A catalytic asymmetric method for the synthesis of γ-unsaturated, β-amino acid derivatives

Article abstract of DOI:10.1021/ja035213d

Catalytic enantioselective synthesis of β-amino acid derivatives is an area of intense interest, due to the importance of these compounds as components in pharmaceutical agents and peptidomimetics. In this report, we present the first catalytic enantiosel

Full text of DOI:10.1021/ja035213d

Published on Web 08/06/2003
A Catalytic Asymmetric Method for the Synthesis of
γ-Unsaturated â-Amino Acid Derivatives
Alice E. Lurain and Patrick J. Walsh*
Contribution from the P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry,
UniVersity of PennsylVania, 231 South 34th Street, Philadelphia, PennsylVania 19104-6323
Received March 18, 2003; E-mail: pwalsh@sas.upenn.edu
Abstract: Catalytic enantioselective synthesis of â-amino acid derivatives is an area of intense interest,
due to the importance of these compounds as components in pharmaceutical agents and peptidomimetics.
In this report, we present the first catalytic enantioselective method for the synthesis of γ-unsaturated â-amino
acids and their corresponding 1,3-amino alcohol derivatives. This methodology takes advantage of a highly
enantioselective vinylzinc addition to an aldehyde to set chirality. The resulting allylic alcohols are then
transformed into the corresponding allylic amines via Overman’s [3,3]-sigmatropic imidate rearrangement,
and subsequent one-pot deprotection-oxidation of a pendant oxygen leads to the γ-unsaturated â-amino
acid derivatives of high enantiopurity.
Introduction
The development of synthetically useful methodology for the
preparation of enantioenriched â-amino acids and their deriva-
tives has gained increasing attention due to the importance of
these compounds as building blocks in a variety of biologically
active natural products and peptidomimetics.1-5 In addition to
serving as synthetic precursors to â-lactams, a class of com-
pounds well-known for its antibiotic properties,6-8 â-amino acids
are the monomers that make up â-peptides. Such â-peptides
have emerged as promising tools for probing the structure-
activity relationships of biologically active molecules. They
exhibit increased resistance to peptidases and proteases, an
important property in the development of pharmaceuticals, and
have been shown to fold into helices, sheets, and turns, the same
kind of structural motifs found in peptides derived from R-amino
acids.9-11 γ-Unsaturated â-amino acids represent an interesting
subclass of compounds, the enantioselective synthesis of which
has been largely unaddressed. One naturally occurring unsatur-
ated â-amino acid that has generated significant synthetic interest
is (2S,3S,8S,9S)-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyl-
4,6-decadienoic acid (Adda, Figure 1).12-15 This amino acid
Figure 1. The Adda residue.
residue appears in the hepatotoxins cyanovirifin RR, nodularin,
motuporin, and the microcystins.15-21
While various diastereoselective methods for the synthesis
of â-amino acids, based on chiral substrates or chiral auxiliaries,
have been developed, there exist relatively few catalytic enantio-
selective methods.1-5 The most common of these employ conju-
gate addition of aminonucleophiles to acrylate derivatives,22-29
hydrogenation of aminoacrylates,30-39 aminohydroxylation of
(14) Kim, H. Y.; Toogood, P. L. Tetrahedron Lett. 1996, 37, 2349-2352.
(15) Davies, S. G.; Fenwick, D. R.; Ichihara, O. Tetrahedron: Asymmetry 1997,
8, 3387-3391.
(16) Maude, A. B.; Mehrotra, A. P.; Gani, D. J. Chem. Soc., Perkin Trans. 1
1997, 2513-2526.
(17) O’Donnell, M. E.; Sanvoisin, J.; Gani, D. J. Chem. Soc., Perkin Trans. 1
2001, 1696-1708.
(18) Webster, K. L.; Maude, A. B.; O’Donnell, M. E.; Mehrotra, A. P.; Gani,
D. J. Chem. Soc., Perkin Trans. 1 2001, 1673-1695.
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9070.
(20) Humphrey, J. M.; Aggen, J. B.; Chamberlin, A. R. J. Am. Chem. Soc. 1996,
118, 11759-11770.
(1) Juaristi, E. EnantioselectiVe Synthesis of â-Amino Acids, 1st ed.; Wiley-
VCH: New York, 1997.
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W. W. Tetrahedron Lett. 1989, 30, 4349-4352.
(2) Cardillo, G.; Tomasini, C. Chem. Soc. ReV. 1996, 117-128.
(3) Cole, D. C. Tetrahedron 1994, 50, 9517-9582.
(4) Juaristi, E.; Quintana, D.; Escalante, J. Aldrichim. Acta 1994, 27, 3-11.
(5) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991-8035.
(6) Hart, D. J.; Ha, D. C. Chem. ReV. 1989, 89, 1447-1465.
(7) Magriotis, P. A. Angew. Chem., Int. Ed. 2001, 40, 4377-4379.
