Synthesis of an optically active, bicyclic 2-pyridone dipeptide mimetic

Article abstract of DOI:10.1021/jo010712n

The eleven-step preparation of the bicyclic 2-pyridone dipeptide mimetic 1 [(3S)-6-(benzyloxycarbonylamino)-5-oxo-l,2,3,5-tetrahydroindolizine-3- carboxylic acid] in optically active form (60% ee) is described. Key steps in the synthesis of I include the osmium-catalyzed asymmetric dihydroxylation of olefin 13 [(6-but-3-enyl-2-methoxypyridin-3-yl)carbamic acid benzyl ester] and the intramolecular cyclization of protected diol 19 [(3'R)-{6-[4'-(tert-butyldimethylsilanyloxy)-3'-hydroxybutyl]-2- methoxypyridin-3-yl}carbamic acid benzyl ester] to afford the pyridinium salt 20 [(3S)-[3-(tert-butyldimethylsilanyloxymethyl)-5-methoxy-2,3-dihydro-1H- indolizin-6-yl]carbamic acid benzyl ester trifuoromethanesulfonic acid salt]. Several alternate methods to prepare olefin 13 are also discussed.

Full text of DOI:10.1021/jo010712n

J . Org. Chem. 2002, 67, 741-746
741
Syn th esis of a n Op tica lly Active, Bicyclic 2-P yr id on e Dip ep tid e
Mim etic
Peter S. Dragovich,* Ru Zhou, and Thomas J . Prins
Pfizer Global Research and DevelopmentsLa J olla/ Agouron Pharmaceuticals, Inc.,
10777 Science Center Drive, San Diego, California 92121-1111
peter.dragovich@pfizer.com
Received J uly 16, 2001
The eleven-step preparation of the bicyclic 2-pyridone dipeptide mimetic 1 [(3S)-6-(benzyloxycar-
bonylamino)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid] in optically active form (60% ee)
is described. Key steps in the synthesis of 1 include the osmium-catalyzed asymmetric dihydroxy-
lation of olefin 13 [(6-but-3-enyl-2-methoxypyridin-3-yl)carbamic acid benzyl ester] and the
intramolecular cyclization of protected diol 19 [(3′R)-{6-[4′-(tert-butyldimethylsilanyloxy)-3′-hy-
droxybutyl]-2-methoxypyridin-3-yl}carbamic acid benzyl ester] to afford the pyridinium salt 20 [(3S)-
[3-(tert-butyldimethylsilanyloxymethyl)-5-methoxy-2,3-dihydro-1H-indolizin-6-yl]carbamic acid
benzyl ester trifuoromethanesulfonic acid salt]. Several alternate methods to prepare olefin 13 are
also discussed.
In tr od u ction
mimicry of certain peptide conformations and may pos-
sess uniquely beneficial physical properties which differ
from those of existing peptide mimetics. Accordingly, we
recently desired to synthesize the bicyclic 2-pyridone 1
for incorporation into potential peptide-based inhibitors
of the human rhinovirus 3C protease. To the best of our
knowledge, no synthesis of 1 has been reported to date,
although preparations of the structurally related bicyclic
pyrimidinones 24 and 3,5 and the indolizidinone 46 have
been detailed. In this report, we describe an efficient
synthesis of 1 which affords this peptide mimetic in
optically active form (60% ee).
The synthesis of rigid, non-peptidic chemical entities
intended to mimic portions of biologically important
peptides has been an area of increasing research in recent
years.1 Many examples of such peptide mimetics have
been prepared by a number of research groups and
evaluated for both their ability to duplicate a given
peptidic structure2 (e.g., â-turn) and to function as an
effector of some targeted biological activity3 (e.g., enzyme
inhibition). Despite the considerable research conducted
in this area to date, there is still a need to prepare
additional novel chemical structures which can position
peptide-related functional groups in spatially restricted
locations. Such structures would allow for additional
(1) For recent reviews of peptide mimics, see: (a) Ripka, A. S.; Rich,
D. H. Curr. Opin. Chem. Biol. 1998, 2, 441. (b) Gante, J . Angew. Chem.,
Int. Ed. Engl. 1994, 33, 1699. (c) Liskamp, R. M. J . Recl. Trav. Chim.
Pays-Bas 1994, 113, 1. (d) Adang, A. E. P.; Hermkens, P. H. H.;
Linders, J . T. M.; Ottenheijm, H. C. J .; van Staveren, C. J . Recl. Trav.
Chim. Pays-Bas 1994, 113, 63. (e) Olson, G. L.; Bolin, D. R.; Bonner,
M. P.; Bo¨s, M.; Cook, C. M.; Fry, D. C.; Graves, B. J .; Hatada, M.; Hill,
D. E.; Kahn, M.; Madison, V. S.; Rusiecki, V. K.; Sarabu, R.; Sepinwall,
J .; Vincent, G. P.; Voss, M. E. J . Med. Chem. 1993, 36, 3039. (f) Giannis,
A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32, 1244. (g) Kahn,
M. Synlett 1993, 821.
(2) For some recent examples, see: (a) J ohannesson, P.; Lindeberg,
G.; Tong, W.; Gogoll, A.; Karle´n, A.; Hallberg, A. J . Med. Chem. 1999,
42, 601. (b) Gosselin, F.; Lubell, W. D. J . Org. Chem. 1998, 63, 7463.
