New Approach to the Coupling if γ-Amino β-Hydroxy Acids and ν,γ-Dihydroxy Acids with α-Amino Acid Esters

Article abstract of DOI:10.1021/jo961219s

α,α-Dichloro β-lactones, readily obtained by a highly diastereoselective cycloaddition of dichloroketene to N-Boc-α-amino aldehydes and α-(silyloxy) aldehydes, coupled efficiently with α-amino acid esters leading, after dehalogenation with H2 over 10percent Pd on charcoal, to peptide mimics under mild reaction conditions.

Full text of DOI:10.1021/jo961219s

9196
J . Org. Chem. 1996, 61, 9196-9201
New Ap p r oa ch to th e Cou p lin g of γ-Am in o â-Hyd r oxy Acid s a n d
â,γ-Dih yd r oxy Acid s w ith r-Am in o Acid Ester s
Claudio Palomo,*,† J ose´ I. Miranda,† and Anthony Linden‡,§
Departamento de Quı´mica Orga´nica, Facultad de Qu´ımica, Universidad del Pais Vasco, Apdo 1072,
20080 San Sebastia´n, Spain, and Organisch-Chemisches Institut der Universita¨t Zu¨rich,
Winterthurerstrasse 190, CH-8057 Zu¨rich, Switzerland
Received J une 27, 1996X
R,R-Dichloro â-lactones, readily obtained by a highly diastereoselective cycloaddition of dichlo-
roketene to N-Boc-R-amino aldehydes and R-(silyloxy) aldehydes, coupled efficiently with R-amino
acid esters leading, after dehalogenation with H2 over 10% Pd on charcoal, to peptide mimics under
mild reaction conditions.
The development of new approaches to the stereocon-
ample, the most efficient approaches to date involve, on
the one hand, the conversion of N,N-dibenzylated R-ami-
no acids into â-keto esters followed by stereoselective
reduction to the corresponding â-hydroxy esters6 and, on
the other hand, the aldol reaction of achiral acetate
enolates with N,N-dibenzyl R-amino aldehydes.7 The
resulting â-hydroxy esters after deprotection and carboxyl
group activation can be incorporated into peptides by
standard procedures. Our recent studies on â-lactam
coupling reactions8 suggest that peptide derivatives
containing γ-amino or γ-hydroxy acids could be directly
obtained by ring opening of â-lactones by R-amino acid
esters. Nevertheless, a literature precedent concerning
the â-lactone cleavage by nitrogen nucleophiles revealed
the O-acyl fission as the major competitive reaction,9 and
only a very limited number of procedures addressing the
desired O-acyl fission have been reported to date.10 The
only work related to the idea of coupling â-lactones with
R-amino acid esters was that of Seebach and co-workers,11
who realized the coupling of (()-â-butyrolactone with (S)-
valine methyl ester. Although their work led to the
expectation that other families of R-unsubstituted â-lac-
tones could also be able to undergo O-acyl cleavage by
R-amino acid esters, we found that the use of R-dichloro
â-lactones allows efficient peptide coupling reactions
under conditions in which the corresponding R-unsub-
stituted lactones are completely inert to ring opening.
trolled synthesis of γ-amino â-hydroxy acids and their
coupling with R-amino acid esters has been a subject of
interest within the context of biologically active peptide
mimics.1 Two well-known representatives are statine (1),
a key component of the naturally occurring peptide
pepstatin (2),2 and the (3S,4S)-4-amino-3-hydroxy-5-
phenylpentanoic acid (3) (AHPPA),3 which has been
employed for the design of HIV protease inhibitors.4
However, most of the investigations on this topic have
(5) For reviews documenting this aspect, see: (a) J urczak, J .;
Golebiowski, A. Chem. Rev. 1989, 89, 149. (b) Reetz, M. T. Angew.
Chem., Int. Ed. Engl. 1991, 30, 1531. (c) Yokomatsu, T.; Yuasa, Y.;
Shibuya, S. Heterocycles 1992, 33, 1051. (d) Dondoni, A. In Antibiotics
and Antiviral Compounds; Khron, K., Kirst, H. A., Maas, H., Eds.;
VCH: Weinheim, 1993; p 57. For a recent asymmetric synthesis see:
(e) Enders, D.; Reinhold, V. Liebigs Ann. Chem. 1996, 11 and references
cited therein.
(6) Reetz, M. T.; Drewes, M. W.; Matthews, B. R.; Lennick, K. J .
Chem. Soc., Chem. Commun. 1989, 1474.
(7) (a) Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem., Int.
Ed. Engl. 1987, 26, 1141. (b) Gennari, C.; Pain, G.; Moresca, D. J . J .
Org.Chem. 1995, 60, 6248.
(8) (a) Palomo, C.; Aizpurua, J . M.; Cuevas, C. J . Chem. Soc., Chem.
Commun. 1994, 1957. (b) Palomo, C.; Aizpurua, J . M.; Galarza, R.;
Mielgo, A. J . Chem. Soc., Chem. Commun. 1996, 663.
(9) For reviews on â-lactones, see: (a) Pommier, A.; Pons, J . M.
Synthesis 1993, 441; Synthesis 1995, 729. (b) Laduwahetty, T. Con-
temp. Org. Synth. 1995, 2, 133. (c) Lowe, C.; Vederas, C. Org. Prep.
Proc. 1995, 27, 305.
dealt with the synthesis of the γ-amino â-hydroxy acid
itself rather than with the contruction of activated species
ready for subsequent peptide coupling steps.5 For ex-
† Universidad del Pais Vasco.
