Practical Method for Chemoselective Formation of MTPA Amide Derivatives from Amino Alcohols and Phenols

Full text of DOI:10.1021/jo960980z

4168
J . Org. Chem. 1997, 62, 4168-4170
Ta ble 1. Am in o Alcoh ol a n d Am in o P h en ol Su bstr a tes
P r a ctica l Meth od for Ch em oselective
F or m a tion of MTP A Am id e Der iva tives
fr om Am in o Alcoh ols a n d P h en ols
6-8 a n d Th eir Con ver sion to MTP A-Am id e Silyl
Eth er s 9-19
Thomas R. Hoye,* Matthew K. Renner, and
Tricia J . Vos-DiNardo
Department of Chemistry, University of Minnesota,
Minneapolis, Minnesota 55455
Received May 28, 1996 (Revised Manuscript Received March
24, 1997 )
Recently, we reported that Mosher’s MTPA (methoxy-
(trifluoromethyl)phenylacetyl) technology could be used
to deduce the absolute configuration (as well as the
enantiomeric excess) of cyclic amines.1 That work built
upon earlier important studies by Rauk2a,b and Braek-
man.2c MTPA esters and amides of chiral alcohols and
primary amines, respectively, are well known.3 Other
chiral derivatizing agents, including O-methylmandelic
acid, have also been applied successfully to secondary
alcohols and primary amines.4
We were interested in applying MTPA amide technol-
ogy to cyclic amines containing alcohol and/or phenol
moieties (cf. 1 to 2). While it is known that primary
amino alcohols can be converted to MTPA amides without
derivatization of the alcohol,3e conversion of cyclic amines
into MTPA amides is a slow process, and our initial
efforts to selectively install MTPA groups into amino
alcohols were unsuccessful.
a
Quenched with TBAF to obtain the corresponding alcohol.
b
The analogous bis-TMS ethers were prepared but are too labile
to be conveniently handled. c Combined yield of diastereomers
after HPLC separation.
These issues prompted us to seek a one-pot method to
install an MTPA amide group into a cyclic amine while
leaving the alcohol or phenol portions of the molecule
unperturbed. It was reported that N-acyl derivatives of
aspartic acid could be prepared conveniently by first
protecting the acid moieties as TMS esters.5 We studied
a similar strategy for the derivatization of substrates 6-8
as summarized in Table 1. Treatment of the substrate
with various silylating agents followed by addition of
MTPA-Cl resulted in derivatized amides in good yields.
While TMS ethers were sufficient to prevent MTPA
derivatization of the alcohols, they tended to cleave
during chromatography, sometimes resulting in poor
yields of the (trimethylsilyl)oxy MTPA-amides. TES and
TBS ethers, on the other hand, are stable to chromato-
graphic purification. Each can be removed subsequently
using mild conditions (TBAF or HF/MeCN) that do not
affect the amide group.
In addition, our attempts to install multiple MTPA
groups into amino alcohols (to generate per-Mosher
derivatives) generally resulted in poor yields. Even when
successfully introduced, multiple MTPA moieties in one
molecule have anisotropic effects that are not entirely
predictable. Also, we found that removal of MTPA esters
in the presence of MTPA amides proved to be surprisingly
troublesome. For example, the bis-Mosher derivative
arising from 2-pyrrolidinemethanol (3) produced only a
moderate yield of both the mono-MTPA amide 4 and the
mono-MTPA ester 5.
(1) Hoye, T. R., Renner, M. K. J . Org. Chem. 1996, 61, 2057.
(2) (a) Khan, M. A.; Tavares, D. F.; Rauk, A. Can. J . Chem. 1982,
60, 2451. (b) Rauk, A.; Tavares, D. F.; Khan, M. A.; Borkent, A. J .;
Olson, J . F. Can. J . Chem. 1983, 61, 2572. (c) Leclerc, S.; Thirionet, I.;
Broeders, F.; Daloze, D.; Vander Meer, R.; Braekman, J . C. Tetrahedron
1994, 50, 8465.
