Application of the N-hydroxymethyl group to the stereoselective synthesis of (3S,4S)-3-aminodeoxystatine derivatives

Article abstract of DOI:10.1016/j.tetasy.2005.10.018

Stereoselective synthesis of two 3-aminodeoxystatine derivatives was achieved. Chiral γ-amino-α,β-unsaturated esters containing an N-aminomethyl group undergo the stereoselective conjugate addition with an internal carbamate or amide nitrogen nucleophile.

Full text of DOI:10.1016/j.tetasy.2005.10.018

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3762–3766
Application of the N-hydroxymethyl group to the
stereoselective synthesis of (3S,4S)-3-aminodeoxystatine derivatives
Dongwon Yoo, Seah Kwon and Young Gyu Kim*
School of Chemical and Biological Engineering, Seoul National University, Seoul 151-744, Republic of Korea
Received 27 September 2005; accepted 17 October 2005
Abstract—Stereoselective synthesis of two 3-aminodeoxystatine derivatives was achieved. Chiral c-amino-a,b-unsaturated esters
containing an N-aminomethyl group undergo the stereoselective conjugate addition with an internal carbamate or amide nitrogen
1
nucleophile. The diastereoselectivity was about 10:1 by H NMR. Thus, the 3-aminodeoxystatine derivatives were prepared from
commercially available N-Boc-L-leucine in nine steps in overall yields of 26% and 20% for the benzyl carbamate and the acetamide
derivatives, respectively.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
needed to study the importance of hydrogen bonding
and electrostatic interaction when the (3S)-hydroxyl
group of 1 was replaced by a basic amino group. The
b-amino group of 2 would be expected to be protonated
at physiological pH. Indeed, some peptides derived from
2 were shown to be more biologically active than the
corresponding congeners with 1.5 As far as the rat renin
inhibition was concerned, the substitution of 1 with 2
resulted in better inhibitory activity for all the peptides
studied. The reason would be the stronger hydrogen
bonding interaction of the aspartyl residues with the
protonated (3S)-amino group of 2 than that with the
(3S)-hydroxyl group of 1. Although it has some interest-
ing biological activities, there are not many reports
about the synthesis of 2 or the biological activities of
the peptides containing it.5,6 We herein report a stereo-
selective synthesis of (3S,4S)-3-aminodeoxystatine
derivatives by an efficient intramolecular conjugate
addition of nitrogen nucleophiles to the c-amino-a,b-
unsaturated ester.
Recently, we have reported an efficient stereoselective
synthesis of statine 1 (Fig. 1).1 The N-hydroxymethyl
group tethered to the amino group of c-amino-
a,b-unsaturated ester 3 was highly effective for the
stereoselective intramolecular conjugate addition to con-
struct the c-amino-b-hydroxycarboxylic acid moiety in
statine.2 As part of an ongoing study on the application
of the N-hydroxymethyl group in natural product syn-
thesis,3 we wanted to synthesize 3-aminodeoxystatine 2
((3S,4S)-3,4-diamino-6-methylheptanoic acid) deriva-
tives by simply replacing the hydroxyl group of 3 with
an amino group.3d
Boc
iBu
Boc
iBu
1. H3O+
2. recryst.
CO2Me
K2CO3
N
N
OH
CO2Me
O
MeOH
> 10:1
3
4
NH2
NH2
iBu
CO2H
iBu
CO2H
2. Results and discussion
NH2
OH
2
1
The required (E)-c-amino-a,b-unsaturated ester 5 with
the N-acetoxymethyl group was prepared from N-Boc-
L-leucine as described previously (Scheme 1).3c The pro-
tected aminomethyl group could be established under the
acid-catalyzed reaction of the N-acetoxymethyl group
with an amide or carbamate nucleophile.7 Initially, we
selected an amide group as a protected nitrogen source.
Thus, conjugated ester 6a containing the amidomethyl
Figure 1. The stereoselective synthesis of (ꢀ)-statine 1.
