Efficient loading of primary alcohols onto a solid phase using a trityl bromide linker

Article abstract of DOI:10.1016/j.tetlet.2008.07.130

The Letter describes an improved, rapid and mild strategy for the loading of primary alcohols onto a polystyrene trityl resin via a highly reactive trityl bromide linker. This protocol facilitates an efficient resin loading even of acid-sensitive or heat-

Full text of DOI:10.1016/j.tetlet.2008.07.130

Tetrahedron Letters 49 (2008) 5890–5893
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient loading of primary alcohols onto a solid phase using a trityl
bromide linker
*
François Crestey, Lars K. Ottesen, Jerzy W. Jaroszewski, Henrik Franzyk
Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark
a r t i c l e i n f o
a b s t r a c t
Article history:
The Letter describes an improved, rapid and mild strategy for the loading of primary alcohols onto a poly-
styrene trityl resin via a highly reactive trityl bromide linker. This protocol facilitates an efficient resin
loading even of acid-sensitive or heat-labile alcohols, which otherwise require expensive or non-com-
mercial resin types. Secondary alcohols were only attached in moderate to low yields, while attempts
to load a tertiary alcohol expectedly failed. Importantly, selective attachment of diols via a primary alco-
hol group in the presence of more hindered alcohol groups proved possible. The effects of activation time
and reagent excess as well as alcohol structure were investigated. This improved method provides a con-
venient access to O-linked resin-bound N-Fmoc-protected amino alcohols that may be employed in SPS of
peptides with C-terminal alcohol functionalities. In the case of a sensitive alcohol containing an activated
aziridine functionality, the use of the trityl bromide linker proved superior to a recently described silver
triflate-assisted trityl chloride resin-based procedure.
Received 13 June 2008
Revised 16 July 2008
Accepted 24 July 2008
Available online 29 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Organic synthesis carried out on solid supports is a key technol-
ogy for rapid and efficient production of compound libraries that
requires a careful choice of resin type and selection of an adequate
linker for anchoring the starting material.1 Recently, we have re-
ported on improved methods for solid-phase synthesis (SPS) of
secondary and tertiary amines2 including philanthotoxin ana-
logs,3,4 amino acid derivatives,5 heterocyclic scaffolds,6 and biolog-
employing a considerably more reactive trityl bromide linker, eas-
ily generated in situ from a trityl alcohol resin.
In solution-phase chemistry it is well established that trityl bro-
mide (TrtBr) is the reagent of choice when a high reactivity is
needed for difficult O-protections.13 By contrast, TrtBr resins have
been surprisingly poorly investigated, and an exhaustive survey of
the literature revealed only applications for loading of carboxylic
acids14 and phenols.15
ically active a
-peptide/b-peptoid oligomers.7
In the present work, we extend our studies on SPS methodology
to the development of a rapid and mild means for the loading of
alcohols onto a solid support with the purpose to circumvent lim-
itations of existing methods. Thus, in order to provide a high de-
gree of versatility, such a protocol should facilitate efficient
loading of alcohols containing acid-sensitive or heat-labile moie-
ties. While a number of strategies8 using dihydropyran- or silyl-
based9,10 as well as trityl linkers11 have previously been described
for this purpose, these methods have limitations mainly due to
prolonged reaction times and harsh conditions and reagents, such
as high temperatures or strong bases. Recently, Lundquist et al.
published a procedure employing silver triflate-assisted attach-
ment of alcohols to a trityl chloride resin,12 a procedure that
evades the limited reactivity of the standard trityl chloride linker,
but suffers from potential problems due to formation of insoluble
silver chloride precipitate on the resin as well as partial degrada-
tion of acid-sensitive alcohols. We now provide an alternative
Thus, we set out to investigate the loading of primary amino
alcohols (Scheme 1) onto a polystyrene TrtBr resin (PS-TrtBr) pre-
pared from a trityl alcohol resin (PS-TrtOH). In addition, experi-
ments with secondary and tertiary alcohols were undertaken.
