Engineering Acyclic Stereocontrol in the Alkylation of Vinylglycine-Derived Dianions: Asymmetric Synthesis of Higher α-Vinyl Amino Acids

Article abstract of DOI:10.1021/jo9918091

A generalizable synthesis of higher L-α-vinyl amino acids is presented. The strategy pursued here involves the introduction of the amino acid side chain via the alkylation of a chiral, vinylglycine-derived dianionic dienolate, bearing the (-)-8-(β-naphthyl)menthyl (d'Angelo) auxiliary. A model is presented that postulates a favored "exo-entended" conformation for this dienolate, leading to C_α-alkylation at the si face. The model invokes internal amidate chelation to control ester enolate geometry and soft-soft interactions between the polarizable β-naphthyl ring of the auxiliary and the extended π-system of the dienolate to shield the re face. Heats of formation for four conformers of this dianion were calculated for their semiempirical optimized geometries (PM3). The results support the notion that in these vinylglycine-derived dianionic dienolates, "exo" conformations are considerable lower in energy than their "endo" counterparts, with the "exo-entended" conformation being most favorable. In fact, the d'Angelo auxiliary gives a greater degree of acyclic stereocontrol in this system when compared with the (-)-8-phenylmenthyl (Corey) and trans-2-(β-naphthyl)-cyclohexyl auxiliaries, using isobutyl iodide and benzyl bromide as model electrophiles. These dianions are generated from the corresponding dehydrobutyrine esters via sequential deprotonation with LDA and n-BuLi (2 equiv). When alkylations are carried out at -78°C in THF-HMPA, they proceed in 65-81% yields, with both regiocontrol (deconjugative α-alkylation is preferred over γ-alkylation) and a great degree of acyclic stereocontrol [91:9 to ≥98:2 diastereomeric ratios (10 examples)]. The auxiliary may be recovered in high yield (generally 90%) using a modification of Gassman's "anhydrous hydroxide" conditions, in which considerably higher temperatures are employed. Among the side chains introduced directly are those of butyrine, leucine, ornithine, phenylalanine, aspartate, valine, and norvaline. The lysine side chain is elaborated via a 4-step sequence from the alkylation product obtained with 1-chloro-4-iodobutane as electrophile. Importantly, to our knowledge, this work represents the first asymmetric synthesis of L-α-vinyl analogues of m-tyrosine, ornithine, and lysine, known time-dependent inhibitors for amino acid decarboxylases.

Full text of DOI:10.1021/jo9918091

J . Org. Chem. 2000, 65, 2907-2918
2907
En gin eer in g Acyclic Ster eocon tr ol in th e Alk yla tion of
Vin ylglycin e-Der ived Dia n ion s: Asym m etr ic Syn th esis of High er
r-Vin yl Am in o Acid s
David B. Berkowitz,* J ill M. McFadden, and Marianne K. Sloss
Department of Chemistry, University of Nebraska, Lincoln, Nebraska 68588-0304
Received November 23, 1999
A generalizable synthesis of higher L-R-vinyl amino acids is presented. The strategy pursued here
involves the introduction of the amino acid side chain via the alkylation of a chiral, vinylglycine-
derived dianionic dienolate, bearing the (-)-8-(â-naphthyl)menthyl (d’Angelo) auxiliary. A model
is presented that postulates a favored “exo-entended” conformation for this dienolate, leading to
CR-alkylation at the si face. The model invokes internal amidate chelation to control ester enolate
geometry and soft-soft interactions between the polarizable â-naphthyl ring of the auxiliary and
the extended π-system of the dienolate to shield the re face. Heats of formation for four conformers
of this dianion were calculated for their semiempirical optimized geometries (PM3). The results
support the notion that in these vinylglycine-derived dianionic dienolates, “exo” conformations are
considerable lower in energy than their “endo” counterparts, with the “exo-entended” conformation
being most favorable. In fact, the d’Angelo auxiliary gives a greater degree of acyclic stereocontrol
in this system when compared with the (-)-8-phenylmenthyl (Corey) and trans-2-(â-naphthyl)-
cyclohexyl auxiliaries, using isobutyl iodide and benzyl bromide as model electrophiles. These
dianions are generated from the corresponding dehydrobutyrine esters via sequential deprotonation
with LDA and n-BuLi (2 equiv). When alkylations are carried out at -78 °C in THF-HMPA, they
proceed in 65-81% yields, with both regiocontrol (deconjugative R-alkylation is preferred over
γ-alkylation) and a great degree of acyclic stereocontrol [91:9 to g98:2 diastereomeric ratios (10
examples)]. The auxiliary may be recovered in high yield (generally 90%) using a modification of
Gassman’s “anhydrous hydroxide” conditions, in which considerably higher temperatures are
employed. Among the side chains introduced directly are those of butyrine, leucine, ornithine,
phenylalanine, aspartate, valine, and norvaline. The lysine side chain is elaborated via a 4-step
sequence from the alkylation product obtained with 1-chloro-4-iodobutane as electrophile. Impor-
tantly, to our knowledge, this work represents the first asymmetric synthesis of L-R-vinyl analogues
of m-tyrosine, ornithine, and lysine, known time-dependent inhibitors for amino acid decarboxylases.
Sch em e 1. r-Vin yl AAs: Ver sa tile In ter m ed ia tes
for r-Br a n ch ed AA Syn th esis
In tr od u ction
Higher (R * H) R-vinyl amino acids (AAs) are an
especially versatile class of R-branched AAs. From the
point of view of mechanism-based enzyme inactivation,
the vinyl branch may serve as a masked trigger for the
suicide inactivation of pyridoxal phosphate (PLP)-de-
pendent enzymes, especially amino acid decarboxylases
(AADCs).1,2 For example, we have found that R-vinylargi-
nine and R-vinyllysine are time-dependent inactivators
of their cognate decarboxylases.1 Perhaps, more impor-
tantly from our perspective, the vinyl branch also serves
as a convenient synthetic precursor for the installation
of other, previously unexplored, potential AADC “suicide
triggers” along the R-branch (Scheme 1).3 Since the amino
acid R group is normally a key recognition element in
the target AADC active site, this strategy is particularly
advantageous. That is, from a given higher R-vinyl AA,
one could generate an array of potential suicide sub-
strates, all targeted at the same AADC active site. A
general strategy for the enantioselective synthesis of
higher R-vinyl AAs would then address the absolute
stereochemical issue for the entire array. Herein, we
provide one such solution, which is generalizable to some
of the most biologically relevant R groups.
(1) For a detailed discussion and set of references on uses of the
R-vinyl trigger to inactivate pyridoxal phosphate (PLP) dependent
enzymes, see: Berkowitz, D. B.; J ahng, W.-J .; Pedersen, M. L. Bioorg.
Med. Chem. Lett. 1996, 6, 2151-2156.
(2) For elegant mechanistic work on the mode of actuation of a
related vinyl trigger, see: Nanavati, S. M.; Silverman, R. B. J . Am.
Chem. Soc. 1991, 113, 9341-9349.
(3) (a) Berkowitz, D. B.; J ahng, W.-J . From R-Vinyl Amino Acids to
Higher R-(2-Fluoro)vinyl Amino Acids; 215th National ACS Meeting,
March 29-April 2, 1998; ORGN-336. (b) Berkowitz, D. B.; Pedersen,
M. L.; J ahng, W.-J . Tetrahedron Lett. 1996, 37, 4309-4312. (c)
Berkowitz, D. B.; Pedersen, M. L. J . Org. Chem. 1995, 60, 5368-5369.
It is important to point out that, in addition to these
applications of free, monomeric R-branched AAs, there
10.1021/jo9918091 CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/19/2000

2908 J . Org. Chem., Vol. 65, No. 10, 2000
Berkowitz et al.
Sch em e 2. F or m a l Vin yla tion of Am in o Acid s
is also much current interest in the incorporation of R,R-
disubstituted AAs into peptides and proteins. Among the
properties that R-branched AAs confer upon their deriva-
tive peptides are the following: (i) R-helicity,4a,d (ii) 310-
helicity,4a-c,e and (iii) resistance to proteolysis.5,6 Of late,
there have also been several creative approaches to the
synthesis of libraries of R-branched AAs for combinatorial
chemistry applications.7 Moreover, the Schultz group has
demonstrated that R-branched AAs may be quite ef-
ficiently inserted into specific positions in proteins of
interest using chemically misacylated tRNA’s under in
vitro translation conditions.8 These peptide/protein en-
gineering applications have involved primarily simple
R-alkyl AAs heretofore, most likely, due to synthetic
accessibility.
Be the application enzyme inhibition, de novo peptide
design, or total synthesis,9 enantiomerically enriched
R-vinyl AAs are desirable. Recent years have seen
extensive activity in the enantioselective synthesis of
R-methyl AAs.10,11 By contrast, though several routes to
optically enriched vinylglycine are available,9d,12 asym-
metric routes to higher R-vinyl amino acids are much
more limited.13 Seebach’s pioneering self-reproduction of
chirality approach (for R-vinylalanine,13a R-vinylbutyrine,13a
and R-vinylphenylalanine13b) stands out in this regard.
Other routes appear to be limited to R-vinylalanine so
far. Hegedus has reported a synthesis of D-R-vinylalanine,
building upon Ojima’s chiral â-lactam-based technology.13c
Frutos13d synthesized scalemic L-R-vinylalanine using
the Beckmann rearrangement of the requisite O-tosyl
oxime generated from the appropriate, enantiomeric
â-ketoester.13e Petasis has recently described an elegant
synthesis of related â,γ-unsaturated AAs via a Mannich-
type condensation reaction involving alkenyl boronate,
amine, and R-keto acid components.14
Resu lts a n d Discu ssion
We described a convenient synthesis of racemic, R-vinyl
AAs from the corresponding amino acids (Scheme 2)15a
and the partial kinetic resolution of these via a lipase-
mediated “reverse transesterification” procedure.15b Par-
allel to our enzymatic resolution studies, we undertook
to develop asymmetric synthetic routes to the target
unsaturated, R-branched analogues of naturally occur-
ring R-AAs. It will be noted that our initial, “racemic”
synthesis involved the formal vinylation of dianions
derived from N-benzoyl-protected amino acid esters.
Ethylene oxide served as a convenient and readily
available vinyl cation equivalent.
We reasoned that it ought to be possible to fashion
chiral versions of these amino acid-derived dianions16
through the appendage of a chiral ester auxiliary and
thereby develop an asymmetric version of this chemistry.
In fact, attachment of the Corey auxiliary [(-)-8-phenyl-
menthol] through an ester linkage to the R-carboxyl
group of N-benzoylalanine proved advantageous. Initial
attempts to formally R-vinylate the resultant chiral
dianion (1), with ethylene oxide as vinyl cation equiva-
lent, including in the presence of BF3‚Et2O, led to complex
(4) (a) Yokum, T. S.; Gauthier, T. J .; Hammer, R. P.; McLaughlin,
M. L. J . Am. Chem. Soc. 1997, 119, 1167-1168. (b) J aun, B.; Tanaka,
M.; Seiler, P.; Ku¨hnle, F. N. M.; Braun, C.; Seebach, D. Liebigs Ann./
Recueil 1997, 1697-1710. (c) Aubry, A.; Bayeul, D.; Pre´cigoux, G.;
Pantano, M.; Formaggio, F.; Crisma, M.; Toniolo, C.; Boesten, W. H.
J .; Schoemaker, H. E.; Kamphuis, J . J . Chem. Soc., Perkin Trans. 2
1994, 525-529. (d) Altmann, K.-H.; Altmann, E.; Mutter, M. Helv.
Chim. Acta 1992, 75, 1198-1210. (e) Valle, G.; Crisma, M.; Toniolo,
C.; Beisswenger, R.; Rieker, A.; J ung, G. J . Am. Chem. Soc. 1989, 111,
6828-6833.
(5) (a) Khosla, A.; Stachowiak, K.; Smeby, R. R.; Bumpus, F. M.;
Piriou, F.; Lintner, K.; Fermandjian, S. Proc. Natl. Acad. Sci. U.S.A.
1981, 78, 757-760.
(6) For example, a family of tripeptidic antithrombotic agents
developed at Lilly contains a D-R-branched amino acid as an essential
component: Sall, D. J .; Shuman, R. T.; Smith, G. F.; Wiley: M. R.
U.S. Patent No. 5,484,772; J uly 16, 1996.
(7) (a) O’Donnell, M. J .; Zhou, C.; Scott, W. L. J . Am. Chem. Soc.
1996, 118, 6070-6071. (b) Scott, W. L.; Zhou, C.; Fang, Z.; O’Donnell,
M. J . Tetrahedron Lett. 1997, 38, 3695-3698. (c) Fornicola, R. S.;
Oblinger, E.; Montgomery, J . J . Org. Chem. 1998, 63, 3528-3529.
(8) Mendel, D.; Ellman, J .; Schultz, P. G. J . Am. Chem. Soc. 1993,
115, 4359-4360.
(9) For the use of R-vinyl AAs or derivatives as synthetic building
blocks, see: (a) Murray, W. V.; Sun, S.; Turchi, I. J .; Brown, F. K.;
Gauthier, A. D. J . Org. Chem. 1999, 64, 5930-5940. (b) Campbell, A.
D.; Raynam, T. M.; Taylor, R. J . K. Tetrahedron Lett. 1999, 40, 5263-
5266. (c) Trost, B. M.; Lemoine, R. C. Tetrahedron Lett. 1996, 37, 9161-
9164. (d) Huwe, C. M.; Blechert, S. Tetrahedron Lett. 1995, 36, 1621-
1624. (e) Krol, W. J .; Mao, S.; Steele, D. L.; Townsend, C. A. J . Org.
Chem. 1991, 56, 728-731. (f) Shaw, K. J .; Luly, J . R.; Rapoport, H. J .
Org. Chem. 1985, 50, 4515-4523.
(10) For reviews, see: (a) Seebach, D.; Sting, A. R.; Hoffman, M.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2708-2748. (b) Duthaler, R.
O. Tetrahedron 1994, 50, 1539-1650. (c) Williams, R. M. Synthesis of
Optically Active Amino Acids; Pergamon Press: Oxford, 1989.
(11) Recent references include: (a) Belokon, Y. N.; North, M.;
Kublitski, V. S.; Ikonnikov, N. S.; Krasik, P. E.; Maleev, V. I.
Tetrahedron Lett. 1999, 40, 6105-6108. (b) Wenglowsky, S.; Hegedus,
L. S. J . Am. Chem. Soc. 1998, 120, 12468-12473. (c) Meyer, L.; Poirier,
J . M.; Duhamel, P.; Duhamel, L. J . Org. Chem. 1998, 63, 8094-8095.
(d) Charette, A. B.; Mellon, C. Tetrahedron 1998, 54, 10525-10535. (e)
J uaristi, E.; Lopez-Ruiz, H.; Madrigal, D.; Ramirez-Quiros, Y.; Escal-
ante, J . J . Org. Chem. 1998, 63, 4706-4710. (f) Chinchilla, R.; Falvello,
L. R.; Galindo, N.; Najera, C. Angew. Chem., Int. Ed. Engl. 1997, 36,
995-997. (g) Ohfune, Y.; Moon, S.-H.; Horikawa, M. Pure Appl. Chem.
1996, 68, 645-648. (h) Ferey, V.; Tuopet, L.; Le Gall, T.; Mioskowski,
C. Angew. Chem., Int. Ed. Engl. 1996, 35, 430-432. (i) J ung, M. E.;
D’Amico, D. C. J . Am. Chem. Soc. 1995, 117, 7, 7379-7388.
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3715. (b) Trost, B. M.; Bunt, R. C. Angew. Chem., Int. Ed. Engl. 1996,
35, 99-102. (c) Berkowitz, D. B.; Smith, M. K. Synthesis 1996, 39-
41. (d) Griesbeck, A. G.; Hirt, J . Liebigs Ann. 1995, 1957-1961. (e)
Carrasco, M.; J ones, R. J .; Kamel, S.; Rapoport, H.; Truong, T. Org.
Synth. 1991, 70, 29-34. (f) Pellicciari, R.; Natalini, B.; Marinozzi, M.
Synth. Commun. 1988, 18, 1715-1721. (g) Barton, D. H. R.; Crich,
D.; Herve, Y.; Potier, P.; Thierry, J . Tetrahedron 1985, 41, 4347-4357.
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(i) Scho¨llkopf, U.; Nozulak, J .; Groth, U. Tetrahedron 1984 40, 1409-
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(13) (a) Weber, T.; Aeschimann, R.; Maetzke, T.; Seebach, D. Helv.
Chim. Acta 1986, 69, 1365-1377. (b) Seebach, D.; Bu¨rger, H. M.;
Schickli, C. P. Liebigs Ann. Chim. 1991, 669-684. (c) Colson, P.-J .;
Hegedus., L. S. J . Org. Chem. 1993, 58, 5918-5924. (d) Frutos, R. P.;
Spero, D. M. Tetrahedron Lett. 1998, 39, 2475-2478.
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(16) (a) For the first work of which we are aware on chiral hippurate-
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Mao, D. T.; Richmond, C. M.; Bergbreiter, D. E.; Newcomb, M. J . Chem.
Res., Synop. 1984, 148-149; J . Chem. Res., Miniprint 1518-1530. For
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1995, 78, 1185-1205. (c) Seebach, D.; Bossler, H.; Gru¨ndler, H.; Shoda,
S.-i.; Wenger, R. Helv. Chim. Acta 1991, 74, 197-224.