(8) Georg, G. The Organic Chemistry of â-Lactams; Blackie: Glasgow, U.K.,
1993.
(22) Horstmann, T. E.; Guerin, D. J.; Miller, S. J. Angew. Chem., Int. Ed. 2000,
39, 3635-3638.
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2826.
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(25) Sibi, M. P.; Liu, M. Org. Lett. 2000, 2, 3393-3396.
(26) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 1998,
120, 6615-6616.
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3232.
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(10) Fletcher, M. D.; Campbell, M. M. Chem. ReV. 1998, 98, 763-795.
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9
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A R T I C L E S
Lurain and Walsh
R,â-unsaturated esters,40-50 and Mannich-type reactions of imine
derivatives with silyl enolates.51-60
Sharpless asymmetric aminohydroxylation42,43,49 of R,â-
unsaturated esters provides entry into syn-R-hydroxy-â-amino
acid derivatives, generally with a high degree of enantioselec-
tivity. The reactions are typically carried out in an alcohol/water
solvent mixture using catalytic K2OsO2(OH)4, an alkaloid-
derived ligand, and the lithium or sodium salt of an N-
halogenated sulfonamide,40,50 alkyl carbamate,47 amide,41 or an
amino-substituted heterocycle.46 Enantioselectivity and regi-
oselectivity, which has a direct impact on reaction yield, can
vary significantly, depending upon the ligand and the nitrogen
source used with a given substrate. One of the earliest and most
outstanding applications of this methodology to the synthesis
of R-hydroxy-â-amino acid derivatives was Sharpless’ large-
scale synthesis of the taxol side chain.44 Starting from isopropyl
cinnamate, the target molecule was obtained in two steps with
68% yield and 99% ee.
Both Sibi25,26,28 and Jørgensen23,27 have utilized bis(oxazo-
line)-derived chiral Lewis acid catalysts in the conjugate addition
of hydroxylamines or aromatic amines as nitrogen nucleophiles
to R,â-unsaturated carboxylic acid derivatives. Jacobsen24 has
demonstrated the conjugate addition of hydrazoic acid to R,â-
unsaturated imides catalyzed by a chiral (salen)Al(III) complex,
and Miller and co-workers22,61 have developed conditions for
the enantioselective conjugate addition of azide ion using a 3.8:1
mixture of TMSN3 and tBuCO2H and a simple peptide catalyst.
In all cases, moderate to good yields and high ee’s are obtained
for substrates with alkyl substitution at the â-position. In the
case of aryl substituents, only Sibi’s system is successful, using
30 mol % of catalyst. In general, the conjugate addition strategy
requires that substrates not commercially available must be
synthesized via Horner-Emmons chemistry.
Another approach that has attracted particular interest lately
is the Mannich-type reaction of aldimines with silyl enolates to
synthesize â-amino esters. Chiral zirconium-based catalysts for
the asymmetric version of this reaction were developed by
Kobayashi53,54,57,58 and Wulff.56 These systems require an N-aryl
substituent with a pendant chelating group for bidentate binding
to the catalyst which must subsequently be removed under
strong oxidizing or reducing conditions. Nonetheless, good
yields and enantioselectivities are obtained with aromatic imines.
More recently, Jacobsen55 has developed a urea-derived catalyst
that allows for the use of Boc-protected aryl imines, and
Kobayashi54,59 has introduced a chiral copper catalyst that shows
good enantioselectivity for the addition of silyl enol ethers
derived from thioesters to N-acylamino esters. A drawback of
the Mannich-type chemistry is the need to preform the silyl
enolate, and Barbas and co-workers51 recently addressed this
issue by developing a system catalyzed by proline in which an
aliphatic aldehyde adds to R-amino ethyl glyoxylate. This
reaction gives very good diastereoselectivity with aldehydes
having a chain length of 5 carbons or more.
A different strategy for the synthesis of â-amino acid
derivatives is the asymmetric hydrogenation of aminoacrylates,
and Zhang and co-workers32-34 have recently made significant
progress in this area. Their Ru-BINAPO catalyst system is the
first to give excellent enantioselectivities for â-aryl-substituted
â-(acylamino)acrylates. Unlike previous systems, which gave
only moderate levels of enantioselectivity, the Ru-BINAPO
system can tolerate an E/Z mixture of substrates.
(32) Tang, W.; Zhang, X. Org. Lett. 2002, 4, 4159-4161.
(33) Zhou, Y.-G.; Tang, W.; Wang, W.-B.; Li, W.; Zhang, X. J. Am. Chem.
Soc. 2002, 124, 4952-4953.
(34) Zhu, G.; Chen, Z.; Zhang, X. J. Org. Chem. 1999, 64, 6907-6910.
(35) Yasutake, M.; Gridnev, I. D.; Higashi, N.; Imamoto, T. Org. Lett. 2001, 3,
1701-1704.