R'
R"
R
R
NHFmoc
R'
HO
HO
NHFmoc
R
R'
N
Fmoc
4b
5b
6b
7b
8b
1b
R = R' = H, R" = Me
R = R' = H
2b
R = R' = Me
R = R' = R" = H
9b R = CH2OH, R' = H
3b R = OH, R' = H
R = sec-Bu, R' = R" = H
R = Ph, R' = R" = H
10b
R = H, R' = OH
NHFmoc
R = R" = H, R'= (S)-CH(Ph)OH
OH
HO
HO
HO
NHFmoc
11b
I
3
12b
13
OMe
O
Ns
Ns = 4-nitrobenzenesulfonyl
Bz = benzoyl
OH
BzO
OBz
N
OBz
14
15
* Corresponding author. Tel.: +45 3533 6255; fax: +45 3533 6040.
E-mail address: hf@farma.ku.dk (H. Franzyk).
Scheme 1. The array of alcohols examined in this study (1b–12b were prepared
from the corresponding unprotected amino alcohols 1a–12a).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.130

F. Crestey et al. / Tetrahedron Letters 49 (2008) 5890–5893
5891
Table 2
Fmoc-protected amino alcohols were employed due to their gen-
Loading of primary alcohol 1b onto a prepared PS-TrtBr resin
eral synthetic utility, ease of preparation, and convenient HPLC
analysis with diode-array detection (HPLC–DAD) of the reaction
mixtures. The versatility of the strategy was exemplified by subse-
quent conversion of the products into an amino acid derivative
Entry AcBr (equiv) Activation (min) 1b (equiv) Loading (min) Yield (%)a
1
2
3
4
5
6
7
8
30
30
30
30
30
10
10
5
90
90
90
90
90
10
30
30
5
5
2
2
2
2
2
2
5
30
10
10
10
10
10
10
73
65
74
38b
66c
44
90
79
containing a C-terminal alcohol as well as a chiral N-(
kyl)-functionalized b-aminosulfonamide.
x-hydroxyal-
First, amino alcohols 1a–12a were N-protected by a standard
procedure described by Calveras et al. (Scheme 2).16 Thus, building
blocks 1b–12b were obtained in excellent yields by using Fmoc–
OSu and a low excess of the corresponding amino alcohols in diox-
ane–water at room temperature (Table 1).17
In order to establish conditions that enable an efficient loading
of alcohols in general, the initial focus was on optimizing the load-
ing of primary alcohol 1b16 onto a commercially available PS-
TrtOH resin (loading: 1.64 mmol/g) via an intermediate PS-TrtBr
resin. This was considered a suitable test reaction that should pref-
erably be achievable at room temperature (Scheme 3).
Several reaction parameters were varied, including the excess of
acetyl bromide (AcBr) and alcohol 1b as well as the activation and
loading time (Table 2). Initially, the conversion to PS-TrtBr resin
was performed by using 30 equiv of AcBr for 90 min in dry dichlo-
romethane (DCM), examining the influence of the amount of 1b
and the loading time (Table 2, entries 1–3). Treatment with 2 equiv
of the alcohol for 10 min with addition of 5 equiv of i-Pr2EtN as
base gave a satisfactory result. The effect of solvent was examined
by exchanging DCM for N-methyl-2-pyrrolidone (NMP),12 but this
resulted in a significantly decreased yield (Table 2, entry 4).
Next, by decreasing the amount of AcBr and varying the activa-
tion time, it was found that 10 equiv and 30 min, respectively,
afforded a high yield (Table 2, entry 7), whereas a smaller amount
of AcBr (Table 2, entry 8) led to a somewhat decreased yield. Thus,
the conditions selected for subsequent studies involving an array
of different alcohols comprised activation with 10 equiv of AcBr
for 30 min, followed by loading of 2 equiv of the alcohol in the
presence of 5 equiv of i-Pr2EtN for 10 min in dry DCM under
nitrogen.18
a
Determined by analytical HPLC–DAD (254 nm) by comparison with a reference
chromatogram of the pure starting material.
b
Dry NMP was used in the loading step.
