884 J . Org. Chem., Vol. 66, No. 3, 2001
Manku et al.
) 7.6 Hz, 2H), 3.03 (t, J ) 7.7 Hz, 2H), 2.08 (m, 2H), 1.32 (t,
J ) 7.2 Hz, 3H). 13C NMR (CD3OD) δ: 135.9, 130.4, 130.3,
128.9, 57.9, 48.9, 46.8, 42.3, 37.7, 36.0, 25.4, 11.6; HRMS (ES)
for C14H26N3 (M+ + H) calcd 236.212673 found 236.212665.
yield). 1H NMR (CD3OD, 300 MHz) δ: 3.70-3.54 (m, 1H), 3.42
(d, J ) 5.7 Hz, 2H), 3.28-3.12 (m, 4H), 3.10-3.02 (t, J ) 7.6
Hz, 2H), 2.99 (t, J ) 6.5 Hz, 2H), 2.22-2.00 (m, 2H), 1.96-
1.76 (m, 4H), 1.30 (t, J ) 6.9 Hz, 3H). 13C NMR (CD3OD, 125.3
MHz) δ: 56.2, 47.0, 42.1, 39.9, 37.8 (2), 26.8, 25.5, 24.2, 11.6.
ES-MS: m/z (intensity) 203.1 (M+ + H, 100), 231.1 (15), 245.1
(40). LC-ESMS: 0.1% MeCN (0.1% TFA): 99.9% H2O (0.1%
TFA), 0.50 mL/min for 10 min: peak corresponding to product
at 1.383 min, mass of 203.2 m/z, purity based on LC-MS 80%.
HRMS (ES) for C10H27N4 (M+ + H) calcd 203.223572 found
203.223771.
[R]25 ) (+) 8.52° (c ) 6.19, MeOH).
D
(4S)-p-Hyd r oxyben zyl-9-a m in o-3,6-d ia za n on a n e Tr is-
(tr iflu or oa ceta tic a cid ) Sa lt (8c). Tyrosine-derivatized resin
7c was constructed from 6c as described above. Cleavage of
the triamine product off of the resin (0.40 g, 0.39 mmol) was
accomplished using method B. To characterize this compound
in its unprotected form, the resulting concentrated crude
residue (0.175 g) was then treated with
a
95:5:5 TFA:
(4R)-((N-ter t-bu toxycar bon yl)-3-m eth ylin dolyl)-9-am in o-
3,6-d ia za n on a n e Tr is(tr iflu or oa ceta tic a cid ) Sa lt (8j).
Tryptophan-derivatized resin 7j was constructed on solid
support from 6j as described above. Cleavage of the triamine
product off of the resin (0.46 g, 0.32 mmol) was accomplished
using method A, except there was no MeOH rinse forward. A
light-brown solid corresponding to 8j was obtained (0.18 g, 79%
crude yield). 1H NMR (CD3OD) δ: 8.14 (d, J ) 8.1 Hz, 1H),
7.71 (s, 1H), 7.64 (d, J ) 7.3 Hz, 2H), 7.30 (m, 2H), 5.00 (br s),
4.00 (m, 1H), 3.50 (dd, J ) 14.1, 7.7 Hz, 1H), 3.40 to 2.95 (m,
9H), 2.10 (m, 2H), 1.66 (s, 9H), 1.32 (t, J ) 7.1 Hz, 3H). 13C
NMR (CD3OD) δ: 150.7, 137.0, 130.8, 126.5, 125.0, 124.1,
119.8, 46.4, 42.0, 37.8, 28.3, 25.9, 25.5, 11.6; HRMS (ES) for
triisopropylsilane:H2O cleavage cocktail for 4 h at room
temperature. The mixture was concentrated under reduced
pressure, and 20 mL of Et2O was added slowly to the residue.
After precipation, the solvent was decanted off, and the residue
was placed under high vacuum for 12 h to give off-white solid
1
8c as a free phenol (0.15 g, 66% overall crude yield). H NMR
(CD3OD) δ: 7.13 (d, J ) 8.4 Hz, 2H), 6.78 (d, J ) 8.4 Hz, 2H),
5.00 (br s), 3.84 (m, 1H), 3.47 (m, 1 H), 3.30-3.05 (m, 5H),
3.01 (t, J ) 7.6 Hz, 3H), 2.85 (dd, J ) 14.4 Hz, 8.7 Hz, 1H),
2.60 (m, 2H), 1.30 (t, J ) 7.2 Hz, 3H). 13C NMR (CD3OD) δ:
158.3, 131.5, 126.1, 117.1, 58.0, 48.9, 46.8, 42.3, 37.7, 35.2, 25.3,
11.6. HRMS (ES) for C14H20N3O (M+ + H) calcd 252.207588
found 252.207932. [R]25 ) (+) 6.63° (c ) 6.42, MeOH).
