A facile and efficient synthesis of 3,3-dimethyl isopropylidene proline from (+)-3-carene

Article abstract of DOI:10.1021/jo9022759

(Chemical Equation Presented) A highly efficient and practical route to 3,4-isopropylidene proline I, starting from (+)-3-carene, was developed. The three continuous stereocenters were constructed using the inherent chirality of the starting natural product 2. The overall yield for the 12-step synthesis is 34%. The optimized sequence leading to 1 has been successfully applied on a multigram scale, thereby establishing the practicality of this route.

Full text of DOI:10.1021/jo9022759

pubs.acs.org/joc
A Facile and Efficient Synthesis of 3,3-Dimethyl
Isopropylidene Proline From (þ)-3-Carene
Latha G. Nair,* Anil Saksena, Raymond Lovey,
Mousumi Sannigrahi, Jesse Wong, Jianshe Kong,
Xiaoyong Fu, and Viyyoor Girijavallabhan
Merck Research Laboratories,
2015 Galloping Hill Road, Kenilworth,
New Jersey 07033
FIGURE 1. Boceprevir (SCH 503034).
latha.nair@spcorp.com
Received October 26, 2009
FIGURE 2. Amino acid 1 and lactam 5.
to structural and nonstructural proteins. The N-terminal
side of the nonstructural protein NS3 contains the NS3
protease, a chymotrypsin-like serine protease which cata-
lyzes the cleavage of the NS3-NS4A, one of essential
processes during replication of the virus. The importance
of this function had made NS3-4A protease inhibitors an
attractive target for drug discovery by several groups3 over
the past decade. Our research in the Schering-Plough Re-
search Institute resulted in many potent HCV NS3 protease
inhibitors including SCH 503034 (Figure 1), Boceprevir,
which is now in clinical trials .
During our lead identification process, an inhibitor con-
taining leucine at P2 was found to possess excellent in vitro
activity but unfortunately lacked activity in the cellular
assay. On the other hand, leads with proline at P2
had moderate enzyme binding and some cellular activity.
Conferring from the above observations and literature pre-
cedence, a nonproteogenic amino acid mimicking a con-
strained leucine moiety, 3,4-dimethylcyclopropyl proline, 1,
was envisioned.
A highly efficient and practical route to 3,4-isopropyli-
dene proline I, starting from (þ)-3-carene, was developed.
The three continuous stereocenters were constructed
using the inherent chirality of the starting natural product
2. The overall yield for the 12-step synthesis is 34%. The
optimized sequence leading to 1 has been successfully
applied on a multigram scale, thereby establishing the
practicality of this route.
An estimated 3% of the world’s population is infected with
the Hepatitis C virus, and this infection is the leading cause of
chronic liver disease.1 To this day, PEGylated R-interferon
alone or in combination with the nucleoside analogue Riba-
virin constitutes the most effective therapy. The current line
of treatment is effective only in 40% of the patient popula-
tion and is known to cause adverse side effects. Due to the
urgent need for a more tolerable and efficacious regimen,
the past decade has seen an emergence of therapies targeting
the key enzymes involved in the replication and maturation
of the virus.2
Madalengoitia and co-workers reported the first synthesis
of the unusual amino acid of type I.4 Their synthesis involved
stereoselective cyclopropanation of pyroglutamic acid de-
rived unsaturated lactam 5 with sulfur ylides (Figure 2).
