Asymmetric hydrogenations for the synthesis of boc-protected 4-alkylprolinols and prolines

Article abstract of DOI:10.1021/jo034214l

The utility of 4-substituted prolinols and their corresponding prolines in peptides, peptidomimetics, and natural products has motivated researchers to find new and efficient routes for their preparation. Herein, we report a general approach to the synthesis of Boc-protected 4-alkylprolinols and prolines via a divergent asymmetric hydrogenation strategy. Intermediate exocyclic olefins were prepared by Wittig-type reactions with ketone 6 and subjected to hydroxyl and sterically directed reductions. The Crabtree catalyst (Ir[COD] PyPCy₃PF₆) proved to be highly effective in diastereoselective hydrogenations to give trans- substituted pyrrolidines (9). Good facial selectivities were also observed in heterogeneous hydrogenations with Raney-nickel to obtain cis-substituted pyrrolidines (11). Employing this strategy, we describe the synthesis of novel prolinol and proline-based building blocks for incorporation into biologically relevant peptidomimetics.

Full text of DOI:10.1021/jo034214l

Asymmetric Hydrogenations for the Synthesis of Boc-Protected
4-Alkylprolinols and Prolines
Juan R. Del Valle and Murray Goodman*
Department of Chemistry and Biochemistry, University of California-San Diego,
La Jolla, California 92093-0343
mgoodman@ucsd.edu
Received February 18, 2003
The utility of 4-substituted prolinols and their corresponding prolines in peptides, peptidomimetics,
and natural products has motivated researchers to find new and efficient routes for their
preparation. Herein, we report a general approach to the synthesis of Boc-protected 4-alkylprolinols
and prolines via a divergent asymmetric hydrogenation strategy. Intermediate exocyclic olefins
were prepared by Wittig-type reactions with ketone 6 and subjected to hydroxyl and sterically
directed reductions. The Crabtree catalyst (Ir[COD]PyPCy3PF6) proved to be highly effective in
diastereoselective hydrogenations to give trans-substituted pyrrolidines (9). Good facial selectivities
were also observed in heterogeneous hydrogenations with Raney-nickel to obtain cis-substituted
pyrrolidines (11). Employing this strategy, we describe the synthesis of novel prolinol and proline-
based building blocks for incorporation into biologically relevant peptidomimetics.
Introduction
tives into peptides and peptidomimetics continues to be
a powerful tool for identifying and elucidating structure-
activity relationships.
The proline residue is the only secondary amine among
the 20 proteinogenic amino acids and thus exhibits
unique conformational properties.1 Substituted prolines
have been used extensively to influence the conformation
of the peptide backbone and to induce desired turns in
host structures.2 The amide-bond geometry of the proline
N-terminus is crucial in the activity and reactivity of a
number of peptides3 and substituted analogues have been
shown to affect the energetic barrier to amide-bond
rotation and the rotameric equillibrium dramatically.4 In
many cases, proline-induced turns in peptides can be
found in close proximity to pharmacophores that are
essential for biological recognition.5 As a result, chimeric
residues, featuring biologically relevant substituents,
have been utilized to project desired functionalities into
defined regions of space.6 Incorporation of these deriva-
In addition to the various peptidic applications of
functionalized proline residues, substitued 2-hydroxy-
methylpyrrolidines have featured as valuable precursors
and key components of natural products7 and other
biologically active compounds.8 For these reasons, much
effort has been devoted to the design and synthesis of
substituted prolinols and their amino acid counterparts.
Still, new and facile methods for their diastereoselective
preparation are desirable.
We have been particularly interested in the synthesis
of 4-substituted prolinols and prolines for use in our
peptidomimetic research programs because of their ac-
(5) (a) Schlechtingen, G.; Zhang, L.; Maycock, A.; DeHaven, R. N.;
Daubert, J. D.; Cassel, J.; Chung, N. N.; Schiller, P. W.; Goodman, M.
J. Med. Chem. 2000, 43, 2698. (b) Tran, T.-A.; Mattern, R.-H.; Afargan,
M.; Amitay, O.; Ziv, O.; Morgan, B. A.; Taylor, J. E.; Hoyer, D.;
Goodman, M. J. Med. Chem. 1998, 41, 2679. (c) Yamazaki, T.; Ro, S.;
Goodman, M.; Chung, N. N.; Schiller, P. W. J. Med. Chem. 1993, 36,
708.
(6) (a) Damour, D.; Herman, F.; Labaudiniere, R.; Pantel, G.;
Vuilhorgne, M.; Mignani, S. Tetrahedron 1999, 55, 10135. (b) Schu-
macher, K. K.; Jiang, J.; Joullie, M. M. Tetrahedron: Asymmetry 1998,
9, 47. (c) Plucinska, K.; Kataoka, T.; Yodo, M.; Cody, W. L.; He, J. X.;
Humblet, C.; Lu, G. H.; Lunney, E.; Major, T. C.; Panek, R. L.;
Schelkun, P.; Skeean, R.; Marshall, G. R. J. Med. Chem. 1993, 36, 1902.
(d) Kataoka, T.; Beusen, D. D.; Clark, J. D.; Yodo, M.; Marshall, G. R.
Biopolymers 1992, 32, 1519.
(1) (a) Yoshioka, H.; Nakatsu, K.; Sato, M.; Tatsuno, T. Chem. Lett.
1973, 1319. (b) Troganis, A.; Gerothanassis, I. P.; Athanassiou, Z.;
Mavromoustakos, T.; Hawkes, G. E.; Sakarellos, C. Biopolymers 2000,
53, 72. (c) Takeuchi, Y.; Marshall, G. R. J. Am. Chem. Soc. 1998, 120,
5363. (d) Saviano, M.; Isernia, C.; Rossi, F.; Di Blasio, B.; Iacovino, R.;
Mazzeo, M.; Pedone, C.; Benedetti, E. Biopolymers 2000, 53, 189.
(2) (a) Beausoleil, E.; L’Archeveque, B.; Belec, L.; Atfani, M.; Lubell,
W. D. J. Org. Chem. 1996, 61, 9447. (b) Holmgren, S. K.; Taylor, K.
M.; Bretscher, L. E.; Raines, R. T. Nature 1998, 392, 666. (c) Holmgren,
S. K.; Bretscher, L. E.; Taylor, K. M.; Raines, R. T. Chem. Biol. 1999,
6, 63. (d) Zhang, R.; Brownewell, F.; Madalengoitia, J. S. J. Am. Chem.
Soc. 1998, 120, 3894.
(3) (a) Lin, L.-N.; Brandts, J. F. Biochemistry 1979, 18, 5037. (b)
Heidemann, E.; Roth, W. Adv. Polym. Sci. 1982, 43, 143. (c) Johnson,
M. E.; Lin, Z.; Padmanabhan, K.; Tulinsky, A.; Khan, M. FEBS Lett.
1994, 337, 4. (d) Richards, N. G. J.; Hinds, M.; Brennand, D. M.;
Glennie, M. J.; Welsh, J. M.; Robinson, J. A. Biochem. Pharm. 1990,
40, 119.
(4) (a) Delaney, N. G.; Madison, V. J. Am. Chem. Soc. 1982, 104,
6635. (b) Renner, C.; Alefelder, S.; Bae, J. H.; Budisa, N.; Huber, R.;
Moroder, L. Angew. Chem., Int. Ed. 2001, 40, 923. (c) Panasik, N., Jr.;
Eberhardt, E. S.; Edison, A. S.; Powell, D. A.; Raines, R. T. Int. J. Pept.
Protein Res. 1994, 44, 262.
(7) (a) Hanessian, S.; Ninkovic, S. J. Org. Chem. 1996, 61, 5418. (b)
Koskinen, A. M. P.; Paul, J. M. Tetrahedron Lett. 1992, 33, 6853. (c)
Wrobel, J. T. In The Alkaloids: Chemistry and Pharmacology; Brossi,
A., Ed.; Academic Press: San Diego, CA, 1985; Vol. 26, Chapter 7, p
327. (d) Michael, J. P.; Wrobel, J. T. In The Alkaloids: Chemistry and
Pharmacology; Cordell, G. A., Ed.; Academic Press: San Diego, CA,
1993; Vol. 44, Chapter 3, p 189.
(8) (a) Westwood, N. B.; Walker, R. T. Tetrahedron 1998, 54, 13391.
(b) Cossy, J.; Mirguet, O.; Pardo, D. G.; Desmurs, J.-R. Tetrahedron
Lett. 2001, 42, 5705. (c) Cossy, J.; Mirguet, O.; Pardo, D. G.; Desmurs,
J.-R. Eur. J. Org. Chem. 2002, 3543.
