A novel, one-pot reductive alkylation of amines by S-ethyl thioesters mediated by triethylsilane and sodium triacetoxyborohydride in the presence of palladium on carbon

Article abstract of DOI:10.1021/jo982125g

The reductive alkylation of primary amines with aldehydes or ketones is an important tool in the synthesis of wide variety of amines. We described here a novel, one-pot reductive alkylation method using multifunctional S- ethyl thioesters as a source for

Full text of DOI:10.1021/jo982125g

1972
J . Org. Chem. 1999, 64, 1972-1978
A Novel, On e-P ot Red u ctive Alk yla tion of Am in es by S-Eth yl
Th ioester s Med ia ted by Tr ieth ylsila n e a n d Sod iu m
Tr ia cetoxybor oh yd r id e in th e P r esen ce of P a lla d iu m on Ca r bon
Yinglin Han and Michael Chorev*
Division of Bone & Mineral Metabolism, Charles A. Dana and Thorndike Laboratories,
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School,
330 Brookline Avenue (HIM 944), Boston, Massachusetts 02215
Received October 22, 1998
The reductive alkylation of primary amines with aldehydes or ketones is an important tool in the
synthesis of wide variety of amines. We described here a novel, one-pot reductive alkylation method
using multifunctional S-ethyl thioesters as a source for in situ generation of aldehydes to alkylate
a range of multifunctional primary amines. The corresponding multifunctional secondary amines
were obtained in good to excellent yields (mostly >90%). This one-pot reductive alkylation included
the treatment of a mixture of protected S-ethyl thioester, primary amine, 10% Pd/C, and sodium
triacetoxyborohydride in N,N-dimethylformamide with triethylsilane for 30 min at temperature
lower than 20 °C. This method has special merit when the aldehyde is not stable enough to allow
isolation and therefore does not lend itself to a stepwise strategy of reductive alkylation. This was
the case with tert-butyl 1(S)-[(9-fluorenylmethoxycarbonyl)amino]-4-oxobutyrate (10) which could
not be obtained from the R-tert-butyl γ-S-ethyl (S)-N-(9-fluorenylmethoxycarbonyl) thioglutamate
(9). However, by our one-pot reductive alkylating method, treatment of 9-fluorenemethyl pheny-
lalaninate (6a ) with 9 afforded tert-butyl 2(S)-[(9-fluorenylmethoxycarbonyl)amino]-4-[[3-phenyl-
1(S)-(9-fluorenylmethoxycarbonyl)propyl]amino]butyrate (11) in 76% yield. Furthermore, the acid
labile tert-butyloxycarbonyl, and the hydogenation labile benzyloxycarbonyl and benzyl protecting
groups, were stable in the one-pot reductive alkylation reaction. While the conjugated double bond
is stable in these reaction conditions, the monosubstituted C-C double bond, as in the allyl
protecting group in R-allyl â-cyclohexyl aspartate, was reduced to the corresponding propyl ester.
In tr od u ction
these, the most commonly used agents are hydrogen,
NaBH3CN, and NaBH(OAc)3.
The reductive alkylation of primary amines by carbonyl
compounds, mostly aldehydes or ketones, in the presence
of reducing agents is an important tool in the synthesis
of secondary amines. A variety of reducing agents, such
as hydrogenation in the presence of metal catalysts,1
sodium cyanoborohydride (NaBH3CN),2 borane-pyridine
complex,3 borohydride exchange resin,4 zinc-acetic acid,5
sodium borohydride-magnesium chloride,6 zinc borohy-
dride-zinc chloride,7 and recently sodium triacetoxy-
borohydride [NaBH(OAc)3]8 and zinc borohydride - silica
gel,9 have been developed for this conversion. Among
Generating the aldehydes, needed for the reductive
alkylation, from the corresponding and readily available
carboxylic acid requires their transformation into deriva-
tives such as acid chlorides, esters, or amides. These can
then be selectively reduced to the aldehydes. Alterna-
tively, the carboxylic acid can be first reduced to the
primary alcohol which then is oxidized to the correspond-
ing aldehyde. Nevertheless, none of the above methods
seems to be applicable to multifunctional compounds.
Recently, reduction of S-ethylesters or S-benzylesters by
triethylsilane to the corresponding aldehydes in either
acetone or DCM in the presence of 10% Pd/C, under
essentially neutral conditions, has been demonstrated.10
Interestingly, under these mild conditions a variety of
functional groups, including O-benzyl and carbon-carbon
double bonds, are stable.11
Reductive alkylation is the synthetic route of choice
to obtain pseudopeptides that include a reduced peptide
bond. This frequently employed amide bond surrogate is
readily generated by the reductive alkylation of a free
R-amino, side chain protected peptide by an N-protected
R-amino aldehyde.12 In general, the most abundant
methods to prepare simple R-amino acyl aldehydes are
* Corresponding author. Tel (617)-667-0901, fax (617)-667-4432.
Email: mchorev@warren.med.harvard.edu.
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M. L. Russ. Chem. Rev. 1980, 49, 14.
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11, 201. (b) Lane, C. F. Synthesis 1975, 135.
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10.1021/jo982125g CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/02/1999

Reductive Alkylation of Amines by S-Ethyl Thioesters
J . Org. Chem., Vol. 64, No. 6, 1999 1973
Sch em e 1a
the following: reduction of R-amino acyl esters with
diisobutyl aluminum hydride at low temperature,13 re-
duction of N′-methoxy-N′-methyl-R-protected-carboxam-
ides by LiAlH4,14 and oxidation of the N-protected amino
alcohol via a modified Moffatt oxidation.15 The N-pro-
tected amino alcohol is generated from the NaBH4-
mediated reduction of the mixed anhydride obtained from
N-tert-butyloxycarbonyl-R-amino acid and isobutyl chlo-
roformate. The reductive alkylation of a free R-amino side
chain protected peptide is carried out by NaBH3CN in
DMF in the presence of 1% acetic acid.16
Recently, we reported the preparation of a novel
dipeptidomimetic synthon, the trisubstituted-1,2,5-hexahy-
dro-3-oxo-1H-1,4-diazepine (DAP).17 A low yield multistep
procedure was used to generate the reduced peptide bond
which is an essential feature in this structure. The
â-carboxyl of tert-butyl N-R-benzyloxycarbonyl-aspartate
was reduced to the alcohol and consecutively oxidized to
the corresponding aldehyde. The later was subsequently
used to reductively alkylate the free amino group of
benzyl phenylalaninate. In this study we report the
development of a general, efficient, one-pot reductive
alkylation of multifunctional amines with multifunctional
S-ethylthioesters by triethylsilane and NaB(OAc)3H in
the presence of Pd/C.
a
(a) i-BuOCOCl, Et3N in THF; (b) NaBH4 in H2O; (c) PCC/silica
gel in DMF; (d) HCl‚tert-butyl (S)-phenylalaninate, NaCNBH3 in
AcOH-MeOH.
Sch em e 2a
Resu lts a n d Discu ssion s
Step w ise Red u ctive Alk yla tion of r-ter t-Bu tyl
â-S-Eth yl (S)-N-F m oc-th ioa sp a r ta te. The potential
application of DAP as a dipeptidomimetic and a molec-
ular scaffold required an optimization of the synthesis
described previously.17 The reported yield for the tert-
butyl 2(S)-benzyloxycarbonylamino-4-[2-phenyl-1(S)-ben-
zyloxycarbonyl-ethylamino]butyrate (III) (Scheme 1), an
essential intermidiate in the synthesis of DAP, starting
from R-tert-butyl N-benzyloxycarbonyl-L-aspartate (I) and
a
(a) EtSH, DCC, DMAP in CH2Cl2, rt, 30 min, 96%; (b) Et3SiH,
10% Pd-C in acetone, ice bath, 30 min, 93%; (c) FmOH, DCC,
DMAP in CH2Cl2, rt, 30 min. 5a : 95%; 5b: 92%; 5c: 95%; (d)
HCl-EtOAc, 6a : 87%; 6b: 91%; 6c: 93%; (e) NaBH(OAc)3 in DMF,
30 min, 7a : 94%; 7b: 92%; 7c: 95%.
