Benzyl 2-cyano-3,3-dimethyl-1-pyrrolidinecarboxylate, a versatile intermediate for the synthesis of 3,3-dimethylproline derivatives

Article abstract of DOI:10.1021/jo7027163

(Chemical Equation Presented) The synthesis of racemic nitrile (±)-9 was accomplished in four steps and 58% overall yield from the known pyrrolidinone 5. Nitrile (±)-9 was resolved via preparative chiral HPLC to afford optically pure nitriles (+)-9 and (-

Full text of DOI:10.1021/jo7027163

dimethylproline has been proposed as a strategy for reducing
the rate of N-terminal amide isomerization in peptides.4
Benzyl 2-Cyano-3,3-Dimethyl-
1-pyrrolidinecarboxylate, a Versatile Intermediate
for the Synthesis of 3,3-Dimethylproline
Derivatives
Jesus R. Medina,* Charles W. Blackledge, Karl F. Erhard,
Jeffrey M. Axten, and William H. Miller
Oncology Center of Excellence for Drug DiscoVery,
GlaxoSmithKline, CollegeVille, PennsylVania 19426
jesus.r.medina@gsk.com
ReceiVed December 20, 2007
FIGURE 1. 3,3-Dimethylproline derivatives.
As part of a medicinal chemistry program,5 we required
access to multigram quantities of both enantiomers of 3,3-
dimethylproline ((+)-1 and (-)-1) and 3,3-dimethylprolinamide
((+)-2 and (-)-2) (Figure 1). During the course of this work,
the only 3,3-dimethylproline derivative commercially available
was the expensive Boc protected (S)-enantiomer 3.6 Although
the synthesis of 3 (in eight steps and 41% overall yield from
4-hydroxy-S-proline) was reported,3b we chose to pursue a route
using the nitrile (()-9 as a common late-stage intermediate
which enables rapid access to (()-1,7 (()-2,5,6 and their
respective enantiomers with an additional resolution step. This
also provided the opportunity to develop analytical HPLC
methods for the determination of the optical purity of the
compounds prepared.
The synthesis of racemic nitrile (()-9 was accomplished in
four steps and 58% overall yield from the known pyrroli-
dinone 5. Nitrile (()-9 was resolved via preparative chiral
HPLC to afford optically pure nitriles (+)-9 and (-)-9, from
which 3,3-dimethylprolines (+)-1 and (-)-1 and 3,3-di-
methylprolinamides (+)-2 and (-)-2 could be accessed in
nearly quantitative yield, without loss of optical purity. The
absolute configurations of the resolved prolines and proli-
namides were determined by correlation with an intermediate
of known absolute stereochemistry.
As outlined in Scheme 1, alkylation of the lithium enolate of
N-TBS-protected 3-pyrrolidinone 48 with methyl iodide, fol-
lowed by treatment with TBAF, provided 3,3-dimethylpyrro-
lidin-2-one (5)9 in 46% overall yield. Deprotonation of 5 with
LHMDS, followed by addition of benzyl chloroformate, afforded
(2) (a) Zhang, K.; Schweizer, F. Synlett 2005, 3111. and references cited
therein. (b) Che, Y.; Marshall, G. R. J. Org. Chem. 2004, 69, 9030. (c) Quancard,
J.; Labonne, A.; Jacquot, Y.; Lavielle, S.; Karoyan, P. J. Org. Chem. 2004, 69,
7940. (d) Cavelier, F.; Vivet, B.; Martinez, J.; Aubry, A.; Didierjean, C.; Vicherat,
A.; Marraud, M. J. Am. Chem. Soc. 2002, 124, 2917. (e) Halab, L.; Lubell,
W. D. J. Am. Chem. Soc. 2002, 124, 2474. (f) Tam, J. P.; Miao, Z. J. Am. Chem.
Soc. 1999, 121, 9013. (g) An, S. S. A.; Lester, C. C.; Peng, J.-L.; Y, J.; Rothwarf,
D. M.; Welker, E.; Thannhauser, T. W.; Zhang, L. S.; Tam, J. P.; Scheraga,
H. A. J. Am. Chem. Soc. 1999, 121, 11558. (h) Beausoleil, E.; Lubell, W. D.
J. Am. Chem. Soc. 1996, 118, 12902. (i) Delaney, N. G.; Madison, V. J. J. Am.
Chem. Soc. 1982, 104, 6635.