Synthesis of Higher R-Vinyl Amino Acids
J . Org. Chem., Vol. 65, No. 10, 2000 2909
Sch em e 3. Alk yla tion s Usin g Vin yl Ca tion
Equ iva len ts Equ ip p ed w ith Bu ilt-in Au xilia r y
Relea ses
chains to be replaced with an unsubstituted vinyl group,
the resulting dienolate π-surface would be extended by
an additional two p-orbitals, and this might enhance
interaction with the polarizable â-naphthyl group.18 This
line of reasoning led us to consider a converse synthetic
strategy; namely, the R-alkylation of chiral vinylglycine-
derived dianionic dienolates.
As a computational test of this working model for
conformational control, we performed a series of semiem-
pirical PM325 geometry optimizations upon the dianion
derived from the 8-(â-naphthyl)menthyl (d’Angelo)
auxiliary.20a Lithium was chosen as the counterion, given
that, experimentally, the first deprotonation is with LDA
and the second with butyllithium.26 The degree of “hy-
dration” (water molecules were used as THF/HMPA
surrogates) was chosen as follows. Several iterations of
geometry optimizations were performed, assuming che-
lation from the amidate nitrogen to the ester enolate
lithium, and varying the numbers of waters per lithium.
(18) Face-to-face π-π interactions have been invoked to rationalize
the conformational control obtained in systems where such arylmenthyl
or arylcyclohexyl auxiliaries are appended to electron-deficient π-sys-
tems such as acrylates (in Diels-Alder or conjugate addition reactions)
or glyoxylates (in oxy-ene or Grignard addition reactions).19,20 As has
been pointed out by Whitesell, examples of the inverse-electron demand
situation are less common.19c However, systems have been described
in which either an electron-rich silyl ketene acetal (hetero-Diels-Alder
reaction),21b an R-alkoxy ester enolate (imine-ester enolate cyclocon-
densation reaction)21c or an AA-derived ester enolate (monoanion
alkylation),21a bears a blocking group of the 8-arylmenthyl or 2-trans-
arylcyclohexyl variety, and in which excellent stereocontrol is achieved.
In these cases, models of the transition state assemblies have been
formulated that correctly predict the sense of asymmetric induction
observed and that, either explicitly or implicitly, invoke favorable π-π
interactions22 for conformational control. Nonetheless, such arguments
remain controversial, particularly with systems in which one of the
π-components is electron rich. Arguing against such interactions,
several elegant model studies on neutral species support the notion
that electrostatic forces dominate face-to-face π-π interactions.23 In
other model systems, however, it appears that dispersion forces can
make significant contributions to such π-π interactions,24 particularly
Sch em e 4
mixtures of products. Pleasingly, the alternative vinyl
cation equivalents, ethyl bromoacetate and 2-iodoethyl
benzyl ether,17 were effectively coupled to dianion 1, and
with good diastereoselection (Scheme 3). Conveniently,
as is the case for ethylene oxide, these electrophiles
possess a built-in auxiliary release that can be actuated
under reductive conditions. Thus, each approach formally
gives D-R-vinylalanine in 86% ee.
Unfortunately, this strategy for engineering a chiral
bias into such amino acid-derived dianions did not prove
general. Thus, the analogous phenylalanine-derived chiral
dianion (5) showed little to no diastereoselection in
alkylation reactions (Scheme 4).
when
a
highly polarizable fused aromatic ring is involved.24b In
the case of the “exo-extended” dienolate working model presented
here, it is conceivable that dispersion forces could lead to a favorable
face-to-face interaction, particularly as the system approaches an
alkylation transition state in which charge is becoming more widely
dispersed.
(19) For a pioneering example of the use of the 8-phenylmenthyl
auxiliary in an asymmetric Diels-Alder reaction, see: Corey, E. J .;
Ensley, H. E. J . Am. Chem. Soc. 1975, 97, 6908-6909.
(20) For reviews on the postulated use of π-π interactions in
asymmetric organic synthesis, see: (a) Dumas, F.; Mezrhab, B.;
d’Angelo, J . J . Org. Chem. 1996, 61, 2293-2304. (b) J ones, G. B.;
Chapman, B. J . Synthesis 1995, 475-497. (c) Whitesell, J . K. Chem.
Rev. 1992, 92, 953-964.
These dianions had been designed with two principal
considerations. On one hand, it was expected that the
R-benzamidate functionality would serve as an ideal
ligand for the ester enolate lithium and thereby “lock”
this enolate into the E geometry. Further, it was hypoth-
esized that a favorable soft-soft (or dipole-induced
dipole) interaction might be available between the po-
larizable aromatic ring in such 8-arylmenthyl-type aux-
iliaries and the π-system of the dianion. Provided that
these interactions persist as the dianion interacts with
the incoming alkyl halide and approaches the relevant
transition state, alkylations would be expected to occur
preferentially at the si face. From the results obtained
here, one might postulate that the introduction of bulky
substituents at the R-carbon (such as Bn, here, and many
of the other natural AA side chains) has a disruptive
effect on such interaction, and thereby compromises
diastereoselection. On the other hand, were such side
(21) (a) Meyer, L.; Poirier, J .-M.; Duhamel, P.; Duhamel, L. J . Org.
Chem. 1998, 63, 8094-8095. (b) Swindell, C. S.; Tao, M. J . Org. Chem.
1993, 58, 5889-5891. (c) Ojima, I.; Habus, I.; Zhao, M.; George, G.;
J ayasinghe, L. R. J . Org. Chem. 1991, 56, 1681-1683.
(22) For a general discussion on factors influencing π-π interactions,
see: Hunter, C. A.; Sanders, J . K. M. J . Am. Chem. Soc. 1990, 112,
5525-5534.
(23) (a) Cozzi, F.; Cinquini, M.; Annuziata, R.; Siegel, J . S. J . Am.
Chem. Soc. 1993, 115, 5330-5331. (b) Muehldorf, A. V.; Van Engen
D.; Warner, J . C.; Hamilton, A. D. J . Am. Chem. Soc. 1988, 110, 6561-
6562.
(24) (a) Williams, V. E.; Lemieux, R. P. J . Am. Chem. Soc. 1998,
120, 11311-11315. (b) Askew, B.; Ballester, P.; Buhr, C.; J eong, K. S.;
J ones, S.; Parris, K.; Williams, K.; Rebek, J ., J r. J . Am. Chem. Soc.
1989, 111, 1082-1090.
(25) The MacSpartan Plus (version 1.1.9) package (Wavefunction,
Inc., Irvine, CA 92612) was used for all geometry optimizations.
Complete tables of atomic Cartesian coordinates, atomic partial
charges, calculated dipole moments and heats of formation for each of
the conformers I-IV are available upon request.
(26) Operationally, CR-alkylations in these dianionic dienolate
systems were found to be most successful if, following initial depro-
tonation with LDA, two equivalents of n-BuLi were employed for the
second deprotonation. Presumably, the first equivalent of n-BuLi is
required to deprotonate the diisopropylamine that is formed in the
initial deprotonation reaction.
(17) Liu, C.; Coward, J . K. J . Med. Chem. 1991, 34, 2094-2101.

2910 J . Org. Chem., Vol. 65, No. 10, 2000
Berkowitz et al.
F igu r e 1. Displayed are the results of semiempirical geometry optimizations (PM325) on rotamers of the vinylglycine-derived
dienolate bearing the d’Angelo auxiliary. All conformers have 231 independent degrees of freedom, and 199 basis functions were
used. Convergence was set at a 0.5 cal/mol energy differential between successive iterations and was achieved after 322, 352,
321, and 317 cycles for conformers I-IV, respectively.
We settled upon solvent coordination numbers of two for
the amidate lithium, and one for the ester enolate
lithium, in that optimized geometries appeared to permit
one favorable cation-π interaction for each lithium center
(vinyl group f amidate Li and phenyl group f enolate
Li).
With this degree of solvent ligation, four local minima
were found for the dianionic dienolate, differing primarily
in dihedral angles with respect to rotations about the
C(1′)-O bond (“exo” versus “endo” rotomers) and about
the C(1)-O bond (“extended” vs “folded”).27 The two endo
conformers are estimated to lie considerably higher in
energy (3-5 kcal/mol in terms of calculated heats of
formation; Figures 1 and 2) than their exo counterparts.
To the extent that ground-state conformational prefer-
ences reflect dianion conformational preferences in the
transition state for this reaction,28 it would appear that
exo-type conformations are greatly favored. Furthermore,
there appears to be a slight preference for exo-extended
conformer I over exo-folded conformer II, consistent with
the preference for si face alkylation that is observed here
(vide infra). In the PM3-optimized geometry for I, re face
F igu r e 2. Shown is a three-dimensional view of the lowest
energy exo conformers. Though modeling was carried out with
all hydrogens in place, they have been omitted here for clarity.
For the exo-entended conformer, the calculated partial charges
for the C-atoms of the polarizable naphthyl blocking group are,
from C(1′′) to C(10′′), respectively, as follows: -0.17; -0.05;
-0.11; -0.13; +0.03; -0.06; -0.13; -0.03; -0.19; +0.08; where
C(2′′) is taken as the point of attachment.
approach is effectively blocked as the atoms of the
dienolate π-surface stretching from the bridging ester
oxygen to the vinyl group [atoms O-C(1)-C(2)-C(3)-
C(4)] are within 2.9-4.2 Å of the nearest carbons of the
â-naphthyl group.29
(27) The “endo/exo” descriptors refer to dianion position with respect
to the cyclohexyl ring. “Endo” here designates conformers possessing
approximately a 0° dihedral angle with respect to rotation about the
C1-O-C1′-cy bond, where cy refers to the bisector of the C6′-C1′-C2′
angle. In the “exo” conformers, the corresponding dihedral angle is
180°. Similarly, “folded” and “extended” conformers are characterized
by dihedral angles of approximately 0° and 180°, respectively, about
the C2-1C-C1′ bond.
(28) Of course, by the Curtin-Hammett principle, if under the
reaction conditions, the interconversion of conformers I and II, say,
were fast relative to their transformation to products, the product
distribution would be governed by the relative energies of the transition
states leading to the products, rather than by the relative energies of
I and II. In such a situation, conformational prefererences in the
transition states need not directly reflect ground state conformational
preferences.
To examine this “exo-extended” working model for
acyclic conformational control in such amino ester-
derived dienolates, a series of substituted cyclohexanol
chiral auxiliaries was installed as indicated in Scheme
5.
(29) In exo-extended conformer I, here, the p-orbitals of the op-
posing π-surfaces are offset, rather than directly overlaid.22 Thus
the atom-to-atom distances we obtain using the MacSpartan Plus
program slightly overestimate the distance between the two π-
surfaces.