(12) (a) J acobson, K. A.; Marr-Leisy, D.; Rosenkraanz, R. P.;
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492. (b) Sasaki, Y.; Coy, D. H. Peptides 1986, 8, 119. (c) Coy, D. H.;
Hocart, S. J .; Sasaki, Y. Tetrahedron 1988, 44, 835. (d) Guichard, G.;
Benkirane, N.; Graff, R.; Muller, S.; Briand J . Pept. Res. 1994, 7, 308.
(e) Chan, W. C.; Mellor, S. L. J . Chem. Soc., Chem. Commun. 1995,
1475.
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23, 3081. (b) Rich, D. H.; Sun, E. T.; Ulm, E. J . Med. Chem. 1980, 23,
27. (c) Hann, M. M.; Sammes, P. G.; Kennewell, P. D.; Taylor, J . J .
Chem. Soc., Perkin Trans. 1 1982, 1, 307. (d) Gol Ebiowski, A.;
J acobsson, U.; J urczak, J . J . Tetrahedron 1987, 43, 3063.
(14) (a) Zemlicka, H.; Murata, M. J . Org. Chem. 1976, 41, 3317. (b)
Nishizawa, R. Saito, T.; Takita, T.; Suda, H.; Umezawa, H. J . Med.
Chem. 1977, 20, 510. (c) Nahm, S.; Weireb, S. Tetrahedron Lett. 1981,
22, 3518. (d) Narite, M.; Otsuka, S.; Kobayeshi, S.; Ohno, M.; Umezawa,
Y.; Morishima, H.; Saito, S.; Umezawa, H. Tetrahedron Lett. 1982, 23,
525. (e) Fehrentz, J . A.; Castro, B. Synthesis 1983, 676. (f) Fehrentz,
J . A.; Castro, B.; Heitz, A.; Cazaubon, C.; Nisato, D. FEBS Lett. 1984,
167, 273. (g) Lubell, W. D.; Rapoport, H. J . Am. Chem. Soc. 1987, 109,
236.
(15) (a) Pfitzner, K.; Moffatt, J . J . Am. Chem. Soc. 1970, 87, 5661.
(b) Evans, D. A.; Takce, J . M.; Hurst, K. M. J . Am. Chem. Soc. 1979,
101, 371. (c) Stanfield, C. F.; Parker, J . E.; Kanellis, P. J . Org. Chem.
1981, 46, 4797. (d) Rittle, K. E.; Homnick, C. F.; Ponticello, G. S.;
Evans, B. E. J . Org. Chem. 1982, 47, 3016. (e) Pyne, S. G.; Hensel, M.
J .; Fuchs, P. L. J . Am. Chem. Soc. 1982, 104, 5719. (f) Hamada, Y.;
Shiori, T. Chem. Pharm. Bull. 1982, 30, 1921. (g) Luly, J . R.; Dellaria,
J . F.; Plattner, J . J .; Soderquist, J . L.; Yi, Y. J . Org. Chem. 1987, 52,
1487. (i) Luly, J . R.; Hsiao, C.-N.; Maung, N. Ba.; Plattner, J . J . J .
Org. Chem. 1988, 53, 6109. (j) Adams, L. L.; Luzzio, F. A. J . Org. Chem.
1989, 54, 5387. (k) J urczak, J .; Golebiowski, A, Chem. Rev. 1989, 89,
149. (l) Tidwell, T. T. Org. React. 1990, 39, 297.
benzyl L-phenylalaninate (II) was less than 25%.17 There-
fore, our initial goal in this study was to optimize the
reductive alkylation leading to multifunctional secondary
amines.
Instead of reducing the â-carboxyl to alcohol and
oxidizing it to the corresponding aldehyde, we reduced
the S-ethyl thioesters with triethylsilane and a catalytic
amount of 10% palladium on carbon in acetone (slightly
lower yields were obtained in dichloromethane). This
reaction was reported to afford the corresponding alde-
hyde in high yield with none or negligible racemization.10
The high yield (93%) of this reaction was obtained
provided the reaction temperature was kept below 20 °C.
The S-ethyl thioesters were prepared by N,N′-dicyclo-
hexylcarbodiimide (DCC)-mediated esterification of the
carboxylic acids with ethanethiol in DMF in the presence
of 0.1 equiv of 4-N,N-(dimethylamino)pyridine (DMAP)
as previously reported.10c On the basis of previous reports,
NaB(OAc)3H in DCM was chosen for the reduction of the
in situ formed imine.8a-c No advantage was observed
when 2% AcOH in DMF was used as solvent.12 Scheme
2 summarizes three examples of stepwise reductive
alkylations in which tert-butyl 2(S)-4-oxo-9-fluorenyl-
methoxycarbonylamino-butyrate (3) was used to reduc-
(16) Spatola, A. F. Chemistry and Biochemistry of Amino Acids,
Peptides and Proteins; Weinstein, B., Ed.; Marcel Dekker: Basel, 1983;
p 267.
(17) Weitz, I. S.; Pellegrini, M.; Mierke, D. F.; Chorev, M. J . Org.
Chem. 1997, 62, 2527.

1974 J . Org. Chem., Vol. 64, No. 6, 1999
Han and Chorev
Sch em e 3a
a
(a) EtSH, DCC, DMAP in CH2Cl2, rt, 30 min, 95%; (b) method A: a mixture of 9, 10% Pd-C in DMF at 4 °C was treated with Et3SiH
followed by the addition of 6a . After 5 min, a solution of NaBH(OAc)3 in DMF was added, 30 min at room temperature, 33% yield; (c)
method B: a mixture of 9, 6a , and 10% Pd-C in DMF at 4 °C was treated with Et3SiH. After 5 min, a solution of NaBH(OAc)3 in DMF
was added, 30 min at room temperature, 45% yield; (d) method C: a mixture of 9, 6a , and 10% Pd-C in DMF at 4 °C was treated with
a solution of NaBH(OAc)3 in DMF, After 5 min, Et3SiH was added, 30 min 10-20 °C, 76-83% yield.
Sch em e 4a
tively alkylate the hydrochlorides of 9-fluorenylmethyl
esters (OFm) of L-Phe, L-Asp(â-OcHex), and L-Arg(NG-
Tos) (6a -c, respectively). Each of the individual steps
in the above syntheses was carried out with yields greater
than 90%.
Attempts to carry out a NaBH3CN-mediated reductive
alkylation of L-Phe-OFm (6a) with aldehyde 3 in methanol/
water resulted in only 34% yield of 7a . More than 50%
of aldehyde 3 was reduced to tert-butyl 2(S)-4-hydroxy-
2-(9-fluorenylmethoxycarbonylamino)butyrate, and the
9-fluorenylmethyl ester of 3 was partially hydrolyzed.
Replacement of methanol/water with either DMF or 2%
a
(a) EtSH, DCC, DMAP in CH2Cl2, rt, 30 min, 93%; (b) Et3SiH,
AcOH in DMF prevented the reduction of the aldehyde.
