Catalytic asymmetric synthesis of protected tryptophan regioisomers

Article abstract of DOI:10.1021/jo025964i

Tryptophan 1 (Trp) is superior to all other naturally occurring peptide residues in its ability to bind cations (the cation - π interaction). In an effort to expand the toolbox of Trp-like amino acids, in this note we report catalytic asymmetric syntheses of Trp regioisomers 2a - e, where the alanine unit is attached not to C-3 of indole but to C-2, C-4, C-5, C-6, or C-7. Excellent asymmetric induction is obtained in each case (generally >97% ee). Ab initio calculations suggest that the indole nuclei of 2a-e will bind Na⁺ with the same affinity as that of Trp.

Full text of DOI:10.1021/jo025964i

2a -e, where the alanine chain is attached not to C-3 of
indole but to C-2, C-4, C-5, C-6, or C-7 (Scheme 1). A
search of the CAS registry file reveals that 2d and 2e
(both free and protected derivatives) have not yet been
described in the literature; amino acid 2c is known only
in its racemic form (registry no. 3569-24-2). Asymmetric
syntheses of (S)-2a (“isotryptophan”)6a and 2b (“neo-
tryptophan”)7 based on stoichiometric use of the Scho¨ll-
kopf auxiliary have recently been described. In this note,
we report a general catalytic asymmetric synthetic route
to protected derivatives of all five Trp regioisomers (S)-
2a -e.
Ca ta lytic Asym m etr ic Syn th esis of
P r otected Tr yp top h a n Regioisom er s
Paul R. Carlier,*,†,‡ Polo C.-H. Lam,†,‡ and
Dawn M. Wong‡
Department of Chemistry, Virginia Tech,
Blacksburg, Virginia 24061, and Department of Chemistry,
Hong Kong University of Science and Technology,
Clear Water Bay, Kowloon, Hong Kong
pcarlier@vt.edu
Received May 23, 2002
Our syntheses of the desired amino acids start with
the corresponding known formylindoles. 2-Formylindole
3a was prepared in two steps from indole-2-carboxylic
acid.8 4- and 6-formylindoles 3b and 3d were prepared
in three steps from 2-bromo-6-nitrotoluene and 4-bromo-
2-nitrotoluene, respectively.9 5-Formylindole 3c was pre-
pared in one step from 5-bromoindole.9 Finally, 7-formylin-
dole 3e was prepared in two steps from 2-nitrobenzalde-
hyde, using the Bartoli indole methodology.10 Anticipat-
ing the need for indole-N-protected amino acids, N-Boc
aldehydes 4a -d were prepared in moderate to excellent
yield. However, N-Boc derivative 4e could not be pre-
pared, perhaps due to the steric hindrance posed by the
7-formyl group (Scheme 2).
These aldehydes were then converted to the corre-
sponding N-acetyl-dehydroamino acid methyl esters (Z)-
5a -e and (Z)-6b-d using the standard Schmidt proto-
col.11 The olefination reactions were slower than expected,
and in the case of N-Boc aldehyde 4a , none of the desired
6a product could be obtained. Chromatography or crys-
tallization of the olefination product yielded stereochemi-
cally pure (Z)-isomers; the alkene geometry was assigned
using Schmidt’s empirical rule (chemical shift of the
â-proton).11 Since the NR-acetyl group can be difficult to
remove from the final amino acid products, we explored
olefination reactions with the N-Cbz Schmidt reagent.
Reactions with N-Boc formyl indoles 4b-d proceeded
smoothly to give pure (Z)-7b-d after chromatography.
However, reactions of unprotected 3c with the N-Cbz
Schmidt reagent gave a mixture of products. Reactions
of 3a and 3e were followed in detail, revealing cyclic
products 8-10 (Scheme 3).
Abstr a ct: Tryptophan 1 (Trp) is superior to all other
naturally occurring peptide residues in its ability to bind
cations (the cation-π interaction). In an effort to expand the
toolbox of Trp-like amino acids, in this note we report
catalytic asymmetric syntheses of Trp regioisomers 2a -e,
where the alanine unit is attached not to C-3 of indole but
to C-2, C-4, C-5, C-6, or C-7. Excellent asymmetric induction
is obtained in each case (generally >97% ee). Ab initio
calculations suggest that the indole nuclei of 2a -e will bind
Na+ with the same affinity as that of Trp.