(3) (a) Perni, R. B.; Almquist, S. J.; Byrn, R. A.; Chandorkar, G.;
Chaturvedi, P. R.; Courtney, L. F.; Decker, C. J.; Dinehart, K.; Gates, C. A.;
Harbeson, S. L.; Heiser, A.; Kalkeri, G.; Kolaczkowski, E.; Lin, K.; Luong,
Y.-P.; Rao, B. G.; Taylor, W. P.; Thomson, J. A.; Tung, R. D.; Wei, Y.; Kwong,
A. D.; Lin, C. Antimicrob. Agents Chemother. 2006, 50, 899–909. (b) Faucher,
A.-M.; Bailey, M. D.; Beaulieu, P. L.; Brochu, C.; Duceppe, J.-S.; Ferland,
J.-M.; Ghiro, E.; Gorys, V.; Halmos, T.; Kawai, S. H.; Poirier, M.; Simoneau,
B.; Tsantrizos, Y. S.; Llinas-Brunet, M. Org. Lett. 2004, 6, 2901–2904. (c)
Venkatraman, S.; Bogen, S.; Arasappan, A.; Bennet, F.; Chen, K.; Jao, E.; Liu,
Y.-T.; Lovey, R.; Hendreta, S.; Huang, Y.; Pan, W.; Parekh, T.; Pinto, P.;
Popov, V.; Pike, R.; Ruan, S.; Santhanam, B.; Vibulbhan, B.; Wu, W.; Yang,
W.; Kong, J.; Liang, X.; Wong, J.; Liu, R.; Butkiewicz, N.; Chase, R.; Hart, A.;
Agrawal, S.; Ingravallo, P.; Pichardo, J.; Kong, R.; Baroudy, B.; Malcolm, B.;
Guo, Z.; Prongay, A.; Madison, V.; Broske, L.; Cui, X.; Cheng, K.-C.;
Hsieh, T. Y.; Brisson, J.-M.; Prelusky, D.; Korfmacher, W.; White, R.;
Bogdanowich-Knipp, S.; Pavlovsky, A.; Bradley, P.; Saksena, A. K.; Ganguly,
A.; Piwinski, J.; Girijavallabhan, V.; Njoroge, F. G. J. Med. Chem. 2006, 49,
6074–6086.
Hepatitis C virus is a 9.6 Kb positive-stranded RNA virus
which encodes a 3000 amino acid polyprotein. The poly-
protein is processed by cellular and virally encoded proteases
(1) (a) Choo, Q.-L.; Kuo, G.; Weiner, A. J.; Overby, L. R.; Bradley,
D. W.; Houghton, M. Science 1989, 244, 359. (b) The Hepatitis C Viruses;
Hagedorn, C. H., Rice, C. M., Eds.; Springer: Berlin, 2000; Curr. Top. Microbiol.
Immunol. 242.
(2) (a) McHutchison, J. G.; Gordon, S. C.; Schiff, E. R.; Shiffman, M. L.;
Lee, W. M.; Rustgi, V. K.; Goodman, Z. D.; Ling, M.-H.; Cort, S.; Albrecht,
J. K. N. Engl. J. Med. 1998, 339, 1485–1492. (b) Davis, G. L.; Esteban-Mur,
R.; Rustgi, V.; Hoefs, J.; Gordon, S. C.; Trepo, C.; Shiffman, M. L.; Zeuzem,
S.; Craxi, A.; Ling, M.-H.; Albrecht, J. N. Engl. J. Med. 1998, 339, 1493–
1499. (c) Zeuzem, S.; Feinman, S. V.; Rasenack, J.; Heathcote, E. J.; Lai,
M.-Y.; Gane, E.; O’Grady, J.; Reichen, J.; Diago, M.; Lin, A.; Hoffman, J.;
Brunda, M. J. N. Engl. J. Med. 2000, 343, 1666–1672.
(4) (a) Zhang, R.; Madalengoitia, J. S. J. Org. Chem. 1999, 64, 330–331.
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DOI: 10.1021/jo9022759
r
Published on Web 01/28/2010
J. Org. Chem. 2010, 75, 1285–1288 1285
2010 American Chemical Society

Nair et al.
JOCNote
SCHEME 1. Oxidation of Carene
SCHEME 3. Oximation
SCHEME 2. Lactonization
transformation turned out to be the most problematic step
in the synthetic route (Scheme 3). Conversion of lactone 3 or
acetate 6 to the oxime 10 using either tert-butyl or isoamyl
nitrite in the presence of potassium tert-butoxide9 gave
variable yields (30-56%).
