Concise Synthesis of Enantiomerically Pure Phenylalanine, Homophenylalanine, and Bishomophenylalanine Derivatives Using Organozinc Chemistry: NMR Studies of Amino Acid-Derived Organozinc Reagents

Article abstract of DOI:10.1021/jo981133u

Protected phenylalanines 23 (seven examples), homophenylalanines 7 (eight examples), and bishomophenylalanines 8 (seven examples) have been prepared by palladium-catalyzed coupling of the amino acid-derived organozinc reagents 13, 5, and 6, respectively, with aryl iodides. While the reactions of the zinc reagent 13 may be conducted in both THF and DMF as solvent, the results obtained in DMF are generally superior. In the case of the reagents 5 and 6 the results are far superior in DMF. NMR investigations on the structure of the zinc reagents 13 in THF suggest that there is strong intramolecular coordination of the urethane carbonyl group, whereas in DMF this interaction is completely suppressed.

Full text of DOI:10.1021/jo981133u

J . Org. Chem. 1998, 63, 7875-7884
7875
Con cise Syn th esis of En a n tiom er ica lly P u r e P h en yla la n in e,
Hom op h en yla la n in e, a n d Bish om op h en yla la n in e Der iva tives
Usin g Or ga n ozin c Ch em istr y: NMR Stu d ies of Am in o
Acid -Der ived Or ga n ozin c Rea gen ts
Richard F. W. J ackson,* Rebecca J . Moore, and Charles S. Dexter
Department of Chemistry, Bedson Building, The University of Newcastle,
Newcastle upon Tyne, NE1 7RU, UK
J ason Elliott† and Charles E. Mowbray‡
Merck Sharpe and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park,
Eastwick Road, Harlow, Essex CM20 2QR, UK and Department of Discovery Chemistry,
Pfizer Central Research, Sandwich, Kent, CT13 9NJ , UK
Received J une 12, 1998
Protected phenylalanines 23 (seven examples), homophenylalanines 7 (eight examples), and
bishomophenylalanines 8 (seven examples) have been prepared by palladium-catalyzed coupling
of the amino acid-derived organozinc reagents 13, 5, and 6, respectively, with aryl iodides. While
the reactions of the zinc reagent 13 may be conducted in both THF and DMF as solvent, the results
obtained in DMF are generally superior. In the case of the reagents 5 and 6 the results are far
superior in DMF. NMR investigations on the structure of the zinc reagents 13 in THF suggest
that there is strong intramolecular coordination of the urethane carbonyl group, whereas in DMF
this interaction is completely suppressed.
There continues to be substantial interest in the
synthesis of nonproteinogenic R-amino acids.1,2 Ana-
logues of phenylalanine, for example homophenylalanine
1 and bishomophenylalanine 2, are significant compo-
nents of a range of biologically active compounds.3,4 We
have developed the use of organozinc reagent 4a and zinc/
copper reagent 4b (each prepared from protected iodo-
alanine 3) as a route for the synthesis of enantiomerically
pure R-amino acids,5,6 including a widely used method
for the synthesis of simple phenylalanine derivatives by
palladium-catalyzed coupling of the organozinc reagent
4a .7-18 The success of this approach encouraged us to
explore the use of homologous reagents 5 and 6 for the
Previous routes to homophenylalanine 7 and bis-
homophenylalanine 8 derivatives have employed enzy-
matic methods,4,19,20 and have also made use of the chiral
pool.21-23 Asymmetric routes have included the reaction
of nucleophilic glycine equivalents with 2-arylethyl- and
3-arylpropyl halides,24 and the reaction of silyl enol ethers
with electrophilic glycine equivalents,25 as well as the use
of catalytic asymmetric hydrogenation.26 An indirect
approach, based on catalytic asymmetric reduction of
trichloromethyl ketones followed by reaction with azide
anion and hydrogenation, has been developed,27 as have
routes relying on precursors prepared by asymmetric
catalysis.28
synthesis of homophenylalanine
phenylalanine 8 derivatives by a similar method.
7
and bishomo-
In preliminary work, we had explored the generation
of the reagent 5 by ultrasonic treatment of the iodide 9
† Merck Sharpe and Dohme Research Laboratories.
‡ Department of Discovery Chemistry, Pfizer Central Research.
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Humphreys, W. G.; J acobs, G. A.; Kocy, O.; Lin, P. F.; Lis, K. A.;
Marella, M. A.; Ryono, D. E.; Sheaffer, A. K.; Spergel, S. H.; Sun, C.
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10.1021/jo981133u CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/14/1998

7876 J . Org. Chem., Vol. 63, No. 22, 1998
J ackson et al.
coupling reaction with an iodohistidine derivative, pro-
vided DMA was used as the solvent.33 Subsequently, it
was reported that simple N-protected iodoethylamine
derivatives could be converted into stable zinc reagents
provided a DMSO/THF mixture was used as the sol-
vent.34 We felt that the use of dipolar aprotic solvents
in these processes might be significant.
While organozinc reagents have usually been prepared
in solvents of moderate Lewis basicity (e.g., THF),30 the
benefits of using dipolar aprotic solvents as a minor
component of the solvent mixture has already been
highlighted.35 It has also been reported that use of DMF
allows the preparation of arylzinc iodides from aryl
iodides,36 a process which does not generally occur
efficiently in THF, except using highly reactive Rieke
zinc.37 The benefits of using DMF for palladium-
catalyzed coupling reactions have been known for some
time.38 We have therefore undertaken a systematic study
of the use of DMF for the preparation of the zinc reagents
4a , 5, 6, and 13, and the subsequent palladium-catalyzed
coupling of reagents 5, 6, and 13 (prepared from the
iodide 14) with aryl iodides.
with zinc/copper couple in benzene/dimethylacetamide
(DMA) (according to the successful method developed for
the zinc reagent 4a ), and also by treatment of iodide 9
with zinc activated using the Knochel procedure employ-
ing 1,2-dibromoethane and chlorotrimethylsilane in tet-
rahydrofuran as solvent.29,30 Although in both cases we
were able to generate the zinc reagent, substantial
amounts of the corresponding 2-aminobutanoic acid
derivative were formed by protonation, presumably due
to the presence of an acidic carbamate proton (in marked
contrast to the behavior of the reagent 4a ). The reaction
conditions required for the formation of the zinc reagent
5 (35 °C, 30 min) were slightly less mild than those
required for the formation of the reagents 4a and 13,
which could both be prepared at ambient temperature,
and this difference was considered responsible for the
protonation observed. The relative ease of formation of
the zinc reagents 4a and 13 is presumably due to the
greater proximity of the electron-withdrawing substitu-
ents. These observations lead us to explore the use of
the fully protected zinc reagent 11, in turn generated
from the iodide 12.31,32 While this proved a successful
tactic, it was slightly limiting. An efficient general
method for the preparation and use of simply protected
amino acid-derived organozinc reagents was clearly
highly desirable.
Iodide 9 had been synthesized previously from N-(tert-
butoxycarbonyl)-L-glutamic acid R-benzyl ester 19 using
a Barton decarboxylative iodination.39 While this method
was convenient on a small scale, the chromatography
necessary to remove excess iodoform was somewhat
tedious, and an alternative preparation of the compound
was used. Treatment of N-(tert-butoxycarbonyl)-L-aspar-
tic acid R-benzyl ester 15 with N-hydroxysuccinimide/
Resu lts a n d Discu ssion
DCC gave succinimide ester 16. Subsequent reduction
gave the homoserine derivative 17, which was converted
into iodide 9 using iodine, triphenylphosphine, and
Two reports encouraged us to explore this area in a
systematic manner. First, it had been reported that use
of an excess of the zinc reagent 5 gave good yields in a
(33) Evans, D. A.; Bach, T. Angew. Chem., Int. Ed. Engl. 1993, 32,
1326-1327.
(27) Corey, E. J .; Link, J . O. J . Am. Chem. Soc. 1992, 114, 1906-
1908.
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Tetrahedron Lett. 1993, 34, 7781-7784.
(29) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J . J . Org. Chem.
1988, 53, 2390-2392.
(30) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117-2188.
(31) Fraser, J . L.; J ackson, R. F. W.; Porter, B. Synlett 1994, 379-
380; Fraser, J . L.; J ackson, R. F. W.; Porter, B. Synlett 1995, 819-
820.
(32) J ackson, R. F. W.; Fraser, J . L.; Wishart, N.; Porter, B.; Wythes,
M. J . J . Chem. Soc., Perkin Trans. 1, 1998, 1903-1912.
(34) Duddu, R.; Eckhardt, M.; Furlong, M.; Knoess, H. P.; Berger,
S.; Knochel, P. Tetrahedron 1994, 50, 2415-2432.
(35) Tamaru, Y.; Ochiai, H.; Nakamura, T.; Tsubaki, K.; Yoshida,
Z.-i. Tetrahedron Lett. 1985, 26, 5559-5562.
(36) Majid, T. N.; Knochel, P. Tetrahedron Lett. 1990, 31, 4413-
4416.
(37) Zhu, L.; Wehmeyer, R. M.; Rieke, R. D. J . Org. Chem. 1991,
56, 1445-1453.
(38) Negishi, E.-i.; Owczarczyk, Z. R.; Swanson, D. R. Tetrahedron
Lett. 1991, 32, 4453-4456.
(39) Barton, D. H. R.; Herve´, Y.; Potier, P.; Thierry, J . Tetrahedron
1988, 44, 5479-5486.

NMR Studies of Amino Acid-Derived Organozinc Reagents
J . Org. Chem., Vol. 63, No. 22, 1998 7877
Ta ble 1. Ch a n ges in Ca r bon yl Sh ifts on Zin c Rea gen t
the ester carbonyl group to zinc in all cases. The
carbamate carbonyl group is also certainly coordinated
to zinc in 4a and 13, but this effect is less pronounced in
the case of 5 and 6.42 The observation that the magni-
tude of ∆δ for the ester carbonyl decreases as the zinc
becomes more remote from the R-center is consistent with
intramolecular coordination of this carbonyl group to zinc,
which we suggest becomes decreasingly favorable as the
ring size increases from 5 (4a , 13) to 7 (6). The coordina-
tion of the carbamate carbonyl group to zinc would be
expected to lead to â-elimination in the case of the
â-aminozinc reagents 4a and 13 (since the zinc can act
as an internal Lewis acid). Similar observations have
been made on other amino acid-derived organozinc
reagents.43
We believe that the (relatively) high stability of the
zinc reagents 4a and 13 in THF is best accounted for by
invoking an internally chelated structure 22. Circum-
stantial evidence for structure 22 is provided by the
significantly different magnetic environments of the two
diastereotopic protons observed for 4a and 13 in THF. A
further piece of evidence that is consistent with this
monomeric structure is that a 1H NMR spectrum of a
racemic mixture of 13 was identical to that observed for
enantiomerically pure 13.44 The fact that the ester
carbonyl binds strongly to zinc in both 4a and 13 can be
used to explain the low rate of â-elimination, since
although the urethane carbonyl is also coordinated to
zinc, the necessary conformation for elimination (either
a syn or anti arrangement of the C-Zn and C-NHBoc
bonds) cannot be achieved.