C
21H35N4O2 (M+ + H) calcd 375.276002 found 375.276561.
D
(4R)-ter t-Bu toxym eth yl-9-a m in o-3,6-d ia za n on a n e Tr is-
(tr iflu or oa ceta tic a cid ) Sa lt (8d ). Serine-derivatized resin
7d was constructed on solid support from 6d as described
above. Cleavage of the triamine product off of the resin (0.48
g, 0.39 mmol) was accomplished using method A mentioned
above except there was no MeOH rinse forward, and the flask
was evaporated in a cooled water bath to minimize clevage of
the tert-butoxy group. A white oily solid corresponding to 8d
was obtained (0.14 g, 61% crude yield). The NMR data shows
partial cleavage (5-10% of the tert-butyl protecting group).
1H NMR (CD3OD) δ: 3.80 (m, 3H), 3.49 (d, J ) 4.7 Hz, 2H),
3.40 (m, 4H), 3.07 (t, J ) 7.6 Hz, 2H), 2.15 (m, 2H), 1.35 (t, J
) 7.2 Hz, 3H), 1.23 (s, 9H); 13C NMR (CD3OD) δ: 75.96, 59.37,
55.7, 47.7, 46.9, 42.2, 37.7, 27.4, 25.3, 11.4; HRMS (ES) for
[R]25 ) (+) 1.62° (c ) 6.56, MeOH).
D
N3,6,9-Tr ipr opyl-12-am in o-(4S)-m eth yl-(7S)-ben zyl-3,6,9-
t r ia za u n d eca n e Tet r a k is(t r iflu or oa cet a t ic a cid ) Sa lt
(11). To the supported borane-amine adduct 12 (obtained
after reduction of 1 not subjected to any workup, 0.250 g, 0.21
mmol, 0.84 mmol/g) swollen in DMF (4.0 mL) in a large PP
vessel was added propionaldehyde (0.77 mL, 10.5 mmol)
followed by vortexing for 10 min. At this time NaBH(OAc)3
(2.44 g, 11.5 mmol) was added, and the suspension was
agitated for 48 h. The suspension was then drained and
washed with DMF (3×), methanol (3×), and dichloromethane
(5×), and the resulting resin 10 was dried in vacuo. A small
sample of the resin (22 mg) was then cleaved giving 11 (17
mg, 100% crude yield). HPLC-MS conditions; column: Zorbax
XDB-C8 (2.1 × 50 mm, 5.0 µm); eluent: 15-85% MeCN (0.1%
TFA) in water (0.1% TFA) over 2 min, and 85% for 4 min, 0.6
mL/min): single peak at 4.581 min corresponding to tet-
raamine product 11. 1H NMR (CD3OD, 300 MHz) δ: 7.45-
7.20 (m, 5H), 3.6-2.52 (m, 20H), 2.18-1.86 (m, 3H), 1.82-
1.42 (m, 4H), 1.44-1.16 (m, 9H), 1.1-0.9 (m, 7H). APT 13C
NMR (CD3OD, 75.5 MHz) δ: 139.6 (C), 130.5 (CH), 130.0 (CH),
129.9 (CH), 127.9 (CH), 62.2 (CH), 58.4 (CH), 54.9 (CH2), 52.0
(CH2), 49.9 (CH2), 46.1 (CH2), 39.6 (CH2), 37.8 (CH2), 35.7
(CH2), 27.6 (CH2), 26.0 (CH2), 25.2 (CH2), 23.1 (CH2), 19.7
(CH2), 19.2 (CH2), 12.1 (CH3), 12.0 (CH3), 11.2 (CH3), 11.0
(CH3), 10.6 (CH3). IR (MeOH cast) in cm-1: 3300-2600 (N-H
stretch), 1674.36 (CdO, TFA salt), 1202.64 (C-N stretch),
C12H30N3O (M+ + H) calcd 232.238888 found 232.238733. [R]25
) (-) 2.17° (c ) 2.49, MeOH).