Functionalization of the lactone using Bredereck’s re-
agent10 to give the corresponding R-dimethylaminomethy-
lene-substituted lactone 11 proceeded smoothly, but
treatment of this lactone with sodium nitrite failed to yield
the desired oxime. Other exploratory experiments to convert
3 to 10 by trapping the enolate of the lactone, 12, with either
sodium nitrite or nitroso tetrafluoroborate were unsuccess-
ful. However, promising results were observed when nitrosyl
chloride11 was used as the electrophile, thus oxime 10 could
be obtained in 42% yield along with quantitative amounts of
leftover starting material (lactone), presumably due to the
instability of the enolate (Scheme 3).
In an effort to optimize the yield of the oximation, we then
attempted trapping the enolate of the lactone with ethyl
formate.12 The reaction proceeded quantitatively but gave a
mixture of the desired compound 13 along with 14, the
product formed by nucleophilic attack of the lactone by
the ethoxide and trapping of the corresponding alcohol with
ethyl formate (Scheme 4).
Fortunately, treatment of this mixture with sodium
nitrite in the presence of acetic acid led to oximation of
both compounds 13 and 14 to yield a mixture of 10 and 15
in 85% yield over the two steps (Scheme 4). The oximated
lactone could be easily reduced to the Boc-protected amine
16 with desired stereoselectivity most likely controlled
by the inherent disposition of the dimethyl cyclopropane
unit. On the other hand, when the oximated acyclic
ester 15 was treated under the same conditions, the Boc-
protected amine 15 was formed exclusively. Variations of
Synthesis of intermediate O,N-acetal 5 was achieved through
a multistep sequence in moderate yield.5 Moreover, the use
of phenyl selynyl bromide to generate the olefin was imprac-
tical due to its prohibitive cost and potential toxicity.
The need to develop an efficient, scalable route to proline
derivative 1 led to the synthetic route described in this report.
The current synthesis started from the commercially avail-
able optically pure (þ)-3-carene possessing the desired ster-
eochemistry at C(3) and C(4). Ring contraction to the five-
carbon skeleton began with Ru-based oxidative cleavage6
of the olefin 2 to the corresponding ketoacid, which in
turn was esterified to obtain the methyl ester in 86% yield.
Baeyer-Villiger oxidation of the ketoester afforded acetate 6
in excellent yield (Scheme 1).
Deacetylation of 6 to 7 was achieved with potassium
carbonate. Unfortunately, attempts to directly lactonize 7
under basic conditions7 resulted in hydrolysis to acid 7.
However, it was possible to convert hydroxyl acid 8 to
lactone 3 by acetylating the alcohol followed by p-TsOH-
catalyzed ring closure to give the desired lactone. Alterna-
tively, the hydroxy ester 7 could be readily cyclized to the
corresponding lactone under refluxing conditions in the
presence of catalytic amounts of DBU (Scheme 2). Attempts
to cyclize the acetate 6 or the corresponding hydrolyzed
product 8 with p-TsOH8 led to the unexpected opening of
the gem-substituted cyclopropane ring followed by rearran-
gement to lactone 9 (Scheme 2).
Introduction of the amine unit on the carbon R to
the carbonyl of 3 was achieved through an oximation,
reduction sequence. However, this fairly straightforward
(9) Czibula, L.; Nemes, A.; Visky, G.; Farkas, M.; szombathelyi, Z;
Karpati, E.; Sohar, P.; Kessel, M; Kreidl, J. Liebigs Ann. Chem. 1993, 221–
229.
(10) Skof, M.; Svete, J.; Kmetic, M.; Golic-Grdadolnik, S.; Stanovnik, B.
Eur. J. Chem. 1999, 1581–1584.
(11) Rasmussen, J. K.; Hassner, A. J. Org. Chem. 1974, 39, 2558–2561.
(12) Kiyama, R.; Hayashi, K.; Hara, M.; Fujimoto, M.; Kawabata, T.;
Kawakami, M.; Nakajima, S. I.; Fujishita, T. Chem. Pharm. Bull. 1995, 43,
960–965.