F or m a tion in THF -d 8
∆δ (δ(R-ZnI) - δ(R-I)
)
4a
5
6
13
carbamate
ester
+2.711
+5.386
+0.526
+1.506
+0.431
+0.848
+2.711
+5.347
imidazole.40 The reduction step was inefficient and the
byproducts formed were the starting material 15 and
lactone 18.3 Work carried out by Miller indicates that
replacement of the R-benzyl ester with an R-tert-butyl
ester could significantly increase the yield of the desired
alcohol by reducing lactonization.41
The alkyl iodide 10 was prepared from N-(tert-butoxy-
carbonyl)-L-glutamic acid R-benzyl ester 19, via the
alcohol 20, in an analogous manner. As observed in the
preparation of iodide 9, the reduction step was inefficient
and significant amounts of the starting material 19 and
lactone 21 were retrieved.
NMR Stu d ies of th e Zin c Rea gen ts in THF . As an
initial measure of zinc reagent stability and structure in
THF, the zinc reagents 4a , 5, 6, and 13 were prepared
in THF-d8 using zinc activated by treatment with 1,2-
dibromoethane and chlorotrimethylsilane. As already
indicated, while the reagents 4a and 13 could be prepared
at ambient temperature, the reagents 5 and 6 required
gentle warming (to 35 °C) to achieve zinc insertion in a
comparable time. 1H NMR spectra of the serine-derived
reagents 4a and 13 indicated efficient formation of the
zinc reagent, whereas the spectra of the homologous
reagents 5 and 6 showed that substantial amounts of
protected 2-aminobutanoic acid and 2-aminopentanoic
acid, respectively, were already present. The sample of
zinc reagent 4a was heated at 50 °C to establish its
stability and the identity of its decomposition products.
Heating for 3 days was required before all the zinc
reagent had decomposed. Some protonation of the zinc
reagent (to give protected alanine) was observed, but the
major decomposition product was benzyl acrylate formed
by â-elimination.
NMR Stu d ies of th e Zin c Rea gen ts in DMF . Given
the precedent for the use of dipolar aprotic solvents for
zinc reagent formation,33,34 we have investigated the
influence of such solvents on the structure of the amino
acid-derived zinc reagents, with a view to establishing
whether the stability of the reagents could be improved,
without compromising their reactivity. Therefore, an
analogous set of NMR spectra of the zinc reagents 4a , 5,
6, and 13 were obtained using DMF-d7 as the solvent,
again employing zinc activated with 1,2-dibromoethane
and chlorotrimethylsilane. The reaction conditions used
for the formation of the reagents were identical to those
used in THF (zinc insertion at ambient temperature for
4a and 13, and at 35 °C for 5 and 6). In this case, the
1H NMR spectra indicated that each of the zinc reagents
4a , 5, 6, and 13 had been formed efficiently, and much
smaller amounts of the corresponding protonated zinc
reagents were detected in the case of the reagents 5 and
6 compared to that observed in THF. The 13C NMR
spectra of the same samples indicated that the carbamate
carbonyl experienced a small upfield shift, while the ester
13C NMR spectra of the same samples were also
informative. One of the most striking aspects of the data
was the downfield shift of the carbonyl carbon resonances
(both of the ester group and the carbamate group) upon
conversion of the starting iodides into the corresponding
alkylzinc iodides. These changes in chemical shift are
reported in Table 1 and are indicative of coordination of
(40) Lange, G. L.; Gottardo, C. Synth. Commun. 1990, 20, 1473-
(42) Nakamura, E.; Shimada, J .-i.; Kuwajima, I. Organometallics
1985, 4, 641-646.
(43) Dexter, C. S.; J ackson, R. F. W. Chem. Commun. 1998, 75-76.
(44) Turner, D. Ph. D. Thesis, University of Newcastle, 1996.
1479.
(41) Lee, B. H.; Gerfen, G. J .; Miller, M. J . J . Org. Chem. 1984, 49,
2418-2423.

7878 J . Org. Chem., Vol. 63, No. 22, 1998
J ackson et al.
Ta ble 2. Ch a n ges in Ca r bon yl Sh ifts on Zin c Rea gen t
Sch em e 2
F or m a tion in DMF -d 7
∆δ (δ(R-ZnI) - δ(R-I)
)
4a
5
6
13
carbamate
ester
-0.896
+5.692
-0.789
+0.831
-0.873
+0.256
-0.868
+5.786
Sch em e 1
Sch em e 3
carbonyl carbon atoms showed similar downfield shifts
to those observed in THF. These results are presented
in Table 2.
the active catalyst is likely to be lower than expected.45
This arises because, in contradiction with usual assump-
tions, dba is a better ligand for the low-ligated active
species than mono-dentate phosphorus-based ligands
such as tri-o-tolylphosphine.
Excellent yields of the cross-coupled products 7 were
obtained. The o-nitro derivative 7b was the only example
for which a modest yield was obtained, even in DMF. This
result is not entirely surprising as unfavorable steric
effects may have influenced the course of this reaction.
The successful preparation of the o-amino derivative 7h
was very pleasing as this had not been possible in THF
even using the organozinc reagent 11, fully protected on
nitrogen.
Conversion of commercially available N-(tert-butoxy-
carbonyl)-(L)-homophenylalanine 24 into the correspond-
ing benzyl ester 7a (Scheme 3)46 gave a material that
exhibited specific rotation identical to that of compound
7a prepared via the palladium-catalyzed cross-coupling
reaction.
The availability of the 2-amino derivative 7h led to the
development of a concise, stereocontrolled route to 3-ami-
nobenzazepin-2-ones. (R)-3-Amino-2,3,4,5-tetrahydro-
1H-[1]benzazepin-2-one ent-25 is an important compo-
nent of some angiotensin converting enzyme (ACE)
inhibitors47 and a novel class of compounds that stimulate
release of growth hormones.48 Previous syntheses have
required fractional crystallization of tartaric acid salts
to obtain a single enantiomer of the 3-aminobenzazepin-
2-one.48 However, more recently the first enantioselective
synthesis of the 3-aminobenzazepin-2-one ent-25 was
published.49
The decrease in ∆δ for the ester carbonyl carbon from
4a to 5 to 6 is again consistent with intramolecular
coordination of this carbonyl group to zinc,42 which
mirrors the behavior in THF. The coordination of the
carbamate carbonyl group to zinc appears to be com-
pletely suppressed in DMF.
Com p a r ison of th e Cou p lin g of Zin c Rea gen t 13
w ith Ar yl Iod id es in THF a n d in DMF . The evidence
that the nature of the zinc reagent 13 is significantly
altered when it is prepared in DMF, rather than THF,
prompted us to undertake a comparative study of the use
of these solvents for the preparation of phenylalanine
derivatives 23a -g (Scheme 1). The zinc reagent 13 was
prepared from the iodide 14 using activated zinc in THF
or DMF at room temperature36 and then coupled under
palladium catalysis with a representative range of aryl
iodides as reported in Table 3.
Some clear trends are evident from the results de-
scribed in Table 3. The results indicate that the coupling
process is more effective in DMF, but that in some cases
in THF, the yield of coupled product can be increased by
conducting the reaction at a higher temperature. The
most significant results are the increased yields with
ortho-substituted aryl iodides when using DMF, and the
most striking result is the successful preparation of the
2-fluorophenyl derivative 23e, which completely eluded
us using our previously developed protocol.5 The ability
to conduct the coupling reaction in DMF at room tem-
perature makes the whole process extremely convenient
to carry out, and these conditions are the best that we
have identified to date for the reaction.
Simply heating benzyl 2-(S)-((tert-butoxycarbonyl)-
amino)-4-(2′-aminophenyl)butanoate 7h 50 in the absence
of solvent leads to the formation of the protected 3-ami-
nobenzazepin-2-one 26 in good yield. Subsequent re-
moval of the Boc group49 afforded (S)-3-amino-2,3,4,5-
tetrahydro-1H-[1]benzazepin-2-one 25 (Scheme 4). The
excellent agreement of the optical rotation for 25 with
the literature value provides additional support for
Syn th esis of Hom op h en yla la n in e Der iva tives.
Given the efficiency with which the organozinc reagent
5 had been prepared in DMF, it was important to
establish whether this reagent could be exploited for the
synthesis of homophenylalanine derivatives. Thus the
organozinc reagent 5 was generated from iodide 9 using
zinc dust, activated by the Knochel method,30 in DMF.
Total conversion into the organozinc reagent 5 occurred
after 30 min at 35 °C. The enhanced stability of the zinc
reagent 5 in DMF meant that these conditions were the
best compromise between the rate of formation of the
reagent and its rate of decomposition. Subsequent pal-
ladium-catalyzed cross-coupling reactions were carried
out at room temperature in the presence of the active
catalyst bis-(tri-o-tolylphosphine)palladium(0) to give the
homophenylalanine deraivatives 7 (Scheme 2, Table 4).
Bis(tri-o-tolylphosphine)palladium(0) was prepared from
Pd2(dba)3 and tri-o-tolylphosphine. A report by Amatore
and co-workers has indicated that the concentration of
(45) Amatore, C.; J utand, A.; Khalil, F.; Mbarki, M. A.; Mottier, L.
Organometallics 1993, 12, 3168-3178.
(46) Hecker, S. J .; Minich, M. L.; Lackey, K. J . Org. Chem. 1990,
55, 4904-4911.
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Finn, B. M. J . Med. Chem. 1985, 28, 1511-1516.
(48) Schoen, W. R.; Pisano, J . M.; Prendergast, T. K.; Wyvratt, M.
J .; Fisher, M. H.; Cheng, K.; Chan, W. W. S.; Butler, B.; Smith, R. G.;
Ball, R. G. J . Med. Chem. 1994, 37, 897-906.
(49) Armstrong, J . D.; Eng, K. K.; Keller, J . L.; Purick, R. M.;
Hartner, F. W.; Choi, W. B.; Askin, D.; Volante, R. P. Tetrahedron Lett.
1994, 35, 3239-3242.
(50) Ito, Y.; Kobayashi, K.; Maeno, M.; Saegusa, T. Chem. Lett. 1980,
487.