Synthesis of Higher R-Vinyl Amino Acids
J . Org. Chem., Vol. 65, No. 10, 2000 2911
Ta ble 1. Ch ir a l Vin ylglycin e-Der ived Dia n ion Dien ola tes: Dia ster eoselectivity a s a F u n ction of Au xilia r y
a
Yield based on recovered starting material.
Our vinylglycine synthesis12c was modified to provide
access to the corresponding benzamido acid. The auxil-
iary could then be installed by direct incubation of this
acid with the auxiliary, under catalysis by p-TsOH. Note
that isomerization from the vinylglycine to the conjugated
dehydrobutyrine system occurs under these conditions.
Ta ble 2
Sch em e 5. Tow a r d Ch ir a l, Vin ylglycin e-Der ived
En ola tes: In sta lla tion of th e Ch ir a l Au xilia r iesa
a
R*OH ) trans-2-naphthylcyclohexanol, (-)-8-phenylmenthol,
or (-)-8-(â-naphthyl)menthol.
Next, three aryl-cyclohexyl-type auxiliaries were evalu-
ated for diastereoselectivity and regioselectivity (R- vs
γ-reactivity) in alkylation reactions of their derivative
dianion dienolates (see Table 1). Benzyl bromide and
isobutyl iodide were initially screened as electrophiles.
Regioselectivity was found to be electrophile-dependent,
with the harder electrophiles (e.g., isobutyl iodide) show-
ing the greatest preference for deconjugative (R) alkyla-
tion. Note that softer electrophiles here are deemed to
be those in which a π-system is adjacent to the C-X bond.
For these systems, π-σ* overlap might be expected. The
trans-2-(â-naphthyl)cyclohexanol auxiliary,20c in which
the aromatic blocking group is attached directly to the
ring, proved less effective than the 8-arylmenthol-type
auxiliaries at controlling the facial approach of the alkyl
halide. While the Corey auxiliary[(-)-8-phenylmenthol]19
showed good diastereoselectivity and yield, the d’Angelo
auxiliary [(-)-8-(â-naphthyl)menthol]20a was clearly su-
perior in this system (BnBr, 70%, 10:1 dr; i-BuI, 81%,
g98:2 dr).
a
Diastereomeric ratios based on 1H NMR (500 MHz). The
vinylic protons are resolved in the spectrum of the diastereomers.
bYields given are total alkylation yields and reflect the sum of R-
and γ -alkylation products, which in most cases were inseparable
by flash chromatography. cIn this case, the R- and γ-alkylation
products could be separated by flash chromatography.
Given the promising results obtained with the d’Angelo
auxiliary, its vinylglycine-derived dianionic dienolate was
further investigated. In fact, as can be seen in Table 3, a
considerable variety of important amino acid side chains
can directly be introduced, including those of m-tyrosine

2912 J . Org. Chem., Vol. 65, No. 10, 2000
Berkowitz et al.
and ornithine, for which the corresponding R-vinyl AAs
(as the racemates) are known AADC suicide substrates.1
Highest yields are obtained in the presence of HMPA as
cosolvent, suggesting that the reactive form of the di-
enolate is monomeric. Under such conditions, yields are
consistently in the 65-80% range and diastereoselectivi-
ties are very good to excellent (82% to g96% de).
Consistent with the initial screening results, R/γ ratios
are most favorable for hard electrophiles. The fact that
secondary alkyl halides (e.g., isopropyl iodide) also react
well with this sterically demanding dienolate is also
worthy of note.
riched R-vinyl amino acids (Table 4). In the two cases
where literature values were available, our optical rota-
tions were consistent with those previously reported by
Seebach’s group [for L-R-vinylbutyrine: [R]D + 30.2 (c 1
H2O); [R]13a +27.7 (c 1 H2O); for L-R-vinylphenyalanine:
[R]D (82% ee) +13.1 (c 1 CH3OH); [R]13b -16.6 (c 1 CH3-
OH) for D-R-vinylphenylalanine].
Ta ble 4. Hyd r olysis to th e F r ee L-r-Vin yl Am in o Acid s
Ta ble 3. Efficien t Au xilia r y Relea se u n d er Eleva ted
Tem p er a tu r e Ga ssm a n Con d ition s
entry
R
yield (%)
er (%)
[R]D
a
b
c
d
e
f
m-(HO)C6H4CH2-
(CH3)2CHCH2-
CH3CH2-
88a
96
63
87
96
85
98a
98
94:6
g98:2
g98:2
96.5:3.5
97:3
91:9
g98:2
g98:2
+7.85
+37.5
+30.2b
+12.6
+18.8
+13.1c
+26.3
+30.7
H2NCH2CH2CH2CH2-
H2NCH2CH2CH2-
PhCH2-
g
h
HO2CCH2-
(CH3)2CH-
a
b
Isolated as the hydrochloride salt. [R]13a ) +27.7 L-R-
vinylbutyrine. c [R]13b ) -16.6 D-R-vinylphenylalanine.
R-benzoamido
recovered
Finally, motivated by our recent observation that (()-
vinyllysine inhibits lysine decarboxylase,1 we sought to
apply this methodology to an asymmetric synthesis of
L-R-vinyllysine. This could be achieved starting from the
alkylation product obtained with 1-chloro-4-iodobutane
(19d ) (Table 2). ꢀ-Halogen exchange is first performed
with NaI, providing iodide 22d , which is then displaced
by azide ion. Reduction of the azide is then accomplished
with PPh3. Hydrolysis of the resulting phosphine imine
yields the free amine.31 Ester deprotection of 25d using
the modified Gassman procedure30 is followed by benza-
mide hydrolysis (see Tables 3 and 4) to give enantiomeri-
cally enriched L-R-vinyllysine (Scheme 6).
entry
R
acid (%)
auxiliary (%)
a
b
c
d
e
f
g
h
i
m-(HO)C6H4CH2-
(CH3)2CHCH2-
CH3CH2-
53
73
62
78
69
76
72
76
78
94
92
90
87
94
90
87
80
72
H2NCH2CH2CH2CH2-a
H2NCH2CH2CH2-b
PhCH2-
HO2CCH2-c
(CH3)2CH-
CH3CH2CH2-
Compound 25d is actually employed here. bHydroxide con-
centration was increased (10 equiv of H2O, 10 equiv of KOtBu) to
prevent formation of the lactam. cThe ethyl ester in the side chain
was also cleaved under the reaction conditions to yield the diacid.
a
These alkylation products may be de-esterified with
recovery of the chiral auxiliary using a modified Gassman
“anhydrous hydroxide” procedure,30 in which dioxane is
substituted for diethyl ether, enabling the reaction to be
run at a higher temperature. At refluxing Et2O temper-
atures, these hindered esters are essentially inert to
cleavage. By contrast, upon heating at a reflux with 2-3
equiv of H2O and 8-10 equiv of KOtBu in dioxane for
about 8 h, one recovers the chiral auxiliary and isolates
the R-benzamido acid in high yield and purity (Table 3).
The two are separated by simple extraction. It is worthy
of note that in cases where 19 contains some γ-alkylation
product, this R,â-unsaturated ester apparently decom-
poses under these basic reaction conditions, essentially
providing for purification of the desired R-alkylated
isomer in situ. This simple modification of the Gassman
ester cleavage protocol is likely to find application
elsewhere for sterically encumbered systems. In an
interesting twist, exposure of the ornithine derivative to
these conditions, results in a mixture of δ-lactam and
δ-amino acid. If desired, one can channel all material to
the δ-amino acid (albeit in slightly lower yield) by
increasing both the amount of H2O and the reaction time
(see entry e and the Experimental Section).
Con clu sion s
In summary, we describe herein a strategy for engi-
neering effective, acyclic stereocontrol elements into
dianionic dienolates derived from vinylglycine and 8-aryl-
menthyl-type auxiliaries. Enolate geometry is envisioned
to be chelation-controlled through a favorable syn ar-
rangement of the amidate nitrogen and the enolate
oxyanion, both ligated to lithium. Facial selectivity is
postulated to be controlled by a favorable soft-soft
interaction between the aryl blocking group of the
auxiliary and the extended π-system of the dianianic
dienolate. Interestingly, semiempirical (PM3) geometry
optimizations and calculated heats of formation, also
identify the model “exo-extended” conformer of the
(d’Angelo auxiliary-derived) dienolate as a particularly
favorable conformer.
Consistent with the model, a high degree of acyclic
stereocontrol (91:9 to g98:2 dr) is achieved in the
alkylation of this dienolate with electrophiles represent-
ing a range of natural and unnatural amino acid side
chains. Following alkylation, the chiral auxiliary may be
recovered in excellent yield using a modified Gassman
“anhydrous hydroxide” procedure that may prove to be
a generally useful method for the cleavage of hindered
Final deprotection of the benzamido acids is accom-
plished using 6 N HCl to obtain enantiomerically en-
(31) For a related Lys side chain elaboration, see: Danzin, C.;
Casara, P.; Claverie, N.; Metcalf, B. W. J . Med. Chem. 1981, 24, 16-
20.
(30) Gassman, P. G.; Schenk, W. N. J . Org. Chem. 1977, 42, 918-
920.

Synthesis of Higher R-Vinyl Amino Acids
J . Org. Chem., Vol. 65, No. 10, 2000 2913
Sch em e 6. Ela bor a tion of th e L-Vin yllysin e Sid e Ch a in
cyclohexanol20c (453 mg, 2.21 mmol) following general proce-
dure A, 11 was obtained [(400 mg, 50% (53% based on
recovered SM)], after flash chromatography (10% EtOAc/
hexane): 1H NMR (500 MHz, CDCl3) δ 1.36-1.59 (m, 3 H),
1.63-1.71 (m, 1 H), 1.65 (d, J ) 7.39 Hz, 3 H), 1.79-1.95 (m,
2 H), 1.97-2.02 (m, 1 H), 2.23-2.30 (m, 1 H), 2.86-2.95 (dt,
J ) 3.8, 12.1 Hz, 1 H), 5.06-5.13 (dt, J ) 4, 11 Hz, 1 H), 6.60
(quart, J ) 7.15 Hz, 1 H), 7.17 (s, 1 H), 7.31-7.52 (m, 6 H),
7.62 (s, 1 H), 7.69-7.80 (m, 3 H), 7.74 (d, J ) 8 Hz, 2 H); 13C
NMR (125 MHz) δ 14.6, 24.5, 25.6, 32.0, 33.6, 49.6, 77.5, 125.2,
125.6, 125.7, 125.8, 126.0, 127.1, 127.4, 127.8, 128.2, 128.3,
131.6, 132.3, 132.4, 133.4, 133.8, 140.4, 163.7, 164.9; IR (ATR)
3325-3364, 1716, 1662 cm-1. Anal. Calcd for C27H27NO3: C,
78.42; H, 6.58; N, 3.38. Found: C, 77.99, H, 6.72; N, 3.15. The
Z-alkene geometry was assumed by analogy with 12 (vide
infra).
esters. To our knowledge, this work reports the first
asymmetric syntheses of a number of biologically rel-
evant, higher R-vinyl amino acids, including L-R-vinyl-
m-tyrosine, L-R-vinylaspartate, L-R-vinylornithine, and
L-R-vinyllysine. Furthermore, given that the pseudo-
enantiomer of the d’Angelo auxiliary is now available via
a chemoenzymatic route developed by Comins and Sal-
vador,32 this approach should also be amenable to the
synthesis of D-R-vinyl amino acids.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were conducted under an
argon atmosphere using flame-dried glassware unless other-
wise noted. Diisopropylamine, MeCN, and CH2Cl2 were dis-
tilled from CaH2. Benzene, toluene, THF, and Et2O were
distilled from sodium benzophenone ketyl. HMPA was dis-
tilled, in vacuo, from Na. n-Butyllithium in hexanes (nominally
1.6 M) was purchased from Aldrich and titrated33 before each
use. Elemental analyses were carried out by M-H-W Labs
(Phoenix, AZ). For chiral dianion alkylations, diastereomeric
(1′R,2′S,5′R)-8′-(â-Na p h t h yl)m en t h yl N-Ben zoyl-(Z)-
d eh yd r obu tyr in a te (12). From (1′R,2′S,5′R)-8′-(â-naphthyl)-
menthol20a (3.20 g, 11.3 mmol) following general procedure A,
12 was obtained (3.40 g, 64%, after flash chromatography (10%
EtOAc/ hexane): [R]D -34.9° (c 1.09, CHCl3); 1H NMR (300
MHz, CDCl3) δ 0.87 (d, J ) 6 Hz, 3 H), 0.88-1.08 (m, 2 H),
1.12 (d, J ) 7 Hz, 3 H), 1.18-1.32 (m, 1 H), 1.25 (s, 3 H), 1.37-
1.53 (m, 1 H), 1.42 (s, 3 H), 1.65-1.83 (m, 2 H), 1.94-1.99 (m,
1 H), 2.18-2.27 (dt, J ) 3, 12 Hz, 1 H), 4.98 (dt, J ) 4, 11 Hz,
1 H), 5.90 (q, J ) 7 Hz, 1 H), 6.34 (s, 1 H), 7.35-7.47 (m, 4 H),
7.49-7.54 (m, 2 H), 7.58-7.60 (m, 3 H), 7.70-7.76 (m, 3 H);
13C NMR (75 MHz, CDCl3) δ 14.1, 21.7, 22.2, 26.3, 30.0, 31.3,
34.5, 39.5, 41.6, 50.1, 74.9, 122.7, 125.1, 125.3, 125.5, 127.2,
127.3, 127.8, 128.4, 131.2, 131.6, 133.4, 134.1, 134.2, 149.7,
163.4, 165.0. IR (ATR) 3220-3400, 1717, 1700, 1696, 1653
1
product ratios (dr’s) were determined by integration of the H
NMR (500 MHz) spectra. The peaks used to assess dr are
indicated in each individual experimental write-up. Where only
one diastereomer is observed, we report g98:2 dr ) g96% de,
assuming a 2% detection limit.
Gen er a l P r oced u r e A. (1′R,2′S,5′R)-8′-P h en ylm en th yl
N-Ben zoyl-(Z)-d eh yd r obu tyr in a te (10). To a solution of 9
(483 mg, 2.36 mmol) in benzene (18 mL) was added (1R,2S,5R)-
8-phenylmenthol19 (476 mg, 2.05 mmol) and p-TsOH (156 mg,
0.82 mmol). The solution was heated at a reflux using a Dean-
Stark trap for 2-3 d. After cooling, NaHCO3 (aqueous, 25 mL)
was added, and the solution was extracted with Et2O (3 × 25
mL), dried (MgSO4), filtered, and evaporated. Flash chroma-
tography (EtOAc 10% /hexane) afforded 10 (442 mg, 51%): 1H
NMR (500 MHz, CDCl3) δ 0.87 (d, J ) 6.4 Hz, 3 H), 0.88-0.99
(m, 2 H), 1.18 (s, 3 H), 1.30 (s, 3 H), 1.47-1.50 (m, 1 H), 1.66
(d, J ) 7.25 Hz, 3 H), 1.68-1.70 (m, 2 H), 1.82-1.87 (m, 2 H),
2.09-2.14 (dt, J ) 3.6, 10.4 Hz, 1 H), 4.90-4.96 (dt, J ) 4.4,
10.8 Hz, 1 H), 6.16 (quart, J ) 7.25 Hz, 1 H), 6.85 (s, 1 H),
7.12 (t, J ) 7.25 Hz, 1 H), 7.21-7.29 (m, 4 H), 7.46 (t, J ) 7.2
Hz, 2 H) 7.53 (t, 7.2 Hz, 1 H), 7.77 (app d, 7.2 Hz, 2 H); 13C
NMR (125 MHz, CDCl3) δ 14.9, 21.7, 23.3, 26.3, 29.3, 31.2,
34.3, 34.4, 39.4, 41.5, 50.5, 75.3, 124.7, 125.9, 127.3, 128.0,
128.5, 131.7, 133.7, 134.2, 152.1, 163.5, 165.1; IR (ATR) 3285-
3373, 1714, 1665 cm-1. Anal. Calcd for C27H33NO3: C, 77.29;
H, 7.97; N, 3.33. Found: C, 76.85; H, 7.65; N, 3.30. The
Z-alkene geometry was assumed by analogy with 12 (vide
infra).
cm-1 Anal. Calcd for C31H35NO3: C, 79.29; H, 7.51; N, 2.98.
.
Found: C, 78.43; H, 7.86; N, 2.89.Long-range carbon-
hydrogen decoupling experiments were employed to find the
three-bond C-H coupling constant between the ester carbonyl
carbon and the vinylic methine proton. The value obtained (3.8
Hz) points to the Z- alkene geometry in 12.34 [The fully proton-
coupled ester carbonyl exhibited a triplet (J 1,3 ) 3-4 Hz).
Decoupling the vinylic proton, produced a doublet (J 1,3 ) 3.1
Hz) for this carbon. Similarly, decoupling the 1′-cyclohexyl
proton, also led to a doublet (J 1,3 ) 3.8 Hz)].
Gen er a l P r oced u r e B. (1′R,2′S,5′R)-8′-P h en ylm en th yl
N-Ben zoyl-L-r-vin ylp h en yla la n in a te (13). To a solution of
diisopropylamine (24 µL, 0.18 mmol) and HMPA (1 mL) in
THF at -78 °C was added n-butyllithium (0.15 mL, 1.3 M in
n-hexane). The resulting solution was stirred for 20 min at 0
°C and then cooled to -78 °C. Then 10 (70 mg, 0.17 mmol) in
THF (4 mL) at -78 °C was added via cannula, followed by
butyllithium (0.26 mL, 1.3 M in n-hexane). The resulting deep-
(()-tr a n s-2-(â-Na p h th yl)cycloh exyl N-Ben zoyl-(Z)-d e-
h yd r obu tyr in a te (11). From (()-trans-2-(â-naphthyl)-
(32) Comins, D. L.; Salvador, J . M. J . Org. Chem. 1993, 58, 4656-
4661.
(33) Winkle, M. R.; Lansinger, J . M.; Ronald, R. C. J . Chem. Soc.,
Chem. Commun. 1980, 87-88.
(34) Marshall, J . L. Carbon-Carbon and Carbon-Proton NMR
Couplings: Applications to Organic Stereochemistry and Conforma-
tional Analysis (Verlag Chemie International, 1983) pp 35-38.