(36) Heller, D.; Holz, J.; Drexler, H.-J.; Lang, J.; Drauz, k.; Krimmer, H.-P.;
Borner, A. J. Org. Chem. 2001, 66, 6816-6817.
(37) Heller, D.; Drexler, H.-J.; You, J.; Baumann, W.; Drauz, K.; Krimmer,
H.-P.; Borner, A. Chem.sEur. J. 2002, 8, 5196-5203.
(38) Ohashi, A.; Kikuchi, S.-i.; Yasutake, M.; Imanoto, T. Eur. J. Org. Chem.
2002, 2535-2546.
(39) Pena, D.; Minnaard, A. J.; de Vries, J. D.; Feringa, B. L. J. Am. Chem.
Soc. 2002, 124, 14552-14553.
(40) Andersson, M. A.; Epple, R.; Fokin, V. V.; Sharpless, K. B. Angew. Chem.,
Int. Ed. 2002, 41, 472-475.
(41) Demko, Z. P.; Bartsch, M.; Sharpless, K. B. Org. Lett. 2000, 2, 2221-
2223.
To our knowledge, only one method has been developed for
the synthesis of enantioenriched γ-unsaturated â-amino acids.
Davies and co-workers15 have applied the diastereoselective
conjugate addition of lithium (S)-(R-methylbenzyl)allylamide
to (E,E)-tert-butyl hex-2,4-dienoate to give the corresponding
γ-unsaturated â-amino acid derivative (Scheme 1). A lengthy
protecting group exchange under somewhat harsh conditions is
required, however, to remove the N-R-methylbenzyl group and
the N-allyl group and to replace them with the more synthetically
useful Boc group. This methodology was utilized by Gani and
co-workers in their synthesis of an abbreviated Adda residue,
which they used to study the effects of structural changes on
the biological activity of nodularin.17
(42) Nilov, D.; Reiser, O. AdV. Synth. Catal. 2002, 344, 1169-1173.
(43) Bodkin, J. A.; McLeod, M. D. J. Chem. Soc., Perkin Trans. 1 2002, 2733-
2746.
(44) Bruncko, M.; Schlingloff, G.; Sharpless, K. B. Angew. Chem., Int. Ed. 1997,
36, 1483-1486.
(45) Rudolph, J.; Sennhenn, P. C.; Vlaar, C. P.; Sharpless, K. B. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2810-2813.
(46) Goosen, L. J.; Liu, H.; Dress, K. R.; Sharpless, K. B. Angew. Chem., Int.
Ed. 1999, 38, 1080-1083.
(47) Reddy, K. L.; Dress, K. R.; Sharpless, K. B. Tetrahedron Lett. 1998, 39,
3667-3670.
(48) Reddy, K. L.; Dress, K. R.; Sharpless, K. B. Tetrahedron Lett. 1998, 39,
3667-3670.
(49) O’Brien, P. Angew. Chem., Int. Ed. 1999, 38, 326-329.
(50) Li, G.; Chang, H.-T.; Sharpless, K. B. Angew. Chem., Int. Ed. 1996, 35,
451-454.
(51) Cordova, A.; Watanabe, S.-i.; Tanaka, F.; Notz, W.; Barbas, C. F., III. J.
Am. Chem. Soc. 2002, 124, 1866-1867.
(52) Knudsen, K. R.; Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.; Jørgensen,
K. A. J. Am. Chem. Soc. 2001, 123, 5843-5844.
(53) Kobayashi, S.; Ishitani, H.; Ueno, M. J. Am. Chem. Soc. 1998, 120, 431-
432.
In this report, we outline the first enantioselective catalytic
method for the synthesis of γ-unsaturated â-amino acids. This
methodology, illustrated in Scheme 2, utilizes the highly enantio-
selective addition of a vinylzinc species to an aldehyde,62-64
which has previously been reported by our group en route to
the synthesis of R-amino acids.65 The allylic alcohol product
(54) Kobayashi, S.; Matsubara, R.; Kitagawa, H. Org. Lett. 2002, 4, 143-145.
(55) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964-
12965.
(56) Xue, S.; Yu, S.; Deng, Y.; Wulff, W. D. Angew. Chem., Int. Ed. 2001, 40,
2271-2274.
(57) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 8180-
8186.
(58) Kobayashi, S.; Kobayashi, J.; Ishiani, H.; Ueno, M. Chem.sEur. J. 2002,
8, 4185-4190.
(62) Oppolzer, W.; Radinov, R. N. HelV. Chim. Acta 1992, 75, 170-173.
(63) Oppolzer, W.; Radinov, R. N. J. Am. Chem. Soc. 1993, 115, 1593-1594.
(64) Oppolzer, W.; Radinov, R. N.; El-Sayed, E. J. J. Org. Chem. 2001, 66,
4766-4770.
(65) Chen, Y. K.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124,
12225-12231.