‡ Organish-Chemisches Institut der Universita¨t Zu¨rich.
§ Author to whom correspondence regarding the X-ray crystal-
lographic determinations should be directed.
X Abstract published in Advance ACS Abstracts, December 1, 1996.
(1) Williams, R. M. In Biologically Active Peptides: Design, Synthesis
and Utilization; Williams, W. V., Weiner, D. B., Eds.; Technomic:
Lancaster, 1993; Vol. 1, p 187.
(2) Umezawa, H.; Aoyagi, T.; Moroshima, H.; Matsuzaki, M.; Ha-
mada, M.; Takeuchi, T. J . Antibiot. 1970, 23, 259.
(3) Omura, S.; Imamura, N.; Kawakita, N.; Mori, Y.; Yamazaki, Y.;
Masuma, R.; Takahashi, Y.; Tanaka, H.; Huang, L.; Woodruff, H. J .
Antibiot. 1986, 39, 1079.
(4) Moore, M. L.; Bryan, W. M.; Fakhoury, S. A.; Magaard, V. W.;
Huffan, W. F.; Dayton, B. D.; Meek, T. K.; Hyland, L. J .; Dreyer, G.
B.; Metcalf, B. W.; Strickler, J . G.; Gorniak, J . G.; Debouck, C. Biochem.
Biophys. Res. Commun. 1989, 159, 420.
(10) (a) Rosenberg, S. H.; Boyd, S. A.; Mantei, R. A. Tetrahedron
Lett. 1991, 32, 6507. (b) Ratemi, E. S.; Vederas, J . C. Tetrahedron Lett.
1994, 35, 7605. For regioselective ring opening with cysteine deriva-
tives, see: (c) Shao, H.; Wang, S. H. H.; Lee, C.-W.; Osapay, G.;
Goodman, M. J . Org. Chem. 1995, 60, 2956.
(11) Griesbeck, A.; Seebach, D. Helv. Chim. Acta 1987, 70, 1236.
(b) Breitschuh, R.; Seebach, D. Synthesis 1992, 83.
S0022-3263(96)01219-4 CCC: $12.00 © 1996 American Chemical Society

Coupling of γ-Amino â-Hydroxy Acids
J . Org. Chem., Vol. 61, No. 26, 1996 9197
Sch em e 1a
The question was, therefore, to establish first whether
the ester 8 was formed after both chlorine atoms were
removed from the â-lactone 6, and if so, whether the
resulting â-lactone could indeed be coupled with R-amino
acid esters. To this end, we have prepared the R-unsub-
stituted â-lactone 7 by performing the dehalogenation of
6 in ethyl acetate, containing triethylamine as above, and
both 6 and 7 were then subjected to treatment with 1.5
equiv of (S)-leucine methyl ester in methylene chloride
at room temperature. While the latter â-lactone did not
react to give the desired dipeptide, the former one cleanly
produced the expected coupling product, which was
isolated as 9 in 85% yield. Likewise, 6 coupled efficently
with (S)-phenylalanine methyl ester to give the expected
dipetide, which after dehalogenation afforded 10 in 87%
yield. To ensure that no epimerization occurred during
the coupling step, products 11 and 12 (Figure 1) were
prepared in the same way as above and submitted to
HPLC analysis. As Figure 1 shows, this â-lactone
coupling method allows an efficient practical synthesis
of short γ-amino â-hydroxy acid peptides with high
enantiomeric purity. However, some limitation arose
when the coupling reaction was applied to dipeptides,
Scheme 2, where yields generally fell to 30-40%. For
instance, treatment of dipeptide (S)-Val-ValOMe with 6,
under the above reaction conditions, furnished the ex-
pected coupling product 13, but only in 40% yield. The
same result was attained when the reaction was carried
out in DMF as the solvent. Therefore, the alternative
conventional coupling methodology was adopted. Namely,
we first prepared the product 14 by reaction of 6 with
(S)-valine benzyl ester and further exposure of the
resulting coupling product to H2 and 10% Pd/C. Subse-
quent DCC coupling of 14 with (S)-valine methyl ester
allowed formation of 13 in 80% yield identical to that
obtained by the earlier route.
On the basis of the above results and taking advantage
of the ready availability of dichloro â-lactones from R-oxy
aldehydes,12 their coupling with R-amino acid esters could
also be anticipated. At this point, however, it should be
mentionated that, prior to our work, the asymmetric
synthesis of â-lactones from either R-amino aldehydes,
vide supra, or R-oxy aldehydes in only one step had
remained unexplored.17 In this context, and contempo-
rary to our work, Romo and co-workers18 have also
addressed this issue, and high levels of diasteroselectivity
have been found in the cycloaddition reaction of (tri-
methylsilyl)ketene with chiral R- and â-(benzyloxy) al-
dehydes. In our case, as Scheme 3 illustrates, the
cycloaddition reaction of 15a with dichloroketene, gener-
ated from trichloroacetyl chloride and Zn/Cu,19 afforded
a
Reagents and conditions: (i) Cl2CHCOCl, NEt3, LiClO4,
CH2Cl2, -78 °C, 4 h; (ii) H2 (1 atm), Pd/C, NEt3, EtOH or EtOAc,
15 h; (iii) (S)-H2NCH(R)CO2Me, CH2Cl2, rt, 24 h.