10.1021/jo034214l CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/15/2003
J. Org. Chem. 2003, 68, 3923-3931
3923

Del Valle and Goodman
FIGURE 1. N-Boc-cis- and trans-4-alkylprolines.
cessibility from naturally abundant trans-4-hydroxproline
(Figure 1). Prolines functionalized with the appropriate
pharamacophores at the 4-position have found wide
application in medicinal chemistry and feature in thera-
peutic agents such as inhibitors of angiotensin-converting
enzyme (ACE)9 and potential inhibitors of proline dehy-
drogenase.10
The synthesis of a variety of 4-alkylprolines are present
in the literature, but many of the methods involve
glutamate or pyroglutamate alkylations that meet with
varying success depending on the nature of the electro-
phile.11 To some degree, substrate-directed hydrogena-
tions have been employed to prepare primarily cis-
substituted prolines and pyroglutamates under hetero-
geneous conditions.9b,12 Despite these reports, most pro-
tocols do not offer an entry into each diastereomer of a
given proline derivative, requiring equillibration of
epimers, difficult separations, or entirely different syn-
thetic routes to obtain other isomers. There is no general
investigation of substrate-directed hydrogenations in the
literature for the synthesis of 4-alkylprolinols and pro-
lines.
In the present work, we provide a versatile approach
to the preparation of 4-alkylprolinols and prolines via
substrate-directed hydrogenations of exocyclic olefin
intermediates. In most cases, we have found this strategy
offers a diastereoselective entry into each isomer of a
given prolinol derivative. This approach has been suc-
cessfully applied to the synthesis of novel 4-substituted
prolinols and prolines for incorporation into biologically
relevant peptidomimetics.
FIGURE 2. Asymmetric Hydrogenations in the Synthesis of
cis- and trans-4-trifluoromethylprolinol.
hydrogen from the less hindered face of the molecule
provides primarily the cis-substituted pyrrolidine under
heterogeneous conditions. Conversely, reduction of the
deprotected hydroxymethyl moeity affords the trans-
isomer by homogeneous hydrogenation with the Crabtree
catalyst (Ir[COD]PyPCy3PF6).14 Utilizing the Ir(I) com-
plex, we observed remarkable diastereoselectivity (>99:1
trans:cis) resulting from coordination of the catalyst to
the directing hydroxyl group.
In an effort to extend this strategy to the synthesis of
4-alkylprolines we sought to prepare a family of struc-
tures based on those shown in Figure 1. Beyond our
investigation of the described methodology, we desired
a facile preparation of novel 4-arylalkyl-substituted pro-
linols for our somatostatin research programs. Thus, a
route amenable to the introduction of a diverse array of
aromatic pharmacophores was of particular interest. We
envisioned that the most efficient way of arriving at
functionalized olefin intermediates for hydrogenation
would be Wittig-type reactions with a suitably protected
4-prolinone derivative.
Our synthesis of the target compounds begins with the
preparation of the desired ketone intermediate (6) start-
ing from trans-4-hydroxyproline (Scheme 1). Although
the synthesis of the monoprotected diol 5 has been
described,15 we found the ester reduction step to be
somewhat inconvenient on a large scale. As an alterna-
tive, we chose to Boc-protect the free amino acid and
carry out the reduction of a mixed anhydride formed in
situ. The anhydride reduction required considerably less
solvent than ester reduction with LiBH4 and resulted in
a less complicated workup. Selective protection of the
primary alcohol with TBDMSCl, as reported previously,
gave compound 5, which was then oxidized with trichlor-
oisocyanuric acid and catalytic TEMPO16 to afford pyr-
rolidinone 6 in 88% yield.
Results and Discussion
Recently, we communicated the synthesis of 4-trifluo-
romethylprolines by asymmetric hydrogenation of the
pyrrolines shown in Figure 2.13 Our divergent approach
utilizes the protecting group on the hydroxymethyl
substituent to dictate the facial selectivity of the hydro-
genations. When protected as the silyl ether, delivery of
(9) (a) Ondetti, M. A.; Cushman, D. W. Science 1977, 196, 441. (b)
Krapcho, J.; Turk, C.; Cushman, D. W.; Powell, J. R.; Deforrest, J. M.;
Spitzmiller, E. R.; Karanewski, 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. Med. Chem. 1988, 31, 1148.
(10) Manfre, F.; Kern, J.-M.; Biellmann, J.-F. J. Org. Chem. 1992,
57, 2060.
Reaction of pyrrolidinone 6 with various triphenylphos-
phoranes gave the desired olefins 7a-d in good yields.17
(13) Del Valle, J. R.; Goodman, M. Angew. Chem., Int. Ed. 2002,
41, 1600.
(11) (a) Thottathil, J. K.; Moniot, J. L.; Mueller, R. H.; Wong, M. K.
Y.; Kissick, T. P. J. Org. Chem. 1986, 51, 3140. (b) Langlois, N.; Rojas,
A. Tetrahedron Lett. 1993, 34, 2477. (c) Ezquerra, J.; Pedregal, C.;
Yruretagoyena, B.; Rubio, A. J. Org. Chem. 1995, 60, 2925. (d)
Koskinen, A. M. P.; Rapoport, H. J. Org. Chem. 1989, 54, 1859.
(12) (a) Moody, C. M.; Young, D. W. J Chem. Soc., Perkin Trans.
1997, 3519. (b) McCafferty, D. G.; Schneider, S. L.; Erickson, B. W. In
Proceedings of the American Peptide Symposium, 16th; Minneapolis,
MN, 2000; p 72. (c) Nevalainen, M.; Kauppinen, P. M.; Koskinen, A.
M. P. J. Org. Chem. 2001, 66, 2061. (d) Tamaki, M.; Han, G.; Hruby,
V. J. J. Org. Chem. 2001, 66, 3593.
(14) (a) Crabtree, R. H.; Felkin, H.; Morris, G. E. J. Organomet.
Chem. 1977, 141, 205. (b) Stork, G.; Kahne, D. E. J. Am. Chem. Soc.
1983, 105, 1072.
(15) For the previously reported preparation and characterization
of compound 5 see: Aoyagi, Y.; Williams, R. M. Tetrahedron 1998, 54,
13045. Diol 4 has been prepared and characterized as described in:
Rajeev, K. G.; Sanjayan, G. J.; Ganesh, K. N. J. Org. Chem. 1997, 62,
5169.
(16) Luca, L. D.; Giacomelli, G.; Porchedu, A. Org. Lett 2001, 3, 3041.
(17) For compounds 7b-f, the E and Z isomeric products were
unresolvable by column chromatography.
3924 J. Org. Chem., Vol. 68, No. 10, 2003

Boc-Protected 4-Alkylprolinols and Prolines
SCHEME 1. Synthesis of 4-Alkylprolines 1 and 2a
a Reagents and conditions: (a) Boc2O, 10% aq Na2CO3/dioxane; (b) isobutyl chlorofomate, NMM, DME; (c) NaBH4 in H2O; (d) TBDMSCl,
TEA, DMAP (cat.), DCM; (e) trichoroisocyanuric acid, TEMPO (cat.), DCM; (f) ylide, THF; (g) 0.5 M TBAF in THF; (h) 3 mol %
of Ir(COD)PyPCy3PF6, H2, DCM; (i) NaClO2, NaClO (cat.), TEMPO, pH 6.7 phosphate buffer (0.67 M NaH2PO4)/MeCN; (j) Raney-Ni,
MeOH, H2.
Likewise, Horner-Wadsworth-Emmons olefination with
diethyl methylphosphonoacetate proceeded to give the
R-â unsaturated ester 7e as a mixture of E- and Z-
isomers. To obtain 7f, Boc-indolyltriphenylphosphonium
bromide was prepared from the corresponding (3-bro-
momethyl)indole18 and reacted with ketone 6 under
standard Wittig conditions. As expected, attempts to
react 6 with the ylide derived from cyclohexyltriphen-
ylphosphonium bromide failed to give any of the tetra-
substituted olefin. Compounds 7b-f were used in sub-
sequent reactions as mixtures of E- and Z-isomers.