NMR Studies of Amino Acid-Derived Organozinc Reagents
J . Org. Chem., Vol. 63, No. 22, 1998 7879
Ta ble 3. P r ep a r a tion of P h en yla la n in e Der iva tives 23
aryl iodide
Ar
Product
yield(%)a in DMFb
yield(%)a in THFb
yield(%)a in THFc
PhI
Ph
23a
23b
23c
23d
23e
23f
23g
64
28
57
57
40
58
69
58
5
41
13
60
36
0
2-NO2-C6H4I
4-NO2-C6H4I
2-MeO-C6H4I
2-F-C6H4I
4-F-C6H4I
1-naphthyl iodide
2-NO2-C6H4
4-NO2-C6H4
2-MeO-C6H4
2-F-C6H4
4-F-C6H4
1-naphthyl
62
19
16
24
57
49
48
a
b
Yields are based on iodide 14. Zinc reagent prepared at room temperature, coupling at room temperature. c Zinc reagent prepared
at 35 °C, coupling reaction conducted at 50 °C.
Ta ble 4. P r ep a r a tion of Hom op h en yla la n in e
Der iva tives 7
Ta ble 5. P r ep a r a tion of Bish om op h en yla la n in e
Der iva tives 8
aryl iodide
product
Ar
yield (%)a
aryl iodide
product
Ar
yield (%)a
PhI
7a
7b
7c
7d
7e
7f
Ph
70
40
84
74
74
87
88
53
PhI
8a
8b
8c
8d
8e
8f
Ph
77
10
75
42
62
84
41
2-NO2-C6H4I
4-NO2-C6H4I
2-MeO-C6H4I
4-MeO-C6H4I
4-Me-C6H4I
1-naphthyl iodide
2-NH2-C6H4I
2-NO2-C6H4
4-NO2-C6H4
2-MeO-C6H4
4-MeO-C6H4
4-Me-C6H4
1-naphthyl
2-NH2-C6H4
2-NO2-C6H4I
4-NO2-C6H4I
2-MeO-C6H4I
4-MeO-C6H4I
4-Me-C6H4I
2-NO2-C6H4
4-NO2-C6H4
2-MeO-C6H4
4-MeO-C6H4
4-Me-C6H4
7g
7h
1-naphthyl iodide
8g
1-naphthyl
a
Yields are based on aryl iodide.
Sch em e 6
a
Yields are based on aryl iodide.
Sch em e 4
preparation of the analogous homophenylalanine deriva-
tive 7b).
Benzyl 2-(S)-amino-5-phenylpentanoate p-toluene-
sulfonate 27 was prepared from benzyl 2-(S)-((tert-
butoxycarbonyl)amino)-5-phenylpentanoate 8a in good
yield (Scheme 6). The specific rotation of this compound
was comparable with the literature value.51
Sch em e 5
Con clu sion s
A general method for the synthesis of enantiomerically
pure 4-aryl and 5-aryl R-amino acids has been estab-
lished. The utility of these compounds has been dem-
onstrated in the concise synthesis of (S)-3-amino-2,3,4,5-
tetrahydro-1H-[1]benzazepin-2-one 25. More importantly,
we have identified the profound beneficial effect of DMF
on the preparation, stability, and cross-coupling reactions
involving organozinc reagents 5 and 6, as well as a
rationalization for the unique behavior of the serine-
derived organozinc reagents 4a and 13 (which can be
prepared and used effectively in both THF and DMF).
complete retention of stereochemical integrity in the
coupling process.
Syn th esis of Bish om op h en yla la n in e Der iva tives.
Organozinc reagent 6 was prepared by treating iodide
10 with zinc in DMF using the same procedure used for
iodide 9. Complete insertion of zinc into the carbon-
iodine bond had occurred after 30 min at 35 °C. Subse-
quent palladium-catalyzed cross-couplings with aryl
iodides employed identical reaction conditions to those
used to generate the protected homophenylalanine de-
rivatives, which gave a range of protected bishomo-
phenylalanine derivatives 8 (Scheme 5, Table 5).
Exp er im en ta l Section
General experimental procedures have already been de-
scribed.5 DMF was distilled from calcium hydride and stored
over 4 Å molecular sieves. Specific rotations were measured
at 20 °C, unless otherwise stated. 1H NMR spectra were
recorded in CDCl3 as solvent at 500 MHz, referenced to TMS,
unless stated otherwise. 13C NMR spectra were recorded at
125 MHz. Coupling constants are given in hertz. Organic
A number of 5-aryl R-amino acids 8 were prepared in
excellent yields. However, in the reactions with ortho-
substituted aromatic iodides (which are more sterically
hindered), the yields were only moderate, and in the
reaction with 1-iodo-2-nitrobenzene the yield of the
product 8b was poor (as had been observed in the
(51) Shimohigashi, Y.; Izumiya, N. Int. J . Pept. Protein Res. 1978,
12, 7.

7880 J . Org. Chem., Vol. 63, No. 22, 1998
J ackson et al.
extracts were dried over MgSO4, and the solvent then removed
using a rotary evaporator.
284.0149). [R]27 -32.6 (c 1.0 in MeOH) (lit. value -33.0 (c
D
1.0 in MeOH)).39 IR (KBr, cm-1) 3356, 2979, 1756, 1680. δH
(200 MHz) 1.42 (9H, s), 2.14-2.22 (1H, m), 2.30-2.38 (1H, m),
3.12 (2H, t, J 7.8), 4.32-4.38 (1H, m), 5.10 (1H, d, J 8.0), 5.16
(2H, s), 7.33-7.35 (5H, m). δC (50 MHz) -0.5, 28.3, 37.0, 54.5,
67.5, 80.3, 128.4, 128.6, 128.7, 135.1, 156.2, 171.5. m/z (EI)
284 (M+ - CO2Bn, 17%).
Ben zyl 2-(S)-((ter t-bu toxyca r bon yl)a m in o)-4-h yd r oxy-
bu tan oate (17). N-tert-Butoxycarbonyl-L-aspartic acid R-benz-
yl ester 15 (3.23 g, 10.0 mmol) and N-hydroxysuccinimide (1.27
g, 11.0 mmol) were dissolved in ethyl acetate (40 mL) with
stirring under nitrogen. The solution was cooled to 0 °C, and
1,3-dicyclohexylcarbodiimide (2.27 g, 11.0 mmol) was added.
The reaction mixture was allowed to warm to room temper-
ature and stirring continued for 6 h. The resulting suspension
was filtered, and the filtrate was dried and concentrated under
reduced pressure to give succinimide ester 16 as a colorless
solid. Sodium borohydride (0.57 g, 15.0 mmol) was dissolved
in a 4:1 mixture of THF and water (40 mL) at 0 °C. The
succinimide ester 16 was dissolved in THF (28 mL) and added
to the sodium borohydride solution. The reaction mixture was
stirred vigorously for several minutes until gas evolution
ceased and then quenched with a saturated aqueous solution
of ammonium chloride (20 mL) and left to stir for 10 min. The
reaction mixture was extracted with ethyl acetate (3 × 50 mL),
and the combined organic extracts were dried. The solvent
was removed to give a colorless oil which was purified by flash
column chromatography on silica gel eluting with 2:1 petro-
leum ether/ethyl acetate to give ester 17 as a colorless oil (1.82
g, 59%). (Found MH+ 310.1668. C16H24NO5 requires 310.1654).
Ben zyl 2-(S)-((ter t-Bu toxyca r bon yl)a m in o)-5-iod op en -
ta n oa te (10). Benzyl 2-(S)-((tert-butoxycarbonyl)amino)-5-
hydroxypentanoate 20 (6.46 g, 20.0 mmol) was treated under
the same reaction conditions as those described in the prepa-
ration of benzyl 2-(S)-((tert-butoxycarbonyl)amino)-4-iodo-
butanoate 9. Purification by flash column chromatography
(5:1 petroleum ether/ethyl acetate) yielded benzyl 2-(S)-((tert-
butoxycarbonyl)amino)-5-iodopentanoate 10 as a colorless oil
(5.89 g, 68%), which solidified with time in the freezer, mp
34-35 °C (from light petroleum ether/Et2O). (Found M+
-
C4H8 377.0125. C13H16INO4 requires 377.0126). [R]27 -19.9
D
(c 1.0 in MeOH). IR (film, cm-1) 3364, 2976, 1743 and 1713.
NMR δH 1.44 (9H, s), 1.71-1.82 (2H, m), 1.85-1.95 (2H, m),
3.11-3.18 (2H, m), 4.34-4.39 (1H, m), 5.06 (1H, d, J 8.2), 5.16
(1H, d, J 12.2), 5.22 (1H, d, J 12.2), 7.34-7.37 (5H, m). δC
5.3, 28.3, 29.2, 33.7, 52.6, 67.2, 80.1, 128.3, 128.5, 128.6, 135.2,
155.3, 172.2. m/z (EI) 377 (M+ - C4H8, 14%).
NMR Stu d ies of th e Zin c Rea gen ts 4a , 5, 6, a n d 13.
Zinc dust (325 mesh, 300 mg, 4.5 mmol) was added to a
nitrogen-purged flask. THF-d8 [or DMF-d7] (0.5 mL) and 1,2-
dibromoethane (19.4 µL, 0.225 mmol) were added, and the
flask was repeatedly heated using a hot water bath and
allowed to cool over a period of 15 min. The reaction mixture
was allowed to cool to room temperature, trimethylsilyl
chloride (6.0 µL, 0.046 mmol) was added, and the resultant
mixture was stirred vigorously for 30 min under nitrogen. The
amino acid-derived iodides 3, 9, 10, or 14 (0.75 mmol) in THF-
d8 [or DMF-d7] (0.5 mL) was added to the flask which was
either stirred at room temp (for 3 and 14) or heated at 35 °C
(for 9 and 10) until no starting material remained (as judged
by TLC, 2:1, petroleum ether:ethyl acetate). The zinc was
allowed to settle, and the supernatant was then transferred
to a nitrogen-filled NMR tube fitted with a Young’s tap (a small
amount of residual zinc dust was unavoidably transferred, but
its presence did not adversely affect the spectra). References
used for the deuterated solvents: DMF-d7 δH 2.9, δC 161.7;
THF-d8 δH 1.8, δC 26.7.
Iod id e 3. δH (DMF-d7) 1.41 (9 H, s), 3.55 (1 H, dd, J 8.5
and 10.2), 3.68 (1 H, dd, J 4.7 and 10.2) 4.45-4.49 (1 H, m),
5.22 (2 H, br s), 7.31 (1 H, br d, J 8.1), 7.32-7.45 (5 H, m); δC
(DMF-d7) 4.0, 27.4, 55.5, 66.4, 78.5, 127.6, 127.8, 128.1, 135.7,
155.2, 169.0. δH 1.50 (THF-d8) (9 H, s), 3.57 (1 H, dd, J 6.2
and 10.0), 3.62-3.66 (1 H, m), 4.54-4.58 (1 H, m), 5.24 (2 H,
s), 6.65 (1 H, d, J 7.2), 7.30-7.46 (5 H, m); δC (THF-d8) 7.9,
30.0, 57.2, 69.1, 81.0, 130.3, 130.4, 130.6, 138.2, 157.2, 171.4.