1 g of PS-TrtOH resin was used.
c
5b with a short aliphatic chain, piperidine derivative 9b, benzyl
alcohol 13, and partially protected methyl glucopyranoside 14
were included. Except for carbohydrate derivative 14, all yields
were only a little lower than that found for compound 1b (Table 3).
In addition, the attachment of (N-nosylaziridin-2-yl)methanol
(15) onto a trityl resin was examined as an example of a procedure
employing a highly sensitive alcohol. As the standard cleavage pro-
cedure led to a complex mixture, aziridine ring-opening6 was sub-
sequently performed by using 10 equiv of 3-phenylpropylamine in
THF at room temperature overnight, to provide a b-amino-b0-
hydroxysulfonamide in 87% overall yield. In this case, the proce-
dure of Lundquist et al.12 gave a significantly lower overall yield
(35%), demonstrating the mildness and efficiency of the present
PS-TrtBr methodology. Subsequently, we examined the potential
of the method for the loading of secondary alcohols 4b, 10b, and
11b, but as expected only quite low yields were obtained in all
cases. Attempts to improve the loading of 4b included use of dry
1,2-dichloroethane (DCE) as solvent at elevated temperature. How-
ever, even increasing the amount of 4b to 4 equiv and extending
the reaction time still resulted in a low loading yield (13–25%).
The use of microwave (MW) irradiation conditions appeared to
be less efficient than conventional heating (Table 3). Likewise, at-
tempts to use a tertiary alcohol (12b) failed to provide useful re-
sults. Thus, this methodology should allow selective loading of
primary alcohols in the presence of secondary or tertiary alcohol
functionalities.
Hence, these optimal conditions were employed for the loading
of several primary alcohols.19 After the standard cleavage proce-
dure employing 2% TFA–DCM,20,21 yields were excellent to good
even for more sterically hindered primary amino alcohols 2b and
6b, while 7b only afforded a moderate yield. In addition, alcohol
Accordingly, the loading of diols 3b and 8b onto PS-TrtBr re-
sulted in yields comparable to those obtained for sterically hin-
dered primary alcohols already examined. Moreover, to confirm
the practical utility of the protocol, compounds 1b, 3b, and 8b (ob-
tained after successive loading and cleavage from 125 mg of start-
ing resin) were reisolated in 70%, 53%, and 55% yields, respectively,
after preparative HPLC–DAD (97–100% purity at 267 nm). To deter-
mine the selectivity between primary and secondary hydroxy
groups in diol 3b, acetylation of the resin with Ac2O–i-Pr2EtN–
Fmoc-protected
1b 12b
i
amino alcohols 1a-12a
amino alcohols
-
Scheme 2. Reagents and conditions: (i) amino alcohol 1a–12a (1.2 equiv), Fmoc-
OSu (1.0 equiv), 1,4-dioxane–water (4:1), rt, 16 h, 37–99%.
Table 1
Synthesis of Fmoc-protected amino alcohols 1b–12b
Product
Yield (%)
1b
97
2b
97
3b
91
4b
5b
97
6b
97
93a
Table 3
Loading of more hindered primary, secondary, and tertiary alcohols as well as diolsa
Product
Yield (%)
7b
99
8b
99
9b
96
10b
96
11b
12b
94
37b
Product
Yield (%)
2b
89
3b
67
4b
5b
85
6b
74
7b
55
8b
58
24b
a
2.2 equiv of 4a was used.
b
Amino alcohol hydrochloride was used; 1.2 equiv of Et3N was added prior to the
addition of Fmoc–OSu.
Product
Yield (%)
9b
66
10b
25
11b
12b
13
71
14
20
15
17c
<1d
87e
a
Using the optimized conditions described above.