3-Aminodeoxystatine 2 is an isosterically modified sta-
tine analogue (Fig. 1).4 The peptides containing 2 were
*
Corresponding author. Tel.: +82 2 880 8347; fax: +82 2 885 6989;
e-mail: ygkim@snu.ac.kr
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.10.018

D. Yoo et al. / Tetrahedron: Asymmetry 16 (2005) 3762–3766
3763
Boc
iBu
O
Boc
iBu
N
N
Boc
iBu
Boc
iBu
NHR
CO2Me
OAc
a
N
N
b
a
N R
CO2Me
N R
CO2Me
6a R = Ac
6b R = Cbz
5
CO2Me
b
trans-9a R = Ac
trans-9b R = Cbz
trans-7a R = Ac
trans-7b R = Cbz
Boc
iBu
R'
R"
Boc
iBu
c
N
N
N R
3
O
O
4
CO2Me
Boc
HN
NH
N
N
CO2Me
R'
R
c
NH
4
syn-8a R=Ac, R'=R"=H
syn-8b R=Cbz, R'=R"=H
iBu
trans-7a R=Ac, R'=H
trans-7b R=Cbz, R'=H
trans-7c R=Ac, R'=OO(t-Bu)
iBu
3
CO2Me
CO2Me
trans-11
trans-10
Scheme 1. Reagents and conditions: (a) PPTS, AcNH2, 83% (6a) or
PPTS, CbzNH2, 82% (6b); (b) NaH, 78%; (c) cat. RuCl3, TBHP then
Pd/C, H2 followed by Cs2CO3 in MeOH, 47% (8a) or cat. RuCl3,
TBHP then 3 N HCl followed by Cs2CO3 in MeOH, 60% (8b).
Scheme 2. Reagents and conditions: (a) cat. RuCl3, NaIO4, CH3CN–
CCl4–H2O = 2:2:3, 98%; (b) Cs2CO3, MeOH; (c) TFA, CH2Cl2, 72%
(two steps, from 9a) or 73% (two steps, from 9b).
ratio was determined to be also about 10:1 based on
1
the H NMR spectrum.
group was obtained in a good yield from the reaction of 5
with acetamide in the presence of a catalytic amount of
PPTS. The use of PPTS instead of p-TsOH was crucial
to give the desired aminal functionality.8 We thought
that the N-amidomethyl group of 6a would be a good
enough nucleophile to undergo a facile intramolecular con-
jugate addition. However, the weak bases such as K2CO3
or KOH that were effective in the synthesis of statine did
not give a desired addition product. Stronger bases such
as NaH or KHMDS were necessary to effect the intramo-
lecular addition to give a diastereomeric mixture of imi-
dazolidine 7a. The addition reaction was fast at room
temperature probably because of the intramolecular nat-
ure of the reaction. The intermolecular conjugate addi-
tion of methanolic ammonia to the similar unsaturated
ester was slow even at higher temperature (80–90 ꢁC,
16 h, 51%, see below).6c The diastereoselectivity in the
conjugate addition was determined at the next stage
because the diastereomers of 7a were not distinguishable
in the 1H NMR spectrum. The ruthenium-catalyzed oxi-
dation of 7a resulted in a mixture of three compounds,
7c, 8c (R = Ac, R0 = CHO, R00 = H), and 8d (R = Ac,
R0 = H, R00 = CHO), that was treated without separa-
tion under the hydrogenolysis conditions to afford 8c
and 8d.9 Subsequent hydrolysis of the N-formyl groups
of 8c and 8d yielded 8a. The diastereomeric ratio of 8a
To determine the relative configuration at the newly
generated stereogenic center of the diastereomers, the
mixture 7 was converted to imidazolidinone 11 as shown
in Scheme 2. A smaller coupling constant of J3,4 (5.4 Hz)
has been reported for the trans-isomer of a similar imi-
dazolidinone, whereas the larger value of J3,4 (7.8 Hz)
was observed for its cis-isomer.6c The same trend has
been well established in oxazolidinone ring systems.1,10
First, the ruthenium-catalyzed oxidation reaction of
the aminal group of 7 gave the N-protected imidazolid-
inone 9.11 Then, both the acetyl (or Cbz) and the Boc
protecting groups were removed by the sequential treat-
ment with Cs2CO3 and TFA, respectively, to afford 11.
