Amino-protecting groups subject to deblocking under conditions of nucleophilic addition to a Michael acceptor. Structure-Reactivity studies and use of the 2-(tert-Butylsulfonyl)-2-propenyloxycarbonyl (Bspoc) group

Article abstract of DOI:10.1021/jo982141d

A new type of amino-protecting group is described in which a Michael acceptor is incorporated into the protectant so that treatment with a nucleophile will trigger deblocking. Comparison of various Michael acceptors showed that for several key electron-withdrawing groups, the order of reactivity was C₆H₅SO₂ > Me₃CSO₂ > COOEt > C₆H₅SO > C₆H₄NO₂-p. The reactivity of the nucleophile (e.g., primary and secondary aliphatic amines) followed an order related to both intrinsic basicity and steric effects. β- Substituents in the Michael acceptor caused significant retardation of the deblocking process. The Bspoc function was chosen for initial elaboration into a practical system for use in peptide synthesis. Bspoc amino acid chlorides were used as coupling agents and silica-tethered secondary amines as deblocking agents. With the latter, deblocking occurs cleanly and no byproducts remain in the organic solvent in which the deblocking is executed.

Full text of DOI:10.1021/jo982141d

J . Org. Chem. 1999, 64, 4315-4323
4315
Am in o-P r otectin g Gr ou p s Su bject to Deblock in g u n d er Con d ition s
of Nu cleop h ilic Ad d ition to a Mich a el Accep tor .
Str u ctu r e-Rea ctivity Stu d ies a n d Use of th e
2-(ter t-Bu tylsu lfon yl)-2-p r op en yloxyca r bon yl (Bsp oc) Gr ou p
Louis A. Carpino* and Michael Philbin
Department of Chemistry, Box 34510, University of Massachusetts, Amherst, Massachusetts 01003-4510
Received October 23, 1998
A new type of amino-protecting group is described in which a Michael acceptor is incorporated into
the protectant so that treatment with a nucleophile will trigger deblocking. Comparison of various
Michael acceptors showed that for several key electron-withdrawing groups, the order of reactivity
was C6H5SO2 > Me3CSO2 > COOEt > C6H5SO > C6H4NO2-p. The reactivity of the nucleophile
(e.g., primary and secondary aliphatic amines) followed an order related to both intrinsic basicity
and steric effects. â-Substituents in the Michael acceptor caused significant retardation of the
deblocking process. The Bspoc function was chosen for initial elaboration into a practical system
for use in peptide synthesis. Bspoc amino acid chlorides were used as coupling agents and silica-
tethered secondary amines as deblocking agents. With the latter, deblocking occurs cleanly and no
byproducts remain in the organic solvent in which the deblocking is executed.
In tr od u ction
butylsulfonyl derivative 6 was obtained by hydrolysis of
known bromide 56 via reaction with sodium formate in
methanol (60-70%).7 For comparison of electron-with-
drawing groups the N-(p-chlorophenyl)urethanes 3 were
Recently a new type of base-sensitive amino-protecting
group has been described in preliminary form.1 In
contrast to classical base-sensitive protectants which are
deblocked by â-elimination reactions, the new groups are
deblocked by nucleophilic addition to a Michael acceptor.
In the present paper experimental details are presented
covering the initial studies which involved (a) basic
structure-activity relationships and (b) applications to
peptide synthesis in solution via a â-unsubstituted
analogue of the 1,1-dioxobenzo[b]thiophene-2-ylmeth-
yloxycarbonyl (Bsmoc) residue described previously which
is based on the cyclic, â-phenylated alcohol 1.
â-Un su b st it u t ed Allylic Syst em s: St r u ct u r e -
Rea ctivity Effects. To determine the relative activating
effects of various electron-withdrawing groups (EWG), a
number of allylic alcohols 2 was synthesized and con-
verted to model urethane derivatives 3 (PCA ) p-
chloroaniline) via reaction with p-chlorophenyl isocyan-
)
(
treated with various primary and secondary amines of
varying steric requirements using 1H NMR spectroscopy
to monitor the disappearance of the CH2O protons.
Results are collected in Table 1. From the tests with
piperidine it is apparent that the p-nitrophenyl group is
a far less potent activator than any of the groups tested
except for the trimethylsilyl residue which did not induce
reaction with any of the amines listed or with the
stronger base 1,1,3,3-tetramethylguanidine. Only with
the highly hindered 2,6-dimethylpiperidine was it pos-
sible to distinguish the phenylsulfonyl and tert-butylsul-
fonyl functions for which a slightly greater reactivity for
the former was found, in agreement with the finding of
McDowell and Stirling8 that Michael additions to sub-
stituted phenyl vinyl sulfones correlated well with the
Hammett relationship. Table 1 also demonstrates the
importance of steric effects in the amino component of
the reaction, with more hindered amines reacting more
slowly.9 All amines listed in Table 1 have comparable
basicities (pKa ∼ 10.6-11) yet differ widely in steric
requirements. Urethane 3 (EWG ) C6H5SO) which
incorporates the weakly activating phenylsulfinyl group
ate. Alternatively, an appropriate chloroformate was
treated with p-chloroaniline to give 3. Known alcohols
(2, EWG ) SiMe3,2 COOEt,3 C6H4NO2-p4) were obtained
by published methods. The phenylsulfinyl and phenyl-
sulfonyl alcohols (2, EWG ) C6H5SO, C6H5SO2) were
readily obtained from sulfide alcohol 45 by m-chloroper-
benzoic acid (MCPBA) oxidation. The analogous tert-
(5) (a) Behzadi, A.; Owen, L. N. J . Chem. Soc., Perkin Trans. 1 1974,
25. (b) J ones, D. N.; Cottam, P. D.; Davies, J . Tetrahedron Lett. 1979,
51, 4977.
(6) Knochel, P.; Normant, J . F. Tetrahedron Lett. 1985, 425.
(7) Harris, M.; Bull, M. J . Synth. Commun. 1985, 15, 1225.
(8) McDowell, S. T.; Stirling, C. J . M. J . Chem. Soc. (B) 1967, 348.
(9) For a study of these steric effects for a variety of primary and
secondary amines, see: McDowell, S. T.; Stirling, C. J . M. J . Chem.
Soc. (B) 1967, 343.
(1) Carpino, L. A.; Philbin, M.; Ismail, M.; Truran, G. A.; Mansour,
E. M. E.; Iguchi, S.; Ionescu, D.; El-Faham, A.; Riemer, C.; Warrass,
R.; Weiss, M. S. J . Am. Chem. Soc. 1997, 119, 9915.
(2) Wells, G. J .; Yan, T. H.; Paquette, L. A. J . Org. Chem. 1984, 49,
3604.
(3) Villieras, J .; Rambaud, M. Synthesis 1982, 924.
(4) Wesseln, B. Acta Chem. Scand. 1967, 21, 718.
10.1021/jo982141d CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/19/1999

4316 J . Org. Chem., Vol. 64, No. 12, 1999
Carpino and Philbin
Ta ble 1. Effect of Electr on -With d r a w in g Gr ou p on th e
Tim e of Deblock in g of 3a ,b
sulfone 10 could be lithiated both regio- and stereoselec-
tively (eq 3).14
(
)
A similar strategy was attempted for the synthesis of
the Z-isomer, although in this case lithiation of cis-
sulfone 12 resulted in loss of stereochemistry to give
again alcohol 11. Therefore, the corresponding cis-sulfide
1315 was first hydroxymethylated and then oxidized to
the Z-alcohol 15. IR and NMR spectral data were
a
To a solution of 0.18 mmol of urethane in 500 µL of CDCl3
was added 3 equiv of the amine and reaction monitored by loss of
(
)
the CH2O signal (60 MHz 1H NMR). NR ) no reaction under
b
the conditions given, NT ) not tested. c Aldrich No. D-18030-0,
d
identified as the cis-isomer. Incomplete reaction under the
conditions studied.
consistent with the structural assignments for the two
alcohols 11 and 15.
clearly shows the retarding influence of an increasingly
bulky environment around the amino group.
Relative reactivities of the phenylsulfonyl and tert-
butylsulfonyl urethanes were compared with three other
systems bearing base-sensitive amino protecting groups,
namely
the
2-chloro-3-indenylmethyloxycarbonyl
(Climoc),10 9-fluorenylmethyloxycarbonyl (Fmoc),11 and
2-(methanesulfonyl)ethyloxycarbonyl (Msc)12 analogues,
using 3 equiv of piperidine in DCM. All three of these
protecting groups undergo deblocking by classic â-elim-
ination reactions. Under conditions which showed no
reaction with the Msc derivative, the two R,â-unsaturated
sulfonyl derivatives (3, EWG ) C6H5SO2, Me3CSO2)
showed reactivity comparable to the Climoc derivative
whereas the Fmoc analogue was only one hundredth as
reactive.
(
)
For comparison with a â-alkyl substituent the meth-
ylated sulfone analogous to 11 was also synthesized.
Eisch reported that phenyl propenyl sulfone 16 could be
lithiated by means of MeLi at -95 °C.16 In our hands
this process was unsuccessful and resulted only in
polymerization with either MeLi or n-BuLi. However, as
Deblocking byproducts were examined in the case of
phenylsulfonyl derivative 7. Depending on the amount
of piperidine used, varying amounts of the mono- and
diadducts 8 and 9 were obtained.13
in the case of 15, the corresponding sulfide 17 was readily
lithiated and the derived sulfide alcohol oxidized to
sulfone alcohol 18. Unsaturated sulfide 17 was obtained
by base-catalyzed rearrangement of the readily available
phenyl allyl sulfide.17 Finally â,â-diphenyl sulfone alcohol
19 was obtained by standard hydroxymethylation of the
corresponding vinyl sulfone which was synthesized from
trimethylsilylmethyl phenyl sulfone 2018 by treatment of
its anion with benzophenone.19
(
)
With 2.3 equiv of piperidine, 69 h were required for
conversion of the initially formed monoadduct 8 to 9
whereas with 10 equiv of piperidine, formation of 9 was
complete within 15 min.