To illustrate the above issue we selected first the
R-dichloro â-lactone 6, which on the basis of our hypoth-
esis should be considered as a simultaneously protected
and activated form of the AHPPA (3). The approach
employs the aldehyde 5, which possesses the required
structural subunit of the γ-amino acid and at the same
time provides the â-lactone 6 with high diastereoselec-
tivity in a single synthetic step (Scheme 1).12 Thus, the
[2 + 2] cycloaddition reaction of dichloroketene, generated
from dichloroacetyl chloride and triethylamine,13 with 5
afforded an oil, which on purification by silica gel flash
chromatography led to the â-lactone 6 in 35% yield.14 The
1H NMR spectrum of the crude product indicated the
exclusive formation of one diastereomer and the relative
configuration of the two stereocenters was determined
from the known ethyl ester 8. Namely, in an attempt to
obtain the R-unsubstituted â-lactone 7 by means of
hydrogenolysis of 6 in EtOH containing triethylamine,
we found that the open product 8 was formed in 81% yield
without traces of the expected â-lactone 7. The ethyl
ester thus obtained was identical to that previously
described by Noyori and co-workers15 and firmly estab-
lished the stereochemical assignment made for the ad-
duct.16 On the other hand, this result suggested that
carrying out this reaction under nonsolvolytic conditions,
but in the presence of other nucleophiles, it would also
be possible to obtain the corresponding acylated products.
(12) Palomo, C.; Miranda, J . I.; Cuevas, C.; Odriozola, J . M. J . Chem.
Soc., Chem. Commun. 1995, 1735.
(13) Ghosez, L.; Montaigne, R.; Roussel, A.; Vanlierde, H.; Mollet,
(17) A recent paper by another group from this laboratory, which
appeared after our preliminary work was published, documents the
synthesis of â-lactones from R-oxy aldehydes via Danheiser reaction.
For pertinent information on this subject see: (a) Arrastia, I.; Lecea,
B.; Cossio, F. P. Tetrahedron Lett. 1996, 37, 245. (b) Danheiser, R. L.;
Nowick, J . S. J . Org. Chem. 1991, 56, 1176. (c) Danheiser, R. L.;
Nowick, J . S.; Lee, J . H.; Miller, R. F.; Huboux, A. H.; Mathre, D. J .;
Shinkai, I. Org Synth. 1995, 73, 61. For related Danheiser â-lactone
synthesis, see: (d) Wedler, C.; Kunath, A.; Schick, H. J . Org. Chem
1995, 60, 758. (e) Wedler, C.; Kleiner, K.; Kunath, A.; Schick, H. Liebigs
Ann. Chem. 1996, 881 and references therein.
(18) (a) Zemribo, R.; Romo, D. Tetrahedron Lett. 1995, 36, 4159. (b)
Zemribo, R.; Champ, M. S.; Romo, D. Synlett 1996, 278. Also, see: (c)
Pommier, A.; Pons, J .-M. Synthesis 1994, 1294. For other synthesis of
â-lactones involving (trialkylsilyl)ketenes, see: (d) Concepcion, A. B.;
Maruoka, K.; Yamamoto, H. Tetrahedron 1995, 51, 4011. (e) Dymock,
B. W.; Kocienski, P. J .; Pons, J .-M. J . Chem. Soc., Chem Commun.
1996, 1053.
P. Tetrahedron 1971, 27, 615. For
a general review on ketene
chemistry, see: Tidwell, T. T. Ketenes; J ohn Wiley: New York, 1995.
(14) The chemical yield of this reaction was found to be variable
between 30 and 45% over several preparations. Only when the reaction
was carried out in the presence of LiClO4 have we obtained a uniform
35% yield. The exact role of this Lewis acid is not clear at present and
other Lewis acids tested, i.e., ZnCl2, BF3‚Et2O... have been completely
unsuccessful. For the effect of lithium perchlorate on the Mukaiyama
aldol reaction, see: Reetz, M. F.; Fox, D. N. A. Tetrahedron Lett. 1993,
34, 1119.
(15) Nishi, T. Kitamura, M. Ohkuma, T.; Noyori, R. Tetrahedron
Lett. 1988, 29, 6327.
(16) We have also prepared the racemic form of the â-lactone 6 and
dehalogenated to (()-7. HPLC analysis of the reaction crude of (()-7
and (-)-7 revealed that no appreciable epimerization had occurred
during cycloaddition reaction and dehalogenation step. Further infor-
mation is available in the Supporting Information.
(19) Brady, W. T.; Liddell, H. G.; Waughan, W. L. J . Org. Chem.
1966, 31, 626.

9198 J . Org. Chem., Vol. 61, No. 26, 1996
Palomo et al.
F igu r e 1. HPLC Chromatograms of (a) product 10, elution time 18.45 min; (b) product 11, elution time 16.40 min; (c) product
12 obtained by coupling of 6 with (()-phenylalanine methyl ester, elution time 16.06 and 17.29 min. Conditions: LiChrosorb Si
60 7 µm, flow 1 mL/min; det 254 nm; mobile phase, EtOAc-hexane 30/70.
Sch em e 2a
corresponding C4-H protons appearing at δ 4.70 ppm for
the anti-isomer and at 4.75 ppm for the syn-isomer. In
an effort to improve this result, dichloroketene was
generated from dichloroacetyl chloride and triethylamine
and treated with 20 at -78 °C for 3 h and then at room
temperature overnight. In this experiment, an analogous
ratio (80:20) of the anti/syn â-lactones 21 was also
produced albeit in somewhat better yield (70%). Both
isomers were not separated; instead, the crude mixture
was transformed into the corresponding opened products
anti-22/syn-22, of which the major isomer, anti-22 was
isolated by crystallization from hexane in 50% yield. The
stereochemistry of this compound was assigned on the
basis of previously reported data.20 In view of this
a
(20) Rague, B.; Chapleur, Y.; Castro, B. J . Chem. Soc., Perkin Trans.