(59) Kobayashi, S.; Matsubara, R.; Nakamura, Y.; Kitagawa, H.; Sugiura, M.
J. Am. Chem. Soc. 2003, 125, 2507-2515.
(60) Murahashi, S.-I.; Imada, Y.; Kawakami, T.; Harada, K.; Yonemushi, Y.;
Tomita, N. J. Am. Chem. Soc. 2002, 124, 2888-2889.
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9
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γ
-Unsaturated
â
-Amino Acid Derivatives
A R T I C L E S
Scheme 1. Davies’ Synthesis of (3R)-(E)-(N-tert-Butyloxycarbonyl)aminohex-4-enoate
of this addition is then subjected to Overman imidate rearrange-
ment conditions66,67 to install the nitrogen, and the chirality
established in the vinylation step is transferred to the resultant
allylic amine. One-pot deprotection and oxidation of a pendant
oxygen leads to the γ-unsaturated â-amino acid derivatives. It
should be noted that both the D and L configurations of the
amino acids are accessible via this methodology.
addition of the vinylborane over the course of 1 h to a stirred
solution of the aldehyde, Et2Zn, and (-)-MIB (4 mol %) at
-30 °C afforded the product allylic alcohols in high ee and
moderate to good yields for a range of aliphatic and aromatic
aldehydes (Scheme 3, Table 1).
Scheme 3. Asymmetric Vinylzinc Addition to Aldehydes
Scheme 2. Synthesis of γ-Unsaturated â-Amino Acid Derivatives
Table 1. Ee’s and Yields for Allylic Alcohol Products from
Scheme 3
Results and Discussion
Vinylzinc Additions to Aldehydes. We have previously
demonstrated the highly enantioselective addition of a series
of vinylzinc species to benzaldehyde65 catalyzed by Nugent’s
MIB ligand.68-70 The vinylzinc reagents were generated in situ
via hydroboration of a terminal alkyne with dicyclohexyl-
borane and transmetalation of the resulting vinylborane with
Et2Zn.62,71,72 While a range of alkyne starting materials was
found to be compatible with this system, the scope of the
reaction for different aldehydes was not explored initially. In
the present study, the terminal alkyne, 1-butyn-3-ol, was pro-
tected as the trityl ether73 (1, Scheme 3) and underwent hydro-
boration regioselectively to give the corresponding vinylborane.
Initial attempts to perform the addition reaction under conditions
used in our previous study65 by transmetalating at -78 °C,
warming to 0 °C, and adding the aldehyde slowly to the vinyl-
zinc species in the presence of MIB resulted in low yields of
the allylic alcohol products. It was found, however, that slow
(66) Overman, L. E. Acc. Chem. Res. 1980, 13, 218-224.
(67) Overman, L. E. J. Am. Chem. Soc. 1976, 98, 2901-2910.
(68) Chen, Y. K.; Costa, A. M.; Walsh, P. J. J. Am. Chem. Soc. 2001, 123,
5378-5379.
(69) Nugent, W. A. J. Chem. Soc., Chem. Commun. 1999, 1369-1370.
(70) Rosner, T.; Sears, P. J.; Nugent, W. A.; Blackmond, D. G. Org. Lett. 2000,
2, 2511-2513.
a Ee’s determined by HPLC Chiralcel OD-H. b Product from reaction
with (-)-MIB. c Product from reaction with (+)-MIB.
(71) Dahmen, S.; Bra¨se, S. Org. Lett. 2001, 3, 4119-4122.
(72) Ji, J.-X.; Qiu, L.-Q.; Yip, C. W.; Chan, A. S. C. J. Org. Chem. 2003, 68,
1589-1590.
The choice of oxygen protecting groups on the alkyne turned
out to be important. Low yields were obtained with a variety
(73) Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 2, 95-98.
9
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A R T I C L E S
Lurain and Walsh
Table 2. Allylic Amine Products from Scheme 4
of silyl protecting groups, and attempts to use the oxidized
alkyne protected as the TIPS ester resulted in none of the desired
vinyl addition product. Fortuitously, not only did the trityl group
(Tr ) CPh3) give improved yields in the vinylation reaction, it
also had the advantage of allowing a one-pot deprotection-
oxidation under acidic conditions to unveil the carboxylic acid
functionality and furnish the â-amino acids, as outlined below.74
The vinylation was carried out successfully with both aro-
matic aldehydes bearing ortho and para substitution and aliphatic
aldehydes. In all cases, except with nonyl aldehyde, ee’s in the
90’s were obtained. The best substrate was ortho-bromoben-
zaldehyde, which gave the corresponding allylic alcohol product
in 99% ee and 83% yield (5, Table 1). Such a substrate is par-
ticularly attractive, because the aryl bromide provides a handle
for further elaboration via coupling reactions with the enan-
tioenriched product. Para-substituted benzaldehyde deriva-
tives p-(trifluoromethyl)benzaldehyde and p-chlorobenzaldehyde
also resulted in products of high ee (97% and 94% respectively;
4 and 6, Table 1) as did the aliphatic aldehydes cyclohexan-
ecarboxaldehyde and isovaleraldehyde (93% and 99%; 8 and
9, Table 1), although yields for these substrates were slightly
lower.