The cation-π interaction is now known to be an im-
portant determinant of protein structure1 and has been
demonstrated to play critical roles in the function of
acetylcholinesterase2 and the nicotinic acetylcholine re-
ceptor.3 Ab initio calculations by Dougherty show that
among all the naturally occurring aromatic amino acids,
the indole nucleus of Tryptophan (Trp) exhibits the
strongest binding to Na+ ion (32.6 kcal/mol, HF/6-31G**//
HF/6-31G**).4 A recent statistical analysis indicated that
over 25% of all Trp residues in the Protein Data Base
(PDB) experience an energetically significant cation-π
interaction.1
We reasoned that unnatural indole-containing amino
acids would prove to be valuable additions to the toolbox
of available, effective cation-π donor amino acids.5
Asymmetric syntheses of several indol-3-yl amino acids
have been described.6 One class of Trp analogues that
we believe merit further exploration are regioisomers
* To whom correspondence should be addressed. Current address:
Department of Chemistry, Virginia Tech, Blacksburg, VA 24061.
† Virginia Tech.
‡ Hong Kong University of Science and Technology.
Apparently, after formation of the intended products,
the indole NH is deprotonated and reacts with the N-Cbz
protecting group, giving 8 and 10 with extrusion of benzyl
alcohol. Compound 9 was formed as a significant side
product in the reaction of 3a , and its identity was
confirmed by NOE difference, HMQC, and HMBC NMR
experiments. The following experiments indicate that the
methyl group in 9 originates from the Schmidt reagent:
treatment of pure 8 with TMG and the Schmidt reagent
(1) Gallivan, J . P.; Dougherty, D. A. Proc. Natl. Acad. Sci. U.S.A.
1999, 96, 9459-9464.
(2) Harel, M.; Quinn, D. M.; Nair, H. K.; Silman, I.; Sussman, J . L.
J . Am. Chem. Soc. 1996, 118, 2340-2346.
(3) Zhong, W.; Gallivan, J . P.; Zhang, Y.; Li, L.; Lester, H. A.;
Dougherty, D. A. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 12088-12093.
(4) Mecozzi, S.; West, A. P., J r.; Dougherty, D. A. Proc. Natl. Acad.
Sci. U.S.A. 1996, 93, 10566-10571.
(5) For the use of fluorinated tryptophans as isosteric Trp analogues
featuring reduced cation-binding ability, see: Zhong, W.; Gallivan, J .
P.; Zhang, Y.; Li, L.; Lester, H. A.; Dougherty, D. A. Proc. Nat. Acad.
Sci. U.S.A. 1998, 95, 12088-12093.
(6) (a) Homotryptophan: Ma, C.; Liu, X.; Li, X.; Flippen-Anderson,
J .; Yu, S.; Cook, J . M. J . Org. Chem. 2001, 66, 4525-4542. (b)
R-Methyltryptophan: Goodman, M.; Zhang, J .; Gantzel, P.; Benedetti,
E. Tetrahedron Lett. 1998, 39, 9589-9592. (c) â-Methyltryptophans:
Hoerner, R. S.; Askin, D.; Volante, R. P.; Reider, P. J . Tetrahedron
Lett. 1998, 39, 3455-3458. (d) â,â-Dimethyltryptophan: Reddy, R.;
J aquith, J . B.; Venugopal, R. N.; Saleh-Hanna, S.; Durst, T. Org. Lett.
2002, 4, 695-697. (e) â-Phenyltryptophan: Xiong, C.; Wang, W.; Cai,
C.; Hruby, V. J . J . Org. Chem. 2002, 67, 1399-1402.
(7) Fauq, A. H.; Hong, F.; Cusack, B.; Tyler, B. M.; Pang, Y.-P.;
Richelson, E. Tetrahedron: Asymmetry 1998, 9, 4127-4134.
(8) Dekhane, M.; Dodd, R. H. Tetrahedron 1994, 50, 6299-6306.
(9) Moyer, M. P.; Shiurba, J . F.; Rapoport, H. J . Org. Chem. 1986,
51, 5106-5110.
(10) Dobson, D. R.; Gilmore, J .; Long, D. A. Synthesis 1992, 79-80.
(11) Schmidt, U.; Griesser, H.; Leitenberger, V.; Lieberknecht, A.;
Mangold, R.; Meyer, R. Synthesis 1992, 487-490.