(c) Polyak, F.; Lubell, W. D. J . Org. Chem. 1998, 63, 5937. (d) Reference
6. (e) Siddiqui, M. A.; Pre´ville, P.; Tarazi, M.; Warder, S. E.; Eby, P.;
Gorseth, E.; Puumala, K.; DiMaio, J . Tetrahedron Lett. 1997, 38, 8807.
(f) Slomczynska, U.; Chalmers, D. K.; Cornille, F.; Smythe, M. L.;
Beusen, D. D.; Moeller, K. D.; Marshall, G. R. J . Org. Chem. 1996, 61,
1198. (g) Li, W.; Hanau, C. E.; d’Avignon, A.; Moeller, K. D. J . Org.
Chem. 1995, 60, 8155.
(3) For some recent examples, see: (a) Bachand, B.; DiMaio, J .;
Siddiqui, M. A. Bioorg. Med. Chem. Lett. 1999, 9, 913. (b) Boatman,
P. D.; Ogbu, C. O.; Eguchi, M.; Kim, H.-O.; Nakanishi, H.; Cao, B.;
Shea, J . P.; Kahn, M. J . Med. Chem. 1999, 42, 1367. (c) Liu, R.; Dong,
D. L.-Y.; Sherlock, R.; Nestler, H. P. Bioorg. Med. Chem. Lett. 1999, 9,
847. (d) Karanewsky, D. S.; Bai, X.; Linton, S. D.; Krebs, J . F.; Wu, J .;
Pham, B.; Tomaselli, K. J . Bioorg. Med. Chem. Lett. 1998, 8, 2757. (e)
Wagner, J .; Kallen, J .; Ehrhardt, C.; Evenou, J .-P.; Wagner, D. J . Med.
Chem. 1998, 41, 3664. (f) Dolle, R. E.; Prasad, C. V. C.; Prouty, C. P.;
Salvino, J . M.; Awad, M. A. M.; Schmidt, S. J .; Hoyer, D.; Ross, T. M.;
Graybill, T. L.; Speier, G. J .; Uhl, J .; Miller, B. E.; Helaszek, C. T.;
Ator, M. A. J . Med. Chem. 1997, 40, 1941.
Resu lts a n d Discu ssion
Retrosynthetic analysis (Scheme 1) of 1 suggested that
the bicyclic 2-pyridone structure could be arrived at via
an intramolecular cyclization event effected on optically
active, monoprotected diol 5. Intermediate 5, in turn, was
envisioned to arise from the asymmetric dihydroxylation
of pyridine 6 with subsequent selective protection of the
(4) Bemis, G.; Golec, J . M. C.; Lauffer, D. J .; Mullican, M. D.;
Murcko, M. A.; Livingston, D. J . International patent application: WO
95/35308, 1995.
(5) Webber, S. E.; Dragovich, P. S.; Prins, T. J .; Littlefield, E. S.;
Marakovits, J . T.; Babine, R. E. U.S. Pat. 5,962,487.
(6) (a) Lombart, H.-G.; Lubell, W. D. J . Org. Chem. 1996, 61, 9437.
(b) Lombart, H.-G.; Lubell, W. D. J . Org. Chem. 1994, 59, 6147. (c)
Mueller, R.; Revesz, L. Tetrahedron Lett. 1994, 35, 4091.
10.1021/jo010712n CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/11/2002

742 J . Org. Chem., Vol. 67, No. 3, 2002
Dragovich et al.
Sch em e 1. Retr osyn th etic An a lysis of Bicyclic
2-P yr id on e 1
Sch em e 2a
a
Reagents and conditions: (a) 1.05 equiv of (CH3)3O‚BF4,
CH2Cl2, 23 °C, 36 h, 92%; (b) 1.4 equiv of NBS, 0.02 equiv of
benzoyl peroxide, CCl4, reflux, 18 h, 12%; (c) 1.0 equiv of
CH2dCHCH2MgBr, THF,
0 °C, 10 min, then 2.0 equiv of
CH2dCHCH2MgBr, THF, 50 °C, 30 min, 37%.
afforded roughly a 1:1 mixture of the desired 10 and the
undesired 11 as qualitatively determined by thin-layer
chromatographic analysis. The desired transformation
was eventually effected in good yield (92%) by exposure
of 9 to trimethyloxonium tetrafluoroborate for 1.5 days
at room temperature. The identical reaction conditions
were previously employed for the selective O-methylation
of related 2-hydroxypyridines.12
primary alcohol present in the resulting diol. To complete
the retrosynthetic analysis, two approaches were con-
sidered for the preparation of pyridine 6. The first (A)
anticipated obtaining 6 from intermediate 7 by either
dianion formation and electrophilic allylation or by
benzylic halogenation and nucleophilic allylic displace-
ment. The second (B) relied on the known benzylic
derivatization of the dianion of 2-hydroxy-6-methylnico-
tinonitrile (8)7,8 with subsequent transformation of the
nitrile functional group. At the outset of our synthetic
efforts, it was not known which (if any) of the above
approaches would successfully afford the desired peptide
mimetic products.