â-Su bstitu ted Allylic System s: Ster ic Reta r d a -
tion . To examine the effect of â-substitution, a series of
urethanes was obtained bearing one or two phenyl
substituents at the â-carbon atom. The alcohol 11 was
obtained by exploiting Yamamoto’s observation that
To determine their relative reactivities, urethanes
derived from these alcohols were compared with a â-un-
substituted analogue toward three cyclic secondary amines
of differing basicities and steric requirements, piperidine,
morpholine, and 2,6-dimethylpiperidine (Table 2). Char-
(10) Carpino, L. A.; Cohen, B. J .; Lin, Y.-Z.; Stephens, K. E.; Triolo,
S. A. J . Org. Chem. 1990, 55, 251.
(11) Carpino, L. A. Acc. Chem. Res. 1987, 20, 401.
(12) Tesser, G. I.; Balvert-Geers, I. C. Int. J . Pept. Protein Res. 1975,
7, 295.
(13) For prior examples of the formation of such diadducts in related
systems, see: (a) Seebach, D.; Knochel, P. Helv. Chim. Acta 1984, 67,
261. (b) Mitra, S.; Lawton, R. G. J . Am. Chem. Soc. 1979, 101, 3097.
(14) Yamamoto, M.; Suzuki, K.; Tanaka, S.; Yamada, K. Bull. Chem.
Soc. J pn. 1987, 60, 1523.
(15) Truce, W. E.; Badiger, V. V. J . Org. Chem. 1964, 29, 3277.
(16) Eisch, J . J .; Galle, J . E. J . Org. Chem. 1979, 44, 3279.
(17) Tarbell, D. S.; McCall, M. A. J . Am. Chem. Soc. 1952, 74, 48.
(18) Craig, D.; Ley, S. V.; Simpkins, N. S.; Whitman, G. H.; Prior,
M. J . J . Chem. Soc., Perkin Trans. 1 1985, 1949.
(19) Ager, D. J . Chem. Commun. 1984, 486.

Bspoc Amino-Protecting Group
J . Org. Chem., Vol. 64, No. 12, 1999 4317
Ta ble 2. Deblock in g of â-Su bstitu ted Su lfon e
attack at the â-carbon atom of both 21 and 22 to give
intermediate 26 which is subsequently isomerized to the
more stable isomer 24. In another connection Doomes and
co-workers21 demonstrated that this rearrangement oc-
Alcoh ol-Der ived Ur eth a n esa
curs readily. Careful monitoring of the reaction by 1H
NMR spectroscopy revealed the labile intermediacy of 26
and its conversion to 24.
Of the various model systems examined, alcohol 6 was
most conveniently obtained on a large scale, and there-
fore the 2-(tert-butylsulfonyl)-2-propenyloxycarbonyl
(Bspoc) group was chosen for first studies in connection
with the testing of Michael-based protective systems in
the development of new rapid routes to peptides via
solution methods. Upon examining the sensitivity of the
Bspoc residue toward conditions pertinent to normal
deblocking processes for the currently most common
amino-protecting groups, stability was demonstrated to
trifluoroacetic acid (TFA) or saturated HCl in HOAc or
dimethylamine (DMA)-free N,N-dimethylformamide
(DMF). As expected, deblocking occurs under conditions
of catalytic or transfer hydrogenolysis (H2/Pd-C or NH4-
OCHO/Pd-C). Depending on the conditions, 2-propenyl
tert-butyl sulfone and/or isopropyl tert-butyl sulfone were
obtained as byproducts of the hydrogenolysis.
a
For the method and abbreviations used, see footnotes a and b
of Table 1. For comparison of the urethane of 18 with 22, see the
general procedure described in the Experimental Section.
acterization data for the various urethanes cited in
Tables 1 and 2 are given in Table 3.
Although the two mono-â-substituted urethanes 21 and
22 are of comparable reactivity toward piperidine, with
the less basic morpholine a significant difference is
noticeable. With 2,6-dimethylpiperidine a single â-phenyl
substituent renders the system totally unreactive. It is
not unusual then that the â,â-diphenylated compound
does not react even with piperidine under these condi-
tions.
UV data indicate lesser conjugative interaction be-
tween the olefinic linkage and the phenyl substituent in
the Z-isomer 21 (λmax 267 nm, ꢀ ) 7500) than in the
corresponding E-form 22 (λmax 270 nm, ꢀ ) 18500),
suggesting a possible rationale for the greater reactivity
of the Z-form. The â-methyl-substituted sulfone urethane
derived from 18 was less soluble than the phenylated
analogue 22, and therefore the reactivity of these two
sulfones was compared at a lower concentration than
used for the other compounds in Table 2 (see footnote 1
of Table 2). Under the conditions chosen, 18 was de-
blocked by morpholine in less than 5 min, whereas 22
required 45 min for complete deblocking. These results
are consistent with the smaller size of a methyl group
relative to a phenyl group20 as well as the greater
resonance interaction of the olefinic double bond with the
phenyl as opposed to the methyl residue.
Curious results were observed when Bspoc-PCA 27 was
treated with the tertiary base pyridine (2 equiv) in
(
)
chloroform solution. The solution became red within 10
min, and after 48 h the urethane was completely con-
sumed. Only PCA (27%) and decarbonylated adduct 28
(60%) were found. Amine 28 could be derived from 27 by
base-catalyzed decomposition or via initial pyridine ad-
ducts 29 or 30.
Piperidine deblocking of 22 gave adduct 24. Although
24 is formally the product of direct SN2 displacement at
Even in the absence of a base, urethanes such as 27
were found not to be completely stable for long periods.
For example a sample of urethane 7 which had been left
on the bench for about one year was found to have
extruded carbon dioxide to give the 2-phenylsulfonyl
analogue of amine 28. The same conversion was ac-
complished simply by brief heating of 7 to 130 °C.
Although no mechanistic evidence is available, these
extrusions can be explained as [3,3] sigmatropic shifts
via the enol tautomer of urethane 7.22 Although clearly
the methylene group of urethane 22, if this reaction
course were followed isomer 21 should yield 25. In fact,
21 yields exclusively the same amine 24 which was
obtained from 22. Although no mechanistic studies were
performed, the results are best explained by Michael
(20) (a) Eliel, E. L.; Willen, S. H.; Mander, L. N. Stereochemistry of
Organic Compounds; Wiley-Interscience: New York, 1994; Table 11.7,
p 696. (b) Yashunsky, V. G.; Terentyev, A. P.; Shvedov, V. I. Zh.
Obschch. Khim. 1995, 25, 2457.
(21) Doomes, E.; Clarke, V.; Neitzel, J . J . J . Org. Chem. 1987, 52,
1540.

4318 J . Org. Chem., Vol. 64, No. 12, 1999
Carpino and Philbin
Ta ble 3. Ch a r a cter iza tion of Mod el Allylic Ur eth a n es Bea r in g a n Electr on -With d r a w in g Gr ou p a t th e 2-P osition a
analytical data calcd (found)
yield,
%
R1
R2
EWG
mp, °C (recrys solv)
1H NMR, δb
mol formula
C
H
N
H
H
SO2C6H5
71
104-6 (CCl4)
4.85 (bs,2), 6.15 (bs,1), 6.5 (bs,1), C16H14ClNO4S 54.63 (54.54) 4.01 (3.99) 3.98 (4.05)
7.05-8.00 (m,10)
H
H
COOEt
65
93-93.5 (CCl4)
46-47d
1.25 (t,3), 4.25 (q,2), 4.9 (s,2), 5.9, C13H14ClNO4
(bs,1), 6.35 (bs,1), 7.15-7.50
(m,4), 8.0 (bs,1)c
55.04 (54.89) 4.97 (4.69) 4.94 (4.89)
H
H
H
H
H
H
H
H
SiMe3
42
84
69
63
0.15 (s,9), 4.8 (t,2), 5.5 (m,1),
5.85 (m,1), 7.1-7.5 (m,5)
4.89 (s,2), 5.68 (s,1), 6.06 (s,1),
6.22 (s,1), 7.15-7.7 (m,19)
4.65 (s,1), 4.70 (s,1), 6.0 (s,1),
6.3 (s,1), 7.1-7.85 (m,10)
5.1 (s,2) 5.62 (s,1), 5.74 (s,1),
6.63 (bs,1), 7.28 (m,4), 7.62
(d,2), 8.22 (d,2)
C13H18ClNO2Si 55.01 (54.80) 6.39 (6.13) 4.93 (4.89)
C28H24ClNO2Si 71.55 (71.51) 5.15 (5.21) 2.98 (2.90)
C16H14ClNO3S 57.23 (56.95) 4.20 (4.14) 4.17 (4.10)
Si(C6H5)3
SOC6H5
C6H4-NO2-p
132-3 (Skelly
B/CCl4)
106-7.5
(CCl4/SkellyB)
130.5-3.1
(10% EtOAc/
Skelly B)
138.5-9.5
(20% EtOAc/
Skelly B)
124-125
(15% EtOAc/
Skelly B)
>250 (dec)
(95% EtOAc/
EtOH)
16.6-8
(30% EtOAc/
Skelly B)
C
C
C
16H13ClN2O4 57.76 (57.95) 3.94 (4.03) 8.42 (8.59)
22H18ClNO4S 61.75 (61.54) 4.24 (4.27) 3.27 (3.11)
22H18ClNO4S 61.75 (61.70) 4.24 (4.09) 3.27 (3.21)
H
C6H5 SO2C6H5
47
79
78
58
5.07 (s,2), 6.52 (bs,1), 7.25-8.08
(m,14), 8.15 (s,1)
C6H5
H
SO2C6H5
5.23 (s,2), 7.05 (bs,1), 7.22-7.83
(m,15)
C6H5 C6H5 SO2C6H5
5.13 (s,2), 6.8 (bs,1), 6.91-7.58
C28H22ClNO4S 66.73 (66.51) 4.40 (4.44) 2.78 (2.54)
C17H16ClNO4S 55.81 (55.85) 4.41 (4.47) 3.83 (3.83)
(m,19)
H
CH3 SO2C6H5
2.27 (d,3), 4.98 (s,2), 6.61 (s,1),
6.75 (q,1), 7.12-8.20 (m,9)
a
Urethanes were made by reaction of the chloroformate with p-chloroaniline or by reaction of p-chlorophenyl isocyanate with the
b
corresponding alcohol as described in the Experimental Section for the Bspoc case. Sample dissolved in CDCl3 unless otherwise specified.