Following hydrogenation and silyl ether deprotection, the
diastereomeric ratios for prolinols 9 and 11 were deter-
reproducibly lower than that obtained with other sub-
strates. We hypothesize that this is due to competing
coordination of the catalyst with the ester side-chain of
8e, instead of with the directing hydroxyl group. The
ability for the Crabtree catalyst to coordinate to a variety
of polar functionalities is well-documented20 and was
confirmed, in our case, upon hydrogenation of 7b under
homogeneous conditions. Despite the presence of the
TBDMS protecting group, the reduction resulted in a 4:1
diastereomeric ratio in favor of the trans-substituted
isomer (9b) after silyl ether deprotection.
In our efforts to obtain the cis-substituted pyrrolidines,
sterically directed hydrogenations were carried out under
a variety of conditions (Table 2). Although Pd/C-catalyzed
reduction of the trifluoromethylpyrroline derivative had
proceeded with good selectivity, reduction of olefins 7a-c
(entries 1-3) exhibited low preference for the cis-
substituted products. These results are in agreement
with existing reports on the reduction of 4-methylenepro-
line derivatives with Pd/C.21 The disparity in selectivity
highlights a marked difference between the heteroge-
neous hydrogenation of endocyclic and exocyclic olefins
in similar systems. In the case of 7f, hydrogenation with
Pd/C also resulted in undesired reduction of the C2-C3
indole double bond. After hydrogenation of 7e in the
presence of Mg/MeOH met with low diastereoselectivity,
we turned to the less commonly employed Raney-nickel.
1
mined by H NMR analysis of concentrated samples.19
To obtain trans-substituted 4-alkylprolinols, silyl ether
deprotection of compounds 7a-f was first carried out to
unmask the hydroxyl directing groups. Treatment of the
resulting olefins (8) with 3 mol % of the Crabtree catalyst,
under H2 atmosphere, gave good to excellent selectivities
for the trans-substituted pyrrolidines (Table 1). In most
cases, the undesired diastereomers were undetected by
1H NMR. There appeared to be no significant compromise
in selectivity in moving from the endocyclic olefin of our
trifluoromethylpyrrole derivative to the exocyclic olefins
of compounds 8a-f. The range of substrates and consis-
tently high selectivities obtained in these hydrogenations
suggest that reduction utilizing the Crabtree catalyst is
an attractive method for setting the C4 stereochemistry.
Although homogeneous hydrogenation of 8e (entry 5)
gave good facial selectivity, the diastereomeric ratio was
In using Raney-nickel as the hydrogenation catalyst
we observed an increase in selectivity over Pd/C for the
reduction of 7a-d. The diastereomeric ratios obtained
in the reduction of 7b-f (entries 2-6) clearly demonstate
the utility of Raney-nickel in preparing cis-substituted
pyrrolidines. While hydrogenation of 7f (entry 6) again
resulted in over-reduction when left to react for extended
(18) See Supporting Information for the experimental procedure. For
the preparation of N-Boc-(3-bromomethyl)indole see: Venkatachalam,
T. K.; Mzengeza, S.; Diksic, M. Org. Prep. Proced. Int. 1993, 25, 249.
(19) In comparing the NMR spectra of each diastereomeric pair of
prolinols, clearly discernible proton resonances were chosen for
integration. Samples for NMR analysis were 100 mg/mL in concentra-
tion and consisted of the diastereomeric mixture 9 + 11. The limit of
detection of the NMR at this concentration was determined to be ∼1%
by doping experiments. Integration values for the impurity peak were
determined to be accurate and reproducible to 2.5 mol % by the same
experiments. Thus, in cases where the minor diastereomer was <2.5%
abundant or undetected, we assume the d.r. to be >40:1.
(20) (a) Crabtree, R. H.; Davis, M. W. J. Org. Chem. 1986, 51, 2655.
(b) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307.
(21) (a) Magerlein, B. J.; Birkenmeyer, R. D.; Herr, R. R.; Kagan,
F. J. Am. Chem. Soc. 1967, 89, 2459. (b) Gray, D. O.; Fowden, L. Nature
1962, 193, 1285.
J. Org. Chem, Vol. 68, No. 10, 2003 3925

Del Valle and Goodman
TABLE 1. Diastereoselectivity in Homogeneous
TABLE 2. Diastereoselectivity of Heterogeneous
Hydrogenations of 8a-f with Ir(COD)PyPCy3PF6
Hydrogenations of 7a-f
a Ratio of 9:11 determined by 1H NMR. b Isolated yield of 9 +
11.
a After TBS ether cleavage. b Ratio of 11:9 determined by 1H
NMR. c Isolated yield of 9 + 11 over 2 steps. d Refluxed in MeOH
under Ar. e Mg in MeOH. f NMR revealed ∼ 3% of the over-reduced
product.
periods of time (>4 h), reduction of the indole double bond
occurred slowly and could be largely avoided with close
monitoring; after 45 min a >20:1 cis:trans ratio was
obtained with ∼3% of the over-reduced species detected
by NMR.
Hydrogenation of compound 7a proved to be resistant
to sterically directed selectivity under a variety of condi-
tions (entry 1). Because we believed the terminal nature
of the olefin to be responsible for the low selectivity,
attempts were made to take advantage of the desulfur-
ization and dehalogenation capabilities of Raney-nickel.
Compounds 13 and 14 were prepared and subjected to
one-pot olefin reduction and carbon-heteroatom hydro-
genolysis conditions (Scheme 2). After silyl ether cleav-
age, both cases resulted in formation of the desired
N-Boc-4-methylprolinol product with only 3:1 cis:trans
3926 J. Org. Chem., Vol. 68, No. 10, 2003

Boc-Protected 4-Alkylprolinols and Prolines
the comparison of 1H NMR, 13C NMR, and optical rotation
data for 9a with that obtained from a previously reported
synthesis of N-Boc-trans-4-methylprolinol.23 This serves
as further evidence that compounds 9 and 11 are the
expected products of hydroxy and sterically directed
hydrogenations, respectively.
SCHEME 2. Alternate Route to 11aa
Conclusions
In summary, we have described the first general
investigation of hydroxy and sterically directed hydro-
genations in the synthesis of 4-alkylprolinols and pro-
lines. The use of the Crabtree catalyst for hydroxyl-
directed hydrogenations has proven to be convenient and
effective for the preparation of trans-4-alkylprolinols.
High diastereoselectivities and a tolerance for various
olefins make homogeneous hydrogenation a viable alter-
native to the alkylation of pyroglutamate derivates. Only
in the case of ester-substituted olefin 7e did we observe
a modest drop in selectivity. To the best of our knowledge,
the described syntheses of trans-substituted prolines
1a-e are among the most diastereoselective preparations
to date.
a Reagents and conditions (see Supporting Information): (a)
Ph2P(O)CH2SPh, n-BuLi, THF; (b) Ph2P(O)CH2Cl, n-BuLi, THF;
(c) Raney-Ni, MeOH, reflux; (d) 0.5 M TBAF in THF.
Investigation of heterogeneous hydrogenations re-
vealed that Raney-nickel generally gives rise to higher
facial selectivities than other commonly used catalysts
and is useful for obtaining some cis-substituted 4-alkyl-
prolinols. Further investigation into the scope and utility
of Raney-nickel in this capacity is warranted.
FIGURE 3. NOE correlation from the ROESY spectrum of
2b (in DMSO-d6).
Last, we have applied this approach to the synthesis
of novel 4-arylalkylprolinols and prolines for use in our
peptidomimetic research program. The results described
herein will find wide application in the synthesis of novel
pyrrolidine-based building blocks.
selectivity. This suggests that the reactions first lead to
intermediate 7a, which is then hydrogenated in situ.
The overall success of our hydrogenation strategy
yielded the cis- and trans-isomers of each 4-arylalkyl-
prolinol (9c,d,f and 11c,d,f) in suitable diastereomeric
purity. These building blocks are currently being incor-
porated into nonpeptidic somatostatin mimetics and
utilized as key components of novel, bicyclic peptidomi-
metic scaffolds. In addition, 4-substituted prolines could
also be obtained from the corresponding prolinols. Fol-
lowing the hydrogenations, the diastereomeric mixtures
9a-e and 11b-e were oxidized cleanly in the presence
of TEMPO, bleach, and sodium chlorite22 to give the
desired amino acid derivatives (1a-e, 2b-e) in good
yields after extractive workup (Scheme 1).
Experimental Section
General. Unless otherwise indicated, all compounds and
reagents were purchased from commercial suppliers and used
without further purification. Proton and carbon nuclear mag-
netic resonance spectra are recorded at either 300 or 400 MHz
in CDCl3 and internally referenced to residual CHCl3. All
chemical shifts (δ) are given in ppm and coupling constants
(J) are given in Hz. Electrospray and MALDI high-resolution
mass spectra were obtained from the Scripps Research Insti-
tute Mass Spectrometry Facility. Optical rotations were
measured with use of a 1.00 dm path length cell.
