Synthesis of Fmoc-protected trans-4-methylproline

Article abstract of DOI:10.1021/jo005726s

Fmoc-protected trans-4-methylproline was synthesized starting from D-serine. The chiral scaffold of serine in the form of olefinated Garner's aldehyde 3 was used to control the diastereoselective formation of the new stereocenter on the hydrogenation of allylic alcohol 4. The diastereoselectivity (syn/anti ratio) of the process was 86:14, attained with Raney nickel. Hydrogen migration seems not to be the sole factor lowering the diastereoselectivity, as nickel is known not to promote doublebond migration. Instead, the moderate stereocontrol is attributed to the mobility of the side chain of 4, which allows the attack of hydrogen on both faces of the olefin (open transition state). A series of transformations led to ring precursor 8, which after recrystallization afforded the syn diastereoisomer in dr = 95:5. Protected trans-4-methylproline 11 was obtained from 8 in a straightforward fashion.

Full text of DOI:10.1021/jo005726s

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J . Org. Chem. 2001, 66, 2061-2066
2061
Syn th esis of F m oc-P r otected tr a n s-4-Meth ylp r olin e
Marta Nevalainen, Pasi M. Kauppinen,† and Ari M. P. Koskinen*
Laboratory of Organic Chemistry, Department of Chemical Technology, Helsinki University of Technology,
FIN-02015 HUT, Finland
ari.koskinen@hut.fi
Received November 8, 2000
Fmoc-protected trans-4-methylproline was synthesized starting from D-serine. The chiral scaffold
of serine in the form of olefinated Garner’s aldehyde 3 was used to control the diastereoselective
formation of the new stereocenter on the hydrogenation of allylic alcohol 4. The diastereoselectivity
(syn/anti ratio) of the process was 86:14, attained with Raney nickel. Hydrogen migration seems
not to be the sole factor lowering the diastereoselectivity, as nickel is known not to promote double-
bond migration. Instead, the moderate stereocontrol is attributed to the mobility of the side chain
of 4, which allows the attack of hydrogen on both faces of the olefin (open transition state). A series
of transformations led to ring precursor 8, which after recrystallization afforded the syn
diastereoisomer in dr ) 95:5. Protected trans-4-methylproline 11 was obtained from 8 in a
straightforward fashion.
In tr od u ction a n d Ba ck gr ou n d
R-carbon, leading to 2:1 or 2:3 mixtures of diastereomers.
Better results in terms of diastereomeric ratios were
attained via Friedel-Craft reaction of benzene with
different trans-4-hydroxyproline derivatives (pure cis-
and trans-4-phenylproline were obtained)1e and from
4-ketoproline (cis-4-phenylproline was obtained pure and
the trans diastereomer as a 9:1 mixture).1f Thottathil and
co-workers1g reported the synthesis of trans-4-cyclohexyl-
proline from pyroglutamic acid, in good yield and com-
plete diastereoselectivity. Recently, Sasaki and co-
workers1h described the synthesis of a proline structure
with two discernible hydroxy functionalities, which ac-
cording to the authors, could provide a range of 4-sub-
stituted proline derivatives.
Proline is known to have profound conformational
effects in the tertiary structures of peptides and proteins.3
In connection with our studies on the structure and
biosynthesis of collagen,4 we needed an efficient synthesis
of trans-4-methylproline,5 suitable for incorporation in
automated peptide synthesis. The free amino acid was
isolated from apples by Hulme and Arthington in 1954,5a,b
and its first synthesis was reported in 1962 by Gray and
Fowden.5c Those authors hydrogenated the naturally
occurring 4-methyleneproline with Adam’s catalyst, ob-
taining cis-4-methylproline as the major diastereoisomer.
