-500 Fourier transform NMR spectrometer at 500 and 125 MHz,
respectively. Chemical shifts are reported in units of parts per million
downfield from tetramethylsilane, and all coupling constants are
reported in Hertz. The infrared spectra were obtained using a Perkin-
Elmer 1600 series spectrometer. Thin-layer chromatography was
performed on Whatman precoated silica gel 60 F-254 plates and
visualized by ultra-violet light or by staining with cerric ammonium
molybdate stain. Silica gel (230-400 mesh, Silicycle) was used for
air-flashed chromatography. Analysis of enantiomeric excess was
performed using a Hewlett-Packard 1050 Series HPLC and a Chiralcel
OD-H column. Absolute configuration was determined by comparison
of optical rotation to literature data for known compounds. All new
compounds were assigned correspondingly.
several days. mp 66-68 °C. [R]25 ) -32.2 (c ) 0.64, CHCl3, 89%
D
1
ee). H NMR (CDCl3, 500 MHz): δ 0.46-0.47 (m, 1H), 0.53-0.57
(m, 1H), 0.65-0.72 (m, 2H), 1.4-1.6 (m, 1H), 4.08 (m, 1H), 6.22
(dd, 1H, J ) 14.7, 5.76 Hz), 6.68 (d, 1H, J ) 15.8 Hz), 6.83 (d, 1H,
J ) 6.7 Hz), 7.29-7.42 (m, 5H) ppm. 13C{1H} NMR (CDCl3, 125
MHz): δ 3.56, 3.71, 15.77, 57.80, 81.5, 126.99, 127.18, 128.4, 129.03,
132.17, 136.68, 161.6 ppm. IR (film): 3333, 1709, 1691.6, 1512, 1492,
1485 cm-1. HRMS-CI m/z 317.0125 [M+; calcd for C14H14Cl3NO:
317.0140].
General procedures are presented below. Synthesis and full char-
acterization of all compounds are provided in the Supporting Informa-
tion.
(S)-3-Cyclopropyl-1-phenyl-prop-2-en-1-ol (2). General Proce-
dure A. To a stirred solution of Cy2BH (22.0 mmol) in hexanes (40
mL) prepared according to Oppolzer’s procedure was added cyclopro-
pylacetylene (1.87 mL, 22.0 mmol) dropwise (Caution: exothermic!).44
The homogeneous reaction mixture was stirred for 15 min at room
temperature, then cooled to -78 °C. Et2Zn (3.08 g, 25.0 mmol) in
hexanes (10 mL) or Me2Zn in toluene (12.5 mL, 2.0 M) was added
followed by (-)-MIB (96 mg, 2.0 mol %, 0.4 mmol). The reaction
was transferred into a 0 °C bath, and benzaldehyde (2.03 mL, 20 mmol)
was added over 30 min. The reaction was stirred at 0 °C for 2 h and
quenched with 5 mL of H2O. After stirring for 1 h, MgSO4 was added,
and the content of the flask was filtered and thoroughly rinsed with
diethyl ether. The filtrate was concentrated in vacuo, and the residue
was chromatographed on silica (5% ethyl acetate in hexanes) to afford
2 in 94% yield (3.27 g, 18.8 mmol) as a colorless oil. [R]25D ) +58.8
(S)-N-(1-Adamantyl-3-phenyl-allyl)-2,2,2-trichloro-acetamide (12).