Oxidations of the indolylprolinol derivatives (9f and
11f) by this method were sluggish and resulted in the
formation of various side products. Attempts to separate
the complex product mixtures were unsuccessful. Despite
exploring mild two-step protocols as an alternative, we
were unable to obtain the indolylprolines in pure form.
We presume that oxidation of the indole ring occurred
simultaneously with that of the alcohol.
The configuration of the newly formed C4 stereocenters
was confirmed by ROESY experiments performed on
compounds 1b and 2b (Figure 3). The presence of a
strong NOE correlation between the C2 and C4 protons
of 2b established the cis relationship between the sub-
stituents of the pyrrolidine ring. No such NOE was
observed for compound 1b, supporting our stereochemical
assignments. In addition, we found good agreement in
(2S,4R)-N-tert-Butyloxycarbonyl-4-hydroxy-2-hydroxy-
methylpyrrolidine (4). A solution of trans-4-hydroxyproline
(10.0 g, 76.2 mmol) in 80 mL of 10% aq Na2CO3 was added
dropwise to a solution of Boc-anhydride (15.8 g, 72.4 mmol)
dissolved in 40 mL of 10:1 THF/dioxane. The mixture was
stirred for 18 h and the THF removed in vacuo. The mixture
was then washed with Et2O, cooled to 0 °C, and acidified
carefully to pH 3 with concentrated HCl. The aqueous layer
was extracted with EtOAc and the organic solution dried (Na2-
SO4) and concentrated to a white solid. The solid was then
dissolved in 70 mL of 1,2-DME, cooled to -20 °C, and treated
with 9.51 mL (72.4 mmol) of isobutyl chloroformate and 7.96
mL (72.4 mmol) of NMM. The reaction was stirred at -20 °C
for 30 min and the resulting white suspension was rapidly
filtered to remove the precipitate. After re-cooling the filtrate,
a solution of NaBH4 in 60 mL of H2O was added to the reaction
dropwise via an addition funnel and the reaction was stirred
for 20 min. The DCE was then removed in vacuo and the
residue was diluted with 1 M NaOH, extracted with EtOAc,
(22) Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.; Grabowski,
E. J. J.; Reider, P. J. Org. Chem. 1999, 64, 2564.
(23) Wang, Q.; Sasaki, N. A.; Potier, P. Tetrahedron 1998, 54, 15759.
J. Org. Chem, Vol. 68, No. 10, 2003 3927

Del Valle and Goodman
dried (Mg2SO4), and concentrated. Purification by silica gel
chromatography (95% EtOAc/Hex) afforded 11.96 g of 4 as a
white solid (76%, three steps). The 1H NMR and optical
rotation data we obtained were in agreement with the values
previously reported by Rajeev et al. (see ref 15). This compound
was converted into the mono-TBS ether by the procedure
described by Aoyagi et al. (ref 15).
(70%). Molecular formula C23H37NO3Si. Molecular weight
403.64; Rf 0.35 (25% EtOAc/Hex). 1H NMR (400 MHz, CDCl3)
δ 7.31-7.10 (m, 5H), 6.38 (2br s, 1H), 4.22-3.87 (m, 3H), 3.71-
3.32 (2m, 2H), 2.97-2.68 (m, 2H), 1.47 (s, 9H), 0.84 and 0.78
(2s, 9H), 0.02-0.00 (M, 6H). ES-MS: 426 [MNa]+.
(S)-2-tert-Butyldimethylsilyloxymethyl-N-tert-butyl-
oxycarbonyl-4-(4′-ethoxyphenyl)methylenepyrrolidine
(7d). Following the procedure described for the preparation
of 7a, a suspension of (4-ethoxy)benzyltriphenylphosphonium
bromide (1.81 g, 3.79 mmol) in 5 mL of dry THF was treated
with 426 mg (3.79 mmol) of potassium tert-butoxide, stirred 1
h, then treated with a solution of ketone 6 (500 mg, 1.517
mmol) in 5 mL of dry THF. After workup the crude material
was purified by silica gel chromatography (5% EtOAc/Hex
eluent) to afford 468 mg of colorless oil 7d as a mixture of E
and Z isomers (69%). Molecular formula C25H41NO4Si. Molec-
(S)- 2-tert-Butyldimethylsilyloxymethyl-N-tert-butyl-
oxycarbonylpyrrolidin-4-one (6). A solution of alcohol 5
(3.36 g, 10.0 mmol) in 50 mL of DCM was cooled to 0 °C and
treated with 2.32 g (10.0 mmol) of trichloroisocyanuric acid.
After 5 min, 156 mg (1.0 mmol) of TEMPO was added and the
reaction was stirred at 0 °C for 1 h. The mixture was then
diluted with DCM and washed with saturated aqueous NaH-
CO3, 1 M HCl, and brine. Drying over MgSO4 and concentra-
tion in vacuo gave the crude residue, which was purified by
silica gel chromatography (20% EtOAc/Hex eluent) to afford
2.91 g of 6 as a colorless oil (88%). Molecular formula C16H31-
NO4Si. Molecular weight 329.51; Rf 0.45 (25% EtOAc/Hex). 1H
NMR (400 MHz, CDCl3) δ 4.36 and 4.25 (2d, J ) 9.6 Hz, 1H,
rotamers), 4.03 (d, J ) 10.0 Hz, 1H), 3.88-3.74 (m, 1H), 3.67-
3.49 (m, 2H), 2.69-2.58 (m, 1H), 2.43 and 2.37 (2s, 1H,
rotamers), 1.46 and 1.45 (2s, 9H, rotamers), 0.81 (s, 9H), -0.02
(s, 6H); 13C NMR (100 MHz, CDCl3) δ 206.1, 156.7, 80.1, 65.5,
64.9, 55.7, 55.2, 54.0, 53.4, 40.8, 40.2, 28.4, 25.7, 18.1, -3.4,
1
ular weight 447.69; Rf 0.38 (10% EtOAc/Hex). H NMR (400
MHz, CDCl3) δ 7.26-6.82 (m, 4H), 6.33 (br s, 1H), 4.38-4.00
(complex m, 3H), 4.02 (m, 2H), 3.66-3.37 (m, 2H), 2.93-2.73
(m, 1H), 1.50 (s, 9H), 1.43 (m, 3H), 0.88 and 0.83 (2s, 9H), 0.52
and -0.25 (2d, 6H, J ) 3.2 H). ES-MS: 448 [MH]+, 446 [M -
H]-, 470 [MNa]+.
(S)-2-tert-Butyldimethylsilyloxymethyl-N-tert-butyl-
oxycarbonyl-4-(carboxymethyl)methylenepyrrolidine
(7e). Following the procedure described for the preparation
of 7a, a solution of methyldiethylphosphonoacetate (280 µL,
1.52 mmol) in 5 mL of dry THF was placed under Ar and
treated with 61 mg (1.52 mmol) of 60% NaH (dispersion in
mineral oil) followed by addition of ketone 6 (250 mg, 759 µmol)
in 5 mL of dry THF. After workup the crude material was
purified by silica gel chromatography (15% EtOAc/Hex eluent)
to afford 249 mg of pale yellow oil 7c as a mixture of E and Z
isomers (85%). Molecular formula C19H35NO5Si. Molecular
weight 385.58; Rf 0.44 (25% EtOAc/Hex). 1H NMR (400 MHz,
CDCl3) δ 5.79 and 5.74 (2s, 1H, isomers), 4.46 (s, 1H), 4.27-
3.75 (m, 2H), 3.71 and 3.70 (2s, 3H), 3.65 (m, 1H), 3.32 (m,
1H), 3.00-2.85 (m, 1H), 2.73-2.68 (m, 1H), 1.47 (s, 9H), 0.83
(s, 9H), 0.00 (s, 6H). ES-MS: 386 [MH]+, 408 [MNa]+.
(S)-2-tert-Butyldimethylsilyloxymethyl-N,N′-di-tert-
butyloxycarbonyl-4-(3′-indolyl)methylenepyrrolidine (7f).