(3) (a) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969,
34, 2543. (b) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95,
512. (c) Sullivan, G. R.; Dale, J . A.; Mosher, H. S. J . Org. Chem. 1973,
38, 2143. (d) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J .
Am. Chem. Soc. 1991, 113, 4092. (e) Kusumi, T.; Fukushima, T.;
Ohtani, I.; Kakisawa, H. Tetrahedron Lett. 1991, 32, 2939.
(4) (a) Trost, B. M.; Bunt, R. C.; Pulley, S. R. J . Org. Chem. 1994,
59, 4202. (b) Latypov, S. K.; Seco, J . M.; Quin˜oa´, E.; Riguera, R. J .
Org. Chem 1995, 60, 1538.
Alternatively, we found that directly quenching the
reaction mixture used to produce the MTPA amide with
either TBAF or HF/MeCN was effective for removal of
any O-silyl groups before purification. Thus, amide
(5) Castano, A. M.; Echavarren, A. M. Tetrahedron Lett. 1992, 48,
3377.
S0022-3263(96)00980-2 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 12, 1997 4169
3.18 (ddd, 1H, J ) 6.5, 8.5, 11.5 Hz), 2.85 (ddd, 1H, J ) 5, 7.5,
11.5 Hz), 1.89 (dddd, 1H, J ) 6, 7.5, 8.5, 13 Hz), 1.70-1.82 (m,
2H), 1.30 (ddddd, 1H, J ) 7.5, 7.5, 7.5, 9.5, 12.5 Hz), 0.94 (t,
9H, J ) 8 Hz), 0.58 (q, 6H, J ) 8 Hz); 13C NMR (CDCl3, 75 MHz)
δ 163.8, 128.8, 127.8, 126.4, 61.5, 59.3, 54.5, 47.2, 25.7, 24.4,
6.31, 4.0; IR (thin film) 2955 (m), 1657 (s), 1263 (m), 1183 (s),
1163 (s) cm-1; MS (EI) m/ z (rel int) 402 (100, M+ - CH2CH3),
299 (12), 286 (41), 242 (21), 189 (81), 105 (17).
alcohols or phenols were isolated directly following chro-
matography.
We chose (S)-2-pyrrolidinemethanol (prolinol, 6); 6,7-
dihydroxy-1,2,3,4-tetrahydroisoquinoline (7); and 2-pip-
eridine-2-propanol (conhydrine, 8) as model compounds
to probe the limits of the technique. The results of these
experiments are shown in Table 1.
(S)-2-P yr r olidin em eth an ol, ter t-Bu tyldim eth ylsilyl Eth er
(S)-MTP A Am id e (11). Prepared by the general procedure: 1H
NMR (CDCl3, 500 MHz) δ 7.51-7.53 (m, 2H), 7.36-7.39 (m, 3H),
4.30 (dddd, 1H, J ≈ 2.5, 4.5, 6.5, 8 Hz), 4.06 (dd, 1H, J ) 4.5, 10
Hz), 3.70 (q, 3H, J ) 1.5 Hz), 3.69 (dd, 1H, J ) 2.5, 10 Hz), 3.18
(ddd, 1H, J ) 6.5, 8, 11 Hz), 2.87 (ddd, 1H, J ) 4.5, 7, 11.5 Hz),
1.87 (m, 1H, ΣJ ’s ) 35 Hz), 1.71-1.82 (m, 2H), 1.31 (m, 1H, ΣJ ’s
) 44 Hz), 0.88 (s, 9H), 0.06 (s, 3H), 0.03 (s, 3H); 13C NMR (CDCl3,
75 MHz) δ 164.2, 133.6, 129.2, 128.2, 126.8, 124.3 (q, J ) 275
Hz), 62.3, 59.7, 54.9 (q, J < 2 Hz), 47.6, 25.9, 25.8, 24.8, 18.1,
-5.5, -5.6; MS (EI, 70 eV): m/ z (rel int) 416 (3, M+ - CH3),
374 (100), 290 (4), 286 (7), 189 (57), 105 (14).