It should be noted that both enantiomers of the MIB ligand
can be easily synthesized from commercially available (R)- and
(S)-camphor in only three steps and one purification.68-70 This
allows easy access to both enantiomers of the allylic alcohol
products and, thus, to both the D and L configurations of the
â-amino acid derivatives.
[3,3]-Sigmatropic Rearrangement. Taking advantage of the
high enantioselectivities achieved in the vinyl addition step, we
utilized Overman’s [3,3]-sigmatropic trichloroacetimidate rear-
rangement66,67 (Scheme 4) to convert allylic alcohols 2-10
(Table 1) into allylic amines 11-19 (Table 2).
a NHTAc ) NHCOCCl3. b 20 mol% DBU, refluxed in toluene. c 120
mol% DBU, refluxed in p-xylene and K2CO3.
Scheme 4. [3,3]-Sigmatropic Rearrangement to Allylic Amine
Derivatives
recrystallization from hexanes led to clean allylic amine products
in moderate to good yields (Table 2).
Deprotection and Oxidation to γ-Unsaturated â-Amino
Acid Derivatives. The trityl ether group on the allylic amines
in Table 2 could be deprotected under acidic conditions to give
the corresponding unsaturated N-protected 1,3-amino alcohols.
Initial attempts to remove the trityl group with 88% formic acid
solution gave a 2:1 mixture of the desired deprotected product
and a cyclic carbamate that resulted from attack of the free
hydroxyl group on the trichloroacetamide (Scheme 5).
Chirality is conserved in the rearrangement, and as a result,
the stereochemistry set in the initial vinylation reaction is
transferred to the allylic amine. Overman’s procedure calls for
treating an allylic alcohol with catalytic potassium hydride and
trichloroacetonitrile to afford the corresponding allylic trichlo-
roacetimide, which then undergoes thermal rearrangement to
the allylic amine in refluxing toluene.66,67 It was found that using
a modified procedure75,76 with DBU (20 mol %) as the catalytic
base, instead of potassium hydride, led to improved yields for
substrates with an aromatic R group (11-16, Table 2). For
aliphatic substrates (17-19, Table 2), 120 mol % of DBU was
used to form the trichloroacetimidates, and the rearrangement
was carried out under basic conditions in refluxing p-xylene
with potassium carbonate.77 Filtration of the crude products and
Scheme 5. Mixture of Products from Deprotection with Formic
Acid
It was found, however, that cyclization could be successfully
avoided and the free alcohol obtained in high yield by using
the Lewis acid Et2AlCl (Scheme 6, Table 3).78 The amino
alcohols could then be oxidized to the corresponding acid
derivatives with Jones reagent (Scheme 6).79 In addition, we
(74) Medgyes, A.; Farkas, E.; Liptak, A.; Pozsgay, V. Tetrahedron 1997, 53,
4159-4178.
(75) Schmidt, U.; Respondek, M.; Lieferknecht, A.; Werner, J.; Fischer, P.
Synthesis 1989, 256-261.
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4313-4316.
(78) Koster, H.; Sinha, N. D. Tetrahedron Lett. 1982, 23, 2641-2644.
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607.
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γ
-Unsaturated
â
-Amino Acid Derivatives
A R T I C L E S
Scheme 6. Deprotection and Oxidation to N-Protected
γ-Unsaturated â-Amino Acids
Table 4. N-Protected γ-Unsaturated â-Amino Acids from
Scheme 6
were pleased to discover that this deprotection-oxidation
sequence could be carried out in one pot. Subjecting the trityl
ether derivatives to 3.5 M sulfuric acid and chromium trioxide
in acetone and dichloromethane solution at 0 °C and gradually
warming to room temperature led to the N-protected γ-unsatur-
ated â-amino acids in good yield (Scheme 6, Table 4).80
Table 3. N-Protected Amino Alcohols from Scheme 6
a Yield for oxidation from amino alcohol. b Yield for one-pot deprotec-
tion-oxidation from trityl ether.
in a Vacuum Atmosphere drybox with an attached MO-40 Dritrain or
by using the standard Schlenk or vacuum line techniques. Dichlo-
romethane, diethyl ether, toluene, and hexanes were dried through
alumina columns. All aldehydes and trichloroacetonitrile were distilled
or recrystallized and sublimed prior to use and stored under N2. Unless
otherwise specified, all chemicals were obtained from Acros, Aldrich,
or GFS Chemicals, and all solvents were purchased from Fischer
Scientific. All aldehydes and terminal alkynes are commercially
a NHTAc ) NHCOCCl3.