General Procedure B. To a stirred solution of (S)-3-adamantyl-1-
phenyl-prop-2-en-1-ol, 5 (1.5 g, 5.3 mmol), in 150 mL of dry ether
was added KH (60 mg, 1.5 mmol) in one portion under a stream of
N2. The reaction was stirred for 15 min until H2 gas evolution ceased
and a yellow to orange appearance was observed. The mixture was
transferred via cannula to a flask containing Cl3CCN (795 µL, 7.95
mmol) in 100 mL of dry ether at 0 °C over 10 min. After being stirred
for 1 h at ambient temperature, the reaction was quenched with 61 µL
of MeOH, filtered, and thoroughly rinsed with ether. The filtrate was
concentrated in vacuo, and 50 mL of dry toluene was added. The
reaction was refluxed for 1-2 h under N2 atmosphere. The toluene
was removed in vacuo to afford 1.81 g of 12 (4.4 mmol, 83% yield)
1
(c ) 0.98, CHCl3, 94.5% ee). H NMR (CDCl3, 500 MHz): δ 0.38-
0.41 (m, 2H), 0.70-0.74 (m, 2H), 1.39-1.42 (m, 1H), 1.83 (s, 1H),
5.15 (d, 1H, J ) 6.8 Hz), 5.29 (dd, 1H, J ) 15.3, 8.8 Hz), 5.74 (dd,
1H, J ) 15.3, 7.0 Hz), 7.25-7.38 (m, 5H) ppm. 13C{1H} NMR (CDCl3,
125 MHz): δ 7.29 (-(CH2)2- are overlapped), 13.90, 75.53, 126.57,
127.91, 128.89, 130.28, 136.98, 143.90 ppm. IR (neat): 3450, 1605,
1550, 1495, 1450. HRMS-CI m/z 174.1052 [M+; calcd for C12H14O:
174.1044].
(S,S)-1,9-Diphenyl-nona-2,7-diene-1,9-diol (7). Inverse-Addition
Procedure. To a stirred solution of Cy2BH (10.0 mmol) in toluene
(10 mL), prepared according to Oppolzer’s procedure (flask A),44 was
after a single recrystallization from hexanes-ethyl acetate. mp 164-
1
165 °C. [R]25 ) -38.6 (c ) 0.50, CHCl3, 99% ee). H NMR (500
D
MHz, CDCl3): δ 1.6-1.79 (m, 12H), 2.07 (s, 3H), 4.27 (t, 1H), 6.21
(dd, 1H, J ) 15.8, 7.7 Hz), 6.6 (d, 1H, J ) 15.8 Hz), 6.79 (d, 1H, J )
9.2 Hz), 7.25-7.42 (m, 5H) ppm. 13C{1H} NMR (125 MHz, CDCl3):
δ 28.6, 37.24, 37.53, 39.19, 62.69, 81.6, 124.50, 126.94, 128.32, 129.02,
133.94, 136.85, 161.6 ppm. IR (KBr): 3423, 1706, 1509, 1449 cm-1
HRMS-CI m/z 411.1010 [M+; calcd for C21H24Cl3NO: 411.0922].
.
(S)-(1-Cyclopropyl-3-phenyl-allyl)-carbamic Acid tert-Butyl Ester
(16). To a 100 mL round-bottom flask charged with (S)-N-(1-
cyclopropyl-3-phenyl-allyl)-2,2,2-trichloro-acetamide, 9 (318 mg, 1.0
mmol), were added absolute ethanol (20 mL) and 2 N NaOH (10 mL).
The reaction was stirred for 14 h at ambient temperature. Excess
(112) Archibald, T. G.; Malik, A. A.; Baum, K.; Unroe, M. R. Macromolecules
1991, 24, 5261-5265.
(113) Harrity, J. P. A.; Kerr, W. J.; Middlemiss, D.; Scott, J. S. J. Organomet.
Chem. 1997, 532, 219-227.
9
12230 J. AM. CHEM. SOC. VOL. 124, NO. 41, 2002

Synthesis of R-Amino Acids and Allylic Amines
A R T I C L E S
(Boc)2O (436.5 mg, 2.0 mmol) was added directly into the reaction
mixture. Disappearance of baseline material deemed the reaction
complete. The reaction mixture was concentrated in vacuo, and the
residue was taken up in CH2Cl2 (30 mL) and washed with H2O (30
mL). The aqueous layer was back extracted twice with CH2Cl2 (10
mL × 2). The combined organic layer was dried with MgSO4 and
concentrated in vacuo. The crude product was recrystallized with
hexanes with a minimum amount of ethyl acetate to afford 223 mg
(0.816 mmol, 81.6% yield) of 16 as white needles. [R]25D ) -3.38 (c
column chromatography (0.25% acetic acid and 20-50% ethyl acetate
in hexanes) to give 18 as a white solid in 75% yield (62 mg, 0.22
1
mmol). mp 60-63 °C. [R]29 ) +35.2 (c ) 0.27, CHCl3). H NMR
D
(CDCl3, 500 MHz): δ 0.93 (t, J ) 7.0 Hz, 3H), 1.34-1.43 (m, 4H),
1.81-1.89 (m, 1H), 2.01-2.08 (m, 1H), 4.63 (dt, J ) 7.3, 5.4 Hz,
1H), 7.15 (d, J ) 7.3 Hz, 1H) ppm. 13C{1H} NMR (CDCl3, 125
MHz): δ 13.5, 21.9, 26.8, 31.2, 53.5, 91.8, 161.4, 176.1 ppm. IR
(KBr): 3420, 2930, 2371, 1707, 1519, 1384, 1246, 828 cm-1. HRMS-
ESI m/z 297.9819 [(M + Na)+; calcd for C8H12Cl3NO3Na: 297.9780].
