Use of the SPhos ligand to suppress racemization in arylpinacolboronate ester Suzuki couplings involving α-amino acids. Synthesis of biaryl derivatives of 4-hydroxyphenylglycine, tyrosine, and tryptophan

Article abstract of DOI:10.1021/jo901899w

(Chemical Equation Presented) α-Amino acid derivatives, particularly those of phenylglycine, can suffer significant racemization in Suzuki couplings. When arylpinacolboronate esters are used as coupling partners this unwanted side reaction can be suppress

Full text of DOI:10.1021/jo901899w

pubs.acs.org/joc
be complex in its details,5,6 there is broad consensus on the
Use of the SPhos Ligand to Suppress Racemization in
Arylpinacolboronate Ester Suzuki Couplings
Involving r-Amino Acids. Synthesis of Biaryl
Derivatives of 4-Hydroxyphenylglycine, Tyrosine,
and Tryptophan
main stages of the catalytic cycle. As a consequence of the
intensive study of this reaction over the last couple of
decades, increasingly complex coupling partners can now
be exploited, including those incorporating multiple func-
tional groups and stereogenic elements.1 The use of such
delicate substrates, however, does bring with it the risk that
their more sensitive stereogenic centers may racemize.7
This issue has been addressed by several groups8-13 and
more systematic investigations have been carried out by both
Hocek14 and ourselves.15 Hocek studied the Suzuki cou-
plings of a phenylalaninylboronic acid with halopurine
derivatives and circumvented racemization by switching
from the Suzuki to a copper-mediated Stille coupling.14 In
our own study we showed that racemization in Suzuki
couplings of brominated hydroxyphenylglycine and tyrosine
derivatives with different arylboronic acids could be avoided
by judicious modification of the conditions of the coupling
reaction itself, allowing enantiomerically pure products to be
obtained.15
Monica Prieto, Silvia Mayor, Paul Lloyd-Williams,*,† and
ꢀ
Ernest Giralt†,‡
†Department of Organic Chemistry, Universitat de Barcelona,
´
ꢀ
Martı i Franques, 1-11, Barcelona, E-08028, Spain, and
‡Institute for Research in Biomedicine, Barcelona Science
Park, Baldiri Reixac 10, Barcelona, E-08028, Spain
lloydwilliams@ub.edu
Received September 2, 2009
R-Amino acid derivatives, particularly those of phenyl-
glycine, can suffer significant racemization in Suzuki
couplings. When arylpinacolboronate esters are used as
coupling partners this unwanted side reaction can be
suppressed by the use of Pd(OAc)2 as Pd(0) source, in
the presence of Buchwald’s SPhos ligand. The syntheses
of biaryl amino acids of tyrosine, phenylglycine, and
tryptophan, including Phg-Trp units similar to those
found in the chloropeptin family of natural products,
are reported.
Here we disclose new results that extend and complement
our previous report. The widely used arylpinacolboronate
esters were chosen as coupling partners rather than aryl-
boronic acids because they do not require strong bases for
their formation from aryl halides and are more amenable to
chromatography on silica gel. We performed Suzuki cou-
plings involving derivatives of 4-hydroxyphenylglycine 1,
The Suzuki coupling1-3 is currently one of the most
effective procedures for the formation of carbon-carbon
bonds. Among its most important advantages is a tolerance
for a wide variety of functional groups in the coupling
partners and the relatively nontoxic byproduct it generates.
Although the mechanism by which it proceeds4 is known to
(6) Braga, A. A. C.; Morgon, N. H.; Ujaque, G.; Maseras, F. J. Am.
Chem. Soc. 2005, 127, 9298–9307.
(7) Benoiton, N. L. Int. J. Peptide Protein Res. 1994, 44, 399–400.
(8) Antonow, D.; Jenkins, T. C.; Howard, P. W.; Thurston, D. E. Bioorg.
Med. Chem. 2007, 15, 3041–3053.
(9) Juricek, M.; Brath, H.; Kasak, P.; Putala, M. J. Organomet. Chem.
2007, 692, 5279–5284.