(5) Baldwin, J. E.; Moloney, M. G.; Shim, S. B. Tetrahedron Lett. 1991,
32, 1379–1380.
(6) Confalonieri, G.; Marrotta, E.; Rama, F.; Righi, P.; Rosini, G.; Serra,
R.; Venturelli, F. Tetrahedron 1994, 50, 3235–3250.
(7) Nair, V.; Prabhakaran, J.; George, T. G. Tetrahedron 1997, 53, 15061–
15068.
(8) Sobti, R.; Dev, S. Tetrahedron 1974, 30, 2927–2929.
1286 J. Org. Chem. Vol. 75, No. 4, 2010

Nair et al.
JOCNote
SCHEME 4. Alternate Route for Oximation
with cold 1 N HCl and then with brine, and dried over anhyd
Na2SO4. Then, it was filtered and evaporated off the solvent,
and the crude product was purified via silica gel column
chromatography with EtOAc-CH2Cl2 to afford 3 (54 g, 95%)
as a colorless oil which solidifies to an amorphous white solid:
IR (thin film, cm-1) 2948, 1727,1458,1377,1253, 1171, 1139,
1072, 976; 1H NMR (CDCl3, 300 MHz) δ 4.71 (dd, J = 7.14 Hz,
1H), 4.04 (dd, J = 6.59 Hz, 1H), 2.75 (dd, J = 7.14 Hz, 1H), 2.16
(dd, J = 5.49 Hz, 1H), 1.16 (s, 3H), 1.27-1.18 (m, 2H), 1.12 (s,
3H); 13C NMR (CDCl3, 500 MHz) δ 176.6, 62.9, 30.6, 28.9, 24.6,
23.2, 18.9, 15.3; EIMS calcd for C8H12O2 [M þ H]þ 141.1797,
found 141.0909; [R]25D -89.07 (c 0.5732, CH2Cl2).
(1S,5E,6R)-7,7-Dimethyl-3-oxabicyclo[4.1.0]heptane-4,5-dione-
5-oxime (10): A solution of 3 (42gm, 300 mmol) in 300 mL of
anhydrous toluene was treated with 90% t-BuONO (102 mL,
720 mmol). To this mixture was added KOtBU (45 g, 400 mmol)
in six portions over 20 min at 35 °C. Then 180 mL of anhydrous
methanol was added, the temperature rose to 40 °C, and stirring
continued at 40 °C for 2.5 h. The mixture was cooled, quenched
with a cold solution of 1.1 L of 10% aqueous sodium dihydrogen
phosphate and 20 mL of 12 N HCl, then extracted with EtOAc.
The extracts were washed with 5% aqueous NaHCO3 and then
brine, dried over anhyd Na2SO4, filtered, and evaporated in
vacuo. The residue (25 g) was chromatographed on 150 g of silica
gel using a gradient of 35:65 EtOAc-CH2Cl2 to obtain29 g (56%)
of 10 as an amorphous solid: IR(thinfilm, cm-1) 2948, 1687, 1611,
1452, 1427, 1330, 1310, 1195, 1139, 1003; 1H NMR (CDCl3, 500) δ
4.82 (dd, J = 5.99 Hz, 1H), 4.55 (dd, J = 12.61 Hz, 1H), 2.40 (d,
J = 8.82 Hz, 1H), 1.52-1.49 (m, 1H), 1.27 (s, 3H), 1.18 (s, 3H);
13C NMR (CDCl3, 500 MHz) δ 161.4, 145.3, 66.9, 27.7, 23.2, 22.9,
16.3 ppm; HRMS(FAB) calcd for C8H11NO3 [M þ H]þ 170.18,
found 170.30; (ESI) calcd for C8H11NO3 [M þ Na þ AcN]þ
SCHEME 5. Ring Contraction via Mitsunobu
233.0902, found 233.0852; [R]25.5 þ184.29 (c 1.1075, CH2Cl2).
D
Anal. Calcd: C, 56.80; H, 6.55; N, 8.28. Found: C, 56.47; H, 6.96;
N, 8.19.