2914 J . Org. Chem., Vol. 65, No. 10, 2000
Berkowitz et al.
red solution was stirred for 5 min at -78 °C. Benzyl bromide
(44 µL, 0.37 mmol) in THF (0.4 mL) at -78 °C was then added
via cannula. After TLC indicated completion of the reaction
[45 min in this case; eluent: 20% EtOAc/hexanes; Rf(10) )
0.5; Rf(13) ) 0.7], the reaction mixture was poured into Et2O
(20 mL) and NH4Cl (aq, 20 mL). After further extraction of
the reaction mixture with Et2O (3 × 10 mL), the combined
organics were dried (MgSO4), filtered, and evaporated. Flash
chromatography on silica gel (10% EtOAc/hexane) provided 13
and its γ-alkylation isomer in a 1:1 ratio (53.1 mg, 62% overall
yield, 74% de for 13). In this case, the vinylic methine protons
were resolved and could be integrated to obtain the dr. For
13: 1H NMR (500 MHz, CDCl3) δ 0.87-0.99 (d, J ) 6.4 Hz, 3
H), 0.94-1.07 (m, 2 H), 1.19 (s, 3 H), 1.30 (s, 3 H), 1.66-1.68
(m, 1 H), 1.77-1.80 (m, 1 H), 1.99-2.02 (m, 1 H), 2.05-2.11
(m, 1 H), 2.38-2.46 (m, 1 H), 2.74-2.70 (m, 1 H), 3.32 (d, J )
13.7 Hz, 1 H), 3.69 (d, J ) 13.7 Hz, 1 H), 4.91-4.96 (dt, J ) 4,
10.4 Hz, 1 H), 5.37 (d, J ) 17.3 Hz, 1 H), 5.30 (d, J ) 10.4 Hz,
1 H), 5.89-5.95 (dd, J ) 10.4, 17.3 Hz, 1 H), 6.88 (s, 1 H),
7.11-7.21 (m, 4 H), 7.26-7.28 (m, 5 H), 7.45-7.48 (m, 2 H),
7.52-7.53 (m, 2 H), 7.72 (d, J ) 8.1 Hz, 2 H); 13C NMR (125
MHz, CDCl3) δ 21.6, 24.2, 26.5, 27.3, 28.6, 31.4, 34.4, 39.3,
41.6, 50.0, 65.5, 78.5, 124.9, 125.4, 125.5, 126.9, 127.4, 128.0,
128.4, 130.5, 131.4, 131.7, 135.9, 136.6, 137.2, 152.0, 163.4,
170.7. Anal. Calcd for C34H39NO3: C, 80.12; H, 7.71; N, 2.75.
Found (with R/γ mixture): C, 79.78; H, 7.93; N, 2.60.
(1′R,2′S,5′R)-8′-P h en ylm en th yl N-Ben zoyl-L-r-vin ylleu ci-
n a te (14). From 10 (40 mg, 0.10 mmol) and isobutyl iodide
(24 µL, 0.21 mmol), following general procedure B, was
obtained 14 (29 mg, 64%, 94% de), after flash chromatography.
In this case, the dr was determined by integration of the vinylic
methine protons: [R]D -1.77 (c 1.2, CHCl3); 1H NMR (500
MHz, CDCl3) δ 0.85-0.91 (m, 9 H), 0.92-1.06 (m, 2 H), 1.21
(s, 3 H), 1.32 (s, 3 H), 1.39-1.47 (m, 2 H), 1.54-1.63 (m, 3 H),
1.80-1.84 (dd, J ) 6, 14.1 Hz, 1H), 2.01-2.07 (dt, J ) 3.2,
12.0 Hz, 1 H), 2.09-2.12 (m, 1 H), 2.41-2.45 (dd, J ) 6, 14.1
Hz, 1 H), 4.83-4.88 (dt, J ) 4.0, 10.4 Hz, 1 H), 5.19 (d, J )
10.4 Hz, 1 H), 5.22 (d, J ) 17.3 Hz, 1 H), 5.72-5.78 (dd, J )
10.4, 17.3 Hz, 1 H), 7.14 (s, 1 H), 7.13-7.29 (m, 5 H), 7.45 (t,
J ) 7.25 Hz, 2 H), 7.51 (t, J ) 7.25 Hz, 1 H), 7.80 (app d, J )
7.25 Hz, 2 H); 13C NMR (125 MHz, CDCl3) δ 21.7, 23.5, 23.8,
24.9, 25.2, 27.3, 29.1, 31.4, 34.4, 20.1, 41.3, 42.8, 49.9, 64.7,
78.4, 115.1, 125.4, 125.7, 126.9, 128.0, 128.5, 131.4, 135.0,
137.1, 150.5, 165.7, 172; IR (ATR) 3390-3400, 1700, 1617,
1559 cm-1. Anal. Calcd for C31H41NO3: C, 78.27; H, 8.68; N,
2.94. Found: C, 77.73; H, 8.22; N, 2.90.
(1′R,2′S,5′R)-8′-(â-Na p h th yl)m en th yl N-Ben zoyl-L-r-vi-
n ylp h en yla la n in a te (17). From 12 (100 mg, 0.21 mmol) and
benzyl bromide (55 µL, 0.64 mmol), following general proce-
dure B, was obtained 17 (83.1 mg, 70%, 82% de, the internal
vinylic proton for each diastereomer was resolved and could
be integrated.), as a 1:1 ratio of R- to γ-alkylation products
after flash chromatography (10% EtOAc/hexane). The R-alky-
lation product, 17 (first eluting) and the γ-alkylation product
isomer (second eluting) could be cleanly separated (baseline
resolution) by silica gel HPLC (gradient elution: 2% f 9%
EtOAc/hexane): 1H NMR (R-alkylation product; 500 MHz,
CDCl3) 0.81-0.84 (m, 2H), 0.86 (d, J ) 6.4 Hz, 3 H), 1.02-
1.09 (m, 2 H), 1.27 (s, 3 H), 1.33 (s, 3 H), 1.42-1.48 (m, 2 H),
2.03-2.05 (m, 1 H), 2.19-2.24 (dt, J ) 3.3, 10 Hz, 1 H), 3.20
(d, J ) 13.7 Hz, 1 H), 3.35 (d, J ) 13.7 Hz, 1 H), 4.90-4.95
(dt, J ) 4.1, 10.7 Hz, 1 H), 5.18 (d, J ) 17 Hz, 1 H), 5.20 (d,
10.5 Hz, 1 H), 5.74-5.79 (dd, 10.5, 17 Hz, 1 H), 6.73 (bs, 1 H)
6.91-6.93 (m, 2 H), 7.11-7.14 (m, 3 H), 7.38-7.50 (m, 5 H),
7.64-7.66 (m, 3 H), 7.74 (d, J ) 8 Hz, 2 H), 7.78-7.79 (m, 2
H); 13C NMR (125 MHz, CDCl3) δ 21.7, 25.5, 27.4, 28.2, 31.4,
34.5, 39.3, 40.2, 41.3, 49.6, 65.2, 78.4, 116.1, 123.3, 124.8, 125.3,
126.0, 126.8, 126.9, 127.4, 127.6, 127.9 (2 C), 128.5, 130.5,
131.5 (2 C), 133.3, 134.9, 135.7, 136.4, 148.4, 166.4, 170.7; IR
(ATR) 3200-3400, 1721, 1719, 1679, 1675 cm-1. Anal. Calcd
for C38H41NO3: C, 81.53; H, 7.39; N, 2.50. Found: C, 81.78;
H, 6.91; N, 2.15.
1H NMR (γ-alkylation product; 500 MHz, CDCl3) 0.87 (d, J
) 6.4 Hz, 3 H), 0.89-0.99 (m, 2 H), 1.21-1.24 (m, 2 H), 1.27
(s, 3 H), 1.41 (s, 3 H), 1.50-1.53 (m, 2 H), 1.68-1.71 (m, 1 H),
1.82-1.99 (m, 3 H), 2.18-2.23 (dt, J ) 3.4, 13 Hz, 1 H); 2.46-
2.49 (m, 2 H); 4.96-5.01 (dt, J ) 4.2, 10.6 Hz, 1 H), 6.03 (t, J
) 7.2 Hz, 1 H), 6.26 (bs, 1 H), 7.10-7.11 (m, 2 H), 7.16-7.19
(m, 1 H), 7.26-7.27 (m, 2 H), 7.37-7.44 (m, 3 H), 7.48-7.55
(m, 4 H), 7.62 (s, 1 H), 7.71 (d, J ) 8 Hz, 2 H), 7.74-7.75 (m,
2 H); 13C NMR (125 MHz, CDCl3) δ 21.7, 23.1, 26.4, 29.3, 30.4,
31.3, 33.9, 34.5, 39.6, 41.5, 50.2, 75.2, 122.9, 124.9, 125.0, 125.3,
125.9, 127.2, 127.3 (2 C), 127.9, 128.3 (2 C), 128.4 (2 C), 131.2,
131.6, 133.4, 135.1, 137.4, 141.3, 149.5, 163.3, 165.6.
(1′R,2′S,5′R)-8′-(â-Na p h th yl)m en th yl N-Ben zoyl-L-r-vi-
n ylleu cin a te (18). From 12 (250 mg, 0.53 mmol) and isobutyl
iodide (0.12 mL, 1.06 mmol), following general procedure B
was obtained 18 (228 mg, 81%, g96% de) after flash chroma-
1
tography (10% EtOAc/hexane): [R]D +8.10 (c 1.1, CHCl3); H
NMR (300 MHz, CDCl3) δ 0.83 (d, J ) 6.5 Hz, 3 H), 0.85 (d, J
) 6.5 Hz, 3 H), 0.89 (d, J ) 6 Hz, 3 H), 0.97-1.12 (m, 3 H),
1.31 (s, 3 H), 1.42 (s, 3 H), 1.44-1.62 (m, 4 H), 1.67-1.74 (dd,
J ) 6.4, 14 Hz, 1 H), 2.11-2.32 (m, 2 H), 2.25-2.32 (dd, J )
6.4 Hz, 14 Hz, 1 H), 4.88-4.96 (dt, J ) 4, 11 Hz, 1 H), 5.13 (d,
J ) 10.5 Hz, 1 H), 5.18 (d, J ) 17 Hz, 1 H), 5.65-5.75 (dd, J
) 10.5, 17 Hz, 1 H), 7.15 (s, 1 H), 7.39-7.57 (m, 6 H), 7.64 (br
s, 1 H), 7.70-7.23 (m, 1 H), 7.34-7.80 (m, 4 H); 13C NMR (75
MHz, CDCl3) δ 21.7, 23.4, 23.7, 24.8, 25.2, 27.4, 28.8, 31.4,
34.4, 40.2, 41.3, 42.2, 49.6, 64.5, 78.4, 115.1, 123.4, 124.8, 125.3,
125.9, 126.9, 127.3, 127.6, 127.9, 128.6, 131.4, 131.5, 133.3,
134.9, 136.9, 148.2, 165.7, 172.5; IR (ATR) 3300-3400, 1733,
1675, 1653 cm-1; MS (FAB,3-NBA) 526 (7, MH+), 355 (30), 281
(47), 146 (100). Anal. Calcd for C35H43NO3: C, 79.96; H, 8.24;
N, 2.66. Found: C, 79.82; H, 8.20; N, 2.58.
(()-tr a n s-(2-Na p h t h yl)cycloh exyl
N-Ben zoyl-r-vi-
n ylp h en yla la n in a te (15). From 11 (105 mg, 0.25 mmol) and
benzyl bromide (76 µL, 0.64 mmol), following general proce-
dure B, was obtained 15 (72.7 mg, 50%, 34% de), as a 3:2 ratio
of R- to γ-alkylation products after flash chromatography (10%
EtOAc/hexane). In this case, both the vinylic methylene and
the benzylic protons were resolved and could be integrated to
obtain the dr.
(()-tr a n s-(2-Na p h t h yl)cycloh exyl
N-Ben zoyl-r-vi-
n ylleu cin a te (16). From 11 (48.5 mg, 0.12 mmol) and isobutyl
iodide (29 µL, 0.26 mmol), following general procedure B, was
obtained 16 (22.1 mg, 52% based on recovered starting
material, 86% de), after flash chromatography. In this case,
the dr was obtained by integration of the vinylic methine
protons: [R]D +0.6 (c 1.2, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 0.69 (d, J ) 6.68 Hz, 3 H), 0.70 (d, J ) 6.68 Hz, 3 H), 1.34-
1.59 (m, 4 H), 1.61-2.05 (m, 5 H), 2.23-2.27 (m, 1 H), 2.35-
2.42 (dd, J ) 5.7, 14.0 Hz, 1 H), 2.85-2.94 (dt, J ) 3.5, 10.9
Hz, 1 H), 4.17 (d, J ) 10.2 Hz, 1 H), 4.56 (d, J ) 17 Hz, 1 H),
5.12-5.19 (m, 1 H), 5.22-5.30 (dd, J ) 10.2, 17 Hz, 1 H), 7.16
(s, 1 H), 7.29-7.35 (m, 1 H), 7.36-7.49 (m, 5 H), 7.58 (app s,
1 H), 7.66 (d, J ) 8.3 Hz, 2 H), 7.72-7.78 (m, 3 H); 13C NMR
(75 MHz, CDCl3) δ 22.7, 23.4, 24.6, 24.7, 25.6, 32.0, 34.0, 42.0,
50.0, 64.5, 78.5, 113.9, 125.3, 125.4, 125.9, 126.4, 126.7, 127.4,
128.0, 128.2, 128.4, 131.3, 132.4, 133.4, 134.8, 136.3, 139.9,
3′-(ter t-Bu tyld im eth ylsilyoxy)ben zyl Iod id e (26). To 3′-
(tert-butyldimethylsilyloxy) benzyl bromide (247 mg, 0.82
mmol) were added acetone (2 mL) and NaI (predried in vacuo
at 210 °C) (369 mg, 2.46 mmol), and this solution was stirred
in the dark for 96 h. The acetone was then evaporated, and
the residue was taken up in Et2O (20 mL) and extracted with
Na2S2O4 (3 × 15 mL), dried (MgSO4), and evaporated to give
26 (238 mg). The iodide was used directly in the next step,
without further purification. However, if desired, an analytical
sample could be obtained by SiO2 chromatography (hexane):
1H NMR (300 MHz, CDCl3) δ 0.19 (s, 6 H), 0.97 (s, 9 H), 4.37
(s, 2 H), 6.68-6.73 (m, 1 H), 6.83-6.85 (m, 1 H), 6.93-6.96
(m, 1 H), 7.09-7.16 (dt, J ) 3.5 Hz, 8 Hz, 1 H); 13C NMR (75
MHz, CDCl3) δ -4.44, 5.51, 18.1, 26.6, 119.6, 120.5, 121.6,
129.6, 140.5, 155.7; IR (ATR) 2929, 1276, 1169 cm-1; MS (FAB
3-NBA) 221 (87 M-I), 147 (100); HRMS (FAB 3-NBA) calcd
for C13H21OSiI (M - I) 221.1361, obsd 221.0857.
165.4, 172.4; IR (ATR) 3327-3407, 1700, 1635, 1559 cm-1
.
Anal. Calcd for C31H35NO5: C, 79.28; H, 7.51; N, 2.98. Found:
C, 79.27; H, 7.11; N, 2,88.

