Fluorous (trimethylsilyl)ethanol: A new reagent for carboxylic acid tagging and protection in peptide synthesis

Article abstract of DOI:10.1021/jo052569u

Starting with a fluorous analogue of 2-(trimethylsilyl)ethanol, we have designed an easy method for preparing a new fluorous tag (^FTMSE) for the protection of carboxylic acids. Because mild conditions are employed in the tag cleavage (TBAF in the presence of 4 A molecular sieves, which prevent racemization), this tag can be advantageously used in the synthesis of peptides and modified peptides, as we have demonstrated with several examples, including the fluorous synthesis of short α- and β-peptides as well as of modified fluorinated retropeptides.

Full text of DOI:10.1021/jo052569u

SCHEME 1
Fluorous (Trimethylsilyl)ethanol: A New Reagent
for Carboxylic Acid Tagging and Protection in
Peptide Synthesis
Santos Fustero,*,†,‡ Amador Garc´ıa Sancho,‡ Gema Chiva,‡
Juan F. Sanz-Cervera,†,‡ Carlos del Pozo,† and
Jose´ Luis Acen˜a‡
means of fluorous solid-phase extraction techniques (F-SPE),
and identifying and analyzing the synthetic intermediates by
means of spectroscopic methods such as NMR.3,4
Departamento de Qu´ımica Orga´nica, UniVersidad de Valencia,
E-46100 Burjassot, Spain, and Laboratorio de Mole´culas
Orga´nicas, Centro de InVestigacio´n Pr´ıncipe Felipe,
E-46013 Valencia, Spain
A fluorous synthesis usually entails attaching a highly
fluorinated moiety (fluorous tag) to a chosen substrate. Not only
must the tag be compatible with the subsequently employed
reaction conditions, but it should also be easy to remove at the
end of the synthetic sequence.5 Thus, one of the difficulties that
the currently available tags present in the fluorous preparation
of peptides is that of cleavage, in which a partial epimerization
of the individual peptidic residues occurs. This is a serious
problem that must be addressed in order to apply fluorous
procedures to efficient peptide preparation. To test the usefulness
of fluorous tagging in the synthesis of peptides and modified
peptides, we examined its implementation in the synthesis of
partially modified retropeptides (PMR) 1, which our group had
described from (R-trifluoromethyl)acryloyl chloride 2 and
various amino acids, both in solution6 and on solid phase7
(Scheme 1). These peptidomimetic molecules contain a con-
figurationally stable trifluoromethyl unit8 which is, however,
easily prone to epimerization under acidic or basic conditions,
and thus they constitute an interesting example of the possibili-
ties of fluorous chemistry.
In our first attempt to adapt our synthesis to fluorous
techniques, we tried a simple fluorous tag derived from
commercially available 3-(perfluorooctyl)propanol 3.9 The
standard coupling of this alcohol with Fmoc-protected L-valine
afforded fluorous amino acid 4 (Scheme 2).9b After deprotection
of the Fmoc group with piperidine, free amine 5 was reacted
with (R-trifluoromethyl)acryloyl chloride 210 to obtain the
Michael acceptor 6 in good yield. The key aza-Michael addition
was tested with L-valine tert-butyl ester hydrochloride under
what we had previously established to be optimal conditions
santos.fustero@uV.es
ReceiVed December 13, 2005
Starting with a fluorous analogue of 2-(trimethylsilyl)ethanol,
we have designed an easy method for preparing a new
fluorous tag (FTMSE) for the protection of carboxylic acids.
Because mild conditions are employed in the tag cleavage
(TBAF in the presence of 4 Å molecular sieves, which
prevent racemization), this tag can be advantageously used
in the synthesis of peptides and modified peptides, as we
have demonstrated with several examples, including the
fluorous synthesis of short R- and â-peptides as well as of
modified fluorinated retropeptides.
Fluorous chemistry is emerging as a powerful technique for
the synthesis of organic molecules in a high-throughput manner1
because the isolation of highly fluorinated (fluorous) compounds
from nonfluorous reagents or byproducts can be performed by
simple liquid-liquid or solid-liquid extractions with per-
fluorinated solvents or fluorous silica gel, respectively.2 More-
over, since the reactions of fluorous substrates and/or reagents
are conducted in solution, they constitute an alternative to
established solid-phase methods. One obvious field for the
application of fluorous chemistry is the preparation of peptides.