Zin c Rea gen t 4a . δH (DMF-d7) 0.49 (1 H, dd, J 9.0 and
12.5), 0.55 (1 H, dd J 7.1 and 12.5), 1.35 (9 H, s), 4.19-4.23 (1
H, m), 5.06 (1 H, d, J 12.7), 5.11 (I H, d, J 12.7), 6.12 (1 H, d,
J 6.6), 7.29-7.39 (5 H, m); δC (DMF-d7) 12.0, 26.9, 53.6, 64.1,
76.8, 126.4, 126.7, 127.3, 135.8, 154.3, 174.7. δH (THF-d8)
0.48-0.56 (1 H, m), 0.62-0.71 (1 H, m), 1.45 (9 H, s), 4.23-
4.28 (1 H, m), 5.14-5.17 (2 H, m), 6.79 (1 H, br s), 7.30-7.78
(5 H, m); δC (THF-d8) 15.0, 30.4, 57.4, 68.3, 82.5, 130.1, 130.6,
138.8, 156.0, 176.8. Remaining signal obscured by peaks at
130.
[R]27 -39.9 (c 1.0, MeOH) (lit. value of enantiomer [R]D +35
D
(c 1.0, MeOH)).52 IR (film, cm-1) 3377, 2977, 1740, 1713.
NMR: δH 1.44 (9H, s), 1.60-1.65 (1H, m), 2.13-2.19 (1H, m),
2.76 (1H, br s), 3.60-3.66 (1H, m), 3.68-3.72 (1H, m), 4.51-
4.55 (1H, m), 5.18 (1H, d, J 12.2), 5.21 (1H, d, J 12.2), 5.41
(1H, d, J 7.7), 7.34-7.37 (5H, m); δC 28.2, 36.1, 50.6, 58.2, 67.3,
80.5, 126.9, 128.2, 128.5, 135.2, 156.4, 172.7. m/z (EI) 310
(MH+, 5%).
Ben zyl 2-(S)-((ter t-Bu toxyca r bon yl)a m in o)-5-h yd r oxy-
p en ta n oa te (20). N-tert-Butoxycarbonyl-L-glutamic acid R-
benzyl ester 19 (3.37 g, 10.0 mmol) was treated under the same
reaction conditions as those described in the preparation of
succinimide ester 16. This led to the formation of succinimide
ester which, without further purification, was reduced using
the procedure developed for the preparation of benzyl 2-(S)-
((tert-butoxycarbonyl)amino)-4-hydroxybutanoate 17. Purifi-
cation by flash column chromatography (2:1 petroleum ether/
ethyl acetate) yielded benzyl 2-(S)-((tert-butoxycarbonyl)amino)-
5-hydroxypentanoate 20 as a colorless oil (1.78 g, 55%).
(Found M+ - C4H8 267.1114. C13H17NO5 requires 267.1107).
[R]27D -3.0 (c 1.0 in CHCl3) (lit. value -2.9 (c 1.0 in CHCl3)).53
IR (film, cm-1) 3373, 2978, 1739, 1704. NMR δH 1.42 (9H, s),
1.52-1.59 (2H, m), 1.69-1.76 (1H, m), 1.86-1.92 (1H, m), 2.74
(1H, br s), 3.58 (2H, t, J 6.1), 4.31-4.36 (1H, m), 5.14 (1H, d,
J 12.5), 5.19 (1H, d, J 12.5), 5.39 (1H, d, J 8.2), 7.33-7.35 (5H,
m). δC 28.2, 29.2, 53.2, 60.4, 61.8, 66.9, 79.9, 128.2, 128.3,
128.5, 135.3, 155.5, 172.6. m/z (EI) 267 (M+ - C4H8, 25%).
Ben zyl
2-(S)-((ter t-Bu t oxyca r b on yl)a m in o)-4-iod o-
bu ta n oa te (9). Triphenylphosphine (6.29 g, 24.0 mmol) and
imidazole (1.63 g, 24.0 mmol) were dissolved in dry dichlo-
romethane (60 mL) with stirring under nitrogen. Iodine (6.10
g, 24.0 mmol) was added slowly, and after 5 min a solution of
benzyl 2-(S)-((tert-butoxycarbonyl)amino)-4-hydroxybutanoate
17 (6.18 g, 20.0 mmol) in dry dichloromethane (20 mL) was
also added. Stirring was continued for 1 h at room tempera-
ture by which time no starting material remained (as judged
by TLC). The solvent was evaporated under reduced pressure,
the residue was filtered through a short column of silica gel
eluting with diethyl ether (300 mL), and the filtrate was
concentrated to give a pale yellow oil. Purification by flash
column chromatography eluting with 5:1 petroleum ether/ethyl
acetate yielded benzyl 2-(S)-((tert-butoxycarbonyl)amino)-4-
iodobutanoate 9 as a colorless solid which was recrystallized
from pentane, mp 54-55 °C (lit. value mp 54 °C)39 (5.70 g,
68%). (Found M+ - CO2Bn 284.0141. C8H15INO2 requires
Iod id e 9. δH (DMF-d7) 1.39 (9 H, s), 2.19-2.36 (2 H, m),
3.33-3.41 (2 H, m), 4.28 (1 H, td, J 4.6 and 13.2), 5.16 (1 H,
d, J 12.5), 5.22 (1 H, d, J 12.5), 6.91 (1 H, br d, J 7.5), 7.31-
7.44 (5 H, m); δC (DMF-d7) 1.8, 27.4, 35.0, 54.4, 65.9, 78.2,
127.5, 127.8, 128.1, 136.0, 155.7, 171.4. δH (THF-d8) 1.48 (9
H, s), 2.21 (1 H, dt, J 8.3 and 14.6), 2.41 (1 H, dt, J 7.9 and
13.5), 3.29 (2 H, t, J 8.3), 4.33 (1 H, dt, J 4.9 and 8.9), 5.19 (1
H, d, J 12.5), 5.22 (1 H, d, J 12.4), 6.61 (1 H, d, J 8.2), 7.33-
7.44 (5 H, m); δC (THF-d8) 2.2, 30.0, 38.7, 56.9, 80.6, 130.2,
130.5, 138.5, 157.8, 173.4. Remaining two signals obscured
by solvent peak, and by peaks at 130, respectively.
(52) Rodriguez, M.; Llinares, M.; Doulut, S.; Heitz, A.; Martinez, J .
Tetrahedron Lett. 1991, 32, 923-926.
(53) Olsen, R. K.; Ramasamy, K.; Emery, T. J . Org. Chem. 1984,
49, 3527-3534.
Zin c Rea gen t 5. δH (DMF-d7) 0.02-0.08 (1 H, m), 0.129
(1 H, dt, J 5.5 and 12.2), 1.35 (9 H, s), 1.84-1.92 (1 H, m),

NMR Studies of Amino Acid-Derived Organozinc Reagents
J . Org. Chem., Vol. 63, No. 22, 1998 7881
1.93-2.01 (1 H, m), 4.00 (1 H, d, J 7.6 and 13.1), 6.62 (1 H, d,
J 7.8), 7.03 (1 H, d, J 7.8), 7.29-7.39 (5 H, m); δC (DMF-d7)
3.5, 26.9, 30.0, 57.8, 64.3, 76.9, 126.5, 126.8, 127.3, 135.6, 154.9,
172.3. δH (THF-d8) 0.11-0.22 (2 H, m), 1.44 (9 H, m), 1.90-
2.08 (2 H, m), 4.05 (1 H, m), 5.16 (2 H, m), 6.23 (1 H, d, J 6.7),
7.31-7.38 (5 H, m); δC (THF-d8) 12.0, 30.2, 32.9, 57.4, 68.3,
80.6, 130.2, 130.6, 130.8, 138.6, 158.3, 174.9.
δC 28.3, 38.4, 52.2, 54.4, 79.9, 127.0, 128.5, 129.3, 136.0, 155.1,
172.4; m/z (EI) 279 (M+, 0.5%).
Meth yl 2-(S)-((ter t-Bu toxyca r bon yl)a m in o)-3-(2′-n itr o-
p h en yl)p r op a n oa t e (23b ). Treatment with 1-iodo-2-ni-
trobenzene gave 23b (0.0681 g, 28%), isolated as fine pale
brown needles, mp 83-84 °C. (Found: C, 55.67; H, 6.22; N,
8.64%:
C15H20N2O6 requires C, 55.55; H, 6.22; N, 8.64%).
[R]20 +42.7 (c 0.185, CH2Cl2). IR (KBr, cm-1) 3362, 1747,
Iod id e 10. δH (DMF-d7) 1.39 (9 H, s), 1.79-1.84 (1 H, m),
1.89-1.97 (3 H, m), 3.26-3.32 (2 H, m), 4.19 (1 H, dt, J 4.5
and 10.0), 5.16 (1 H, d, J 12.5), 5.21 (1 H, d, J 12.5), 7.26 (1 H,
d, J 7.9), 7.33-7.43 (5 H, m): δC (DMF-d7) 6.0, 27.5, 31.8, 52.8,
54.4, 65.7, 78.0, 127.5, 127.7, 128.1, 136.1, 155.6, 172.0 δH
(THF-d8) 1.38 (9 H, s), 1.64-1.69 (1 H, m), 1.80-1.88 (3 H,
m), 4.23 (1 H, td, J 8.8 and 4.6), 5.08 (1 H, d, J 12.5), 5.11 (1
H, d, J 12.5), 6.45 (1 H, d, J 8.6), 7.23-7.34 (5 H, m): δC (THF-
d8) 7.3, 30.0, 32.2, 35.3, 56.3, 80.6, 130.1, 130.2, 130.5, 138.7,
157.8, 175.0. Remaining signal obscured by solvent peak.
Zin c Rea gen t 6. δH (DMF-d7) 0.04-0.15 (2 H, m), 1.35 (9
H, s), 1.55-1.74 (4 H, m), 4.08-4.15 (1 H, m), 5.08 (1 H, d, J
12.5), 5.17 (1 H, d, J 12.5), 6.84 (1 H, d, J 7.9), 7.29-7.39 (5
H, m); δC (DMF-d7) 7.6, 23.8, 26.9, 36.2, 53.0, 64.6, 77.0, 126.5,
126.8, 127.4, 135.4, 154.8, 172.2. δH (THF-d8) 0.22-0.24 (2
H, m), 1.45 (9 H, s), 1.58-1.74 (3 H, m), 1.76-1.85 (1 H, m),
4.30-4.38 (1 H, m), 5.12 (1 H, d, J 12.5), 5.16 (1 H, d, J 12.5),
6.42 (1 H, d, J 6.0), 7.30-7.42 (5 H, m); δC (THF-d8) 15.6, 30.3,
55.8, 68.2, 80.8, 130.1, 130.5, 130.6, 138.7, 158.2, 175.0. The
two remaining methylene peaks are not easily assigned due to
other degradation products.