The 1H NMR analysis of the major isomer of 11 showed
the vicinal coupling constant of J3,4 to be 5.1Hz, which
is consistent with the values reported for the trans-iso-
mers of the imidazolidinone and the oxazolidinone ana-
logs as mentioned above. The J3,4 value of the minor cis-
isomer was determined to be 7.7 Hz from the about 1:1
diastereomeric mixture of 11.12 The diastereomeric ra-
tios of the imidazolidinones 9, 10, and 11 obtained here
1
were all about 10:1 by their H NMR spectra, which
confirmed the initial assessment of the stereoselectivity
of the intramolecular conjugate addition in Scheme 1.
1
was shown to be about 10:1 by H NMR. Similar selec-
The diastereoselection observed in the present study can
be rationalized with the more favorable H-eclipsed
allylic conformation (Fig. 2). The attack by the pro-
tected amino group on the same side as the allylic amino
group to the double bond would result in the trans
product.13
tivity was consistently observed with imidazolidinones 9,
10, and 11 (Scheme 2, see below).
With the synthesis of the (3N)-Ac and (4N)-Boc deriva-
tive 8a of 3-aminodeoxystatine being successful, we
needed to prepare another derivative with orthogonal
protecting groups for the two amino groups. The two
independent protecting groups would be important for
the selective formation of a peptide bond at a desired
amino group in the target peptides. In this regard, a ben-
zyl carbamate should be good enough to be a protected
nitrogen source. Moreover, separation of the syn-diaste-
reomer of the methyl ester derivative 8b from its anti-
diastereomer by column chromatography has been
reported.6a The desired 8b with the (3N)-Cbz and (4N)-
Boc protecting groups was then readily obtained follow-
ing the same protocol (Scheme 1). The diastereomeric
R
Boc
Bn
H
N
NH
N
R
Boc
CO2Me
N
CO2Me
Ph
trans-7
Figure 2. Favored conformation for the major product trans-7.

3764
D. Yoo et al. / Tetrahedron: Asymmetry 16 (2005) 3762–3766
3. Conclusion
4.62 (dd, 1H, J = 13.9 and 6.2), 4.97–5.09 (m, 2H),
5.82 (d, 1H, J = 15.9), 6.89 (dd, 1H, J = 15.9 and 6.0),
7.33 (br s, 5H); 13C NMR d 21.7, 22.8, 24.5, 28.2,
40.5, 51.4, 54.1, 55.3, 66.7, 81.0, 121.0, 128.0, 128.4,
136.1, 147.7, 155.5, 155.8, 166.5; MS (CI) 435
([M+1]+, 45), 379 (35), 274 (14), 184 (100), 91 (46);
HRMS (CI) calcd for C23H35N2O6 435.2495 ([M+1]+),
found 435.2494.
In summary, we have presented a stereoselective synthe-
sis of two 3-aminodeoxystatine derivatives using an
intramolecular conjugate addition of the N-amino-
methyl group. The N-aminomethyl group was intro-
duced from the amidation reaction of the N-
acetoxymethyl group under mild acidic conditions.
The diastereoselectivity of the intramolecular addition
1
reaction was about 10 to 1 by H NMR. Thus, the 3-
4.2. (4S,5S)-3-Benzyloxycarbonyl-1-(tert-butoxycarbon-
yl)-5-isobutyl-4-methoxycarbonylmethylimidazolidine
7b
aminodeoxystatine derivatives were prepared from com-
mercially available N-Boc-L-leucine in nine steps with
overall yields of 26% and 20% for the benzyl carbamate
and acetamide derivatives, respectively. The orthogo-
nally protected N-Cbz and N-Boc derivative 8b should
be useful for the selective formation of a peptide bond
at the desired amino group in the target peptides. The
method reported in the present study should be useful
also for the efficient synthesis of other related b,c-diami-
nocarboxylic acids with different side chains.
To a solution of 6b (166 mg, 0.38 mmol) in THF (5 mL)
was added NaH (3.48 mg, 0.38 mmol). The mixture was
stirred for 1h at room temperature. Then cold 1N aq
HCl solution was added to the resulting solution
and the mixture was extracted with Et2O (2 · 20 mL).