Conclusions
We have successfully developed a catalytic asymmetric
method for the synthesis of γ-unsaturated â-amino acid deriva-
tives, which are important building blocks in peptidomimetics
and pharmaceutical agents. Utilizing a highly enantioselective
vinylzinc addition to an aldehyde to set chirality, followed by
a [3,3]-sigmatropic trichloroacetimidate rearrangement and one-
pot deprotection-oxidation of a pendant oxygen, we have
demonstrated a general approach to the synthesis of both the D
and L configuration of this important class of â-amino acid
derivatives.
1
available. The H NMR and 13C{1H} NMR spectra were obtained on
a Bruker 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 ultraviolet 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.
Experimental Section
General Methods. All reactions were carried out under a nitrogen
atmosphere with oven-dried glassware. The progress of all reactions
was monitored by thin-layer chromatography to ensure the reactions
had reached completion. All manipulations involving dicyclohexylbo-
rane and dialkylzinc reagents were carried out using an inert atmosphere
General procedures are presented below. Synthesis and full char-
acterization of all compounds are provided in the Supporting Informa-
tion.
(S)-1-Phenyl-5-(trityloxy)pent-2-en-1-ol (2). General Procedure
A. To a stirred solution of Cy2BH (0.75 mmol) in toluene (1 mL),
(80) Wulff, W. D.; McCallum, J. S.; Kunng, F.-A. J. Am. Chem. Soc. 1988,
110, 7419-7434.
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A R T I C L E S
Lurain and Walsh
prepared according to Oppolzer’s procedure62 (flask A), was added a
solution of trityl-protected 3-butyn-1-ol (234 mg, 0.75 mM in toluene)
dropwise. The homogeneous reaction mixture was stirred for 30 min
at room temperature. To a separate flask (B) at -30 °C was added 0.5
mL of toluene and (-)-MIB (4.8 mg, 0.02 mmol), followed by
benzaldehyde (51 µL, 0.5 mmol) and then Et2Zn (1.0 mL, 1.0 M) or
Me2Zn (0.5 mL, 2.0 M) in toluene. The contents of flask A were then
transferred dropwise to flask B over 1 h with a syringe pump. The
reaction was stirred at -30 °C for 3.5 h and quenched with saturated
NH4Cl solution. The aqueous layer was extracted with diethyl ether,
and the combined organic layers were washed with H2O and dried over
MgSO4. The filtrate was concentrated in vacuo, and the residue was
chromatographed on silica (10% ethyl acetate in hexanes) to afford
2354, 2339, 1694, 1605, 1553, 1501, 1442, 1375, 1323, 1271, 1227
cm-1; HRMS-CI (m/z) 592.1535 [(M + Na)+], calcd for C32H34Cl3-
NO2Na 592.1553.
(S)-2,2,2-Trichloro-N-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)allyl]-
acetamide (22). General Procedure D. Et2AlCl (920 µL, 1.8 M in
toluene) was added dropwise to a stirred solution of (S)-2,2,2-trichloro-
N-[3-(4-fluorophenyl)-1-(2-(trityloxy)ethyl)allyl]acetamide (16) (64.0
mg, 0.11 mmol) in 3.0 mL of dry dichloromethane. After being stirred
for 20 min at room temperature, the reaction was quenched with
saturated NaHCO3. The organic layer was extracted with dichlo-
romethane, washed with H2O, and dried over MgSO4. The filtrate was
concentrated in vacuo, and the residue was chromatographed on silica
(20-30% EtOAc in hexanes) to afford the title compound as a colorless
oil in 95% yield (35 mg, 0.10 mmol): [R]20 ) -60.6 (c ) 0.52,
the title compound in 75% yield (158 mg, 0.38 mmol) as a colorless
D
1
1
oil: [R]20 ) +14.8 (c ) 1.05, CHCl3, 90% ee); H NMR (CDCl3,
CHCl3); H NMR (500 MHz, CDCl3) δ 1.85-1.90 (m, 1H), 2.05 (br
D
s, 1H), 2.11-2.16 (m, 1H), 3.84-3.92 (m, 2H), 4.80-4.82 (m, 1H),
6.10 (dd, 1H, J ) 15.9, 6.0 Hz), 6.58 (d, 1H, J ) 15.9 Hz), 7.01
(t, 2H, J ) 8.6 Hz), 7.26-7.36 (m, 2H), and 7.71 (br d, 1H, J ) 6.6
Hz) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 36.0, 51.5, 59.4, 80.8,
115.5, 115.7, 126.7, 128.08, 128.14, 130.8, 132.31, 132.34, 161.6, 161.8,
and 163.5 ppm; IR (neat) 3314, 3036, 2953, 2921, 1694, 1602, 1506,
1229, 1158 cm-1; HRMS-CI (m/z) 338.9991 (M+), calcd for C13H13-
Cl3FNO2 338.9996.