10.1021/jo025964i CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/23/2002
6256
J . Org. Chem. 2002, 67, 6256-6259

TABLE 1. Asym m etr ic Hyd r ogen a tion of Deh yd r oa m in o
Acid Der iva tives 5-7
SCHEME 1. Tr yp top h a n a n d Regioisom er s (S)-2a -e
dehydro-
regio- amino
% ee
entry amino acid R1 R2 isomer acida (column)b
solvent
SCHEME 2. Syn th esis of Deh yd r oa m in o Acid
Der iva tivesa
1
2
5a
5b
5c
5d
5e
6b
6c
6d
7b
7c
7d
H
H
H
H
H
Ac
Ac
Ac
Ac
Ac
2-yl
4-yl
5-yl
6-yl
7-yl
4-yl
5-yl
6-yl
11a c 98.6 (AD) ethyl acetate
11b 99.1 (OD) MeOH
11c 98.0 (OD) MeOH
11d 96.7 (AD) MeOH
11e 99.5 (OD) MeOH
12b 98.9 (OD) MeOH
12c 98.6 (OD) CH2Cl2
12d 98.5 (OD) MeOH
13bd 98.9 (OD) MeOH
13ce 97.5 (AD) CH2Cl2
13d e 96.9 (OD)f MeOH
3
4
5
6
Boc Ac
Boc Ac
Boc Ac
Boc Cbz 4-yl
Boc Cbz 5-yl
Boc Cbz 6-yl
7
8
9
10
11
a
Protected amino acid products were isolated in quantitative
yield, except where indicated. The absolute configuration of
products derived from (S,S)-DuPhos ligands is assumed to be S.
b
Determination of % ee was carried out by HPLC on a Daicel
Chiralcel OD or Chiralpak AD column, as indicated. c Only 92%
d
conversion after 4 days. (S,S)-MeDuPhos catalyst was used.
e (R,R)-MeDuPhos catalyst was used, giving the (R)-product. f This
product was converted to the 2′,3′-dihydro-NR-acetyl derivative (H2,
Pd/C, 4:1 MeOH/Ac2O, 12 h) for % ee determination.
tained (Table 1). The high catalyst loading is undesirable,
but at less than 1 mol % catalyst, the enantiomeric excess
decreased significantly and reactions would not go to
completion.14 At 2-3 mol % catalyst, the hydrogenation
was insensitive to solvent: methanol, ethanol, ethyl
acetate, dichloromethane, and acetone all gave acceptable
yields and % ee. To improve reaction rates, the use of
higher pressures (40 psi) was explored. However, under
these conditions, Nin-Boc-dehydroamino acid esters 6 and
7, as well as 5e, gave significant amounts of byproducts
resulting from hydrogenation of the pyrrole portion of the
indole. Nin-Boc-NR-Cbz dehydroamino ester 7c proved to
be susceptible to overhydrogenation even at atmospheric
pressure; however, in this case, use of dichloromethane
or acetone as a solvent successfully prevented overhy-
drogenation.
a
Reagents and conditions: (i) 1.2 equiv of KOt-Bu, 1.5 equiv of
Boc2O, 0 °C f rt, 3 days. (ii) 1.5 equiv of (MeO)2P(O)CH-
(NHAc)CO2Me, 1.5 equiv of TMG, THF, -78 °C f rt, 3 days. (iii)
1.5 equiv of (MeO)2P(O)CH-(NHCbz)CO2Me, 1.5 equiv of TMG,
THF, -78 °C f rt, 3 days.
SCHEME 3. Rin g-Closed Olefin a tion P r od u cts of
3a a n d 3ea
We envision that amino acids 2a -e will prove to be
useful as substitutions for the naturally occurring cat-
ion-π donor amino acids Trp, tyrosine (Tyr), and phen-
ylalanine (Phe). Substitution of 2b for Tyr11 in neuro-
tensin(8-13) analogues was shown to greatly improve
affinity for the human neurotensin (type 1) receptor.15
Regioisomer 2a is sterically much like Trp; 2c and 2d
combine a Phe-like steric presence close to the peptide
backbone with the cation-π binding superiority of Trp.
All of these unnatural regioisomers may also confer a
a
Reagents and conditions: 1.5 equiv of (MeO)2P(O)CH-
(NHCbz)CO2Me, 1.5 equiv of TMG, THF, -78 °C f rt, 3 days.
leads to formation of 9; however, no new products form
upon treatment of compound 8 with TMG alone.
(12) Burk, M. J .; Feaster, J . E.; Nugent, W. A.; Harlow, R. L. J .