Initially, we chose to examine the synthetic pathway
suggested by retrosynthetic analysis A. Accordingly, the
known 2-hydroxypyridine 9 was prepared from 2-hy-
droxy-6-methylpyridine-3-carboxylic acid via Curtius re-
arrangement followed by condensation of the resulting
isocyanate (not shown) with benzyl alcohol (Scheme 2).9
Selective transformation of 9 to the O-methylation prod-
uct 10 proved to be somewhat challenging. In accordance
with literature precedent, derivatization of the sodium
salt of 9 with iodomethane afforded the corresponding
N-alkylation adduct 11 nearly exclusively in 91% yield.10
Employment of silver-mediated alkylation conditions11
Attempted formation of the dianion of 10 and subse-
quent benzylic allylation under a variety of conditions
were unsuccessful at producing the key olefin intermedi-
ate 13. These failures presumably resulted from the
inability of the deprotonated Cbz NH moiety to function
as an appropriate activator for benzylic deprotonation.7
Alternatively, 10 was converted to bromide 12 through
a radical halogenation process, and the latter intermedi-
ate was transformed into 13 by displacement with
allylmagnesium bromide (Scheme 2). Although this se-
quence successfully provided olefin 13, it suffered from
several drawbacks. First, the radical bromination of 10
to give 12 was a highly variable, often low-yielding
reaction that did not transfer well to large scale.13 Similar
difficulties in effecting the radical halogenation of related
pyridines have been described in the literature.11a,b In
addition, the desired bromide 12 was difficult to purify
from both the starting material 10 and several reaction
side products. Second, the conversion of 12 to 13 also
proceeded in low yield, required a somewhat tedious
purification process, and was not easily amenable to
scale-up. These factors combined to severely limit the
throughput of material from the readily available 10 to
the desired olefin 13 and prompted us to develop an
alternate synthesis of the latter intermediate.
(7) DeJ ohn, D.; Domagala, J . M.; Kaltenbronn, J . S.; Krolls, U. J .
Heterocyclic Chem. 1983, 20, 1295, and references therein.
(8) For clarity purposes, several chemical entities are described and
depicted as 2-hydroxypyridines rather than the corresponding 2-py-
ridone tautomers. Single isomers of such compounds were always
observed in their 1H NMR spectra, but no attempt was made to
rigorously determine the precise structure of these isomers.
(9) Sanderson, P. E. J .; Lyle, T. A.; Cutrona, K. J .; Dyer, D. L.;
Dorsey, B. D.; McDonough, C. M.; Naylor-Olsen, A. M.; Chen, I.-W.;
Chen, Z.; Cook, J . J .; Cooper, C. M.; Gardell, S. J .; Hare, T. R.; Krueger,
J . A.; Lewis, S. D.; Lin, J . H.; Lucas, B. J ., J r.; Lyle, E. A.; Lynch, J .
J ., J r.; Stranieri, M. T.; Vastag, K.; Yan, Y.; Shafer, J . A.; Vacca, J . P.
J . Med. Chem. 1998, 41, 4466. A slightly modified workup procedure
was employed in the present work.
(10) For general references on the alkylation of 2-hydroxypyridines,
see: (a) Scriven, E. F. V. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, U.K.,
1984; Vol. 2, pp 165-314. (b) Tieckelmann, H. In Pyridine and Its
Derivatives; Abramovitch, R. A., Ed.; Wiley-Interscience: New York,
1974; Vol. 14, Supplement 3, Chapter 12, pp 597-1180.
An improved preparation of olefin 13 which eventually
provided the bicyclic 2-pyridone 1 was realized by pursuit
of the synthesis illustrated in retrosynthetic analysis
pathway B (Scheme 1). As depicted in Scheme 3, slow
(11) For examples of O-alkylation of 2-hydroxypyridines effected by
silver salts, see: (a) Pomel, V.; Rovera, J . C.; Godard, A.; Marsais, F.;
Que´guiner, G. J . Heterocyclic Chem. 1996, 33, 1995. (b) Gray, M. A.;
Konopski, L.; Langlois, Y. Synth. Commun. 1994, 24, 1367. (c)
Carabateas, P. M.; Brundage, R. P.; Gelotte, K. O.; Gruett, M. D.;
Lorenz, R. R.; Opalka, C. J ., J r.; Singh, B.; Thielking, W. H.; Williams,
G. L.; Lesher, G. Y. J . Heterocyclic Chem. 1984, 21, 1857. (d) Honma,
Y.; Sekine, Y.; Hashiyama, T.; Takeda, M.; Ono, Y.; Tsuzurahara, K.
Chem. Pharm. Bull. 1982, 30, 4314.
(12) Beak, P. B.; Covington, J . B.; Smith, S. G.; White, J . M.; Zeigler,
J . M. J . Org. Chem. 1980, 45, 1354.