D
1684. NMR δH 1.34 (9 H, s), 3.20-3.27 (1 H, dd, J 9 and 14),
3.48-3.53 (1 H, dd, J 5.8 and 14), 3.70 (3 H, s), 4.65-4.66 (1
H, m), 5.16 (1 H, d, J 6.7), 7.36-7.40 (2 H, m), 7.53 (1 H, t, J
7.3), 7.91-7.96 (1 H, d, J 7.9); δC 28.2, 35.6, 52.6, 54.0, 80.0,
125.1, 128.1, 131.8, 133.1, 133.0, 149.7, 154.9, 172.0; m/z (EI)
265 (M+ - C2H3O2, 2%).
Meth yl 2-(S)-((ter t-Bu toxyca r bon yl)a m in o)-3-(4′-n itr o-
ph en yl)pr opan oate (23c). Treatment with 1-iodo-4-nitroben-
zene gave 23c (0.1370 g, 57%), isolated as fine brown needles,
mp 95-97 °C (lit. value55 mp 92-94 °C). (Found C, 55.25; H,
5.91; N, 8.51%: C15H20N2O6 requires C, 55.55; H, 6.22; N, 8.64).
[R]20 +30.4 (c 1.055, CH2Cl2). IR (KBr, cm-1) 3358, 1735,
D
1730, 1689, 1676. NMR δH 1.41 (9 H, s), 3.12 (1 H, dd, J 6.1
and 13.5), 3.27 (1 H, dd, J 6.1 and 13.5), 3.74 (3 H, s), 4.64-
4.67 (1 H, m), 5.01-5.09 (1 H, d, J 6.4), 7.31 (2 H, d, J 8.6),
8.16 (2 H, d, J 8.6); δC 28.3, 38.4, 52.5, 54.1, 80.4, 123.7, 130.2,
144.0, 147.2, 154.9, 171.6; m/z (EI) 324 (M+, 0.05%).
Meth yl 2-(S)-((ter t-Bu toxyca r bon yl)a m in o)-3-(2′-m eth -
oxyp h en yl)p r op a n oa te (23d ). Treatment with 2-iodoanisole
gave 23d (0.1272 g, 57%), isolated as pale orange oil, which
solidified with time, mp 75-76 °C. (Found C, 62.36; H, 7.55;
N, 4.53% C16H23NO5 requires C, 62.12; H, 7.49; N, 4.53%).
[R]20D +14.9 (c 0.68, CH2Cl2). IR (film, cm-1) 3379, 2976, 1746,
1716. NMR δH 1.38 (9 H, s), 3.02-3.11 (2 H, m), 3.69 (3 H, s),
3.82 (3 H, s), 4.51 (1 H, dd, J 7.3 and 13.7), 5.22 (1 H, d, J
7.3), 6.86 (1 H, d, J 8.2,), 6.89 (1 H, t, J 7.3), 7.09 (1 H, dd, 1.5
and 7.3), 7.23 (1 H, dt, J 1.5 and 8.2); δC 28.3, 32.4, 52.0, 54.0,
55.3, 79.5, 110.4, 120.6, 124.7, 131.2, 155.3, 157.6, 172.9; m/z
(EI) 309 (M+, 0.3%).
Iod id e 14. δH (DMF-d7) 1.42 (9 H, s), 3.49 (1 H, dd, J 8.2
and 10.0), 3.62 (1 H, dd, J 4.5 and 10.0), 3.71 (3 H, s), 4.40 (1
H, m), 7.21 (1H, br d, J 8.2); δC (DMF-d7) 4.1, 27.4, 51.7, 55.3,
78.5, 155.1, 169.6. δH (THF-d8) 1.49 (9 H, s), 3.53 (1 H, dd, J
6.1 and 10.0), 3.61 (1 H, dd, J 4.5 and 10.0), 3.78 (3 H, s), 4.50
(1 H, m), 6.59 (1 H, br d, J 7.0); δC (THF-d8) 8.1, 30.0, 57.0,
58.6, 81.0, 157.2, 171.9.
Zin c Rea gen t 13. δH (DMF-d7) 0.38 (1 H, dd, J 8.5 and
12.8), 0.42 (1 H, dd, J 7.6 and 12.8), 1.31 (9 H, s), 3.53 (3 H,
s), 4.09 (1 H, m), 6.99 (1 H, br d, J 6.7); δC (DMF-d7) 12.0,
28.6, 50.0, 53.3, 76.8, 154.2, 175.4. δH (THF-d8) 0.44 (1 H, m),
0.58 (1 H, m), 1.47 (9 H, s), 3.70 (3 H, s), 4.16 (1 H, m), 6.38 (1
H, br); δC (THF-d8) 14.9, 30.3, 53.6, 57.2, 82.5, 159.9, 177.3.
Rea ction w ith Ar om a tic Iod id es w ith Zin c Rea gen t 13.
Gen er a l P r oced u r e for r ea ction s in THF . The zinc
reagent 13 was prepared in THF from iodoalanine 14 (0.75
mmol), using an identical procedure to that used for THF-d8,
but it was not removed from the excess zinc. The aromatic
iodide (1 mmol) was added, followed by Pd2(dba)3 (20 mg, 0.019
mmol) and P(o-tol)3 (22 mg, 0.076 mmol). The reaction mixture
was stirred at 50 °C for 1 h. The mixture was filtered,
partitioned between ethyl acetate (25 mL) and water (25 mL),
and washed with brine (25 mL) and water (25 mL). The
organic extracts were dried, filtered, and evaporated. The
crude product was purified by flash column chromatography
using a petroleum ether:ethyl acetate gradient to give the pure
phenylalanine derivatives 23a -g.
Meth yl 2-(S)-((ter t-Bu toxyca r bon yl)a m in o)-3-(2′-flu o-
r op h en yl)p r op a n oa te (23e). Treatment with 2-fluoro-1-
iodobenzene gave 23e (0.0923 g, 40%), isolated as a pale yellow
oil. (Found C, 60.53; H, 4.57; N, 6.78% C15H20NO4F requires
C, 60.60; H, 4.71; N, 6.78%). [R]19 +40.0 (c 1.02, CH2Cl2). IR
D
(film, cm-1) 3440, 2979, 1747, 1717. NMR δH 1.40 (9 H, s),
3.08 (1 H, dd, J 6.8 and 13.8), 3.18 (1 H, dd, J 5.8 and 13.8),
3.73 (3 H, s), 4.59 (1 H, dd, J 6.4 and 14.1), 5.06 (1 H, d, J
7.6), 7.03 (1 H, t, J 8.9), 7.10 (1 H, dt, J 0.9 and 7.3), 7.15 (1
H, dt, J 1.5 and 7.7), 7.10-7.25 (1 H, m); δC 28.3, 31.9, 52.33,
53.6, 79.9, 115.4 (d, J CF 22.7), 123.2 (d, J CF 66), 124.1, 128.9
(d, J CF 8.25), 131.7 (d, J CF 4.1), 155.0, 161.4 (d, J CF 243.8),
172.2; m/z (EI) 297 (M+, 0.4%).
Meth yl 2-(S)-((ter t-Bu toxyca r bon yl)a m in o)-3-(4′-flu o-
r op h en yl)p r op a n oa te (23f). Treatment with 4-fluoro-1-
iodobenzene gave 23f (0.1203 g, 58%), isolated as beige needles,
mp 38-41 °C. (Found M+ 297.1355. C15H20NO4F requires
297.1376). [R]20 +30.5 (c 0.1, CH2Cl2). IR (KBr, cm-1) 3356,
D
Rea ction w ith Ar om a tic Iod id es. Gen er a l P r oced u r e
for Rea ction s in DMF . The zinc reagent 13 was prepared
in DMF using an identical procedure to that used for DMF-
d7, but it was not removed from the excess zinc. The coupling
reaction was carried out at room temp according to the
procedure described for above for THF.
1738, 1689, 1512, 1219, 1162; NMR δH 1.42 (9 H, s), 3.01 (1
H, dd, J 6.1 and 14), 3.10 (1 H, dd, J 5.8 and 14), 3.71 (3 H, s),
4.57 (1 H, dd, J 6.1 and 13.8), 4.98 (1 H, d, J 7.3), 6.96-7.00
(2 H, m), 7.07-7.12 (2 H, m); δC 28.3, 37.6, 52.3, 54.4, 80.0,
115.4 (d, J CF 20.7), 130.8 (d, J CF 7.3), 131.8, 155.0, 162.0 (d,
J CF 245.0), 172.2; m/z (EI) 297 (M+).
All the following data refer to compounds prepared using
DMF as solvent.
Meth yl 2-(S)-((ter t-Bu toxyca r bon yl)a m in o)-3-n a p h th -
ylp r op a n oa te (23g). Treatment with 1-iodonaphthalene
gave 23g (0.1714 g, 69%), isolated as a pale brown oil. (Found
Meth yl 2-(S)-((ter t-Bu toxyca r bon yl)a m in o)-3-p h en yl-
p r op a n oa te (23a ). Treatment with iodobenzene gave 23a
(0.1314 g, 64%), isolated as a colorless oil which solidified with
time, mp 41-42 °C. [R]20D +46.9 (c 3.43, CH2Cl2). [R]23D -5.6
(c 1.0, MeOH), lit. value54 [R]27D -4.6 (c 1.0, MeOH). IR (film,
cm-1) 3367, 1716. NMR δH 1.42 (9 H, s), 3.05 (1 H, dd, J 6.1
and 13.7), 3.12 (1 H, dd, J 5.5 and 13.7), 3.71 (3 H, s), 4.59 (1
H, dd, J 6.1 and 13.4), 4.98 (1 H, d, J 7.0), 7.22-7.31 (5 H, m);
M+ 329.1631. C19H23NO4 requires 329.1627). [R]20 +27.5 (c
D
1.47, CH2Cl2). IR (film, cm-1) 3369, 2977, 1745, 1713. NMR
δH 1.39 (9 H, s), 3.46 (1 H, dd, J 6.7 and 13.7), 3.56-3.60 (1 H,
m), 3.60 (3 H, s), 4.72 (1 H, dd, J 6.8 and 13.7), 5.09 (1 H, d,
J 7.3), 7.26 (1 H, d, J 7.0), 7.38 (1 H, t, J 7.9), 7.47 (1 H, t, J
7.2), 7.53 (1 H, t, J 7.1), 7.75 (1 H, d, J 8.0), 7.84 (1 H, d, J
8.0), 8.07 (1 H, d, J 8.5); δC 28.3, 35.6, 52.1, 54.3, 79.9, 123.6,
(54) Takeda, K.; Akiyama, A.; Nakamura, H.; Takizawa, S.; Mizuno,
Y.; Takayanagi, H.; Harigaya, Y. Synthesis 1994, 1063-1066.
(55) Tokutake, S.; Imanishi, Y.; Sisido, M. Mol. Cryst. Liq. Cryst.
1989, 170, 245-257.

7882 J . Org. Chem., Vol. 63, No. 22, 1998
J ackson et al.