(S)-2-P yr r olidin em eth an ol, ter t-Bu tyldim eth ylsilyl Eth er
(R)-MTP A Am id e (12). Prepared by the general procedure: 1H
NMR (CDCl3, 500 MHz) δ 7.51-7.53 (m, 2H), 7.34-7.38 (m, 3H),
4.28 (dddd, 1H, J ) 3.5, 4, 5.5, 8.5 Hz), 3.86 (dd, 1H, J ) 5.5, 10
Hz), 3.81 (dd, 1H, J ) 3, 10 Hz), 3.65 (q, 3H, J ) 1.5 Hz), 3.43
(ddd, 1H, J ) 7, 7, 11 Hz), 2.45 (ddd, 1H, J ) 6, 7.5, 11.5 Hz),
1.91 (dddd, 1H, J ) 4, 5.5, 7, 12.5 Hz), 1.80 (dddd, 1H, J ) 8, 8,
8, 12.5 Hz), 1.75 (ddddd, 1H, J ) 7, 7, 7, 7, 12.5 Hz), 1.63 (ddddd,
1H, J ) 6, 6, 7.5, 7.5, 12.5 Hz), 0.86 (s, 9H), 0.07 (s, 3H), 0.06 (s,
3H); 13C NMR (CDCl3, 75 MHz) δ 164.2, 133.8, 129.0, 128.1,
127.0, 123.8 (q, J ) 290 Hz), 61.9, 59.8, 55.3 (q, J ) 2.4 Hz),
47.0, 26.0, 25.9, 24.7, 18.2, -5.4+; -5.4-; IR (thin film) 2953 (m),
1654 (s), 1181 (s), 1163 (m), 1103 (m) cm-1; MS (EI, 70 eV): m/ z
(rel int) 416 (3, M+ - CH3), 374 (100), 290 (4), 286 (10), 189
(45), 105 (11); HRMS (CI, isobutane) calcd for C21H33F3NO3Si
(M + H+) 432.2182, found 432.2188.
Clearly, this is a valuable technique for the derivati-
zation of amines containing alcohol or phenol functional-
ity. The yields for these several-step transformations are
comparable to those for the single derivatizations of
simple cyclic amines as described previously.1
Tetrahydroisoquinoline 7 was a useful model com-
pound for uncovering reaction conditions potentially
applicable to the michellamines,6 a family of highly-
oxygenated dimeric naphthyltetrahydroisoquinoline al-
kaloids that have shown promising anti-HIV activity. The
described techniques were successfully applied to a series
of structurally related compounds, including ancistro-
brevine B.7 The results of these experiments and analy-
sis of the resulting spectral data will be described
elsewhere.
Finally, it should be emphasized that this methodology
is both practical and general. For example, other acy-
lating agents (e.g., ethyl chloroformate) can be success-
fully used in place of the MTPA-Cl. Thus, the strategy
should be applicable to a variety of chemoselective
transformations of amines containing other hydroxyl
functionality.