Using 4 equiv of 4b at rt for 1 h, 2 equiv of 4b at 50 °C for 1 h in DCE, or 4 equiv
b
ii, iii
i
of 4b at 60 °C for 1 h in DCE under MW irradiation conditions gave yields of 25%,
1b
Trt OH
(75 mg of resin)
Trt Br
13%, and 21%, respectively.
c
Addition of amino alcohol was performed in DCM–DMF (4:1).
Obtained with 4 equiv of 12b at rt for 1 h.
Determination of the loading of 15 required a subsequent ring-opening using 3-
d
e
Scheme 3. Reagents and conditions: (i) AcBr, dry DCM, rt, N2; (ii) 1b, i-Pr2EtN, dry
phenylpropylamine as 15 is unstable under the cleavage conditions.
DCM, rt, N2; (iii) washing procedure then cleavage with 2% TFA–DCM.

5892
F. Crestey et al. / Tetrahedron Letters 49 (2008) 5890–5893
4. Olsen, C. A.; Witt, M.; Jaroszewski, J. W.; Franzyk, H. J. Org. Chem. 2004, 69,
i, ii
RO
NHFmoc
Trt Br
6149–6152.
OR'
5. Crestey, F.; Witt, M.; Frydenvang, K.; St
Org. Chem. 2008, 73, 3566–3569.
6. Olsen, C. A.; Christensen, C.; Nielsen, B.; Mohamed, F. M.; Witt, M.; Clausen, R.
P.; Kristensen, J. L.; Franzyk, H.; Jaroszewski, J. W. Org. Lett. 2006, 8, 3371–3374.
7. Olsen, C. A.; Bonke, G.; Vedel, L.; Adsersen, A.; Witt, M.; Franzyk, H.;
Jaroszewski, J. W. Org. Lett. 2007, 9, 1549–1552.
ꢀrk, D.; Jaroszewski, J. W.; Franzyk, H. J.
R=H, R'=Ac 16
R=Ac, R'=H 17
Scheme 4. Reagents and conditions: (i) 3b (2 equiv), i-Pr2EtN (5 equiv), dry DCM,
rt, 10 min, N2; (ii) Ac2O–DIPEA–DMF (1:2:3), 60 °C, 4 h, washing procedure, then
cleavage with 2% TFA–DCM.
8. For a recent review on anchoring of alcohols and phenols to solid supports, see:
Nam, N.-H.; Sardari, S.; Parang, K. J. Comb. Chem. 2003, 5, 479–546.
9. (a) Graham, K. A. N.; Wang, Q.; Eisenhut, M.; Haberkorn, U.; Mier, W.
Tetrahedron Lett. 2002, 43, 5021–5024; (b) Ramaseshan, M.; Dory, Y. L.;
Deslongchamps, P. J. Comb. Chem. 2000, 2, 615–623; (c) Thompson, L. A.;
Ellman, J. A. Tetrahedron Lett. 1994, 35, 9333–9336.
10. (a) Schmidt, D. R.; Kwon, O.; Schreiber, S. L. J. Comb. Chem. 2004, 6, 286–292;
(b) Doi, T.; Yoshida, M.; Hijikuro, I.; Takahashi, T. Tetrahedron Lett. 2004, 45,
5723–5726; (c) Thompson, L. A.; Moore, F. L.; Moon, Y.-C.; Ellman, J. A. J. Org.
Chem. 1998, 63, 2066–2067.
R
R
Gly-Fmoc
HO
N
H
iii
18
i, ii
Trt O
Trt Br
R
NH2
Ns
11. (a) Agarwarl, H. K.; Parang, K. Nucleosides Nucleotides Nucleic Acids 2007, 26,
iv
Bn
ˇ
317–322; (b) Stanger, K. J.; Krchnák, V. J. Comb. Chem. 2006, 8, 435–439; (c)
NH-Ns
Chen, C.; Ahlberg Randall, L. A.; Miller, R. B.; Jones, A. D.; Kurth, M. J. J. Am.