Methyl (2S)-[(tert-Butoxycarbonyl)amino][(1R,3S)-3-(hydroxy-
methyl)-2,2-dimethylcyclopropyl]acetate (4): A solution of 16 (35 g,
137 mmol) in 350 mL of anhyd methanol was treated with K2CO3
(12 g, 86 mmol) at room temperature for 2 h. Volatiles were
evaporated off, and then the mixture was quenched with 0.6 L of
10% aq KH2PO4. It was extracted with ethyl acetate, and the
organic layer was washed with brine, dried over anhyd Na2SO4,
filtered, and evaporated off to get 33 g of 4 (8:2 mixture of R-S/
R-R). This was not separated to proceed to the next step. For
analytical purposes, a portion was chromatographed with
Et2O-hexane (60:40) to obtain a pure R-S-epimer of the title
compound: IR (thin film, cm-1) 3358, 2954, 1741, 1690, 1511,
1366, 1158, 1016; 1H NMR (CDCl3, 500 MHz) δ 5.2 (br s, 1H),
4.05 (br s, 1H), 3.81 (m, 1H), 3.76 (s, 3H), 3.65 (m, 1H), 1.43 (s,
9H), 1.14 (s, 3H), 1.05 (s, 3H), 1.05 (m, 1H), 0.86 (m, 1H); 13C
NMR (CDCl3, 125 MHz) δ 173.6, 155.8, 81.0, 59.7, 52.8, 30.9,
29.6, 29.2, 28.7, 19.9, 16.1 ppm; HRMS calcd for C14H25NO5
[M þ Na]þ 310.1630, found 310.1621; [R]25D -62.9 (c 1, MeOH).
Anal. Calcd: C, 58.52; H, 8.77; N, 4.87. Found: C, 58.48; H, 8.75;
N, 5.10.
Further elution provided the R-R-epimer (17): IR (thin film,
cm-1) 3353, 2954, 1691, 1514, 1365, 1158, 1016; 1H NMR
(CDCl3, 500 MHz) δ 4.95 (br s, 1H), 4.03 (m, 1H), 3.82 (m,
1H), 3.78 (s, 3H), 3.71 (m, 1H), 1.44 (s, 9H), 1.13 (m, 1H), 1.10 (s,
3H), 1.08 (s, 3H), 0.86 (m, 1H); 13C NMR (CDCl3, 125 MHz) δ
174.6, 155.7, 80.7, 60.1, 53.3, 50.3, 30.4, 29.2, 19.6, 16.1, 15.3
ppm; HRMS calcd for C14H25NO5 [M þ H]þ 288.1811, found
288.1776; [R]25D -32.8 (c 1, MeOH). Anal. Calcd: C, 58.52; H,
8.77; N, 4.87. Found: C, 58.46; H, 8.69; N, 4.74.
either the catalyst or solvent did not affect the outcome of
this reaction.
Fortuitously, when the crude reaction from the oximation
reaction was treated with Cs2CO3 in MeOH, oxime 15
spontaneously cyclized to give 10. Methanolysis of the
lactone 16 gave hydroxy N-Boc esters 4 and 17 as a mixture
of epimers at C-2 (4:1). Attempts to cyclize 4 via the
corresponding mesylate or the imidazoyl ester activated by
methyl iodide led mainly to lactone 9 (Scheme 2). Subjecting
the epimeric mixture of 4 and 17 under Mitsunobu condi-
tions gave the desired substituted proline 18. Finally, when
the epimeric ester 18 was hydrolyzed using LiOH, the desired
thermodynamically favored 3,4-isopropylidene proline 1
was formed exclusively in 80% yield (Scheme 5).
In summary, a highly efficient route to 3,4-isopropylidene
proline was developed starting from an inexpensive starting
material and common laboratory reagents. The inherent
chirality of (þ)-3-carene is elegantly utilized to make the
process highly efficient and to introduce the third stereo-
center in the title compound 1. The 12-step sequence leading
to the peptidomimetic core 1, with an overall yield of 32%,
has been optimized and successfully applied on a multigram
scale (100 g), establishing the practicality of this route.