(S)-6-Chloro-2-(2,2,2-trichloro-acetylamino)-hexanoic Acid (25).
The product was prepared according to procedure C using (S)-N-(5-
chloro-1-styryl-pentyl)-2,2,2-trichloro-acetamide, 13 (369 mg, 1.0
mmol), NaIO4 (941 mg, 4.4 mmol), and RuCl3‚3H2O (4.1 mg, 0.02
mmol). After column chromatography on silica (15-50% ethyl acetate
in hexanes and 0.25% glacial acetic acid), the reaction afforded 252
1
) 0.33, CHCl3, 99% ee). H NMR (C6D6, 500 MHz, at 343 K): δ
0.09-0.18 (m, 1H), 0.27-0.34 (m, 3H), 0.63-0.72 (m, 1H), 1.47 (s,
9H), 3.87 (br, 1H), 4.37 (br, 1H), 6.01 (dd, 1H, J ) 15.9, 5.8 Hz),
6.49 (d, 1H, J ) 16.0 Hz), 7.02-7.21 (m, 5H) ppm. 13C{1H} NMR
(C6D6, 500 MHz, at 343 K to detect missing carbons because of
restricted bond rotation): δ 2.99, 3.01, 16.36, 28.58, 56.48, 78.85,
126.85, 127.56, 128.70, 130.30, 130.51, 137.73, 155.32 ppm. IR
(KBr): 3367, 1679, 1525, 1444 cm-1. HRMS-ESI m/z 273.1724 [M+;
calcd for C17H23NO2: 273.1729].
mg (0.81 mmol, 81% yield) of 25 as a viscous oil. [R]25 ) +36.8 (c
D
1
) 0.50, CHCl3, 93.3% ee). H NMR (CDCl3, 500 MHz): δ 1.58-
1.62 (m, 2H), 1.84-1.91 (m, 3H), 2.0-2.10 (m, 1H), 3.55-3.58 (t, J
) 6.3 Hz, 2H), 4.63-4.67 (dt, 1H, J ) 7.2 Hz), 6.8-7.3 (br, 1H,
-CO2H), 7.25 (d, 1H, J ) 7.3 Hz) ppm. 13C{1H} NMR (CDCl3, 125
MHz): δ 22.67, 31.38, 32.09, 44.70, 53.97, 92.42, 162.19, 175.96 ppm.
IR (KBr): 3330, 1702, 1515, 1420 cm-1. HRMS-CI m/z 309.9556
[MH+; calcd for C8H12Cl4NO3: 309.9569].
(S)-(1-Adamantyl-3-phenyl-allyl)-carbamic Acid Benzyl Ester
(17b). To a 50 mL round-bottom flask charged with (S)-N-(1-adamantyl-
3-phenyl-allyl)-2,2,2-trichloro-acetamide, 12 (210 mg, 0.5 mmol), were
added absolute ethanol (30 mL) and 2 N NaOH (10 mL). The reaction
was refluxed for 4 h and monitored by TLC for the disappearance of
starting material. The reaction mixture was concentrated in vacuo, and
the residue was taken up in CH2Cl2 (10 mL) and saturated NaHCO3
(10 mL). The biphasic mixture was cooled to 0 °C, and 107 µL of
Cbz-Cl (0.75 mmol) was added dropwise. After 14 h of stirring at room
temperature, the organic layers were separated, and the aqueous layer
was extracted twice with CH2Cl2 (10 mL × 2). The combined organic
layer was dried with MgSO4 and concentrated in vacuo. The residue
was chromatographed (5% ethyl acetate in hexanes) on silica to afford
157 mg (0.39 mmol, 78% yield) of 17b as white foam. [R]25D ) -5.15
(S)-2-(2,2,2-Trichloro-acetylamino)-hexanoic Acid Methyl Ester
(27). General Procedure D. Ozone was passed through a stirred
solution of 100 mg (0.3 mmol) of (S)-N-(1-butyl-3-phenyl-allyl)-2,2,2-
trichloro-acetamide, 8, in 10 mL of dichloromethane and 1.0 mL of
2.5 M methanolic sodium hydroxide at -78 °C. After 1 h, the
characteristic blue color of ozone persisted in the reaction mixture. At
this point, oxygen was bubbled through the reaction mixture for 15
min. It was then diluted with dichloromethane and water, allowed to
warm slowly to room temperature, and extracted with dichloromethane.