Chem. Soc. 1994, 116, 2661–2662; (d) Fréchet, J. M. J.; Haque, K. E. Tetrahedron
Lett. 1975, 16, 3055–3056.
R
=-(CH2)3-
N
HO
N
H
Bn
19
20
12. Lundquist, J. T., IV; Satterfield, A. D.; Pelletier, J. C. Org. Lett. 2006, 8, 3915–3918.
13. (a) Naemura, K.; Mizo-oku, T.; Kamada, K.; Hirose, K.; Tobe, Y.; Sawada, M.;
Takai, Y. Tetrahedron: Asymmetry 1994, 5, 1549–1558; (b) Komiotis, D.; Currie,
B. L.; Lebreton, G. C.; Venton, D. L. Synth. Commun. 1993, 23, 531–534; (c)
Reddy, M. P.; Rampal, J. B.; Beaucage, S. L. Tetrahedron Lett. 1987, 28, 23–26.
14. Zikos, C. C.; Ferderigos, N. G. Tetrahedron Lett. 1994, 35, 1767–1768.
15. Olsen, C. A.; Jørgensen, M. R.; Hansen, S. H.; Witt, M.; Jaroszewski, J. W.;
Franzyk, H. Org. Lett. 2005, 7, 1703–1706.
Scheme 5. Reagents and conditions: (i) 1b (2 equiv), i-Pr2EtN (5 equiv), dry DCM,
rt, 10 min, N2; (ii) 20% piperidine–DMF, rt, 2 ꢀ 30 min; (iii) Fmoc-Gly-OH (3 equiv),
TBTU (3 equiv), i-Pr2EtN (6 equiv), dry DMF, rt, 1 h, washing procedure then
cleavage with 2% TFA–DCM, 92% overall yield; (iv) 19 (2 equiv), MW, 80 °C, 15 min,
washing procedure then cleavage with 2% TFA–DCM, 74% overall yield.
16. Calveras, J.; Bujons, J.; Parella, T.; Crehuet, R.; Espelt, L.; Joglar, J.; Clapés, P.
Tetrahedron 2006, 62, 2648–2656.
17. Typical procedure for Fmoc protection of amino alcohols: To a solution of 3-
amino-2,2-dimethyl-1-propanol (2a; 1.1 g, 10.7 mmol, 1.2 equiv) in a mixture
of dioxane–water (20 mL) was added Fmoc-OSu (3.0 g, 6.7 mmol) over 5 min.
The reaction mixture was stirred for 16 h at room temperature and
concentrated in vacuo. Workup as previously described by Calveras et al.16
gave 9H-fluoren-9-ylmethyl (3-hydroxy-2,2-dimethylpropyl)carbamate (2b)
as a white powder (2.8 g, 97%). Mp 118–121 °C. TLC Rf = 0.5 (heptane–EtOAc,
1:1). 1H NMR (300 MHz, CDCl3) d: 7.77 (d, J = 7.4 Hz, 2H), 7.58 (d, J = 7.4 Hz,
2H), 7.40 (t, J = 7.4 Hz, 2H), 7.32 (t, J = 7.4 Hz, 2H), 5.12 (br s, 1H), 4.45 (d,
J = 6.6 Hz, 2H), 4.21 (t, J = 6.6 Hz, 1H), 3.22 (br s, 1H), 3.18 (s, 2H), 3.03 (d,
J = 5.5 Hz, 2H), 0.83 (s, 6H). Anal. Calcd for C20H23NO3: C, 73.82; H, 7.12; N,
4.30. Found: C, 73.91; H, 6.98; N, 4.33.
DMF (1:2:3) at 60 °C for 4 h prior to cleavage provided acylated
compound 16. Its purity and identity were confirmed by analytical
HPLC–DAD and by 1H NMR analysis (a characteristic downfield
shift of CHOAc was observed), respectively. Since compound 17
was not detected, a very high selectivity for the primary hydroxy
group was proved (Scheme 4).