However, the reaction was slowed, and a partial loss of
NaBH(OAc)3, 10% Pd-C in DMF, 30 min 4 °C, 87%.
the 9-fluorenylmethyl ester was observed. Trial reduc-
tions of the in situ formed imine with Zn(BH4)2 proceeded
very slowly. Less than 30% conversion to the reductively
alkylated product 7a was observed after 2 days at room
temperature, and the 9-fluorenylmethyl ester was mostly
removed.
The difficulty to purify the thiobenzyl esters corre-
sponding to 2 from the excess of benzylmercaptan and
the sustained repelling stench of the latter discouraged
us from employing these esters in our syntheses.
In summary, the stepwise reductive alkylations used
in this study are compatible with synthetic strategies
employing Fmoc/Boc and OFm/O-tert-butyl as orthogonal
protecting groups.
On e-P ot Red u ctive Alk yla tion of r-ter t-Bu tyl γ-S-
E t h yl (S)-N-(9-F lu or en ylm et h yloxyca r b on yl)t h io-
glu ta m a te (9). The urgency to develop a novel, one-pot
reductive alkylation followed failed attempts to obtain
aldehyde 10 (Scheme 3) by the method used successfully
to synthesize of the homologous aldehyde 3 (see Scheme
2). Addition of triethylsilane to an ice-cooled mixture of
thioester 9 in DMF and 10% Pd/C was followed by the
addition of the amine 6a . After 5 min NaBH(OAc)3 was
added and allowed to react for 30 min (method A),
yielding 33% yield of the anticipated reductive alkylation
product 11. Alternatively, modifying the reaction by
including amine 6a in the ice-cold mixture of the thioester
9 and 10% Pd/C in DMF prior the addition of triethyl-
silane (method B) led to a slightly improved yield (45%)
of the secondary amine 11. Finally, adding NaBH(OAc)3
to an ice-cold mixture of the thioester 9, 10% Pd/C, and
the amine 6a in DMF, followed, after 5 min, by the
additon of triethylsilane (method C) resulted in the
highest yield (76%) of 11. However, when thioester 2 was
used, irrespective of the version of one-pot reductive
alkylation method used, the secondary amine 7a was
always obtained in very high yields (90-95%). These
results clearly suggest that the aldehyde, generated in
situ, is trapped by the primary amine to form the imine
which is subsequently reduced irreversibly to form the
anticipated secondary amine. Evidently, when the in situ
generated aldehyde is inherently unstable, e.g. aldehyde
10, reduction of the thioester in the presence of all the
other reactants results in the highest yield (method C).
The order of adding the reactants did not make any
difference when the in situ generated aldehyde is stable,
e.g. aldehyde 3. In such a case, the reductive alkylation
product, the secondary amine 7a , was always obtained
in high yield. Importantly, a reaction temperature higher
than 20 °C caused dramatic decrease in the yield of 11.
The secondary amine 11 decomposes slowly upon storage
at room temperature.
Scop e a n d Lim ita tion of th e Novel On e-P ot Re-
d u ctive Alk yla tion . Starting from R-tert-butyl â-S-ethyl
(S)-N-Fmoc-thioaspartate (2), all three secondary amines
7a -c, synthesized by the stepwise manner described
above (Scheme 2), could also be prepared by the one-pot
reductive alkylation in very high yields, 90-95%.
Due to the importance of the tert-butyloxycarbonyl
(Boc) protecting group in peptide chemistry, we tested
whether this group is compatible with the one-pot reduc-
tive alkylation conditions described above. The thioes-
terification of â-9-fluorenylmethyl L-N-Boc-aspartate (12)
yielded 93% of the thioester 13 (Scheme 4). One-pot
reductive alkylation of the tert-butyl L-phenylalaninate
hydrochloride 14 with 13 resulted in 87% yield of the
anticipated secondary amine 15. Interestingly, amine 15
was unstable at room temperature. After several days it
cyclized spontaneously to the corresponding 1-[[1(S)-(tert-
butyloxycarbonyl)-2-phenyl]ethyl]-4(S)-[(tert-butyloxycar-

Reductive Alkylation of Amines by S-Ethyl Thioesters
J . Org. Chem., Vol. 64, No. 6, 1999 1975
Sch em e 5a
Sch em e 7a
a
(a) NaB(OAc)3H, 10% Pd-C, Et3SiH in DMF, 30 min 4 °C.
Sch em e 8a
a
(a) EtSH, DCC, DMAP in CH2Cl2, rt, 30 min 4 °C, yield 95%;
(b) Et3SiH, 10% Pd-C in acetone, 30 min, 95%; (c) Et3SiH,
NaBH(OAc)3, 10% Pd-C in DMF, 30 min 4 °C, yield 94%; (d)
NaBH(OAc)3 in DMF, 30 min 4 °C, yield 95%.
a
(a) NaB(OAc)3H, 10% Pd-C, Et3SiH in DMF, 30 min, 4 °C.
Sch em e 6a
demonstrates the significant improvement of our novel,
one-pot reductive alkylation over the previously pub-
lished stepwise synthesis of an identical secondary amine
III (III and 24 are identical) which was obtained in less
than 25% overall yield starting from alcohol Ia (Scheme
1).17
Unfortunately, the allyl ester is susceptible to the
reductive conditions used in the one-pot reductive alky-
lation (Scheme 7). The reductive alkylation of â-cyclo-
hexyl R-allyl (S)-aspartate (25) by the thioester 2 resulted
in two reductively alkylated products, none of them
containing the original allyl ester moiety. The predomi-
nant product (87% yield) was the free acid 26 which was
obtained in the presence of minute amount of the
n-propyl ester 27. We assume that the reduction of the
allyl ester to the n-propyl one was followed by a fast
hydrolysis leading to the accumulation of the free acid
(Scheme 7).
Reduction of thioethyl esters containing R,â-unsatur-
ated carbonyl moieties and trisubstituted carbon-carbon
double bonds with triethylsilane and Pd/C in acetone
yielded the corresponding aldehydes.10a Under these
conditions the di- and trisubstituted carbon-carbon
double bonds remained intact. Reductive alkylation of
R-amino esters by N-allyloxycarbonyl (Alloc) protected
R-alaninal with NaBH3CN/ZnCl2 in methanol yielded
59% of the corresponding Alloc-protected secondary
amine.8d In our novel, one-pot reductive alkylation of
benzyl L-phenylalninate hydrochloride (23) by S-ethyl
trans-thiocinnamate (28) we obtained the secondary
amine 29 in 92% yield (Scheme 8). Therefore, under these
conditions, conjugated carbon-carbon double bonds are
stable. However, Alloc/allyl protecting groups are sus-
ceptible and should be avoided.
a
(a) EtSH, DCC, DMAP in CH2Cl2, rt, 30 min, 96%; (b) Et3SiH,
NaBH(OAc)3, 10% Pd-C in DMF, 30 min 4 °C, yield 94%.
bonyl)amino]pyrrolidin-2-one (16) (Scheme 4). This syn-
thesis also demonstrates that similar to â- and γ-thioesters
(2 and 9, respectively) R-thioesters also are compatible
with the novel, one-pot reductive alkylation procedure.
Comparison of the stepwise versus the one-pot syn-
thesis in which an R-thioester is the precursor for the
aldehyde was addressed in the reductive alkylation of
tert-butyl L-phenylalaninate hydrochloride 14 by γ-tert-
butyl R-S-ethyl N-Fmoc-L-thioglutamate 18 (Scheme 5).