c Sample analyzed in CDCl3-DMSO-d6. Sample purified by chromatography was used directly for elemental analysis.
d
of importance with regard to the long-term storage of
Bspoc-protected amines, this interesting reaction did not
interfere with the use of these intermediates under
normal conditions.
Bspoc protection of amino acids was achieved using the
chloroformate of 6 in the Bolin technique23 or via the tert-
butyl esters of the appropriate amino acids. An alternate
general method which is often used for the introduction
of protective groups into free amino acids involves an
active ester such as 31.24 Attempts to synthesize 31 were
unsuccessful, only the decarbonylated material 32 being
at the desired site and at the second electrophilic center,
the Michael acceptor. Such premature deblocking pro-
cesses could lead to the formation of substitution or
insertion products. In fact small incursions of such
reactions could be observed. Thus treatment of phen-
ylalanine tert-butyl ester with Bspoc-Phe-Cl gave the
desired dipeptide ester in 94.3% yield. HPLC analysis of
the reaction mixture showed 2.09% and 0.32% of two
byproducts, which, while not isolated from the reaction
mixture, showed HPLC retention times which agreed
with those of 33 and 34, respectively. Authentic samples
of 33 and 34 were synthesized, 33 by reaction of Bspoc-
Phe-O-t-Bu with tert-butyl phenylalaninate, and 34 from
Bspoc-Phe-Phe-O-t-Bu by treatment with a catalytic
amount of an aminomethylpiperidinyl silica gel 3510 in
DCM for a period of 4 days. Amino-loaded silica gel
reagents such as 35 and 36 have previously been used
isolated. This suggests that at some stage the N-hydroxy-
succinimide anion acts as a potent nucleophilic deblock-
ing agent for the Bspoc residue.
Bspoc amino acids could be converted to their acid
chlorides via reaction with thionyl chloride in dichlo-
romethane (DCM) and the acid chlorides used in peptide
coupling processes.25 Generally two-phase couplings were
carried out using DCM/H2O/NaHCO3. Use of a highly
reactive acylating reagent such as an acid chloride should
guarantee the highest discrimination between reaction
for the deblocking of other base-sensitive protecting
groups but not always with satisfactory results.10 They
are particularly suited for application to systems which
incorporate Michael acceptors such as those described
here. An example is provided below.
(22) For a related base-catalyzed extrusion, see: Foucaud, A.; El
Guemmout, F. Bull. Soc. Chim. Fr. 1989, 405.
(23) Bolin, D. R.; Sytwu, I.; Humiec, F.; Meienhofer, J . Int. J . Pept.
Protein Res. 1989, 33, 353.
(24) Compare: Paquet, A. Can. J . Chem. 1982, 60, 976.
(25) (a) Carpino, L. A.; Cohen, B. J .; Stephens, K.; Sadat-Aalaee,
S.; Tien, J .-H.; Langridge, D. J . Org. Chem. 1986, 51, 3732. (b) Carpino,
L. A.; Beyermann, M.; Wenschuh, H.; Bienert, M. Acc. Chem. Res. 1996,
29, 268.
When Bspoc-Phe-Phe-O-t-Bu was deblocked via basic
resin 35 (15 equiv of NH per equivalent of the protected

Bspoc Amino-Protecting Group
J . Org. Chem., Vol. 64, No. 12, 1999 4319
dipeptide), HPLC analysis revealed none of the theoreti-
cally possible premature product 34. This result contrasts
with that obtained in the case of the simple model 27
which with the same silica reagent (5 equiv of NH per
eq. of Bspoc-PCA) led to the formation of 95.1% of PCA
and 3.88% of a side product which had the same HPLC
retention time as that of 28. Increasing the ratio of active
NH to 15 equiv gave 97.2% of PCA and reduced the
amount of material assigned as 28 to 0.55%. For the less
reactive piperazino silica reagent 36,26 these figures were
7.73% and 0.82%, respectively. With a low molecular
weight deblocking base (piperidine) only 0.17-0.18% of
28 was observed with either 5 or 15 equiv of base. Steric
factors may play a role in the lesser reactivity observed
with the amino acid derivatives versus the simple PCA
analogues.
The deblocked free amino dipeptide derived from the
silica reagent, being free of any detectable byproducts,
was treated directly with a second equivalent of Bspoc-
Phe-Cl by the same technique. The resulting tripeptide
was obtained cleanly in 75% yield.
Following these preliminary observations Fmoc-pro-
tected leucine enkephalin 3725a [Fmoc-Tyr(Bn)-Gly-Gly-
Phe-Leu-OBn] was synthesized in a single sequence of
steps without isolation of any intermediates. All cou-
plings were carried out via Bspoc amino acid chlorides
except for the last, for which Fmoc-Tyr(Bn)-Cl was used.
Deblocking was carried out with the aminomethylpip-
eridine resin.
Substitution of a polymeric active ester for the acid
chloride should allow for a complete inverse Merrifield
cycle not subject to any of the disadvantages encountered
earlier.10 Protected pentapeptide 37 was obtained in a
yield of 59% (crude). The properties of 37 agreed with
those previously recorded and catalytic deblocking gave
free leucine enkephalin.27 Gas chromatographic analysis28
on a chiral column following hydrolysis revealed the
absence of racemization (<0.1% D-form) at the Bspoc-
introduced phenylalanine residue. This agreed with
preliminary racemization studies involving the synthesis
of a model dipeptide, Bspoc-Phe-Leu-OMe, and its con-
version following deblocking to the corresponding N-
benzoyl dipeptide methyl ester (<0.1% by HPLC).29
Acid chloride couplings were used in the present
studies since this work was carried out prior to the
discovery of the stability and applicability of Fmoc and
other protected amino acid fluorides.30 Presumably it will
be possible to synthesize the Bspoc amino acid fluorides
or make use of some of the newer, highly efficient in situ
activators31 directly with the Bspoc amino acids them-
selves. Indeed the acid fluorides of the related Bsmoc
amino acids have already been used with good results1
but so far none of the Bspoc analogues have been tested.
Additional solution and solid phase syntheses involving
Bspoc chemistry are anticipated for comparison with
those previously reported in the Bsmoc case.
Con clu sion s
It has been shown in this study that urethanes derived
from allylic alcohols bearing 2-(alkyl- or arylsulfonyl)
residues are, as Michael acceptors, sensitive to the
addition of secondary amines at the R,â-unsaturated site.
Nucleophilic addition is followed by quick fragmentation
to liberate carbon dioxide and the amine built into the
urethane unit. The overall process represents a new
concept in amino group protection. Structural effects
which control the speed of the deblocking step were
surveyed. By using a polymeric secondary amine for
deblocking, it is possible to scavenge any low molecular
weight byproducts generated from the Michael acceptor
moiety and simply evaporate the solution to obtain the
desired amine. An example of the practical application
of such a system to the solution assembly of a simple
pentapeptide is described.
Exp er im en ta l Section
Gen er a l. Melting points and boiling points were uncor-
rected. Elemental analyses were carried out by the University
of Massachusetts Microanalytical Laboratory under the direc-
tion of Greg Dabkowski.
2-(P h en ylsu lfon yl)-2-p r op en yl Alcoh ol. A mixture of
5.03 g (30.3 mmol) of 2-(phenylthio)-2-propenyl alcohol5 and
12.74 g (62.7 mmol) of 85% m-chloroperbenzoic acid in 250 mL
of DCM was stirred overnight at room temperature. The
mixture was extracted with three 100-mL portions of saturated
NaHCO3, followed by 100 mL of water. The organic layer was
dried over MgSO4 and filtered, and the solvent was removed
in vacuo from a water bath at 45 °C. The residue was
chromatographed on silica gel (100-200 mesh, 50 g/gram of
compound) with 40% EtOAc/Skelly B as eluent, to give 4.30 g
(72%) of the sulfone as a colorless oil; IR (neat) 3500, 1580,
1440, 1300, 1170, 1130, 1050, 950, 900, 750, 690 cm-1; 1H NMR
(CDCl3) δ 3.70 (bs, 1), 4.20 (bs, 2), 6.05 (bs, 1), 6.35 (bs, 1),
7.30-7.95 (m, 5). Anal. Calcd for C9H10O3S: C, 54.53; H, 5.08;
S, 16.17. Found: C, 54.57; H, 5.13; S, 16.02.