(10) Miller, S. P.; Morgan, J. B.; Nepveux, F. J.; Morken, J. P. Org. Lett.
2004, 6, 131–133.
(11) Kasak, P.; Brath, H.; Dubovska, M.; Juricek, M.; Putala, M.
Tetrahedron Lett. 2004, 45, 791–794.
(12) Gong, Y.; He, W. Org. Lett. 2002, 4, 3803–3805.
(13) Kasak, P.; Miklas, R.; Putala, M. J. Organomet. Chem. 2001, 637,
318–326.
*To whom correspondence should be addressed. Phone: 34-93-402-1260.
Fax: 34-93-339-7878.
(1) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4442–4489.
(2) Suzuki, A. J. Organomet. Chem. 2002, 653, 83–90.
(3) Lloyd-Williams, P.; Giralt, E. Chem. Soc. Rev. 2001, 30, 145–157.
(4) Mathew, J. S.; Klussmann, M.; Iwamura, H.; Valera, F.; Futran, A.;
Emanuelsson, E. A. C.; Blackmond, D. G. J. Org. Chem. 2006, 71, 4711–
4722.
(14) Capek, P.; Pohl, R.; Hocek, M. J. Org. Chem. 2005, 70, 8001–8008.
guez, K.; Lloyd-Williams, P.; Giralt, E.
J. Org. Chem. 2007, 72, 1047–1050.
(5) Goossen, L. J.; Koley, D.; Hermann, H. L.; Thiel, W. J. Am. Chem.
Soc. 2005, 127, 11102–11114.
(15) Prieto, M.; Mayor, S.; Rodrı
´
9202 J. Org. Chem. 2009, 74, 9202–9205
Published on Web 10/29/2009
DOI: 10.1021/jo901899w
r
2009 American Chemical Society

Prieto et al.
JOCNote
TABLE 1. Racemization in Suzuki Couplings Involving Phg, Tyr, and Trp
coupling partners
biaryl
conditionsa
yield (%)
racemization
1 (X1 = Br) þ 10 (X2 = Bpin)
1 (X1 = Br) þ 10 (X2 = Bpin)
2 (X1 = Br) þ 10 (X2 = Bpin)
1 (X1 = Bpin) þ 10 (X2 = Br)
2 (X1 = Bpin) þ 10 (X2 = Br)
1 (X1 = Br) þ 13 (X3 = Bpin)
1 (X1 = Br) þ 14 (X3 = Bpin)
1 (X1 = Bpin) þ 3 (X4 = Br)
1 (X1 = Bpin) þ 4 (X3 = Br)
1 (X1 = Br) þ 3 (X4 = Bpin)
1 (X1 = Br) þ 4 (X4 = Bpin)
11
11
12
11
12
5
6
7
8
7
std
rsp
std
std
std
rsp
rsp
std
std
rsp
rsp
68
84
87
50
63
98
94
52
55
75
85
48b
100b
100b
36b
60b
96b
92b
44c
26d
0d
0d
32d
20d
2d
4d
28.0e
36c
32.0e
0.5e
90c
8
72c
5.9e
astd = “standard”, rsp = “racemization-suppressing”. bee (%). cde (%). d% unwanted enantiomer. e% racemization at Phg and at Trp.
with 10 (X2 = Bpin) gave the biaryl product 12 in yields of up
to 87%. HPLC analysis showed that this product was
enantiomerically pure.
SCHEME 1. Model Reactions
Nevertheless, racemization in the coupling of 1 (X1 = Br)
with 10 (X2 = Bpin) could be completely avoided by using
“racemization suppressing conditions”. After 6 h of reaction
time, enantiomerically pure 11 was obtained in a yield of
84%.
When the coupling partner roles were swapped,22 racemi-
zation became a more challenging problem since amino acids
1 and 2 must themselves first be converted into arylpinacol-
boronate esters before being submitted to Suzuki reaction.