Following the procedure described for the preparation of 7a,
a suspension of (N-Boc)-indolyltriphenylphosphonium bromide
(1.22 g, 2.12 mmol) in 3 mL of dry THF was placed under Ar
and treated with 244 mg (2.18 mmol) of potassium tert-
butoxide followed by addition of ketone 6 (350 mg, 1.06 mmol)
in 2 mL of dry THF. After workup, purification by silica gel
chromatography (5% EtOAc/Hex eluent) gave 369 mg of white
foam 7d as a mixture of E and Z isomers (64%). Molecular
formula C30H46N2O5Si. Molecular weight 542.31; Rf 0.42 (10%
EtOAc/Hex). 1H NMR (300 MHz, CDCl3) δ 8.14 (t, 1H, J ) 8.1
Hz), 7.59-7.24 (m, 4H), 6.52 and 6.51 (2br s, 1H), 4.29-4.03
(m, 3H), 3.71-3.35 (m, 2H), 2.99-2.80 (m, 2H), 1.69 and 1.68
(2s, 9H), 1.51 (s, 9H), 0.91 (m, 9H), -0.03 (m, 6H). ES-MS:
543 [MH]+, 565 [MNa]+.
General Procedure for Silyl Ether Deprotection and
Homogeneous Olefin Hydrogenation: Preparation of
N-Boc-trans-4-alkylprolinols (9a-f). The appropriate olefin
was treated with 2.0 equiv of a 0.5 M solution of TBAF in THF
at room temperature. After being stirred for 6 h, the solution
was concentrated in vacuo and the crude oil was purified by
silica gel chromatography (note: care must be taken to remove
residual TBAF as we found that it can effectively diminish or
destroy the activity of the catalyst in the next step). The alcohol
was then taken up in dry DCM (0.2 M substrate concentration)
and treated with 3 mol % of Ir(COD)PyPCy3PF6. The solution
was promptly put under H2 atmosphere (1 atm), stirred at
room temperature for 18 h, and concentrated to give an orange
oil. The products were purified as described below to isolate
the isomeric mixture (9 + 11) for NMR analysis. In each case,
chemical shifts are given for the major diastereomer.
-5.5, -5.5. ES-MS: 330 [MH]+, 352 [MNa]+. [R]20 +2.5 (c
D
1.0, CHCl3).
(S)-2-tert-Butyldimethylsilyloxymethyl-N-tert-butyl-
oxycarbonyl-4-methylenepyrrolidine (7a). A suspension
of methyltriphenylphosphonium bromide (2.710 g, 7.59 mmol)
in 15 mL of dry THF was placed under Ar and treated with
851 mg (7.59 mmol) of potassium tert-butoxide. The mixture
quickly became bright yellow and was stirred at room tem-
perature for 1 h. A solution of ketone 6 (1.00 g, 3.04 mmol) in
10 mL of dry THF was then added to the mixture via cannula
and stirred until no more starting material was being con-
sumed (1-4 h). The mixture was poured into water, extracted
with Et2O, dried over MgSO4, and concentrated in vacuo. The
crude material was purified by silica gel chromatography (5%
EtOAc/Hex eluent) to afford 776 mg of 7a as a colorless oil
(78%). Molecular formula C17H33NO3Si. Molecular weight
327.54; Rf 0.33 (10% EtOAc/Hex). 1H NMR (400 MHz, CDCl3)
δ 4.93-4.96 (m, 2H), 4.05-3.89 (m, 2H), 3.80 and 3.76 (2d,
1H, J ) 2.4 Hz, rotamers), 3.60 and 3.58 (2d, 1H, J ) 3.6 Hz,
isomers), 3.57 and 3.33 (2t, 1H, J ) 8.8 Hz, rotamers), 2.58
(m, 2H), 1.42 (s, 9H), 0.83 (s, 9H), -0.01 (m, 6H). ES-MS: 350
[MNa]+. [R]20 -20.0 (c 1.0, CHCl3).
D
(S)-2-tert-Butyldimethylsilyloxymethyl-N-tert-butyl-
oxycarbonyl-4-propylenepyrrolidine (7b). Following the
procedure described for the preparation of 7a, a suspension
of propyltriphenylphosphonium bromide (1.17 g, 3.04 mmol)
in 5 mL of dry THF was treated with 341 mg (3.04 mmol) of
potassium tert-butoxide, stirred 1 h, then treated with a
solution of ketone 6 (400 mg, 1.214 mmol) in 5 mL of dry THF.
After workup the crude material was purified by silica gel
chromatography (5% EtOAc/Hex eluent) to afford 306 mg of
colorless oil 7b as a mixture of E and Z isomers (71%).
Molecular formula C19H37NO3Si. Molecular weight 355.56; Rf
0.49 (10% EtOAc/Hex). 1H NMR (400 MHz, CDCl3) δ 5.26 (br
s, 1H), 3.96 (d, 1H, J ) 14.8 Hz), 3.86 (m, 2H), 3.34 (m, 1H),
2.57 and 2.49 (2m, 2H), 1.94 (m, 2H), 1.46 (s, 9H), 0.94 (m,
3H), 0.86 (s, 9H), 0.02 (s, 6H). ES-MS: 378 [MNa]+.
(S)-2-tert-Butyldimethylsilyloxymethyl-N-tert-butyl-
oxycarbonyl-4-(phenyl)methylenepyrrolidine (7c). Fol-
lowing the procedure described for the preparation of 7a, a
suspension of benzyltriphenylphosphonium bromide (3.29 g,
7.59 mmol) in 25 mL of dry THF was treated with 851 mg
(7.59 mmol) of potassium tert-butoxide, stirred 1 h, then
treated with a solution of ketone 6 (1.00 g, 3.04 mmol) in 10
mL of dry THF. After workup the crude material was purified
by silica gel chromatography (5% EtOAc/Hex eluent) to afford
860 mg of colorless oil 7b as a mixture of E and Z isomers
(2S,4R)-N-tert-Butyloxycarbonyl-2-hydroxymethyl-4-
methylpyrrolidine (9a). Yield of 8a (after silyl ether depro-
3928 J. Org. Chem., Vol. 68, No. 10, 2003

Boc-Protected 4-Alkylprolinols and Prolines
tection): 85%. After hydrogenation the residue was purified
by silica gel chromatography (50% EtOAc/Hex eluent) to give
a pale orange oil (90%, dr >40:1). Molecular formula C11H21-
13C NMR (100 MHz, CDCl3) δ 156.8, 149.4, 135.1, 130.1, 124.1,
122.7, 122.2, 118.6, 115.1, 83.4, 80.2, 67.5, 64.7, 59.3, 52.4, 37.1,
34.8, 28.4, 28.2. ES-MS: 431 [MH]+, 453 [MNa]+. [R]20D -12.4
(c 1.0, CHCl3).
1
NO3. Molecular weight 215.29; Rf 0.33 (50% EtOAc/Hex). H
NMR (400 MHz, CDCl3) δ 4.58 (br s, 1H), 3.95 (m, 1H), 3.58-
3.57 (m, 2H), 3.42 (dd, 1H, Ja ) 10.0 Hz, Jb ) 6.4 Hz), 2.88 (t,
J ) 8.4 Hz, 1H), 2.30 (m, 1H), 1.65 (m, 1H), 1.55 (m, 1H), 1.41
(s, 9H), 0.96 (d, 3H, J ) 6.4 Hz); 13C NMR (100 MHz, CDCl3)
δ 157.1, 80.3, 67.8, 60.0, 54.7, 36.9, 31.9, 28.7, 18.1. ES-MS:
General Procedure for Raney-Nickel Olefin Hydro-
genation and Silyl Ether Deprotection: Preparation of
N-Boc-cis-4-alkylprolinols (11b-f). To a 0.1 M solution of
the appropriate olefin in MeOH was added Raney-Ni (10:1 w/w
Raney-Ni/olefin) that had been washed successively with
MeOH. The mixture was placed under H2 atmosphere (1 atm)
and stirred at room temperature for 18 h (note: the mixture
was refluxed in the case of 7d; reaction time was 45 min in
the case of 7f). The mixture was then filtered through a pad
of Celite and rinsed successively with DCM (Caution! the
filter cake should not be allowed to dry during filtration as
Raney-nickel can rapidly ignite). The organic solution was
dried over MgSO4, concentrated in vacuo, and treated with 2
equiv of 0.5 M TBAF solution in THF. After being stirred at
room temperature for 6 h, the solution was concentrated to
give a bronze oil. The products were purified as described
below to isolate the isomeric mixture (9 + 11) for NMR
analysis. In each case, chemical shifts are given for the major
diastereomer.
216 [MH]+. [R]20 -38.2 (c 1.0, CHCl3).