125.6, 125.7, 126.3, 127.4, 127.9, 128.8, 132.2, 132.5, 133.9,
155.0, 172.6. m/z 329 (M+, 1%).
(1H, dd, J 7.3 and 1.5), 7.15-7.19 (1H, m), 7.33-7.36 (5H, m);
δC 26.2, 28.4, 32.4, 53.6, 55.1, 66.9, 79.7, 110.2, 120.5, 127.5,
128.2, 128.4, 128.6, 129.1, 130.0, 135.5, 155.4, 157.3, 172.6.
m/z (EI) 399 (M+, 1%), 343 (M+ - C4H8, 11).
P r ep a r a tion of P r otected Hom op h en yla la n in es (7).
Gen er a l P r oced u r e. Zinc dust (325 mesh, 0.40 g, 6.0 mmol)
was placed in a nitrogen-purged flask. Dry DMF (0.45 mL)
and 1,2-dibromoethane (25.9 µL, 0.3 mmol) were added, and
the flask was heated at 60 °C for 30 min using a hot water
bath. The mixture was allowed to cool to room temperature,
trimethylsilyl chloride (8.0 µL, 0.06 mmol) was added, and the
resulting mixture was stirred vigorously for 30 min. A solution
of benzyl 2-(S)-((tert-butoxycarbonyl)amino)-4-iodobutanoate 9
(0.42 g, 1.0 mmol) in dry DMF (0.45 mL) was added to the
activated zinc. The reaction mixture was heated to 35 °C for
30 min, after which time TLC analysis (5:1 petroleum ether/
ethyl acetate) revealed that no starting material remained.
The reaction mixture was cooled to room temperature, and
then Pd2(dba)3 (17.3 mg, 0.02 mmol), tri-o-tolylphosphine (22.8
mg, 0.08 mmol), and the aromatic iodide (0.75 mmol) were
added sequentially. Stirring was continued for 3 h at room
temperature. The reaction mixture was diluted with ethyl
acetate (50 mL), and the organic layer was washed with brine
(3 × 30 mL), dried, and concentrated under reduced pressure
to give the crude product as an oil. Purification by flash
column chromatography (petroleum ether/ethyl acetate gradi-
ent) afforded the pure 4-aryl R-amino acid derivative.
Ben zyl 2-(S)-((ter t-Bu toxyca r bon yl)a m in o)-4-(4′-m eth -
oxyp h en yl)bu ta n oa te (7e). Treatment with 4-iodoanisole
(0.18 g, 0.75 mmol) yielded benzyl 2-(S)-((tert-butoxycarbonyl)-
amino)-4-(4′-methoxyphenyl)butanoate 7e as a yellow oil (0.22
g, 74%). (Found M+ 399.2048. C23H29NO5 requires 399.2045).
[R]19 +7.2 (c 1.0, CH2Cl2). IR (film, cm-1) 3364, 2977, 2835,
D
1740, 1715. NMR δH 1.45 (9H, s), 1.87-1.94 (1H, m), 2.08-
2.14 (1H, m), 2.50-2.61 (2H, m), 3.77 (3H), 4.36-4.40 (1H,
m), 5.07 (1H, d, J 7.7), 5.12 (1H, d, J 12.2), 5.19 (1H, d, J 12.2),
6.79 (2H, d, J 8.6), 7.02 (2H, d, J 8.6), 7.34-7.37 (5H, m); δC
28.3, 30.6, 34.6, 53.3, 55.2, 67.0, 79.9, 113.9, 128.3, 128.4, 128.6,
129.3, 132.8, 135.4, 155.7, 158.0, 172.5. m/z (EI) 399 (M+, 4%),
343 (M+ - C4H8, 42).
Ben zyl 2-(S)-((ter t-Bu toxyca r bon yl)a m in o)-4-(4′-m eth -
ylp h en yl)bu ta n oa te (7f). Treatment with 4-iodotoluene
(0.16 g, 0.75 mmol) yielded benzyl 2-(S)-((tert-butoxycarbonyl)-
amino)-4-(4′-methylphenyl)butanoate 7f as a pale orange oil
which solidified on standing, mp 60.5-61.5 °C (0.25 g, 87%).
(Found M+ 383.2099. C23H29NO4 requires 383.2096). [R]17
D
+6.9 (c 1.0, CH2Cl2). IR (film, cm-1) 3362, 2976, 1740, 1716.
NMR δH 1.44 (9H, s), 1.88-1.95 (1H, m), 2.09-2.15 (1H, m),
2.30 (3H, s), 2.54-2.62 (2H, m), 4.37-4.41 (1H, m), 5.06 (1H,
d, J 8.0), 5.12 (1H, d, J 12.2), 5.22 (1H, d, J 12.2), 7.00 (2H, d,
J 7.9), 7.07 (2H, d, J 7.9), 7.34-7.37 (5H, m); δC 21.0, 28.3,
31.1, 34.5, 53.5, 67.1, 79.9, 128.2, 128.3, 128.4, 128.6, 129.1,
135.4, 135.6, 137.6, 155.3, 172.5. m/z (EI) 383 (M+, 1%), 327
(M+ - C4H8, 19).
Ben zyl 2-(S)-((ter t-Bu toxyca r bon yl)a m in o)-4-p h en yl-
bu ta n oa te (7a ). Treatment with iodobenzene (83.9 µL, 0.75
mmol) yielded benzyl 2-(S)-((tert-butoxycarbonyl)amino)-4-
phenylbutanoate 7a as a pale yellow oil which solidified on
standing, mp 45-46 °C (0.19 g, 70%). (Found M+ - C4H8
313.1311. C18H19NO4 requires 313.1314). [R]17 +7.7 (c 1.0,
D
CH2Cl2). IR (film, cm-1) 3369, 2978, 1740, 1715. NMR δH 1.45
(9H, s), 1.90-1.97 (1H, m), 2.11-2.17 (1H, m), 2.55-2.68 (2H,
m), 4.38-4.43 (1H, m), 5.09-5.12 (2H, m), 5.19 (1H, d, J 12.2),
7.11 (2H, d, J 7.4), 7.18 (1H, t, J 7.4), 7.26 (2H, t, J 7.4), 7.33-
7.37 (5H, m); δC 28.3, 31.5, 34.4, 53.4, 67.0, 79.9, 126.1, 128.2,
128.3, 128.4, 128.5, 128.6, 135.3, 140.7, 155.3, 172.5. m/z (EI)
313 (M+ - C4H8, 60%).
Ben zyl 2-(S)-((ter t-Bu toxyca r bon yl)a m in o)-4-n a p h th -
ylbu ta n oa te (7g). Treatment with 1-iodonaphthalene (109.5
µL, 0.75 mmol) yielded benzyl 2-(S)-((tert-butoxycarbonyl)-
amino)-4-naphthylbutanoate 7g as a pale yellow oil which
solidified on standing, mp 84-85 °C (0.28 g, 88%). (Found
M+ 419.2089. C26H29NO4 requires 419.2096). [R]17 +13.3 (c
D
1.0, CH2Cl2). IR (film, cm-1) 3355, 2977, 1735, 1714. NMR
δH 1.47 (9H, s), 2.06-2.13 (1H, m), 2.25-2.31 (1H, m), 3.00-
3.14 (2H, m), 4.49-4.54 (1H, m), 5.15 (1H, d, J 12.2), 5.20 (1H,
d, J 12.2), 5.22 (1H, d, J 8.2), 7.25 (1H, d, J 7.0), 7.33-7.37
(6H, m), 7.43-7.47 (2H, m), 7.70 (1H, d, J 8.3), 7.82-7.85 (1H,
m), 7.87-7.89 (1H, m); δC (125 MHz, CDCl3) 28.3, 33.6, 53.6,
60.4, 67.2, 79.1, 123.4, 125.5, 125.9, 126.1, 126.9, 127.0, 128.3,
128.4, 128.5, 128.6, 128.8, 131.6, 133.9, 135.3, 155.3, 172.3.
m/z (EI) 419 (M+, 2%), 363 (M+ - C4H8, 30).
Ben zyl 2-(S)-((ter t-Bu toxyca r bon yl)a m in o)-4-(2′-n itr o-
p h en yl)bu ta n oa te (7b). Treatment with 1-iodo-2-nitroben-
zene (0.18 g, 0.75 mmol) yielded benzyl 2-(S)-((tert-butoxycar-
bonyl)amino)-4-(2′-nitrophenyl)butanoate 7b as an orange oil
(0.12 g, 40%). (Found MH+ - C4H8 359.1260. C18H19N2O6
requires 359.1243). [R]17 +24.5 (c 1.0, CH2Cl2). IR (film,
D
cm-1) 3374, 2978, 1740 and 1713, 1610, 1577, 1527, 1500, 1391,
1366, 1349. NMR δH 1.46 (9H, s), 2.00-2.04 (1H, m), 2.17-
2.23 (1H, m), 2.88-2.93 (2H, m), 4.41-4.45 (1H, m), 5.16-
5.19 (2H, m), 5.22 (1H, d, J 12.2), 7.34-7.37 (7H, m), 7.49-
7.52 (1H, m), 7.92 (1H, d, J 8.3); δC 28.3, 29.2, 33.5, 53.5, 67.3,
80.1, 124.8, 125.0, 127.4, 128.5, 128.6, 132.2, 133.2, 135.3,
136.1, 149.1, 155.4, 172.1. m/z (EI) 359 (MH+ - C4H8, 1%).
Ben zyl 2-(S)-((ter t-Bu toxyca r bon yl)a m in o)-4-(4′-n itr o-
p h en yl)bu ta n oa te (7c). Treatment with 1-iodo-4-nitroben-
zene (0.18 g, 0.75 mmol) yielded benzyl 2-(S)-((tert-butoxycar-
bonyl)amino)-4-(4′-nitrophenyl)butanoate 7c as an orange oil
(0.26 g, 84%). (Found M+ 414.1793. C22H26N2O6 requires
Ben zyl 2-(S)-((ter t-Bu toxyca r bon yl)a m in o)-4-(2′-a m i-
n op h en yl)bu ta n oa te (7h ). Treatment with 2-iodoaniline
(0.16 g, 0.75 mmol) yielded benzyl 2-(S)-((tert-butoxycarbonyl)-
amino)-4-(2′-aminophenyl)butanoate 7h as a pale yellow oil
which solidified on standing, mp 112-113 °C (0.15 g, 53%).