The experimental conditions required to effect this conver-
sion typically involve treating 1 (X1 = Br) and 2 (X1 = Br)
with bis(pinacolato)diboron in the presence of a Pd(0) source
and a weak base such as KOAc. Nevertheless, even this base
can present a risk to the chiral integrity of sensitive molecules
especially since reaction times of several hours may be
required in order to achieve acceptable yields. Once formed,
the arylpinacolboronate derivative must then be subjected to
Suzuki coupling with the concomitant exposure to a second,
stronger base such as K3PO4 that this entails. These two
separate contacts with basic conditions make racemization
correspondingly more likely.
tyrosine 2, and tryptophans 3 and 4 under reaction condi-
tions that are generally considered to be typical [PdCl2(dppf)
as catalyst and K3PO4 as base in 1,4-dioxane, (hereafter
referred to as “standard conditions”, see Table 1)]. We then
measured the amount of unwanted enantiomer in the biaryl
products15,16 and found that significant racemization could
occur. As no improvement was discernible on changing to
Pd(Ph3P)4 as Pd(0) source, nor to Na2CO3 or sodium
succinate as base, we were gratified to discover that racemi-
zation could be suppressed using conditions described by
Buchwald17-19 [Pd(OAc)2 as Pd(0) source, SPhos ligand 9,
and K3PO4 as base, in a mixture of toluene-water (9:1)
(hereafter referred to as “racemization-suppressing condi-
tions”, see Table 1)]. We also report on the synthesis of
indolylphenylglycines 5 and 6 and of Phg-Trp biaryl bis-
amino acids 7 and 8 that are similar to those present in the
chloropeptins.20,21
We focused initially on the model reactions shown in
Scheme 1. Suzuki couplings between (R)-phenylglycine 1
(X1 = Br) and 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,
2-dioxaborolane 10 (X2 = Bpin) under “standard condi-
tions” gave biaryl amino acid 11 in yields up to 68%, after 20
h at reflux. HPLC analysis of this compound on a chiral
stationary phase showed that up to 26% of the (S) enantio-
mer was present. Similar couplings of tyrosine 2 (X1 = Br)
The arylpinacolboronate esters 1 (X1 = Bpin) and 2 (X1 =
Bpin) were prepared with use of conditions similar to those
described for the synthesis of 10 (X2 = Bpin) (see the
Supporting Information) in yields of 28% and 33%, respec-
tively, after chromatography. We believe that these rather
low yields are due to partial decomposition of the products
during workup and purification on silica gel. HPLC analysis
revealed the presence of the unwanted enantiomer in both
cases. In 1 (X1 = Bpin) up to 22% of the (S)-enantiomer was
detected and, somewhat more surprisingly, in 2 (X1 = Bpin)
up to 10% of the (R)-enantiomer was found. Hocek has
reported on a similar result with phenylalanine derivatives.14
Attempts to prepare enantiomerically pure samples of
these arylpinacolboronate esters from 1 (X1 = Br) or 2
(X1 = Br), using Pd(OAc)2, ligand 9, and KOAc or K3PO4 as
base, in toluene-water (9:1) or 1,4-dioxane were unsuccess-
ful. Only poor yields of 1 (X1=Bpin) and 2 (X1=Bpin) were
obtained together with large amounts of dehalogenated side
products [1 (X1 = H) and 2 (X1 = H)]. Stadlweiser23 has
reported similar observations. We did not, however,
(16) Steinauer, R.; Chen, F. M. F.; Benoiton, N. L. J. Chromatogr. 1985,
325, 111–126.
(17) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461–1473.
(18) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 4685–4696.
(19) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2004, 43, 1871–1876.
~
(22) Prieto, M.; Zurita, E.; Rosa, E.; Munoz, L.; Lloyd-Williams, P.;
(20) Shinohara, T.; Deng, H. B.; Snapper, M. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2005, 127, 7334–7336.
(21) Deng, H. B.; Jung, J. K.; Liu, T.; Kuntz, K. W.; Snapper, M. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 9032–9034.
Giralt, E. J. Org. Chem. 2004, 69, 6812–6820.
(23) Stadlwieser, J. F.; Dambaur, M. E. Helv. Chim. Acta 2006, 89, 936–
946.
J. Org. Chem. Vol. 74, No. 23, 2009 9203

Prieto et al.