The yield of the S-ethyl thioester 18 was 92%. Reduction
of the thioester 18 to the corresponding aldehyde 19 was
carried out with triethylsilane in acetone in the presence
of 10% Pd/C at room temperature. Both the stepwise and
the one-pot reductive alkylations resulted in the second-
ary amine 20 obtained in very high yields of 95% (Scheme
5). Unlike the inherent instability of the secondary amine
15 the secondary amine 20 was stable. Apparently,
compared to the facile cyclization of 15 to form the
pyrrolidone (Scheme 4), the steric hindrance of the γ-tert-
butyl ester 20 does not allow the cyclization to the
corresponding piperidinone.
Benzyloxycarbonyl and benzyl esters are two common
protecting groups on the amino and carboxyl functions,
respectively. These groups are orthogonal to the Boc/tert-
butyl and Fmoc/9-fluorenylmethyl protecting groups and
therefore very useful in syntheses employing multifunc-
tional building blocks. One-pot reductive alkylation of
benzyl L-phenylalaninate hydrochloride (23) with R-tert-
butyl â-S-ethyl N-benzyloxycarbonyl-L-thioaspartate (22)
yielded 94% of the anticipated secondary amine 24
(Scheme 6). Both benzyloxycarbonyl and benzyl ester
protecting groups are stable under the reaction conditions
used in the one-pot reductive alkylation. This synthesis
Previous reports demonstrated that the reduction of
N-protected R-amino thioesters to the corresponding
aldehydes10a-c and the following reductive alkylation12c
proceed with retention of optical purity. LC-ESI-MS
analysis of the crude products 20 and 15, obtained
through our one-pot reductive alkylation of 14 with
R-amino protected thioethyl esters 18 or 13, respectively,
could not identify any detectable racemization. LC-ESI-
MS analysis revealed the presence of only one component
with molecular mass corresponding to the anticipated
product (results not shown). LC-ESI-MS analysis of

1976 J . Org. Chem., Vol. 64, No. 6, 1999
Han and Chorev
with S-ethyl thioesters as precursors of unstable alde-
hydes generated in situ.
Exp er im en ta l Section
Gen er a l Meth od s. Thin-layer chromatography (TLC) was
performed on plastic plates coated with (0.20 mm) silica gel
60 F254 (Aldrich). Open column chromatography was carried
out on silica gel 60 (200-400 mesh, Aldrich). Final organic
solutions were dried over MgSO4. Analytical reverse-phase
high performance liquid chromatography (RP-HPLC) was
carried out on a Waters 100 RP-18 column (5 µm, 19 × 150
mm) at a flow rate of 1 mL/min. Preparative RP-HPLC was
carried out on Vydac 300 A C18 (15-20 µm, 47 × 300 mm) at
a flow rate of 70 mL/min. The solvent system used in RP-HPLC
included the following: solvent A, 0.1% (v/v) TFA in H2O;
solvent B, 0.1% TFA in CH3CN. The effluent was monitored
at 220 nm. Melting points were determined with a capilliary
melting point apparatus and are uncorrected. Elementary
microchemical analysis was carried out at E+R Microanalyti-
cal Laboratory, Inc, NY 11368. Analytical results were within
0.3% of the theoretical values. Mass spectroscopy was per-
formed at the Mass Spectra Laboratory of the Chemistry
Department at Harvard University using a fast atom bom-
bardment (FAB) ion source or in our laboratory using an
electron-spray ionization (ESI) source in-line with a liquid
chromatograph (LC-ESI-MS). N,N-Dimethylformamide (DMF)
was dried with 4 Å molecular sieve for 48 h before use. Other
commercially available chemicals were used without further
treatment. Catalytic hydrogenations were carried out in the
presence of 10% Pd/C.
F igu r e 1. LC-ESI-MS analysis of the one-pot reductive
alkylation reaction mixtures obtained from tert-buty (S)-
phenylalaninate‚HCl and either the (S)- or (R)-isomers of R-S-
ethyl â-(9-fluorenemethyl) N-(tert-butyloxycarbonyl)thioaspar-
tate (13). Panel A: RP-HPLC (C18, 0.2 mL/min, 220 nm, linear
gradient of 45-55% A in B in 30 min) tracings of the reaction
mixture generating either the (SS)- or the (RS)-diastereomers
tR )19.78 and 16.83 min (upper and middle tracings), respec-
tively. The lowest tracing represents a coinjection of reaction
mixtures generating either the (SS)- or (RS)-diastereomers.
Panel B: The electron spray ionization mass spectra of the
reaction mixture generating the (SS)-isomer whose M + H+
mass corresponds to m/z ) 601.
To avoid the strong stench from the mercaptans used during
the synthesis of the thioesters 2, 9, 13, 22, and 28, all the
manipulations were carried out in the hood. All the generated
waste was treated overnight with Clorox.
r-ter t-Bu tyl â-S-Eth yl (S)-N-(9-F lu or en ylm eth oxyca r -
bon yl)th ioaspar tate (2). N,N′-Dicyclohexylcarbodiimide (DCC)
(2.27 g, 11 mmol) was added to a solution of R-tert-butyl (S)-
N-(fluorenylmethoxycarbonyl)aspartate (3.15 g, 10 mmol),
ethanthiol (0.81 mL, 11 mmol), and 4-N,N-(dimethylamino)-
pyridine (DMAP) (122 mg, 1 mmol) in dichloromethane (DCM)
(10 mL) and stirred at room temperature for 30 min and then
filtered and concentrated in vacuo. Purification on silica gel
column afforded 4.37 g of 2 (96% yield) as a colorless oil which
solidified at room temperature: mp 69-70 °C; Rf ) 0.46
(EtOAc/hexane, 20:80); [R]20 -18.7° (c ) 0.88, MeOH); 1H
crude reaction mixtures of the diastereomers (SS)-15 and
(RS)-15, which eluted at distinct retention times, could
detect only one diastereomer (Figure 1). We therefore
conclude that there is no significant racemization of
either R-thioester or the in situ generated R-aldehyde
under the conditions employed in the one-pot reductive
alkylation synthesis reported above.
D
NMR (CDCl3) (δ in ppm) 7.33-7.79 (m, 8H), 5.68 (d, J ) 8.7
Hz, 1H), 4.53 (m, 1H), 4.39 (m, 2H), 4.35 (t, J ) 7 Hz, 1H),
2.92 (dd, J ) 4.5, 8.7 Hz, 1H), 2.93 (q, J ) 7.4 Hz, 2H), 1.49
(s, 9H), 1.28 (t, J ) 7.4 Hz, 3H); 13C NMR 197.1, 169.6, 156.0,
144.1, 141.5, 127.9, 127.3, 125.4, 120.2, 83.0, 67.4, 51.6, 47.4,
45.6, 28.1, 23.8, 14.9; FAB-MS m/z ) 456 (M + H)+. Anal.
Calcd for C25H29NO5S: C, 65.91; H, 6.42; N 3.07. Found: C,
66.07; H, 6.58; N, 3.04.
ter t-Bu tyl 4-Oxo 2(S)-[(9-F lu or en ylm eth oxyca r bon yl)-
a m in o]bu tyr a te (3). Triethylsilane (0.80 mL, 5 mmol) was
added to a solution of thioester 2 (455 mg, 1 mmol) and 10%
Pd-C (20 mg) in ice cold acetone (2 mL). Stirring was
maintained for 30 min at 10-20 °C and then filtered through
a Celite bed which was then washed with acetone. The
combined filtrates were concentrated in vacuo and purified on
a silica gel column to give 367 mg of 3 (93% yield) as colorless
oil which solidified at room temperature: mp 68-69 °C; Rf )
Con clu sion s
We report here a novel, one-pot reductive alkylation
method of polyfunctionalized primary amines by S-ethyl
thioesters with sodium triacetoxyborohydride and tri-
ethylsilane in the presence of Pd-C. The results pre-
sented above indicate that this method is very general,
efficient, and powerful with good to excellent yields. Many
protecting groups which are sensitive to acid (tert-
butyloxycarbonyl and tert-butyl) or base (9-fluorenyl-
methoxycarbonyl and 9-fluorenemethyl) or hydrogenation
(benzyl, benzyloxycarbonyl and conjugated double bond)
can withstand these conditions. This method is not
compatible with compounds containing monosubstituted
double carbon-carbon bonds. The most important ad-
vantage of this method is the use of the stable thioesters
instead of the labile aldehydes as the starting materials.