Later on, Lavergne and co-workers5d obtained a 1:1
Substituted prolines are interesting targets as they are
considered to be constrained analogues of natural amino
acids.1 Thus, their incorporation into bioactive peptides
renders conformationally constrained peptides. Such so-
called peptidomimetics (or peptide mimics) are useful
tools for the development of superior pharmaceutical
agents and for establishing structure-bioactivity rela-
tionships, which could aid in the understanding of
biological processes.1
While efficient asymmetric syntheses of 3- and 5-sub-
stituted prolines have been achieved,2 only a few ap-
proaches have been reported for 4-substituted prolines.1
Thus, in 1989, Koskinen and Rapoport1a described the
synthesis of various cis- and trans-4-alkyl- and -phenyl-
prolines by conversion of 4-substituted glutamic acid
esters to the corresponding 5-hydroxypentanoic acids,
followed by separation of diastereoisomers and intramo-
lecular nitrogen alkylation. trans-4-Phenylproline has
also been synthesized from 4-hydroxyproline1b by tosyl
formation and further substitution of that group with
lithium diphenylcuprate.1c,d Although the reaction pro-
ceeds with retention of configuration at the carbon
bearing the tosyloxy group, participation of the N-Boc
protecting group results in the epimerization of the
† Present address: Primco Ltd, Valtatie 26, FIN-03600 Karkkila,
Finland.
(3) (a) Dyson, H. J .; Rance, M.; Houghton, R. A.; Lerner, R. A.;
Wright, P. E. J . Mol. Biol. 1988, 210, 161-200. (b) Dyson, H. J .; Cross,
K. J .; Houghton, R. A.; Wilson, I. A.; Wright, P. E.; Lerner, R. A. Nature
1985, 318, 480-483.
(4) (a) Bauer, U.; Koskinen, A. M. P. Electron. Conf. Trends Org.
Chem. [CD-ROM] 1996, Meeting Date 1995, Paper 60. Editor(s):
Rzepa, Henry S.; Leach, Christopher; Goodman, J onathan M. Pub-
lisher: Royal Society of Chemistry. (b) Gefflaut, T.; Bauer, U.; Airola,
K.; Koskinen, A. M. P. Tetrahedron: Asymmetry 1996, 7, 3099-3102.
(c) Koskinen, A. M. P.; Schwerdtfeger, J .; Edmonds, M. Tetrahedron
Lett. 1997, 38, 5399-5402.
(5) (a) Hulme, A. C.; Arthington, W. Nature 1954, 173, 588-589.
(b) Dalby, S.; Kenner, G. W.; Sheppard, R. C. Nature 1961, 189, 394-
395. (c) Gray, D. O.; Fowden, L. Nature 1962, 193, 1285-1286. (d)
Titouani, S. L.; Lavergne, J .-P.; Viallefont, PH. Tetrahedron 1980, 36,
2961-2965. (e) Belokon, Y. N.; Bulychev, A. G.; Pavlov, V. A.; Fedorova,
E. B.; Tsyryapkin, A.; Bakhmutov, V. A.; Belikov, V. M. J . Chem. Soc.,
Perkin Trans. 1 1988, 2075-2083.
(1) (a) Koskinen, A. M. P.; Rapoport, H. J . Org. Chem. 1989, 54,
1859-1866. (b) Remuzon, P. Tetrahedron 1996, 52, 13803-13835. (c)
Thottathil, J . K.; Moniot, J . L. Tetrahedron Lett. 1986, 27, 151-154.
(d) Hashimoto, K.; Shima, Y.; Shirahama, H. Heterocycles 1996, 42,
489-492. (e) Kronenthal, D. R.; Mueller, R. H.; Kuester, P. L.; Kissik,
T. P.; J ohnson, E. J . Tetrahedron Lett. 1990, 31, 1241-1244. (f)
Krapcho, J .; Turk, C.; Cushman, D. W.; Powell, J . R.; DeForrest, J .
M.; Spitzmiller, E. R.; Karanewsky, D. S.; Duggan, M.; Rovnyak, G.;
Schwartz, J .; Natarajan, S.; Godfrey, J . D.; Ryono, D. E.; Neubeck, R.;
Atwal, K. S.; Petrillo, E. W., J r. J . Med. Chem. 1988, 31, 1148-1160.
(g) Thottathil, J . K.; Moniot, J . L.; Mueller, R. H.; Wong, M. K. Y.;
Kissick, T. P. J . Org. Chem. 1986, 51, 3140-3143. (h) Wang, Q.; Sasaki,
N. A.; Potier, P. Tetrahedron 1998, 54, 15759-15780.
(2) (a) Sasaki, N. A.; Dockner, M.; Chiaroni, A.; Riche, C.; Potier, P.