The combined organic layers were dried with MgSO4, fil-
tered, and concentrated under reduced pressure. The res-
idue was purified with SiO2 column chromatography (4:1
hexane/EtOAc) to give 7b (144 mg, 87%) as a colorless
oil. Compound trans-7b: Rf = 0.4 (2:1hexane/EtOAc);
1H NMR (DMSO-d6, 1 00ꢁC): d 0.90 (d, 3H, J = 6.4),
0.91(d, 3H, J = 6.6), 1.38–1.39 (m, 2H), 1.42 (s,
9H), 1.73–1.79 (m, 1H), 2.46–2.56 (m, 1H), 2.59 (dd,
1H, J = 15.0 and 4.8), 3.60 (s, 3H), 3.87–3.97 (m, 1H),
4.02–4.10 (m, 1H), 4.59 (d, 1H, J = 7.1), 4.72 (d, 1H,
J = 7.1), 5.13 (br s, 2H), 7.25–7.42 (m, 5H); 13C NMR
(DMSO-d6): d 21.5, 22.3, 24.0, 27.5, 36.7, 41.3, 50.8,
57.3, 58.3, 58.5, 66.0, 79.4, 126.9, 127.3, 127.8, 136.1,
151.8, 152.2, 169.8; MS (CI) 435 ([M+1]+, 61), 379
(56), 335 (100), 91 (14), 57 (7); HRMS (CI) calcd for
C23H35N2O6 435.2495 ([M+1]+), found 435.2490.
4. Experimental
Materials were obtained from commercial suppliers and
were used without further purification. Methylene chlo-
ride was distilled from calcium hydride immediately
prior to use. Likewise benzene and THF were distilled
from sodium benzophenone ketyl. Air or moisture sen-
sitive reactions were conducted under nitrogen atmo-
sphere using oven-dried glassware and standard
syringe/septa techniques. The reactions were monitored
with a SiO2 TLC plate under UV light (254 nm) fol-
lowed by visualization with a molybdenum or ninhy-
drin staining solution. Column chromatography was
performed on silica gel 60 (70–230 mesh). Optical rota-
tions were determined at ambient temperature with a
digital polarimeter and are the average of five measure-
4.3. Methyl (3S,4S)-3-(benzyloxycarbonyl)amino-4-(tert-
butoxycarbonyl)amino-6-methylheptanoate 8b
1
ments. H and 13C NMR spectra were measured at 300
To a mixture of 7b (64 mg, 0.15 mmol) in benzene was
added a mixture of RuCl3 hydrate (3.1mg, 0.02 mmol)
and TBHP (91mL, 0.44 mmol) and the reaction mixture
was stirred for 10 h at room temperature. Then, 1 N aq
HCl solution was added to the resulting solution and the
mixture was extracted with Et2O (2 · 20 mL). The com-
bined organic layers were dried with MgSO4, filtered,
and concentrated under reduced pressure. The residue
was dissolved in methanol and then Cs2CO3 (49 mg,
0.15 mmol) was added to the solution. The mixture
was stirred for 30 min. The resulting mixture was parti-
tioned between H2O (2 · 10 mL) and Et2O (2 · 1 0 mL).
The combined organic layers were dried with MgSO4,
filtered, and concentrated under reduced pressure. The
residue was purified with SiO2 column chromatography
(4:1hexane/EtOAc) to give 8b (38 mg, 60%) as an about
and 75 MHz, respectively, in CDCl3 unless stated
otherwise and data were reported as follows in ppm
(d) from the internal standard (TMS, 0.0 ppm): chemi-
cal shift (multiplicity, integration, coupling constant in
hertz).
4.1. Methyl (E)-(4S)-4-(N-benzyloxycarbonylamino-
methyl-N-tert-butoxycarbonyl)amino-6-methylhept-2-
enoate 6b
To a solution of 5 (600 mg, 1.71 mmol) in CH2Cl2
(40 mL) was added NH2Cbz (3.34 g, 17.1 mmol) and
PPTS (43 mg, 0.171 mmol). The mixture was heated
under reflux for 18 h. The resulting mixture was parti-
tioned twice between H2O (20 mL) and Et2O (20 mL).
