Stereoselective synthesis of Boc-protected cis and trans-4-trifluoromethylprolines by asymmetric hydrogenation reactions

Article abstract of DOI:10.1002/1521-3773(20020503)41:9<1600::AID-ANIE1600>3.0.CO;2-V

Stereocontrolled synthesis of cis and trans-substituted prolines by a divergent approach, leads to the preparation of cis-(4S)- and trans-(4R)-trifluoromethyl-Lproline from hydroxyproline. The key pyrroline intermediates were subjected to hydrogenation (s

Full text of DOI:10.1002/1521-3773(20020503)41:9<1600::AID-ANIE1600>3.0.CO;2-V

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[10] Spectral data for 5: red-brown solid; m.p. 92 938C; 1H NMR
(300 MHz, [D6]benzene, TMS): d ˆ 0.15 (s, 6H), 1.17(s, 36H), 2.06
(s, 12H), 2.81 (s, 6H), 6.73 (s, 4H); 13C{1H} NMR (75.5 MHz,
[D6]benzene, TMS): d ˆ À3.2, 22.5, 25.8, 30.3, 30.6, 128.8, 139.1, 139.2,
143.6; 29Si{1H} NMR (59.6 MHz, [D6]benzene, TMS): d ˆ 31.4, 146.9
selectivity. In connection with our studies on bioactive and
highly ordered peptides, we undertook the synthesis of both
stereoisomers of 4-trifluoromethyl-l-proline. These building
blocks are expected to have profound conformational effects
on their host structures, which arise from the electronegative
nature of the trifluoromethyl group.
Our strategy for the preparation of the title compounds
employs asymmetric hydrogenation of the pyrrolines shown
in Scheme 1. For the synthesis of the cis isomer, the facial
ˆ
(Si Ge); HRMS m/z: calcd for C36H64GeSi3: 654.3536, found:
654.3531; UV/Vis (hexane) lmax(e): 237 (31700), 289 (8700), 430 nm
(5300).
[11] We recently reported stable germasilenes: a) 2-disilagermirene: V. Ya.
Lee, M. Ichinohe, A. Sekiguchi, N. Takagi, S. Nagase, J. Am. Chem.
Soc. 2000, 122, 9034; b) 1,2-disila-3-germacyclopenta-2,4-diene: V. Ya.
Lee, M. Ichinohe, A. Sekiguchi, J. Am. Chem. Soc. 2000, 122, 12604;
ˆ
c) (tBu2MeSi)2Si GeMes2: M. Ichinohe, Y. Arai, A. Sekiguchi, N.
Takagi, S, Nagase, Organometallics 2001, 20, 4141.
R1
OPG2
N
PG1
cis isomer
A
B
R1
OR2
N
PG1
R1
R2 = H or PG2
OH
Stereoselective Synthesis of Boc-Protected cis
and trans-4-Trifluoromethylprolines by
Asymmetric Hydrogenation Reactions**
N
PG1
trans isomer
Scheme 1. Strategies for the asymmetric hydrogenation of pyrroline
intermediates. A ˆ Sterically directed hydrogenation, B ˆ hydroxy-direct-
ed hydrogenation.
Juan R. Del Valle and Murray Goodman*
The effect of the proline residue on peptide conforma-
3]
tion[1 has been the impetus for the design of various
selectivity of the hydrogenation was expected to depend on
steric factors, which result from protection of the hydroxy
functionality as an ether or ester moiety. We were unable to
find previous syntheses of trans-substituted prolines that
exploit the potential for hydroxy-directed hydrogenation of
pyrroline intermediates. We envisioned this as a viable route
towards the trans-proline isomer as well as related analogues.
The retrosynthesis in Scheme 2 shows Boc-4-prolinone
(Boc ˆ tert-butoxycarbonyl) as a precursor to the desired
pyrrolines.
unnatural substituted prolines. These amino acid surrogates
have featured in a number of biologically active[4 7] and highly
ordered peptides.[8, 9] Prolines substituted at the 4-position
have been shown to enhance the thermal stability of collagen-
mimetic triple helices, with trans-4-fluoroproline yielding the
12]
most striking results.[10 The nature of the functional group
and the steric constraints imposed by the C4 substituent can
greatly influence the conformation of the pyrrolidine ring, as
well as the rate of cis trans isomerization about the amide
bond.[13 15] For these reasons, the preparation of 4-substituted
prolines is an attractive goal in peptidomimetic chemistry.