Bicyclic 2-Pyridone Dipeptide Memetic
J . Org. Chem., Vol. 67, No. 3, 2002 743
Sch em e 3a
Ta ble 1. Osm iu m -Ca ta lyzed Asym m etr ic
Dih yd r oxyla tion of Olefin 13 Em p loyin g Va r iou s Ch ir a l
Cin ch on a Alk a loid Liga n d s
entry
ligand
yield of 18a (%)
eeb (%)
ref
1
2
3
4
(DHQD)2-PHAL
(DHQD)2-PYR
(DHQD)2-AQN
(DHQ)2-AQN
96
91
98
96c
55.5
75.1
83.4
78.0
16a
16b
16c
16c
a
Isolated yield after purification by silica gel chromatography.
b Determined by chiral HPLC analysis (see Supporting Information
for additional details). c Enantiomer of 18.
pyridine provided olefin 13 in excellent yield following
purification by flash column chromatography. The em-
ployment of 2,6-di-tert-butylpyridine in the conversion of
17 to 13 dramatically reduced the appearance of side
products which presumably resulted from acid-effected
olefin decomposition. It should be noted that the synthetic
operations which convert 8 to 17 were performed without
silica gel purification of the reaction products and were
readily amenable to multigram scale operations.
Having developed a synthesis which reliably afforded
relatively large quantities of olefin 13, we then examined
the asymmetric dihydroxylation of this intermediate.15
A variety of cinchona alkaloid ligands have been em-
ployed for the osmium-catalyzed, asymmetric dihydroxy-
lation of monosubstituted terminal olefins such as 13,
although none have been indicated to give optimal results
for every such substrate.16 Accordingly, we examined all
such commercially available cinchona alkaloid ligands for
their ability to assist in the transformation of olefin 13
to optically active diol 18. As seen in Table 1, osmium-
catalyzed dihydroxylation of 13 employing any of the
above ligands provided the desired diol 18 in excellent
yields. The (DHQD)2-AQN ligand, however, afforded 18
with the highest levels of enantioselectivity and was
therefore selected for the large-scale preparation of this
intermediate.17 Utilization of the related (DHQ)2-AQN
ligand for the dihydroxylation of 13 provided the enan-
tiomer of 18 (not shown) in good yield and nearly equally
high ee (Table 1, entry 4).
Protection of the primary alcohol present in 18 was
accomplished by exposure to an excess of tert-butyldi-
methylsilyl chloride in the presence of catalytic amounts
of 4-(dimethylamino)pyridine and provided the mono-silyl
ether 19 in good yield. Minor quantities of unreacted 18
and the corresponding di-silyl ether (not characterized
or shown) were also observed during this transformation.
Treatment of 19 at low temperature with trifluoro-
methanesulfonic anhydride in the presence of excess 2,6-
lutidine, followed by subsequent warming to room tem-
perature, resulted in clean conversion to the pyridinium
salt 20 which could surprisingly be isolated by flash
column chromatography in good yield. Simultaneous
O-demethylation and desilylation was accomplished by
a
Reagents and conditions: (a) 2.5 equiv of LDA, 1.5 equiv of
CH2dCHCH2Br, THF, 0f23 °C, 30 min, 58%; (b) H2O2, 1:2 EtOH:
10% NaOH, 50 °C, 18 h, 100%; (c) 10% KOH, reflux, 20 h, 92%;
(d) 2.0 equiv of Et3N, 1.5 equiv of (PhO)2P(O)N3, 1,4-dioxane,
reflux, 7.5 h, then 2.0 equiv of BnOH, reflux, 16 h, 49%; (e) 1.2
equiv of (CH3)3O‚BF4, 0.6 equiv of 2,6-di-tert-butylpyridine, CH2Cl2,
23 °C, 65 h, 91%; (f) 0.01 equiv of (DHQD)2-AQN, 3.0 equiv of
K3Fe(CN)6, 3.0 equiv of K2CO3, 0.004 equiv of K2OsO4‚2H2O, 1:1
tert-BuOH:H2O, 0 °C, 20 h, 98%; (g) 2.5 equiv of Et3N, 1.6 equiv
of (TBS)Cl, 0.045 equiv of DMAP, CH2Cl2, 23 °C, 19 h, 82%; (h)
4.0 equiv of 2,6-lutidine, 1.5 equiv of Tf2O, CH2Cl2, -78f+23 °C,
1 h; (i) 3.0 equiv of TBAF, THF, 23 °C, 1 h, 58% from 19; (j) 2.6
equiv of DMSO, 1.3 equiv of oxalyl chloride, 5.0 equiv of Et3N, 5.5
equiv of AcOH, CH2Cl2, -78 °C, 2 h; (k) 5% KMnO4, 2:3 5%
NaH2PO4:tert-BuOH, 23 °C, 5 min, 30% from 21.
addition of solid 8 to 2.5 equiv of lithium diisopropyla-
mide in cold tetrahydrofuran (THF) provided a solution
of the corresponding dilithium salt in accordance with
the reported literature method.7 The dilithio intermediate
thus obtained was quenched with allyl bromide to give
the allylated pyridine 14 in good yield. Hydrolysis of the
nitrile moiety present in 14 was accomplished by a two-
step procedure which involved initial peroxide-mediated
conversion to the primary amide 15.14 Extended exposure
of 15 to refluxing aqueous KOH then provided the
carboxylic acid 16 in good yield. Curtius rearrangement
of 16 was effected in a manner analogous to that
described for the preparation of 9 above (Scheme 2), and
trapping of the resulting isocyanate (not shown) with
benzyl alcohol afforded the desired carbamate 17 in
moderate yield. Treatment of 17 with trimethyloxonium
tetrafluoroborate in the presence of 2,6-di-tert-butyl-
(15) For a review of catalytic asymmetric dihydroxylation methods,
see: Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483.