Thus, reductive alkylation can be carried out effectively
0.28 (EtOAc/hexane, 30:70). [R]20 -28.4° (c ) 0.69, MeOH);
D
1H NMR (CDCl3) δ 9.77 (s, 1H), 7.25-7.75 (m, 8H), 5.71 (d, J
) 8.7 Hz, 1H), 4.54 (m, 1H), 4.40 (m, 2H), 4.22 (t, J ) 7 Hz,
1H), 3.07 (dd, J ) 4.5, 8.7 Hz, 1H), 3.00 (dd, J ) 4.5, 8.7 Hz,
1H), 1.46 (s, 9H); 13C NMR 199.5, 169.8, 156.1, 144.0, 143.8,
141.5, 127.9, 127.2, 125.3, 120.2, 83.2, 67.4, 49.8, 47.3, 46.3,
28.0; FAB-MS m/z ) 396 (M + H)+. Anal. Calcd for C23H25
-
NO5: C, 69.86; H, 6.37; N, 3.54. Found: C, 69.57; H, 6.35; N,
3.48.
9-F lu or en em eth yl (S)-P h en yla la n in a te Hyd r och lor id e
(6a ). DCC (2.27 g, 11 mmol) was added to a solution of N-(tert-

Reductive Alkylation of Amines by S-Ethyl Thioesters
J . Org. Chem., Vol. 64, No. 6, 1999 1977
butyloxycarbonyl)-(S)-phenylalanine (2.65 g, 10 mmol), 9-fluo-
renemethanol (2.16 g, 11 mmol), and DMAP (122 mg, 1 mmol)
in DCM (10 mL) and stirred at room temperature for 30 min
and then filtered and concentrated in vacuo to give 4.21 g of
5a (95% yield) as a white solid. Crystallization from EtOAc/
hexane afforded white crystals: mp 125-126 °C (lit.18 125-
126 °C); [R]20 -6.3° (c 0.93, CHCl3) [lit.19 [R]20 -6° (c 0.84,
(M + H)+. Anal. Calcd for C46H46N2O6‚1/8TFA: C, 75.36; H,
6.31; N, 3.79. Found: C, 75.78; H, 6.18; N, 3.39.
On e-P ot Red u ctive Alk yla tion . Meth od A. Triethylsi-
lane (0.80 mL, 5 mmol) was quickly added to an ice cold
solution of thioester 2 (455 mg, 1 mmol) and 10% Pd-C (35
mg) in DMF (5 mL), followed by the addition of 6a (527 mg,
1.1 mmol) and, after 5 min, sodium triacetoxyborohydride (424
mg, 2 mmol) in DMF (2 mL). The resulting mixture was stirred
at room temperature for 30 min and then filtered through a
Celite bed which was washed with ether (30 mL). Following
the workup procedure described above afforded 672 mg of 7a
as a viscous oil (93% yield).
Meth od B: Triethylsilane (0.80 mL, 5 mmol) was quickly
added to an ice-cold mixture of thioester 2 (455 mg, 1 mmol),
amine 6a (527 mg, 1.1 mmol), and 10% Pd-C (35 mg) in DMF
(5 mL). After 5 min sodium triacetoxyborohydride (424 mg, 2
mmol) in DMF (2 mL) was added, and the resulting mixture
was stirred at room temperature for 30 min. Workup proce-
dure, as described in method A, afforded 665 mg of 7a (92%
yield).
D
D
CHCl3)]. ESI-MS m/z ) 444 (M + H)+.
Crude 5a was dissolved in EtOAc (30 mL), saturated with
HCl (gas), and left overnight at room temperature. The
precipitate was filtered off and washed with EtOAc for three
times to give 3.30 g of 6a (87% yield) as white crystals: mp
169-170 °C; 13C NMR 169.8, 144.1, 143.8, 141.5, 135.5, 130.2,
129.4, 128.6, 128.0, 126.0, 125.9, 120.9, 107.7, 67.8, 54.0, 46.7,
36.5. ESI-MS m/z ) 344 (M + H)+.
r-(9-F lu or en em eth yl) â-Cycloh exyl L-Asp a r ta te Hy-
d r och lor id e (6b). DCC (2.27 g, 11 mmol) was added to a
solution of â-cyclohexyl-N-(tert-butyloxycarbonyl)-L-aspartic
acid (3.15 g, 10 mmol), 9-fluorenemethanol (2.16 g, 11 mmol),
and DMAP (122 mg, 1 mmol) in DCM (10 mL) and stirred at
room temperature for 30 min and then filtered and concen-
trated in vacuo. Purification by silica gel column afforded 4.53
g (92% yield) of 5b as a white solid. Crystallization from
EtOAc/hexane gave white crystals: mp 87-88 °C; Rf ) 0.51
(EtOAc/hexane, 20:80); 1H NMR (CDCl3) δ 7.25-7.77 (m, 8H),
5.56 (d, J ) 9 Hz, 1H), 4.75 (m, 1H), 4.70 (m, 1H), 4.42 (m,
2H), 4.22 (t, J ) 7 Hz, 1H), 3.00 (dd, J ) 4.5, 17.0 Hz, 1H),
2.80 (dd, J ) 4.5, 17.0 Hz, 1H), 1.20-1.79 (m, 19H); 13C NMR
171.5, 170.6, 155.6, 143.8, 143.7, 141.4, 128.0, 127.4, 125.3,
120.2, 80.4, 73.9, 68.0, 50.2, 46.9, 31.7, 28.5, 25.4, 23.9; FAB-
MS m/z ) 494 (M + H)+. Anal. Calcd for C29H35NO6: C, 70.57;
H, 7.15; N, 2.84. Found; C, 70.77; H, 7.00; N, 2.72.
Meth od C. Sodium triacetoxyborohydride (424 mg, 2 mmol)
was added to an ice-cold mixture of amine 6a (527 mg, 1.1
mmol), thioester 2 (455 mg, 1 mmol), and 10% Pd-C (35 mg)
in DMF (5 mL), followed by quick addition of triethylsilane
(0.8 mL, 5 mmol). The resulting mixture was stirred at 10∼20
°C for 30 min. The workup procedure described above afforded
7a with 90-95% yield.
ter t-Bu tyl 2(S)-[(9-F lu or en ylm eth oxyca r bon yl)a m in o]-
4-[1(S)-(9-F lu or en ylm eth oxyca r bon yl)-2-(cycloh exyloxy-
ca r bon yl)eth yla m in o]bu tyr a te (7b). Synthesis followed
method C, described above for 7a , and afforded 733 mg of 7b
(95% yield) as a viscous oil. An aliquot of the oil was dissolved
in H2O-CH3CN-TFA (30:70:0.1, v/v/v) and lyophilized to
afford a white powder: mp 81-82 °C; Rf ) 0.35 (EtOAc/
5b was dissolved in EtOAc (30 mL), saturated with HCl
(gas), and left overnight at room temperature. The residue
obtained after evaporation solidified under vacuum. Treatment
of the residue with ether afforded 3.30 g of 6b (91% yield) as
white powder: mp 102-103 °C; 13C NMR 168.4, 143.2, 127.9,
127.2, 125.3, 120.2, 73.3, 67.6, 48.4, 46.0, 34.3, 30.9, 24.8, 23.1.