Although peptide synthesis is routinely performed on solid
phase, fluorous chemistry can offer numerous advantages, such
as the possibility of working on a larger scale, better solution
kinetics compared to solid phase, purifying intermediates by
(3) For the fluorous synthesis of peptidic chains, see: (a) Mizuno, M.;
Goto, K.; Miura, T.; Hosaka, D.; Inazu, T. Chem. Commun. 2003, 972-
973. (b) Mizuno, M.; Goto, K.; Miura, T.; Matsuura, T.; Inazu, T.
Tetrahedron Lett. 2004, 45, 3425-3428.
(4) Fluorous moieties have also been attached to peptides at the end of
a solid-phase synthesis so that fluorous techniques could be used for their
purification. See: (a) de Visser, P. C.; van Helden, M.; Filippov, D. V.;
van der Marel, G. A.; Drijfhout, J. W.; van Boom, J. H.; Noort, D.;
Overkleeft, H. S. Tetrahedron Lett. 2003, 44, 9013-9016. (b) Montanari,
V.; Kumar, K. J. Am. Chem. Soc. 2004, 126, 9528-9529.
(5) Zhang, W. Curr. Op. Drug Discuss. DeV. 2004, 7, 784-797.
(6) Sani, M.; Bruche´, L.; Chiva, G.; Fustero, S.; Piera, J.; Volonterio,
A.; Zanda, M. Angew. Chem., Int. Ed. 2003, 42, 2060-2063.
(7) Volonterio, A.; Chiva, G.; Fustero, S.; Piera, J.; Sa´nchez-Rosello´,
M.; Sani, M.; Zanda, M. Tetrahedron Lett. 2003, 44, 7019-7022.
(8) Zanda, M. New J. Chem. 2004, 28, 1401-1411.
(9) For the use of fluorous alcohols as phase tags, see: (a) Wipf, P.;
Methot, J.-L. Org. Lett. 1999, 1, 1253-1255. (b) Zhang, W.; Lu, Y. Org.
Lett. 2003, 5, 2555-2558. (c) Nagashima, T.; Zhang, W. J. Comb. Chem.
2004, 6, 942-949.
(10) (a) Hanzawa, Y.; Suzuki, M.; Kobayashi, Y.; Taguchi, T.; Iitaka,
Y. J. Org. Chem. 1991, 56, 1718-1725. (b) Yamazaki, T.; Ichige, T.; Takei,
S.; Kawashita, S.; Kitazume, T.; Kubota, T. Org. Lett. 2001, 3, 2915-
2918.
† Universidad de Valencia.
‡ Centro de Investigacio´n Pr´ıncipe Felipe.
(1) (a) Studer, A.; Hadida, S.; Ferritto, R.; Kim, S.-Y.; Jeger, P.; Wipf,
P.; Curran, D. P. Science 1997, 275, 823-826. (b) Zhang, W. Tetrahedron
2003, 59, 4475-4489. (c) Handbook of Fluorous Chemistry; Gladysz, J.
A., Curran, D. P., Horva´th, I. T., Eds.; Wiley-VCH: Weinheim, 2004.
(2) Curran, D. P. Synlett 2001, 1488-1496.
10.1021/jo052569u CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/10/2006
J. Org. Chem. 2006, 71, 3299-3302
3299

SCHEME 2
SCHEME 3
SCHEME 4
(DABCO, CCl4)6 to furnish compound 7 as a mixture of
diastereoisomers in a 27:1 ratio. This selectivity, determined
with the aid of 19F NMR spectroscopy, was not only comparable
to the diastereomeric ratio previously reported using the
corresponding nonfluorous compound (33:1),6 but much better
than that observed on solid phase (4.8:1).7 Obviously, both
reactions in solution (fluorous and nonfluorous) benefit from
the same transition state that determines the high level of
diastereoselectivity, in contrast to the results obtained on solid
phase. It should also be noted that all of the synthetic
intermediates were easily purified through fluorous solid-phase
extraction (F-SPE) to remove any excess nonfluorinated re-
agents, thereby speeding up and simplifying the purification
steps.11
Having proved that the attachment of a simple fluorous tag
was compatible with the synthetic plan and did not affect the
diastereoselectivity of the aza-Michael process, we unfortunately
found that its removal was an impossible task, due to the fact
that mild reaction conditions were required to preserve the
peptidic structure, particularly the configuration of the CF3
group. Although several transesterification reactions were tried,
they were ineffective in all cases.12 For this reason, we embarked
on the development of a new tag that would be easier to remove.
