Efficient preparation of chiral diamines via Red-Al reduction of N-Boc-protected amino acid-derived secondary amides

Article abstract of DOI:10.1016/j.tetlet.2006.01.056

Conditions have been developed for the selective reduction of N-Boc-protected amino acid-derived secondary amides, avoiding the formation of overreduction and cyclic urea byproducts. The method is showcased by the efficient formal synthesis of NK-1 antagonist LY303870.

Full text of DOI:10.1016/j.tetlet.2006.01.056

Tetrahedron Letters 47 (2006) 1717–1720
Efficient preparation of chiral diamines via Red-Al reduction
of N-Boc-protected amino acid-derived secondary amides
Eric A. Voight,* Matthew S. Bodenstein, Norihiro Ikemoto and Michael H. Kress
Merck Research Laboratories, Department of Process Research, Merck & Co., 466 Devon Park Drive, Wayne, PA 19087, USA
Received 1 December 2005; revised 11 January 2006; accepted 12 January 2006
Abstract—Conditions have been developed for the selective reduction of N-Boc-protected amino acid-derived secondary amides,
avoiding the formation of overreduction and cyclic urea byproducts. The method is showcased by the efficient formal synthesis
of NK-1 antagonist LY303870.
ꢀ 2006 Published by Elsevier Ltd.
Vicinal diamines are commonly encountered as syn-
thetic intermediates, drug targets, chiral auxiliaries,
and ligands in asymmetric catalysis.1 For this reason,
the efficient preparation of chiral molecules containing
a 1,2-diamino moiety is an important objective. Chiral
vicinal diamines 1 (Scheme 1), containing a free dialkyl
secondary amine and a carbamate protected primary
amine, are attractive as peptide surrogates2 and as pre-
cursors to a variety of heterocycles.3 Several methods
have been reported for their synthesis (Scheme 1).
can be opened with primary amines.5 Unfortunately,
syntheses of 2 and 3 can be lengthy, and aldehyde 2 is
prone to racemization. An alternative reductive amina-
tion approach involves the one-pot conversion of thio-
esters 4 to 1.6 Imidazolidines 5 can be deprotonated with
sec-butyllithium/(ꢀ)-sparteine and reacted with alkyl
halides enantioselectively, giving 1 after deprotection.7
So far, this method remains substrate limited. Finally,
thioamide8 and amide reduction have been utilized to
convert amides 6 to diamines 1. This route appeared
particularly attractive for our purposes.
Intermediates 2–6 have been reported as precursors to
diamines 1 (Scheme 1). a-Aminoaldehydes 2 are com-
monly used to prepare diamines 1 via reductive amina-
tion with a primary amine.4 Alternatively, aziridines 3
While conceptually superior to alternative methods, a
general and high-yielding method for the direct reduc-
tion of readily available tert-butoxycarbonyl(Boc)-pro-
tected amino acid-derived secondary amides 6b to Boc-
diamines 1 has, to our knowledge, not been reported
in the primary literature.9 To this end, chemoselective
borane reductions of aminoamides 6b have been
reported to give low to moderate yields of secondary
amines, due to incomplete reactions and difficulty cleav-
ing the B–N bond following reduction.10 Notably, the
use of lithium aluminum hydride (LAH) leads to signi-
ficant amounts of cyclic urea 7 and overreduction prod-
uct 8, again resulting in low to moderate yields (Scheme
2).11 These shortcomings are frequently avoided via
deprotection prior to reduction, thus losing the differen-
tial functional group handle, or through the choice of
less desirable amino acid protecting groups.12
R
R
O
SEt
PHN
PHN
PN
R
O
2
H
N
4
PHN
PHN
R'
R'
R
1
PHN
NR'
3
5
R
H
N
P = Boc or CBz
R, R' = Alkyl, Aryl
X
6a, X = S
6b, X = O
Scheme 1.