Synthesis of Higher R-Vinyl Amino Acids
J . Org. Chem., Vol. 65, No. 10, 2000 2915
(1′′R,2′′S,5′′R)-8′′-(â-Na p h th yl)m en th yl N-Ben zoyl-3′-O-
(ter t-bu tyldim eth ylsilyl)-L-r-vin yl-m-tyr osin ate (19a). From
12 (200 mg, 0.43 mmol) and 3′(tert-butyldimethylsilyloxy)-
benzyl iodide 26 (32.9 mg, 0.94 mmol) following general
procedure B, was obtained 19a (189.1 mg, 65%, 88% de, based
upon integration of the vinylic methine protons) as a 2:1 ratio
of R to γ after flash chromatography (10% EtOAc/hexane): 1H
NMR (R-product, 500 MHz, CDCl3) δ 0.18 (s, 6 H), 0.80-0.88
(m, 5 H), 0.90 (s, 9 H), 0.91-1.06 (m, 2 H), 1.33 (s, 3 H), 1.41
(s, 3 H), 1.50-1.56 (m, 1 H), 2.02-2.05 (m, 1 H), 2.16-2.23
(dt, J ) 1.3, 8.0 Hz, 1 H), 2.41 (t, J ) 7.4 Hz, 1 H), 3.15 (d, J
) 13.7 Hz, 1 H), 3.37 (d, J ) 13.7, 1 H), 4.89-4.95 (dt, J )
3.3, 7.4 Hz, 1 H), 5.18 (d, J ) 17.4 Hz, 1 H), 5.22 (d, J ) 11.1
Hz, 1 H), 5.75-5.81 (dd, J ) 11.1, 17.4 Hz, 1 H), 6.52-6.71
(m, 3 H), 6.79 (s, 1 H), 6.98-7.01 (t, J ) 7.6 Hz, 1 H), 7.38-
7.59 (m, 6 H), 7.62-7.66 (m, 1 H), 7.69-7.81 (m, 5 H); 13C NMR
(125 MHz, CDCl3) δ -4.5, 21.6, 25.6, 27.4, 28.4, 31.4, 33.8,
34.5, 39.4, 41.2, 41.6, 45.4, 49.7, 65.1, 78.4, 116.0, 118.5, 122.3,
123.2, 123.4, 123.5, 124.8, 125.0, 125.3, 125.9, 126.9, 127.2,
127.3, 127.9, 128.4, 128.5, 131.4, 131.5, 133.3, 134.8, 136.5,
benzaldehyde and then with 5%MeOH/ CH2Cl2 [1% NH4OH
(sat′d aq)]to elute 19e (164 mg, 74%, 94% de, as judged from
the vinylic methine integrals): [R]D +2.49 (c 1.00, CHCl3); 1H
NMR (500 MHz, CDCl3) δ 0.80-0.90 (m, 2 H), 0.88 (d, J ) 6.4
Hz,3 H), 1.22-1.40 (m, 2H), 1.32 (s, 3 H), 1.42 (s, 3 H), 1.32-
1.55 (m, 2 H), 1.77-1.82 (m, 1 H), 2.05-2.08 (m, 1 H), 2.14-
2.28 (m, 6H), 2.59-2.66 (m, 2 H), 4.92-4.97 (dt, J ) 4, 10.4
Hz, 1 H), 5.09 (d, J ) 10.8 Hz, 1 H), 5.17 (d, J ) 17.3 Hz, 1 H),
5.73-5.79 (dd, J ) 10.8, 17.3 Hz, 1 H), 7.39-7.45 (m, 5 H),
7.47-7.51 (m, 2 H), 7.56 (s, 1 H), 7.64(s, 1 H), 7.70 (d, J ) 8.8
Hz, 1H), 7.77 (d, J ) 6 Hz, 1 H), 7.79 (app d, J ) 8 Hz, 2 H);
13C NMR (125 MHz, CDCl3) δ 21.7, 25.6, 26.8, 27.3, 28.4, 31.3,
31.9, 34.4, 20.2,41.3, 41.3, 49.5, 64.4, 77.8, 115.3, 123.4, 124.8,
125.2, 125.8, 127.0, 127.2, 127.5,127.9, 128.4, 131.4, 131.5,
133.3, 134.7, 135.8, 148.3, 165.9, 171.8; IR (ATR) 3300, 3400,
1725, 1665, 1599 cm-1. Anal. Calcd for C34H42N2O3: C, 77.53;
H, 8.03; N, 5.31. Found: C, 77.13; H, 8.33; N, 5.17.
r-(1′R,2′S,5′R)-8-(â-Na p h th yl)m en th yl â-Eth yl N-Ben -
zoyl-L-r-vin yla sp a r ta te (19 g). From 12 (200 mg, 0.43 mmol)
and ethyl bromoacetate (100 µL, 852 µmol) following general
procedure B was obtained 19g (110 mg, g96% de) and the
corresponding γ-alkyation product 27 (54.6 mg) for a 70% total
yield (2:1 ratio of of R- to γ-alkylation products) after flash
chromatography (10% EtOAc, hexane). For 19g: [R]D -4.0 (c
0.5, CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.79-0.84 (m, 1 H),
0.87 (d, J ) 6 Hz, 3 H),0.90-0.97 (q, J ) 12 Hz, 1 H), 1.03-
1.06 (m, 1 H), 1.17-1.20 (t, J ) 7 Hz, 3 H), 1.32(s, 3 H), 1.42
(s, 3 H), 1.44-1.58 (m, 3 H), 2.13-2.19 (m, 2 H), 2.82 (d, J )
17 Hz, 1H), 3.52 (d, J ) 17 Hz, 1 H), 3.99-4.09 (m, 2 H), 4.95-
5.00 (dt, J ) 4, 10.5 Hz, 1 H),5.12-5.15 (dd, J ) 1, 10.5 Hz, 1
H), 5.23-5.26 (dd, J ) 1, 17 Hz, 1 H), 5.54-5.60 (dd, J ) 10.5,
17 Hz, 1 H), 7.40-7.45 (m, 4 H), 7.47-7.50 (m, 2 H), 7.58 (br
s, 1 H), 7.65 (br s, 1 H), 7.76-7.79 (m, 3 H), 7.78 (app d, J )
8 Hz, 2 H); 13C NMR (125 MHz, CDCl3) δ 14.1, 21.7, 25.5, 27.4,
28.6, 31.3, 34.5, 38.3, 40.3, 41.0, 49.6, 60.6, 62.0, 78.4, 116.7,-
123.5, 124.8, 125.4, 125.9, 127.0, 127.3, 127.6, 127.9, 128.5,
131.5, 131.6, 133.4, 134.0, 134.6, 148.2, 165.8, 170.2, 170.6;
IR (ATR) 3310-3400, 1733, 1670, 1653 cm-1; MS (FAB 3-NBA)
556 (5 MH+) 281 (42) 147 (100); HRMS (FAB 3-NBA) calcd
for C35H41NO5 (MH+) 556.3063, obsd 556.3059.
r-(1′R,2′S,5′R)-8′-(â-Na p h th yl)m en th yl δ-Eth yl N-Ben -
zoyld eh yd r oh om oglu ta m a te (27): [R]D +0.8 (c 0.7, CHCl3);
1H NMR (500 MHz, CDCl3) δ 0.87 (d, J ) 6 Hz, 3 H), 0.89-
1.02 (m, 2 H), 1.17-1.21 (m, 1 H), 1.24 (t, J ) 7.5 Hz, 3 H),
1.26 (s, 3 H), 1.42 (s, 3 H), 1.46-1.52 (m, 1 H), 1.68-1.70 (m,
1 H), 1.76-1.82 (m, 1 H), 1.86-1.91 (m, 2 H), 1.93-1.97 (m, 1
H), 2.05-2.24 (m, 3 H), 4.09-4.13 (q, J ) 7 Hz, 2 H), 4.95-
5.00 (dt, J ) 4, 10.5 Hz, 1 H), 5.70 (t, J ) 7.5 Hz, 1 H), 6.98 (s,
1 H), 7.37-7.42 (m, 2 H), 7.44 (t, J ) 8.0 Hz, 2 H), 7.50-7.53
(m, 2 H), 7.64-7.67 (m, 3 H), 7.72 (d, J ) 5.6 Hz, 1 H), 7.76
(d, J ) 9 Hz, 2 H); 13C NMR (125 MHz, CDCl3) δ 14.2, 21.7,
23.3, 23.4, 26.5, 29.2, 31.3, 32.1, 34.6, 39.7, 41.5, 50.2, 60.5,
75.5, 123.0, 125.0, 125.3, 125.9, 126.4, 127.2, 127.3, 127.3,
127.9, 128.4, 131.2, 131.7, 133.5, 134.0, 134.8, 149.6, 163.2,
172.6, 173.0; IR (ATR) 3320-3415, 1731, 1678 cm-1; MS (FAB
3-NBA) 556 (32 MH+) 221 (50), 147 (100); HRMS (FAB 3-NBA)
calcd for C35H41NO5 (MH+) 556.2985, obsd 556.3061.
(1′R,2′S,5′R)-8′-(â-Na p h th yl)m en th yl N-Ben zoyl-L-r-vi-
n ylva lin a te (19h ). From 12 (200 mg, 0.43 mmol) and isopro-
pyl iodide (0.11 mL, 1.06 mmol) following general procedure
B was obtained 19h (218 mg, 66%, g96% de) after flash
chromatography (10% EtOAc/hexane): [R]D -5.9 (c 1.0, CHCl3);
1H NMR (500 MHz, CDCl3) δ 0.56 (d, J ) 7 Hz, 3 H), 0.81 (d,
J ) 7 Hz, 3 H), 0.84-0.97 (m, 2 H), 0.89 (d, J ) 6 Hz, 3 H),
1.09-1.12 (m, 1 H), 1.28 (s, 3 H), 1.42-1.51 (m, 1 H), 1.45 (s,
3 H), 1.56-1.61 (m, 3 H), 2.19-2.24 (m, 2 H), 4.83-4.88 (dt,
J ) 4, 10.5 Hz, 1 H), 4.96-5.00 (dd, J ) 1, 17 Hz, 1 H), 5.09-
5.12 (dd, J ) 1, 10.5 Hz, 1 H), 5.92 (s, 1 H), 6.06-6.12 (dd, J
) 10.5, 17 Hz, 1 H), 7.41-7.45 (m, 3 H), 7.49 (t, J ) 22 Hz, 2
H), 7.55-7.59 (m, 2 H), 7.66 (br s, 1 H), 7.70-7.73 (m, 3 H),
7.74-7.76 (m, 1 H); 13C NMR (125 MHz, CDCl3) d 16.4, 17.5,
21.8, 26.6, 27.2, 27.3, 31.4, 33.6, 34.7, 40.0, 41.3, 49.1, 66.9,
77.6, 115.2, 123.1, 124.9, 125.2, 125.8, 127.0, 127.1, 127.2,
127.9, 128.5, 131.3, 131.4, 132.0, 133.4, 135.0, 149.2, 166.0,
177.3; IR (ATR) 3210-3380, 1733, 1675, 1652 cm-1; (FAB
148.4, 166.1, 170.8; IR (ATR) 3300-3400, 1684, 1652 cm-1
.
Anal. Calcd for C44H55NO4Si: C, 76.59; H, 8.03; N, 2.02.
Found: C, 76.29; H, 8.20; N, 1.93.
(1′R,2′S,5′R)-8′-(â-Na p h th yl)m en th yl N-Ben zoyl-L-r-vi-
n ylbu tyr in a te (19c). From 12 (100 mg, 0.21 mmol) and ethyl
iodide (25 µL, 0.30 mmol), following general procedure B, was
obtained 19c (69.9 mg, 66%, g96% de), as a 12:1 ratio of R- to
γ-alkylation products after flash chromatography (10% EtOAc/
hexane): [R]D +4.08 (c 0.9, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 0.76 (t, J ) 7 Hz, 3 H), 0.77-0.86 (m, 1 H), 0.88 (d, J ) 6
Hz, 3 H), 0.97-1.10 (m, 2 H), 1.33 (s, 3 H), 1.41 (s, 3 H), 1.42-
1.58 (m, 3 H), 1.86-1.93 (m, 1 H), 2.04-2.15 (m, 2 H), 2.41-
2.48 (m, 1 H), 4.91-5.00 (dt, J ) 4, 10.5 Hz, 1 H), 5.11 (d, J )
10.5 Hz, 1 H), 5.20 (d, J ) 17 Hz, 1 H), 5.68-5.77 (dd, J )
10.5, 17 Hz, 1 H), 7.03 (s, 1 H), 7.39-7.57 (m, 7 H), 7.63-7.66
(m, 1 H), 7.67-7.74 (m, 1 H), 7.75-7.82 (m, 3 H); 13C NMR
(75 MHz, CDCl3) δ 7.9, 21.7, 25.2, 27.3, 27.5, 29.0, 31.4, 34.4,
40.3, 41.4, 49.6, 66.4, 77.9, 115.5, 123.4, 124.8, 125.3, 125.9,
126.9, 127.2, 127.3, 127.5, 127.9, 128.5, 131.5, 133.3, 134.8,
135.8, 148.1, 165.6, 172.1; IR (ATR) 3220-3400, 1717, 1674,
1669 cm-1. Anal. Calcd for C33H39NO3: C, 79.64; H, 7.89; N,
2.81. Found: C, 79.24; H, 7.60, N, 2.82.
(1′′R,2′′S,5′′R)-8′′-(â-Na p h th yl)m en th yl N-Ben zoyl-L-r-
(4′-ch lor o)bu tyl-r-vin ylglycin a te (19d ). From 12 (200 mg,
0.43 mmol) and 1-chloro-4-iodobutane (0.16 mL, 1.27 mmol)
following general procedure B was obtained 19d (170 mg, 72%,
90% de, as judged from the vinylic methine integrals), after
flash chromatography (10% EtOAc/hexane): [R]D +8.55 (c 0.5,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.82-0.86 (m, 1 H), 0.88
(d, J ) 6 Hz, 3 H), 1.04-1.13 (m, 2 H), 1.22-1.33 (m, 3 H),
1.31 (s, 3 H), 1.40 (s, 3 H), 1.42-1.58 (m, 2 H), 1.66-1.74 (m,
2 H), 1.79-1.85 (dt, J ) 4.8, 13 Hz, 1 H), 2 0.07-2.10 (m, 1
H), 2.15-2.21 (dt, J ) 3.6, 12.4 Hz, 1 H), 2.39-2.44 (dt, J )
4, 12.8 Hz, 1 H), 3.40-3.45 (m, 1 H), 3.48-3.53 (m, 1 H), 4.93-
4.98 (dt, J ) 4, 10.4 Hz, 1 H), 5.09 (d, J ) 10.4 Hz, 1 H), 5.19
(d, J ) 17 Hz, 1 H), 5.58-5.64 (dd, J ) 10.4, 17 Hz, 1 H), 7.13
(s, 1 H), 7.40-7.53 (m, 7 H), 7.63-7.64 (m, 1 H), 7.72-7.79
(m, 4 H); 13C NMR (125 MHz, CDCl3) δ 21.1, 21.7, 25.6, 27.4,
28.5, 31.4, 32.2, 33.2, 34.3, 40.2, 41.4, 44.8, 49.5, 64.8, 78.2,
115.7, 123.4, 124.8, 125.3, 125.9, 126.9, 127.0, 127.3, 127.5,
127.8, 128.6, 131.6, 133.3, 134.3, 135.7, 148.1, 165.7, 171.9;
IR (ATR) 3310-3418, 1717, 1653 cm-1. Anal. Calcd for C35H42
-
NO3Cl: C, 75.04; H, 7.55; N, 2.50. Found: C, 74.91; H, 7.25;
N, 2.35.
(1R,2′S,5′R)-8′-(â -Na p h t h yl)m en t h yl N-Ben zoyl-L-r-
vin ylor n ith in a te (19e). From 12 (200 mg, 0.43 mmol) and
1-benzaldimino-3-iodopropane31 (255 mg, 0.94 mmol), general
procedure B was followed as before. However, in this case the
crude product mixture was taken up in THF (4 mL) and 3 N
HCl (4 mL) and was allowed to stir at 25 °C for 14 h (to remove
the benzylidene side chain protecting group). A solution of 1
N Na2CO3(15 mL) was then added, and the resulting mixture
was extracted with Et2O (3 × 20 mL). The combined organics
were dried (MgSO4), filtered, and evaporated. Chromatography
was then carried out initially with 20% EtOAc/Hex to remove