Experimental Section
3-tert-Butyl 2-methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo-
[3.1.0]hexane-2,3-dicarboxylate (18): A solution of Ph3P
(21.6 g, 82.4 mmol) in 250 mL of anhydrous THF was cooled to
-10 °C and treated with DIPA (16.2 g, 80.2 mmol) in drops.
(1S,6R)-7,7-Dimethyl-3-oxabicyclo[4.1.0]heptan-4-one (3): A
solution of 7 (70 g, 406 mmol) in 1.1 L of xylenes was refluxed
with DBU (30.9 g, 203 mmol) for 18 h, and methanol was
removed from the distillate. The solution was cooled, washed
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Nair et al.
JOCNote
After 5 min, the mixture was treated with a solution of 4 (mixture
of R and S, 19.7 g, 68.5 mmol) in 35 mL of THF and stirred for
10 min, and then heated at reflux for 3 h, cooled, and evaporated
off in vacuo. The residue was diluted with 450 mL of methanol-
water (1:1) and then extracted with hexane (7 ꢀ 200 mL). The
combined extracts were washed with 20 mL of methanol-water
(1:1) and brine, dried over anhydrous Na2SO4, filtered, and the
filtrate evaporated in vacuo. The residue was taken up in 400 mL
of hexane, suction-filtered through a pad of 30 g silica gel, and
the silica pad was eluted with an additional 210 mL of EtOAc-
hexane (1:9). The combined filtrates were evaporated in vacuo
to leave 18 (14.5 g, 78%) as a mixture of two epimers (analytical
data provided in Supporting Information).
(1R,2S,5S)-3-(tert-Butoxycarbonyl)-6,6-dimethyl-3-azabicyclo-
[3.1.0]hexane-2-carboxylic acid (1): A solution of 18 (14.5 g,
53.8 mmol) in 1,4-dioxane (270 mL) was treated with 135 mL of
1 M aqueous LiOH, and the mixture was heated at 80 °C for 4 h.
The mixture was cooled, concentrated in vacuo to half volume,
diluted with 200 mL of water, and extracted with hexane. The
aqueous layer was chilled and treated with a solution of 9 mL of
12 N HCl in 50 mL of 10% aqueous KH2PO4, and then extracted
with EtOAc. The extract was washed with brine, dried over
anhydrous Na2SO4, filtered, and evaporated in vacuo to afford
1 (11.9 g, 86%), rotameric mixture because of Boc: IR (thin
film, cm-1) 2976, 1744, 1699, 1390, 1367, 1170, 1128; 1H NMR
(CDCl3, 300 MHz) δ 9.77 (br s, 1H, COΟH), 4.20 (d, J = 30.75
Hz, 1H), 3.62 (m, 1H), 3.44 (m,1H), 1.55 (m, 1H), 1.43 and1.39 (s,
9H), 1.25 (m, 1H), 1.03 (s, 3H), 0.97and 0.95 (s, 3H); 13C NMR
(CDCl3, 75 MHz) δ 178.3, 178.1, 154.9, 153.7, 80.9, 80.5, 60.1,
46.8, 46.5, 32.2, 30.9, 28.6, 27.4, 27.7, 19.3, 12.8ppm; HRMS calcd
for C13H21NO4 [M þ H]þ 256.1548, found 256.1547; [R]25
D
þ23.77 (c 0.5636, CH2Cl2). Anal. Calcd: C, 61.16; H, 8.29; N,
5.49. Found: C, 60.95; H, 8.18; N, 5.65.
Acknowledgment. The authors wish to thank Dr. F. George
Njoroge, Dr. S. Bogen, Dr. Ronald Doll, and Dr. F. Velazquez
for their insightful comments during the preparation of this
manuscript. L.G.N. wishes to thank Dr. Adom Brystol for his
help in IR spectra, and Ibrahim Darro for his help in mass
spectral analysis.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1288 J. Org. Chem. Vol. 75, No. 4, 2010