J . Org. Chem. 1997, 62, 765-770. (b) Dockner, M.; Sasaki, N. A.; Potier,
P. Heterocycles 1996, 42, 529-532.
10.1021/jo005726s CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/23/2001

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2062 J . Org. Chem., Vol. 66, No. 6, 2001
Nevalainen et al.
Sch em e 1. Retr osyn th etic An a lysis of
4-Su bstitu ted P r olin es
yield by reduction of the ester functionality of 3 with
DIBAL-H in toluene. We hoped that the hydroxyl moiety
could interact strongly with the catalyst, providing a
more rigid transition state that could favor the diastereo-
facial discrimination. Initially, hydrogenation of 4 was
carried out on 10% Pt/C. Slightly surprisingly, the
deoxygenated compound (5a ) was formed as the major
product of the hydrogenation reaction (80% yield), even
in hexane. In light of the literature,6 the acidic character
of charcoal seems to be responsible for the large extent
of the deoxygenation process. To avoid the cleave of the
allylic C-O bond, neutral catalysts in basic media were
tested. The results obtained are summarized in Table 1.
mixture of cis- and trans-4-methylproline by cyclization
of δ-chlorinated compounds obtained by irradiating N-
chloro-L-amino acids. In 1988, Belokon and co-workers5e
described the synthesis of a 2:1 cis/trans-4-methylproline
mixture, via condensation of glycine with activated
olefins.
The deoxygenated product (5a ) was not detected in any
experiment, which confirmed that its formation is an
acid-catalyzed process. Clean formation of saturated
alcohol 5b occurred with moderate selectivity. Palladium
was discarded as it is the most active deoxygenating
catalyst.10 Platinum oxide was used instead. Although it
is known that platinum promotes less hydrogen migra-
tion than palladium,10 only a 75:25 syn/anti ratio was
afforded with platinum oxide (Table 1, entry 1). The use
of iridium was attempted, as according to Rylander,11
iridium is the metal with the greatest ability to deliver
hydrogen in a cis manner, which is essential to attain
selectivity. Iridium on charcoal in ethyl acetate turned
out to be inactive even to promote deoxygenation of allylic
alcohol 4. In view of those results, we decided to turn to
Raney Nickel, catalyst that does not promote isomeriza-
tion (Table 1, entries 4-11).10 As the diastereoselectivity
increased only to a maximum of 86:14 syn/anti ratio,
other factors in addition to double bond migration are
envisaged to work against the diastereoselectivity of the
process. Namely, the conformational mobility of allylic
alcohol 4 must allow the complexation of the metal on
the two faces of the double bond, lowering the diastereo-
facial selectivity.
In view of the mentioned results, we were challenged
to develop a new synthetic strategy for trans-4-methyl-
proline. In this paper, we describe the synthesis of Fmoc-
protected trans-4-methylproline. We believe that this
route also constitutes a general synthetic pathway to
4-substituted prolines.
On the basis of retrosynthetic analysis, the 4-substi-
tuted proline structure can be reached from serine-
derived R-enoates, as outlined in Scheme 1.
Some of our preliminary results on the hydrogenation
of E-enoates derived from fully protected serinal6 prompted
us to further studies on the selectivity of the process, and
to develop a synthetic route to 4-alkylprolines.
Resu lts a n d Discu ssion
The synthetic pathway proposed for Fmoc-protected
trans-4-methylproline is based on a diastereoselective
approach, starting from the Garner’s aldehyde (1, Scheme
2).7
A Wittig reaction between phosphorane 2 and the
Garner’s aldehyde (1) provided R,â-unsaturated ester 36
in 72% yield, with the E/Z ratio g96:4 (the Z-enoate was
not observed by 1H NMR), as we have already described.6
The enantiomeric excess of 3 was determined following
the method described by Mann and co-workers.8 Thus,
the hemiaminal moiety of 3 was hydrolyzed (p-TsOH in
MeOH, rt, 2 h), and the resulting alcohol group was
treated with Mosher’s reagent.9 Analysis of the resulting
Mosher ester by HPLC (Chiralcel OD column, Hex/IPA
95:5, 1 mL/min, 254 nm; tR(R))16.8 min, tR(S))19.0 min)
Replacement of the hydroxy functionality of compound
5b (86:14 syn/anti) by chloride (PPh3, K2CO3, CCl4 in
MeCN)12 had as a drawback the difficult separation of
the phosphorus-containing compounds from the target
molecule, which resulted in a lower yield of chloride 6a .