(16) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G.
A.; Hartung, J .; J eong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-
M.; Xu, D.; Zhang, X.-L. J . Org. Chem. 1992, 57, 2768. (b) Crispino, G.
A.; J eong, K.-S.; Kolb, H. C.; Wang, Z.-M.; Xu, D.; Sharpless, K. B. J .
Org. Chem. 1993, 58, 3785. (c) Becker, H.; Sharpless, K. B. Angew.
Chem., Int. Ed. Engl. 1996, 35, 448. See also: Hoye, T. R.; Mayer, M.
J .; Vos, T. J .; Ye, Z. J . Org. Chem. 1998, 63, 8554.
(13) Deoxygenation of the halogenation reaction medium and use
of the corresponding Boc-protected aminopyridine as a halogenation
substrate did not result in significant yield improvements.
(14) Sakamoto, T.; Kondo, Y.; Yamanaka, H. Heterocycles 1988, 27,
453.
(17) The absolute configuration shown for diol 18 is based on
literature precedent.16 The absolute configurations of intermediates
19-22 and compound 1 are derived from that of 18.

744 J . Org. Chem., Vol. 67, No. 3, 2002
Dragovich et al.
mmol, 2.0 equiv) was added, and reflux was continued for an
additional 23 h. The dark brown reaction mixture was cooled
to 23 °C, and the volatiles were removed under reduced
pressure. The resulting dark brown oil was partitioned be-
tween water (300 mL) and CH2Cl2 (2 × 300 mL), and the
combined organic layers were dried over MgSO4, gravity
filtered, and concentrated. The solid thus obtained was
triturated with EtOAc (250 mL) and was filtered through a
medium frit, washed with Et2O (3 × 70 mL), and air-dried to
give 9 (21.3 g, 52%) as a tan powder: mp ) 171-172 °C; Rf )
0.23 (50% EtOAc in hexanes); IR (cm-1) 3388, 3323, 1732, 1643;
1H NMR (CDCl3) δ 2.13 (s, 3H), 5.13 (s, 2H), 5.98 (d, 1H, J )
7.5), 7.28-7.43 (m, 5H), 7.70 (d, 1H, J ) 7.5), 8.22 (s, 1H),
11.92 (s, 1H); 13C NMR (CDCl3) δ 18.1, 65.9, 103.7, 123.1,
125.9, 127.7, 127.9, 128.4, 136.6, 137.6, 153.2, 157.8; Anal.
Calcd for C14H14N2O3‚0.10H2O: C, 64.65; H, 5.50; N, 10.77.
Found: C, 64.65; H, 5.46; N, 10.85.
(2-Meth oxy-6-m eth ylp yr id in -3-yl)ca r ba m ic Acid Ben z-
yl E st er (10). Trimethyloxonium tetrafluoroborate (12.7 g,
86.2 mmol, 1.05 equiv) was added to a solution of 9 (21.2 g,
82.1 mmol, 1 equiv) in CH2Cl2 at 23 °C. The resulting
suspension was stirred at 23 °C for 36 h and then was
partitioned between CH2Cl2 (2 × 200 mL) and 10% aqueous
NaOH solution (300 mL). The combined organic layers were
dried over Na2SO4 and concentrated, and the residue was
purified by flash column chromatography (20% EtOAc in
hexanes) to afford 10 (20.6 g, 92%) as a colorless oil: Rf ) 0.32
(60% EtOAc in hexanes); IR (cm-1) 3436, 1732; 1H NMR
(CDCl3) δ 2.39 (s, 3H), 3.95 (s, 3H), 5.20 (s, 2H), 6.71 (d, 1H,
J ) 7.8), 7.11 (s, br, 1H), 7.33-7.43 (m, 5H), 8.16 (s, br, 1H);
13C NMR (CDCl3) δ 23.6, 53.6, 67.2, 116.1, 120.0, 125.6, 128.5,
128.5, 128.8, 136.2, 148.8, 152.2, 153.5; Anal. Calcd for
exposure of 20 to tetrabutylammonium fluoride for
several hours at room temperature and provided pyridone
21 in good yield after purification on silica gel. When
conducting large-scale operations, pyridinium salt 20 was
not routinely isolated and the crude mono-silyl ether 19
was instead converted directly to pyridone 21 in moderate
overall yield.