(Found M+ 384.2053. C22H28N2O4 requires 384.2049). [R]19
D
+6.7 (c 1.0, CH2Cl2). IR (KBr, cm-1) 3435, 3354 2970, 1735
and 1678. NMR δH 1.44 (9H, s), 1.93-2.00 (1H, m), 2.12-
2.17 (1H, m), 2.41-2.47 (1H, m), 2.50-2.55 (1H, m), 3.56 (2H,
s), 4.40-4.45 (1H, m), 5.14 (1H, d, J 12.2), 5.19-5.21 (2H, m),
6.64 (1H, dd, J 7.6 and 1.2), 6.68-6.71 (1H, m), 6.94 (1H, dd,
J 7.4 and 1.2), 7.00-7.04 (1H, m), 7.33-7.36 (5H, m); δC 26.9,
28.3, 31.7, 53.5, 67.1, 80.0, 115.7, 118.8, 124.9, 127.4, 128.4,
128.5, 128.6, 129.4, 135.3, 144.1, 155.4, 172.4. m/z (EI) 384
(M+, 34%), 328 (M+ - C4H8, 40).
414.1791). [R]17 +10.8 (c 1.0, CH2Cl2). IR (film, cm-1) 3379,
D
2978, 1740, 1714, 1605, 1576, 1520, 1499, 1391, 1367, 1347.
NMR δH 1.45 (9H, s), 1.92-1.99 (1H, m), 2.14-2.20 (1H, m),
2.63-2.69 (1H, m), 2.72-2.78 (1H, m), 4.38-4.42 (1H, m),
5.11-5.14 (2H, m), 5.24 (1H, d, J 12.2), 7.23 (2H, d, J 8.6),
7.35-7.38 (5H, m), 8.10 (2H, d, J 8.6). δC 28.3, 31.4, 33.9, 53.2,
67.3, 80.2, 123.6, 123.7, 128.5, 128.6, 129.2, 135.1, 146.5, 148.6,
155.0, 172.0. m/z (EI) 414 (M+, 0.1%), 358 (M+ - C4H8, 3).
Ben zyl 2-(S)-((ter t-Bu toxyca r bon yl)a m in o)-4-(2′-m eth -
oxyp h en yl)bu ta n oa te (7d ). Treatment with 2-iodoanisole
(97.6 µL, 0.75 mmol) yielded benzyl 2-(S)-((tert-butoxy-
carbonyl)amino)-4-(2′-methoxyphenyl)butanoate 7d as a pale
orange oil which solidified on standing, mp 51-52 °C (0.22 g,
74%). (Found M+ 399.2059. C23H29NO5 requires 399.2045).
P r ep a r a tion of a n Au th en tic Sa m p le of En a n tiom er i-
ca lly P u r e Ben zyl 2-(S)-(ter t-bu toxyca r bon yl)a m in o)-4-
p h en ylb u t a n oa t e (7a ). N-(tert-Butoxycarbonyl)-(L)-homo-
phenylalanine 25 (0.42 g, 1.5 mmol, purchased from BACHEM
in its enantiomerically pure form) was dissolved in dry DMF
(3 mL) under nitrogen. Sodium hydrogen carbonate (0.32 g,
3.8 mmol) followed by benzyl bromide (0.54 mL, 4.5 mmol)
were added to the reaction mixture, and it was heated at 60
°C for 4 h. The mixture was then allowed to cool to room
temperature, and it was diluted with water. The aqueous
layer was extracted with ethyl acetate (30 mL), and the organic
extract was subsequently washed with water (2 × 50 mL) and
brine (50 mL). The organic extract was dried and concentrated
under reduced pressure to give an oil which was purified by
[R]17 +6.7 (c 1.0, CH2Cl2). IR (film, cm-1) 3371, 2975, 1740,
D
1716, 1589, 1559 1495 1384, 1367. NMR δH 1.45 (9H, s), 1.93-
1.98 (1H, m), 2.08-2.14 (1H, m), 2.64 (2H, t, J 7.8), 3.78 (3H),
4.36-4.40 (1H, m), 5.10 (1H, d, J 12.3), 5.14 (1H, d, J 12.3),
5.18 (1H, d, J 8.3), 6.82 (1H, d, J 8.0), 6.84-6.87 (1H, m), 7.04

NMR Studies of Amino Acid-Derived Organozinc Reagents
J . Org. Chem., Vol. 63, No. 22, 1998 7883
flash column chromatography (10:1 petroleum ether/ethyl
acetate). This yielded benzyl 2-(S)-((tert-butoxycarbonyl)-
amino)-4-phenylbutanoate 7a as a colorless solid, mp 45-46
J 8.3 and 1.3); δC 26.3, 28.3, 32.3, 32.5, 53.2, 67.1, 79.9, 124.7,
126.8, 127.1, 128.4, 128.6, 131.8, 132.9, 135.3, 136.7, 149.2,
155.3, 172.5. m/z (EI) 373 (MH+ - C4H8, 3%).
°C (0.53 g, 96%). [R]16 +7.7 (c 1.0, CH2Cl2) [compared with
Ben zyl 2-(S)-((ter t-Bu toxyca r bon yl)a m in o)-5-(4′-n itr o-
p h en yl)p en ta n oa te (8c). Treatment with 1-iodo-4-nitroben-
zene (0.18 g, 0.75 mmol) yielded benzyl 2-(S)-((tert-butoxycar-
bonyl)amino)-5-(4′-nitrophenyl)pentanoate 8c as an orange oil
(0.24 g, 75%). (Found MH+ 429.2022. C23H29N2O6 requires
D
[R]17 +7.7 (c 1.0, CH2Cl2) from the sample of 7a prepared via
D
the palladium-catalyzed cross-coupling reaction]. All other
data was consistent with that quoted above.
(S)-(2-Oxo-2,3,4,5-t et r a h yd r o-1H -[1]b en za zep in -3-yl)-
ca r ba m ic Acid ter t-Bu tyl Ester (26). Benzyl 2-(S)-((tert-
butoxycarbonyl)amino)-4-(2′-aminophenyl)butanoate 7h (0.38
g, 1.0 mmol) was heated at 180 °C for 16 h under an
atmosphere of nitrogen. The crude product was allowed to cool
and then purification by flash column chromatography (pe-
troleum ether/ethyl acetate gradient) afforded (2-oxo-2,3,4,5-
tetrahydro-1H-[1]benzazepin-3-yl)carbamic acid tert-butyl es-
ter 26 as a colorless crystalline solid, mp 233-235 °C (0.19 g,
68%). (Found M+ 276.1470. C15H20N2O3 requires 276.1474).
[R]20D -189.6 (c 1.0, MeOH). IR (KBr, cm-1) 3290 3192, 2980,
1719, 1679. NMR δH 1.41 (9H, s), 1.96-2.02 (1H, m), 2.62-
2.70 (2H, m), 2.90-2.96 (1H, m), 4.27-4.32 (1H, m), 5.53 (1H,
d, J 7.3), 7.01 (1H, d, J 7.3), 7.12-7.15 (1H, m), 7.20-7.23
(2H, m), 8.36 (1H, s); δC 28.3, 28.6, 36.7, 50.5, 79.7, 122.5,
126.4, 127.7, 129.8, 134.0, 136.2, 155.1, 173.3. m/z (EI) 276
(M+, 1%), 220 (M+ - C4H8, 36).
(S)-3-Am in o-2,3,4,5-t e t r a h yd r o-1H -[1]b e n za ze p in -2-
on e (25). (2-Oxo-2,3,4,5-tetrahydro-1H-[1]benzazepin-3-yl)-
carbamic acid tert-butyl ester 26 (55.3 mg, 0.2 mmol) was
dissolved in dry dichloromethane (2 mL) at 0 °C under an
atmosphere of nitrogen. Trifluoroacetic acid (TFA) (0.5 mL)
was added, and the reaction mixture was stirred for 1.5 h,
during which time the temperature was allowed to warm to
room temperature. The reaction mixture was concentrated,
and the residue was dissolved in water (10 mL). The pH of
the aqueous solution was brought up to 10 using solid
potassium carbonate, and then the solution was extracted with
dichloromethane (4 × 10 mL). The organic extracts were
combined, dried, and concentrated. This yielded (S)-3-amino-
2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one 25 as a pale yellow
solid, mp 147-149 °C (22.9 mg, 65%). (Found M+ 176.0947.
429.2022). [R]24 -1.6 (c 1.0, CH2Cl2). IR (film, cm-1) 3390,
D
2977, 1741, 1713, 1605, 1599, 1519, 1499, 1384, 1367, 1346.
NMR δH 1.44 (9H, s), 1.58-1.70 (3H, m), 1.83-1.87 (1H, m),
2.63-2.76 (2H, m), 4.39-4.42 (1H, m), 5.07-5.12 (2H, m), 5.21
(1H, d, J 12.2), 7.23 (2H, d, J 8.6), 7.32-7.36 (5H, m), 8.09
(2H, d, J 8.6); δC 26.4, 28.2, 32.2, 34.9, 53.0, 67.1, 80.0, 123.6,
128.3, 128.5, 128.6, 129.1, 135.2, 146.4, 149.5, 155.3, 172.3.
m/z (EI) 373 (MH+ - C4H8, 4%).
Ben zyl 2-(S)-((ter t-Bu toxyca r bon yl)a m in o)-5-(2′-m eth -
oxyp h en yl)p en ta n oa te (8d ). Treatment with 2-iodoanisole
(97.6 µL, 0.75 mmol) yielded benzyl 2-(S)-((tert-butoxy-
carbonyl)amino)-5-(2′-methoxyphenyl)pentanoate 8d as an
orange oil (0.13 g, 42%). (Found M+ 413.2224. C24H31NO5
requires 413.2202). [R]24D +1.0 (c 1.0, CH2Cl2). IR (film, cm-1
)
3379, 2977, 1741, 1715. NMR δH 1.43 (9H, s), 1.61-1.67 (3H,
m), 1.82-1.89 (1H, m), 2.56-2.64 (2H, m), 3.78 (3H), 4.34-
4.39 (1H, m), 5.01 (1H, d, J 7.7), 5.12 (1H, d, J 12.3), 5.19 (1H,
d, J 12.3), 6.81-6.86 (2H, m), 7.04 (1H, dd, J 6.1 and 1.3),
7.15-7.18 (1H, m), 7.31-7.36 (5H, m); δC 25.5, 28.3, 29.5, 32.3,
53.5, 55.2, 66.9, 79.8, 110.2, 120.3, 127.1, 128.2, 128.3, 128.6,
129.2, 129.8, 135.5, 155.3, 157.4, 172.3. m/z (EI) 413 (M+,
0.2%), 357 (M+ - C4H8, 20).
Ben zyl 2-(S)-((ter t-Bu toxyca r bon yl)a m in o)-5-(4′-m eth -
oxyp h en yl)p en ta n oa te (8e). Treatment with 4-iodoanisole
(0.18 g, 0.75 mmol) yielded benzyl 2-(S)-((tert-butoxycarbonyl)-
amino)-5-(4′-methoxyphenyl)pentanoate 8e as an orange oil
(0.19 g, 62%). (Found M+ 413.2216. C24H31NO5 requires
413.2202). [R]19 -1.0 (c 1.0, CH2Cl2). IR (film, cm-1) 3372,
D
2977, 1742, 1714. NMR δH 1.43 (9H, s), 1.61-1.66 (3H, m),
1.80-1.84 (1H, m), 2.47-2.59 (2H, m), 3.78 (3H), 4.34-4.39
(1H, m), 5.00 (1H, d, J 8.0), 5.12 (1H, d, J 12.2), 5.20 (1H, d,
J 12.2), 6.79 (2H, d, J 8.6), 7.02 (2H, d, J 8.6), 7.31-7.36 (5H,
m); δC 27.1, 28.3, 32.2, 34.3, 53.4, 55.3, 66.9, 79.8, 113.8, 128.3,
128.6, 129.2, 129.3, 133.7, 135.4, 155.3, 157.8, 172.7. m/z (EI)
413 (M+, 3%), 357 (M+ - C4H8, 58).