Exp er im en ta l Section
(S)-2-P yr r olid in em eth a n ol (S)-MTP A Am id e (13). (S)-
2-Pyrrolidinemethanol (23 mg, 0.227 mmol) and triethylamine
(150 µL, 1.1 mmol, 4.8 equiv) were dissolved in methylene
chloride (1 mL) and stirred while chlorotriethylsilane (42 µL,
0.25 mmol, 1.1 equiv) was added via syringe. The reaction
mixture was stirred for 10 min. DMAP (1 mg) and (R)-MTPA-
Cl (47 µL, 0.25 mmol, 1.1 equiv) were added, and the mixture
was stirred for 14 h. Added to the reaction mixture were
methylene chloride (2 mL) and TBAF trihydrate (315 mg, 1
mmol, 4.5 equiv), and the mixture was stirred for 3 h. The
mixture was diluted with water, the layers were separated, and
the aqueous layer was extracted with methylene chloride (3 ×
2 mL). The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure to give an amber liquid
(479 mg). This liquid was purified by flash chromatography
(SiO2, 1:1 Hx:EtOAc) to provide the S-amide 13 as a clear liquid
(54 mg, 75%): 1H NMR (CDCl3, 500 MHz) δ 7.47-7.48 (m, 2H),
7.39-7.41 (m, 3H), 4.39 (dddd, 1H, J ) 3, 6, 7.5, 10.5 Hz), 4.26
(dd, 1H, J ) 3.5 7.5 Hz), 3.72 (ddd, 1H, J ) 3, 7.5, 11.5 Hz),
3.66 (q, 3H, J ) 1.5 Hz), 3.66 (ddd, 1H, J ) 3, 7.5, 11.5 Hz),
3.61 (ddd, 1H, J ) 5.5, 7, 11.5 Hz), 2.37 (ddd, 1H, J ) 7.5, 7.5,
12 Hz), 2.01 (dddd, 1H, J ) 6.5, 6.5, 7.5, 13.5 Hz), 1.60-1.72
(m, 2H), 1.48 (dddd, 1H, J ) 6, 7, 7, 13 Hz); IR (thin film) 3442
(br), 1652 (s), 1179 (s), 1163 (s), 1079 (m) cm-1; MS (EI, 70 eV)
m/ z (rel int) 317 (4, M+), 286 (26, M+ - CH2OH), 189 (100), 128
(80).
6,7-Bis(tr ieth ylsiloxy)-1,2,3,4-tetr ah ydr oisoqu in olin e (R)-
MTP A Am id e (15). Amine hydrobromide 7 (20 mg, 0.081
mmol) was suspended in triethylamine (70 µL, 0.50 mmol, 6.2
equiv) and methylene chloride (1 mL) and stirred while chlo-
rotriethylsilane (30 µL, 0.18 mmol, 2.2 equiv) was added slowly.
The mixture was stirred for 45 min, and DMAP (2 mg) and (S)-
MTPA-Cl (20 µL, 0.107 mmol, 1.3 equiv) were added. The
mixture was then stirred overnight and concentrated under
reduced pressure to leave an oily solid. This solid was taken
up in 1 M NH4Cl (1.5 mL), extracted into methylene chloride (3
× 2 mL), dried over MgSO4, and concentrated under reduced
pressure to give a brown liquid (58 mg). The liquid was purified
by flash chromatography (SiO2, 10:1 Hx:EtOAc) to provide the
(R)-amide 15 as a clear oil (42 mg, 82%): 1H NMR (CDCl3, 500
MHz) δ 7.53-7.54 (m, 2H), 7.45-7.47 (m, 2H), 7.37-7.40 (m,
3H, 7.22-7.26 (m, 3H), 6.56 (s, 1H), 6.49 (s, 1H), 6.40 (s, 1H),
All 1H NMR chemical shifts are referenced to TMS (δTMS
0.00) and all 13C NMR shifts to CDCl3 (δCDCl3 ) 77.0).
)
Gen er a l P r oced u r e: (S)-2-P yr r olid in em eth a n ol, Tr ieth -
ylsilyl Eth er (R)-MTP A Am id e (10). (S)-2-Pyrrolidinemetha-
nol (61 mg, 0.60 mmol) and triethylamine (420 µL, 3.0 mmol, 5
equiv) were dissolved in methylene chloride and stirred at room