JOCNote
attempt their preparation from the corresponding aryl io-
dides or chlorides.
SCHEME 2a
When 1 (X1 = Bpin) and 2 (X1 = Bpin) were submitted to
Suzuki coupling with 10 (X2 = Br) under standard condi-
tions biaryl amino acids 11 and 12 were obtained in yields of
50% and 63%, respectively. HPLC analysis of the purified
products revealed that the percentages of unwanted enantio-
mer were up to 10% greater than those initially observed in
the amino acid arylpinacolboronate ester precursors.
Although this additional racemization, engendered in the
Suzuki couplings themselves, could be suppressed by using
Buchwald’s conditions, the amount produced initially in the
formation of the arylpinacolboronate esters could not, as has
been seen above. Consequently, when the amino acid was
made to act as the arylpinacolboronate partner in our model
Suzuki couplings we were unable to obtain enantiomerically
pure biaryls.
aReagents and conditions: (a) Pd(OAc)2, (1.5 equiv), AcOH, 130 °C,
24 h; (b) H2, [(COD)Rh(R,R)-Et-DuPHOS]þ TfO-, MeOH-CH2Cl2,
rt, 24 h.
the products. Up to 28% of the diastereomer resulting from
phenylglycine racemization was detected in the case of 7 and
up to 32% in the case of 8 (see Table 1). As discussed above,
the major portion (≈22%) occurred in the formation of the
arylpinacolboronate ester 1 (X1 = Bpin), while the remain-
der occurred in the Suzuki coupling itself. In contrast, no
racemization was detected in the tryptophan moiety.
On the other hand, the racemization suppressing effect of
the SPhos ligand 9 was clearly illustrated in Suzuki couplings
in which the coupling partner roles were reversed, i.e. in
which the phenylglycine derivative was the aryl bromide.
Such couplings first required the conversion of bromotryp-
tophans 3 (X4 = 5-Br) and 4 (X4 = 6-Br) into their corres-
ponding arylpinacolboronate esters 3 (X4 = 5-Bpin) and 4
(X4 = 6-Bpin) and were achieved in yields of 69% and 83%,
respectively, after chromatographic purification. HPLC
analysis revealed the presence of up to 5% of the unwanted
(S) enantiomer in 3 (X4 = 5-Bpin) and up to 9% in 4 (X4 = 6-
Bpin). These levels of racemization are similar to that
suffered by tyrosine 2 (X2 = Br) on conversion to its
arylpinacolboronate ester 2 (X2 = Bpin).
In the case of the sensitive phenylglycine 1 (X1=Bpin), the
significant racemization observed may not have been un-
expected. Nevertheless, the level of unwanted enantiomer
detected in the case of the relatively robust chiral substrate
tyrosine 2 (X1 = Bpin) was more noteworthy. As seen above,
2 (X1 = Br) suffered no racemization when acting as the aryl
halide component in couplings with arylpinacolboronate
ester 10 (X1 = Bpin) even under standard conditions. In
view of this we suggest that R-amino acid derivatives should,
wherever possible, be made to act as the aryl halide compo-
nents in Suzuki couplings.
As a first stage in the synthesis of Phg-Trp bis-amino acid
derivatives, phenylglycine 1 (X1 = Br) was coupled under
racemization-suppressing conditions with N-tosylindole
derivatives22 13 (X3 = 5-Bpin) and 14 (X3 = 6-Bpin). After
chromatography this furnished the N-tosylindolylphenylgly-
cines 5 and 6 in yields of 98% and 94%, respectively. HPLC
analysis of these compounds indicated the presence of only
2% of the (S) enantiomer in 5 (96% ee) and 4% of the (S)
enantiomer in 6 (92% ee) (see Table 1).
Suzuki coupling of arylpinacolboronate esters 3 (X4 = 5-
Bpin) and 4 (X4 = 6-Bpin) with protected phenylglycine 1
(X1 = Br) under racemization-suppressing conditions then
furnished the biaryl bis-amino acids 7 (indol-5-yl) and 8
(indol-6-yl) in yields of 85% and 75%, respectively. HPLC
analysis of these biaryls revealed that no racemization of the
phenylglycine moiety had occurred during Suzuki coupling
in the case of 7 and less than 5% was detected in the case of 8.