Moreover, cleavage of the hemiaminal protecting group
leading to 7a occurred to a large extent during flash
chromatography, even using pretreated moisture-free
silica gel. On the other hand, exchange of the alcohol
group by bromide was a much easier reaction to work
up and rendered compound 6b in high yield (90%).
Hydrolysis of the hemiaminal moiety of 6b was achieved
with 80% AcOH at 50 °C (91%).13 Benzoylation of the
alcohol group of 7a and 7b (PhCOCl, Py, 95%) rendered
ring precursors 8a and 8b, respectively, as white solids.
Recrystallization of 8a (dr ) 86:14) from hexane/ether
4:1 provided diasteromer (2R,4S)-8 in dr ) 95:5. The
diastereomeric purity of compound 8b was also increased
by recrystallization (the conditions were not optimized).
1
and H NMR gave 96% ee for 3, revealing that minimal
racemization had occurred. This result is in agreement
with that of Mann and co-workers,8 who reported 98%
ee for a compound similar to 3 (containing a hydrogen
atom instead of the 2-methyl group).
Previous studies carried out in our laboratory on the
reduction of the double bond of 3 using different hetero-
geneous catalysts gave as the best result a 5:1 syn/anti
diastereomeric ratio for the corresponding saturated ester
(using Pt/C in Hex).6 The moderate diastereoselectivity
was rationalized on the basis of a hydrogen migration,
which results in the isomerization of the double bond.4
With the aim to improve those results, we next attempted
the hydrogenation of allylic alcohol 4, obtained in 88%
Cyclization of (2R,4S)-8 (dr ) 95:5) was carried out in
tetrahydrofuran, using KHMDS as the base. The yield
(6) (a) Kauppinen, P. M.; Koskinen, A. M. P. Tetrahedron Lett. 1997,
38, 3103-3106. (b) Kauppinen, P. M. Thesis, Acta Universitatis
Ouluensis, A 329, Oulu 1999.
(7) (a) Garner, P.; Park, J . M. J . Org. Chem. 1987, 52, 2361-2364.
(b) Garner, P.; Park, J . M. Org. Synth. 1992, 70, 18-27.
(8) J ako, I.; Uiber, P.; Mann, A.; Taddei, M.; Wermuth, C.-G.
Tetrahedron Lett. 1990, 31, 1011-1014.
(9) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543-2549.
(10) Augustine, R. L. Catalytic Hydrogenation; Marcel Dekker: New
York, 1965.
(11) Rylander, P. N. Catalytic Hydrogenation in Organic Synthesis;
Academic Press: New York, 1979.
(12) J ones, L. A.; Sumner, C. E., J r.; Franzus, B.; Huang, T. T. S.;
Snyder, E. I J . Org. Chem. 1978, 43, 2821-2827
(13) Otsomaa, L. A.; Koskinen, A. M. P. Tetrahedron 1997, 53,
6473-6484.

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Synthesis of Fmoc-Protected trans-4-Methylproline
J . Org. Chem., Vol. 66, No. 6, 2001 2063
Sch em e 2. Syn th esis of F m oc-P r otected tr a n s-4-Meth ylp r olin e
Ta ble 1. Hyd r ogen a tion of Allylic Alcoh ol 4
hydroxymethyl moiety of 10 to carboxylic acid with J ones
reagent in acetone15 provided Fmoc-protected trans-4-
methylproline (dr ) 95:5, ee ) 96%).
metal catalyst
syn/anti
entrya (substrate/catalyst)
solvent
EtOH
additiveb
ratioc
1
2
3
4
5
Pt2O (4:1)
Pt2O (4:1)
NaNO2
Et3N
75:25
70:30
70:30
80:20
70:30
Hex
Con clu sion s
Pt2O (8:1)
Hex
Et3N
Raney Ni (1.5:1)
Raney Ni (2.7:1)
EtOH
EtOH/AcOEt
20:80
We have developed a new direct route to trans-4-
alkylprolines, using a substrate directed hydrogenation
reaction for the synthesis of alcohol 5b. The route
involves eight steps, renders only the trans diastereo-
isomer (after recrystallization), and should be applicable
to other targets of the same family. We are currently
investigating new approaches to improve the diastereo-
selectivity of the hydrogenation step. Moreover, the target
trans-4-methylproline is being incorporated into small
peptides in order to obtain backbone and side chain
conformationally constrained peptides to mimic â-turns
in proteins.