The combined organic layers were dried with MgSO4,
filtered, and concentrated under reduced pressure. The
residue was purified with SiO2 column chromatography
10:1 diastereomeric mixture and colorless oil. Com-
25
D
pound trans-8b: Rf = 0.31(2:1hexane/EtOAc); ½aŠ
¼
ꢀ40 (c 0.6, MeOH); 1H NMR (toluene-d8, 1 00ꢁC):
d 0.80 (d, 3H, J = 6.6), 0.82 (d, 3H, J = 5.9), 0.98–1.23
(m, 2H), 1.38 (s, 9H), 1.48–1.67 (m, 1H), 2.31 (dd, 1H,
J = 15.6 and 6.6), 2.42 (dd, 1H, J = 15.6 and 5.9), 3.35
(s, 3H), 3.72–3.81(m, 1H), 3.90–4.03 (m, 1H), 4.32 (br
d, 1H, J = 7.9), 5.02 (br s, 2H), 5.13 (br d, 1H,
J = 8.2), 6.98–7.25 (m, 5H); 13C NMR d 21.9, 23.2,
(8:1hexane/EtOAc) to give 6b (617 mg, 83%) as a color-
26
D
less oil. Rf = 0.50 (2:1hexane/EtOAc);
½aŠ ¼ ꢀ34
1
(c 0.94, CHCl3); H NMR (DMSO-d6, 1 00ꢁC): d 0.87
(d, 3H, J = 5.7), 0.89 (d, 3H, J = 5.7), 1.36–1.55 (m,
2H), 1.42 (s, 9H), 1.73–1.79 (m, 1H), 3.66 (s, 3H),
4.26–4.42 (m, 1H), 4.54 (dd, 1H, J = 13.9 and 6.4),

D. Yoo et al. / Tetrahedron: Asymmetry 16 (2005) 3762–3766
3765
24.8, 28.3, 37.5, 41.6, 51.8, 52.4, 52.5, 66.8, 79.5, 128.0,
128.5, 136.5, 156.2, 156.4, 171.6; MS (CI) 423
([M+1]+, 12), 367 (34), 323 (100), 215 (12), 186 (7),
130 (7), 91 (12), 57 (10); HRMS (CI) calcd for
C22H35N2O6 423.2495 ([M+1]+), found 423.2493.
to give 11 (33 mg, 86%) as an about 10:1 diastereomeric
mixture and colorless oil. Compound trans-11: Rf = 0.11
(1:2 hexane/EtOAc); H NMR d 0.91(d, 3H, J = 6.6),
0.97 (d, 3H, J = 6.8), 1.27–1.39 (m, 1H), 1.44–1.56 (m,
1H), 1.59–1.73 (m, 1H), 2.51–2.66 (m, 2H), 3.39–3.47
(m, 1H), 3.66–3.72 (m, 1H), 3.71 (s, 3H), 5.35–5.60 (m,
2H); 13C NMR d 21.9, 23.1, 25.1, 39.7, 44.5, 52.0,
55.3, 56.4, 163.1, 171.6; MS (CI) 215 ([M+1]+, 100),
157 (2), 140 (3), 103 (1); HRMS (CI) calcd for
C10H19N2O3 215.1395 ([M+1]+), found 215.1394.
1
4.4. (4S,5S)-3-Benzyloxycarbonyl-1-(tert-butoxycar-
bonyl)-5-isobutyl-4-methoxycarbonylmethylimidazol-
idin-2-one 9b
To a mixture of 7b (114 mg, 0.26 mmol) in a mixture of
solvents (CH3CN 2 mL, CCl4 2 mL and H2O 3 mL) was
added a mixture of RuCl3 hydrate (5.39 mg, 0.03 mmol)
and NaIO4 (168 mg, 0.79 mmol) and the reaction mix-
ture was stirred for 10 h at room temperature. The
resulting mixture was partitioned between H2O
(2 · 20 mL) and Et2O (2 · 20 mL). The combined
organic layers were dried with MgSO4, filtered, and
concentrated under reduced pressure. The residue was
purified with SiO2 column chromatography (8:1hex-
ane/EtOAc) to give 9b (107 mg, 0.24 mmol) as an about
10:1 diastereomeric mixture and colorless oil. Com-
Acknowledgement
We thank the Brain Korea 21Program by the Ministry
of Education and Human resources for financial
support.