The organic layer was dried over MgSO4 and concentrated under
reduced pressure. The crude product was then purified by column
chromatography (20% ethyl acetate in hexanes) to give 27 as a colorless
1
(c ) 0.86, CHCl3, 99% ee). H NMR (500 MHz, CDCl3): δ 1.57-
1.75 (m, 12H), 2.03 (s, 3H), 4.02 (br, 1H), 4.91 (br, 1H), 5.15 (s, 2H),
6.18 (dd, 1H, J ) 15.8, 7.5 Hz), 6.53 (d, 1H, J ) 15.7 Hz), 7.26-7.40
(m, 10H) ppm. 13C{1H} NMR (CDCl3, 125 MHz): δ 28.75, 37.02,
37.37, 39.21, 62.77, 67.27, 126.53, 127.91, 128.55, 128.84, 132.45,
137.01, 137.33, 156.3 ppm (two 4° carbons were not detected). IR
(KBr): 3330, 1697, 1530, 1448 cm-1. HRMS-ESI m/z 424.2244 [(M
+ Na)+; calcd for C27H31NaNO2: 424.2255].
(S)-2-(2,2,2-Trichloro-acetylamino)-hexanoic Acid (18). General
Procedure C. To a stirred solution of 100 mg (0.3 mmol) of (S)-N-
(1-butyl-3-phenyl-allyl)-2,2,2-trichloro-acetamide, 8, in 1.0 mL of
carbon tetrachloride, 1.0 mL of acetonitrile, and 1.5 mL of water was
added 260 mg (1.2 mmol) of sodium periodate. Once all of the sodium
periodate had dissolved, 1.7 mg (0.008 mmol) of ruthenium trichloride
hydrate was added, and the reaction mixture was stirred vigorously
overnight at room temperature. It was then extracted with dichlo-
romethane; the combined organic extracts were dried over MgSO4 and
concentrated under reduced pressure to give a deep purple oil. The
crude product was then redissolved in dichloromethane and stirred for
30 min with 28 µL (50 equiv with respect to the ruthenium catalyst)
of dimethyl sulfoxide and 2 g of silica gel. The solvent was removed
in vacuo, and the product, now preadsorbed to silica, was purified by
oil in 84% yield (73 mg, 0.25 mmol). [R]23 ) -35.7 (c ) 1.63,
D
1
CHCl3). H NMR (CDCl3, 500 MHz): δ 0.84 (t, J ) 7.0 Hz, 3H),
1.19-1.31 (m, 4H), 1.69-1.74 (m, 1H), 1.88-1.93 (m, 1H), 3.74 (s,
3H), 4.51 (dt, J ) 7.2, 5.4 Hz, 1H), 7.16 (d, J ) 5.7 Hz, 1H) ppm.
13C{1H} NMR (CDCl3, 125 MHz): δ 13.8, 22.2, 27.0, 31.7, 52.8, 53.9,
92.0, 161.4, 171.8 ppm. IR (neat): 3345, 2958, 1711, 1519, 1218, 827
cm-1. HRMS-ESI m/z 311.9930 [(M + Na)+; calcd for C9H14Cl3NO3-
Na: 311.9937].
Acknowledgment. This research is dedicated to our col-
league, Professor Ralph Hirschmann, on the occasion of his 80th
birthday for his seminal work in bioorganic chemistry. This work
was supported by the National Institutes of Health. P.J.W. is a
Camille Dreyfus Teacher Scholar.
Supporting Information Available: Conditions for the reso-
lution of racemates (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
JA027271P
9
J. AM. CHEM. SOC. VOL. 124, NO. 41, 2002 12231