6
7
Raney Ni (1.5:1)
Raney Ni (1.5:1)
MeOH
MeOH/H2O
20:80
85:15
75:25
8
9
10
11
Raney Ni (8:1)
Raney Ni (20:1)
Raney Ni (2:1)
Raney Ni (2:1)
MeOH
MeOHd
MeOHd
MeOH
85:15
80:20
80:20
86:14
a
Reactions conducted at room temperature and 1 atm, using a
concentration of 0.8%. Raney Ni as a 50% w/w slurry in H2O (pH
d
) 10). b 1% w/w of catalyst. c Determined by NMR. Concentration
) 10%.
Exp er im en ta l Section
of the cyclization process is not affected by the temper-
ature or the nature of the halogen (for 8a : 70% yield after
15 min at 40 °C and 72% yield at 0 °C; for 8b: 69% yield
after 15 min at 0 °C). This fact can be expected taking
into account the fast reaction rate. The reaction yield
decreases as a result of the competing basic hydrolysis
(aminolysis) of the Boc and benzoyl groups promoted by
the base (KHMDS). The resulting amino alcohol is very
soluble in water and is lost during work up. This problem
is overcome when protected prolinol 9 is not isolated (vide
infra).
Gen er a l Meth od s. 1H NMR spectra were recorded on a
Varian Unity-400 at 400 MHz and are reported in ppm
downfield from SiMe4. J values are given in Hz. 13C NMR
spectra were recorded on a Varian Unity-400 at 100 MHz.
HRMS were conducted on J EOL J MS-DX303 (EI+) and
Micromass LCT (ES+) spectrometers. Optical rotations were
measured on a Perkin-Elmer 343 polarimeter at room tem-
perature, using a cell of 1 dm of length and λ ) 598 nm. Data
are reported as follows: [R]T (solvent, concentration in g/100
D
mL). HPLC analyses were performed using a Waters system
with UV detector, on a Chiralpak AS (Daicel) column. Melting
points (mp) were performed on a Gallenkamp apparatus, using
open capillary tubes. Values are given in degrees Celsius
(uncorrected). Analytical thin-layer chromatography (TLC) was
performed on Merck silica gel plates with QF-254 indicator.
Various attempts to deprotect the benzoyl group of 9
under basic conditions (NaOH) led to mixtures of com-
pounds in which cleavage of the Boc group was observed.
The problem was solved by hydrolyzing both the Boc and
the benzoyl groups under acidic conditions (1 N HCl, 100
°C). The crude amino alcohol hydrochloride obtained was
converted quantitatively into Fmoc-protected amino al-
cohol 10 under Schotten-Baumann conditions.14 Com-
pound 10 can be obtained directly from 8a (without
isolation of 9) in 88% yield. Finally, oxidation of the
(14) (a) Atherton, E.; Cameron, L. R.; Sheppard, R. C. Tetrahedron
1988, 44, 843-57. (b) Atherton, E.; Sheppard, R. C. Peptides (N.Y.)
1987, 9, 1-38. (c) Atherton, E.; Sheppard, R. C. Solid-Phase Peptide
Synthesis: A Practical Approach; Oxford University Press: Oxford,
1989.
(15) Bowers, A.; Halsall, T. G.; J ones, E. R. H.; Lemin, A. J . J . Chem.
Soc. 1953, 2548-2560.

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2064 J . Org. Chem., Vol. 66, No. 6, 2001
Nevalainen et al.
Visualization was accomplished with UV light, iodine or 1%
KMnO4 in H2O. Flash chromatography was performed using
Merck silica gel 60 (40-63 µm). The detector wavelength, flow
rate and solvents were as denoted. The retention times (tR)
for the enantiomers are reported.