To overcome these obstacles, a general and efficient
reduction protocol to Boc-diamines 11 using inexpensive
and widely available Boc-protected amino acids 9 was
*
Corresponding author. Tel.: +1 215 652 1566; fax: +1 215 993
2100; e-mail: eric_voight@merck.com
0040-4039/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.01.056

1718
E. A. Voight et al. / Tetrahedron Letters 47 (2006) 1717–1720
R
R
R
R
Boc-Phe-Leu-OH (12, Scheme 3) to the corresponding
Boc-aminoalcohol 1316 in 97% isolated yield. Of the
three carbonyls in 12, only the amide and carboxylic
acid were reduced, with no evidence of carbamate reduc-
tion. Furthermore, tripeptide Boc-Met-Leu-Phe-OH
(14) was reduced to diaminoalcohol 1516 in 79% yield
under the same conditions. Using this method, a large
variety of chiral aminoalcohols should be easily accessi-
ble starting from readily available Boc-polypeptides.18
H
N
H
N
H
N
LAH
PHN
R'
PHN
R'
MeHN
R'
HN
O
NR'
O
6b
1
7
8
Scheme 2.
sought. Our experience with borane and LAH reduc-
tions of amides 10 gave no improvement over previously
reported results in terms of impurity profile or conver-
sion. In contrast, we have found the use of sodium
bis(2-methoxyethoxy)aluminum hydride (Red-Al), to
be remarkably effective for this transformation.13 Rou-
tinely provided as an inexpensive 65 wt % solution in
toluene, this reagent was found to reduce secondary
amides 10 in good to excellent yields with good volume
efficiency, reasonable reaction times and temperatures,
and minimal amounts of overreduction and cyclic urea
byproducts. The results of our studies are shown in
Table 1.
To further demonstrate the utility of this procedure, we
carried out a formal synthesis of Eli Lilly NK-1 antago-
nist LY303870 (Scheme 4).12 In the published route to
this drug target, the authors encountered typical amide
reduction problems with Boc-protected secondary
amide 17. For this reason, the triphenylmethyl (trityl)
amine protecting group was employed, requiring the
use of
a
noncommercially available tryptophan
derivative.
For our formal synthesis, commercially available Boc-D-
tryptophan (16) underwent amide bond formation with
ortho-methoxybenzylamine, giving 17. Amide 17 was
then cleanly reduced using 5 equiv Red-Al at 35 ꢁC.
Acetylation of the crude Boc-diamine gave acetylamine
18 in 75% overall yield over three steps. To determine
Starting from commercially available Boc-protected
amino acids 9 (a–g), mixed anhydride formation using
N-methylmorpholine (NMM), and iso-butylchlorofor-
mate was followed by the addition of a primary amine
(R0NH2).14,15 Aqueous workup gave crude amides 10
(a–g) which, without further purification, were reduced
with Red-Al in 2:1 toluene/THF between 35 and
65 ꢁC.15 In all cases, good to excellent yields of isolated
Boc-diamines 11 (a–g)16 were observed after aqueous
workup and column chromatography. Amino acid R
groups from alanine (entries a–c), phenylalanine (entries
d–f), and valine (entry g) performed well. Aryl (entries a
and g), benzylic (entries b and f), and alkyl (entries c–e)
amides were all tolerated in the reaction. Entries e and f,
with more sterically hindered amides, required higher
temperatures and gave slightly lower yields than other
examples.17
Ph
Ph
O
OH
10 equiv Red-Al
2:1 PhCH3/THF
H
H
N
N
BocHN
OH
BocHN
18 h, 55 oC
97%
O
12
13
S
S
Ph
Ph
OH
O
H
H
N
N
OH
BocHN
N
H
BocHN
N
H
O
O
14
15
A particularly noteworthy extension of this methodol-
ogy was observed in the selective reduction of dipeptide
Scheme 3.