500 MHz) δ 1.85 (s, 1H), 2.36 (dt, 2H, J ) 6.4, 6.3 Hz), 3.13 (t, 2H,
J ) 6.6 Hz), 5.15 (d, 1H, J ) 6.0 Hz), 5.70-5.81 (m, 2H), and 7.19-
7.42 (m, 20H) ppm; 13C{1H} NMR (CDCl3, 125 MHz) δ 32.7, 62.7,
74.8, 86.2, 125.9, 126.6, 127.3, 127.5, 128.2, 128.4, 129.0, 133.8, 142.9,
and 144.0 ppm; IR (neat) 3372, 3060, 2922, 1597, 1491, 1448, 1220
cm-1; HRMS-CI(m/z) found 443.2007 [(M + Na)+], calcd for C30H28O2-
Na 443.1987.
(S)-2,2,2-Trichloro-N-[3-phenyl-1-(2-(trityloxy)ethyl)allyl]aceta-
mide (11). General Procedure B. DBU (2.4 µL, 0.016 mmol) was
added to a stirred solution of (S)-1-phenyl-5-(trityloxy)pent-2-en-1-ol
(2) (33.5 mg, 0.08 mmol) in 2 mL of dry diethyl ether. The reaction
flask was cooled to -5 °C, and Cl3CCN (12.0 µL, 0.12 mmol) was
added dropwise. After being stirred for 1 h with gradual warming from
-5 °C to rt (room temperature), the reaction was filtered quickly
through a plug of silica gel, rinsing thoroughly with diethyl ether. The
filtrate was concentrated in vacuo, and 5 mL of dry toluene was added.
The reaction was refluxed 17 h under a N2 atmosphere, and then the
toluene was removed in vacuo to afford 32 mg of the title compound
(0.06 mmol, 70% yield) as a white solid after recrystallization from
hexanes: mp 82-86 °C; [R]20D ) -15.1 (c ) 0.35, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 1.85-1.89 (m, 1H), 2.04-2.08 (m, 1H), 3.26-
3.30 (m, 2H), 4.68-4.71 (m, 1H), 5.89 (dd, 1H, J ) 15.9, 6.3 Hz),
6.41 (d, 1H, J ) 16.0 Hz), and 7.14-7.37 (m, 21H) ppm; 13C{1H}
NMR (125 MHz, CDCl3) δ 33.7, 51.7, 60.0, 87.4, 126.3, 126.7, 126.9,
127.5, 127.7, 128.2, 128.4, 131.4, 136.0, 143.3, and 161.0 ppm; IR
(KBr) 3423, 3063, 3031, 2924, 2367, 2344, 1690, 1654, 1508, 1448
cm-1; HRMS-ESI (m/z) 586.1109 [(M + Na)+], calcd for C32H28Cl3-
NO2Na 586.1083.
7-Methyl-3-((2,2,2-trichloroacetyl)amino)oct-4-enoic acid (32).
General Procedure E. A solution of 2,2,2-trichloro-N-[5-methyl-1-
(2-hydroxyethyl)hex-2-enyl]acetamide (23) (33.6 mg, 0.11 mmol) in
1 mL of acetone and 1 mL of dichloromethane was cooled to 0 °C,
and 94 µL of Jones’ reagent was added dropwise. After being stirred
at 0 °C for 3 min, the reaction was warmed to rt. The reaction was
stirred at rt for 20 min and filtered through Celite, and the acetone was
removed in vacuo. The remaining aqueous solution was extracted with
dichloromethane, and the organic layer was washed with sat. NaHCO3.
This aqueous layer was then acidified to pH 2 with 2 M HCl. The
resulting aqueous layer was extracted with dichloromethane, and the
combined organic layers were dried over MgSO4. The crude product
was purified by column chromotagraphy (1% MeOH in dichlo-
romethane to 1% MeOH and 0.5% AcOH in dichloromethane) to afford
the title compound in 95% yield (33.2 mg, 0.105 mmol) as a white
solid: [R]20D ) -7.4 (c ) 0.57, CHCl3); 1H NMR (500 MHz, CDCl3)
δ 0.86 (d, 6H, J ) 6.2 Hz), 1.58-1.67 (m, 1H), 1.94 (t, 2H, J ) 6.7
Hz), 2.79 (br d, 2H, J ) 7.2 Hz), 4.75 (m, 1H), 5.49 (dd, 1H, J )
15.3, 6.1 Hz), 5.73 (dt, 1H, J ) 15.2, 6.9 Hz), and 7.59 (br d, 1H, J )
8.3 Hz) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 22.1, 22.2, 28.0,
37.8, 41.4, 49.2, 127.0, 133.5, 161.1, and 176.1 ppm; IR (neat) 3336,
3025, 2955, 2919, 2861, 1710, 1517, 1466, 1408, 1367, 1290, 1261
cm-1; HRMS-CI (m/z) 316.0269 [(M + H)+], calcd for C11H17Cl3NO3
316.0274.