2 L three-necked round-bottomed flask were placed Raney Ni
(13.0 g, 50% w/w slurry in water, 50 mol %) and [2E,3(4S)]-
2-methyl-3-[N-[(1,1-dimethyl)ethoxycarbonyl]-2,2-dimethyl-
1,3-oxazolidin-4-yl]propenyl alcohol (13.0 g, 46.8 mmol) in
MeOH (1300 mL). The flask was filled with hydrogen, the
mixture was stirred at room temperature for 18 h and filtered
through a pad of Celite, and the solvent was eliminated under
reduced pressure. The residue was taken up in Et2O (100 mL)
and washed with H2O (2 × 50 mL). The organic layer was dried
(MgSO4) and filtered and the solvent removed under reduced
pressure. 5 was obtained as a clear oil (12.1 g, 44.4 mmol, 95%)
Solvents were dried using standard procedures.16 D-Serine
was purchased from Fluka. DIBAL-H (1 M in toluene) was
obtained from Aldrich and KHMDS (0.5 M in toluene) was
obtained from Fluka. 10% Pt/C, Pt2O, and Raney Nickel (50%
w/w slurry in H2O, pH ) 10) were purchased from Aldrich,
and 5% Ir/C from Alfa. Garner’s aldehyde7,17 and phosphorane
218 were synthesized as described in the literature.
with dr ) 86:14 (two rotamers): [R]20 +32.6 (c 0.98, CHCl3)
D
[2E,3(4S)]-2-Met h yl-3-[N-[(1,1-d im et h yl)et h oxyca r bo-
for dr ) 70:30; [R]20 ) +34.5 (c 1.06, CHCl3) for dr ) 86:14;
D
n yl]-2,2-d im et h yl-1,3-oxa zolid in -4-yl]p r op en oic
Acid
1H NMR (400 MHz, CDCl3) δ 4.20-4.00 (bs, 1H), 4.00-3.80
(m, 1H), 3.80-3.64 (m, 1H), 3.60-3.38 (bs, 2H), 3.24-3.00 (bs,
1H), 1.80-1.66 (m, 2H), 1.66-1.50 (m, 4H), 1.50-1.34 (m,
12H), 1.02-0.86 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 152.6,
152.4, 161.6, 93.6, 93.2, 93.1, 80.4, 79.5, 68.5, 68.2 67.9, 67.6,
67.2, 67.0, 55.8 (minor diastereoisomer), 55.6 and 55.1 (major
diastereoisomer), 38.1 (minor diastereoisomer), 37.4 and 37.1
(major diastereoisomer), 33.6, 33.0, 32.9, 28.5, 28.4, 27.7, 26.6,
26.9, 24.5, 24.4, 23.2, 18.4 and 18.1 (minor diastereoisomer),
16.5 and 16.0 (major diastereoisomer); HRMS calcd for M+
(C14H27NO4) 273.1933, found 273.1938.
Meth yl Ester (3). In a 1 L three-necked round-bottomed flask
was placed under argon (R-carbomethoxyethylidene)triphenyl-
phosphorane (38.6 g, 110 mmol, 110 mol %) in dry CH2Cl2 (500
mL). The solution was cooled to 0 °C, and (4R)-4-formyl-2,2-
dimethyloxazolidine-3-carboxylic acid tert-butyl ester (22.9 g,
100 mmol) in dry CH2Cl2 (200 mL) was dropwise added. The
ice/water bath was removed, and the mixture was stirred at
room temperature for 18 h. The solution was concentrated
under reduced pressure. The residue (150 mL) was treated
with hexane (500 mL), cooled to 0 °C, and stirred at that
temperature for 30 min. The solid was filtered washed with
hexane (2 × 100 mL). The solvent was evaporated from the
filtrate at reduced pressure, and the residue was purified by
flash chromatography (silica, Hex/AcOEt 5:1). A clear oil was
[2R,3(4S)]-1-Ch lor o-2-m eth yl-3-[N-[(1,1-dim eth yl)eth oxy-
ca r bon yl]-2,2-d im eth yl-1,3-oxa zolid in -4-yl]p r op a n e (6a ).