Among the naturally occurring amino acids, proline has a
unique conformationally restricted structure resulting from its
side chain and the R-amino group being contained within a five-
membered ring. Consequently, proline can induce a reversal in
the direction of the peptide backbone and can impart a dramatic
effect on the secondary structure of many peptides and proteins,
directing and switching peptide chains into favorable topolo-
gies.1 Expanded interest in the effect of proline congeners on
protein structure and stability led to the preparation of analogues
that were incorporated into peptides to study their structural
and biological properties.2 The use of proline congeners is also
common in the small molecule peptide arena. For instance,
ꢀ-alkylprolines have been used to develop enzyme inhibitors
and peptidomimetics exhibiting improved bioactivity and meta-
bolic stability.3 In particular, replacement of proline by 3,3-
(3) (a) Raghavan, S.; Lu, Z.; Beeson, T.; Chapman, K. T.; Schleif, W. A.;
Olsen, D. B.; Stahlhut, M.; Rutkowski, C. A.; Gabryelski, L.; Emini, E.; Tata,
J. R. Bioorg. Med. Chem. Lett. 2007, 17, 5432. (b) Sharma, R.; Lubell, W. D.
J. Org. Chem. 1996, 61, 202 and references cited therein.
(4) Beausoleil, B.; Sharma, R.; Michnick, S. W.; Lubell, W. D. J. Org. Chem.
1998, 63, 6572.
(5) Axten, J. M.; Medina, J. R. Patent WO 2007016364 A 2 2007.
(6) After this work was completed, 3,3-dimethylprolinamide (()-2 became
commercially available (see the Supporting Information).
(7) (a) Robl, J. A.; Sulsky, R. B.; Augeri, D. J.; Magnin, D. R.; Hamann,
L. G.; Betebenner, D. A. Patent WO 2001068603 A2 2001. (b) Morgan, B. A.;
Schafer, D. J. Patent DE 260915 4 1976.
(8) Padwa, A.; Coats, S. J.; Harring, S. R.; Hadjiarapoglou, L.; Semones,
M. A. Synthesis 1995, 8, 973.
(9) Although 3,3-dimethylpyrrolidin-2-one 5 can be prepared in a one-pot
procedure from N-TMS-protected pyrrolidinone, we preferred to work with the
less moisture-sensitive TBS-protected material. Ahn, Y.; Cardenas, G. I.; Yang,
J.; Romo, D. Org. Lett. 2001, 3, 751.
(1) (a) Che, Y.; Marshall, G. R. Biopolymers 2006, 81, 392. (b) Richardson,
J. S. AdV. Protein Chem. 1981, 34, 167.
3946 J. Org. Chem. 2008, 73, 3946–3949
10.1021/jo7027163 CCC: $40.75 2008 American Chemical Society
Published on Web 04/23/2008

SCHEME 1. Synthetic Route to 3,3-Dimethylproline Derivatives
SCHEME 2. Synthesis and Resolution of 3,3-Dimethylproline ((()-1)
SCHEME 3. Synthesis of (-)-10, (+)-1•HCl, and 11 from
Optically Pure (+)-9
the protected lactam 6 in 69% yield. Reduction10 to the
hemiaminal 7 was accomplished by the slow addition of NaBH4
to lactam 6 at -5 °C. Treatment of 7 with catalytic PPTS in
methanol smoothly formed 8, which was reacted with trimeth-
ylsilyl cyanide in the presence of BF3 ·OEt211 to afford racemic
nitrile (()-9 in 85% overall yield from 6. Following the
Katritzky protocol,12 nitrile (()-9 was converted to carboxamide
(()-10, which was resolved in gram quantities by preparative
chiral HPLC (Chiralpak AD column) to afford (+)-10 and (-)-
10 in >98% ee.13 The Cbz group was removed by hydrogenoly-
sis using 10% Pd/C in MeOH under a hydrogen atmosphere to
afford 3,3-dimethylprolinamides (-)-2 and (+)-2 in 93% yield.