Am. Chem. Soc. 1993, 115, 10125-10138.
With the desired protected dehydroamino acids (Z)-5-7
in hand, we explored asymmetric hydrogenation using
both Rh and Ru catalysts. In the end, the most generally
useful catalyst system was the Burk DuPhos system,12
with the EtDuPhos ligand affording slightly higher % ee
than the MeDuPhos analogue.13 The best reaction condi-
tions proved to be 2-3 mol % catalyst, atmospheric
pressure, for 3 days: under these conditions, 100%
conversion and greater than 97% ee was normally ob-
(13) For the use of the Burk ligand system in asymmetric synthesis
of NR-Cbz-Nin-Boc-5-bromo-Trp, see: Wang, W.; Xiong, C.; Yang, J .;
Hruby, V. J . Tetrahedron Lett. 2001, 42, 7717-7719.
(14) Rh-DuPhos catalyst loadings for asymmetric hydrogenation
of R,â,γ,δ-unsaturated amino acid esters approach 1 mol % (see: Burk,
M. J .; Bedingfield, K. M.; Kiesman, W. F.; Allen, J . G. Tetrahedron
Lett. 1999, 40, 3093-3096).
(15) Tyler, B. M.; Douglas, C. L.; Faug, A.; Pang, Y.-P.; Stewart, J .
A.; Cusack, B.; McCormick, D. J .; Richelson, E. Neuropharmacol. 1999,
38, 1027-1034.
J . Org. Chem, Vol. 67, No. 17, 2002 6257

TABLE 2. Ca lcu la ted Na + Bin d in g En er gies of In d ole (14A) a n d Meth yla ted In d oles (15A-21A)
Na+ binding energies
(kcal/mol)a
ligand
indole (14a )
η6-(benzo)
η5-(pyrrolo)
∆E (kcal/mol)
-32.6
-33.7
-34.2
-33.2
-33.5
-33.4
-33.4
-33.6
-29.0
-30.0
-30.2
-30.0
-29.8
-30.3
-30.4
-29.8
-3.6
-3.7
-4.0
-3.2
-3.8
-3.1
-3.0
-3.8
N-methylindole (15a )
2-methylindole (16a )
3-methylindole (17a )
4-methylindole (18a )
5-methylindole (19a )
6-methylindole (20a )
7-methylindole (21a )
a
Binding energies are calculated from HF/6-31G**//HF/6-31G** energies, without zero-point vibrational energy correction (see
Experimental Section).
degree of peptidase resistance to peptides in which they
are incorporated. Furthermore, it is likely that the
alternative placement of the indole ring in 2a -e relative
to Trp will in some cases geometrically facilitate cation-π
interaction, either in the normal benzo-face mode4 or in
the pyrrolo-face mode recently observed by Gokel.16 To
determine if the position of the attachment of the alanine
chain would affect the cation-binding ability of the indole
ring, we calculated Na+ binding energies of indole 14a ,
N-methylindole 15a , and the corresponding C-methylated
isomers 16a -21a at the HF/6-31G**//HF/6-31G** level,
as recommended by Dougherty17 (Table 2).
Vibrational frequency analysis confirmed that all of the
η6-(benzo) Na+ complexes (14b-21b) and η5-(pyrrolo) Na+
complexes (14c-21c) were local minima. The calculated
Na+ η6-binding energy of indole (-32.6 kcal/mol)4 matches
Dunbar’s recent experimental value (-34 ( 3 kcal/mol)18
quite well. As reported previously at the B3LYP/6-31G*
level, η6-binding of indole 14a is preferred to η5-binding
by about 4 kcal/mol,19 and this energy difference is
maintained for the methylated indoles 15a -21a . Finally,
Na+ η6-binding energies of the C-methylated indoles
16a -21a vary by only 1 kcal/mol (i.e., <3%). We thus
conclude that there will be no intrinsic difference in
cation-binding ability between Trp and regioisomers 2a -
e. The catalytic asymmetric syntheses presented here are
offered in the hope that they will facilitate further
exploration of (S)- and (R)-Trp-regioisomers 2a -e for
peptide modification, de novo peptide design, and as
fluorescence probes.20
were reagent grade and used as received. Formyl indoles were
prepared according to the literature: 2-formylindole 3a ,8 4-, 5-,
and 6-formylindoles 3b-d , respectively,9 and 7-formylindole
3e.10 N-Acetyl-R-phosphonoglycine trimethyl ester was prepared
according to the literature.21 N-Cbz-R-Phosphonoglycine tri-
methyl ester was purchased commercially. The DuPhos ligands
and Rh(COD)2(OTf) were also purchased commercially. Rh
Catalysts derived from (S,S)-EthylDuPhos, (S,S)-MethylDuPhos,
and (R,R)-MethylDuPhos were prepared using Schlenk tech-
niques according to the literature.12 Catalysts were stored and
dispensed in a nitrogen-filled drybox.