2,2,2-Trichloro-N-[3-cyclohexyl-1-(2-(trityloxy)ethyl)allyl]aceta-
mide (17). General Procedure C. DBU (62 µL, 0.41 mmol) was added
to a stirred solution of 1-cyclohexyl-5-(trityloxy)pent-2-en-1-ol (8) (146
mg, 0.34 mmol) in 2.0 mL of dry dichloromethane. The reaction flask
was cooled to 0 °C, and Cl3CCN (51 µL, 0.51 mmol) was added
dropwise. After being stirred for 1 h with gradual warming from 0 °C
to rt, the reaction was quenched with about 0.5 mL of saturated NH4-
Cl. The reaction mixture was then filtered quickly through a plug of
silica gel and NaSO4, rinsing thoroughly with dichloromethane. The
filtrate was concentrated in vacuo and dissolved in 5.0 mL of p-xylene,
and K2CO3 (10 mg) was added. The reaction was refluxed 20 h under
a N2 atmosphere and then filtered. The solvent was removed in vacuo
to afford 128 mg of the title compound (0.22 mmol, 66% yield) after
recrystallization from hexanes: mp: 80-82 °C; [R]20D ) -19.6 (c )
0.69, CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.88-0.92 (m, 2H), 1.04-
1.09 (m, 1H), 1.11-1.20 (m, 2H), 1.51-1.57 (m, 3H), 1.60-1.63 (m,
2H), 1.73-1.82 (m, 2H), 1.90-1.97 (m, 1H), 3.17-3.22 (m, 2H), 4.45-
4.49 (m, 1H), 5.11 (dd, 1H, J ) 15.6, 6.2 Hz), 5.44 (dd, 1H, J ) 15.6,
6.5 Hz), 7.10 (br d, 1H), 7.11-7.17 (m, 3H), 7.22 (t, 6H, J ) 7.9 Hz),
and 7.35 (d, 6H, J ) 7.2 Hz) ppm; 13C{1H} NMR (125 MHz, CDCl3)
δ 26.2, 26.3, 32.9, 33.0, 34.4, 40.4, 51.9, 60.5, 87.7, 125.1, 127.3, 128.1,
128.9, 138.9, 143.9, and 161.1 ppm; IR (KBr) 3451, 3058, 2917, 2843,
3-((2,2,2-Trichloroacetyl)amino)-5-(4-(trifluoromethyl)phenyl)-
pent-4-enoic Acid (27). General Procedure F. A solution of 2,2,2-
trichloro-N-[3-(4-(trifluoromethyl)phenyl)-1-(2-(trityloxy)ethyl)allyl]-
acetamide (27) (35.5 mg, 0.056 mmol) in 1.0 mL of acetone and 1.0
mL of dichloromethane was cooled to 0 °C, and 50 µL of Jones’ reagent
was added dropwise. After being stirred at 0 °C for 3 min, the reaction
was warmed to rt. The reaction was stirred at rt for 4 h and filtered
through Celite, and then the organic solvent was removed in vacuo.
The remaining aqueous solution was extracted with dichloromethane.
After washing of the organic layer with saturated NaHCO3, the resulting
aqueous layer was acidified to pH 2 with 2 M HCl and extracted with
dichloromethane. The combined organic layers were dried over MgSO4,
and the crude product was purified by column chromotagraphy (1%
MeOH in dichloromethane to 1% MeOH and 0.5% AcOH in dichlo-
romethane) to afford the title compound in 97% yield (22.0 mg, 0.054
mmol) as a white solid: [R]20D ) -34.1 (c ) 0.17, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 2.80-2.89 (m, 2H), 4.89-4.92 (m, 1H), 6.26
(dd, 1H, J ) 15.9, 6.4 Hz), 6.61 (d, 1H, J ) 15.9 Hz), 7.39 (d, 2H, J
) 8.1 Hz), 7.50 (d, 2H, J ) 8.1 Hz), and 7.72 (br d, 1H, J ) 8.5 Hz)
9
10682 J. AM. CHEM. SOC. VOL. 125, NO. 35, 2003

γ-Unsaturated
â
-Amino Acid Derivatives
A R T I C L E S
ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 29.7, 49.3, 92.7, 125.6, 125.7,
126.9, 128.2, 128.9, 131.6, 161.4, and 173.9 ppm; IR (neat) 3331, 2921,
2849, 1709, 1614, 1514, 1408, 1320, 1261, 1161 cm-1; HRMS-CI
(m/z) 402.9742 (M+), calcd for C14H11Cl3F3NO2 402.9757.
work was supported by the National Institutes of Health (Grant
NIGMS 058101). P.J.W. is a Dreyfus Teacher Scholar.
Supporting Information Available: Synthesis and full char-
acterization of all compounds and conditions for the resolution
of racemates (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. We thank our colleague Young K. Chen
for helpful discussions during the course of this project. This
JA035213D
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