2-(Meth ylsu lfon yl)eth yl N-p-Ch lor op h en yl Ca r ba m -
a te. A solution of 2.06 g (16.6 mmol) of 2-(methylsulfonyl)-
ethyl alcohol and 2.55 g (16.6 mmol) of p-chlorophenyl isocy-
anate in 15 mL of benzene was refluxed for 30 min. The solvent
was removed in vacuo from a water bath at 45 °C to give a
solid which was recrystallized from CHCl3 to give 2.98 g (65%)
of the urethane, mp 147-147.5 °C; IR (KBr) 3360, 1720, 1600,
1490, 1310, 1230, 1130, 1070, 830, 760 cm-1; 1H NMR (DMSO-
d6-CDCl3) δ 3.0 (s, 3), 3.40 (t, 2,), 4.60 (t, 2), 7.15-7.55 (m,
4), 9.20 (bs, 1). Anal. Calcd for C10H12ClNO4S: C, 43.25; H,
4.36; N, 5.04. Found: C, 43.16; H, 4.14; N, 4.99.
2-(Tr ip h en ylsilyl)-2-p r op en yl N-p-Ch lor op h en yl Ca r -
ba m a te. To a stirred solution of 4.55 g (0.012 mol) of
(1-bromovinyl)triphenylsilane32 in 30 mL of dry ether at -24
°C (CCl4/dry ice) was added dropwise under
a nitrogen
(26) Carpino, L. A.; Mansour, E. M. E.; Knapczyk, J . J . Org. Chem.
1983, 48, 666.
(27) (a) Carpino, L. A.; Chao, H.-G.; Tien, J .-H. J . Org. Chem. 1989,
54, 4302. (b) Garbay-J aureguiberry, C.; Roque, B. P.; Oberlin, R.;
Anteunis, M.; Combrisson, S.; Lallemand, J . Y. FEBS Lett. 1977, 76,
93.
(28) Meienhofer, J . Biopolymers 1981, 20, 1761.
(29) Carpino, L. A.; Rice, N. W.; Mansour, E. M. E.; Triolo, S. A. J .
Org. Chem. 1984, 49, 836.
(30) (a) Carpino, L. A.; Sadat-Aalaee, D.; Chao, H.-G.; DeSelms, R.
H. J . Am. Chem. Soc. 1990, 112, 9651. (b) Carpino, L. A.; Mansour, E.
M. E.; Sadat-Aalaee, D. J . Org. Chem. 1991, 56, 2611.
(31) (a) Carpino, L. A. J . Am. Chem. Soc. 1993, 115, 4397. (b)
Carpino, L. A.; El-Faham, A.; Minor, C. A.; Albericio, F. J . Chem. Soc.,
Chem. Commun. 1994, 201. (c) Carpino, L. A.; El-Faham, A. J . Am.
Chem. Soc. 1995, 117, 5401.
atmosphere 20.8 mL of 1.20 M n-BuLi (0.024 mol) in hexane.
Upon completion of the addition, the yellow mixture was
allowed to stir at -24 °C for 90 min. Gaseous formaldehyde,
generated by heating paraformaldehyde at 170 °C, was passed
through a tube 5 mm in diameter into the reaction mixture
with the aid of a slow stream of nitrogen until the yellow color
of the solution had disappeared. The reaction mixture was
stirred at room-temperature overnight, poured into 50 mL of
5% HCl, and diluted with 50 mL of ether. The aqueous layer
was separated, the organic layer was extracted with two 50-
(32) Brook, A. G.; Duff, J . M.; Legrow, G. E. J . Organomet. Chem.
1976, 122, 31.

4320 J . Org. Chem., Vol. 64, No. 12, 1999
Carpino and Philbin
mL portions of water, dried over MgSO4, filtered, and the
solvent was removed in vacuo from a water bath at 45 °C to
give a white solid which was recyrstallized from Skelly B to
give 2.4 g (61%) of 2-(triphenylsilyl)-2-propenyl alcohol, mp 121
allowed to cool to room temperature and extracted with three
75-mL portions of DCM. The organic layer was dried over
MgSO4 and filtered, and the solvent was removed in vacuo
from a water bath at 45 °C. The residue was recrystallized
from 40% benzene/Skelly B to give 6.33 g (75%) of 2-(tert-
butylsulfonyl)-2-propenyl alcohol, mp 49-51 °C. This sample
of alcohol was less pure than that, mp 53.5-54.5 °C, obtained
via sodium formate. The crude alcohol was treated with
phosgene as described above to give the chloroformate. Three
recrystallizations gave 4.64 g (60%) of the chloroformate which
still showed a depressed melting point, mp 52-53.5 °C. The
impure chloroformate was extracted with 15% ether/Skelly B
by means of a Soxhlet extraction apparatus. The residue
remaining in the thimble was recrystallized from 50% ether/
Skelly B to give 0.28 g (2%) of the ether, mp 99-100 °C; IR
(KBr) 2975, 1300, 1280, 1100, 1080, 1000, 945, 765, 750, 715,
°C; IR (KBr) 3320, 3060, 1420, 1105, 1020, 940, 740, 700 cm-1
;
1H NMR (CDCl3) δ 1.34 (s, 1), 4.35 (s, 2), 5.63 (s, 1), 6.24 (s,
1), 7.30-7.70 (m, 15). Without further purification the alcohol
was treated with p-chlorophenyl isocyanate according to
footnote a of Table 3 (see Table 3 for characterization data).
2-(ter t-Bu tylsu lfon yl)-2-p r op en yl Alcoh ol (6). A mixture
of 8.55 g (35.5 mmol) of 2-(tert-butylsulfonyl)-2-propenyl
bromide6 and 5.31 g (78.1 mmol) of sodium formate in 150 mL
of methanol was refluxed overnight. The solution was allowed
to cool and concentrated to 50 mL with the aid of a water
aspirator, resulting in the precipitation of excess sodium
formate. The residue was diluted with 150 mL of water and
extracted with five 50-mL portions of DCM. The organic layer
was dried over MgSO4 and filtered, and the solvent was
removed in vacuo from a water bath at 45 °C. The crude
alcohol was recrystallized from 15% EtOAc/Skelly F to give
4.30 g (68%) of the pure alcohol as a colorless solid, mp 53.5-
54.5 °C; IR (KBr) 3470, 3120, 3000, 1450, 1370, 1270, 1095,
1050, 960, 900, 800, 750, 630 cm-1; 1H NMR (CDCl3) δ 1.39 (s,
9), 2.57 (t, 1), 4.56 (d, 2), 6.30 (s, 1), 6.31 (s, 1). Anal. Calcd for
C7H14O3S: C, 47.17; H, 7.92; S, 17.99. Found: C, 47.07; H,
7.95; S, 17.70.
1
695, 670; H NMR (CDCl3) δ 1.4 (s, 18), 4.4 (s, 4), 6.38 (s, 2),
6.43 (s, 2); 13C NMR (CDCl3) δ 144.5 (dCH2), 132.0 (dC), 69.5
(CH2O), 60.5 (SO2CMe3), 24.0 (SO2C(CH3)3). Anal. Calcd for
C14H26O5S2: C, 49.68; H, 7.74; S, 18.94. Found: C, 49.43; H,
7.82; S, 18.68.
(E)-3-P h en yl-2-(ph en ylsu lfon yl)-2-pr open yl Alcoh ol (11).
To a stirred solution of 2.0 g (8.2 mmol) of trans-phenyl â-styryl
sulfone in 50 mL of dry THF at -78 °C was added dropwise
under a nitrogen atmosphere 6.0 mL (8.4 mmol) of 1.4 M
n-BuLi within 5 min. The reddish-purple solution was stirred
at -78 °C for 30 min. Gaseous formaldehyde, generated by
heating paraformaldehyde at 170 °C, was passed through a
tube 5 mm in diameter into the reaction mixture with the aid
of a slow stream of nitrogen at -78 °C for 45 min. The mixture
was allowed to come to room temperature over a period of 30
min while continuing to pass formaldehyde through the
reaction mixture until a pale yellow solution was obtained. The
reaction mixture was quenched with 75 mL of 5% HCl and
extracted with 50 mL of ether. The organic layer was washed
with two 50-mL portions of water, dried over MgSO4 and
filtered, and the solvent was removed in vacuo from a water
bath at 45 °C to give 2.1 g (93%) of the crude alcohol as a brown
oil. The oil was flash chromatographed in two 1.05-g batches
on silica gel (230-400 mesh, 4 × 19-cm column) with 50%
ether/Skelly B as eluent to give a total of 0.99 g (44%) of a
light yellow solid, mp 85-87 °C. Recrystallization from 40%
ether/Skelly B gave the pure colorless alcohol, mp 88-89 °C;
UV (MeOH) λmax ) 221 nm, ꢀ ) 12500, λmax ) 270 nm, ꢀ )
23500; IR (KBr) 3470, 1625, 1445, 1285, 1145, 1020, 770, 755,
2-(ter t-Bu tylsu lfon yl)-2-p r op en yl Ch lor ofor m a te. To a
solution of 6.67 g (37.4 mmol) of 2-(tert-butylsulfonyl)-2-
propenyl alcohol in 27 mL of dry THF at 0 °C was added in
one portion 27 mL of phosgene. The solution was stirred for 1
h at 0 °C and allowed to stand at room temperature overnight.