Table 1. Results of Red-Al reduction
R
R
NMM, THF, -15 oC;
i-BuO2CCl; R'NH2
OH
NHR'
BocHN
BocHN
NHR'
O
O
9
10
R
Red-Al
2:1 PhCH3/THF
BocHN
11
Entry
R=
R0=
Reduction time (h)
Reduction temperature (ꢁC)
Red-Al (equiv)
Yielda (%) (9!11)
a
b
c
d
e
Me
Me
Me
Bn
Ph
Bn
Et
Et
t-Bu
40
24
17
36
27
35
35
35
35
65
3
5
3
5
5
82
75
93
76
57
Bn
f
Bn
16
65
40
5
5
68
87
g
i-Pr
Ph
14
a Isolated yields after flash column chromatography.

E. A. Voight et al. / Tetrahedron Letters 47 (2006) 1717–1720
1719
intermediate: (b) Hu, X. E.; Kim, N. K.; Leoussal, B.
Org. Lett. 2002, 4, 4499; (c) Salituro, F. G.; Baker, C. T.;
Court, J. J.; Deininger, D. D.; Kim, E. E.; Li, B.; Novak,
P. M.; Rao, B. G.; Pazhanisamy, S.; Porter, M. D.;
Schairer, W. C.; Tung, R. D. Bioorg. Med. Chem. Lett.
1998, 8, 3637; (d) Sajiki, H.; Ong, K. Y.; Nadler, S. T.;
Wages, H. E.; McMurry, T. J. Synth. Commun. 1996, 26,
2511.
NMM, THF, -15 oC;
i-BuO2CCl;
NH
OH
NH
MeO
H2N
H
N
BocHN
16
BocHN
O
O
OMe
17
6. Han, Y.; Chorev, M. J. Org. Chem. 1999, 64, 1972.
7. (a) Ashweek, N. J.; Coldham, I.; Haxell, T. F. N.;
Howard, S. Org. Biomol. Chem. 2003, 1, 1532; (b)
Coldham, I.; Copley, R. C. B.; Haxell, T. F. N.; Howard,
S. Org. Lett. 2001, 3, 3799.
1) Red-Al (5 equiv), 35 oC
2:1 PhCH3/THF, 19 h
NH
AcCl, MeOH
Ac
N
2) Ac2O, Et3N, PhCH3
DCM
86%
BocHN
75% overall from 16
OMe
8. For example, see Ref. 2b.
18
9. During the preparation of this manuscript, an isolated
example of the Red-Al reduction of a chiral Boc-protected
amino acid-derived secondary amide was found in the
recent patent literature: Liebeschuetz, J. W.; Sheehan, S.
M.; Watson, B. M. WO 2004/60872 A1, 22 July 2004.
10. For examples, see Refs. 2c and (a) Manku, S.; Laplante,
C.; Kopac, D.; Chan, T.; Hall, D. G. J. Org. Chem. 2001,
66, 874; (b) Jacobsen, E. J.; Stelzer, L. S.; TenBrink, R. E.;
Belonga, K. L.; Carter, D. B.; Im, H. K.; Im, W. B.; Sethy,
V. H.; Tang, A. H.; VonVoigtlander, P. F.; Petke, J. D.;
Zhong, W.; Mickelson, J. W. J. Med. Chem. 1999, 42,
1123.
N
Cl
NH2
NH
N
1 step
ref. 12
Cl
Ac
Ac
N
N
H3N
O
N
H
OMe
OMe
19
LY303870
Scheme 4.
11. For example, see: He, X.; Raymon, L. P.; Mattson, M. V.;
Eldefrawi, M. E.; de Costa, B. R. J. Med. Chem. 1993, 36,
4075.
12. For example, see: Hipskind, P. A.; Howbert, J. J.; Cho, S.;
Cronin, J. S.; Fort, S. L.; Ginah, F. O.; Hansen, G. J.;
Huff, B. E.; Lobb, K. L.; Martinelli, M. J.; Murray, A. R.;
Nixon, J. A.; Staszak, M. A.; Copp, J. D. J. Org. Chem.