R ep r esen t a t ive P r oced u r e for Syn t h esis of N-Boc-
F or m ylin d oles: N-Boc-5-F or m ylin d ole (4c).22 A 250 mL
round-bottom flask was charged with potassium t-butoxide (0.79
g, 7 mmol) and freshly distilled THF (100 mL). After dissolution
of the base, 5-formylindole 3c (1.02 g, 7 mmol) was added and
stirred, cooled to 0 °C, and di-tert-butyl-dicarbonate (1.81 g, 8.3
mmol) was added to the solution. Following stirring at 0 °C for
1 h, the ice bath was removed and the reaction was allowed to
stir at room temperature overnight. Water (100 mL) was added,
and the product was extracted with ethyl acetate (2 × 100 mL).
The combined organic extracts were dried with Na2SO4, filtered,
concentrated in vacuo, and purified by flash chromatography to
yield the desired N-Boc-5-formylindole 4c (1.7 g, 100%) as a
yellow solid: mp 58-60 °C; 1H NMR (CDCl3) δ 1.69 (s, 9H), 6.69
(d, 3J ) 3.8 Hz, 1H), 7.69 (d, 3J ) 3.7 Hz, 1H), 7.85 (dd, 3J ) 8.6
Hz, 4J ) 1.5 Hz, 1H), 8.09 (d, 4J ) 1.0 Hz, 1H), 8.29 (d, 3J ) 8.6
Hz, 1H), 10.59 (s, 1H); 13C NMR (CDCl3) δ 28.08, 84.61, 107.78,
115.55, 124.18, 125.11, 127.65, 130.64, 131.67, 138.70, 149.18,
192.08; MS (CI) m/z 246 [M + H]+. Anal. Calcd for C14H15NO3:
C, 68.56; H, 6.16; N, 5.71. Found: C, 68.51; H, 6.12; N, 5.70.
Rep r esen ta tive P r oced u r e for Sch m id t Olefin a tion s:
(Z)-NR-Acet yl-Nin -Boc-2,3-d eh yd r o-3-(in d ol-5-yl)-a la n in e,
Meth yl Ester (6c). The following procedure is based on
Schmidt:11
a 10 mL round-bottom flask was charged with
N-acetyl-R-phosphonoglycine trimethyl ester (1.44 g, 6 mmol)
and THF (5 mL) and cooled to -78 °C. 1,1,3,3-Tetrameth-
ylguanidine (TMG, 0.753 mL, 6 mmol) was added and stirred
for 5 min, followed by N-Boc-5-formylindole 4c (0.98 g, 4 mmol).
After stirring at -78 °C for 1 h, the dry ice bath was removed,
and the reaction was allowed to stir at room temperature over
3 days, at which point TLC analysis indicated substantial
conversion of starting material. Water (10 mL) was then added,
the product was extracted with ethyl acetate (2 × 40 mL). The
Exp er im en ta l Section
Gen er a l. THF was distilled from Na/benzophenone. CH2Cl2
was distilled from CaH2. Acetone, ethyl acetate, and methanol
(16) De Wall, S. L.; Meadows, E. S.; Barbour, L. J .; Gokel, G. W. J .
Am. Chem. Soc. 1999, 121, 5613-5614.
(17) Mecozzi, S.; West, A. P., J r.; Dougherty, D. A. J . Am. Chem.
Soc. 1996, 118, 2307-2308.
(18) Ryzhov, V.; Dunbar, R. C. J . Am. Chem. Soc. 1999, 121, 2259-
2268.
(19) Dunbar, R. C. J . Phys. Chem. A 1998, 102, 8946-8952.
(20) Ross, J . B.; Szabo, A. G.; Hogue, C. W. In Methods in Enzymol-
ogy; Brand, L., J ohnson, M. L., Eds.; Academic Press: San Diego, 1997;
Vol. 278; pp 151-190.
(21) Kober, R.; Steglich, W. Liebigs Ann. Chem. 1983, 599-609.