temperature. Chlorotriethylsilane (125 µL, 0.744 mmol, 1.2
equiv) was added slowly, and the reaction mixture was stirred
for 40 min. (S)-MTPA-Cl (125 µL, 0.668 mmol, 1.1 equiv) was
then added dropwise, and the mixture was stirred for 14 h. The
reaction mixture was concentrated under reduced pressure and
taken up in 1 M NH4Cl (5 mL). The insoluble brown oil was
extracted into methylene chloride (3 × 12 mL), dried over
MgSO4, and concentrated under reduced pressure to leave a
brown liquid (276 mg), which was purified by flash chromatog-
raphy (SiO2, 10:1 Hx:EtOAc) to give the (R)-MTPA amide 10 as
a pale yellow liquid (199 mg, 82%): 1H NMR (CDCl3, 500 MHz)
δ 7.52-7.53 (m, 1H), 7.40-7.44 (m, 2H), 7.35-7.38 (m, 2H), 4.27
(dddd, 1H, J ) 4, 4, 6, 8 Hz), 3.84 (dd, 1H, J ) 3.5, 10 Hz), 3.81
(dd, 1H, J ) 5.5, 10 Hz), 3.65 (q, 3H, J ) 1.5 Hz), 3.41 (ddd, 1H,
J ) 7, 7, 11 Hz), 2.45 (ddd, 1H, J ) 6, 7.5, 11 Hz), 1.92 (dddd,
1H, J ) 4, 6, 7.5, 13 Hz), 1.82 (dddd, 1H, J ) 5.5, 5.5, 5.5, 12.5
Hz), 1.74 (ddddd, 1H, J ) 7, 7, 7.5, 7.5, 12.5 Hz), 1.63 (ddddd,
1H, J ) 5.5, 5.5, 5.5, 7, 13.5 Hz), 0.94 (t, 9H, J ) 7.5 Hz), 0.60
(q, 6H, J ) 7.5 Hz); IR (thin film) 2955 (m), 1656 (s), 1265 (m),
1182 (s), 1163 (s) cm-1; MS (EI, 70 eV) m/ z (rel int) 402 (80, M+
- CH2CH3), 299 (14), 286 (47), 242 (21), 189 (100), 105 (11).
(S)-2-P yr r olid in em eth a n ol, Tr ieth ylsilyl Eth er (S)-MT-
P A Am id e (9). Prepared by the general procedure: 1H NMR
(CDCl3, 500 MHz) δ 7.52-7.55 (m, 2H), 7.37-7.41 (m, 3H), 4.29
(dddd, 1H, J ) 2.5, 4.5, 6, 8 Hz), 4.04 (dd, 1H, J ) 4.5, 10.5 Hz),
3.70 (q, 3H, J ) 1.5 Hz, OMe), 3.69 (dd, 1H, J ) 2.5, 10.5 Hz),
(6) (a) Manfredi, K. P.; Blunt, J . W.; Cardellina, J . H., II; McMahon,
J . B.; Pannell, L. K.; Cragg, G. M.; Boyd, M. R. J . Med. Chem. 1991,
34, 3402 (b) Boyd, M. R.; Hallock, Y. F.; Cardellina, J . H., II; Manfredi,
K. P.; Blunt, J . W.; McMahon, J . B.; Buckheit, R. W., J r.; Bringmann,
G.; Schaeffer, M.; Cragg, G. M.; Thomas, D. W.; J ato, J . G. J . Med.
Chem. 1994, 37, 1740.
(7) Bringmann, G.; Zagst, R.; Reuscher, H.; Assi, L. A. Phytochem-
istry 1992, 31, 4011.

4170 J . Org. Chem., Vol. 62, No. 12, 1997
Notes
5.92 (s, 1H), 4.75 (d, 1H, J ) 17 Hz), 4.58 (d, 1H, J ) 17 Hz),
4.30 (d, 1H, J ) 16 Hz), 4.09 (d, 1H, J ) 16 Hz), 4.02 (ddd, 1H,
J ) 6, 6, 12.5 Hz), 3.72 (q, 3H, J ) 1.5 Hz), 3.67 (ddd, 1H, J )
5, 8, 13 Hz), 3.64 (q, 3H, J ) 1.5 Hz), 3.47 (ddd, 1H, J ) 4, 8, 13
Hz), 3.38 (ddd, 1H, J ) 5, 6.5, 13.5 Hz), 2.83 (ddd, 1H, J ) 5.5,
8, 16 Hz), 2.70 (ddd, 1H, J ) 5.5, 5.5, 16 Hz), 2.34 (ddd, 1H, J
) 4.5, 6.5, 16 Hz), 1.96 (ddd, 1H, J ) 5, 8, 16 Hz), 0.91-1.00
(m, 18H), 0.61-0.76 (m, 12H); IR (thin film) 2954 (m), 1654 (s),
1514 (s), 1269 (m), 1183 (m), 1161 (m) cm-1; MS (EI, 70 eV) m/ z
(rel int) 578 (1, M+ - CH2CH3), 392 (29), 391 (75), 362 (41), 189
(16), 115 (15), 87 (100), 59 (53). The 1H NMR spectral data for
14, the enantiomer of 15, were identical to those for 15.