1 1982, 2063.
Reagents and conditions: (i) (S)-Val-ValOMe, CH2Cl2, rt, 15
h; (ii) H2 (1 atm), Pd/C, NEt3, EtOAc, 15 h; (iii) (S)-ValOBn,
CH2Cl2, rt, 24 h; (iv) (S)-ValOMe, DCC, N-hydroxybenzotriazole,
THF, 0 °C, 1 h.
(21) Although the precise origin of asymmetric induction requires
further study, analysis of Cram’s rule formulation via the Felkin-
Anh model may account for the results obtained with R-(silyloxy)
aldehydes, while in the case of R-amino aldehydes the observed
stereoselectivity can be attributed to the prior formation of a five-
membered chelate and/or and assisted hydrogen-bonding model be-
tween the 2-amino group and the carbonyl oxygen function, as
postulated for [4 + 2] cycloadditions involving R-amino aldehydes. For
more detailed information on this latter subject, see: (a) J urczak, J .;
Golebiowski, A. In Antibiotics an Antiviral Compounds; Krohn, K.,
Kirst, H. A., Maag, H., Eds.; VCH: Weinheim, 1993; p 343. (b)
Golebiowski, A; J urczak, J . Synlett 1993, 241. (c) Mulzer, J . In Organic
Synthesis Highlights; Mulzer, J ., Altenbach, H.-J ., Braun, M., Krohn,
K., Reissig, H. V., Eds.; VCH: Weinheim, 1991; p 3. In addition, a
chelation-controlled model has also been proposed by Romo to account
for the stereochemical outcome of the reaction of the (trimethylsilyl)-
ketene with R- and â-(benzyloxy) aldehydes under the influence of
Lewis acids; see ref 18a,b.
after aqueous workup an oil that on purification by silica
gel flash chromatography led to the â-lactone 16a in 85%
yield. In a similar way, 15b on treatment with dichlo-
roketene afforded the â-lactone 16b in 60% yield after
purification by column chromatography. In both cases,
1
examination of the crude product by H-NMR indicated
that only one diastereomer had been formed. With 20,
however, the cycloaddition was found to be less stereo-
selective, giving in 60% yield a mixture of the â-lactones
anti-21/syn-21 in a ratio of 70:30, respectively, as deter-
mined by 1H-NMR (300 MHz) by integration of the

Coupling of γ-Amino â-Hydroxy Acids
J . Org. Chem., Vol. 61, No. 26, 1996 9199
Sch em e 3a
derived coupling products.22 From these results it is
interesting to note that peptide mimics in which the
γ-amino moiety has been replaced by the hydroxy func-
tionality can also be made accessible without the need
to initially prepare the corresponding R-substituted â,γ-
dihydroxy carboxylic acid in its free form. Therefore, we
have demonstrated that R,R-dichloro â-lactones, which
can be obtained in a single synthetic step and with
virtually complete diastereoselectivity, are able to un-
dergo O-acyl fission by R-amino acid esters providing a
new dipeptide coupling methodology. On the basis of the
results presented here, the approach developed comple-
ments the existing available protocols to synthesize
γ-amino â-hydroxy acid and â,γ-dihydroxy acid derived
peptides and will find further applications in oxetanone
chemistry.
Exp er im eta l Section
Melting points were determined with a capillary apparatus
and are uncorrected. Proton nuclear magnetic resonance (300
MHz) spectra and 13C spectra (75 MHz) were recorded at room
temperature for CDCl3 solutions, unless otherwise stated. All
chemical shifts are reported as δ values (ppm) relative to
residual CDCl3 δH (7.26 ppm) and CDCl3 δC (77.0 ppm) as
internal standards, respectively. Mass spectra were obtained
on
a mass spectrometer (70 eV) using GC-MS coupling
(column: fused silica gel, 15 m, 0.25 mm, 0.25 mn phase SPB-
5). Optical rotations were measured at 25 ( 0.2 °C in
methylene chloride unless otherwise stated. HPLC analyses
were performed on analytical columns (25 cm, phase Li-
chrosorb-Si60) and (25 cm, phase Chiralcel OD) with flow rates
using 1 mL/min and 0.5 mL/min, respectively, using a DAD
detector. Flash chromatography was executed with Merck
Kiesegel 60 (230-400 Mesh) using mixtures of ethyl acetate
and hexane as eluants. Ether was distilled over sodium and
benzophenone (indicator). Methylene chloride was shaken
with concentrated sulfuric acid, dried over potasium carbonate,
and distilled. Commercially available compounds were used
without further purification.
a
Reagents and conditions: (i) Cl3CCOCl, Zn-Cu, Et2O, rt, 4
h; (ii) (S)-ValOMe, CH2Cl2, 24 h; (iii) H2 (1 atm), Pd/C, Et3N,
AcOEt, 15 h; (iv) n-Bu4NF, THF; (v) MeOH, NaOMe (cat), rt,
overnight.
result,21 we elected to use â-lactones 16a and 16b for
coupling reactions. For example, 16a , upon exposure to
(S)-valine methyl ester in methylene chloride at room
temperature overnight, furnished the expected coupling
product, which on dehalogenation led to 18a in 90% yield.