We reasoned that a fluorous analogue of 2-(trimethylsilyl)-
ethanol would react with carboxylic acids to afford fluorous
(trimethylsilyl)ethyl (FTMSE) esters, and the later removal of
the resulting fluorous tag should be carried out easily by a
transesterification reaction in the presence of TBAF (Scheme
3).
commercially available 3-(perfluorooctyl)propyl iodide 8 (Scheme
4). Metalation of 8 with tert-butyllithium followed by reaction
with either chloro(dimethyl)vinylsilane (route a) or allylchloro-
dimethylsilane (route b) afforded compounds 9 and 10, respec-
tively. While hydroboration of 9 with several borane reagents
(BH3‚SMe2, BH3‚THF complex, 9-BBN) only produced a low
yield (15% using 9-BBN, route a) of the desired alcohol 11,
ozonolysis of 10 and subsequent reduction of the resulting
ozonide with LiAlH4 was a much more effective route to
synthetically useful yields of 11 (80%, route b).13
Coupling the thus-obtained fluorous alcohol 11 with N-Fmoc-
protected L-valine or L-alanine gave compounds 12a and 12b,
respectively, in good yield after fluorous SPE purification
(Scheme 5). At this point, we decided to test the detagging
conditions on 12a and found that its treatment with TBAF in
the presence of benzyl bromide removed both the fluorous tag
and the Fmoc group to afford valine benzyl ester 13 with no
loss of optical purity. In this case, purification by means of
F-SPE served to remove the fluorinated byproducts. In contrast,
deprotection of the Fmoc group with piperidine yielded free
amines 14a,b with the fluorous chain intact.
We next used fluorous amino acids 14 to prepare some
examples of simple peptides. Thus, condensation with different
N-Boc-protected R- or â-amino acids afforded compounds 15a-
e, which were detagged as before to produce dipeptides 16a-e
(Table 1). Starting from 15e, the fluorous tag was alternatively
removed in the presence of allyl bromide to afford dipeptide
16f. It was also possible to obtain directly the corresponding
carboxylic acid as demonstrated in the reaction of 15e with
TBAF solely, to produce 16g. For the preparation of longer
peptidic chains, fluorous dipeptide 15a was deprotected with
Thus, the reagent 2-(dimethyl-(3-(perfluorooctyl)propyl)silyl)-
ethanol 11 (FTMSE-OH) was prepared in two steps from
(11) Alternatively, purification by means of standard flash column
chromatography was also possible.
(12) For instance, enzymatic transesterification with Candida rugosa
lipase (Beier, P.; O’Hagan, D. Chem. Commun. 2002, 1680-1681) yielded
the desired cleaved product without epimerization, but in very low
conversion (between 5 and 10%), even after 3 days at rt. (CH3)3SnOH
(Nicolaou, K. C.; Estrada, A. A.; Zak, M.; Lee, S. H.; Safina, B. S. Angew.
Chem., Int. Ed. 2005, 44, 1378-1382), Verkade’s superbase (Ilankumaran,
P.; Verkade, J. G. J. Org. Chem. 1999, 64, 3086-3089), and distannoxanes
(Otera, J.; Dan-oh, N.; Nozaki, H. J. Org. Chem. 1991, 56, 5307-5311)
also failed to catalyze the ester hydrolysis.
(13) Surprisingly, the ozonide derived from 9 was so stable that it failed
to react with Me2S or NaBH4 and had to be reduced with LiAlH4.
3300 J. Org. Chem., Vol. 71, No. 8, 2006

SCHEME 5
SCHEME 6
TABLE 1. Synthesis of Dipeptides 15 and 16
SCHEME 7
14
R
15
R1
n
yielda (%)
16
R2
yielda (%)
14a i-Pr 15a R-Me
15b R-Ph
0
0
1
0
0
80
64
85
87
80
16a Bn
16b Bn
16c Bn
16d Bn
16e Bn
16f allyl
16g Hb
92
79
92
85
81
82
78
15c â-Me
14b Me 15d R-s-Bu
15e R-Bn
a Isolated yields. b The reaction was carried out in the presence of TBAF
only. FTMSE ) CF3(CF2)7(CH3)3SiMe2(CH2)2.
TFA and the corresponding free amine was coupled with N-Boc-
L-phenylglycine to give 17, which was detagged to yield
tripeptide 18 (Scheme 6).