Moreover, no further racemization had occurred in the
tryptophan moiety in either 7 or 8 (see Table 1).
In summary, this work shows that R-amino acid deriva-
tives can suffer significant degradation of their chiral integ-
rity when they are submitted to Suzuki coupling under
reaction conditions that are considered to be typical. To
avoid this, careful assignment of the coupling partner roles is
important (where possible the R-amino acid should be the
aryl halide component), as is judicious choice of reaction
conditions;Buchwald’s racemization-suppressing S-Phos
ligand 9 gives excellent results.
Synthesis of the desired Phg-Trp biaryl bis-amino acids
themselves required the preparation of tryptophan deriva-
tives 3 and 4 as shown in Scheme 2.
Heck reaction between N-tosylindoles 13 (X3 = Br) and 14
(X3 = Br) and methyl 2-acetamidoacrylate 15 furnished the
dehydrotryptophans 16 (X4 = Br) and 17 (X4 = Br), in
yields of 41% and 38%, respectively. NMR studies estab-
lished that in both cases the Z isomers were produced, as
previously reported by Yokoyama.24 Asymmetric catalytic
hydrogenation with [(COD)Rh(R,R)-Et-DuPHOS]þ TfO-
as catalyst25,26 then furnished enantiomerically pure (R)-5-
and 6-bromotryptophans 3 (X4 = 5-Br) and 4 (X4 = 6-Br) in
yields of 84% and 89%, respectively.
Suzuki coupling of these bromotryptophans with pro-
tected phenylglycine 1 (X1 = Bpin), under standard condi-
tions, gave protected biaryl bis-amino acids 7 (indol-5-yl)
and 8 (indol-6-yl), in yields of 52% and 55%, respectively.
However, as expected, severe racemization was observed in
the phenylglycine moiety as evidenced by HPLC analysis of
Phenylglycine derivative 1 is a useful probe molecule
for assaying the reaction conditions of Suzuki couplings
for possible racemization in the coupling partners. Such is
the sensitivity of 1 that most other chiral substrates would
be expected to be less vulnerable to this unwanted side
reaction.
(24) Yokoyama, Y.; Takahashi, M.; Takashima, M.; Kohno, Y.;
Kobayashi, H.; Kataoka, K.; Shidori, K.; Murakami, Y. Chem. Pharm.
Bull. 1994, 42, 832–838.
Experimental Section
(25) Burk, M. J. Acc. Chem. Res. 2000, 33, 363–372.
(26) Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am.
Chem. Soc. 1993, 115, 10125–10138.
Methyl (R)-N-(tert-Butoxycarbonyl)-3-(4-methoxyphenyl)-4-
methoxyphenylglycinate (11). Arylpinacolboronate ester (10,
9204 J. Org. Chem. Vol. 74, No. 23, 2009

Prieto et al.
JOCNote
X2 = Bpin) (0.066 g, 0.28 mmol), methyl (R)-N-(tert-butoxycar-
bonyl)-3-bromo-4-methoxyphenylglycinate (1, X1 = Br) (0.070 g,
0.19 mmol), K3PO4 (0.079 g, 0.37 mmol), Pd(OAc)2 (0.5 mg,
0.002 mmol), and ligand 9 (1.6mg, 0.004 mmol) were suspendedin
toluene (0.3 mL) and H2O (0.03 mL) under Ar in a Schlenk tube.