Likewise, the â-lactone 16b, coupled with (S)-valine
methyl ester to give, after dehalogenation of the resulting
intermediate, 18b in 92% yield. Both compounds were
then isolated as 19a and 19b in 75% and 60% yields,
respectively, after purification by column chromatogra-
phy. To corroborate the influence of electron-withdraw-
ing groups at the R-position of the â-lactone ring,
compound 17b was prepared from 16b and subjected to
treatment with (S)-valine methyl ester. Once again, no
reaction was observed under those conditions that caused
the â-lactone 16b to react and the starting â-lactone 17b
was recovered unchanged. Finally, the â-lactone 17b was
submitted to a single-crystal X-ray analysis to further
confirm the stereochemistry assigned for the adducts and
P r ep a r a tion of th e r-Dich lor o â-La cton e 6. A solution
of dichloroacetyl chloride (1.55 mL, 16 mmol) in dry methylene
chloride (30 mL) was added dropwise to a stirred solution
containing (2S)-[(tert-butoxycarbonyl)amino]-3-phenylpropanal
(0.99 g, 4 mmol), triethylamine (18 mmol), and LiClO4 (0.42
gr, 4 mmol) in dry methylene chloride under nitrogen atmo-
sphere at -78 °C. The resulting mixture was stirred for 4 h
at the same temperature and then was allowed to warm to
room temperature. The mixture was washed with water (25
mL), 0.1 N HCl (25 mL), and a saturated solution of NaHCO3
(25 mL). The organic layer was dried over MgSO4 and filtered,
and the solvent was evaporated under reduced pressure to give
a crude that was purified by column chromatography using
EtOAc /Hex (1:10) as eluent. Yield: 0.50 g (35%). Mp: 124-
125 °C (Et2O). [R]25 ) +32.3 (c ) 1, CH2Cl2). IR (KBr) ν:
D
3362 cm-1 (NH); 1858 cm-1 (CdO), 1684 cm-1 (CdO). 1H-NMR
(CDCl3, δ ppm): 7.18-7.01 (m, 5H); 4.72 (d, 1H, J ) 5.9 Hz);
4.43 (d, 1H, J ) 9.1 Hz); 4.05 (m, 1H); 2.81 (m, 2H); 1.19 (s,
9H). 13C-NMR (solid, δ ppm): 160.0, 156.1, 137.2, 129.2, 87.2,
80.9, 55.5, 35.6, 28.9. Anal. Calcd for C16H19Cl2NO4
(360.23): C, 53.34; H, 5.31; N, 3.88. Found: C, 53.10; H, 5.58;
N, 4.01.
(22) Crystal data for compound 17b: C27H30O3Si, Mr ) 430.61,
tetragonal, space group P42212, a ) 14.061(2) Å, c ) 24.703(3) Å, V )
4884(1) Å3, Z ) 8, Dc ) 1.171 g cm-3, T ) -100 °C, Mo KR radiation,
λ ) 0.710 69 Å, µ ) 0.121 mm-1. The structure was solved by direct
methods and refined on F by full-matrix least-squares methods to give
R ) 0.0461, wR ) 0.0377, S ) 1.322 using 280 refined parameters
and 2974 observed reflections with I > 2σ(I) from the 4961 collected
with 5° < 2θ < 55°. The enantiomorph was fixed by the known
configuration at C(5) and supported by refinement of the absolute
structure parameter [x ) 0.1(2)], although in this case this parameter
has a large standard deviation. The author has deposited atomic
coordinates for this structure with the Cambridge Crystallographic
Data Centre. The coordinates can be obtained, on request, from the
Director, Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge, CB2 1EZ, UK.
Gen er a l P r oced u r e for th e P r ep a r a tion of r-Dich lor o
â-La cton es 16. To a suspension of Zn/Cu and the correspond-
ing R-(silyloxy) aldehyde (4 mmol) in dry diethyl ether (30 mL)
at room temperature was added dropwise a solution of trichlo-
roacetyl chloride (5 mmol) in dry diethyl ether (5 mL). The
resulting solution was stirred for 4 h at the same temperature,
and then hexane (50 mL) was added and the mixture washed
with a saturated solution of NaHCO3 (30 mL). The solid
obtained was filtered off through a pad of Celite, and the
organic layer was washed with 0.1 N HCl (25 mL) and a
saturated solution of NaHCO3 (30 mL). The organic layer was
dried over MgSO4 and filtered, and the solvent was evaporated

9200 J . Org. Chem., Vol. 61, No. 26, 1996
Palomo et al.
under reduced pressure to give a crude that was used without
further purification.
evaporated at reduced pressure to give the corresponding
peptide, which was purified by column chromatography. 9.