We also examined the direct conversion of nitrile (()-9 to
racemic 3,3-dimethylproline ((()-1), followed by resolution to
(+)-1 and (-)-1 (Scheme 2). Treatment of (()-9 with aqueous
HCl in dioxane hydrolyzed the nitrile and carbamate groups to
afford (()-1·HCl. Racemic (()-1·HCl was resolved by chiral
HPLC (Chirobiotic T column) to provide the amino acid
enantiomers (-)-1 and (+)-1 in >98% optical purity.13
allow access to the proline derivatives (-)-1 and (+)-1 and
prolinamides (-)-2 and (+)-2 from (()-9 using a single
resolution step, provided that the optical purity would not be
compromised during the subsequent chemical transformation.
Chiral HPLC resolution of nitrile (()-9 was accomplished
using a Chiralcel OJ column to afford (+)-9 and (-)-9 in 99%
ee and 97% ee, respectively.13 When nitrile (+)-9 (>99% ee)
was converted to the carboxamide derivative (-)-10, analytical
HPLC analysis indicated the product to be >98% ee (Scheme
3). Likewise, when nitrile (+)-9 was converted to dimethyl-
proline (+)-1•HCl, HPLC analysis indicated that this compound
had an optical purity of >98% ee. Furthermore, the free base
was identical (HPLC analysis) to the reference sample (+)-1
described in Scheme 2.
Although we had reliable methods for the resolution of
prolinamides (()-10 and prolines (()-1, we investigated the
resolution of the versatile intermediate nitrile (()-9. This would
(10) Wijnberg, J. B. P. A.; Schoemaker, H. E.; Speckamp, W. N. Tetrahedron
1978, 34, 179.
(11) (a) Katoh, T.; Nagata, Y.; Kobayashi, Y.; Arai, K.; Minami, J.;
Terashima, S. Tetrahedron 1994, 50, 6221. (b) For a review of the chemistry of
N-acyliminium ions, see: Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000,
56, 3817.
Finally, the absolute configurations of enantiomers (-)-2/
(+)-2, (-)-/(+)-1, and (-)-9/(+)-9 were determined by cor-
(12) Katritzky, A. R.; Pilarski, B.; Urogdi, L. Synthesis 1989, 949.
(13) See the Supporting Information.
J. Org. Chem. Vol. 73, No. 10, 2008 3947

CHCl3/EtOAc) confirmed that the reaction was complete. The
reaction mixture was poured onto a slurry of saturated aqueous
NH4Cl (500 mL) and crushed ice. After being stirred for 16 h, the
aqueous mixture was extracted with Et2O (2 × 200 mL), and the
combined organic extracts were dried (MgSO4), filtered, and
concentrated to afford N,O-hemiacetal 7 (11.8 g) as a clear oil which
was used without further purification. To N,O-hemiacetal 7 (11.8
g, 48 mmol) in MeOH (100 mL) was added PPTS (1.19 g, 4.8
mmol), and the solution was stirred for 45 min at 20 °C. The
reaction was quenched with Et3N (3 mL) and concentrated. The
resulting crude oil was purified by flash chromatography on silica
gel (CHCl3/EtOAc) to provide methoxyaminal 8 (11.2 g) as a clear
relation with the stereochemistry of compound 11. Sulfonylation
of enantiomer (+)-2, derived from the hydrogenolysis of (-)-
10, produced the crystalline compound 11 (Scheme 3), which
upon X-ray analysis indicated R-stereochemistry.13
In summary, a short and practical preparation of the enanti-
omers of 3,3-dimethylproline and 3,3-dimethylprolinamide,
starting from 3,3-dimethylpyrrolidinone and based on the
resolution of (()-9, was accomplished. The conversion of the
optically enriched nitriles to the corresponding carboxamide and
carboxylic acid derivatives occurs without loss of optical purity,
as determined by chiral HPLC analysis. The absolute configura-
tions of the proline and prolinamides prepared were confirmed
by correlation with an intermediate of known absolute stereo-
chemistry as determined by X-ray crystallography. The methods
described herein can be performed on gram scale, making nitriles
(-)-9 and (+)-9 valuable and versatile intermediates for the
synthesis of optically pure 3,3-dimethylproline analogues.