D
(2S,4R)-N-tert-Butyloxycarbonyl-2-hydroxymethyl-4-
propylpyrrolidine (9b). Yield of 8b (after silyl ether depro-
tection): 80%. After hydrogenation the residue was purified
by silica gel chromatography (50% EtOAc/Hex eluent) to give
a pale orange oil (95%, dr >40:1). Molecular formula C13H25-
1
NO3. Molecular weight 243.35; Rf 0.22 (25% EtOAc/Hex). H
NMR (400 MHz, CDCl3) δ 4.42 (br s, 1H), 3.98 (br s, 1H), 3.61-
3.42 (m, 3H), 2.91 (m, 1H), 2.15 (m, 1H), 1.69 (m, 1H), 1.61
(m, 1H), 1.43 (s, 9H), 1.28 (m, 4H), 0.88 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ 156.9, 80.0, 67.8, 59.5, 52.8, 36.9, 35.9,
34.5, 28.4, 21.2, 14.2. ES-MS: 244 [MH]+. [R]20D -30.0 (c 1.0,
CHCl3).
(2S,4R)-N-tert-Butyloxycarbonyl-4-benzyl-2-hydroxy-
methylpyrrolidine (9c). Yield of 8c (after silyl ether depro-
tection): 81%. After hydrogenation the residue was purified
by silica gel chromatography (50% EtOAc/Hex eluent) to give
a colorless oil (93%, dr >40:1). Molecular formula C17H25NO3.
(2S,4S)-N-tert-Butyloxycarbonyl-2-hydroxymethyl-4-
propylpyrrolidine (11b). Yield of 10b (after hydrogena-
tion): 87%. After silyl ether deprotection the residue was
purified by silica gel column (20% EtOAc/Hex eluent) to give
a colorless oil (94%, dr 13:1). Molecular formula C13H25NO3.
1
Molecular weight 291.39; Rf 0.42 (50% EtOAc/Hex). H NMR
1
(400 MHz, CDCl3) δ 7.37-7.08 (m, 5H), 4.54 (br s, 1H), 4.05
(m, 1H), 3.57 (m, 2H), 3.39 (dd, 1H, Ja ) 10.4 Hz, Jb ) 6.4
Hz), 3.13 (dd, 1H, Ja ) 11.2 Hz, Jb ) 7.2 Hz), 2.61 (m, 2H),
2.43 (s, 1H, J ) 7.6 Hz), 1.83-1.60 (complex m, 2H), 1.46 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 157.1, 140.1, 128.8, 128.4,
126.4, 80.5, 67.8, 59.7, 52.6, 39.8, 39.6, 34.5, 28.8. ES-MS: 292
Molecular weight 243.35; Rf 0.26 (25% EtOAc/Hex). H NMR
(300 MHz, CDCl3) δ 4.67 (br s, 1H), 3.85 (m, 1H), 3.58 (m, 3H),
2.72 (t, 1H, J ) 10.8 Hz), 2.10 (m, 1H), 1.97 (m, 1H), 1.41 (s,
9H), 1.26 (m, 4H), 0.85 (m, 1H), 0.81 (m, 3H); 13C NMR (100
MHz, CDCl3) δ 156.6, 80.0, 67.6, 61.0, 53.1, 37.1, 35.5, 35.0,
28.5, 21.2, 15.3. ES-MS: 244 [MH+] calcd, 242 [M - H] -, 266
[MH+], 314 [MNa]+. [R]20 -13.6 (c 1.0, CHCl3).
[MNa+]. [R]20 -43.5 (c 1.0, CHCl3).
D
D
(2S,4R)-N-tert-Butyloxycarbonyl-4-(4′-ethoxy)benzyl-
2-hydroxymethylpyrrolidine (9d). Yield of 8d (after silyl
ether deprotection): 77%. After hydrogenation the residue was
purified by silica gel chromatography (25% EtOAc/Hex eluent)
to give a pale orange oil (90%, dr >40:1). Molecular formula
C19H29NO4. Molecular weight 335.44; Rf 0.16 (25% EtOAc/Hex).
1H NMR (400 MHz, CDCl3) δ 7.02 (d, 2H, J ) 8.0 Hz), 6.83 (d,
2H, J ) 8.4 Hz), 4.52 (br s, 1H), 4.00 (m, 3H), 3.58 (m, 2H),
3.38 (dd, 1H, Ja ) 10.4 Hz, Jb ) 6.8 Hz), 3.12 (dd, 1H, Ja )
11.2 Hz, Jb ) 7.2 Hz), 2.55 (d, 2H, J ) 6.4 Hz), 2.39 (m, 1H),
1.74-1.62, (m, 2H), 1.46 (s, 9H), 1.40 (t, 3H, J ) 6.8 Hz); 13C
NMR (100 MHz, CDCl3) δ 157.1, 131.7, 129.3, 114.4, 114.3,
80.6, 67.8, 63.3, 59.4, 52.2, 39.1, 38.3, 34.1, 28.5, 14.9. ES-
(2S,4S)-N-tert-Butyloxycarbonyl-4-benzyl-2-hydroxy-
methylpyrrolidine (11c). Yield of 10c (after hydrogena-
tion): 95%. After silyl ether deprotection the residue was
purified by silica gel chromatography (40% EtOAc/Hex eluent)
to give a colorless oil (89%, dr 16:1). Molecular formula C17H25-
1
NO3. Molecular weight 291.39; Rf 0.44 (50% EtOAc/Hex). H
NMR (400 MHz, CDCl3) δ 7.31-7.12 (m, 5H), 5.36 (br s, 1H),
3.89 (q, J ) 8.0 Hz, 1H), 3.68-3.55 (m, 3H), 2.92 (t, J ) 10.4
Hz, 1H), 2.72-2.55 (m, 2H), 2.31 (m, 1H), 2.06 (m, 1H), 1.47
(s, 9H), 1.18 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 156.9,
140.0, 129.0, 128.4, 128.6, 126.4, 80.6, 67.9, 61.5, 53.3, 39.5,
35.6, 28.8. ES-MS: 292 [MH+], 314 [MNa+]. [R]20 -65.1 (c
D
1.0, CHCl3).
MS: 336 [MH]+, 358 [MNa]+. [R]20 -12.9 (c 1.0, CHCl3).
D
(2S,4S)-N-tert-Butyloxycarbonyl-4-(4′-ethoxy)benzyl-
2-hydroxymethylpyrrolidine (11d). Yield of 10d (after
hydrogenation): 80%. After silyl ether deprotection the residue
was purified by silica gel chromatography (25% EtOAc/Hex
eluent) to give a colorless oil (79%, dr 16:1). Molecular formula
C19H29NO4. Molecular weight 335.44; Rf 0.20 (30% EtOAc/Hex).
1H NMR (400 MHz, CDCl3) δ 7.03 (d, 2H, J ) 7.6 Hz), 6.81 (d,
2H, J ) 8.4 Hz), 5.29 (d, 1H, J ) 8.0 Hz), 4.01 (q, 2H, J ) 6.8
Hz), 3.90 (q, 1H, J ) 8.0 Hz), 3.62 (m, 3H), 2.91 (t, 1H, J )
10.0 Hz), 2.66-2.55 (m, 2H), 2.28 (m, 1H), 2.08 (m, 1H), 1.48
and 1.46 (2s, 9H, rotamers), 1.41 (t, 3H, J ) 7.2 Hz), 1.16 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 157.1, 131.8, 129.5, 129.3,
114.2, 80.3, 67.7, 63.3, 61.2, 52.9, 39.3, 38.1, 35.2, 28.4, 14.9.
(2S,4S)-N-tert-Butyloxycarbonyl-2-hydroxymethyl-4-
(methoxycarbonyl)methylpyrrolidine (9e). Yield of 11e
(after silyl ether deprotection): 80%. After hydrogenation the
residue was purified by silica gel chromatography (50% EtOAc/
Hex eluent) to give an pale yellow oil (92%, dr 16:1). Molecular
formula C13H23NO5. Molecular weight 273.33; Rf 0.20 (50%
EtOAc/Hex). 1H NMR (400 MHz, CDCl3) δ 4.34 (2br s, 1H),
3.94 (m, 1H), 3.60 (s, 3H), 3.53 (m, 3H), 2.96 (t, 1H, J ) 8.0
Hz), 2.54 (m, 1H), 2.30 (m, 2H), 1.78 (m, 1H), 1.63 (m, 1H),
1.38 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.4, 156.6, 80.5,
67.1, 59.4, 52.6, 51.9, 37.9, 35.4, 34.4, 33.9, 28.8. ES-MS: 274
[MH]+, 296 [MNa]+. [R]20 -20.2 (c 1.0, CHCl3).