The resulting mixture was stirred at 100 °C for 6 h. The solvents
were evaporated and the resulting crude was purified by column
chromatography [silica gel, AcOEt in hexanes (0-12%)] furnish-
ing the product as a white semisolid (0.063 g, 84%). Mp 129-
132 °C (lit.15 mp 129-132 °C); IR (film NaCl) 3377, 2956, 2933,
from tryptophanylpinacolboronate ester (3, X4 = Bpin) (0.11 g,
0.20 mmol), methyl (R)-N-(tert-butoxycarbonyl)-3-bromo-4-
methoxyphenylglycinate (1, X1 = Br) (0.046 g, 0.13 mmol),
K3PO4 (0.052 g, 0.25 mmol), Pd(OAc)2 (0.3 mg, 0.001 mmol),
and ligand 9 (1.0 mg, 0.002 mmol) in toluene (0.3 mL) and H2O
(0.03 mL). Chromatography [silica gel, AcOEt in hexanes
(25-65%)] furnished the product as a colorless oil (0.074 g,
85%). IR (film NaCl) 3377, 2956, 1744, 1713, 1503, 1465, 1439,
1370, 1173 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.43 (9H, s), 1.93
(3H, s), 2.36 (3H, s), 3.19 (1H, dd, J1 = 14.8Hz, J2 = 5.6Hz), 3.26
(1H, dd, J1 = 14.8 Hz, J2 =5.6Hz), 3.65 (3H, s), 3.72 (3H, s), 3.79
(3H, s), 4.92 (1H, dt, J1 = 7.4 Hz, J2 = 5.6 Hz), 5.28 (1H, d, J =
7.2 Hz), 5.57-5.62 (1H, m), 6.08 (1H, d, J = 7.2 Hz), 6.95 (1H, d,
J =8.4 Hz), 7.26 (3H, m), 7.31 (1H, dd, J1 = 8.4 Hz, J2 = 2.0 Hz),
7.36 (1H, s), 7.44 (1H, dd, J1 = 8.4 Hz, J2 = 1.6Hz), 7.55 (1H, dd,
J1 = 5.6 Hz, J2 = 0.8 Hz), 7.77 (2H, d, J = 8.4 Hz), 7.97 (1H, d,
J = 8.8 Hz); 13C NMR (100 MHz, CDCl3) δ 21.5 (CH3), 23.1
(CH3), 27.5 (CH2), 28.3 (CH3), 52.3 (CH3), 52.4 (CH), 52.7 (CH3),
55.7 (CH3), 80.1 (C), 111.4 (CH), 113.2 (CH), 117.2 (C), 120.1
(CH), 124.5 (CH), 126.8 (CH), 127.5 (CH), 129.1 (C), 129.8 (C),
129.9 (CH), 130.6 (C), 130.9 (C), 133.3 (C), 134.1 (C), 135.2 (C),
145.0 (C), 156.5 (C), 169.7 (C), 171.1 (C), 171.9 (C); MS m/z 746
[(M þ K)þ, 21%] 730 [(M þ Na)þ, 100%]; HRMS calcd for
C36H41N3NaO10S (M þ Na)þ 730.2410, found 730.2404;
[R]D -68.33 (CH2Cl2, c 0.60).
Methyl (R)-N-(tert-Butoxycarbonyl)-3-[(R)-methoxy-N-acetyl-
1-tosyltryptophan-6-yl]-4-methoxyphenylglycinate (8). As for
7, from tryptophanylpinacolboronate ester (4, X4 = Bpin)
(0.18 g, 0.35 mmol), methyl (R)-N-(tert-butoxycarbonyl)-3-bro-
mo-4-methoxyphenylglycinate (1, X1 = Br) (0.087 g, 0.14 mmol),
K3PO4 (0.099 g, 0.46 mmol), Pd(OAc)2 (0.6 mg, 0.002 mmol), and