2916 J . Org. Chem., Vol. 65, No. 10, 2000
Berkowitz et al.
3-NBA) 512 (26, MH+), 401 (14), 248 (100), 147 (57). Anal.Calcd
for C34H41NO3: C, 79.80; H, 8.07; N, 2.73. Found: C, 79.92;
H, 8.17; N, 2.61.
) 7.04 Hz, 2 H), 7.52 (t, J ) 7.26 Hz, 1H), 7.71 (d, J ) 8.0 Hz,
2 H); 13C NMR (125 MHz, CD3OD) δ 41.9, 66.6, 115.8, 118.3,
122.6, 128.0, 128.1, 129.6, 130.0, 132.7, 136.0, 138.3, 138.6,
158.2, 169.4, 174.6; IR (ATR) 3489, 1700, 1684, 1559 cm-1; MS
(FAB 3-NBA + Na+) 334 (33, M + Na+), 322 (50), 172 (100);
HRMS (FAB 3-NBA + Na+) calcd for C18H17NO4Na (M + Na+)
334.1055, obsd 334.1051.
(1′R,2′S,5′R)-8′-(â-Na p h th yl)m en th yl N-Ben zoyl-L-r-vi-
n yln or va lin a te (19i). From 12 (200 mg, 0.43 mmol) and
1-iodopropane (91 µL, 0.94 mmol) following general procedure
B was obtained 19i [108 mg, 50%, (58% based on recovered
starting material), g96% de] after flash chromatography as a
3:1 mixture of R/γ alkylation products: 1H NMR (500 MHz,
CDCl3) δ 0.89-0.92 (m, 4 H), 0.88 (s, 3 H), 0.96-1.08 (m, 2
H), 1.16-1.30 (m, 2 H), 1.32 (s, 3 H), 1.42 (s, 3 H), 1.43-1.58
(m, 3 H), 1.78-1.84 (dt, J ) 4.4, 13.3 Hz, 1 H), 2.04-2.07 (m,
1 H), 2.13-2.18 (dt, J ) 4, 13 Hz, 1 H), 2.35-2.41 (dt, J ) 4,
13 Hz, 1H), 4.93-5.00 (dt, J ) 4.4, 10.4 Hz, 1 H), 5.09 (d, J )
10.4, 1 H), 5.19, (d, J ) 17.3, 1 H), 5.69-5.75 (dd, J ) 10.4,
17.3, 1 H), 7.00 (s, 1 H), 7.40-7.56 (m, 7 H), 7.63 (app s, 1 H),
7.73-7.79 (m, 4 H); 13C NMR (125 MHz, CDCl3) δ 13.9, 17.1,
21.7, 25.2, 27.3, 28.9, 31.3, 34.4, 36.5, 41.3, 49.6, 50.2, 64.9,
77.9, 115.3, 123.4, 124.8, 125.3, 126.9, 127.3, 127.5, 127.9,
128.4, 128.5, 131.4, 131.5, 133.3, 134.9, 136.0, 148.1, 165.6,
172.1; IR (ATR) 3300-3400, 1684, 1652 cm-1. Anal. Calcd for
N-Ben zoyl-L-r-vin ylleu cin e (20b). From 18 (200 mg, 0.38
mmol) following general procedure C, was obtained 20b (73.5
mg, 74%) and 28 (98.6 mg, 92%): [R]D (g96% ee) -9.5 (c 0.6,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.90 (d, J ) 7 Hz, 3 H),
0.93 (d, J ) 7 Hz, 3 H), 1.71 (m, 1 H), 2.00-2.07 (dd, J ) 7.5,
14 Hz, 1 H), 2.54-2.61 (dd, J ) 5.5, 14 Hz, 1 H), 5.27 (d, J )
10.5 Hz, 1 H), 5.29 (d, J ) 17 Hz, 1 H), 6.06-6.16 (dd, J )
10.5, 17 Hz, 1 H), 7.60 (s, 1 H), 7.42-7.47 (m, 2 H), 7.50-7.53
(m, 1 H), 7.80 (app d, J ) 8 Hz, 2 H); 13C NMR (125 MHz,
CDCl3) δ 22.8, 23.8, 24.7, 43.2, 64.5, 115.6, 127.0, 128.7, 131.9,
134.2, 136.9, 166.6, 176.6; IR (ATR) 3294-3356, 1726, 1696,
1656 cm-1; MS (EI) 261 (0.41 M+) 203 (13) 105 (100); HRMS
(EI) calcd for C15H19NO3 (M+) 261.1365, obsd 261.13581.
N-Ben zoyl-L-r-vin yllysin e (20d ). From 25d (115 mg, 0.21
mmol) following general procedure C, were obtained 20d (45.5
mg, 78%) and 28 (52.1 mg, 87%). For purification, the solution
was acidified with 10% HCl (15 mL), extracted with Et2O (3
× 15 mL), dried (MgSO4), filtered, and evaporated to yield 20d .
After evaporation of the aqueous layer with mild heating (t
e50 °C), the residue was applied to a Dowex 50 × 8 ion-
exchange column. After the column was washed with several
volumes of H2O, elution with 1.3 M NH4OH afforded 20d : [R]D
(92% ee) +12.6 (c 1.2, D2O); 1H NMR (500 MHz, D2O) δ 1.27-
1.31 (m, 1 H); 1.35-1.40 (m, 1 H), 1.67-1.72 (m, 2 H), 2.09-
2.15 (dt, J ) 4.3, 12.9 Hz, 1 H), 2.38-2.44 (dt, J ) 4.3, 12.9
Hz, 1 H), 2.98 (appt. t, J ) 7.2 Hz, 2 H), 5.22 (d, J ) 10.8 Hz,
1 H), 5.24 (d, J ) 17.3 Hz, 1 H), 6.11-6.17 (dd, J ) 10.8, 17.3
Hz, 1 H), 7.56-7.59 (m, 2 H), 7.64-7.67 (m, 1 H), 7.83-7.84
(m, 2 H); 13C NMR (125 MHz, D2O) δ 21.7, 27.5, 34.4, 40.0,
67.4, 114.5, 127.6, 129.7, 133.0, 134.8, 139.2, 169.5, 178.3; MS
(FAB 3-NBA + Na+) 299 (100, M + Na+) 254 (13), 154 (9);
HRMS (FAB 3-NBA) calcd for C15H20N2Na (M + Na+) 299.1372,
obsd 299.1365.
C
34H41NO3: C, 79.80; H, 8.076; N, 2.74. Found: C, 79.79; H,
7.82; N, 2.52.
(1′′R,2′′S,5′′R)-8′′-(â-Na p h th yl)m en th yl N-Ben zoyl-L-r-
(3′-tr im eth ylsilyl)p r op a r gyl-r-vin ylglycin a te (19j). From
12 (100 mg, 0.21 mmol) and 3-bromo-1(trimethylsilyl)-1-
propyne (60.2 µL, 0.15 mmol) following general procedure B
was obtained 19j (76.5 mg, 70%, 94% de, as judged from the
vinylic methine integrals) as a 4:1 ratio of R/γ after flash
chromatography (10% EtOAc/Hex): 1H NMR (R-alkylation
product, 500 MHz, CDCl3) δ 0.42 (s, 9 H), 0.87 (d, J ) 6 Hz, 3
H), 1.03-1.14 (m, 1 H), 1.32 (s, 3 H), 1.39 (s, 3 H), 1.41-1.55
(m, 3 H), 2.14-2.20 (m, 2 H), 2.81 (d, J ) 17 Hz, 1 H), 3.42 (d,
J ) 17 Hz, 1 H), 4.9-5.0 (dt, J ) 4, 10.4 Hz, 1 H), 5.09 (d, J
) 10 Hz, 1 H), 5.24 (d, J ) 17 Hz, 1 H), 5.46-5.51 (dd, J )
10.4, 17.7 Hz, 1 H), 7.29 (s, 1 H), 7.41-7.52 (m, 6 H), 7.62
(app s, 1 H), 7.75-7.80 (m, 5 H); 13C NMR (125 MHz, CDCl3)
δ -0.061, 21.7, 21.8, 25.3, 26.2, 27.3, 28.8, 31.4, 34.4, 40.2,
41.1, 49.5, 50.2, 63.8, 78.4, 88.1, 101.1, 117.0, 123.4, 125.3,
125.4, 125.9, 127.0, 127.2, 127.3, 127.6, 127.8, 128.5, 131.5,
131.5, 134.0, 148.0, 166.1, 170.5; IR (ATR) 3340-3401, 2178,
1724, 1674 cm-1. Anal. Calcd for C37H43NO3Si: C, 76.90; H,
7.50; N, 2.42. Found: C, 77.06; H, 7.15; N, 2.05.
N-Ben zoyl-L-r-vin ylor n ith in e (20e). From 19e (139 mg,
0.26 mmol) following general procedure C was obtained 1.7:1
mixture of 20e (32.3 mg, 47%) and δ-lactam 29 (18.4 mg, 28%),
as well as 28 (69.8 mg, 94%). For purification, the solution
was acidified with 10% HCl (15 mL), extracted with Et2O (3
× 15 mL). The organics were dried (MgSO4), filtered, and
evaporated to yield auxiliary 28. The aqueous layer was then
extracted with EtOAc (3 × 15 mL), dried (MgSO4), filtered,
and evaporated to yield 29. After evaporation of the aqueous
layer with mild heating (T e 50 °C), the residue was applied
to a Dowex 50 × 8 ion-exchange column. After the column was
washed with several elutions of H2O, elution with 1.3 M NH4-
Gen er a l P r oced u r e C. N-Ben zoyl-L-r-vin ylb u t yr in e
(20c). KOtBu (320 mg, 2.85 mmol), and H2O (13.6 µL, 0.76
mmol) were added to a solution of 19c (165 mg, 0.33 mmol) in
(3 mL) of 1,4-dioxane, and the resulting solution was heated
to 105 °C for 8 h. After cooling, 10% HCl (20 mL) was added,
and the solution was extracted with Et2O (3 × 10 mL). The
organic layer was extracted with NaHCO3 (satd aqueous, 10
mL). The aqueous layer is further extracted with Et2O (2 ×
10 mL). The combined organics were dried (MgSO4), filtered
and evaporated to yield recovered (1R,2S,5R)-8-(â-naphthyl)-
menthol (28, 86.3 mg, 90%). The H2O layer was acidified to
pH 2 with 6 N HCl and extracted with Et2O (3 × 10 mL). The
organic layer was dried (MgSO4), filtered, and evaporated to
yield 20c (48.5 mg, 62%): mp 168-170 °C [R]D (g96% ee)
-13.4 (c 0.9, CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.91-0.94
(t, J ) 14.5 Hz, 3 H), 2.14-2.21 (m, 1 H), 2.45-2.52 (m, 1 H),
5.30 (d, J ) 17.3 Hz, 1 H), 5.32 (d, J ) 10.1 Hz, 1 H), 6.11-
6.18 (dd, J ) 10.8, 17.3 Hz, 1 H), 6.97 (s, 1 H), 7.43 (t, J )
7.65 Hz, 2 H), 7.51 (t, J ) 7.26 Hz, 1 H), 7.80 (d, J ) 7.6 Hz,
2 H); 13C NMR (125 MHz, CDCl3) δ 8.2, 28.6, 77.2, 116.2, 127.1,
128.8, 132.0, 133.9, 136.2, 167.1, 174.8; IR (ATR) 3350-3440,
1750, 1652 cm-1; MS (FAB 3-NBA + Li+) 240 (M + Li+), 160
1
OH afforded 20e: [R]D (94% ee) +11.6 (c 1.5, D2O); H NMR
(500 MHz, D2O) δ 1.56-1.61 (m, 1 H), 1.66-1.71 (m, 1 H),
2.16-2.21 (dt, J ) 4.4, 12.7 Hz, 1 H), 2.42-2.49 (dt, J ) 4.4,
12.7 Hz, 1 H) 3.03 (appt. t, J ) 7.6 Hz, 2 H), 5.25 (d J ) 10.4
Hz, 1 H), 5.26 (d, J ) 17.3 Hz, 1 H), 6.12-6.18 (dd, J ) 10.4,
17.3 Hz, 1 H), 7.57 (t, J ) 7.7 Hz, 2 H), 7.66 (t, J ) 7.7 Hz, 1
H), 7.84 (app d, J ) 7.7 Hz, 2 H); 13C NMR (125 MHz, D2O) δ
23.0, 31.8, 41.1, 67.0, 114.9, 127.6, 129.7, 133.1, 134.7, 138.9,
169.7, 177.8; MS (FAB 3-NBA) 263 (29 MH+), 307 (100); HRMS
(FAB 3-NBA) calcd for C14H18N2O3 (MH+) 263.1395, obsd
263.1397.
For 29: [R]D -40.5 (c 0.6 CHCl3); 1H NMR (500 MHz, CDCl3)
δ 1.65-1.68 (m, 1 H), 1.86-1.89 (m, 1 H), 1.94-1.99 (m, 1 H),
2.82-2.34 (dt, J ) 4.03, 13.3 Hz, 1 H), 2.77-2.80 (m, 1 H),
3.31-3.34 (m, 1 H), 3.44-3.49 (dt, J ) 4.84, 11.2 Hz, 1 H),
5.35 (d, J ) 10.8 Hz, 1 H), 5.38 (d, J ) 17.3 Hz, 1 H), 6.01 (s,
1 H), 6.19-6.25 (dd, J ) 10.4, 17.3 Hz, 1 H), 7.39 (t, J ) 7.25
Hz, 2 H), 7.47 (t, J ) 7.25 Hz, 1 H), 7.78 (app d, J ) 7.25 Hz,
2 H); 13C NMR (125 MHz, CDCl3) δ 19.3, 30.7, 42.1, 61.1, 117.6,
127.0, 128.4, 131.5, 134.5, 137.3, 166.6, 171.5; IR (ATR) 3240-
3252, 1601, 1559 cm-1; MS (FAB 3-NBA) 245 (100 MH+), 207
(100), 136 (7); HRMS (FAB 3-NBA + Na+) calcd for C13H15
NO3Na (M + Na+) 256.0949, obsd 256.0952.
-
N-Ben zoyl-L-r-vin yl-m -tyr osin e (20a ). From 19a (298
mg, 0.43 mmol, mixture of R- to γ-alkylation products) follow-
ing general procedure C was obtained 20a (47.6 mg, 53%) and
28 (102 mg, 84%): mp 86-90 °C; [R]D (88% ee) +11.3 (c 1.8,
1
CD3OD); H NMR (500 MHz, CD3OD) δ 3.43 (d, J ) 13.3 Hz,
1 H), 3.53 (d, J ) 13.3 Hz, 1 H), 5.27 (d, J ) 10.8 Hz, 1 H),
5.32 (d, J ) 17.3 Hz, 1 H), 6.16-6.23 (dd, J ) 10.8, 17.3 Hz,
1 H), 6.61-6.64 (m, 3 H), 6.96-7.07 (m, 1 H), 7.40-7.45 (t, J
(44); HRMS (FAB 3-NBA) calcd for
245.12903, obsd 245.1286.
C
14H16N2O2 (MH+)