(22) Billedeau, R. J .; Broka, C. A.; Campbell, J . A.; Chen, J . J .;
Dankwardt, S. M.; Delaet, N.; Robinson, L. A.; Walker, K. A. M. PCT
Int. Appl. WO 0037436, 2000.
6258 J . Org. Chem., Vol. 67, No. 17, 2002

combined organic extracts were washed with water, dried with
Na2SO4, and concentrated in vacuo. Recrystallization from ethyl
acetate gave pure (Z)-6c (1.02 g, 71%): mp 161-162 °C; 1H NMR
(CDCl3) δ 1.67 (s, 9H), 2.16 (s, 3H), 3.85 (s, 3H), 6.56 (br s, 1H),
7.07 (br s, 1H), 7.45 (d, 3J ) 7.9 Hz, 1H), 7.52 (s, 1H), 7.60 (s,
1H), 7.68 (s, 1H), 8.11 (3J ) 8.2 Hz, 1H); 13C NMR (CDCl3) δ
23.33, 28.12, 52.53, 84.05, 107.36, 115.05, 122.79, 123.05, 125.69,
126.66, 128.01, 130.52, 133.59, 135.30, 149.26, 165.80, 169.09;
MS (CI) m/z 359 [M + H]+. Anal. Calcd for C19H22N2O5: C, 63.68;
H, 6.19; N, 7.82. Found: C, 63.46; H, 6.19; N, 7.84.
) 3.1 Hz, 1H), 6.88 (dd, 3J ) 7.1 Hz, 4J ) 1.2 Hz, 1H), 6.93 (t,
3J ) 7.4 Hz, 1H), 7.22 (d, 3J ) 3.2 Hz, 1H), 7.43 (dd, 3J ) 7.5
4
Hz, J ) 1.4 Hz, 1H); 13C NMR (CD3OD) δ 22.31, 34.64, 52.60,
54.17, 102.80, 120.01, 120.16, 120.49, 122.79, 125.46, 129.58,
136.40, 173.01, 173.59; MS (CI) m/z 261 [M + H]+; HRMS (FAB)
calcd for C14H17N2O3 [M + H]+ 261.1239, found 261.1241.
(R)-NR-Cbz-Nin -Boc-3-(in d ol-6′-yl)-a la n in e, Meth yl Ester
[(R)-13d ]. The (R,R)-MeDuPhos catalyst was used: [R]25D +8.50
2
(c 0.20, MeOH); 1H NMR (CD3OD) δ 1.62 (s, 9H), 3.05 (dd, J )
3
2
3
13.8 Hz, J ) 8.7 Hz, 1H), 3.24 (dd, J ) 13.7 Hz, J ) 5.6 Hz,
(Z)-NR-Acetyl-2,3-d eh yd r o-3-(in d ol-7′-yl)-a la n in e, Meth yl
Ester (5e). Compound 5e was isolated as a yellow solid by
recrystallization from ethyl acetate and flash chromatography
(diethyl ether) of the remaining mother liquor (90% yield): mp
3
2
1H), 3.68 (s, 3H), 4.50 (dd, J ) 8.7 Hz, 5.6 Hz, 1H), 4.96 (d, J
2
3
) 12.6 Hz, 1H), 5.02 (d, J ) 12.6 Hz, 1H), 6.54 (d, J ) 3.7 Hz,
1H), 7.05 (dd, 3J ) 8.0 Hz, 4J ) 1.3 Hz, 1H), 7.19-7.27 (m, 5H),
7.43 (d, 3J ) 8.0 Hz, 1H), 7.54 (d, 3J ) 3.8 Hz, 1H), 8.01 (br s,
1H); 13C NMR (CDCl3) δ 28.15, 38.70, 52.32, 55.14, 66.94, 83.62,
107.03, 115.92, 120.94, 123.92, 125.98, 128.04, 128.10, 128.47,
129.59, 131.70, 135.51, 136.25, 142.47, 155.65, 172.03; MS (CI)
m/z 453 [M + H]+; HRMS (FAB) calcd for C25H29N2O6 [M + H]+
453.2026, found 453.2022.