ESI-MS m/z ) 394 (M + H)+.
hexane, 30:70); [R]20 -18.4° (c ) 0.77, MeOH); 1H NMR
D
(CDCl3) δ 7.75-7.24 (m, 16 H), 5.96 (d, J ) 8 Hz, 1 H), 4.76
(m, 1H), 4.12-4.52 (m, 8 H), 3.61 (m, 1H), 2.32-2.74 (m, 4H),
1.80 (m, 2H), 1.21-1.75 (m, 19H); 13C NMR 199.4, 171.4, 170.0,
169.7, 156.1, 144.0, 143.8, 143.5, 141.5, 128.0, 127.9, 127.4,
127.2, 125.4, 125.0, 120.1, 83.2, 73.9, 67.3, 67.1, 60.6, 57.6, 52.9,
49.8, 47.3, 47.0, 46.3, 31.6, 25.4, 23.8, 21.2. ESI-MS m/z ) 773
(M + H)+. Anal.Calcd for C47H52N2O8‚1/6TFA: C, 71.79; H, 6.64;
N, 3.54. Found: C, 71.48; H, 6.47; N, 3.56.
r-(9-F lu or en em eth yl)-NG-p-Tosyl L-Ar gin in a te Hyd r o-
ch lor id e (6c). Preparation followed the procedure described
above for 6b and afforded 4.54 g of 6c (93% yield) as white
powder: mp 88-90 °C; 1H NMR (d6-DMSO) δ 8.63 (s, 2H),
7.28-7.90 (m, 12H), 6.95 (broad, 1H), 5.22 (broad, 3H), 4.73
(dd, J ) 5.5, 5.8 Hz, 1H), 4.52 (dd, J ) 5.5, 5.8 Hz, 1H), 4.33
(t, J ) 5.8 Hz, 1H), 3.94 (m, 1H), 2.94 (m, 2H), 3.31 (s, 3H),
1.12-1.71 (m, 4H); 13C NMR 169.5, 156.8, 143.4, 143.2, 140.9,
129.1, 127.9, 127.8, 127.3, 127.2, 125.7, 125.3, 125.1, 120.2,
66.7, 51.5, 46.2, 27.3, 24.4, 21.0; ESI-MS m/z ) 507 (M + H)+.
ter t-Bu tyl 2(S)-[(9-F lu or en ylm eth oxyca r bon yl)a m in o]-
4-[[2-P h en yl-1(S)- (9-F lu or en ylm eth oxyca r bon yl)eth yl]-
a m in o]bu t yr a t e (7a ). St ep w ise P r oced u r e. To a stirred
solution of aldehyde 3 (395 mg, 1 mmol) and amine 6a (527
mg, 1.1 mmol) in DMF (2 mL) at room temperature was added
sodium triacetoxyborohydride (424 mg, 2 mmol) in DMF (2
mL). After 30 min the reaction mixture was diluted with ether
(30 mL), washed with diluted NaHCO3 (3 × 5 mL), water (10
mL), and brine (5 mL), dried, and concentrated in vacuo.
Purification on silica gel column afforded 678 mg of 7a (94%
yield) as a colorless oil. An aliquot of the oil was dissolved in
H2O-CH3CN-TFA (30:70:0.1, v/v/v) and lyophilized to afford
a white powder: mp 56-57 °C; Rf ) 0.34 (EtOAc/hexane )
30:70). [R]20D -17.5° (c ) 0.84, MeOH); 1H NMR (CDCl3) 7.44-
7.77 (m, 21 H), 6.06 (d, J ) 8.6 Hz, 1H), 4.05-4.46 (m, 8H),
3.53 (m, 1H), 2.90 (dd, J ) 4.5, 8.6 Hz, 1H), 2.85 (dd, J ) 4.5,
8.6 Hz, 1H), 2.67 (m, 1H), 2.46 (m, 1H), 1.73-1.91 (m, 2H),
1.47 (s, 9H); δ 13C NMR 174.9, 17.4, 156.5, 144.1, 144.0, 143.7,
143.5, 141.5, 141.4, 129.4, 128.9, 128.8, 128.5, 128.1, 127.9,
127.5, 127.4, 127.2, 125.3, 125.1, 125.0, 120.2, 120.1, 82.5, 67.2,
66.7, 62.7, 53.1, 47.3, 47.0, 44.2, 31.6, 28.2; ESI-MS m/z ) 723
ter t-Bu tyl (S)-[(9-F lu or en ylm eth oxyca r bon yl)a m in o]-
4-[4-(NG-p - t osylgu a n id in o)-1(S)-(9-F lu or en ylm et h oxy-
ca r bon yl)bu tyla m in o]bu tyr a te (7c). Synthesis followed
method C, described above for 7a , and afforded 733 mg of 7c
(95% yield) as a viscous oil. An aliquot was dissolved in H2O-
CH3CN-TFA (30:70:0.1, v/v/v) and lyophilized to afford a white
solid: mp 79-80 °C; Rf ) 0.48 (EtOAc/hexane: MeOH, 45:48:
1
7); [R]20 -21.1° (c ) 0.88, MeOH); H NMR (CDCl3) δ 7.14-
D
7.74 (m, 20H), 6.36 (m, 1H), 6.08 (s, 1H), 6.94 (m, 1H), 5.29 (s,
1H), 4.11-4.55 (m, 8H), 3.04 (m, 2H), 2.56 (m, 1H), 2.01-2.33
(m, 4H), 1.82-1.91 (m, 2H), 1.43 9S, 9H); 13C NMR 175.8,
171.2, 157.1, 156.7, 143.8, 143.3, 142.0, 141.5, 129.3, 128.1,
127.8, 127.3, 126.0, 125.2, 124.7, 120.1, 82.8, 67.3, 66.4, 60.4,
52.6, 47.1, 47.0, 44.1, 28.0, 21.5; ESI-MS m/z ) 887 (M + H)+.
Anal. Calcd for C50H55N5O8S‚1/6TFA: C, 66.79; H, 6.14; N, 7.74.
Found: C, 66.52; H, 6.20; N, 7.61.
r-ter t-Bu tyl γ-S-Eth yl (S)-N-(9-F lu or en ylm eth oxyca r -
bon yl)th ioglu ta m a te (9). Preparation followed procedure
described above for 2 and afforded 4.46 g of 9 (95% yield) as a
colorless oil which solidified at room temperature. Crystal-
lization from EtOAc/hexane afforded white crystals: mp 62-
63 °C; Rf ) 0.41 (EtOAc/hexane, 20:80); [R]20D -20.1° (c ) 1.04,
MeOH); 1H NMR (CDCl3) δ 7.27-7.77 (m, 8H), 5.43 (d, J ) 8
Hz, NH, 1H), 4.27-4.30 (m, 3H), 4.22 (t, J ) 6.8 Hz, 1H), 2.87
(q, J ) 7.5 Hz, 2H), 2.56-2.60 (m, 2H), 2.21 (m, 1H), 2.00 (m,
1H), 1.48 (s, 9H), 1.24 (t, J ) 7.5 Hz, 3H); 13C NMR 198.8,
171.0, 156.1, 144.1, 143.9, 141.5, 127.9, 127.2, 125.3, 120.2,
82.8, 67.2, 53.9, 47.3, 40.0, 28.5, 28.2, 23.6, 14.9; ESI-MS m/z
) 470 (M + H)+. Anal. Calcd for C26H31NO5S: C, 66.50; H,
6.65; N, 2.98. Found: C, 66.75; H, 6.95; N, 3.08.