Synthesis of Higher R-Vinyl Amino Acids
J . Org. Chem., Vol. 65, No. 10, 2000 2917
Alternatively, a slight modification of general procedure C
was used. Namely, to 19e (65.6 mg, 0.12 mmol) were added
KOtBu (120 mg, 1.1 mmol), H2O (22 µL, 1.2 mmol), and 1,4-
dioxane (1.6 mL) and this solution was heated for 18 h at 105
°C. Purification was carried out as above (without EtOAc
extraction) to obtain 20e (22.6 mg, 69%) and 28 (31.6 mg, 90%).
N-Ben zoyl-L-r-vin ylp h en yla la n in e (20f). From 17 (156
mg, 0.28 mmol) (1:1 mixture of R to γ), following general
procedure C, were obtained 20f (32.6 mg, 80% from R) and 28
D2O) δ 3.15 (d, J ) 14.1 Hz, 1 H), 3.46 (d, J ) 14.1 Hz, 1 H),
5.43 (d, J ) 17.7 Hz, 1 H), 5.56 (d, J ) 10.8 Hz, 1 H), 6.19-
6.25 (dd, J ) 10.8, 17.7 Hz, 1 H), 6.78 (appt. s, 1 H), 6.71 (d,
J ) 7.65 Hz, 1 H), 6.89 (d, J ) 7.25 Hz, 1 H), 7.29 (t, J ) 8 Hz,
1 H); 13C NMR (125 MHz, D2O) δ 41.9, 65.7, 116.0, 117.9, 119.2,
123.2, 131.3, 133.9, 135.2, 156.6, 172.5; MS (FAB 3-NBA) 208
(100, M•+); HRMS (FAB 3-NBA) calcd for C11H14NO2 (M•+
208.0974, obsd 208.0966.
)
L-r-Vin ylleu cin e (21b). From 20b (70.0 mg, 0.27 mmol),
following general procedure D, was obtained 21b (40.4 mg,
96%): [R]D (g96% ee) +26.3 (c 1.1, H2O); 1H NMR (500 MHz,
D2O) δ 0.98 (d, J ) 6 Hz, 3 H), 1.02 (d, J ) 6 Hz, 3 H), 1.78
(m, 1 H), 1.83-1.87 (dd, J ) 4.8, 14.9 Hz, 1 H), 2.01-2.05 (dd,
J ) 7, 14 Hz, 1 H), 5.36 (d, J ) 17.7 Hz, 1 H), 5.42 (d, J ) 10.8
Hz, 1 H), 6.12-6.17 (dd, J ) 10.8, 17.7 Hz, 1 H); 13C NMR
(125 MHz, D2O) δ 23.0, 24.4, 45.0, 66.0, 116.5, 137.4, 175.5.
(FAB-glycerol) 158 (100, MH+), 112 (16), 93 (12); HRMS (FAB
glycerol) calcd for C8H15NO2 (MH+) 158.1181, obsd 158.1174.
L-r-Vin yllysin e (21d ). From 20d (32.5 mg, 0.12 mmol),
following general procedure D, was obtained 21d (14.5 mg,
71%): [R]D (92% ee) +13.6 (c 0.7 D2O); 1H NMR (500 MHz,
D2O) δ 1.31-1.38 (m, 1 H), 1.45-1.53 (m, 1 H), 1.71-1.79 (m,
3 H), 1.95-2.01 (m, 1 H), 3.05 (t, J ) 5.6 Hz, 2 H), 5.30 (d, J
) 10.8 Hz, 1 H), 5.32 (d, J ) 17.7 Hz, 1 H), 6.09-6.15 (dd, J
) 10.8, 17.7 Hz, 1 H) 13C NMR (500 MHz, D2O) δ 21.3, 27.8,
37.7, 40.0, 65.0, 115.2, 140.0, 179.2; MS (FAB glycerol) 173
(100, M•+), 115 (8); HRMS (FAB glycerol) calcd for C8H17N2O2
(M•+) 173.1290, obsd 173.1286.
1
(77.0 mg, 98%): [R]D (82% ee) +12.4 (c 1.3, CDCl3); H NMR
(500 MHz, CDCl3) δ 3.52 (d, 13.7 Hz, 1 H), 3.74 (d, J ) 13.7
Hz, 1 H), 5.34 (d, J ) 17 Hz, 1 H), 5.38 (d, J ) 10.4 Hz, 1 H),
6.17-6.23 (dd, J ) 10.4, 17 Hz, 1 H), 6.93 (s, 1 H), 7.17-7.19
(m, 2 H), 7.22-7.26 (m, 3 H), 7.40 (t, J ) 7.6 Hz, 2 H), 7.50 (t,
J ) 7.6 Hz, 1 H), 7.66 (app d, J ) 7.2 Hz, 2 H); 13C NMR (125
MHz, CDCl3) δ 40.4, 65.6, 116.8, 126.9, 127.2, 128.4, 128.7,
130.1, 131.9, 134.1, 135.2, 135.9, 167.4, 175.5; MS (EI) 295
(0.67, M+), 204 (11), 105 (100); HRMS (EI) calcd for C18H17
-
NO3 (M+) 295.1208, obsd 295.12099.
N-Ben zoyl-L-r-vin yla sp a r ta te (20 g). From 19g (90 mg,
0.16 mmol), following general procedure C, were obtained 20g
(30.7 mg, 72%) and 28 (39.8 mg, 87%): 1H NMR (300 MHz,
CD3OD) δ 3.27 (d, J ) 16.4 Hz, 1 H), 3.52 (d, J ) 16.4 Hz, 1
H), 5.24 (d, J ) 10 Hz, 1 H), 5.32 (d, J ) 17.3 Hz, 1 H), 6.11-
6.21 (dd, J ) 10, 17.3 Hz, 1 H), 7.45 (t, J ) 7.8 Hz, 2 H), 7.54
(t, J ) 7.3 Hz, 1 H), 7.79 (app d, J ) 7.3 Hz, 2 H); 13C NMR
(125 MHz, CD3OD) δ 40.2, 63.8, 116.1, 128.1, 129.6, 132.8,
135.9, 137.7, 168.7, 173.9; MS (FAB 3-NBA + Na+) 286 (M +
Na+, 25), 413 (100); HRMS (FAB 3-NBA + Na+) calcd for
L-r-Vin ylor n ith in e (21e). From 20e (30.1 mg, 0.11 mmol),
C
13H13NO5Na (M + Na+) 286.0691, obsd 286.0686.
N-Ben zoyl-L-r-vin ylva lin e (20h ). From 19h (112 mg, 0.22
following general procedure D, was obtained 21e (17.7 mg,
1
96%): [R]D (94% ee) +18.8 (c 0.8, H2O); H NMR (500 MHz,
mmol), following general procedure C, were obtained 20h (40.9
mg, 76%) and 28 (49.5 mg, 80%): [R]D (g 96% ee) -4.9 (c 0.9,
CDCl3); 1H NMR (500 MHz, CDCl3) δ 1.03 (d, J ) 6 Hz, 3 H),
1.04 (d, J ) 6 Hz, 3 H), 2.51 (app h, J ) 7 Hz, 1 H), 5.20 (d, J
) 17 Hz, 1 H), 5.33 (d, J ) 10.5 Hz, 1 H), 6.29-6.35 (dd, J )
10.5, 17 Hz, 1 H), 6.62 (s, 1 H), 7.43-7.46 (t, J ) 7.25 Hz, 2
H), 7.51-7.54 (t, J ) 7.25 Hz, 1 H), 7.78-7.80 (app d, J )
7.25 Hz, 2 H); 13C NMR (125 MHz, CDCl3) δ 17.1, 17.5, 34.5,
67.9, 115.8, 127.1, 128.8, 132.1, 133.6, 133.8, 167.7, 174.6; MS
D2O) δ 1.56-1.62 (m, 1 H), 1.66-1.74 (m, 2 H), 1.88-1.95 (m,
2 H), 2.97 (appt. t, J ) 17.7 Hz, 2 H), 5.22 (d, J ) 10.8 Hz, 1
H), 5.25 (d, J ) 17.7 Hz, 1 H), 6.03-6.08 (dd, J ) 10.8, 17.7
Hz, 1 H); 13C NMR (125 MHz, D2O) δ 22.9, 35.4, 40.2, 64.4,
115.0, 140.4, 179.6; MS (FAB 3- NBA) 159 (100 M•+), HRMS
(FAB 3-NBA) calcd for C7H15N2O2 (M•+) 159.1133, obsd
159.1139.
21e (6.0 mg, 83%) was also obtained from 29 (11.1 mg, 0.05
mmol) following a slight modification of general procedure D,
in which the reaction was done in a pressure vessel for 10 h
at 105 °C.
(EI) 203 (3.9 M+-CO2), 105 (100); HRMS (EI) calcd for C14H17
-
NO3 (M+) 247.1208, obsd 203.12992 (M+- CO2).
N-Ben zoyl-L-r-vin yln or va lin e (20i). From 19i (83.0 mg,
0.16 mmol), following general procedure C, were obtained 20i
(31.5 mg, 78%) and 28 (32.6 mg, 72%): mp 91-94 °C; [R]D (g
96% ee) -10.2 (c 0.6, CHCl3); 1H NMR (500 MHz, CDCl3) δ
0.91-0.94 (t, J ) 7.25 Hz, 3 H), 1.19-1.26 (m, 1 H), 1.32-
1.41 (m, 1 H), 2.05-2.11 (dt, J ) 4.8, 13.7 Hz, 1 H), 2.46-2.52
(dt, J ) 4.4, 13.3 Hz, 1 H), 5.28 (d, J ) 10.4 Hz, 1 H), 5.31 (d,
J ) 17.3 Hz, 1 H), 6.10-6.16 (dd, J ) 10.4, 17.3 Hz, 1 H), 7.14
(s, 1 H), 7.42-7.45 (t, J ) 7.6 Hz, 2 H), 7.50-7.53 (t, J ) 7.2
Hz, 1 H), 7.79-7.81 (d, 8.8 Hz, 2 H); 13C NMR (125 MHz,
CDCl3) _ 13.9, 17.3, 37.2, 65.0, 115.8, 127.0, 128.7, 131.9, 134.1,
136.3, 166.8, 175.9. IR (ATR) 3313-3394, 1751, 1696, 1554
cm-1; MS (FAB 3-NBA + Na+) 270 (8,M + Na+), 207 (43), 105
(100); HRMS (FAB 3-NBA + Na+) calcd for C14H17NO3Na (M
+ Na+) 270.1105, obsd 270.1097.
Gen er a l P r oced u r e D. L-r-Vin ylbu tyr in e (21c). A sus-
pension of 20c (34.6 mg, 0.15 mmol) in 6 N HCl (1.11 mL)
was heated at a reflux for 4 h. After extraction with CH2Cl2
(3 × 10 mL), the aqueous layer was evaporated in vacuo with
mild heating (T e 50 °C). The residue was applied to a Dowex
50 × 8 ion-exchange column. After the column was washed
with several elutions of H2O, elution with 1.3 M NH4OH
afforded 21c (12.1 mg, 63%): mp 168-170 °C (g96% ee); [R]D
+30.2 (c 0.6, H2O); 1H NMR (500 MHz, D2O) δ 1.00 (t, J )
7.25 Hz, 3 H), 1.91-1.96 (m, 1 H), 2.08-2.13 (m, 1 H), 5.37
(d, J ) 17.7 Hz, 1 H), 5.45 (d, J ) 11.3 Hz, 1 H), 6.09-6.15
(dd, J ) 11.3, 17.7 Hz, 1 H); 13C NMR (125 MHz, D2O) δ 8.0,
29.6, 66.9, 117.4, 136.3, 175.3; (FAB-glycerol) 130 (19, MH+),
185 (100); HRMS (FAB glycerol) calcd for C6H11NO2 (MH+)
130.0868 obsd 130.0865.
L-r-Vin ylp h en yla la n in e (21f). From 20f (42.5 mg, 0.14
mmol), following general procedure D, 21f was obtained (18.5
mg, 85%): mp 212-214 °C; [R]D (82% ee) +13.1 (c 0.8, MeOH);
1H NMR (500 MHz, D2O) δ 3.09 (d, J ) 14.1 Hz, 1 H), 3.42 (d,
J ) 14.1 Hz, 1 H), 5.31 (d, J ) 17.7 Hz, 1 H), 5.42 (d, J ) 10.8
Hz, 1 H), 6.16-6.22 (dd, J ) 10.8, 17.7 Hz, 1 H), 7.27-7.29
(m, 2 H), 7.36-7.41 (m, 3 H); 13C NMR (125 MHz, D2O) δ 42.0,
66.8, 117.3, 128.6, 129.6, 130.8, 134.2, 135.8, 174.3; MS (FAB
3-NBA) 192 (100 M+) 146 (33); HRMS (FAB 3-NBA) calcd for
C
11H14NO2 (M+) 192.1024, obsd 192.1023.
L-r-Vin yla sp a r ta te (21 g). From 20g (30.0 mg, 0.11 mmol),
following general procedure D, was obtained 20g (21.9 mg,
98%): [R]D (g96% ee) +37.5 (c 0.9, H2O); 1H NMR (500 MHz,
D2O) δ 3.09 (d, J ) 18 Hz, 1 H), 3.38 (d, J ) 18 Hz, 1 H), 5.56
(d, J ) 17.7 Hz, 1 H), 5.59 (d, J ) 10.8 Hz, 1 H), 6.05-6.11
(dd, J ) 10.8, 17.7 Hz, 1 H); 13C NMR (125 MHz, D2O) δ 39.6,
62.9, 120.2, 133.3, 172.8, 174.1; MS (FAB-glycerol) 160 (100,
MH+), 158 (55), 130 (31), 115 (32); HRMS (FAB glycerol) calcd
for C6H9NO4 (MH+) 160.0609, obsd 160.0605.
L-r-Vin ylva lin e (21h ). From 20h (16.6 mg, 0.07 mmol),
following general procedure D, was obtained 20h (11.1 mg,
97%): [R]D (g96% ee) +30.7 (c 0.6, D2O); 1H NMR δ (500 MHz,
D2O) δ 0.95 (d, J ) 7.25 Hz, 3 H), 0.96 (d, J ) 7.25 Hz, 3 H),
2.39-2.41 (h, J ) 7.25 Hz, 1 H), 5.31 (d, J ) 17.7 Hz, 1 H)
5.46 (d, J ) 11.2 Hz, 1 H), 6.14-6.17 (dd, J ) 11.2, 17.3 Hz,
1 H); 13C NMR (125 MHz, D2O) δ 16.2, 17.1, 33.8, 70.5, 116.5,
136.3, 175.0; MS (FAB glycerol) 144 (100, MH+), 115 (13);
HRMS (FAB glycerol) calcd for C7H13NO2 (MH+) 144.10243,
obsd 144.1023.
(1′′R,2′′S,5′′R)-8′′-(â-Na p h th yl)m en th yl N-Ben zoyl-L-r-
(4′-iod o)bu tyl-r-vin ylglycin a te (22d ). To a solution of 19d
(400 mg, 0.71 mmol) in acetone (9.7 mL) was added NaI (dried
prior to use, 200 °C in vacuo) (429 mg, 2.85 mmol), and the
L-r-Vin yl-m -tyr osin e (21a ). From 20a (37.6 mg, 0.12
mmol), following general procedure D, was obtained 21a (24.0
mg, 83%): [R]D (88% ee) +7.9 (c 1.2 D2O); 1H NMR (500 MHz,