Two examples of SPS applications of the developed PS-TrtBr
protocol are depicted in Scheme 5. With freshly prepared PS-TrtBr
as a starting point, an N-alkylated amino acid derivative containing
a C-terminal alcohol 18 was prepared in 92% overall yield by using
standard SPS procedures.22 Moreover, compound 20 was prepared
in high purity and good yield by performing a MW-assisted ring-
opening procedure, as recently described by Crestey et al.,5 with
(S)-N-(p-nitrobenzenesulfonyl)-2-benzylaziridine 19.23 These re-
sults demonstrate that construction of peptides as well as amino-
sulfonamides is feasible. Likewise, SPPS starting from diol 3b
enables preparation of N-terminal peptide aldehydes via a post-
cleavage oxidation.24
In conclusion, a novel, mild, highly selective, and rapid (<2 h)
method for preparation of resin-bound primary alcohols in good
yields has been developed. The protocol offers the advantage of
avoiding otherwise long loading times by using a cheap commer-
cial starting resin, which only requires a simple activation prior
to the loading step. Notably, similarly mild alcohol attachments
(e.g., via silyl-based linkers) require expensive or non-commercial
resin types, which in addition are cleaved under less mild condi-
tions and in some instances require special equipment.10a,c Further
studies concerning construction of new scaffolds from the O-linked
resin-bound intermediates are in progress.
18. Typical procedure for successive activation of trityl alcohol resin and alcohol
attachment: AcBr (91 lL, 1.23 mmol, 10 equiv) was added to PS-TrtOH resin
(1.64 mmol/g, 75 mg, 0.12 mmol) swollen in dry DCM (2 mL) under N2 at room
temperature. The mixture was agitated for 30 min, then drained and washed
with dry DCM (3 ꢀ 2 mL for 5 min).
A
solution of the desired alcohol
(0.25 mmol, 2 equiv) and i-Pr2EtN (107
lL, 0.62 mmol, 5 equiv) in dry DCM
(2.5 mL) was added and the reaction mixture was stirred for 10 min under N2.
The resin was drained, washed with DMF, dioxane, MeOH, and DCM (each
3 ꢀ 5 mL for 5 min), and then cleaved with 2% TFA–DCM (2 ꢀ 2 mL for 30 min).
The resin was further eluted with DCM (2 mL), and the resulting solutions were
combined and co-evaporated with toluene in vacuo. The crude material was
purified by preparative reversed-phase HPLC–DAD using a 21.2 ꢀ 250 mm
Phenomenex C18 column (5
preparative-scale pumps, an autosampler and
detector.
l
m, 100 Å) in
a
system consisting of two
a multiple-wavelength UV
19. Elementary analyses for novel Fmoc-protected amino alcohols were obtained
with satisfactory results: compound 3b: Anal. Calcd for C18H19NO4: C, 68.99; H,
6.11; N, 4.47. Found: C, 69.04; H, 6.05; N, 4.47; compound 9b: Anal. Calcd for
C
21H23NO3: C, 74.75; H, 6.87; N, 4.15. Found: C, 74.65; H, 6.83; N, 4.19.
compound 10b: Anal. Calcd for C20H21NO3: C, 74.28; H, 6.55; N, 4.33. Found: C,
74.68; H, 6.79; N, 4.61.
20. A minor peak, assumed to be the trifluoroacetate of the alcohol formed during
the TFA treatment, was usually observed in HPLC–DAD analysis of the reaction
mixtures after our standard cleavage procedure with 2% TFA–DCM. An
alternative cleavage procedure,21 employing successive additions of DCM
(1.5 mL), 0.5 M HCl in DCM (1.0 mL), water (25
lL), and triisopropylsilane (TIS,
25 lL), followed by shaking for 1 h, was tested with a resin loaded with alcohol
1b. In this case, formation of the by-product was avoided; a 95% yield of the
desired compound was observed.