Yield: 85%. Mp ) 120-122 °C (Et2O-hexane). [R]25D ) -29.3
(c ) 1, CH2Cl2). IR (film) ν: 3550, 3533 cm-1 (N-H), 1753 cm-1
(CdO), 1693 cm-1 (CdO), 1659 cm-1 (CdO). 1H-NMR (CDCl3,
δ ppm): 7.35-7.22 (m, 5H); 6.37 (m, 1H), 5.02 (d, 1H, J )
9.71 Hz); 4.60 (m, 1H); 4.00 (d, 1H, J ) 7.5 Hz); 3.79 (m, 1H);
3.76 (s, 3H); 2.92 (d, 2H, J ) 7.6 Hz); 2.54 (dd, 1H, J ) 15.3,
9.8 Hz); 2.28 (dd, 1H, J ) 15.3, 3.1 Hz); 1.70 (m, 3H); 1.44 (s,
9H); 0.97 (d, 6H, J ) 5.1 Hz). 13C-NMR (CDCl3, δ ppm): 173.2,
172.4, 156.3, 138.2, 129.3, 128.3, 126.2, 79.4, 68.1, 55.2, 52.2,
50.8, 45.7, 40.9, 40.1, 38.8, 28.5, 24.7, 22.7, 21.7. Anal. Calcd
for C23H36N2O6 (436.53): C, 63.27; H, 8.31; N, 6.41. Found:
C, 63.39; H, 8.36; N, 6.42. 10. Yield: 87%. Mp: 96-98 °C
(4S)-3,3-Dich lor o-4-[(1S)-[(ter t-bu tyld iph en ylsilyl)oxy]-
eth yl]oxeta n -2-on e (16a ). The general procedure was fol-
lowed starting from 2(S)-[(tert-butyldiphenylsilyl)oxy]propanal.
Yield: 0.33 g (85%), oil. [R]25 ) -20.7 (c ) 1, CH2Cl2). IR
D
(film) ν: 1860 cm-1 (CdO). 1H NMR (CDCl3, δ ppm): 7.34-
7.20 (m, 10H); 4.65 (d, 1H, J ) 7.7 Hz); 4.10 (qd, 1H, J ) 7.7,
6.4 Hz); 1.20 (d, 3H, J ) 6.4 Hz); 1.06 (s, 9H). 13C-NMR
(CDCl3, δ ppm): 160.9, 135.9, 135.8, 133.6, 132.4, 130.1, 129.9,
127.8, 127.6, 89.3, 68.1, 26.8, 19.2, 19.1.
(4S)-3,3-Dich lor o-4-[(1S)-[(ter t-bu tyld iph en ylsilyl)oxy]-
2-p h en yleth yl]oxeta n -2-on e (16b). The general procedure
was followed starting from 2(S)-[(tert-butyldiphenylsilyl)oxy]-
(Et2O). [R]25 ) +3.3 (c ) 1, CH2Cl2). 1H-NMR (CDCl3, δ
D
3-phenylpropanal. Yield: 1.14 g (60%), oil. [R]25 ) -12.6 (c
D
ppm): 7.31-7.08 (m, 5H); 6.69 (d, 1H, J ) 7.69 Hz); 5.02 (d,
1H, J ) 9.7 Hz); 4.77 (dd, 1H, J ) 13.36, 7.1 Hz); 3.90 (m,
1H); 3.75 (m, 1H); 3.67 (s, 3H); 3.12 (dd, 1H, J ) 13.9, 5.7
Hz); 3.01 (dd, 1H, J ) 13.9, 6.9 Hz); 2.87 (d, 2H, J ) 7.6 Hz);
2.38 (dd, 1H, J ) 15.0, 9.0 Hz); 2.19 (dd, 1H, J ) 15.0, 4.0
Hz); 1.38 (s, 9H). 13C-NMR (CDCl3, δ ppm): 172.2, 171.8, 156.2,
138.1, 135.7, 129.3, 129.1, 128.5, 128.3, 127.0, 126.3, 79.4, 68.1,
55.3, 53.3, 52.3, 40.0, 38.4, 37.5, 28.3. Anal. Calcd for
C26H34N2O6 (470.54): C, 66.36; H, 7.28; N, 5.95. Found: C,
66.11; H, 7.32; N, 6.04. 13. Yield: 40%. Mp: 170-172 °C
) 1, CH2Cl2); IR (film) ν: 1860 cm-1 (CdO). 1H NMR (CDCl3,
δ ppm): 7.74-7.69 (m, 4H); 7.49-7.37 (m, 7H); 7.20-7.15 (m,
3H); 6.84-6.79 (m, 1H); 4.56 (d, 1H, J ) 3.9 Hz); 4.36 (ddd,
1H, J ) 9.7, 5.1, 3.9 Hz); 3.13 (dd, J ) 13.8, 9.7 Hz); 2.85 (dd,
J ) 13.8, 5.1 Hz); 1.08 (s, 9H). 13C-NMR (CDCl3, δ ppm):
161.0, 136.2, 136.0, 135.9, 135.5, 130.3, 130.1, 129.2, 128.7,
127.9, 127.8, 127.7, 127.6, 127.0, 87.5, 72.9, 39.5, 26.8, 19.3.
Gen er a l P r oced u r e for th e P r ep a r a tion of r-Un su b-
stitu ted â-La cton es. To a solution of the corresponding 3,3-
dichloro-â-lactone (1 mmol) and triethylamine (2.5 mmol) in
dry EtOAc (10 mL) was added 10% palladium on charcoal (50
mg), and the mixture was kept under hydrogen (1 atm) at room
temperature for 24 h. Then the suspension was filtered
through a pad of Celite, and the filtrate was washed with 0.1
N HCl (10 mL) and then with a saturated solution of NaHCO3
(10 mL). The organic layer was dried over MgSO4 and filtered,
and the solvent was evaporated at reduced pressure to give
the corresponding â-lactone, which was purified by column
chromatography and further crystallization.