1
oil as a mixture of rotamers. H NMR (400 MHz, CDCl3): δ 7.38
(m, 5H), 5.08-5.29 (m, 2H), [4.68 (s) and 4.57 (s)] (1H), 3.47-3.58
(m, 2H), [3.31 (s) and 3.46 (s)] (3H), 1.94 (m, 1H), 1.49-1.67 (m,
1H), [1.11 (s) and 1.09 (s)] (3H), [0.95 (s) and 0.93 (s)] (3H). 13
C
NMR (125 MHz, CDCl3): δ 22.1, 25.0, (34.7 and 35.6), (42.0
and 42.8), (44.2 and 44.5), (56.5 and 57.0), (66.8 and 67.2), (95.4
and 95.8), (127.6 and 128.0), (128.0 and 128.0), 128.5, (136.6 and
136.8), (155.6 and 156.3). This compound was dissolved in CH2Cl2
(200 mL), and the solution was cooled to -78 °C. Trimethylsilyl
cyanide (6.32 g, 64 mmol) was added followed by BF3 ·OEt2 (9.09
g, 64 mmol), and the reaction mixture was stirred for 1 h. The
reaction was quenched by the addition of saturated aqueous
NaHCO3 ,and the mixture was allowed to warm to 20 °C. After
2 h of vigorous stirring, the mixture was separated and the aqueous
phase was extracted with CH2Cl2 (2 × 100 mL). The combined
organic extracts were dried (MgSO4), filtered, and concentrated to
afford product (()-9 (10.8 g, 85% from 6) as a clear oil as a mixture
Experimental Section
3,3-Dimethyl-2-pyrrolidinone (5). To a solution of diisopro-
pylamine (17.9 g, 177 mmol) in THF (300 mL) at 0 °C was added
n-butyllithium (77.1 mL, 193 mmol, 2.5 M solution in hexanes)
over 5 min. After 0.5 h, the reaction mixture was cooled to -78
°C, and a solution of 4 (34.3 g, 161 mmol) in THF (80 mL) was
added dropwise, keeping the reaction temperature below -60 °C.
The reaction mixture was warmed to 20 °C and stirred at this
temperature for 1 h. The reaction was cooled back to -78 °C, and
a solution of iodomethane (25.1 g, 177 mmol) in THF (10 mL)
was added dropwise over 10 min. The reaction was warmed to 20
°C and stirred for 16 h. The reaction mixture was quenched by
addition of saturated NH4Cl (300 mL), the layers were separated,
and the aqueous phase was extracted with EtOAc (2 × 150 mL).