2918 J . Org. Chem., Vol. 65, No. 10, 2000
Berkowitz et al.
solution was heated to 40 °C for 7 d. After evaporation of the
acetone, the residue was taken up in Et2O (25 mL), extracted
with 1 M sodium thiosulfate (3 × 20 mL), dried (MgSO4),
evaporated, and chromatographed (10% EtOAc/hexane) to
yield 22d (435 mg, 93%): [R]D (92% de) +7.6 (c 0.9, CHCl3);
1H NMR (500, CDCl3) δ 0.83-0.92, (m, 1 H), 0.89 (s, 3 H),
1.03-1.27 (m, 2 H), 1.29-1.32 (m, 1 H), 1.31 (s, 3 H), 1.40 (s,
3 H), 1.42-1.57 (m, 4 H), 1.69-1.84 (m, 3 H), 2.10-2.12 (m, 1
H), 2.17-2.22 (m, 1 H), 2.38-2.44 (dt, J ) 4.4, 13 Hz, 1 H),
3.04-3.09 (m, 1 H), 3.13-3.18 (m, 1 H), 4.93-4.98 (dt, J )
4.0, 10.4 Hz, 1 H), 5.10 (d, J ) 10.4 Hz, 1 H), 5.19 (d, J ) 17
Hz, 1 H), 5.58-5.64 (dd, J ) 10.4, 17 Hz, 1 H), 7.10 (s, 1 H),
7.41-7.54 (m, 7 H), 7.62-7.64 (m, 1 H), 7.72-7.79 (m, 4 H);
13C NMR (125 MHz, CDCl3) δ 21.8, 24.7, 25.7, 27.3, 28.5, 31.5,
32.9, 33.1, 34.4, 40.2, 41.6, 49.6, 64.8, 77.3, 78.2, 115.7, 123.4,
124.8, 125.3, 125.9, 126.9, 127.2, 127.3, 127.6, 127.9, 128.6,
131.6, 133.4, 134.8, 135.8, 148.1, 165.7, 171.8; IR (ATR) 3310-
3400, 1718, 1671 cm-1; MS (FAB 3-NBA) 652 (50, MH+) 388
(100), 169, (96); HRMS (FAB 3-NBA) calcd for C35H42NO3I
(MH+) 652.2287, obsd 652.2291.
(1′′R,2′′S,5′′R)-8′′-(â-Na p h th yl)m en th yl N-Ben zoyl-r-(4′-
a zid o)bu tyl-L-r-vin ylglycin a te (23d ). NaN3 (59.8 mg, 0.92
mmol) and 15-crown-5 (13.5 mg, 60 µmol) were added to a
solution of 22d (400 mg, 0.61 mmol) in DMF (6.7 mL), and
the solution was heated to 70 °C for 5 h. After cooling, the
solution was taken up in Et2O (25 mL) and extracted with H2O
(3 × 25 mL), dried (MgSO4), filtered, and evaporated. Flash
chromatography (10% EtOAc/hexane) yielded 23d (316 mg,
91%): [R]D (92% de) +3.6 (c 1.00 CHCl3); 1H NMR (500 MHz,
CDCl3) δ0.81-0.87 (m, 1 H), 0.89 (s, 3 H), 1.03-1.15 (m, 2 H),
1.21-1.29 (m, 2 H), 1.32 (s, 3 H), 1.41 (s, 3 H), 1.42-1.61 (m,
5 H), 1.79-1.85 (dt, J ) 4.4, 13.3 Hz, 1 H), 2.07-2.09 (m, 1
H), 2.17-2.22 (dt, J ) 3.23, 12.0 Hz, 1 H), 2.36-2.42 (dt, J )
4.8, 13.3 Hz, 1 H), 3.13-3.19 (m, 1 H), 3.21-3.26 (m, 1 H),
4.93- -4.98 (dt, J ) 4.4, 10 Hz, 1 H), 5.10 (d, J ) 10.4, 1 H),
5.20 (d, J ) 17.3, 1 H), 5.59-5.66 (dd, J ) 10.4, 17.3 Hz, 1 H),
7.09 (s, 1 H), 7.40-7.47 (m, 5 H), 7.49-7.53 (m, 2 H), 7.64 (br
s, 1 H), 7.72 (d, J ) 8.8 Hz, 1 H), 7.76-7.79 (m, 3 H); 13C NMR
(125 MHz, CDCl3) δ 20.9, 21.7, 25.7, 27.3, 28.4, 28.5, 31.3, 33.4,
34.3, 40.2, 41.4, 49.6, 51.0, 64.8, 78.2, 115.7, 123.4, 124.7, 125.3,
125.9, 126.9, 127.2, 127.3, 127.5, 127.8, 128.5, 131.5, 133.4,
134.7, 135.8, 148.1, 165.7, 171.8; IR (ATR) 3320-3410, 2142,
1751, 1700 cm-1. Anal. Calcd for C35H42N4O3: C, 74.17; H, 7.46;
N, 9.89. Found: C, 74.19; H, 7.07, N, 9.96.
(1′R,2′S,5′R)-8′-(â-Na p h th yl)m en th yl N-Ben zoyl-L-r-vi-
n yllysin a te (25d ). 24d was suspended in 3 N HCl and heated
to 60 °C for 32 h. After cooling, the reaction mixture was taken
up in 1 N Na2CO3 (25 mL), extracted with Et2O (3 × 25 mL),
dried (Na2SO4), filtered, and evaporated. Chromatography was
carried out initially with 20% EtOAc/hexane and then with
5% MeOH/CH2Cl2 [(1% NH4OH (satd aq)] yields 25d (126 mg,
1
55% over two steps): [R]D (92% de) +0.40 (c 1.0, CHCl3); H
NMR (500 MHz, CDCl3) δ 0.78-0.83 (m, 1 H), 0.87 (d,J ) 6.4
Hz, 3 H), 1.0-1.08 (m, 2 H), 1.32 (s, 3 H), 1.40 (s, 3 H), 1.21-
1.37 (m, 4 H), 1.39-1.55 (m, 5 H), 1.79-1.85 (dt, J ) 4.03,
14.3 Hz, 1 H), 2.04-2.07 (m, 1 H), 2.13-2.18 (dt, J ) 3.2, 12.0,
1 H), 2.35-2.41 (dt, J ) 4.8, 13.2 Hz, 1 H), 2.59-2.63 (m, 2
H), 4.92-4.97 (dt, J ) 4.0, 10.8 Hz, 1 H), 5.08 (d, J ) 10.8 Hz,
1 H), 5.19 (d, J ) 17.3 Hz, 1 H), 5.65-5.71 (dd, J ) 10.8, 17.3
Hz, 1 H), 7.10 (s, 1 H), 7.39-7.51 (m, 7 H), 7.62 (app s, 1 H),
7.70-7.79 (m, 4 H); 13C NMR (125 MHz, CDCl3) δ 20.9, 21.6,
25.4, 27.2, 28.6, 31.2, 33.2, 33.9, 34.3, 40.1, 41.4, 41.7, 49.5,
64.8, 77.8, 115.3, 123.3, 124.7, 125.2, 125.8, 126.9, 127.2, 127.5,
127.8, 128.4, 131.4, 131.4, 133.2, 134.7, 135.8, 148.0, 165.6,
171.9. IR (ATR) 3310-3370, 1700, 1669, 1580 cm-1. Anal.
Calcd for C35H44N2O3: C, 77.74; H, 8.20; N, 5.18. Found: C,
77.88; H, 7.89; N, 4.99.
Ack n ow led gm en t. Financial support from the Na-
tional Institutes of Health (CA 62034) is gratefully
acknowledged. D.B.B. is an Alfred P. Sloan Research
Fellow (1997-2001). The authors wish to thank J ason
P. Bynum and Kris L. Kaiser (both University of
NebraskasLincoln undergraduates) for assistance with
several experiments and Prof. Stephen DiMagno for
helpful discussions. We thank Dr. Richard K. Shoe-
maker for assistance with 2D NMR experiments and
Dr. Ron Cerny (Nebraska Center for Mass Spectrom-
etry) for high-resolution mass spectra. This research
was facilitated by grants for NMR and GC/MS instru-
mentation from the NIH (SIG 1-S10-RR06301) and the
NSF (CHE-93000831), respectively.
Su p p or tin g In for m a tion Ava ila ble: Detailed synthetic
procedures and spectral characterization data for compounds
2-9 and copies of 1H NMR spectra for compounds 2, 3, 6-18,
19a ,c-e,g-j, 20a -i, 21a -h , 22d , 23d , 25d , 26, 27, and 29.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(1′′R,2′′S,5′′R)-8′′-(â-Na p h th yl)m en th yl N-Ben zoyl-L-r-
[4′-im in o-(t r ip h en ylp h osp h in o)]b u t yl-r-vin ylglycin a t e
(24d ). To a solution of 23d (239 mg, 0.42 mmol) in toluene
(2.5 mL) was added triphenylphosphine (309 mg, 1.18 mmol)
and the solution was heated to 110 °C for 72 h. After
evaporation of the crude 24d was obtained.
J O9918091