r-Eth yl-2-p ip er id in em eth a n ol Tr ieth ylsilyl Eth er (R)-
MTP A Am id es (16 a n d 17). Prepared by the general procedure
from conhydrine. HPLC separation gave rise to a major isomer
having the following spectral data: 1H NMR (CDCl3, 500 MHz)
δ 7.56-7.57 (m, 2H), 7.38-7.40 (m, 3H), 4.63-4.67 (m, 1H), 4.10
(ddd, 1H, J ) 4, 5.5, 9.5 Hz), 3.87 (dd, 1H, J ) 4.5 ,14 Hz), 3.69
(q, 3H, J ) 1.5 Hz), 2.89 (ddd, 1H, J ) 3.5, 13.5, 13.5 Hz), 1.93
(dddd, 1H, J ) 3.5, 3.5, 3.5, 13.5 Hz), 1.45-1.61 (m, 3H), 1.33-
1.41 (m, 1H), 1.24-1.29 (m, 1H), 0.97 (t, 3H, J ) 7 Hz), 0.95 (t,
9H, J ) 7.5 Hz), 0.9 (m, 1H), 0.61 (dq, 3H, J ) 7, 10 Hz), 0.60
(dq, 3H, J ) 7, 9.5 Hz), 0.10 (ddddd, 1H, J ) 5, 5, 12, 12, 12
Hz); 13C NMR (CDCl3, 75 MHz) δ 129.1, 128.1, 126.8, 70.9, 55.5,
51.7, 41.2, 26.8, 23.2, 24.0, 18.8, 8.0, 7.0, 5.4; MS (EI, 70 eV)
m/ z (rel int) 454 (1, M+ - CH2CH3), 444 (8), 415 (14), 300 (68),
189 (100), 173 (28), 115 (27); HRMS (CI, isobutane) calcd for
C
24H39F3NO3Si (M + H+) 474.2651, found 474.2649.
r-Eth yl-2-p ip er id in em eth a n ol Tr im eth ylsilyl Eth er (R)-
MTP A Am id es (18 a n d 19). Prepared by the general procedure
from conhydrine. HPLC separation gave rise to a major isomer
having the following spectral data: 1H NMR (CDCl3, 500 MHz)
δ 7.56-7.57 (m, 2H), 7.38-7.41 (m, 3H), 4.63-4.66 (m, 1H), 4.04
(ddd, 1H, J ) 5.5, 5.5, 8 Hz), 3.88 (dd, 1H, J ) 5.5, 14 Hz), 3.70
(q, 3H, J ) 1.5 Hz), 2.88 (ddd, 1H, J ) 3.5, 13.5, 13.5 Hz), 1.92
(dddd, 1H, J ) 3, 3, 3, 13.5 Hz), 1.42-1.60 (m, 3H), 1.32-1.39
(m, 1H), 1.27-1.29 (m, 1H), 0.96 (t, 3H, J ) 7.5 Hz), 0.91 (br d,
1H, J ) 13.5 Hz), 0.12 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ
129.1, 128.1, 126.8, 71.3, 55.6, 52.3, 41.1, 27.2, 23.4, 23.1, 18.7,
8.7, 0.7; MS (EI, 70 eV) m/ z (rel int) 416 (3, M+ - CH3), 373 (9),
300 (45), 189 (100), 131 (18); HRMS (CI, isobutane) calcd for
C21H33F3NO3Si (M + H+) 432.2182, found 432.2124; calcd for
C15H17F3NO2 (M+ - TMSOCHEt) 300.1211, found 300.1216.
Ack n ow led gm en t. This work was supported by
Grant Nos. GM-13246 and CA-60284 awarded by the
DHHS.
J O960980Z