C
10H12N2O requires 176.0950). -445.7 (c 0.5, MeOH) (lit.
value -446 (c 1.0, MeOH)).48 IR (KBr, cm-1) 3355, 3180, 2942,
1684. NMR δH 1.75 (2H, br s), 1.90-1.96 (1H, m), 2.48-2.56
(1H, m), 2.63-2.67 (1H, m), 2.88-2.95 (1H, m), 3.45 (1H, br
s), 6.99 (1H, d, J 7.6), 7.13-7.16 (1H, m), 7.23-7.26 (2H, m),
8.03 (1H, br s); δC 29.1, 39.1, 51.5, 122.0, 126.1, 127.6, 129.7,
134.5, 136.6, 177.5. m/z (EI) 176 (M+, 37%).
Ben zyl 2-(S)-((ter t-Bu toxyca r bon yl)a m in o)-5-(4′-m eth -
ylp h en yl)p en ta n oa te (8f). Treatment with 4-iodotoluene
(0.16 g, 0.75 mmol) yielded benzyl 2-(S)-((tert-butoxycarbonyl)-
amino)-5-(4′-methylphenyl)pentanoate 8f as a yellow oil (0.25
g, 84%). (Found M+ - C4H8 341.1623. C20H23NO4 requires
P r ep a r a t ion of 5-Ar yl r-Am in o Acid s (8). Gen er a l
P r oced u r e. Zinc reagent 6 was prepared from iodide 10 in
DMF on a 1 mmol scale and then coupled to aryl iodides (0.75
mmol) to give the 5-aryl R-amino acids 8, in an identical
manner to that described above for zinc reagent 5.
341.1627). [R]17 -1.5 (c 1.0, CH2Cl2). IR (film, cm-1) 3374,
D
2977, 1741, 1715. NMR δH 1.43 (9H, s), 1.61-1.67 (3H, m),
1.81-1.85 (1H, m), 2.30 (3H, s), 2.50-2.60 (2H, m), 4.34-4.38
(1H, m), 5.00 (1H, d, J 7.9), 5.12 (1H, d, J 12.2), 5.20 (1H, d,
J 12.2), 6.99 (2H, d, J 7.9), 7.05 (2H, d, J 7.9), 7.31-7.35 (5H,
m); δC 21.0, 27.0, 28.3, 32.2, 34.8, 53.3, 66.9, 79.8, 128.2, 128.3,
128.4, 128.6, 129.0, 135.3, 135.4, 138.5, 155.3, 172.7. m/z (EI)
341 (M+ - C4H8, 7%).
Ben zyl 2-(S)-((ter t-Bu toxyca r bon yl)a m in o)-5-p h en yl-
p en ta n oa te (8a ). Treatment with iodobenzene (83.9 µL, 0.75
mmol) yielded benzyl 2-(S)-((tert-butoxycarbonyl)amino)-5-
phenylpentanoate 8a as a yellow oil (0.22 g, 77%). (Found
MH+ 384.2196. C23H30NO4 requires 384.2174). [R]17D -0.8 (c
1.0, CH2Cl2). IR (film, cm-1) 3371, 2977, 1741, 1715. NMR
δH 1.43 (9H, s), 1.61-1.69 (3H, m), 1.81-1.86 (1H, m), 2.53-
2.63 (2H, m), 4.36-4.40 (1H, m), 5.02 (1H, d, J 7.6), 5.11 (1H,
d, J 12.2), 5.18 (1H, d, J 12.2), 7.10 (2H, d, J 7.3), 7.16 (1H, t,
J 7.3), 7.24 (2H, t, J 7.3), 7.32-7.36 (5H, m); δC 26.9, 28.3,
32.2, 35.2, 53.3, 66.9, 79.9, 125.9, 128.2, 128.3, 128.4, 128.5,
128.6, 135.4, 141.6, 155.3, 172.7. m/z (EI) 384 (MH+, 1%), 327
(M+ - C4H8, 10).
Ben zyl 2-(S)-((ter t-Bu toxyca r bon yl)a m in o)-5-n a p h th -
ylpen tan oate (8g). Treatment with 1-iodonaphthalene (109.5
µL, 0.75 mmol) yielded benzyl 2-(S)-((tert-butoxycarbonyl)-
amino)-5-naphthylpentanoate 8g as a yellow oil (0.13 g, 41%).
(Found M+ 433.2245. C27H31NO4 requires 433.2253). [R]24
D
+0.3 (c 1.0, CH2Cl2). IR (film, cm-1) 3371, 2977, 1741, 1714.
NMR δH 1.43 (9H, s), 1.73-1.85 (3H, m), 1.93-1.98 (1H, m),
2.99-3.13 (2H, m), 4.39-4.44 (1H, m), 5.02 (1H, d, J 8.0), 5.11
(1H, d, J 12.5), 5.17 (1H, d, J 12.5), 7.25 (1H, d, J 6.1), 7.28-
7.36 (6H, m), 7.45-7.49 (2H, m), 7.70 (1H, d, J 8.3), 7.82-
7.85 (1H, m); 7.96-7.98 (1H, m). δC 26.3, 28.3, 32.4, 53.3, 60.5,
67.0, 79.9, 123.7, 125.4, 125.5, 125.8, 126.0, 126.7, 127.0, 128.2,
128.4, 128.6, 128.8, 131.6, 133.9, 135.4, 155.4, 172.7. m/z (EI)
433 (M+, 2%), 377 (M+ - C4H8, 48).
Ben zyl 2-(S)-((ter t-Bu toxyca r bon yl)a m in o)-5-(2′-n itr o-
p h en yl)p en ta n oa te (8b). Treatment with 1-iodo-2-nitroben-
zene (0.18 g, 0.75 mmol) yielded benzyl 2-(S)-((tert-butoxycar-
bonyl)amino)-5-(2′-nitrophenyl)pentanoate 8b as an orange oil
(0.03 g, 10%). (Found MH+ - C4H8 373.1399. C19H21N2O6
requires 373.1400). [R]18D -4.0 (c 0.5, CH2Cl2). IR (film, cm-1
)
3378, 2977, 1741, 1713, 1609, 1577, 1526, 1499, 1391, 1366,
1349. NMR δH 1.43 (9H, s), 1.62-1.75 (3H, m), 1.89-1.94 (1H,
m), 2.81-2.88 (2H, m), 4.37-4.42 (1H, m), 5.06 (1H, d, J 8.2),
5.14 (1H, d, J 12.2), 5.21 (1H, d, J 12.2), 7.25 (1H, dd, J 7.6
and 1.5), 7.32-7.37 (6H, m), 7.46-7.49 (1H, m), 7.89 (1H, dd,
Ben zyl 2-(S)-Am in o-5-p h en ylp en ta n oa te p-Tolu en e-
su lfon a te (27). Redistilled trifluoroacetic acid (TFA) (2 mL)
was added to a stirred solution of benzyl 2-(S)-((tert-butoxy-
carbonyl)amino)-5-phenylpentanoate 8a (95.8 mg, 0.25 mmol)
in dry dichloromethane (2 mL) at - 10 °C under an atmo-

7884 J . Org. Chem., Vol. 63, No. 22, 1998
J ackson et al.
sphere of nitrogen. The cooling bath was removed, and the
solution was stirred at room temperature for 1 h, after which
time TLC analysis showed that no starting material remained.
Concentration under reduced pressure gave an oil which was
redissolved in dichloromethane (10 mL). Neutralization by
careful addition of a saturated aqueous solution of sodium
hydrogen carbonate was carried out, and then the organic layer
was further washed with aqueous sodium hydrogen carbonate
(3 × 5 mL, 1 M), water (3 × 5 mL), and brine (5 mL). Drying
and concentrating under reduced pressure gave an oil which
was purified by flash column chromatography (petroleum
ether/ethyl acetate gradient). This yielded benzyl 2-(S)-amino-
5-phenylpentanoate as a straw-colored oil, which was dissolved
in ethanol (2 mL), and p-toluenesulfonic acid monohydrate
(47.5 mg, 0.25 mmol) in ethanol (5 mL) was added to the
solution. The mixture was left at room temperature for 16 h,
after which time a colorless solid had precipitated. This was
filtered and rinsed with cold diethyl ether leaving benzyl 2-(S)-
amino-5-phenylpentanoate p-toluenesulfonate 27 as a colorless
crystalline solid, mp 125-126 °C (lit.51 value mp 125-127 °C)
(68.0 mg, 60%). (Found M+ - TsOH 283.1558. C18H21NO2
8.26 (3H, s); δC 21.3, 26.0, 29.9, 34.9, 53.0, 67.8, 125.8, 126.1,
128.2, 128.3, 128.4, 128.5, 128.5, 128.9, 134.7, 140.6, 140.9,
141.2, 169.3. m/z (EI) 283 (M+ - TsOH, 0.5%).
Ack n ow led gm en t. We thank Pfizer Central Re-
search (studentship award to R.J .M.), EPSRC (student-
ship to C.S.D.) and Merck Sharpe and Dohme (CASE
award to C.S.D.) for support, and the Nuffield Founda-
tion for a One Year Science Research Fellowship
(R.F.W.J ). We also thank Dr. N. Wishart for developing
the techniques for measuring NMR spectra of amino
acid derived zinc reagents, Drs. M.N.S. Hill and Dr.
N.H. Rees for recording NMR spectra, and Dr. D. Turner
for the initial preparation of substituted phenylalanine
derivatives from 14 in THF, and the NMR spectra of
racemic 13.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for all compounds (78 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
requires 283.1572). [R]15 +1.8 (c 1.0, CHCl3). (lit.51 value
D
[R]20 +1.6 (c 1.0, CHCl3)). IR (KBr, cm-1) 3062, 2937, 1743.
D
NMR δH 1.43-1.50 (1H, m), 1.60-1.68 (1H, m), 1.80-1.85 (2H,
m), 2.28 (3H, s), 2.34-2.38 (2H, m), 4.01-4.05 (1H, m), 4.94
(1H, d, J 12.2), 5.09 (1H, d, J 12.2), 6.92 (2H, dd, J 7.9 and
1.7), 7.05 (2H, d, J 8.0), 7.10-7.28 (8H, m), 7.72 (2H, d, J 8.0),
J O981133U