1
148-149 °C; H NMR (CDCl3) δ 1.99 (s, 3H), 3.83 (s, 3H), 6.48
3
3
3
(d, J ) 3.2 Hz, 1H), 7.05 (t, J ) 7.7 Hz, 1H), 7.25 (d, J ) 3.2
Hz, 1H), 7.46 (d, 3J ) 7.6 Hz, 1H), 7.59 (d, 3J ) 7.9 Hz, 1H),
7.83 (s, 1H); 13C NMR (CDCl3) δ 22.55, 52.80, 102.68, 117.00,
119.37, 122.36 (2C), 124.90 (2C), 128.39, 129.43, 133.70, 165.59,
169.94; MS (CI) m/z 259 [M + H]+. Anal. Calcd for C14H14N2O3:
C, 65.11; H, 5.46; N, 10.85. Found: C, 64.86; H, 5.51; N, 10.78.
(Z)-NR-Cb z-Nin -Boc-2,3-Deh yd r o-3-(in d ol-6′-yl)-a la n in e,
Meth yl Ester (7d ). Compound 7d was isolated by flash chro-
matography (20% ethyl acetate in hexane) as a yellow oil (47%
yield): 1H NMR (CD3OD) δ 1.63 (s, 9H), 3.79 (br s, 3H), 5.14 (br
Com p u ta tion a l Meth od . Equilibrium geometries of all
indoles and their η5- and η6-Na+ complexes were determined at
the HF/6-31G** level using Spartan ‘02 Windows.23 All geom-
etries were characterized as local minima by vibrational fre-
quency analysis (no imaginary frequencies). Zero-point vibra-
tional energies (ZPVE) were scaled by 0.8992,24 and ZPVE values
were found to be very similar (95.8 ( 0.1 kcal/mol) for all the
η5- and η6-complexes of methylated indoles 15a -21a ; these data
are reported in Supporting Information. ZPVE correction re-
duced calculated binding energies by approximately 1.1 kcal/
mol, as has been noted previously by other investigators.17,19
Basis set superposition error (BSSE) corrections have been
shown to reduce calculated cation-π binding energies by 0.2-4
kcal/mol.17,19,25 However, we did not perform BSSE corrections,
since the appropriate BSSE computational model is unre-
solved,18,19 and since published studies17,25 show that BSSE
corrections to cation-π binding energies are very similar across
a series of related compounds. Binding energies reported in
Table 2 are derived from uncorrected HF/6-31G** energies, since
Dougherty has shown that uncorrected HF/6-31G** energies
match well experimentally determined binding enthalpies.17
Dougherty has also shown that MP2/6-31G** energies are too
high but approach experimental values when ZPVE and BSSE
corrections are applied.17
3
3
s, 2H), 6.60 (d, J ) 3.7 Hz, 1H), 7.21-7.54 (m, 7H), 7.67 (d, J
) 3.8 Hz, 1H), 8.51 (br s, 1H); 13C NMR (CD3OD) δ 28.40, 52.94,
68.13, 85.32, 108.19, 117.72, 121.84, 125.12, 126.05, 128.73,
128.84, 129.24, 130.72, 133.07, 135.96, 136.42, 137.78, 150.55,
156.93, 167.58 (20 C found); MS (CI) m/z 451 [M + H]+. Anal.
Calcd for C25H26N2O6: C, 66.66; H, 5.82; N, 6.22. Found: C,
66.43; H, 5.88; N, 6.15.
Gen er a l P r oced u r e for Asym m etr ic Hyd r ogen a tion s. In
a nitrogen-filled drybox, a Schlenk tube was charged with
catalyst (1 mg), sealed with a septum, and brought out of the
drybox. Unless otherwise noted, the catalyst used was [Rh-
(COD)L]+ TfO- (L ) (S,S)-EtDuPhos). The dehydroamino acid
(20 mg) was weighed into a 5 mL round-bottom flask, dissolved
in 3 mL of MeOH (unless otherwise noted), capped with a
septum, and ultrasonicated. After three vacuum/N2 cycles, the
substrate was cannulated to the Schlenk tube. After three
vacuum/H2 cycles, the tube was set to an initial pressure of 1
atm H2. Assuming use of EtDuPhos, catalyst loadings are thus
1.8, 2.6, and 3.2% for dehydroamino acids 5, 6, and 7, respec-
tively. The reactions were allowed to continue at room temper-
ature for 3 days. Afterward, the reactions were concentrated in
vacuo; the residue was dissolved in ethyl acetate, and the
solution was passed through a short SiO2 column to remove the
catalyst. 1H and 13C NMR analyses and the enantiomeric
excesses were determined directly with the crude products thus
obtained. For each substrate below, hydrogenations were per-
formed with both (S,S)- and (R,R)-catalysts. Comparison of the
respective HPLC traces thus allowed enantiomeric peaks to be
assigned. Unless otherwise noted, reactions went to 100%
conversion, with no overhydrogenation of the pyrrole portion of
the indole ring.