TABLE 2. Synthesis of Retropeptides 20 and 1
yielda
(%)
dr
dr
yielda
(%)
20
R
X
(fluorous)b (nonfluorous)c
1
Finally, the fluorous synthesis of retropeptides 1 with the new
tag was also carried out starting from compound 14a (Scheme
7). The Michael aceptor 19 was produced in good yield under
the usual conditions, and the subsequent addition of a variety
of amino acids afforded fluorous retropeptides 20a-d in
essentially the same diastereomeric ratios as in the corresponding
nonfluorous experiments6,14 (Table 2). However, in this case
the removal of the fluorous tag was more problematic because
the reaction with TBAF/BnBr caused the epimerization of the
CF3 group, thus giving an almost equimolecular mixture of
diastereoisomers. To circumvent this problem, we added
activated 4 Å molecular sieves to minimize the presence of
water, which we thought might be responsible for the epimer-
ization.15 Retropeptides 1a-d were thus obtained with no
variation in their diastereomeric ratios compared to their
20a i-Pr
20b i-Bu Bn
20c s-Bu t-Bu
Bn
87
99
92
88
39:1
21:1
27:1
15:1
38:1
11:1
23:1
14:1
1a
1b
1c
1d
77
70
60d
81
20d Me
Me
a Isolated yields. b Determined by 19F NMR spectroscopy in the crude
reaction mixture. c Reference 6. d 73% brsm yield.
precursors 20. After F-SPE extraction, standard column chro-
matography on silica gel was used to isolate pure retropeptides
1, the spectroscopic data of which was identical to that for the
same compounds prepared with nonfluorous precursors.16
In summary, we have prepared a new fluorous alcohol for
the convenient protection and tagging of carboxylic acids and
(15) Rigby, J. H.; Laxmisha, M. S.; Hudson, A. R.; Heap, C. H.; Heeg,
M. J. J. Org. Chem. 2004, 69, 6751-6760.
(16) Retropeptides 1a,b,d were previously described in ref 6. Compound
1c was also synthesized in two steps in a manner analogous to that described
therein.
(14) The same reactions on solid phase (ref 7) also showed much lower
diastereoselectivities. For instance, the corresponding carboxylic acids of
compounds 20a and 20d were obtained after release from the solid support
in 15:1 and 2.1:1 diastereomeric ratios, respectively.
J. Org. Chem, Vol. 71, No. 8, 2006 3301

δ 18.5, 28.4, 38.6, 48.4, 55.8, 67.3, 80.4, 127.1, 128.3, 128.6, 128.8,
129.5, 135.5, 136.7, 155.6, 171.1, 172.5. HRMS (FAB): calcd for
C24H31N2O5 (M+ + 1) 427.2233, found 427.2233.
demonstrated its usefulness in the fluorous synthesis of peptides
and retropeptides, even on substrates that are easily epimerized,
thanks to the mild reaction conditions needed for the removal
of the fluorous (trimethylsilyl)ethyl (FTMSE) group. Further
investigations on the applications of this fluorous tag are
currently underway.
Synthesis of Boc-Phe-Ala-OCH2CHdCH2, 16f. Following
general procedure A (employing allyl bromide), from 15e (26 mg,
0.029 mmol), 9 mg of 16f was obtained as a colorless oil (82%
yield). [R]25 ) -25.0 (c 0.4, CHCl3). 1H NMR (CDCl3, 300
D
MHz): δ 1.31 (d, J ) 7.2 Hz, 3H), 1.35 (s, 9H), 3.00-3.03 (m,
2H), 4.29 (br, 1H), 4.43-4.56 (m, 3H), 4.91 (br, 1H), 5.18-5.29
(m, 2H), 5.76-5.89 (m, 1H), 6.35 (d, J ) 6.9 Hz, 1H), 7.13-7.27
(m, 5H). 13C NMR (CDCl3, 75.5 MHz): δ 18.5, 28.2, 38.3, 48.2,
55.7, 66.0, 80.3, 118.8, 127.0, 128.7, 129.4, 131.4, 136.5, 155.3,
170.7, 172.1. HRMS (FAB): calcd for C20H29N2O5 (M+ + 1)
377.2076, found 377.2065.