In a 1 L three-necked round-bottomed flask under argon was
placed [2R,3(4S)]-2-methyl-3-[N-[(1,1-dimethyl)ethoxycarbo-
nyl]-2,2-dimethyl-1,3-oxazolidin-4-yl]propanol (12.0 g, 44.2
mmol) of dr ) 86:14 in acetonitrile (650 mL). K2CO3 (12.3 g,
89.7 mmol, 200 mol %), Ph3P (29.6 g, 164.9 mmol, 250 mol %),
and CCl4 (43 mL) were added. The mixture was stirred at room
temperature for 1 h and the solvent evaporated under reduced
pressure. The residue was purified by flash chromatography
(silica, Hex/AcOEt 4:1 and 2:1). Two fractions were obtained:
the target molecule (6a ) as an oil (1.8 g, 6.0 mmol, 14%), and
the hemiaminal cleaved product (7a ) also as an oil (5.4 g, 21.4
mmol, 48%). 6a (two rotamers): [R]20D +22.5 (c ) 1.13, CHCl3);
1H NMR (400 MHz, CDCl3, 45 °C) δ 4.15-3.77 (bs, 1H), 3.91
(m, 1H), 3.70 (d, J ) 8.8 Hz, 1H), 3.44 (bs, 2H), 1.85-1.60 (bs,
3H), 1.55 (m, 3H), 1.46-1.40 (m, 12H), 1.04 (bs, 3H); 13C NMR
(100 MHz, CDCl3) δ 152.1, 151.5, 93.7, 93.2, 80.0, 79.7, 66.9,
66.8, 55.5, 55.5, 51.3, 51.2, 38.0, 37.3, 33.4, 28.4, 27.7 (rotamer),
26.9, 24.5 (rotamer), 23.2, 17.4, 17.1; HRMS calcd for M+
(C14H26NO3Cl) 291.1575, found 291.1578.
obtained (21.5 g, 71.9 mmol, 72%): Rf ) 0.41 (silica, Hex/
1
AcOEt 5:2); [R]20 +19.3 (c 0.55, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 6.66 (bs, 1H), 4.78-4.59 (bs, 1H), 4.12 (dd, J ) 8.8
Hz, J ) 6.4 Hz, 1H), 3.76 (s, 3H), 3.71 (dd, J ) 8.8, 3.0 Hz,
1H), 1.91 (m, 3H), 1.63 (m, 3H), 1.55-1.40 (m, 12H); 13C NMR
(100 MHz, CDCl3) δ 168.1, 152.0 (rotamer), 151.7, 140.9, 140.6
(rotamer), 128.8 (rotamer), 127.8, 94.4, 93.8 (rotamer), 80.4
(rotamer), 80.0, 67.6, 55.3, 51.8, 28.3, 27.2 (rotamer), 26.2, 25.0
(rotamer), 24.1, 12.5; HRMS calcd for M+ (C15H25NO5) 299.1726,
found 299.1733.
[2E,3(4S)]-2-Met h yl-3-[N-[(1,1-d im et h yl)et h oxyca r bo-
n yl]-2,2-d im et h yl-1,3-oxa zolid in -4-yl]p r op en yl Alcoh ol
(4). In a 250 mL two-necked round-bottomed flask under argon
was placed DIBAL-H (1 M in toluene, 90 mL, 90 mmol, 180
mol %) and the mixture cooled to -50 °C. A solution of [2E,3-
(4S)]-2-methyl-3-[N-[(1,1-dimethyl)ethoxycarbonyl]-2,2-dimethyl-
1,3-oxazolidin-4-yl]propenoic acid methyl ester (15.0 g, 50.3
mmol) in dry toluene (15 mL) was dropwise added. The
mixture was stirred at -50 °C for 5 h, quenched with acetone
(60 mL), and allowed to warm to room temperature by removal
of the dry ice/CHCl3 bath. When the mixture started to jellify,
it was poured into a solution of sodium potassium tartrate (113
g) in H2O (300 mL), with the aid of Et2O (2 × 10 mL). The
biphasic mixture was stirred vigorously at room temperature
for 1 h, the layers were separated, and the aqueous layer was
extracted with Et2O (3 × 100 mL). The combined organic
extracts were dried (MgSO4) and filtered, and the solvent was
evaporated under reduced pressure. The crude product was
purified by flash chromatography (silica, Hex/AcOEt 3:1). A
clear oil was obtained (12.0 g, 44.2 mmol, 88%): Rf ) 0.34
[2R,3(4S)]-1-Br om o-2-m eth yl-3-[N-[(1,1-dim eth yl)eth oxy-
ca r bon yl]-2,2-d im eth yl-1,3-oxa zolid in -4-yl]p r op a n e (6b).