Acknowledgments
21. For additional information concerning trifluoroacetylation of alcohols during
TFA treatment, see: Atkinson, G. E.; Fisher, P. M.; Chan, W. C. J. Org. Chem. 2000,
65, 5048–5056 and references cited therein.
22. Wadhwani, P.; Afonin, S.; Ieronimo, M.; Buerck, J.; Ulrich, A. S. J. Org. Chem.
2006, 71, 55–61.
We thank the Lundbeck Foundation for financial support to F.C.
and the Brødrene Hartmanns Fond (Copenhagen) for a grant.
23. Typical procedure for MW-assisted ring-opening: To a resin loaded with alcohol
1b, prepared according to the above procedure using PS-TrtOH (100 mg,
0.16 mmol), was added 20% piperidine–DMF (3 mL). The resin was stirred for
0.5 h and then drained. This was repeated once, followed by washings with
DMF, MeOH, and CH2Cl2 (each 3 ꢀ 2 mL for 5 min), and lyophilization
overnight. After addition of aziridine 19 (104 mg, 0.33 mmol, 2 equiv) in DCE
(2 mL), the resin was heated to 80 °C under MW irradiation for 15 min. The
References and notes
1. Guillier, F.; Orain, D.; Bradley, M. Chem. Rev. 2000, 100, 2091–2157.
2. Olsen, C. A.; Witt, M.; Jaroszewski, J. W.; Franzyk, H. Org. Lett. 2004, 6, 1935–
1938.
3. Olsen, C. A.; Witt, M.; Franzyk, H.; Jaroszewski, J. W. Tetrahedron Lett. 2007, 48,
405–408 and references cited therein.

F. Crestey et al. / Tetrahedron Letters 49 (2008) 5890–5893
5893
resin was drained, washed with DMF, MeOH, and CH2Cl2 (each 3 ꢀ 2 mL for
5 min), and then the product was cleaved with TFA–DCM (2:98) (2 ꢀ 2 mL for
0.5 h). The resin was further eluted with DCM (2 mL) and the resulting
solutions were combined and co-evaporated with toluene in vacuo. The crude
material was purified by preparative reversed-phase HPLC to give the
trifluoroacetic acid salt of N-{(1S)-1-benzyl-2-[(3-hydroxypropyl)amino]-
ethyl}-4-nitrobenzenesulfonamide 20 as a colorless oil (61 mg, 74% overall
yield). 1H NMR (300 MHz, CD3OD) d: 8.10 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 8.5 Hz,
2H), 6.87–7.02 (m, 5H), 3.72–3.83 (m, 3H), 3.08–3.36 (m, 4H, partially under
the solvent peak), 2.77 (dd, J = 14.0 Hz and J = 4.7 Hz, 1H), 2.46 (dd, J = 14.0 Hz
and J = 9.9 Hz, 1H), 1.96 (q, J = 6.0 Hz, 2H). 13C NMR (75 MHz, CD3OD) d: 150.2,
145.4, 135.3, 129.2 (2C), 129.1 (2C), 128.2 (2C), 127.5, 124.7 (2C), 62.2, 53.7,
52.2, 49.5, 39.1, 27.5. RP-HPLC (267 nm): >99.9% purity. HRMS (m/z): [M+H]+
calcd for [C18H24N3O5S]+ 394.1437; found 394.1421;
DM 4 ppm.
24. (a) Lelièvre, D.; Buré, C.; Laot, F.; Delmas, A. Tetrahedron Lett. 2001, 42, 235–
238; (b) Li, X.; Zhang, L.; Hall, S. E.; Tam, J. P. Tetrahedron Lett. 2000, 41, 4069–
4073; (c) Lelièvre, D.; Chabane, H.; Delmas, A. Tetrahedron Lett. 1998, 39, 9675–
9678.