(18) Bednarek, M. A. Bodanszky, M. Int. J . Peptide Protein Res.
1983, 21, 196.
(19) Pozdnev, V. F. Int. J . Pept. Protein Res. 1992, 40, 407.
ter t-Bu tyl 2(S)-[(9-F lu or en ylm eth oxyca r bon yl)a m in o]-
5-[2-P henyl-1(S)-(9-Fluorenylmethoxycarbonyl)ethylamino]-

1978 J . Org. Chem., Vol. 64, No. 6, 1999
Han and Chorev
ca p r oa te (11). Synthesis followed the described procedure for
7a . The amine 11 was obtained as a viscous oil (33%, 45%,
and 76% yields were achieved using methods A, B, and C
respectively). An aliquot of the oil was dissolved in H2O-CH3-
CN-TFA (30:70:0.1, v/v/v) and lyophilized to afford a white
ter t-Bu tyl 4(S)-[(9-F lu or en ylm eth oxyca r bon yl)a m in o]-
5-[[2-P h en yl-1(S)- (ter t-bu tyloxyca r bon yl)eth yl]a m in o]-
ca p r oa te (20). Preparation by either the stepwise or one-pot
method C described above for 7a afforded 20 as a colorless oil
with 95% and 94% yields, respectively. An aliquot of the oil
was dissolved in H2O-CH3CN-TFA (30:70:0.1, v/v/v) and
powder: mp 53-54 °C; Rf ) 0.33(EtOAc/hexane, 30:70); [R]20
D
1
-20.1° (c ) 0.73, MeOH); H NMR (CDCl3) δ 7.44-7.77 (m,
lyophilized to afford a white powder: mp 34-36 °C; Rf ) 0.41
21 H), 6.05 (d, J ) 8.6 Hz, 1H), 4.03-4.47 (m, 8H), 3.53 (m,
1H), 2.90 (dd, J ) 4.5, 8.6 Hz, 1H), 2.85 (dd, J ) 4.5, 8.6 Hz,
1H), 2.67 (m, 1H), 2.46 (m, 1H), 1.63-1.91 (m, 4H), 1.44 (s,
9H); 13C NMR 174.9, 17.4, 156.5, 144.1, 144.0, 143.7, 143.5,
141.5, 141.4, 129.4, 128.9, 128.8, 128.5, 128.1, 127.9, 127.5,
127.4, 127.2, 125.3, 125.1, 125.0, 120.2, 120.1, 82.5, 67.2, 66.7,
62.7, 53.1, 47.3, 47.0, 44.2, 31.6, 28.2; ESI-MS m/z ) 737 (M
+ H)+. Anal. Calcd for C47H48N2O6: C, 76.61; H, 6.57; N, 3.80.
Found: C, 76.38; H, 6.39; N, 3.85.
1
(EtOAc/hexane ) 40:60); [R]20 + 5.6° (c ) 1.02, MeOH); H
D
NMR (CDCl3) 6.95-7.50 (m, 13H), 6.37 (d, J ) 7.5 Hz, 1H),
4.03 (d, J ) 8 Hz, 2H), 3.92 (m, 1H), 3.81 (m, 1H), 3.72 (m,
1H), 3.10 (m, 2H), 2.92 (m, 1H), 2.79 (m, 1H), 2.07 (m, 1H),
1.56 (m, 1H), 1.16 (s, 9H), 1.05 (s, 9H); 13C NMR 172.8, 167.2,
157.8, 144.1, 143.8, 141.4, 133.7, 129.6, 129.1, 128.0, 127.3,
125.5, 120.1, 85.2, 81.5, 67.8, 61.9, 51.2, 49.2, 47.1, 35.9, 31.7,
28.2, 27.8, 27.1; ESI-MS m/z ) 615 (M + H)+.
r-S-Eth yl â-(9-F lu or en em eth yl) (S)-N-(ter t-Bu tyloxy-
ca r bon yl)th ioa sp a r ta te (13). Preparation followed the pro-
cedure described above for 2 and afforded 423 mg of 13 (93%
yield) as a colorless oil which solidified at room temperature.
Crystallization from EtOAc/hexane afforded white crystals:
mp 109-110 °C; Rf ) 0.42 (EtOAc/hexane, 20:80); 1H NMR
(CDCl3) δ 7.25-7.77 (m, 8H), 5.48 (d, J ) 8.5 Hz, 1H), 4.63
(m, 1H), 4.45 (m, 2H), 4.23 (t, J ) 7 Hz, 1H), 3.20 (dd, J ) 4.5,
17 Hz, 1H), 3.08 (dd, J ) 4.5, 17 Hz, 1H), 2.87 (q, J ) 7.5 Hz,
2H), 1.46 (s, 9H), 1.23 (t, J ) 7.5 Hz, 3H,); 13C NMR 197.5,
171.3, 155.6, 143.9, 143.8, 141.6, 128.2, 127.5, 125.4, 120.3,
80.6, 68.0, 50.7, 47.0, 45.6, 28.6, 23.9, 14.9; FAB-MS m/z )
456 (M + H)+. Anal. Calcd for C25H29NO5S: C, 65.91; H, 6.42;
N 3.07. Found: C, 66.18; H, 6.50; N, 3.09.
r-ter t-Bu tyl â-S-Eth yl (S)-N-(Ben zyloxyca r bon yl)th io-
a sp a r ta te (22). Preparation followed the procedure describe
for 2. Purification of the crude product on silica gel column
afforded 352 mg 22 (96% yield) as a colorless oil: Rf ) 0.48
(EtOAc/hexane, 25:75); [R]20 -23.4° (c ) 1.32, MeOH); 1H
D
NMR (CDCl3) 7.35 (m, 5H), 5.72 (d, J ) 8 Hz, 1H), 5.11 (s,
2H), 4.49 (m, 1H), 3.17 (dd, J ) 4.5, 16.5 Hz, 1H), 3.15 (dd, J
) 4.5, 16.5 Hz, 1H), 2.87 (m, J ) 7.5 Hz, 2H), 1.44 (s, 9H),
1.24 (t, J ) 7.5 Hz, 3H); 13C NMR 196.9, 169.5, 156.0, 136.4,
128.6, 128.2, 128.1, 82.7, 67.0, 51.4, 45.5, 28.0, 23.6, 14.8; ESI-
MS m/z 368 (M + H)+.
ter t-Bu tyl 2(S)-[(Ben zyloxycar bon yl)am in o]-4-[[2-P h en -
yl-1(S)-(Ben zyloxyca r bon yl)eth yl]a m in o]bu tyr a te (24).17
Prepared according to method C described above for 7a .
Purification of the crude product on a silica gel column afforded
513 mg of 24 (94% yield) as a colorless oil. An aliquot was
dissolved in H2O-CH3CN-TFA (30:70:0.1, v/v/v) and lyoph-
ilized to afford a white powder: mp 42-43 °C; Rf ) 0.46
9-Flu or en em eth yl 3(S)-[(ter t-Bu tyloxycar bon yl)am in o]-
4-[2-P h en yl-1(S)- (ter t-Bu tyloxyca r bon yl)eth yla m in o]bu -
tyr a te (15) a n d 1-[1(S)-(ter t-Bu tyloxyca r bon yl)-2-P h en yl-
eth yl]-4(S)-[(ter t-Bu tyloxyca r bon yl)a m in o]p yr r olid in -2-
on e (16). Synthesis followed the procedure for method C
described above for 7a . The crude product purified on a silica
gel column afforded 261 mg of 15 as a viscous oil (87% yield).