In a 25 mL two-necked round-bottomed flask under argon was
placed [2R,3(4S)]-2-methyl-3-[N-[(1,1-dimethyl)ethoxycarbo-
nyl]-2,2-dimethyl-1,3-oxazolidin-4-yl]propanol (280 mg, 1.03
mmol) of dr ) 80:20 in dry THF (10 mL). Ph3P (538 mg, 2.06
mmol, 200 mol %) and CBr4 (682 mg, 2.06 mmol, 200 mol %)
were added, followed by (iPr)2EtNH (359 µL, 2.06 mmol, 200
mol %). The mixture was stirred at room temperature for 1 h,
diluted with Et2O (75 mL), and extracted with 0.5 N H3PO4 (2
× 25 mL), saturated Na2CO3 (25 mL), and brine (25 mL). The
acidic and neutral extracts were washed with Et2O (2 × 25
mL), the combined organic extracts were dried (MgSO4) and
filtered, and the solvent was evaporated under reduced pres-
sure. The residue was treated with Hex/AcOEt 4:1 (10 mL),
cooled to 0 °C, and filtered. The solid was washed with Hex/
AcOEt 4:1 (5 mL), and the combined filtrates were evaporated
to dryness under reduced pressure. The residue was filtered
through a short pad of silica with the aid of Hex/AcOEt 4:1
(50 mL). The target molecule was obtained as an oil (310 mg,
(silica, Hex/AcOEt 1:1); [R]20 -16.5 (c 0.61, CHCl3); 1H NMR
D
(400 MHz, CDCl3) δ 5.46, 5.27 (d, J ) 9.2 Hz, 1H), 4.72-4.52
(bs, 1H), 4.07 (dd, J ) 8.8, 6.4 Hz, 1H), 4.02 (s, 2H), 3.66 (dd,
J ) 8.8, 3.2 Hz, 1H), 1.80-1.34 (m, 19H); 13C NMR (100 MHz,
CDCl3) δ 152.1, 137.1, 135.9 (rotamer), 125.5 (rotamer), 125.2,
93.9, 80.1, 68.6, 68.0, 55.1, 28.5, 27.1 (rotamer), 26.4, 25.2
(rotamer), 24.0, 13.8; HRMS calcd for M+ (C14H25NO4) 271.1777,
found 271.1709.
0.92 mmol, 90%) (two rotamers): [R]20 ) -14.2 (c ) 0.62,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 4.06-3.80 (bs, 1H), 3.92
(m, 1H), 3.73 (dd, J ) 8.8 Hz, J ) 1.2 Hz, 1H), 3.52-3.24 (bs,
2H), 2.00-1.60 (bs, 3H), 1.60-1.50 (m, 3H), 1.50-1.40 (m,
12H), 1.08 (bs, 3H); 13C NMR (100 MHz, CDCl3) δ 152.2, 151.5,
93.7, 93.3, 80.1, 79.7, 66.9, 65.7, 55.5, 55.5, 50.1, 41.4, 40.9,
39.4, 38.9, 38.3, 36.8, 36.5, 33.0, 31.6, 28.5, 28.4, 28.3, 27.8
(rotamer), 26.9, 24.5 (rotamer), 23.2, 20.1, 19.8, 18.5, 18.2;
HRMS calcd for M+ - 71 (C10H19NO2Br) 264.0595, found
264.0566.
[2R,3(4S)]-2-Meth yl-3-[N-[(1,1-d im eth yl)eth oxyca r bo-
n yl]-2,2-d im eth yl-1,3-oxa zolid in -4-yl]p r op a n ol (5b). In a
(16) Furniss, B. S.; Hannaford, A. J .; Smith, P. W. G.; Tatchell, A.
R. Vogel’s Textbook of Practical Organic Chemistry, 5th ed.; Long-
man: Harlow, U.K., 1989.
(17) Williams, L.; Zhang, Z.; Shao, F.; Carroll, P. J .; J oullie´, M. M.
Tetrahedron 1996, 52, 11673-11694.
(18) Isler, O. Von; Gutmann, H.; Montavon, M.; Ru¨egg, R.; Ryser,
G.; Zeller, P. Helv. Chim. Acta 1957, 139, 1242-1249.