Excess phosgene and solvent were removed under reduced
pressure with the aid of a water aspirator. Recrystallization
from 25% ether/Skelly B gave 8.23 g (91%) of the chloroformate
as a colorless solid, mp 56.5-57.7 °C; IR (KBr) 2980, 1755,
1430, 1380, 1290, 1140, 1100, 965, 915, 810, 750, 680, 630
cm-1; 1H NMR (CDCl3) δ 1.41 (s, 9), 5.11 (s, 2), 6.37 (s, 1), 6.47
(s, 1). Anal. Calcd for C8H13ClO4S: C, 39.92; H, 5.44; S, 13.32.
Found: C, 40.10; H, 5.40; S, 13.07.
Repr esen tative Exam ple of Ur eth an e Syn th esis: 2-(ter t-
Bu tylsu lfon yl)-2-p r op en yl N-(p-Ch lor op h en yl)ca r ba m -
a te. To a solution of 0.24 g (1.0 mmol) of 2-(tert-butylsulfonyl)-
2-propenyl chloroformate in 3 mL of benzene at 0 °C was added
dropwise 0.26 g (2.0 mmol) of p-chloroaniline in 3 mL of
benzene. A white precipitate separated almost immediately.
After the addition was complete the mixture was stirred at 0
°C for 10 min and for 2 h at room temperature. The mixture
was diluted with 15 mL of benzene and extracted with two
15-mL portions of 5% HCl, followed by 15 mL of water. The
organic layer was dried over MgSO4 and filtered, and the
solvent was removed in vacuo from a water bath at 45 °C. The
crude urethane was recrystallized from 20% EtOAc/Skelly B
to give 0.26 g (79%) of the pure urethane, mp 124-125 °C.
The same compound was obtained in 85% yield by treatment
of 2-(tert-butylsulfonyl)-2-propenyl alcohol with p-chlorophenyl
isocyanate in refluxing benzene; IR (KBr) 3340, 3120, 2980,
1730, 1600, 1490, 1430, 1280, 1210, 1070, 975, 915, 830, 750,
1
735, 700, 680 cm-1; H NMR (CDCl3) δ 2.63 (t, 1), 4.37 (d, 2),
7.27-8.13 (m, 11). Anal. Calcd for C15H14O3S: C, 65.67; H,
5.14; S, 11.69. Found: C, 65.60; H, 5.12; S, 11.31.
3,3-Dip h en yl-2-(p h en ylsu lfon yl)-2-p r op en yl Alcoh ol
(19). To a stirred solution of 1.25 g (3.90 mmol) of 2,2-diphenyl-
1-(phenylsulfonyl)ethene in 20 mL of dry THF at -78 °C was
added dropwise under a nitrogen atmosphere 2.8 mL of 1.4 M
n-BuLi (3.90 mmol). The dark black solution was stirred at
-78 °C for 30 min. Gaseous formaldehyde, generated as noted
for the preparation of 11, was passed through the reaction
mixture which was then worked up as noted. The residual oil
was flash chromatographed on silica gel (230-400 mesh, 5 ×
16-cm column) with 30% ether/Skelly B as eluent to give 0.47
g (34%) of the colorless alcohol. In a melting point capillary
the compound does not melt but decomposes above 290 °C with
blackening; IR (KBr) 3480, 3040, 1590, 1480, 1440, 1370, 1280,
1130, 1020, 960, 790, 730, 700, 680, 610 cm-1; 1H NMR (CDCl3)
δ 3.47 (t, 1), 4.61 (d, 2), 6.75-7.58 (m, 15). Anal. Calcd for
C21H18O3S: C, 71.98; H, 5.18; S, 9.15. Found: C, 71.97; H, 5.22;
S, 9.02.
(Z)-3-P h en yl-2-(p h en ylm er ca p to)-2-p r op en yl Alcoh ol
(14). To a solution of 2.0 g (9.4 mmol) of phenyl cis-â-styryl
sulfide in 25 mL of dry tetrahydrofuran (THF) at -78 °C was
added dropwise under a nitrogen atmosphere 6.7 mL (9.4
mmol) of 1.4 M n-BuLi within 5 min. The light yellow solution
was stirred at -78 °C for 30 min, treated with gaseous
formaldehyde, and worked up as noted above. Flash chroma-
tography on silica gel (230-400 mesh, 4 × 24-cm packed
column) with 20% EtOAc/Skelly B as eluent gave 1.1 g (48%)
of the alcohol, mp 64.0-65.0 °C; IR (KBr) 3240, 3140, 1580,
620 cm-1 1H NMR (CDCl3) δ 1.4 (s, 9), 4.0 (t, 2), 6.3 (s, 1),
;
6.35 (s, 1), 7.15-7.5 (m, 5). Anal. Calcd for C14H18ClNO4S: C,
50.68; H, 5.47; N, 4.22. Found: C, 50.46; H, 5.47; N, 4.28.
For other urethanes made similarly, see Table 3.
2-(ter t-Bu tylsu lfon yl)-2-p r op en yl N-P h en ylca r ba m a te.
A solution of 1.24 g (6.96 mmol) of 2-(tert-butylsulfonyl)-2-
propenyl alcohol and 0.83 g (6.97 mmol) of phenyl isocyanate
in 10 mL of benzene was treated as described for the p-chloro
derivative. Recrystallization from 25% EtOAc/Skelly B gave
in 70% yield the colorless urethane, mp 138.5-140.0 °C; IR
(KBr) 3460, 1740, 1600, 1520, 1450, 1290, 1220, 1110, 1070,
1
760 cm-1; H NMR (CDCl3) δ 1.4 (s, 9), 5.0 (t, 2), 6.3 (m, 2),
6.9-7.45 (m, 6). Anal. Calcd for C14H19NO4S: C, 56.55; H, 6.44;
N, 4.71. Found: C, 56.27; H, 6.19; N, 4.78.
Bis-2-(ter t-bu tylsu lfon yl)-2-p r op en yl Eth er . A solution
of 11.45 g (0.047 mol) of 2-(tert-butylsulfonyl)-2-propenyl
bromide and 5.19 g (0.062 mol) of NaHCO3 in 145 mL of 50%
acetone/water was refluxed for 60 min. The mixture was

Bspoc Amino-Protecting Group
J . Org. Chem., Vol. 64, No. 12, 1999 4321
1470, 1090, 1070, 1010, 740, 695 cm-1; 1H NMR (CDCl3) δ 1.82
110 mg (29%) of the mono adduct as a colorless solid, mp 64-
65 °C; IR (KBr) 2940, 1440, 1295, 1130, 955, 740, 685, 660,
630 cm-1; 1H NMR (CDCl3) δ 1.25 (bs, 6), 2.15 (bs, 4), 3.15 (s,
(broad, 1), 4.17 (d, 2), 7.15-7.75 (m, 11). Anal. Calcd for C15H14
-
OS: C, 74.35; H, 5.82; S, 13.23. Found: C, 74.35; H, 5.90; S,
13.18.
2), 6.0 (t, 1), 6.5 (s, 1), 7.3-8.2 (m, 5). Anal. Calcd for C14H19
-
(Z)-3-P h en yl-2-(ph en ylsu lfon yl)-2-pr open yl Alcoh ol (15).
A mixture of 0.90 g (3.71 mmol) of (Z)-3-phenyl-2-(phenyl-
mercapto)-2-propenyl alcohol and 1.55 g (7.63 mmol) of 85%
m-chloroperbenzoic acid in 20 mL of DCM was stirred at room-
temperature overnight. The mixture was diluted with 40 mL
of DCM and extracted with two 25-mL portions of saturated
NaHCO3. The organic layer was dried over MgSO4 and filtered,
and the solvent was removed in vacuo from a water bath at
45 °C to give a clear oil. The oil was recrystallized from 20%
EtOAc/Skelly B to give 0.72 g (71%) of the sulfone, mp 67.5-
69.0 °C; UV (MeOH) λmax ) 225 nm, ꢀ ) 11000, λmax ) 270
nm, ꢀ ) 6500; IR (KBr) 3280, 3180, 1445, 1300, 1150, 1080,
1025, 990, 750, 730, 650, 610 cm-1; 1H NMR (CDCl3) δ 2.85 (s,
1), 4.67 (s, 2), 7.21-7.83 (m, 11). Anal. Calcd for C15H14O3S:
C, 65.67; H, 5.14; S, 11.69. Found: C, 65.45; H, 4.97; S, 11.82.
(E)-3-Meth yl-2-(ph en ylsu lfon yl)-2-pr open yl Alcoh ol (18).
To a solution of 1.08 g (7.19 mmol) of trans-1-propenyl phenyl
sulfide in 15 mL of dry THF at -24 °C was added dropwise
under a nitrogen atmosphere 7.6 mL of 1.4 M n-BuLi within
5 min. The light yellow solution was stirred at -24 °C for 30
min and treated with gaseous formaldehyde as noted above
except that the temperature was held at -24 °C rather than
-78 °C for 90 min. Workup gave an oil which was flash
chromatographed on silica gel (230-400 mesh, 4 × 20-cm
packed column) with 20% EtOAc/Skelly B as eluent to give
NO2S: C, 63.37; H, 7.22; N, 5.28. Found: C, 63.23; H, 6.99;
N, 5.41.
1,3-Bis[N-(P iper idin yl)]-2-(ph en ylsu lfon yl)pr opan e (9).