The combined organic extracts were dried (MgSO4), filtered, and
concentrated. The resulting crude oil was purified by silica gel flash
chromatography (EtOAc/hexanes) to provide the desired dimeth-
ylpyrrolidinone derivative as a yellow oil. This oil was immediately
dissolved in THF (250 mL), the resulting solution was cooled to 5
°C, and tetrabutylammonium fluoride (194 mL, 194 mmol, 1 M
solution in THF) was added over 30 min. The reaction mixture
was warmed to 20 °C, stirred for 2 h, and then concentrated. The
resulting crude oil was purified by flash chromatography on silica
gel (CH2Cl2/MeOH) to afford product 5 (8.13 g, 46%) as a white
1
of rotamers. H NMR (400 MHz, CDCl3): δ 7.31-7.52 (m, 5H),
5.21 (m, 2H), [4.25 (s) and 4.17 (s)] (1H), 3.46-3.71 (m, 2H),
1.97-2.06 (m, 1H), 1.77 (m, 1H), [1.37 (s) and 1.35 (s)] (3H),
1.16 (s, 3H). 13C NMR (125 MHz, CDCl3): δ (24.0 and 24.1),
(25.47 and 25.53), (36.9 and 37.8), (41.5 and 42.6), (44.8 and 45.1),
(58.0 and 58.3), (67.5 and 67.8), (117.0 and 117.1), (127.9 and
128.0), 128.2, 128.5, (135.8 and 136.0), (153.9 and 154.5). HRMS:
calcd for C15H19N2O2 (MH+) 259.1441, found 259.1441. A portion
of this material was resolved using preparative chiral HPLC
(Chiralcel OJ column).13
Benzyl 2-(Aminocarbonyl)-3,3-dimethyl-1-pyrrolidinecarboxy-
late ((()-10). To a solution of (()-9 (10.7 g, 41 mmol) in DMSO
(30 mL) was added K2CO3 (2.14 g, 16 mmol), and the mixture
was cooled to 10 °C (avoid freezing). A 30% aqueous solution of
H2O2 (5.5 mL) was added dropwise, keeping the internal temper-
ature <15 °C. After the reaction ceases to outgas (a bubbler was
used to monitor gas evolution), it was allowed to warm to 20 °C
and stirred for 2 h. The reaction was diluted with H2O (300 mL)
and extracted with CH2Cl2 (3 × 100 mL). The combined organic
extracts were dried (MgSO4), filtered, and concentrated to provide
carboxamide (()-10 (12.2 g) as a clear oil as a mixture of rotamers.
This material was resolved using preparative chiral HPLC (Chiral-
pak AD column).13
1
solid. H NMR (400 MHz, CDCl3): δ 6.52 (bs, 1H), 3.32 (t, J )
6.8 Hz, 2H), 1.97 (t, J ) 6.8 Hz, 2H), 1.18 (s, 6H). 13C NMR (125
MHz, CDCl3): δ 24.2, 36.4, 38.7, 39.6, 183.8.
Benzyl 3,3-Dimethyl-2-oxo-1-pyrrolidinecarboxylate (6). To a
solution of 5 (8.13 g, 72 mmol) in THF (200 mL) at -78 °C was
added LHMDS (79 mL, 79 mmol, 1 M solution in THF) over 15
min. The solution was stirred for 30 min, benzyl chloroformate
(13.5 g, 79 mmol) was added, and the reaction mixture was warmed
to room temperature. After 16 h, the reaction was concentrated to
1/3 total volume and diluted with EtOAc (500 mL). The organic
solution was washed sequentially with 1 M HCl (2 × 200 mL),
H2O (200 mL), and brine (100 mL), dried (MgSO4), filtered, and
concentrated. Purification by flash chromatography on silica gel
(EtOAc/hexanes) provided product 6 (12.3 g, 69%) as a light yellow
3,3-Dimethyl-D-prolinamide ((+)-2). To a solution of (-)-10
(0.11 g, 0.41 mmol) in MeOH (10 mL) was added Degussa type
10% palladium/carbon (5 mg), and the mixture was stirred for 3 h
at 20 °C under atmospheric H2. The catalyst was removed by
filtration, and the filtrate was concentrated to afford the title
1
compound (54 mg, 93%) as a white solid. H NMR (400 MHz,
DMSO-d6, TFA): δ 9.44 (bs, 1H), 8.59 (bs, 1H), 7.85 (s, 1H), 7.74
(s, 1H), 3.68 (m, 1H), 3.28 (m, 2H), 1.82 (m, 2H), 1.19 (s, 3H),
0.93 (s, 3H). 13C NMR (125 MHz, DMSO-d6, TFA): δ 22.2, 26.2,
38.3, 41.5, 42.9, 67.2, 167.9. HRMS: calcd for C7H15N2O (MH+)
1
oil. H NMR (400 MHz, CDCl3): δ 7.46 (m, 2H), 7.30-7.43 (m,
3H), 5.31 (s, 2H), 3.75 (t, J ) 7.0 Hz, 2H), 1.89 (t, J ) 7.1 Hz,
2H), 1.22 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 24.2, 32.9, 42.1,
42.7, 67.9, 128.0, 128.3, 128.5, 135.3, 151.8, 178.8. MS m/e 270.2
[M + Na]+. Anal. Calcd for C14H17NO3: C, 68.00; H, 6.93; N,
5.66. Found: C, 68.00; H, 7.06; N, 5.73.
143.1184, found 143.1179. [R]20 ) +24.5 (c 1.05, CH3OH).