References
1. Yoo, D.; Oh, J. S.; Kim, Y. G. Org. Lett. 2002, 4, 1213–
1215.
pound trans-9b: Rf = 0.33 (2:1hexane/EtOAc);
1H
2. For a review, see: (a) Rich, D. H. In Proteinase Inhibitors;
Barrett, A. J., Salvesen, G., Eds.; Elsevier: New York,
1986; p 179; (b) Venkatesan, N.; Kim, B. H. Curr. Med.
Chem. 2002, 9, 2243–2270, and references cited therein.
3. (a) Hyun, S. I.; Kim, Y. G. Tetrahedron Lett. 1998, 39,
4299–4302; (b) Yoo, D.; Oh, J. S.; Lee, D.-W.; Kim, Y. G.
J. Org. Chem. 2003, 68, 2979–2982; (c) Yoo, D.;
Kim, H.; Kim, Y. G. Synlett 2005, 1707–1710; (d) Yoo,
D. Ph.D. Thesis, Seoul National University, August,
2004.
4. (a) Bradbury, R. H.; Rivette, J. E. J. Med. Chem. 1991, 34,
151–157; (b) Bursavich, M. G.; Rich, D. H. J. Med. Chem.
2002, 45, 541–558; (c) Hom, R. K.; Fang, L. Y.; Mamo, S.;
Tung, J. S.; Guinn, A. C.; Walker, D. E.; Davis, D. L.;
Gailunas, A. F.; Thorsett, E. D.; Sinha, S.; Knops, J. E.;
Jewett, N. E.; Anderson, J. P.; John, V. J. Med. Chem.
2003, 46, 1799–1802; (d) Johansson, P.-O.; Chen, Y.;
Belfrage, A. K.; Blackman, M. J.; Kvarnstrom, I.;
Jansson, K.; Vrang, L.; Hamelink, E.; Hallberg, A.;
Rosenquist, A.; Samuelsson, B. J. Med. Chem. 2004, 47,
3353–3366.
NMR d 0.96 (d, 6H, J = 6.6), 1.44–1.51 (m, 2H), 1.54
(s, 9H), 1.71–1.85 (m, 1H), 2.62 (dd, 1H, J = 15.9 and
9.7), 2.83 (dd, 1H, J = 15.9 and 3.2), 3.69 (s, 3H),
3.87–3.96 (m, 1H), 4.14–4.22 (m, 1H), 5.29 (d, 1H,
J = 12.6), 5.35 (d, 1H, J = 12.6), 7.27–7.46 (m, 5H);
13C NMR d 21.3, 23.7, 24.0, 28.0, 36.9, 42.2, 52.0,
53.7, 56.0, 68.4, 83.6, 127.8, 128.3, 128.5, 135.0, 147.6,
149.7, 151.7, 170.1; MS (CI) 449 ([M+1]+, 2), 439 (8),
393 (29), 349 (100), 305 (17), 215 (9), 91 (34), 57 (17);
HRMS (CI) calcd for C23H33N2O7 449.2288 ([M+1]+),
found 449.2291.
4.5. (4S,5S)-5-Isobutyl-4-methoxycarbonylmethyl-
imidazolidin-2-one 11
To a mixture of 9b (97 mg, 0.22 mmol) in dry MeOH
(5 mL) was added Cs2CO3 (70 mg, 0.21mmol) at room
temperature and the mixture was stirred for 30 min.
Then, a cold 1N aq HCl solution was added to the
resulting solution and the mixture was extracted with
Et2O (2 · 20 mL). The combined organic layers were
dried with MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified with SiO2
column chromatography (2:1hexane/EtOAc) to give
10 (58 mg, 85%) as an about 10:1 diastereomeric mixture
and colorless oil. Compound trans-10: Rf = 0.07 (2:1
5. Jones, D. M.; Sueiras-Diaz, J.; Szelke, M.; Leckie, B. J.;
Beattie, S. R.; Morton, J.; Neidle, S.; Kuroda, R. J.