1995, 60, 7033.
whether any epimerization had taken place in the reduc-
tion step, the enantiomer of 18 was prepared, and each
compound was found to have >99% ee by chiral
SFC.19 Deprotection of 18 was accomplished with meth-
anolic HCl, giving bis-HCl salt 19 with characterization
data identical to that in the literature.12
In conclusion, a general and high-yielding procedure has
been reported using Red-Al for the reduction of a vari-
ety of chiral amino acid-derived Boc-protected second-
ary amides. Extension of this methodology to Boc-
polypeptide reduction has also been accomplished.
Finally, using this procedure, an efficient formal synthe-
sis of an NK-1 antagonist has been carried out, demon-
strating the utility of the method. This protocol should
provide an attractive alternative to previously reported
methods for chiral Boc-diamine synthesis.
13. An achiral Boc-glycine derivative has been reduced with
Red-Al previously: Beylin, V. G.; Colbry, N. L.; Giordani,
A. B.; Goel, O. P.; Johnson, D. R.; Leeds, R. L.; Leja, B.;
Lewis, E. P.; Lustgarten, D. M.; Showalter, H. D. H.;
Secrcel, A. D.; Reily, M. D.; Uhlendorf, S. E.; Zisek, K. A.
J. Heterocycl. Chem. 1991, 28, 517.
14. Shendage, D. M.; Frohlich, R.; Haufe, G. Org. Lett. 2004,
6, 3675.
15. For example, entry g: Boc-Val-OH (1.0 g, 4.60 mmol) was
dissolved in THF (10.0 mL) and cooled to ꢀ20 ꢁC under
N2. N-Methylmorpholine (0.531 mL, 4.83 mmol) was
added and the mixture was allowed to stir for 10 min.
Then, iso-butylchloroformate (0.635 mL, 4.83 mmol) was
added dropwise over 5 min, keeping the temperature
6ꢀ14 ꢁC. The reaction was allowed to stir for 20 min.
Aniline (0.462 mL, 5.06 mmol) was added dropwise over
5 min, maintaining the temperature between ꢀ20 and
ꢀ30 ꢁC. The reaction was kept at ꢀ20 ꢁC, then allowed to
warm to room temperature over 30 min. Toluene (10 mL)
and 1 N HCl (10 mL) were added and the layers were
separated. The organic layer was washed with water
(2 · 10 mL), dried over MgSO4, filtered, and concentrated,
giving a glassy solid. THF (1.5 mL) and toluene (3.1 mL)
were added with stirring, and the mixture was cooled to
<5 ꢁC. Red-Al (6.90 mL, 23.0 mmol) was added dropwise,
keeping the temperature 620 ꢁC. The clear solution was
heated to 40 ꢁC. After 14 h, the solution was cooled to
<5 ꢁC and 5 N NaOH (10 mL) was added carefully,
keeping the temperature <25 ꢁC. After stirring for 20 min
at room temperature, toluene (30 mL) was added, the
layers were separated, and the organic layer was washed
with 5 N NaOH (2 · 10 mL) and concentrated. Purifica-
tion by flash column chromatography (10–30% MTBE/
hexanes) gave 11g (R = i-Pr, R0 = Ph, 1.11 g, 3.99 mmol,
87% yield).
References and notes
1. For a review, see: Lucet, D.; Gall, T. L.; Mioskowski, C.
Angew. Chem., Int. Ed. 1998, 37, 2580.
2. For examples, see: (a) Thierry, J.; Servajean, V. Tetra-
hedron Lett. 2004, 45, 821; (b) Guziec, F. S.; Wasmund, L.
M. Tetrahedron Lett. 1990, 31, 23; (c) Oyamada, H.; Ueki,
M. Bull. Chem. Soc. Jpn. 1987, 60, 267, and references
cited therein.
3. For example, see: Lewis, R. T.; Macleod, A. M.;
Merchant, K. J.; Kelleher, F.; Sanderson, I.; Herbert, R.
H.; Cascieri, M. A.; Sadowski, S.; Ball, R. G.; Hoogsteen,
K. J. Med. Chem. 1995, 38, 923.
4. For examples, see Refs. 3 and (a) Dinsmore, C. J.;
Bergman, J. M.; Bogusky, M. J.; Culberson, J. C.;
Hamilton, K. A.; Graham, S. L. Org. Lett. 2001, 3, 865;
(b) Harre, M.; Nickisch, K.; Schulz, C.; Weinmann, H.