D
3,3-Dimethyl-L-prolinamide ((-)-2). [R]20 ) -31.8 (c 1.00,
D
CH3OH).
Benzyl 2-Cyano-3,3-dimethyl-1-pyrrolidinecarboxylate ((()-
9). To a solution of 6 (12.2 g, 49 mmol) in MeOH (100 mL) at
-10 °C was added NaBH4 (9.35 g, 25 mmol) in portions,
maintaining an internal temperature below -5 °C. TLC (90:10
3,3-Dimethylproline ((()-1·HCl). Nitrile (()-9 (0.10 g, 0.29
mmol) was dissolved in dioxane (2 mL) and aqueous HCl (2 mL,
12 M), and the mixture was heated at 80 °C for 15 h. The solvents
were evaporated, and the residue was triturated with acetonitrile to
3948 J. Org. Chem. Vol. 73, No. 10, 2008

afford the product (HCl salt, 68 mg, 99%) as an off-white solid.
1H NMR (400 MHz, D2O): δ 3.91 (m, 1H), 3.50 (m, 2H), 1.99 (m,
2H), 1.32 (s, 3H), 1.02 (s, 3H). 13C NMR (125 MHz, D2O): δ 21.1,
25.5, 38.6, 41.6, 43.4, 68.4, 170.8. A portion of this material was
resolved using preparative chiral HPLC (Chirobiotic T column).13
5.66 (m, 4H), 3.62-3.67 (m, 1H), 3.53 (s, 1H), 3.23-3.29 (m,
1H), 1.77-1.84 (m, 1H), 1.39-1.44 (m, 1H), 1.07 (s, 3H), 0.75
(s, 3H). 13C NMR (125 MHz, CDCl3): δ 23.5, 27.5, 38.5, 42.7,
47.5, 71.6, 128.6, 129.3, 132.6, 134.7, 172.7. MS: m/e 361.0, 363.0
[MH]+. HRMS: calcd for C13H18N2O3S (MH+) 361.0222, found
361.0215. [R]23 ) +119 (c 0.65, CHCl3).
D
1-[(4-Bromophenyl)sulfonyl]-3,3-dimethyl-D-prolinamide (11).
To a solution of (-)-10 (0.20 g, 0.72 mmol) in MeOH (5 mL) was
added Degussa type 10% palladium/carbon (0.02 g), and the mixture
was stirred for 3 h at 20 °C under atmospheric H2. The catalyst
was filtered, and the reaction was concentrated to afford 3,3-
dimethyl-D-prolinamide ((+)-2) (0.112 g) as a white solid. CH2Cl2
(10 mL) and Et3N (0.2 mL, 1.4 mmol) were added followed by
4-bromobenzenesulfonyl chloride (0.18 g, 0.72 mmol), and the
reaction mixture was stirred for 15 h at room temperature. The
mixture was poured onto CH2Cl2 and saturated aqueous NaHCO3,
and the organic layer was separated, dried (MgSO4), filtered, and
concentrated to afford 238 mg of crude material. This material was
recrystallized from EtOH/hexanes to afford X-ray quality crystals.
1H NMR (400 MHz, CDCl3): δ 7.70-7.76 (m, 4H), 6.43 (bs, 1H),
Acknowledgment. We thank Dr. Amy A. Sarjeant at Johns
Hopkins University for the X-ray analysis of compound 11 as
well as Dr. Jacques Briand for assistance with NMR experiments.
Supporting Information Available: Copies of 1H NMR and
13C NMR spectra, X-ray crystallographic data (CIF) for 11,
analytical details for the resolution of (()-1, (()-9 and (()-10,
as well as the ee determination of their respective enantiomers.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO7027163
J. Org. Chem. Vol. 73, No. 10, 2008 3949