To a solution of 83.3 mg (0.24 mmol) of 2-(phenylsulfonyl)-2-
propenyl N-(p-chlorophenyl)carbamate in 400 µL of CDCl3 was
added 235 µL (10 equiv) of piperidine. Conversion to the
diadduct was complete within 15 min. The solution was
chromatographed on a preparative TLC plate with 7% EtOH/
Skelly B as eluent to give 42 mg (50%) of the sulfone diamine
as a colorless solid, mp 113.5-114.5 °C; IR (KBr) 2930, 1440,
1290, 1130, 760, 730 cm-1; 1H NMR (CDCl3) δ 1.3 (s, 12), 2.25
(s, 8), 2.55 (q, 2), 2.85 (q, 2), 3.25 (quintet, 1), 7.4-8.0 (m, 5).
Anal. Calcd for C19H30O2N2S: C, 65.11; H, 8.63; N, 7.99.
Found: C, 64.97; H, 8.81; N, 7.84.
Reactivity of 2-(ter t-Bu tylsu lfon yl)-2-pr open yl N-P h en -
ylca r ba m a te tow a r d Ca ta lytic Hyd r ogen a tion . To a solu-
tion of 0.78 g (2.6 mmol) of Bspoc-NHC6H5 in 40 mL of 100%
EtOH in a 500-mL pressure bottle was added 120 mg of 10%
Pd/C. The pressure bottle was charged with 45 psi of hydrogen
and shaken at room temperature for 48 h. The catalyst was
filtered and the filtrate diluted with 40 mL of DCM. The
organic layer was extracted with two 40-mL portions of 5%
HCl. The organic layer was dried over MgSO4 and filtered,
and the solvent was removed in vacuo from a water bath at
45 °C. The crude product was bulb-to-bulb distilled in a
Kugelrohr apparatus at 80 °C/0.7 Torr to give 0.30 g (60%) of
tert-butyl isopropyl sulfone; IR (neat) 2980, 1480, 1275, 1110,
1
0.28 g (22%) of the alcohol as an oil; H NMR (CDCl3) δ 1.92
(d of t, 4), 4.08 (bs, 2), 6.32 (q of t, 1), 7.25 (bs, 5). Without
further purification 0.28 g (1.55 mol) of the sulfide alcohol and
0.65 g (3.20 mmol) of 85% m-chloroperbenzoic acid in 10 mL
of DCM was stirred at room-temperature overnight. The
mixture was diluted with 40 mL of DCM, filtered, and
extracted with 50 mL of saturated NaHCO3. The organic layer
was dried over MgSO4 and filtered, and the solvent was
removed in vacuo from a water bath at 45 °C to give 0.29 g
(88%) of the sulfone alcohol as a clear oil; IR (KBr) 3460, 2920,
1
1050, 880, 805, 700, 630 cm-1; H NMR (CDCl3) δ 1.4 (d, 6),
1.42 (s, 9), 3.4 (sept, 1). Anal. Calcd for C7H16SO2: C, 51.18;
H, 9.82; S, 19.52. Found: C, 51.05; H, 9.80; S, 19.11.
ter t-Bu tyl N-(2-(ter t-Bu tylsu lfon yl)-2-p r op en yl)p h en yl-
a la n in a te (33). A solution of 0.494 g (2.05 mmol) of 2-(tert-
butylsulfonyl)-2-propenyl chloroformate and 0.623 g (2.05
mmol) of tert-butyl phenylalaninate hydrophosphite in 20 mL
of DCM was stirred with 25 mL of 5% NaHCO3 at room
temperature for 3 h. The aqueous phase was separated, and
the organic phase was washed with two 25-mL portions of 5%
HCl. The organic layer was dried over MgSO4 and filtered,
and the solvent was removed in vacuo from a water bath at
1635, 1440, 1290, 1140, 1070, 1000, 840, 720, 685 cm-1 1H
;
NMR (CDCl3) δ 2.10 (d, 3), 2.88 (s, 1), 4.32 (s, 2), 6.48 (q, 1),
7.28-8.10 (m, 5). Anal. Calcd for C10H12O3S: C, 56.59; H, 5.70;
N, 15.10. Found: C, 56.47; H, 5.86; N, 14.89.
Gen er a l P r oced u r e for Mon itor in g th e Deblock in g of
Ur eth a n es 3, 7, 21, 22, 23, a n d 27 by Mea n s of 60 a n d 200
MHz 1H NMR. To a solution of 0.18 mmol of the urethane in
500 µL of CDCl3 was added an appropriate amount of amine.
The reaction was monitored by the disappearance of the CH2O
protons at 60 MHz. For urethane 22 and that of alcohol 18, a
solution of 0.01 mmol of urethane in 500 µL of CDCl3 was
treated with 25 equiv of morpholine. The reaction was
monitored by the disappearance of the CH2O protons at 200
MHz. See Tables 1 and 2.
1
45 °C to give 0.87 g (100%) of an oil, which according to H
NMR analysis was essentially pure tert-butyl 2-(tert-butylsul-
fonyl)-2-(propenyloxycarbonyl)-L-phenylalaninate. To the oil
was added 80 mg (0.36 mmol, 0.18 equiv) of tert-butyl phenyl-
alaninate. After standing at room temperature for 48 h, 20
mL of Skelly F was added, and the solvent was removed in
vacuo to give a white solid. Recrystallization from 50% Skelly
B/Skelly F gave 0.56 g (72%) of the ester as a colorless solid,
mp 58.5-59.0 °C; IR (KBr) 3320, 1720, 1365, 1285, 1115, 1095,
1
740, 715 cm-1; H NMR (CDCl3) δ 1.32 (s, 9), 1.39 (s, 9), 1.81
Gen er a l P r oced u r e for Mon itor in g th e Deblock in g of
2-(ter t-Bu t ylsu lfon yl)-2-p r op en yl N-(p -Ch lor op h en yl)-
ca r ba m a te by HP LC for th e P r esen ce of P r em a tu r e
Deblock ed Ad d u ct. To a solution of 2-(tert-butylsulfonyl)-2-
propenyl N-(p-chlorophenyl)carbamate in DCM was added an
appropriate amount of amine. In the case of silica-based
reagents the solution was filtered. For liquid amines the
solution was injected directly onto an HPLC column. HPLC
analysis was carried out on a Waters Radial Pak 10-µm silica
column (0.8 × 10-cm) under the following conditions: 18%
2-propanol in hexane as the mobile phase, flow rate 0.5 mL/
min, injection volume 5-10 µL, detector 254 nm, attentuation
0.05, Retention times (min) were 13.0 for 27, 15.0 for 28, and
17.8 for p-chloroaniline.
N-(2-(P h en ylsu lfon yl)-2-p r op en yl)p ip er id in e (8). To a
solution of 0.50 g (1.42 mmol) of 2-(phenylsulfonyl)-2-propenyl
N-(p-chlorophenyl)carbamate in 2 mL of DCM was added 0.15
mL (1.1 equiv) of piperidine. The solution was stirred for 5
min, and the solvent was removed in vacuo from a water bath
at 45 °C. The residue was chromatographed on silica gel (100-
200 mesh, 100 g) with 10% EtOH/Skelly B as eluent to give a
solid fraction which was recrystallized from Skelly B to give
(bs, 1), 2.91 (m, 2), 3.34-3.65 (m, 3), 6.05 (s, 1), 6.19 (s, 1),
7.19-7.40 (m, 5); 13C NMR (CDCl3) δ 173.9, 146.0, 137.9, 130.2,
129.9, 128.8, 127.1, 82.1, 62.9, 60.6, 48.5, 40.3, 28.5, 24.0; [R]
-11.0° (c ) 1, CH2Cl2); [R] -12.5° (c ) 1, CH2Cl2). Anal. Calcd
for C20H31NO4S: C, 62.96; H, 8.19; N, 3.67. Found: C, 62.70;
H, 8.17; N, 3.59.
2-(ter t-Bu tylsu lfon yl)-2-pr open yl-N-p-ch lor oan ilin e (28).
A solution of 0.634 g (1.91 mmol) of 2-(tert-butylsulfonyl)-2-
propenyl N-(p-chlorophenyl)carbamate and 306 µL (3.82 mmol)
of pyridine in 4.2 mL of DCM was allowed to stand for 48 h.
The solvent was removed in vacuo from a water bath at 45 °C
to give a dark red residue. The residue was flash chromato-
graphed on silica gel (230-400 mesh, 4.5 × 18.0-cm column)
with 40% ether/Skelly B as eluent, to give a colorless solid
which was recrystallized from 5% EtOAc/Skelly B to give 0.33
g (60%) of the allylamine, mp 127.0-128.5 °C; IR (KBr) 3395,
1600, 1520, 1490, 1280, 1265, 1090, 970, 820, 750, 620 cm-1
;
1H NMR (CDCl3) δ 1.40 (s, 9), 4.20 (bs, 3), 6.15 (s, 1), 6.25 (s,
1), 6.45-7.20 (m, 4); 13C NMR (CDCl3) δ 145.1, 144.5, 130.1,
129.3, 123.1, 114.3, 60.4, 45.6, 23.6. Anal. Calcd for C13H18
-
ClNO2S: C, 54.25; H, 6.30; N, 4.87. Found: C, 54.49; H, 6.22;
N, 4.77.

4322 J . Org. Chem., Vol. 64, No. 12, 1999
Carpino and Philbin
2-(P h en ylsu lfon yl)-2-pr open yl-N-p-ch lor oan ilin e. A neat
sample of solid 2-(phenylsulfonyl)-2-propenyl N-(p-chlorophen-
yl)carbamate, mp 104-106 °C, was stored in an ordinary vial
at room temperature. After about 1 year it was noted that the
melting point was lower (mp 69-73 °C). The sample was
recrystallized from 70% CCl4/Skelly B which gave the allyl-
amine, mp 76.5-77.0 °C; IR (KBr) 3400, 1590, 1500, 1440,
1300, 1260, 1170, 1070, 970, 820, 750, 720, 680 cm-1; 1H NMR
(CDCl3) δ 3.97 (s, 2), 4.12 (bs, 1), 5.93 (s, 1), 6.41 (s, 1), 6.25-
7.02 (m, 4), 7.54-7.92 (m, 5); 13C NMR (CDCl3) δ 147.8, 145.6,
139.4, 134.6, 130.1, 129.7, 128.8, 125.5, 123.5, 114.5, 43.8.