With the bicyclic 2-pyridone framework assembled, we
then examined the oxidation of the alcohol moiety present
in 21 to the carboxylic acid level. After some experimen-
tation, a two-step procedure was found to be most
effective and commenced with Swern oxidation of 21 to
afford aldehyde 22.18 A low-temperature quench was
employed in this operation in order to minimize possible
racemization of the stereogenic center contained in 22.19
Aldehyde 22 was not purified but was instead further
oxidized by exposure to buffered, aqueous KMnO4 to give
the desired pyridone 1 in moderate overall yield after
flash column chromatography.20,21 Pyridone 1 prepared
in this manner was typically of sufficient purity for
subsequent chemical transformations (e.g., amide bond
formation). Comparison to an independently prepared
racemic standard determined the optical purity of 1 to
be 60% (ee) and indicated that the synthetic operations
which convert diol 18 to 1 resulted in minor racemization
(see Supporting Information for additional details).
In summary, we describe the preparation of optically
active bicyclic 2-pyridone 1 in eleven steps from com-
mercially available 2-hydroxy-6-methylnicotinonitrile (3.3%
overall yield). Although certain aspects of this first-
generation synthesis may possibly be improved upon in
the future, we believe that the present route affords 1 in
quantities sufficient to allow its incorporation into a
variety of peptidomimetic structures.
C
15H16N2O3: C, 66.16; H, 5.92; N, 10.29. Found: C, 66.37; H,
5.93; N, 10.38.
(1,6-Dim et h yl-2-oxo-1,2-d ih yd r op yr id in -3-yl)ca r b a m -
ic Acid Ben zyl Ester (11). Tetrabutylammonium bromide
(4.00 g, 12.4 mmol, 2.0 equiv), sodium hydroxide (0.50 g, 12.5
mmol, 2.0 equiv), and iodomethane (3.86 mL, 62.0 mmol, 10.0
equiv) were added sequentially to a biphasic solution of 9 (1.60
g, 6.19 mmol, 1 equiv) in a 2:1 mixture of CH2Cl2 and water
(90 mL). The pale green reaction mixture was stirred at 23 °C
for 1 h and then was partitioned between water (150 mL) and
CH2Cl2 (2 × 100 mL). The organic layers were combined, dried
over Na2SO4, and concentrated. Purification of the residue by
flash column chromatography (60% EtOAc in hexanes) af-
forded 11 (1.54 g, 91%) as a light brown solid: mp ) 76-78
°C; Rf ) 0.40 (60% EtOAc in hexanes); IR (cm-1) 3254, 1714,
1647; 1H NMR (CDCl3) δ 2.32 (s, 3H), 3.57 (s, 3H), 5.20 (s,
2H), 6.08 (d, 1H, J ) 7.3), 7.30-7.41 (m, 5H), 7.82 (s, br, 1H),
7.91 (d, 1H, J ) 7.3); 13C NMR (CDCl3) δ 20.4, 31.9, 67.0, 106.3,
120.0, 126.6, 128.2, 128.3, 128.7, 136.2, 137.6, 153.5, 158.2;
Anal. Calcd for C15H16N2O3: C, 66.16; H, 5.92; N, 10.29.
Found: C, 66.17; H, 5.90; N, 10.28.
Exp er im en ta l Section 22
All reactions were performed in septum-sealed flasks under
a slight positive pressure of argon unless otherwise noted. All
commercial reagents were used as received from their respec-
tive suppliers with the following exceptions. Tetrahydrofuran
was distilled from sodium-benzophenone ketyl prior to use.
Dichloromethane (CH2Cl2) was distilled from calcium hydride
prior to use. 1H and 13C NMR spectra were recorded at 300
and 75 MHz, respectively. 1H and 13C NMR chemical shifts
are reported in parts per million (δ) downfield relative to
internal tetramethylsilane or residual solvent peaks, and
coupling constants are given in hertz. Melting points were
determined using a Mel-Temp II apparatus and are uncor-
rected.
(2-Hyd r oxy-6-m eth ylp yr id in -3-yl)ca r ba m ic Acid Ben z-
yl Ester (9).9 Triethylamine (44.6 mL, 320 mmol, 2.0 equiv)
and diphenylphosphoryl azide (51.7 mL, 240 mmol, 1.5 equiv)
were added sequentially to a suspension of 2-hydroxy-6-
methylpyridine-3-carboxylic acid (24.5 g, 160 mmol, 1 equiv)