Tetrahedron Lett. 1998, 39, 2555.
5. See Refs. 2a and (a) Fukushi, H.; Mabuchi, H.; Terashita,
Z.; Nishikawa, K.; Sugihara, H. Chem. Pharm. Bull. 1994,
42, 551; Tosylate or mesylate displacement has also been
reported, potentially also going through an aziridine

1720
E. A. Voight et al. / Tetrahedron Letters 47 (2006) 1717–1720
1
16. Selected characterization data: 11a: H NMR (CDCl3): d
7.3–7.1 (m, 2H), 6.8–6.6 (m, 3H), 4.52 (br s, 1H), 4.0–3.9
(br m, 1H), 3.15 (ABX, JAB = 12.5 Hz, JAX = 5 Hz,
JBX = 7.5 Hz, DmAB = 24.5 Hz, 2H), 1.46 (s, 9H), 1.23 (d,
J = 6.5 Hz, 3H); 13C NMR (CDCl3): d 156.0, 147.9,
129.3 · 2, 117.8, 113.0 · 2, 79.6, 50.8, 46.4, 28.4 · 3, 19.1.
Compound 11b: 1H NMR (CDCl3): d 7.4–7.2 (m, 5H),
3.80 (ABq, JAB = 13.5 Hz, DmAB = 13 Hz, 2H), 3.8–3.7 (br
m, 1H), 2.64 (ABX, JAB = 12 Hz, JAX = 5 Hz,
JBX = 6.5 Hz, DmAB = 12.5 Hz, 2H), 1.46 (s, 9H), 1.15 (d,
J = 6.5 Hz, 3H); 13C NMR (CDCl3): d 155.7, 140.4,
128.4 · 2, 128.1 · 2, 127.0, 79.1, 59.2, 54.5, 53.8, 28.5 · 3,
19.3. Compound 11c: 1H NMR (CDCl3): d 4.74 (br s, 1H),
3.8–3.6 (br m, 1H), 2.7–2.5 (m, 4H), 1.42 (s, 9H), 1.10 (d,
J = 6.5 Hz, 3H), 1.06 (t, J = 7 Hz, 3H); 13C NMR
(CDCl3): d 155.7, 79.1, 54.9, 46.2, 44.0, 28.4 · 3, 19.3,
15.3. Compound 11d: 1H NMR (CDCl3): d 7.3–7.1 (m,
5H), 4.90 (d, J = 7 Hz, 1H), 4.0–3.8 (br m, 1H), 2.9–2.5
(m, 6H), 1.39 (s, 9H), 1.04 (t, J = 7 Hz, 3H); 13C NMR
(CDCl3): d 155.8, 138.2, 129.4 · 2, 128.4 · 2, 126.3, 79.1,
51.9, 51.5, 44.0, 39.3, 28.4 · 3, 15.3. Compound 11e: 1H
NMR (CDCl3): d 7.4–7.1 (m, 5H), 4.90 (br s, 1H), 3.9–3.7
(br m, 1H), 2.89 (dd, J = 13.5, 6 Hz, 1H), 2.74 (dd,
J = 13.5, 7.5 Hz, 1H), 2.7–2.5 (m, 2H), 1.42 (s, 9H), 1.05
(s, 9H); 13C NMR (CDCl3): d 155.7, 138.5, 129.4 · 2,
128.4 · 2, 126.3, 79.1, 52.2, 50.2, 44.5, 39.0, 29.1 · 3,
28.4 · 3. Compound 11f: 1H NMR (CDCl3): d 7.4–7.1 (m,
10 H), 4.84 (d, J = 7 Hz, 1H), 3.90 (br s, 1H), 3.75 (q,
J = 6.5 Hz, 2H), 2.84 (br d, J = 6.5 Hz, 2H), 2.55 (ABX,
(CDCl3): d 7.3–7.0 (m, 2H), 6.8–6.5 (m, 3H), 4.54 (br d,