The synthesis of cis-4-phenylproline by a hydrogenolysis
reaction, which starts from hydroxyproline was recently
described by Hruby and co-workers.[16] In addition, Nevalai-
nen et al. reported a preparation of Fmoc-trans-4-methylpro-
line (Fmoc ˆ 9-fluorenylmethoxycarbonyl) by asymmetric
hydrogenation, which yields the desired isomer in a 6:1
diastereomeric ratio before purification.[17] Although these
and other syntheses of 4-substituted prolines are in the
literature,[18 21] a number of desirable targets continue to pose
a synthetic challenge. In particular, several trans-substituted
prolines have been difficult to synthesize with high stereo-
O
F3C
CH2OR1
CO2CH3
Hyp-OMe
N
N
Boc
Boc
R
1 = H, or PG2
Scheme 2. Retrosynthesis of Boc-4-trifluormethyl-l-proline; Hyp ˆ hy-
droxyproline.
The
synthesis
of
Boc-4-trifluoromethyl-l-proline
(Scheme 3) begins with the methyl ester of commercially
available and inexpensive trans-4-hydroxyproline (1). Boc-
protection was carried out under normal conditions, followed
by oxidation using trichloroisocyanuric acid and catalytic
2,2,6,6-tetramethyl-1-piperidinoxyl (free radical; TEMPO)[22]
to give ketone 3.
With the protected prolinone in hand, the trifluoromethyl
group was introduced by treatment of 3 with trimethyl(tri-
fluoromethyl)silane, in the presence of a fluoride initiator[23, 24]
to afford the tertiary alcohol 4 in 56% yield. Compound 4 was
[*] Prof. Dr. M. Goodman, J. R. Del Valle
Department of Chemistry and Biochemistry
University of California, San Diego
La Jolla, CA 92093 (USA)
Fax : (‡1)858-534-0202
E-mail: mgoodman@ucsd.edu
[**] The authors wish to thank Dr. Peter Gantzel for X-ray diffraction
studies. This work was supported by a grant from the NSF (DMR-
0111617). J.R.D. gratefully acknowledges the support of a San Diego
Fellowship; Boc ˆ tert-butoxycarbonyl.
a
single diastereomer which we presumed to be the
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
2S,4S isomer from the steric implications of the reaction.
1600
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HO
HO
O
F3C
F3C
F3C
a
b
b
a
CO2CH3
CO2CH3
CH2OTBS
CH2OH
CO2H
CO2CH3
N
H
N
N
N
N
N
94%
94%
94%
78%
Boc
2
Boc
3
Boc
Boc
Boc
1
8
9
7
OH
OH
c
85%
F3C
F3C
c
d
e
89%
CO2CH3
CH2OH
F3C
F3C
F3C
N
N
56%
94%
Boc
4
Boc
5
b
d
CH2OH
CO2H
CH2OH
N
N
N
96%
91%
Boc
Boc
Boc
OH
N
F3C
11
12
F3C
10
f,g
Scheme 4. Reagents and conditions: a) H2 (1 atm), Pd/C, EtOAc, RT, 8 h,
99:1 d.r. after flash chromatography (See Table 1); b) NaClO, NaClO2,
TEMPO, MeCN:pH 6.7NaH 2PO4 buffer (0.67m), 458C, 24 h; c) TBAF,
THF, RT, 30 min; d) H2 (1 atm), 2 mol% [Ir(cod)(py)PCy3], CH2Cl2, RT,
4 h, 158:1 d.r. (see Table 2).
CH2OTBS
CH2OTBS
N
76%
Boc
Boc
6
7
Scheme 3. Reagents and conditions: a) Boc2O, triethylamine (TEA),
CH2Cl2, 18 h; b) Trichloroisocyanuric acid, TEMPO (cat.), CH2Cl2,
20 min, 08C; c) 2 equiv CF3TMS (TMS ˆ trimethylsilyl), 2.1 equiv TBAF
(tetrabutylammonium fluoride), 08C !RT, 24 h; d) NaBH4, LiCl,
EtOH:THF (2:1), RT, 18 h; e) TBDMSCl, TEA, 4-dimethylaminopyridine
(DMAP), CH2Cl2, RT, 18 h; f) TosCl (Tos ˆ tosyl), NaH, THF, 08C !RT,
2 h; g) 2 equiv tBuOK, THF, À408C, 2 h.
Oxidation of 8 was carried out using a slight modification to
the method described by Zhao et al.[26] The Boc-amino acid 9
was sufficiently pure after work up for use in peptide
synthesis. The absolute stereochemistry of Boc-(4S)-trifluor-
omethyl-l-proline (9) was confirmed by X-ray diffraction
(Figure 1).
The dehydration of 4 posed a challenge as few reports deal
with the effects of trifluoromethyl groups on this transforma-
tion. In our initial efforts, reaction of 4 with SOCl2/pyridine,
para-toluenesulfonic acid/benzene, and POCl3/DBU yielded
none of the desired product. A study on the dehydration of
tertiary a-trifluoromethyl alcohols carried out by Nagai and
co-workers[25] found that base-promoted elimination of the
corresponding tosylates gave the desired olefins in satisfac-
tory yield. Therefore, 4 was treated with lithum borohydride
and the resulting primary alcohol was selectively protected as
the tert-butyl trimethylsilyl (TBDMS) ether to give 6.