Anal. Calcd for C15H14ClNO2S: C, 58.53; H, 4.58; N, 4.55.
Found: C, 58.27; H, 4.65; N, 4.57.
2-(ter t-Bu tylsu lfon yl)-2-p r op en yloxyca r bon ylp h en yl-
a la n yl Ch lor id e. To a stirred solution of 2.50 g (6.77 mmol)
of 2-(tert-butylsulfonyl)-2-propenyloxycarbonylphenylalanine
in 15 mL of dry DCM was added dropwise under a nitrogen
atmosphere a solution of 4.9 mL (10 equiv) of thionyl chloride
in 10 mL of dry DCM. Upon completion of the addition, the
solution was refluxed for 2 h. The solution was cooled to room
temperature, and excess thionyl chloride and solvent were
removed under reduced pressure with the aid of a vacuum
pump. The crude residue was recrystallized from 30 mL of 33%
DCM/pentane to give 2.13 g (82%) of the acid chloride, mp
100.0-100.5 °C; IR (KBr) 3400, 1810, 1790, 1720, 1510, 1295,
1250, 1105, 760, 710, 630 cm-1; 1H NMR (CDCl3) δ 1.38 (s, 9),
3.27 (m, 2), 4.88 (m, 3), 5.27 (d, 1), 6.10 (s, 1), 6.27 (s, 1), 7.15-
7.45 (m, 5); [R] +15.3° (c ) 1, CH2Cl2); [R] +18.7° (c ) 1, CH2-
Cl2). Anal. Calcd for C17H22ClNO5S: C, 52.64; H, 5.72; N, 3.61.
Found: C, 52.32; H, 5.39; N, 3.55.
ter t-Bu t yl 2-(ter t-Bu t ylsu lfon yl)-2-p r op en ylp h en yl-
a la n ylp h en yla la n in a te (34). A mixture of 300 mg (0.524
mmol) of tert-butyl 2-(tert-butylsulfonyl)-2-propenyloxycarbo-
nylphenylalanylphenylalaninate and 52 mg (0.1 equiv) of
aminomethylpiperidinyl silica gel in 5 mL of DCM was allowed
to stand for 4 days. The silica gel was filtered and the solvent
removed in vacuo from a water bath at 45 °C. The residue was
recrystallized from Skelly B to give 210 mg (84%) of the
colorless dipeptide derivative, mp 105.0-106.0 °C; IR (KBr)
2-(ter t-Bu tylsu lfon yl)-2-p r op en yloxyca r bon yl Glycin e.
A mixture of 3.34 g (13.9 mmol) of 2-(tert-butylsulfonyl)-2-
propenyl chloroformate and 2.95 g (13.8 mmol) of tert-butyl
glycinate hydrophosphite in 85 mL of DCM was stirred in the
presence of 100 mL of 5% NaHCO3 at room temperature for 4
h. Workup and treatment of the intermediate tert-butyl ester
with TFA in DCM gave an oil which was recrystallized from
30% EtOAc/Skelly B to give 3.25 g (84%) of the acid, mp 105.0-
105.5 °C; IR (KBr) 3355, 1765, 1695, 1560, 1290, 1190, 1100,
1050, 770 cm-1; 1H NMR (CDCl3) δ 1.41 (s, 9), 4.05 (d, 2), 4.94
3360, 3320, 2980, 1730, 1660, 1290, 1150, 1100, 950, 900 cm-1
;
1H NMR (CDCl3) δ 1.28 (s, 9), 1.49 (s, 9), 2.55-3.65 (m, 7),
4.80 (q, 1), 5.85 (s, 1), 6.18 (s, 1), 7.05-7.70 (m, 12); [R] -12.0°
(c ) 1, CHCl3); [R] -13.2° (c ) 1, CHCl3). Anal. Calcd for
C
29H40N2O5S: C, 65.88; H, 7.63; N, 5.30. Found: C, 65.66; H,
(s, 2), 5.44 (t, 1), 6.26 (s, 1), 6.33 (s, 1). Anal. Calcd for C10H17
-
7.42; N, 5.27.
NO6S: C, 43.00; H, 6.13; N, 5.01. Found: C, 43.00; H, 6.03;
N, 4.97.
N-[2-(ter t-Bu t ylsu lfon yl)-2-p r op en yloxy]su ccin im id e
(32). To a stirred solution of 0.25 g (2.17 mmol) of N-
hydroxysuccinimide and 300 µL (2.15 mmol) of triethylamine
in 14 mL of dioxane was added 0.523 g (2.17 mmol) of 2-(tert-
butylsulfonyl)-2-propenyl chloroformate. A precipitate sepa-
rated immediately. The mixture was stirred for 3.5 h, filtered,
and washed with 10 mL of dioxane. The solvent was removed
in vacuo to give a white solid which was recrystallized from
40% EtOAc/Skelly B to give 0.58 g (97%) of the oxysuccinimide,
mp 159-161 °C; IR (KBr) 2980, 1730, 1480, 1450, 1380, 1295,
2-(ter t-Bu t ylsu lfon yl)-2-p r op en yloxyca r b on yl Glycyl
Ch lor id e. Obtained in 91% yield as described for the phenyl-
alanine analogue, mp 61.5-62.5 °C; IR (KBr) 3400, 1800, 1740,
1510, 1280, 1100, 1050, 945, 790, 750, 625 cm-1 1H NMR
;
(CDCl3) δ 1.41 (s, 9), 4.39 (d, 2), 4.95 (s, 2), 5.57 (bs, 1), 6.25
(s, 1), 6.35 (s, 1). Anal. Calcd for C10H16ClNO5S: C, 40.34; H,
5.42; N, 4.70. Found: C, 40.51; H, 5.30; N, 4.83.
Byp r od u ct F or m a tion d u r in g th e P r ep a r a tion of ter t-
Bu tyl 2-(ter t-Bu tylsu lfon yl)-2-pr open yloxycar bon ylph en -
yla la n ylp h en yla la n in a te. A solution of 51.5 mg (0.129
mmol) of 2-(tert-butylsulfonyl)-2-propenyloxycarbonylphenyl-
alanyl chloride and 39.4 mg (0.130 mmol) of tert-butyl phenyl-
alaninate hydrophosphite in 10 mL of DCM was stirred with
20 mL of saturated NaHCO3 at room temperature for 10 min.
The aqueous phase was separated, and the organic layer was
washed with two 20-mL portions of saturated NaHCO3 and
two 20-mL portions of 5% HCl. The organic layer was dried
over MgSO4 and filtered, and the solvent was removed in vacuo
from a water bath at 45 °C. The crude residue was injected
for HPLC analysis. Analysis was carried out on a Waters
Radial Pak 10-µm C18 reverse phase column (0.8 × 10 cm)
under the following conditions: 58% methanol in 0.1% tri-
fluoroacetic acid/water as the mobile phase, flow rate 2 mL/
min, injection volume 5-10 µL, detector 254 nm, attenuation
0.05. Four peaks were observed having retention times of 3.1,
4.1, 9.2, and 19.6 min. These peaks were assigned to residual
Bspoc-Phe-OH (1.9%), 33 (2.1%), 34 (0.3%), and the desired
dipeptide ester (94.3%), respectively.
La ck of Byp r od u ct F or m a tion d u r in g th e Deblock in g
of ter t-Bu tyl 2-(ter t-Bu tylsu lfon yl)-2-p r op en yloxyca r bo-
n ylp h en yla la n ylp h en yla la n in a te by Mea n s of 4-(a m i-
n om eth yl)p ip er id in e (4-AMP ) Silica Rea gen t (35). A
mixture of 25 mg of Bspoc-Phe-Phe-O-t-Bu and 0.436 g (10
equiv) of 4-AMP silica reagent 35 in 2 mL of DCM was stirred
for 15 min. The mixture was filtered and injected for HPLC
analysis which was carried out on a Waters Radial Pak 10-
µm C18 reverse phase column (0.8 × 10 cm) under the following
conditions: 58% methanol in 0.1% trifluoroacetic acid/water
as the mobile phase, flow rate 2 mL/min, injection volume
5-10 µL, detector 254 nm, attenuation 0.05. The free dipeptide
was formed in 95% purity with no detectable contamination
by 34 (<0.1%).
1200, 1110, 1000, 910, 830, 810, 750, 640 cm-1 1H NMR
;
(CDCl3) δ 1.3 (s, 9), 2.7 (s, 4), 4.8 (s, 2), 6.55 (s, 1), 6.7 (s, 1).
Anal. Calcd for C11H17NO5S: C, 47.99; H, 6.22; N, 5.09.
Found: C, 48.22; H, 6.29; N, 5.17.
ter t-Bu tyl 2-(ter t-Bu tylsu lfon yl)-2-p r op en yloxyca r bo-
n ylp h en yla la n in a te. To a stirred solution of 0.185 g (0.768
mmol) of 2-(tert-butylsulfonyl)-2-propenyl chloroformate in 2
mL of benzene at 0 °C was added dropwise a solution of 0.34
g (1.53 mmol) of tert-butyl phenylalaninate in 5 mL of benzene.