(Et2O). [R]25 ) -26.5 (c ) 1, CH2Cl2). 1H-NMR (CDCl3, δ
D
ppm): 7.39-7.24 (m, 5H); 6.73 (m, 2H), 5.08 (d, 1H, J ) 9.6
Hz); 4.54 (dd, 1H, J ) 8.7, 5.0 Hz); 4.31 (m, 1H); 3.98 (m, 1H);
3.77 (s, 3H); 2.95 (2H, J ) 7.6 Hz); 2.55 (dd, J ) 14.9, 9.5 Hz);
2.32 (1H, J ) 14.9, 3.1 Hz); 2.15 (m, 2H); 1.44 (s, 9H); 0.99-
0.89 (m, 12H). 13C-NMR (CDCl3, δ ppm): 172.6, 172.1, 170.9,
156.2, 139.1, 129.3, 126.3, 79.5, 68.1, 58.7, 57.2, 55.4, 52.2, 40.1,
38.4, 31.0, 30.9, 28.3, 19.1, 18.9, 18.1, 17.7. Anal. Calcd for
C27H43N3O7 (521.63): C, 62.16; H, 8.30; N, 8.05. Found: C,
61.85; H, 8.71; N, 7.77. 18a . Yield: 90%, oil. [R]25 ) +1.4
D
(c ) 1.20, CH2Cl2). IR (film) ν: 3304 cm-1 (NH), 2949 cm-1
(OH), 2849 cm-1 (OH), 1735 cm-1 (CdO), 1652 cm-1 (CdO).
1H-NMR (CDCl3, δ ppm): 7.69-7.64 (m, 4H); 7.44-7.33 (m,
6H); 6.62 (d, 1H, J ) 8.7 Hz); 4.53 (dd, 1H, J ) 8.7, 4.5 Hz);
3.93 (m, 1H); 3.81 (dd, 1H, J ) 6.2, 4.1 Hz); 3.74 (s, 3H); 3.2
(sb, 1H); 2.34 (d, 2H, J ) 6.2 Hz); 2.16 (m, 1H); 1.06 (s, 9H);
1.04 (d, 3H, J ) 6.2 Hz); 0.92 (d, 3H, J ) 6.2 Hz); 0.90 (d, 3H,
J ) 6.8 Hz). 13C-NMR (CDCl3, δ ppm): 172.4, 171.6, 135.6,
133.8, 133.2, 129.7, 129.6, 127.7, 127.4, 72.5, 72.0, 56.9, 51.9,
(4S)-4-[(1S)-[(ter t-Bu t oxyca r b on yl)a m in o]-2-p h en yl-
eth yl]oxeta n -2-on e (7). The general procedure was followed
starting from 6. Yield: 0.28 g (97%). Mp: 114-116 °C (Et2O).
[R]25D ) -9.4 (c ) 0.56, CH2Cl2). IR (KBr) ν: 3335 cm-1 (NH),
1819, 1773 cm-1 (CdO). 1H-NMR (CDCl3, δ ppm): 7.39-7.25
(m, 5H); 4.72 (d, 1H, J ) 9.3 Hz); 4.53 (m, 1H); 4.24 (m, 1H);
3.40 (dd, J ) 16.7, 5.7 Hz); 3.30 (dd, J ) 16.7, 4.4 Hz); 3.00
(dd, J ) 13.5, 7.1 Hz); 2.88 (dd, J ) 13.5, 8.7 Hz); 1.44 (s, 9H).
13C-NMR (CDCl3, δ ppm): 167.7, 156.0, 136.5, 129.5, 129.2,
128.7, 126.9, 80.3, 70.4, 52.3, 39.7, 38.5, 28.1. Anal. Calcd
for C16H21NO4 (291.34): C, 65.96; H, 7.26; N, 4.80. Found:
C, 65.90; H, 7.30; N, 4.89.
38.4, 30.8, 26.9, 19.1, 18.8, 17.7. 18b. Yield: 90%, oil. [R]25
D
) +1.6 (c ) 0.98, CH2Cl2); IR (film) ν: 3318 cm-1 (NH), 2947
cm-1 (OH), 2849 cm-1 (OH), 1744 cm-1 (CdO), 1645 cm-1
(CdO). 1H-NMR (CDCl3, δ ppm): 7.76-7.66 (m, 2H); 7.62-
7.57 (m, 2H); 7.48-7.32 (m, 6H); 7.25-7.09 (m, 3H); 6.86 (m,
2H); 6.44 (d, 1H, J ) 8.6 Hz); 4.49 (dd, 1H, J ) 8.7, 4.9 Hz);
4.05 (m, 1H); 3.88 (m, 1H); 3.70 (s, 3H); 2.7 (m, 2H); 2.3 (m,
2H); 2.1 (m, 1H); 1.04 (s, 9H); 0.91 (d, 3H, J ) 6.8 Hz); 0.87
(d, 3H, J ) 6.8 Hz). 13C-NMR (CDCl3, δ ppm): 172.3, 172.2,
137.5, 135.8, 133.4, 133.3, 129.7, 129.6, 129.2, 128.1, 127.6,
127.5, 126.1, 77.3, 70.5, 56.9, 51.9, 39.2, 37.6, 30.9, 26.9, 19.2,
(4R)-4-[(1S)-[(ter t-Bu t yld ip h en ylsilyl)oxy]-2-p h en yl-
eth yl]oxeta n -2-on e (17b). The general procedure was fol-
lowed starting from 14b. Yield: 0.40 g (95%). Mp: 126-128
°C (Et2O). [R]25 ) +1.2 (c ) 1, CH2Cl2). IR (KBr) ν: 1819
D
cm-1 (CdO). 1H-NMR (CDCl3, δ ppm): 7.80-7.75 (m, 4H);
7.52-7.41 (m, 6H); 7.21-7.16 (m, 3H); 6.80-6.75 (m, 3H);
4.35-4.30 (m, 2H); 3.60 (d, 1H, J ) 15.9, 4.2 Hz); 3.52 (d, 1H,
J ) 15.9, 5.8 Hz); 2.79 (d, 1H, J ) 13.6, 4.4 Hz); 2.48 (d, 1H,
J ) 13.6, 9.4 Hz); 1.13 (s, 9H). 13C-NMR (CDCl3, δ ppm): 167.9,
136.2, 135.9, 133.8, 132.1, 130.1, 130.0, 129.0, 128.6, 127.8,
126.8, 72.1, 71.2, 40.4, 37.5, 26.8, 19.5. Anal. Calcd for
C27H30O3Si (430.595): C, 75.30; H, 7.02. Found: C, 75.28; H,
7.02.