D
ES-MS: 336 [MH]+, 358 [MNa]+. [R]20 -33.8 (c 1.0, CHCl3).
D
(2S,4R)-N,N′-Di-tert-butyloxycarbonyl-2-hydroxymeth-
yl-4-(3′-indolylmethyl)pyrrolidine (9f). Yield of 8f (after
silyl ether deprotection): 83%. After hydrogenation the residue
was purified by silica gel chromatography (25% EtOAc/Hex
eluent) to give a white foam (94%, dr >40:1). Molecular
formula C24H34N2O5. Molecular weight 430.55; Rf 0.24 (25%
EtOAc/Hex). 1H NMR (400 MHz, CDCl3) δ 8.13 (br s, 1H),
7.49-7.21 (m, 4H), 4.58 (m, 1H), 4.09 (m, 1H), 3.59 (m, 2H),
3.45 (dd, 1H, Ja ) 10.4 Hz, Jb ) 6.4 Hz), 3.20 (dd, 1H, Ja )
10.0 Hz, Jb ) 6.4 Hz), 2.70 and 2.68 (2s, 2H, rotamers), 2.58
(m, 1H), 1.82 (m, 1H), 1.71 (m, 1H), 1.66 (s, 9H), 1.46 (s, 9H);
(2S,4R)-N-tert-Butyloxycarbonyl-2-hydroxymethyl-4-
(methoxycarbonyl)methylpyrrolidine (11e). Yield of 8e
(after hydrogenation): 85%. After silyl ether deprotection the
residue was purified by silica gel chromatography (50% EtOAc/
Hex eluent) to give a colorless oil (80%, dr 15:1). Molecular
formula C13H23NO5. Molecular weight 273.33; Rf 0.15 (50%
EtOAc/Hex). 1H NMR (400 MHz, CDCl3) δ 5.19 (br s, 1H), 3.93
(q, 1H, J ) 7.2 Hz), 3.78 (t, 1H, J ) 8.0 Hz), 3.65 (s, 3H), 3.56
(m, 1H), 2.84 (t, 1H, J ) 10.4 Hz), 2.45 (m, 1H), 2.36 (m, 2H),
2.21 (m, 1H), 1.43 (s, 9H), 1.15 (m, 1H); 13C NMR (100 MHz,
J. Org. Chem, Vol. 68, No. 10, 2003 3929

Del Valle and Goodman
CDCl3) δ 172.0, 157.0, 80.4, 67.3, 60.9, 52.6, 51.6, 37.0, 35.1,
59.3, 59.1, 52.2, 51.7, 39.5, 38.7, 37.9, 36.4, 34.8, 29.5, 28.7,
33.6, 28.4. ES-MS: 274 [MH]+, 296 [MNa]+. [R]20 -32.3 (c
28.3, 20.9, 15.8; HR-FTMS [MNa]+ calcd for 1c 328.1519, found
D
1.0, CHCl3).
328.1529; [R]20 -36.7 (c 1.0, CHCl3).
D
(2S,4S)-N,N′-Di-tert-butyloxycarbonyl-2-hydroxymethyl-
4-(3′-indolylmethyl)pyrrolidine (11f). Yield of 8f (after
hydrogenation): 84%. After silyl ether deprotection the residue
was purified by silica gel chromatography (20% EtOAc/Hex
eluent) to give a colorless oil (78%, dr 22:1. Molecular formula
C24H34N2O5. Molecular weight 430.55; Rf 0.21 (25% EtOAc/
(2S,4R)-N-tert-Butyloxycarbonyl-4-(4′-ethoxy)benzyl-
proline (1d). Yield: white solid (80%, dr >40:1). Molecular
formula C19H27NO5. Molecular weight 349.43; Rf 0.16 (50%
EtOAc/Hex). 1H NMR (300 MHz, CDCl3) δ 8.95 (br s, 1H), 7.06
(m, 2H), 6.70 (m, 2H), 4.39 and 4.26 (2d, 1H, J ) 5.7 Hz,
rotamers), 4.02 (m, 2H), 3.67 and 3.50 (2m, 1H), 3.11 and 3.03
(2m, 1H, J ) 6.9 Hz, rotamers), 2.60 (m, 3H), 2.34 and 2.04
(2m, 1H), 2.05 and 1.82 (2m, 1H), 1.47-1.41 (m, 12H); 13C
NMR (100 MHz, CDCl3) δ 178.6, 175.0, 157.5, 155.6, 131.6,
129.7, 114.6, 81.7, 80.5, 63.7, 59.0, 52.2, 51.6, 39.7, 38.4, 36.4,
34.5, 28.7, 21.6, 15.2; HR-FTMS [MNa]+ calcd for 1d 372.1781,
1
Hex). H NMR (400 MHz, CDCl3) δ 8.11 (d, 1H, J ) 7.5 Hz),
7.20-7.50 (m, 4H), 5.30 (br s, 1H), 3.91 (m, 1H), 3.76-3.55
(m, 3H), 2.95 (m, 1H), 2.73 (m, 2H), 2.49 (m, 1H), 2.16 (m,
1H), 1.66 (s, 9H), 1.56 (m, 1H), 1.44 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 157.0, 149.8, 135.6, 130.5, 124.6, 123.0, 122.6,
119.0, 115.5, 83.8, 80.7, 68.0, 61.5, 53.5, 37.6, 35.9, 31.9, 28.8,
found 372.1791; [R]20 -19.6 (c 1.0, CHCl3).
D
28.4, 23.0, 21.0, 14.5. ES-MS: 431 [MH]+, found 431. [R]20
-28.3 (c 1.0, CHCl3).
D
(2S,4S)-N-tert-Butyloxycarbonyl-4-(methoxycarbon-
yl)methylproline (1e). Yield: colorless oil (84%, dr 16:1).
Molecular formula C13H21NO6. Molecular weight 287.31; Rf
0.46 (75% EtOAc/Hex). 1H NMR (300 MHz, CDCl3) δ 7.40 (br
s, 1H), 4.37 and 4.24 (2d, 1H, J ) 8.4 Hz, rotamers), 3.76 (m,
1H), 3.65 and 3.68 (2s, 3H, rotamers), 3.03 (m, 1H), 2.67 (m,
1H), 2.41 (m, 2H), 2.24 (m, 1H), 1.80-1.97 (m, 1H), 1.37 and
1.42 (2s, 9H, rotamers); 13C NMR (100 MHz, CDCl3) δ 177.4,
175.1, 172.0, 155.3, 153.6, 81.1, 80.5, 58.6, 51.8, 51.1, 37.0, 36.0,
34.6, 33.7, 32.9, 28.3; HR-FTMS [MNa]+ calcd for 1e 310.1261,
Representative Procedure for Oxidation of N-Boc-4-
alkylprolinols: Preparation of N-Boc-4-alkylprolines
(1a-e and 2b-e). Two oxidant solutions were prepared prior
to carrying out the reaction. The first consisted of 84 mg (742
µmol) of 80% NaClO2 dissolved in 0.4 mL of water (∼2 M).
The second was comprised of 22 µL of bleach diluted with 0.4
mL of water. The desired alcohol (371 µmol) was dissolved in
5 mL of a 3:2 mixture of MeCN:NaH2PO4 buffer (pH 6.6, 0.67
M) and warmed to 45 °C. The reaction mixture was treated
with 6 mg (37 µmol) of TEMPO followed by the dropwise,
simultaneous addition (over 1 h) of the two oxidant solutions
described above. Stirring was maintained at 45 °C until TLC
showed complete consumption of starting material (usually 24
h). The reaction was cooled to room temperature and a
saturated Na2SO3 solution was added dropwise until the
reaction mixture became colorless. The MeCN was removed
in vacuo and the resulting mixture basified to pH >10 with 1
M NaOH and washed twice with Et2O. The solution was then
carefully acidified with 1 M HCl to pH <3 and extracted 6
times with Et2O. The organic layers were dried over Na2SO4
and concentrated to give the carboxylic acid products.
found 310.1253; [R]20 -24.5 (c 1.0, MeOH).
D
(2S,4S)-N-tert-Butyloxycarbonyl-4-propylproline (2b).