Upon addition, a white precipitate began to separate. The
slurry was stirred at room temperature for 30 min, poured
into 15 mL of ether, and washed with three 15-mL portions of
5% HCl, and 15 mL of water. The organic layer was dried over
MgSO4 and filtered, and the solvent was removed in vacuo
from a water bath at 45 °C. The resulting oil was recrystallized
from 20% ether/pentane to give 0.23 g (70%) of the colorless
ester, mp 67-69 °C; IR (KBr) 3410, 2980, 1715, 1510, 1365,
1290, 1155, 1095, 1060, 940, 750, 700, 625 cm-1 1H NMR
;
(CDCl3) δ 1.45 (s, 9), 1.50 (s, 9), 3.12 (m, 2), 4.56 (q, 1), 4.90 (s,
2), 5.38 (d, 1), 6.14 (s, 1), 6.29 (s, 1), 7.15-7.40 (m, 5); [R] +25.4°
(c ) 1, CH2Cl2); [R] +30.9° (c ) 1, CH2Cl2). Anal. Calcd for
C
21H31NO6S: C, 59.27; H, 7.34; N, 3.29. Found: C, 59.31; H,
7.45; N, 3.23.
2-(ter t-Bu tylsu lfon yl)-2-p r op en yloxyca r bon ylp h en yl-
a la n in e. A solution of 18.6 mmol of tert-butyl 2-(tert-butyl-
sulfonyl)-2-propenyloxycarbonylphenylalaninate in 36 mL of
50% DCM/TFA was stirred at room temperature for 2 h.
Excess TFA and solvent were removed in vacuo from a water
bath at 45 °C. The resulting oil was recrystallized from 40%
ether/Skelly B to give 6.35 g (91%) of the colorless acid, mp
88.0-89.5 °C; IR (KBr) 3270, 1760, 1690, 1520, 1290, 1200,
1
1100, 1060, 960, 755, 700, 630 cm-1; H NMR (CDCl3) δ 1.40
(s, 9), 3.20 (m, 2), 4.75 (q, 1), 4.90 (s, 2), 5.35 (d, 1), 6.15 (s, 1),
6.32 (s, 1), 7.15-7.40 (m, 5); [R] -31.0° (c ) 0.5, DMF); [R]
-37.5° (c ) 0.5, DMF). Anal. Calcd for C17H23NO6S: C, 55.27;
H, 6.27; N, 3.79. Found: C, 55.02; H, 6.47; N, 3.71.
Con tin u ou s Solu tion Assem bly of F m oc-Tyr (Bn )-Gly-
Gly-P h e-Leu -OBn (37). A solution of 0.42 g (1.08 mmol) of
Bspoc-Phe-Cl and 0.42 g (1.07 mmol) of H-Leu-OBn‚HOTs in

Bspoc Amino-Protecting Group
J . Org. Chem., Vol. 64, No. 12, 1999 4323
10 mL of DCM was stirred in the presence of 50 mL of
saturated NaHCO3 for 15 min. The aqueous phase was
separated and the organic layer washed with 25 mL of 5% HCl.
The organic layer was dried over MgSO4 and filtered, and the
solvent was removed in vacuo from a water bath at 45 °C to
give the crude protected dipeptide which was dissolved in 10
mL of DCM and the solution added to a stirred mixture of 15.0
g (1 mmol NH per gram) of 4-(aminomethyl)piperidine func-
tionalized silica gel, 35, in 40 mL of DCM. The mixture was
stirred for 15 min and filtered, and the silica was washed with
three 20-mL portions of DCM. The solvent was removed in
vacuo from a water bath at 45 °C to give the free dipeptide. A
solution of the free dipeptide and 0.30 g (1.00 mmol) of Bspoc-
Gly-Cl in 10 mL of DCM was stirred in the presence of 50 mL
of saturated NaHCO3 for 15 min. The aqueous phase was
separated, and the organic layer was washed with 25 mL of
5% HCl. The organic layer was dried over MgSO4 and filtered,
and the solvent was removed in vacuo from a water bath at
45 °C to give the crude protected tripeptide [1H NMR (CDCl3)
δ 0.92 (d, 6), 1.25-1.80 (m, 12), 3.10 (d, 2), 3.90 (d, 2), 4.58 (q,
1), 4.75 (q, 1), 4.95 (s, 2), 5.20 (s, 2), 5.70 (t, 1), 6.21 (s, 1), 6.30
(s, 1), 6.78 (d, 1), 7.20-7.50 (m, 11)] which was dissolved in
10 mL of DCM and the solution added to a stirred mixture of
15.0 g of 35 (recovered from the run described above) in 40
mL of DCM. The mixture was stirred for 15 min and filtered,
and the silica was washed with three 20-mL portions of DCM.
The solvent was removed in vacuo from a water bath at 45 °C
to give the free tripeptide. A solution of the free tripeptide and
0.30 g (1.00 mmol) of Bspoc-Gly-Cl in 10 mL of DCM was
stirred in the presence of 50 mL of saturated NaHCO3 for 15
min. The aqueous phase was separated, and the organic layer
was washed with 25 mL of 5% HCl. The organic layer was
dried over MgSO4 and filtered, and the solvent was removed
in vacuo from a water bath at 45 °C to give the crude protected
tetrapeptide [1H NMR (CDCl3) δ 0.92 (d, 2), 1.35-1.85 (m, 12),
3.14 (d, 2), 3.97 (m, 4), 4.65 (q, 1), 4.85 (q, 1), 4.98 (s, 2), 5.20
(s, 2), 5.98 (t, 1), 6.32 (s, 1), 6.39 (s, 1), 6.92 (d, 1), 7.01 (s, 1),
7.15-7.42 (m, 11)] which was dissolved in 10 mL of DCM and
the solution added to a stirred mixture of 15.0 g of 35
(recovered from the run described above) in 40 mL of DCM.
The mixture was stirred for 15 min and filtered, and the silica
was washed with three 20-mL portions of DCM. The solvent
was removed in vacuo from a water bath at 45 °C to give the
free tetrapeptide which was stirred with a solution of 0.47 g
(0.92 mmol) of Fmoc-Tyr(Bn)-Cl in 10 mL of DCM and 50 mL
of saturated NaHCO3 for 20 min. The aqueous phase was
separated, and the organic layer was washed with 25 mL of
5% HCl. The organic layer was dried over MgSO4 and filtered,
and the solvent was removed in vacuo from a water bath at
45 °C to give 0.61 g (59%) of the crude protected peptide as a
yellow solid. TLC analysis showed that the crude product
contained Fmoc-Tyr(Bn)-OH and dibenzofulvene along with
the protected pentapeptide. Flash chromatography on silica
gel (230-400 mesh, 5 × 15 cm column) with 99% EtOAc/HOAc
as eluent gave 0.31 g (30% overall) of the protected pentapep-
tide as a colorless solid, mp 173-175 °C (lit.25a mp 178 °C); 1H
NMR (CDCl3) δ 0.82 (s, 6), 1.30-1.80 (m, 3), 2.85-3.20 (m, 4),
4.10 (m, 5), 4.25 (m, 3), 4.70 (m, 2), 4.85 (s, 4), 5.01 (d, 1), 5.25
(bs, 2), 6.75-7.80 (m, 27), 7.90 (bs, 1), 8.17 (bs, 1); [R] -17.1°
(c ) 0.55, DMF), lit. [R] -16.9° (c ) 0.9, DMF), also [R] -19.6°
(c ) 0.55, DMF).
Leu cin e En k ep h a lin . To a solution of 100 mg (0.10 mmol)
of Fmoc-Tyr(Bn)-Gly-Gly-Phe-Leu-OBn in 20 mL of 1:1 95%
EtOH/EtOAc in a 500-mL pressure bottle were added 50 mg
of palladium acetate and 50 mg of 10% Pd/C. The pressure
bottle was charged with 45 psi of hydrogen and shaken at room
temperature for 24 h. The catalyst was filtered, and the solvent
was removed in vacuo from a water bath at 45 °C to give an
oil which was triturated with ether and filtered to give 35 mg
(58%) of the free pentapeptide, mp 149-152 °C (lit.33 mp 155-
158 °C); [R] -25.8° (c ) 0.5, DMF), lit.34 [R] -26.1 (c ) 1.0,
DMF). The 1H NMR spectrum was superimposable on that
published by Garbay and co-workers27b [1H NMR (DMSO-d6)
δ 0.9 (m, 6), 1.45-1.70 (m, 3), 2.6, 2.8, 2.9, 3.1 (m, 4), 3.5 (m,
1), 3.6 (m, 2), 4.1 (m, 1), 4.50 (m, 1). 6.7, 7.0 (d, 4), 7.2 (m, 5),
7.9 (m, 2), 8.2 (m, 1), 8.6 (m, 1)]. For the optically pure amino
acid introduced using Bspoc protection (Phe) the standard
racemization test using a chiral GC column28 showed 0.11%
of the D-isomer.
Ack n ow led gm en t. We are indebted to the National
Science Foundation and the National Institutes of
Health for support of this work. The National Science
Foundation is also thanked for grants used to purchase
the high-field NMR spectrometers used in this research.
Su p p or tin g In for m a tion Ava ila ble: Selected additional
experimental procedures for synthesis of methyl, benzyl, and
tert-butyl esters of Bspoc-substituted amino acid and peptide
esters, studies of the stability of the Bspoc residue, and copies
of IR and NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(33) Anwer, M.; Spatola, A. F. Synthesis 1980, 929.
(34) Plucinski, T.; Kupryszewski, G. Pol. J . Chem. 1981, 55, 573.
J O982141D