18.7, 17.6. 19b. Yield: 90%. Mp: 68-70 °C. [R]25 ) +5.9
D
(c ) 1, CH2Cl2). IR (film) ν: 3285 cm-1 (NH), 2949 cm-1 (OH),
2918 cm-1 (OH), 1735 cm-1 (CdO), 1648 cm-1 (CdO). 1H-NMR
(CDCl3, δ ppm): 7.31-7.20 (m, 5H); 6.62 (sb, 1H); 4.51 (dd,
1H, J ) 8.7, 5.0 Hz); 4.20 (m, 1H); 3.9 (m, 1H); 3.80 (m, 1H);
3.70 (s, 3H); 2.93 (dd, 1H, J ) 13.8, 3.6 Hz); 2.68 (dd, 1H, J )
13.8, 9.0 Hz); 2.53 (d, 2H, J ) 3.9 Hz); 2.14 (m, 1H); 0.92 (d,
3H, J ) 6.8 Hz); 0.88 (d, 3H, J ) 6.9 Hz). 13C-NMR (CDCl3,
δ ppm): 172.8, 172.7, 138.1, 129.4, 128.5, 126.5, 74.7, 71.3,
Gen er a l P r oced u r es for th e Cou p lin g of â-La cton es
w ith r-Am in o Acid Ester s. To a solution of the correspond-
ing R,R-dichloro â-lactone (0.5 mmol) in dry methylene chloride
was added the R-amino acid ester (0.75 mmol), and the
resulting mixture was stirred for 24 h at room temperature.
The mixture was then washed with 1 N HCl and a saturated
solution of NaHCO3. The organic layer was dried over MgSO4
and filtered, and the solvent was evaporated at reduced
pressure to give the corresponding coupling product, which was
dissolved in dry EtOAc (10 mL). Triethylamine (2.5 mmol)
and 10% palladium on charcoal (50 mg) were added, and the
mixture was kept under hydrogen (1 atm) at room temperature
for 24 h. The suspension was then filtered through a pad of
Celite, and the filtrate was washed with 0.1 N HCl (10 mL)
and a saturated solution of NaHCO3 (10 mL). The organic
layer was dried over MgSO4 and filtered, and the solvent was
57.2, 52.2, 39.1, 37.8, 30.8, 18.9, 17.7. Anal. Calcd for C17H25
-
NO5 (323.38): C, 63.13; H, 7.79; N, 4.33. Found: C, 63.26; H,
7.71; N, 4.28.
P r ep a r a tion of Meth yl Ester 22. To a suspension of Zn/
Cu and isopropylidene-D-glyceraldehyde (4 mmol, 0.52 g) in
dry diethyl ether (30 mL) at room temperature was added
dropwise a solution of trichloroacetyl chloride (5 mmol, 0.55
mL) in dry diethyl ether (5 mL). The resulting solution was
stirred for 4 h at the same temperature, and then hexane (50
mL) was added and the mixture washed with a saturated
solution of NaHCO3 (30 mL). The solid obtained was filtered
off through a pad of Celite, and the organic layer was washed

Coupling of γ-Amino â-Hydroxy Acids
J . Org. Chem., Vol. 61, No. 26, 1996 9201
with 0.1 N HCl (25 mL) and a saturated solution of NaHCO3
(30 mL). The organic layer was dried over MgSO4 and filtered,
and the solvent was evaporated at reduced pressure to give a
crude. This crude was dissolved in dry methanol (20 mL),
sodium methoxide (0.4 mmol) was added, and the resulting
mixtutre was stirred overnight at room temperature. The
solvent was then evaporated, and the resulting crude was
dissolved in dichloromethane (30 mL) and successively washed
with saturated solutions of NH4Cl (20 mL) and NaHCO3 (20
mL). The organic layer was dried over MgSO4 and filtered,
and the solvent was evaporated at reduced pressure to give a
crude that was crystallized in hexane. anti-22. Mp: 100-
+3.6 (c ) 1, ethanol)). syn-22. Oil. [R]25 ) -10.6 (c ) 1,
D
ethanol).
Ack n ow led gm en t. Financial support of this work
by Gobierno Vasco (Project PI 95/93) is greatly appreci-
ated. A grant from the Ministerio de Educacio´n y
Ciencia to J .I.M. is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Copies of spectra (34
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.
102 °C. [R]25 ) +3.2 (c ) 1, ethanol). syn-22. Oil. [R]25
)
)
D
D
-10.4 (c ) 1, ethanol) (lit.20 anti-22. Mp: 100 °C. [R]25
J O961219S
D