Experimental Section
Synthesis of Allyl(dimethyl)(3-(perfluorooctyl)propyl)silane,
10. A solution of 3-(perfluorooctyl)propyl iodide 8 (2.0 g, 3.4 mmol)
in Et2O (70 mL) was added to a flask containing a stirred solution
of t-BuLi (1.7 M in pentane, 5.0 mL, 8.5 mmol) at -78 °C, and
the mixture was warmed to -10 °C. After being stirred for 30 min,
the reaction was again cooled to -78 °C and a solution of
allylchlorodimethylsilane (1.2 mL, 5.1 mmol) in Et2O (12 mL) was
added. After the mixture was stirred at rt for 5 h, the reaction was
quenched with water and the phases were separated. The organic
layer was washed with brine, dried over Na2SO4, and concentrated
at reduced pressure. The crude material was purified by means of
flash column chromatography with hexane to give 1.3 g of 10 as
a colorless oil (70% yield). Rf ) 0.96 (hexane). 1H NMR (CDCl3,
300 MHz): δ 0.02 (s, 6H), 0.57-0.63 (m, 2H), 1.51-1.67 (m,
4H), 1.99-2.17 (m, 2H), 4.82-4.89 (m, 2H), 5.70-5.84 (m, 1H).
Synthesis of Boc-Phe-Ala-OH, 16g. Following general proce-
dure A (employing TBAF only), from 15e (17 mg, 0.019 mmol),
5 mg of 16g was obtained as a white solid (78% yield). Mp: 92-
93 °C. [R]25 ) +0.7 (c 0.5, CHCl3). 1H NMR (CDCl3, 300
D
MHz): δ 1.22-1.32 (m, 12H), 2.97 (br, 2H), 4.41 (br, 2H), 5.29
(br, 1H), 6.88 (br, 1H), 7.11-7.20 (m, 5H). 13C NMR (CDCl3, 75.5
MHz): δ 18.2, 28.4, 38.6, 48.7, 55.8, 80.7, 127.2, 128.8, 129.6,
136.7, 156.0, 171.8, 176.1. HRMS (FAB): calcd for C17H25N2O5
(M+ + 1) 337.1763, found 337.1757.
General Procedure for the Detagging of Fluorous Retropep-
tides (General Procedure B). A 0.01 M solution of TBAF (1.3
equiv) in THF was stirred over powdered, activated 4 Å molecular
sieves (ca. 200 mg/mL of TBAF solution) for 20 min, after which
a solution of the corresponding fluorous retropeptide (1.0 equiv)
in THF (0.1 M) and BnBr (1.5 equiv) was added. After the mixture
was stirred at rt for 1.5 h, the crude was filtered, concentrated at
reduced pressure, and purified by means of F-SPE. The resulting
mixture of retropeptides was separated with the aid of flash column
chromatography.
13C NMR (75.5 MHz, CDCl3): δ -3.4, 15.2, 15.4 (t, JCF ) 3.7
3
Hz), 23.5, 35.1 (t, 2JCF ) 22.7 Hz), 113.6, 135.2, (the signals from
the C8F17 group were obscured due to their low intensity). 19F NMR
(CDCl3, 282.4 MHz): δ -81.3 (t, 3JFF) 8.4 Hz, 3F), -114.9 (br,
2F), -122.4 (br, 6F), -123.2 (br, 2F), -124.1 (br, 2F), -126.6
(br, 2F).