D
(4R )-(t er t -B u t y l)t h i o m e t h y l-9-a m i n o -3,6-d i a z a -
n on a n e Tr is(tr iflu or oa ceta tic a cid ) Sa lt (8e). Cysteine-
derivatized resin 7e was constructed on solid support from 6e
as described above. Cleavage of the triamine product off of the
resin (0.46 g, 0.45 mmol) was accomplished using method B
mentioned above except there was no MeOH rinse forward. A
pale yellow oil corresponding to 8e was obtained (0.20 g, 79%
crude yield). 1H NMR (CD3OD) δ: 5.05 (br s), 3.77 (m, 1H),
3.49 (d, J ) 5.5 Hz, 2H), 3.34-2.93 (m, 7H), 2.97 (dd, J ) 13.7,
7.1 Hz, 1H), 2.13 (m, 2H), 1.35 (t, J ) 7.2 Hz, 3H), 1.35 (s,
1.35, 9H); 13C NMR (CD3OD) δ: 56.4, 48.9, 46.9, 44.7, 42.1,
37.7, 31.0, 28.1, 25.2, 11.5. HRMS (ES) for C12H30N3S (M+
+
1133.99 (C-N stretch) ESMS m/z (intensity): 515.5 (M+
+
H) calcd 248.216045 found 248.215786. [R]25D ) (+) 6.72° (c )
11.94, MeOH).
TFA, 10), 419.5 (M+ + H, 100), 317.4 (B-N compound, 20).
HRMS (ES) for C26H51N4 (M+ + H) calcd 419.411373 found
419.410714.
(4S)-(2′-Meth ylth io)eth yl-9-am in o-3,6-diazan on an e Tr is-
(tr iflu or oa ceta tic a cid ) Sa lt (8f). Methionine-derivatized
resin 7f was constructed on solid support from 6f as described
above. Cleavage of the triamine off of the resin (0.48 g, 0.46
mmol) was accomplished using method B, except there was
no MeOH rinse forward. A pale yellow oil corresponding to 7f
N3,6,9-Tr iisobu tyr yl-12-a m in o-(4S)-m eth yl-(7S)-ben zyl-
3,6,9-tr iazau n decan e Tetr akis(tr iflu or oacetatic acid) Salt
(14). The supported borane-adduct 12 (0.84 mmol/g resin, 0.21
mmol) was treated with isobutyraldehyde (0.96 mL 10.5 mmol)
and NaBH(OAc)3 (2.44 g 11.5 mmol) as described above for
11. A small sample of the resin (24 mg) was then cleaved with
5% TFA in CH2Cl2 giving 14 (20 mg, 100% crude yield). HPLC-
MS conditions; column: Zorbax XDB-C8 (4.6 × 50 mm, 3.5
µm); eluent: 25-85% MeCN (0.1% TFA) in water (0.1% TFA)
over 5 min, and 85% for 7 min, 0.7 mL/min): single peak at
6.258 min corresponding to product 14. 1H NMR (CD3OD, 300
MHz) δ: 7.40-7.18 (m, 5H), 3.6-2.70 (m, 13H), 2.55-2.45 (m,
1H), 2.40-2.25 (m, 1H), 2.20-1.85 (m, 4H), 1.8-1.6 (m, 1H),
1.5-0.78 (m, 29H). APT 13C NMR (CD3OD, 75.5 MHz) δ: 139.7
(C), 130.4 (2x CH), 129.9 (2x CH), 127.9 (CH), 63.1 (CH), 61.2
(CH), 60.5 (CH), 56.8 (CH2), 53.3 (CH2), 52.0 (CH2), 46.4 (CH2),
39.8 (CH2), 37.9 (CH2), 37.3 (CH2), 28.0 (CH3), 26.2 (CH3), 25.8
(CH3), 25.6 (CH3), 25.2 (CH2), 22.9 (CH3), 21.3 (CH3), 21.2
(CH3), 21.0 (CH3), 20.9 (CH3), 20.6 (CH3), 11.7 (CH3), 10.3
1
was obtained (0.20 g, 78% crude yield). H NMR (CD3OD) δ:
4.90 (br s), 3.71 (m,1H), 3.43 (d, J ) 5.3 Hz, 2H), 3.31-3.10
(m, 4H), 3.06 (t, J ) 7.6 Hz, 2H), 2.65 (m, 2H), 2.12 (s, 3H),
2.16-1.98 (m, 4H), 1.34 (t, J ) 7.1 Hz, 3H); 13C NMR (CD3-
OD) δ: 66.9, 55.8, 48.8, 46.9, 42.1, 37.8, 30.0, 29.3, 25.3, 15.1,-
11.6; HRMS (ES) for C10H26N3S (M+ + H) calcd 220.184745
found 220.185011. [R]25 ) (+) 7.69° (c ) 5.88, MeOH, turbid
D
solution).
(4S)-(3′-Am in o)p r op yl-9-a m in o-3,6-d ia za n on a n e Tet-
r a k is(tr iflu or oa ceta tic a cid ) Sa lt (8i). Glutamine-deriva-
tized resin 7i was constructed on solid support from 6i as
described above. Cleavage of the triamine off of the resin (52
mg, 0.044 mmol) was accomplished using method A. A pale
yellow oil corresponding to 7f was obtained (30 mg, 95% crude