ligand 9 (2.0 mg, 0.005 mmol), furnishing the product as a
colorless oil (0.12 g, 85%). IR (film NaCl) 3318, 2954, 1754,
1713, 1666, 1503, 1368, 1173 cm-1; 1H NMR (400 MHz, CDCl3)
δ 1.45 (9H, s), 1.99 (3H, s), 2.36 (3H, s), 3.21 (1H, dd, J1 = 14.8
Hz, J2 = 5.2 Hz), 3.29 (1H, dd, J1 = 14.8 Hz, J2 = 5.6 Hz), 3.71
(3H, s), 3.76 (3H, s), 3.83 (3H, s), 4.95 (1H, dt, J1 = 7.6 Hz, J2 =
5.2 Hz), 5.34 (1H, d, J = 6.8 Hz), 5.57 (1H, d, J = 6.8 Hz), 6.06
(1H, d, J = 7.2 Hz), 6.99 (1H, d, J = 8.4 Hz), 7.26 (2H, m), 7.30
(1H, d, J = 2.0 Hz), 7.33-7.39 (3H, m), 7.46 (1H, d, J = 8.0 Hz),
7.77 (2H, d, J1 = 8.4 Hz), 8.13 (1H, d, J = 0.8 Hz); 13C NMR
(100 MHz, CDCl3) δ 21.6 (CH3), 23.2 (CH3), 27.5 (CH2), 28.3
(CH3), 52.5 (CH3), 52.7 (CH), 55.7 (CH3), 57.0 (CH3), 80.2 (C),
111.6 (CH), 114.8 (CH), 116.9 (C), 118.7 (CH), 124.7 (CH),
125.0 (CH), 126.9 (CH), 127.5 (CH), 129.3 (C), 129.9 (C), 131.0
(CH), 134.8 (C), 134.9 (C), 135.2 (C), 145.0 (C), 154.8 (C), 156.5
(C), 169.7 (C), 171.1 (C), 171.8 (C); MS m/z 746 [(M þ K)þ,
100%] 730 [(M þ Na)þ, 88%]; HRMS calcd for C36H41-
N3NaO10S (M þ Na)þ 730.2410, found 730.2394; [R]D -85.1
(CH2Cl2, c 0.58).
1
2838, 1746, 1715, 1519, 1495, 1248, 1167, 1049, 1030 cm-1; H
NMR (400 MHz, CDCl3) δ 1.44 (9H, s), 3.72 (3H, s), 3.80 (3H, s),
3.84 (3H, s), 5.29 (1H, d, J = 7.2 Hz), 5.51 (1H, d, J = 6.0 Hz),
6.92-6.96 (3H, m), 7.27-7.29 (2H, m), 7.42-7.46 (2H, m); 13
C
NMR (100 MHz, CDCl3) δ 28.3 (CH3), 52.6 (CH3), 55.3 (CH3),
55.6 (CH3), 57.0 (CH), 80.1 (C), 111.4 (CH), 113.5 (CH), 127.0
(CH), 129.1 (C), 129.3 (CH), 130.2 (C), 130.6 (CH), 130.8 (C),
154.8 (C), 156.5 (C), 158.8 (C), 171.9 (C); MS m/z 440 [(M þ K)þ,
97%] 424 [(M þ Na)þ, 100%]; HRMS calcd for C22H27NO6
(M)•þ 401.1838, found 401.1856; [R]D -95.9 (CHCl3, c 1.30).
Methyl (R)-N-(tert-Butoxycarbonyl)-3-(1-tosylindol-5-yl)-4-
methoxyphenylglycinate (5). As for 11, from indolylpinacolboro-
nate ester (13, X3=Bpin) (0.050 g, 0.13 mmol), methyl (R)-N-
(tert-butoxycarbonyl)-3-bromo-4-methoxyphenylglycinate (1,
X1 = Br) (0.031 g, 0.084 mmol), K3PO4 (0.036 g, 0.17 mmol),
Pd(OAc)2 (0.2 mg, 0.001 mmol), and ligand 9 (0.7 mg, 0.002
mmol) in toluene (0.2 mL) and H2O (0.02 mL), stirring for 8 h.