Yield: white solid (85%, dr 13:1). Molecular formula C13H23-
1
NO4. Molecular weight 257.33; Rf 0.24 (50% EtOAc/Hex). H
NMR (400 MHz, CDCl3) δ 10.06 (br s, 1H), 4.26 and 4.17 (2s,
1H, rotamers, J ) 8.0 Hz), 3.78 and 3.66 (2dd, 1H, rotamers,,
Ja ) 10.4 Hz, Jb ) 8.0 Hz), 2.96 (m, 1H), 2.43 (m, 1H), 2.13
(m, 1H), 1.71-1.55 (m, 2H), 1.48 and 1.39 (2s, 9H, rotamers),
1.35 (m, 4H), 0.89 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 178.5,
153.4, 80.7, 80.3, 59.3, 52.5, 51.9, 38.2, 37.8, 37.2, 35.6, 34.8,
28.4, 28.2, 21.3, 14.4; HR-FTMS [MNa]+ calcd for 2b 280.1519,
found 280.1525; [R]20 -86.8 (c 1.0, CHCl3).
D
(2S,4S)-4-Benzyl-N-tert-butyloxycarbonylproline (2c).
(2S,4R)-N-tert-Butyloxycarbonyl-4-methylproline (1a).
Yield: colorless oil (84%, dr >40:1). Molecular formula C11H19-
Yield: colorless oil (89%, dr 15:1). Molecular formula C17H23-
1
NO4. Molecular weight 305.37; Rf 0.48 (75% EtOAc/Hex). H
1
NO4. Molecular weight 229.28; Rf 0.42 (75% EtOAc/Hex). H
NMR (400 MHz, CDCl3) δ 8.95 (br s, 1H), 7.12-7.32 (m, 5H),
4.30 and 4.16 (2t, 1H, J ) 8.0 Hz), 3.60 and 3.75 (2dd, 1H,
Ja ) 10.0 Hz, Jb ) 7.2 Hz), 3.11 (m, 1H), 2.72 (m, 2H), 2.30-
2.47 (complex m, 2H), 1.71-1.92 (m, 1H), 1.46 and 1.39 (2s,
9H, rotamers); 13C NMR (100 MHz, CDCl3) δ 178.9, 176.3,
153.7, 139.8, 129.0, 128.7, 126.5, 81.4, 80.8, 59.5, 52.6, 52.1,
40.5, 40.2, 39.1, 37.1, 35.3, 28.7, 28.6; HR-FTMS [MNa]+ calcd
NMR (400 MHz, CDCl3) δ 10.02 (br s, 1H), 4.36 and 4.24 (2d,
1H, J ) 8.0 Hz, rotamers), 3.71 and 3.54 (2dd, 1H, Ja ) 10.4
Hz, Jb ) 7.6 Hz, rotamers), 2.83-2.96 (2t, 1H, J ) 8.8 Hz,
rotamers), 2.35 (m, 1H), 2.09-2.29 (m, 1H), 1.72-1.89 (m, 1H),
1.48 and 1.38 (2s, 9H, rotamers), 1.00 and 1.02 (2s, 3H,
rotamers); 13C NMR (100 MHz, CDCl3) δ 178.1, 175.4, 155.7,
153.6, 81.0, 80.2, 59.2, 53.7, 59.0, 38.3, 36.6, 32.1, 31.2, 29.7,
28.4, 17.4, 17.1; HR-FTMS [MNa]+ calcd for 1a 252.1206, found
for 2c 328.1519, found 328.1524; [R]20 -65.1 (c 1.0, CHCl3).
D
(2S,4S)-N-tert-Butyloxycarbonyl-4-(4′-ethoxy)benzyl-
proline (2d). Yield: white solid (85%, dr 16:1). Molecular
formula C19H27NO5. Molecular weight 349.43; Rf 0.20 (50%
252.1200 [MNa]+; [R]20 -74.7 (c 1.0, CHCl3).
D
(2S,4R)-N-tert-Butyloxycarbonyl-4-propylproline (1b).
Yield: white solid (81%, dr >40:1). Molecular formula C13H23-
1
EtOAc/Hex). H NMR (400 MHz, CDCl3) δ 7.04 (m, 2H), 6.81
1
NO4. Molecular weight 257.33; Rf 0.23 (50% EtOAc/Hex). H
(m, 2H), 4.29 and 4.18 (2t, 1H, J ) 8.0 Hz, rotamers), 4.00 (m,
2H), 3.72-3.60 (m, 1H), 3.09 (m, 1H), 2.63 (m, 2H), 2.34 (m,
2H), 1.90 and 1.69 (2m, 1H), 1.48-1.38 (m, 12H); 13C NMR
(100 MHz, CDCl3) δ 178.9, 176.4, 157.5, 131.8, 129.7, 129.6,
114.7, 63.7, 59.5, 52.6, 52.1, 40.4, 38.2, 37.1, 35.0, 28.7, 21.1,
15.2; HR-FTMS [MNa]+ calcd for 2d 372.1781, found 372.1786;
NMR (300 MHz, CDCl3) δ 10.22 (br s, 1H), 4.38 and 4.26 (2d,
1H, J ) 7.2 Hz, rotamers), 3.73 and 3.58 (2dd, 1H, Ja ) 10.0
Hz, Jb ) 8.4 Hz, rotamers), 2.94 and 2.84 (2t, 1H, J ) 9.6 Hz,
rotamers), 2.33-2.25 (m, 2H), 1.71-1.67 (m, 1H), 1.46-1.23
(m, 14H), 0.88 (m, 3H); 13C NMR (100 MHz, CDCl3) 178.9,
175.8, 156.2, 153.9, 81.4, 80.5, 59.4, 52.6, 52.0, 35.4, 35.3, 35.0,
30.0, 28.7, 28.2, 21.5, 14.5; HR-FTMS [MNa]+ calcd for 1b
[R]20 -42.7 (c 1.0, CHCl3).
D
(2S,4R)-N-tert-Butyloxycarbonyl-4-(methoxycarbon-
yl)methylproline (2e). Yield: colorless oil (84%, dr 15:1).
Molecular formula C13H21NO6. Molecular weight 287.31; Rf
0.46 (75% EtOAc/Hex). 1H NMR (400 MHz, CDCl3) δ 8.21 (br
s, 1H), 4.33 and 4.20 (2t, 1H, J ) 7.2 Hz), 3.81 (m, 1H), 3.66
and 3.68 (2s, 3H,, rotamers), 3.06 (m, 1H), 2.57 (m, 1H), 2.46
(m, 3H), 1.91 and 1.65 (2m, 1H, rotamers), 1.39 and 1.48 (2s,
9H, rotamers); 13C NMR (100 MHz, CDCl3) δ 178.1, 175.0,
172.0, 155.6, 153.3, 81.5, 80.6, 58.9, 52.1, 51.8, 51.5, 37.0, 36.6,
34.6, 34.3, 34.1, 33.9, 29.7, 28.4, 28.3; HR-FTMS [MNa]+ calcd
280.1519, found 280.1518; [R]20 -33.7 (c 1.0, CHCl3).
D
(2S,4R)-4-Benzyl-N-tert-butyloxycarbonylproline (1c).
Yield: colorless oil (86%, dr >40:1). Molecular formula C17H23-
1
NO4. Molecular weight 305.37; Rf 0.48 (75% EtOAc/Hex). H
NMR (400 MHz, CDCl3) δ 9.75 (br s, 1H), 7.31-7.13 (m, 5H),
4.40 and 4.26 (2d, 1H, J ) 7.2 Hz, rotamers), 3.71 and 3.50
(2dd, 1H, Ja ) 10.4 Hz, Jb ) 7.2 Hz), 3.02 and 3.15 (2t, 1H,
J ) 10.0 Hz, rotamers), 2.55-2.71 (m, 3H), 1.81-2.30 (m, 2H),
1.44 and 1.39 (2s, 9H, rotamers); 13C NMR (100 MHz, CDCl3)
δ 178.5, 175.5, 156.0, 153.8, 139.6, 128.7, 126.5, 81.5, 80.6, 72.4,
for 2e 310.1261, found 310.1263; [R]20 -60.4 (c 1.0, MeOH).
D
3930 J. Org. Chem., Vol. 68, No. 10, 2003

Boc-Protected 4-Alkylprolinols and Prolines
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for 13 and 14, 1H NMR spectra
for compounds 1b-e, 2a-e, 6, 7a, 9b-f, and 11a-f. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We gratefully acknowledge the
National Institutes of Health (NIH DK 15410) for
financial support of this research. We also thank An-
tonia de Capua and Elisabetta Bosa for performing
ROESY experiments on 1b and 2b and Christoph Zapf
for helpful discussions.
JO034214L
J. Org. Chem, Vol. 68, No. 10, 2003 3931