J = 8 Hz, 1H), 4.04 (br s, 1H), 3.8–3.6 (br m, 1H), 3.27
(dd, J = 12, 4 Hz, 1H), 3.04 (br t, J = 12 Hz, 1H), 1.88
(oct, J = 7 Hz, 1H), 1.47 (s, 9H), 1.01 (d, J = 7 Hz, 3H),
0.98 (d, J = 7 Hz, 3H); 13C NMR (CDCl3): d 156.7, 148.5,
129.3 · 2, 117.3, 112.7 · 2, 79.5, 55.6, 47.1, 30.6, 28.4 · 3,
19.5, 18.1. Compound 13: 1H NMR (CDCl3): d 7.4–7.1
(m, 5H), 4.60 (br s, 1H), 3.80 (br m, 1H), 3.59 (dd,
J = 10.5, 4 Hz, 1H), 3.22 (dd, J = 10.5, 6.5 Hz, 1H), 2.82
(ABX,
JAB = 13.5 Hz,
JAX = 6.5 Hz,
JBX = 7 Hz,
DmAB = 24.5 Hz, 2H), 2.65 (d, J = 6 Hz, 2H), 2.7–2.5 (m,
1H), 1.59 (non, J = 7 Hz, 1H), 1.42 (s, 9H), 1.4–1.1 (m,
2H), 0.88 (d, J = 7 Hz, 3H), 0.88 (d, J = 7 Hz, 3H); 13C
NMR (CDCl3): d 155.9, 137.9, 129.3 · 2, 128.5 · 2, 126.5,
79.5, 63.7, 57.0, 51.9, 49.8, 41.4, 39.4, 28.4 · 3, 25.0, 23.1,
22.7. Compound 15: 1H NMR (CDCl3): d 7.4–7.0 (m, 5H),
5.10 (br s, 1H), 3.7–3.5 (br m, 1H), 3.60 (dd, J = 10.5,
3.5 Hz, 1H), 3.35 (dd, J = 10.5, 5.5 Hz, 1H), 2.9–2.2 (m,
10H), 2.07 (s, 3H), 1.7–1.3 (m, 3H), 1.42 (s, 9H), 1.3–1.0
(m, 3H), 1.16 (s, 3H), 0.84 (d, J = 6.5 Hz, 6H); 13C NMR
(CDCl3): d 155.9, 139.0, 129.2 · 2, 128.5 · 2, 126.3, 79.2,
63.3, 55.9, 50.6, 50.4, 50.1, 42.7, 38.4, 32.8, 31.0, 28.5 · 3,
27.0, 25.0, 23.1, 22.8, 15.7.
17. The stereochemical integrity of each reduction was
assumed based on the analysis of compound 18 (Scheme
4).
18. Fmoc-Phe-Ala-OMe has been previously reduced in 60%
yield using LiBH4/TMSCl: Giannis, A.; Sandhoff, K.
Angew. Chem. 1989, 101, 220.
JAB = 12.5 Hz, JAX = 6 Hz, JBX = 5.5 Hz, DmAB
=
19. Chiral SFC method: Chiralpak AD-H column; 4%
MeOH/CO2, ramp to 40% MeOH/CO2 at 2% per min
with a 3 min hold at 40% MeOH; 1.5 mL/min; 200 bar;
35 ꢁC; 215 nm; retention times: (R)-18 = 16.8 min, (S)-
18 = 15.5 min.
13.5 Hz, 2H), 1.46 (s, 9H), 1.36 (d, J = 6.5 Hz, 3H);
13C NMR (CDCl3): d 155.7, 145.7, 138.3, 129.5 · 2,
128.5 · 2, 128.4 · 2, 127.0, 126.8 · 2, 126.4, 79.1, 58.3,
1
51.6, 50.1, 39.0, 28.5 · 3, 24.3. Compound 11g: H NMR