in 1,4-dioxane (500 mL) at 23 °C. The resulting solution was
heated to reflux for 18 h, then benzyl alcohol (33.1 mL, 320
(6-Br om om eth yl-2-m eth oxypyr idin -3-yl)car bam ic Acid
Ben zyl Ester (12). N-Bromosuccinimide (18.3 g, 103 mmol,
1.4 equiv) and benzoyl peroxide (0.357 g, 1.47 mmol, 0.02
equiv) were added sequentially to a solution of 10 (20.05 g,
73.6 mmol, 1 equiv) in CCl4 at 23 °C. The resulting suspension
was heated to reflux for 18 h and then was cooled to 23 °C
and filtered through a medium frit. The red/brown filtrate was
concentrated under reduced pressure, and the residue was
passed through a plug of silica gel, eluting with 15% EtOAc
in hexanes. Fractions containing the desired product were
combined and concentrated, and the residue was allowed to
stand overnight. The resulting red/brown solid was triturated
with CH3OH (50 mL), filtered through a medium frit, and
washed with hexanes (30 mL) to provide 12 (3.06 g, 12%) as a
yellow solid: mp ) 88-89 °C; Rf ) 0.48 (10% EtOAc in
hexanes; 2 elutions); IR (cm-1) 3433, 1734; 1H NMR (CDCl3) δ
3.99 (s, 3H), 4.45 (s, 2H), 5.21 (s, 2H), 6.99 (d, 1H, J ) 7.4),
7.22 (s, br, 1H), 7.33-7.43 (m, 5H), 8.28 (d, 1H, J ) 7.4); 13C
NMR (CDCl3) δ 34.5, 54.0, 67.5, 117.1, 122.6, 125.1, 128.6,
(18) (a) Tidwell, T. T. Synthesis 1990, 857. (b) Mancuso, A. J .; Swern,
D. Synthesis 1981, 165.
(19) DeCamp, A. E.; Kawaguchi, A. T.; Volante, R. P.; Shinkai, I.
Tetrahedron Lett. 1991, 32, 1867.
(20) Abiko, A.; Roberts, J . C.; Takemasa, T.; Masamune, S. Tetra-
hedron Lett. 1986, 27, 4537.
(21) Caution must be exercised during the conversion of 22 to 1 since
prolonged reaction times (>15 min) resulted in extensive decomposition
of the 2-pyridone ring system. The use of buffered NaClO2 to effect
the 22 to 1 transformation was unpredictable and often resulted in
the formation of chlorinated 2-pyridone side products.
(22) General experimental procedures and instrumentation are
described in: Dragovich, P. S.; Prins, T. J .; Zhou, R. J . Org. Chem.
1995, 60, 4922.
128.7, 128.9, 135.9, 146.5, 152.4, 153.3; Anal. Calcd for C15H15
-
BrN2O3: C, 51.30; H, 4.30; N, 7.98. Found: C, 51.72; H, 4.31;
N, 8.01.

Bicyclic 2-Pyridone Dipeptide Memetic
J . Org. Chem., Vol. 67, No. 3, 2002 745
(6-Bu t -3-en yl-2-m et h oxyp yr id in -3-yl)ca r b a m ic Acid
Ben zyl Ester (13). Allylmagnesium bromide (19.5 mL of a
1.0 M solution in Et2O, 19.5 mmol, 1.0 equiv) was added via
cannula over 10 min to a solution of 12 (6.84 g, 19.4 mmol, 1
equiv) in THF (200 mL) at 0 °C. Upon completion of the
addition, the reaction mixture was warmed to 50 °C where-
upon a second portion of allylmagnesium bromide (38.9 mL of
a 1.0 M solution in Et2O, 38.9 mmol, 2.0 equiv) was added.
The resulting orange solution was maintained at 50 °C for 30
min, then was cooled to 23 °C, and was partitioned between
0.5 M HCl (150 mL) and a 1:1 mixture of EtOAc and hexanes
(2 × 150 mL). The combined organic layers were dried over
Na2SO4 and were concentrated. Purification of the residue by
careful flash column chromatography (5% EtOAc in hexanes)
afforded 13 (2.24 g, 37%) as a pale yellow oil (containing minor
5.07 (m, 2H), 5.72-5.85 (m, 1H), 6.56 (d, 1H, J ) 7.5), 8.28 (d,
1H, J ) 7.5), 13.26 (s, br, 1H), 14.64 (s, br, 1H); 13C NMR
(DMSO-d6) δ 31.7, 32.0, 107.9, 113.7, 116.3, 136.5, 146.0, 156.5,
165.1, 165.1; Anal. Calcd for C10H11NO3‚0.10H2O: C, 61.59;
H, 5.79; N, 7.18. Found: C, 61.67; H, 5.71; N, 7.17.
(6-Bu t -3-en yl-2-h yd r oxyp yr id in -3-yl)ca r b a m ic Acid
Ben zyl Ester (17). Triethylamine (13.9 mL, 99.7 mmol, 2.0
equiv) and diphenylphosphoryl azide (16.1 mL, 74.7 mmol, 1.5
equiv) were added sequentially to a suspension of 16 (9.63 g,
49.8 mmol, 1 equiv) in 1,4-dioxane (450 mL) at 23 °C. The
resulting solution was heated to reflux for 7.5 h, then benzyl
alcohol (10.3 mL, 99.5 mmol, 2.0 equiv) was added, and reflux
was continued for an additional 16 h. The dark brown reaction
mixture was cooled to 23 °C, and the volatiles were removed
under reduced pressure. The resulting dark brown oil was
partitioned between water (300 mL) and EtOAc (2 × 250 mL)
and the combined organic layers were dried over Na2SO4 and
concentrated. The solid thus obtained was triturated with Et2O
(150 mL) and was filtered through a medium frit, washed with
Et2O (2 × 50 mL), and air-dried to give 17 (7.34 g, 49%) as an
off-white powder: mp ) 179-180 °C; Rf ) 0.34 (50% EtOAc
1
impurities by H NMR): Rf ) 0.84 (50% EtOAc in hexanes);
1
IR (cm-1) 3432, 1733; H NMR (CDCl3) δ 2.42-2.49 (m, 2H),
2.73 (t, 2H, J ) 7.6), 3.96 (s, 3H), 4.94-5.07 (m, 2H), 5.20 (s,
2H), 5.80-5.94 (m, 1H), 6.71 (d, 1H, J ) 7.9), 7.11 (s, br, 1H),
7.32-7.43 (m, 5H), 8.16 (s, br, 1H); 13C NMR (CDCl3) δ 33.3,
36.4, 53.3, 67.0, 114.7, 115.4, 120.0, 125.2, 128.3, 128.3, 128.6,
135.9, 138.2, 151.6, 152.1, 153.3; Anal. Calcd for C18H20N2O3:
C, 69.21; H, 6.45; N, 8.97. Found: C, 69.35; H, 6.44; N, 8.94.