Chromatography [silica gel, AcOEt in hexanes (0-20%)] furn-
ished the product as a colorless oil (0.046 g, 98%). IR (film NaCl)
1
3402, 2979, 1744, 1713, 1499, 1370, 1250, 1169, 1131 cm-1; H
NMR (400 MHz, CDCl3) δ 1.43 (9H, s), 2.35 (3H, s), 3.72 (3H, s),
3.79 (3H, s), 5.29 (1H, d, J = 7.2 Hz), 5.53 (1H, d, J = 6.8 Hz),
6.67 (1H, d, J = 3.6 Hz), 6.95 (1H, d, J = 8.4 Hz), 7.23-7.32
(4H, m), 7.44 (1H, dd, J1 = 8.8 Hz, J2 = 1.6 Hz), 7.56 (1H, d, J =
3.6 Hz), 7.64 (1H, d, J = 1.2 Hz), 7.80 (2H, d, J = 8.4 Hz), 7.99
(1H, d, J = 8.4 Hz); 13C NMR (100 MHz, CDCl3) δ 21.5 (CH3),
28.3 (CH3), 52.7 (CH3), 55.7 (CH3), 57.0 (CH), 80.1 (C), 109.1
(CH), 111.4 (CH), 113.0 (CH), 122.2 (CH), 126.3 (CH), 126.6
(CH), 126.9 (CH), 127.3 (CH), 129.1 (C), 129.8(CH), 129.9 (CH),
130.7 (C), 131.1 (C), 133.1 (C), 134.0 (C), 135.3 (C), 144.9 (C),
154.8 (C), 156.5 (C), 171.8 (C); MS m/z 603 [(M þ K)þ, 100%],
587 [(M þ Na)þ, 29%]; HRMS calcd for C30H32N2O7S (M)•þ
564.1930, found 564.1950; [R]D -59.3 (CH2Cl2, c 0.14).
Methyl (R)-N-(tert-butoxycarbonyl)-3-(1-tosylindol-6-yl)-4-
methoxyphenylglycinate (6). As for 5, from indolylpinacolboro-
nate ester (14, X3 = Bpin) (0.050 g, 0.13 mmol) and methyl (R)-
N-(tert-Butoxycarbonyl)-3-bromo-4-methoxyphenylglycinate (1,
X1 = Br) (0.031 g, 0.084 mmol), furnishing the product as a color-
less oil (0.044 g, 94%). IR (film NaCl) 3400, 2977, 1746, 1713,
1499, 1370, 1250, 1173 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.45
(9H, s), 2.35 (3H, s), 3.75 (3H, s), 3.82 (3H, s), 5.34 (1H, d, J = 6.8
Hz), 5.57 (1H, d, J = 6.8 Hz), 6.65 (1H, d, J = 3.2 Hz), 6.98 (1H,
d, J = 8.4 Hz), 7.25 (2H, d, J = 8.4 Hz), 7.31-7.37 (3H, m), 7.53
(1H, d, J = 8.4 Hz), 7.58 (1H, d, J = 4.0 Hz), 7.81 (2H, d, J = 8.4
Hz), 8.15 (1H, s); 13C NMR (100 MHz, CDCl3) δ 21.5 (CH3), 28.3
(CH3), 52.7 (CH3), 55.7 (CH3), 57.0 (CH), 80.2 (C), 108.8 (CH),
111.5 (CH), 114.6 (CH), 120.7 (CH), 125.0 (CH), 126.7 (CH),
126.9 (CH), 127.4 (CH), 129.2 (C), 129.8 (C), 129.9 (CH), 130.0
(CH), 131.2 (C), 134.4 (C), 134.7 (C), 135.3 (C), 144.9 (C), 154.8
(C), 156.5 (C), 171.8 (C); MS m/z 603 [(M þ K)þ, 100%] 587
[(M þ Na)þ, 62%]; HRMS calcd for C30H32N2O7S (M)•þ
564.1930, found 564.1916; [R]D -66.1 (CH2Cl2, c 0.44).
Acknowledgment. This work was supported by funds
from MEC-FEDER (Bio 2005-00295), MEC (CTQ2006-
12460/BQU), and Generalitat de Catalunya (SGR and
CeRBa).
Supporting Information Available: Comprehensive experi-
mental procedures for the synthesis of compounds 1-8, 10-14,
16, and 17 together with their characterization data, copies of
the 1H and 13C NMR spectra for these compounds, and HPLC
traces for the ee determinations for compounds 1-8, 11, and 12.
This material is available free of charge via the Internet at http://
pubs.acs.org.
Methyl (R)-N-(tert-Butoxycarbonyl)-3-[(R)-methoxy-N-acetyl-
1-tosyltryptophan-5-yl]-4-methoxyphenylglycinate (7). As for 5,
J. Org. Chem. Vol. 74, No. 23, 2009 9205