Ack n ow led gm en t. We thank the Hong Kong Re-
search Grants Council (HKUST6181/99P), the J effress
Memorial Trust, and the Virginia Tech Department of
Chemistry for financial support of this work.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
and MS data for all new compounds; enantiomeric excess
determination protocols for protected amino acid derivatives
11-13; and absolute energies, ZPVE, and equilibrium geom-
etries for indoles 14a -21a and their corresponding η6- and
η5-Na+ complexes. This material is available free of charge via
the Internet at http://pubs.acs.org.
(S)-NR-Acetyl-Nin -Boc-3-(in d ol-5′-yl)-a la n in e, Meth yl Es-
ter [(S)-12c]. The hydrogenation was performed in CH2Cl2.
HPLC analysis (OD column) indicated 98.6% ee: [R]25 +26.9
D
1
(c 0.95, MeOH); H NMR (CD3OD) δ 1.65 (s, 9H), 1.89 (s, 3H),
J O025964I
3.01 (dd, 2J ) 13.8 Hz, 3J ) 8.8 Hz, 1H), 3.21 (dd, J ) 13.8 Hz,
2
5.8 Hz, 1H), 3.67 (s, 3H), 4.68 (dd, 3J ) 8.8 Hz, 5.8 Hz, 1H),
6.55 (d, 3J ) 3.8 Hz, 1H), 7.13 (dd, 3J ) 8.5 Hz, 4J ) 1.7 Hz,
(23) Spartan ‘02; Wavefunction, Inc.: Irvine, CA, 2002. Except for
molecular mechanics and semiempirical models, the calculation meth-
ods used in Spartan ‘02 have been documented in: Kong, J .; White,
C. A.; Krylov, A. I.; Sherrill, C. D.; Adamson, R. D.; Furlani, T. R.;
Lee, M. S.; Lee, A. M.; Gwaltney, S. R.; Adams, T. R.; Ochsenfeld, C.;
Gilbert, A. T. B.; Kedziora, G. S.; Rassolov, V. A.; Maurice, D. R.; Nair,
N.; Shao, Y.; Besley, N. A.; Maslen, P. E.; Dombrowski, J . P.; Daschel,
H.; Zhang, W.; Korambath, P. P.; Baker, J .; Byrd, E. F. C.; Voorhis, T.
V.; Oumi, M.; Hirata, S.; Hsu, C.-P.; Ishikawa, N.; Florian, J .; Warshel,
A.; J ohnson, B. G.; Gill, P. M. W.; Head-Gordon, M.; Pople, J . A. J .
Comput. Chem. 2000, 21, 1532.
1H), 7.38 (d 4J ) 1.1 Hz, 1H), 7.57 (d, J ) 3.7 Hz, 1H), 8.01 (d
3
3J ) 8.5 Hz, 1H); 13C NMR (CD3OD) δ 22.27, 28.40, 38.43, 52.64,
55.68, 84.83, 108.14, 115.76, 122.24, 126.24, 127.01, 132.08,
132.32, 135.41, 150.81, 172.91, 173.43; MS (CI) m/z 361 [M +
H]+; HRMS (FAB) calcd for C19H25N2O5 [M + H]+ 361.1763,
found 361.1744.
(S)-NR-Acetyl-3-(in d ol-7′-yl)-a la n in e, Meth yl Ester [(S)-
11e]. HPLC analysis (OD column) indicated 99.5% ee: [R]25
D
1
-1.61 (c 1.055, MeOH); H NMR (CD3OD) δ 1.89 (s, 3H), 3.25
(24) Scott, A. P.; Radom, L. J . Phys. Chem. 1996, 100, 16502-16513.
(25) Minoux, H.; Chipot, C. J . Am. Chem. Soc. 1999, 121, 10366-
10372.
(dd, 2J ) 14.2 Hz, 3J ) 7.9 Hz, 1H), 3.34 (dd, 2J ) 14.2 Hz, 3J
3
3
) 6.9 Hz, 1H), 3.59 (s, 3H), 4.78 (t, J ) 7.4 Hz, 1H), 6.44 (d, J
J . Org. Chem, Vol. 67, No. 17, 2002 6259