Synthesis of 2-(Dimethyl-(3-(perfluorooctyl)propyl)silyl)-
ethanol, 11. Ozone was bubbled into a cold (-78 °C) solution of
10 (1.02 g, 1.82 mmol) in CH2Cl2 (90 mL) until a blue color
appeared. The reaction mixture was then concentrated at reduced
pressure. The residue was dissolved in Et2O (45 mL) and cooled
to 0 °C, and LiAlH4 (270 mg, 7.2 mmol) was added. After the
mixture was stirred at rt for 16 h, the reaction was quenched with
0.27 mL of water, followed by 0.27 mL of NaOH (10% aq) and
1.08 mL of water. The suspension was filtered, dried over Na2-
SO4, and concentrated at reduced pressure. The crude material was
purified by means of flash chromatography (hexane/EtOAc 4:1) to
give 820 mg of 11 as a white solid (80% yield). Rf ) 0.36 (hexane/
EtOAc 4:1). Mp: 41-42 °C. 1H NMR (CDCl3, 300 MHz) δ 0.04
(s, 6H), 0.57-0.63 (m, 2H), 0.95-1.01 (m, 2H), 1.39 (br, 1H),
1.56-1.67 (m, 2H), 1.99-2.16 (m, 2H), 3.71-3.77 (m, 2H). 13C
Synthesis of BnO-Val-CF3-Ile-OtBu, 1c. Following general
procedure B, from 20c (22 mg, 0.023 mmol), 7 mg of 1c was
obtained as a white solid (60% yield, 73% brsm yield). Mp: 48-
50 °C. [R]25 ) +7.1 (c 1.1, CHCl3). 1H NMR (300 MHz,
D
CDCl3): δ 0.77-0.82 (m, 9H), 0.88 (d, J ) 6.9 Hz, 3H), 1.00-
1.14 (m, 1H), 1.33-1.45 (m, 1H), 1.49 (s, 9H), 1.53-1.63 (m,
1H), 1.77 (br, 1H), 2.11-2.22 (m, 1H), 2.91-3.03 (m, 4H), 4.55
(dd, J ) 8.8, 4.7 Hz, 1H), 5.05 (d, J ) 12.2 Hz, 1H), 5.14 (d, J )
12.2 Hz, 1H), 7.24-7.32 (m, 5H), 7.49 (d, J ) 8.8 Hz, 1H). 13C
NMR (CDCl3, 75.5 MHz): δ 12.0, 15.8, 17.9, 19.4, 25.9, 28.4,
31.2, 38.9, 45.8 (q, 3JCF ) 2.9 Hz), 51.3 (q, 2JCF ) 24.7 Hz), 57.7,
1
67.4, 67.5, 81.9, 124.9 (q, JCF ) 280.0 Hz), 128.7, 128.8, 128.9,
3
135.7, 166.8 (q, JCF ) 1.7 Hz), 172.1, 172.0, 174.9; 19F NMR
3
NMR (CDCl3, 75.5 MHz) δ -3.0, 15.2 (t, JCF) 3.7 Hz), 15.7,
(CDCl3, 282.4 MHz) δ -66.7 (d, JHF ) 8.7 Hz, 3F). HRMS
(FAB): calcd for C26H40F3N2O5 (M+ + 1) 517.2889, found
517.2901.
20.8, 34.9 (t, 2JCF) 21.9 Hz), 60.2, (the signals from the C8F17 group
were obscured due to their low intensity). 19F NMR (CDCl3, 282.4
3
MHz): δ -81.3 (t, JFF) 10.5 Hz, 3F), -114.9 (br, 2F), -122.4
(br, 6F), -123.2 (br, 2F), -124.1 (br, 2F), -126.6 (br, 2F).
General Procedure for the Detagging of Fluorous Peptides
(General Procedure A). To a stirred solution of the corresponding
fluorous peptide (1.0 equiv) in THF (0.01 M) were added TBAF
(1 M in THF, 1.3 equiv) and benzyl or allyl bromide (1.5 equiv).
After the mixture was stirred at rt for 1 h, the crude was
concentrated at reduced pressure and purified by means of F-SPE.
Synthesis of Boc-Phe-Ala-OBn, 16e. Following general pro-
cedure A (employing BnBr), from 15e (13 mg, 0.015 mmol), 5
Acknowledgment. We thank the Ministerio de Educacio´n
y Ciencia (BQU2003-01610) and the Generalitat Valenciana
of Spain (GR03-193 and GV05/079) for financial support.
A.G.S. thanks the Centro de Investigacio´n Pr´ıncipe Felipe
(CIPF) for a predoctoral fellowship, and C.P. thanks the MEC
for a Ramo´n y Cajal contract.
Supporting Information Available: Experimental procedures
and characterization data for compounds 1a-b, 1d, 4-7, 9, 12-
15, 16a-d, and 17-20 and copies of NMR spectra of all new
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
mg of 16e was obtained as a colorless oil (81% yield). [R]25
)
D
1
-6.0 (c 1.35, CHCl3). H NMR (CDCl3, 300 MHz): δ 1.29 (d, J
) 7.2 Hz, 3H), 1.33 (s, 9H), 2.99 (d, J ) 7.0 Hz, 2H), 4.32 (br,
1H), 4.45-4.55 (m, 1H), 5.02 (br, 1H), 5.08 (s, 2H), 6.52 (d, J )
6.6 Hz, 1H), 7.11-7.30 (m, 10H). 13C NMR (CDCl3, 75.5 MHz):
JO052569U
3302 J. Org. Chem., Vol. 71, No. 8, 2006