Tosylation of the tertiary alkoxide of 6 proceeded normally
and treatment of the product with potassium tert-butoxide
furnished the key pyrroline intermediate 7 in good yield.
Analysis of the crude product mixture revealed a small
amount (8%) of the 3,4-olefin that was removed during
purification.
Heterogenous hydrogenation of 7 was carried out under a
variety of conditions (Table 1). Curiously, hydrogenations
with Pd/C resulted in nearly complete removal of the TBDMS
protecting group. Despite this, good facial selectivities were
observed with the sterically directed cis 2S,4S isomer 8 as the
major product in each case. The best selectivity, a 15:1
cis:trans ratio, was obtained by using 5% Pd/C in ethyl
acetate. The minor diastereomer can be removed by column
chromatography to give the cis product 8 in 78% isolated
yield and >98% diastereomeric excess (Scheme 4).
Figure 1. Crystal Structure of 9.
To prepare the pyrroline intermediate for hydroxy-directed
asymmetric hydrogenation, 7 was deprotected to unmask the
primary alcohol. The results of the hydrogenations of 10 are
summarized in Table 2.
Prior to attempting homogenous reduction, some hetero-
geneous catalysts were tested. Because the previous hydro-
Table 2. Hydrogenation of pyrroline 10.
Table 1. Hydrogenations of pyrroline 7.
Catalyst
Solvent
cis:trans[a]
Yield[b]
Catalyst
Solvent
cis:trans[a]
Yield[b]
Raney-Ni
5% Pd/C
5% Pd/C
[Ir(cod)(py)PCy3][c]
[Ir(cod)(py)PCy3][d]
MeOH
PhH
EtOAc
CH2Cl2
CH2Cl2
70:30
52:48
55:45
5:95
98%
92%
95%
96%
95%
10% Pd/C
5% Pd/C
5% Pd/C
Rh/C
THF
90:10
92:8
94:6
86%
81%
85%
UD
EtOH
EtOAc
EtOAc
78:22
1:158
[a] Determined by 19F NMR analysis of crude mixtures. [b] Crude com-
[a] Determined by 19F NMR analysis of crude mixtures. [b] Crude
bined yield (8 ‡ 11). UD ˆ undetermined.
combined yield (8 ‡ 11). [c] 15 mol% catalyst. [d] 2 mol% catalyst.
Angew. Chem. Int. Ed. 2002, 41, No. 9
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genations with Pd/C heavily favored the cis product despite
loss of the TBDMS group, we did not expect a significant
coordination of the hydroxy group to the palladium catalyst.
Nevertheless, reduction of 10 with 5% Pd/C gave appreciable
amounts of the trans isomer. After careful chromatographic
separation the 1:1 diastereomeric ratio rendered these con-
ditions suitable for preparing both isomers simultaneously. In
attempting homogenous hydrogenation, however, we found a
divergent approach to be equally practical for the preparation
of these building blocks.
Among the numerous catalysts available for homogenous
hydrogenation,[27, 28] the IrI compound introduced by Crabtree
et al.[29] has consistently shown excellent selectivity in the
32]
hydroxy-directed reduction of cyclic olefins.[30 By employ-
ing the IrI complex, we observed a dramatic increase in the
trans selectivity.[33] Under optimal conditions, treatment of 10
with 2 mol% of [Ir(cod)(py)PCy3] (cod ˆ cyclootadiene, py ˆ
pyridine) under H2 resulted in complete conversion into the
desired product. The trans:cis ratio was 158:1, measured by 19
F
NMR spectroscopy. Subsequent removal of the catalyst by
filtration through a plug of silica gel provided Boc-(4R)-
trifluoromethyl-l-prolinol (11) in a diastereomerically pure
form.
Prolinol 11 was oxidized as described above in 96% yield.
The 19F NMR spectrum of 12 contained two doublet signals in
a 1.5:1 ratio. Incremental increases in temperature resulted in
the gradual coalescence of the NMR peaks of 12, confirming
the rotamer effect and ruling out epimerization during the
oxidation. Thus, the trans isomer, Boc-(4R,2S)-trifluoro-
methylproline, was synthesized in good overall yield and with
complete diastereoselectivity, from hydroxyproline.
In summary, we have described the preparation of both cis
and trans-4-trifluoromethyl-l-proline employing stereoselec-
tive substrate-directed hydrogenation reactions. Most note-
worthy is the outstanding facial selectivity achieved in the
reduction of 10 with the Crabtree catalyst (158:1 d.r.). These
results will be applied in the synthesis of various substituted
prolines for incorporation into peptides and peptidomimetics.
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Received: January 11, 2002 [Z18513]
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TBAF by column chromatography as it has an adverse effect on the IrI
catalyst.
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1602
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4109-1602 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 9