Peptide Res. 1997, 50, 109–121.
6. The 3-aminodeoxystatine derivatives: (a) Schostarez, H. J.
J. Org. Chem. 1988, 53, 3628–3631; (b) Seo, R.; Ishizuka,
T.; Abdel-Aziz, A. A.-M.; Kunieda, T. Tetrahedron
Lett. 2001, 42, 6353–6355; The related compounds: (c)
Doherty, A. M.; Kornberg, B. E.; Reily, M. D. J.
Org. Chem. 1993, 58, 795–798; (d) Reetz, M. T.; Ro¨hrig,
D.; Harms, K.; Frenking, G. Tetrahedron Lett. 1994,
35, 8765–8768; (e) Cook, G. R.; Shanker, P. S.; Parara-
jasingham, K. Angew. Chem., Int. Ed. 1999, 38, 110–
113.
1
hexane/EtOAc); H NMR d 0.95 (d, 3H, J = 4.2), 0.97
(d, 3H, J = 4.4), 1.44–1.48 (m, 1H), 1.53 (s, 9H), 1.56–
1.73 (m, 2H), 2.53 (dd, 1H, J = 16.5 and 5.7) 2.63 (dd,
1H, J = 16.5 and 8.1), 3.58–3.64 (m, 1H), 3.69 (s, 3H),
3.82–3.87 (m, 1H), 6.07 (br s, 1H).
7. Van Benthem, R. A. T. M.; Hiemstra, H.; Longarela, G.
R.; Speckamp, W. N. Tetrahedron Lett. 1994, 35, 9281–
9284.
To a mixture of 10 (58 mg, 0.18 mmol) in CH2Cl2
(4 mL) was added TFA (1mL) at room temperature
and the reaction mixture was stirred for 30 min. The
resulting mixture was evaporated. To completely
remove TFA, another 4 mL of CH2Cl2 was added to
the residue and then the solution was concentrated. This
sequence was repeated 3 times. The residue was purified
with SiO2 column chromatography (2:1hexane/EtOAc)
8. The use of p-TsOH as an acid catalyst7 resulted in mostly
the deacetoxymethylation as shown below.
Boc
iBu
Boc
iBu
N
OAc
CO2Me
NH
p
-TsOH
CH2Cl2,
CO2Me
80%

3766
D. Yoo et al. / Tetrahedron: Asymmetry 16 (2005) 3762–3766
9. Murahashi, S.-I.; Naota, T.; Kuwabara, T.; Saito, T.;
The diastereomeric ratio of 11 was also about 1:1 by its 1H
NMR spectrum. The smaller coupling constant of 5.1Hz
was attributed to the trans-isomer, whereas the larger
coupling constant of 7.7 Hz to the cis-isomer.
Kumobayashi, H.; Akutagawa, S. J. Am. Chem. Soc. 1990,
112, 7820–7822.
10. (a) Rich, D. H.; Sun, E. T. O. J. Med. Chem. 1980, 23, 27–
33; (b) Thoen, J. C.; Morales-Ramos, A. I.; Lipton, M. A.
Org. Lett. 2002, 4, 4455–4458.
i. NH3, 80- 90 oC
O
Boc
16 h, 51%
NH
HN
11. Carlsen, P. H. J.; Katsuki, T.; Martin, U. S.; Sharpless,
K. B. J. Org. Chem. 1981, 46, 3936–3938.
NH
3
ii. HCl
iii. phosgene
TEA
iBu
CO2Me
iBu
4
12. The approximately 1:1 diastereomeric mixture of 11 was
prepared as follows. Conjugate addition of methanolic
ammonia to 12 under pressure gave an about 1:1 mixture
of adducts that was converted to imidazolidinone 11 after
deprotection of the Boc group of the adducts with aq HCl.
CO2Me
12
11
35% (3 steps)
13. (a) Johnson, F. Chem. Rev. 1968, 68, 375–413; (b)
Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1860.