Rf ) 0.36 (EtOAc/hexane, 35:65); ESI-MS m/z ) 601 (M + H)+.
15 was unstable at room temperature and converted to 16
after a few days. Purification by semipreparative RP-HPLC
on Vydac C-18, λ ) 220 nm, employed a linear gradient of
0-40% (v/v) B in 15 min and followed by 40-80% B in 55 min,
(EtOAc/hexane, 35:65); [R]20 -10.5° (c ) 1.14, MeOH); ESI-
D
MS m/z ) 547 (M + H)+; 1H and 13C NMR were identical with
those previously reported.17
ter t-Bu tyl 2(S)-[(9-F lu or en ylm eth oxyca r bon yl)a m in o]-
4-[[(2-Cycloh exyloxyca r bon yl)-1(S)-(Hyd r oxyca r bon yl)-
eth yl]a m in o]bu tyr a te (26) a n d ter t-Bu tyl 2(S)-[(9-
F lu or en ylm et h oxyca r b on yl)a m in o]-4-[[(2-Cycloh exyl-
oxyca r b on yl)-1(S )-(p r op yloxyca r b on yl)e t h yl]a m in o]-
bu tyr a te (27). Preparation followed method C described above
for 7a . Purification of the crude product by preparative RP-
HPLC on Vydac C-18, 220 nm (linear gradient of 0-30% (v/v)
B in 20 min followed by 30-80% B in 65 min) and lyophiliza-
tion of the pure fractions afforded 126 mg of 26 (87% yield)
afforded 126 mg of a colorless oil; [R]20 -72.1° (c ) 1.20,
D
MeOH); 1H NMR (CDCl3) 7.17-7.32 (m, 5H), 5.15 (m, 1H),
4.95 (m, 1H), 4.00 (m, 1H), 3.43 (m, 1H), 3.20 (m, 1H), 2.96
(m, 1H), 2.52 (m, 1H), 1.79 (m, 1H), 1.45 (s, 9H); δ 13C NMR
173.4, 169.3, 156.0, 136.4, 128.8, 128.6, 127.2, 82.7, 80.2, 56.1,
52.3, 41.9, 35.4, 28.7, 28.3, 28.1; ESI-MS m/z ) 405. Anal.
Calcd for C22H32N2O5: C, 65.32; H, 7.97; N, 6.93. Found: C,
70.87; H, 6.87; N, 5.19.
γ-ter t-Bu tyl r-S-Eth yl (S)-N-(F lu or en ylm eth oxyca r bo-
n yl)th ioglu ta m a te (18). Synthesis followed the procedure for
2 deiscribed above and afforded 444 mg of 18 (92% yield) as a
white solid. Crystallization from EtOAc/hexane afforded white
needles: mp 110-111 °C; Rf ) 0.43 (EtOAc/hexane, 20:80);
and 5 mg of 27 as white powders. 26: mp 152-153 °C; [R]20
D
-2.2° (c ) 1.89, MeOH); 1H NMR (d6-DMSO) δ 7.30-7.86 (m,
8H), 4.43 (m, 1H), 4.31 (m, 1H), 4.22 (m, 1H), 4.13 (m, 1H),
3.14 (m, 2H), 2.94 (m, 2H), 2.24 (m, 2H), 1.77 (m, 1H), 1.71
(m, 1), 1.32-1.45 (m, 20H); 13C NMR 170.6, 168.3, 167.8, 155.4,
142.8, 142.6, 139.9, 126.6, 126.0, 124.1, 118.7, 80.8, 79.0, 64.9,
55.2, 49.0, 47.0, 46.0, 33.5, 30.2, 26.9, 26.7, 26.6; ESI-MS: MW
calcd for C32H42N2O8: 582.6942, found: m/z ) 583 (M + H)+.
27: mp 39-40 °C; ESI-MS m/z ) 623 (M + H)+.
[R]20 -34.5° (c ) 0.96, MeOH); 1H NMR (CDCl3) δ 7.25-7.76
D
(m, 8H), 5.69 (d, J ) 8.5 Hz, 1H), 4.49 (dd, J ) 7, 10.5 Hz,
1H), 4.45 (m, 1H), 4.33 (dd, J ) 7.5, 10.5 Hz, 1H), 4.22 (t, J )
7 Hz, 1H), 2.88 (q, J ) 7.3 Hz, 2H), 2.34 (m, 2H), 2.18 (m,
1H), 1.94 (m, 1H), 1.45 (s, 9H), 1.25 (t, J ) 7.3 Hz, 3H); 13C
NMR 200.9, 172.5, 156.1, 144.0, 143.8, 141.4, 127.9, 127.2,
125.3, 120.1, 81.2, 67.3, 60.8, 47.3, 31.7, 28.2, 27.7, 23.5, 14.6;
FAB-MS m/z ) 470 (M + H)+. Anal. Calcd for C26H31NO5S:
C, 66.50; H, 6.65; N, 2.98. Found; C, 66.61; H, 6.77; N, 2.98.
5-ter t-Bu tyl1-Oxo-2(S)-[(9-Flu or en ylm eth oxyca r bon yl)-
a m in o]ca p r oa te (19). Synthesis followed procedure described
above for 3 and afforded 388 mg of 19 (95%) as a colorless oil
which solidified at room temperature: mp 64-65 °C; Rf ) 0.33
Ben zyl N-(3-P h en yla llyl) (S)-P h en yla la n in a t e (29).
Preparation followed method C described above for 7a . Puri-
fication of the crude product on a silica gel column afforded
343 mg of 29 (92% yield) as a colorless oil which upon
lyophilization afforded a white powder: mp 105-106 °C; Rf )
1
0.42 (EtOAc/hexane, 6:4); [R]20 +3.7° (c ) 2.68, MeOH); H
D
NMR (CDCl3) δ 7.09-7.38 (m, 15 H), 6.51 (d, J ) 16 Hz, 1H),
6.23 (m, 1H), 5.06 (m, 1H), 4.08 (m, 1H), 3.80 (m, 1H), 3.42
(m, 1H), 3.22 (m, 1H), 2.60 (m, 1H), 2.05 (m, 1H); 13C NMR
168.4, 139.2, 135.2, 134.2, 133.9, 129.4, 129.0, 128.9, 128.3,
127.8, 127.0, 126.6, 117.8, 68.2, 60.1, 48.9, 36.5, 36.5; ESI-MS
m/z ) 372 (M + H)+.
(EtOAc/hexane, 35:65). [R]20 -28.4° (c ) 0.69, MeOH); 1H
D
NMR (CDCl3) δ 9.56 (s, 1H), 7.29-7.76 (m, 8H), 5.69 (d, J )
7 Hz, 1H), 4.18-4.24 (m, 4H), 1.85-2.36 (m, 4H), 1.44 (s, 9H);
13C NMR 199.0, 172.5, 156.4, 143.9, 143.8, 141.4, 172.9, 127.2,
125.2, 120.2, 81.3, 67.2, 59.8, 47.3, 31.0, 28.2, 24.1; ESI-MS
m/z ) 410 (M + H)+. Anal. Calcd for C24H27NO5: C, 70.40; H,
6.65; N, 3.42. Found: C, 70.17; H, 6.80; N, 3.24.
J O982125G