6-Bu t -3-en yl-2-h yd r oxyn icot in on it r ile (14). n-Butyl-
lithium (100 mL of a 1.6 M solution in hexanes, 160 mmol,
2.5 equiv) was added via cannula over 10 min to a solution of
diisopropylamine (22.4 mL, 160 mmol, 2.5 equiv) in THF (600
mL) at -78 °C. The resulting pale yellow solution was stirred
at -78 °C for 5 min and then was warmed to 0 °C for an
additional 5 min. 2-Hydroxy-6-methylnicotinonitrile (8) (8.58
g, 64.0 mmol, 1 equiv) was added as a solid in small portions
over 15 min, and the deep orange solution thus obtained was
stirred for 1 h at 0 °C. Allyl bromide (8.31 mL, 96.0 mmol, 1.5
equiv) was then added, and the reaction mixture was warmed
to 23 °C, maintained at that temperature for 30 min, and
partitioned between 1.0 M HCl (300 mL) and EtOAc (2 × 250
mL). The combined organic layers were dried over Na2SO4 and
were concentrated. The resulting orange solid was triturated
with boiling Et2O (100 mL) and subsequently cooled to 23 °C
and then was filtered through a medium frit, washed with
Et2O (2 × 50 mL), and air-dried to give 14 (6.42 g, 58%) as a
tan solid: mp ) 122-125 °C; Rf ) 0.48 (10% CH3OH in CH2-
1
in hexanes); IR (cm-1) 3386, 1727, 1645; H NMR (CDCl3) δ
2.39-2.46 (m, 2H), 2.65 (t, 2H, J ) 7.5), 4.97-5.07 (m, 2H),
5.21 (s, 2H), 5.73-5.87 (m, 1H), 6.10 (d, 1H, J ) 7.5), 7.32-
7.44 (m, 5H), 7.68 (s, br, 1H), 8.06 (s, br, 1H), 12.74 (s, br,
1H); 13C NMR (CDCl3) δ 32.3, 32.9, 67.2, 105.8, 116.3, 123.1,
126.6, 128.4, 128.5, 128.8, 136.2, 136.7, 140.4, 153.5, 159.3;
Anal. Calcd for C17H18N2O3: C, 68.44; H, 6.08; N,. 9.39.
Found: C, 68.25; H, 6.20; N, 9.38.
(6-Bu t -3-en yl-2-m et h oxyp yr id in -3-yl)ca r b a m ic Acid
Ben zyl Ester (13) (Alter n a te P r ep a r a tion ). Trimethyloxo-
nium tetrafluoroborate (2.0 g, 13.5 mmol, 1.2 equiv) and 2,6-
di-tert-butylpyridine (1.52 mL, 6.76 mmol, 0.6 equiv) were
added to a solution of 17 (3.36 g, 11.26 mmol, 1 equiv) in CH2-
Cl2 (80 mL) at 23 °C. The reaction mixture was stirred at that
temperature for 65 h and then was partitioned between water
(100 mL) and CH2Cl2 (2 × 200 mL). The combined organic
layers were dried over Na2SO4 and were concentrated. The
residue was purified by flash column chromatography (5%
EtOAc in hexanes) to afford 13 (3.19 g, 91%) as colorless oil.
(3′R)-[6-(3′,4′-Dih yd r oxybu tyl)-2-m eth oxyp yr id in -3-yl]-
ca r ba m ic Acid Ben zyl Ester (18). To a 1:1 mixture of
t-BuOH and water (300 mL) at 0 °C was sequentially added
(DHQD)2-AQN (0.148 g, 0.164 mmol, 0.01 equiv), K3Fe(CN)6
(16.2 g, 49.2 mmol, 3.0 equiv), K2CO3 (6.8 g, 49.2 mmol, 3.0
equiv), and potassium osmate dihydrate (0.024 g, 0.066 mmol,
0.004 equiv), followed by a solution of 13 (5.13 g, 16.4 mmol,
1 equiv) in t-BuOH (25 mL). The resulting mixture was stirred
at 0 °C for 20 h, then was warmed to room temperature, and
Na2SO3 (30 g) was added carefully. The mixture was then
stirred at room temperature for 2 h, and the volatiles were
removed under reduced pressure. The residue was partitioned
between water (200 mL) and EtOAc (3 × 200 mL), and the
combined organic layers were dried over Na2SO4 and concen-
trated. The residue was purified by flash column chromatog-
raphy (2% CH3OH in CH2Cl2) to afford 18 (5.57 g, 98%) as
pale yellow oil. The enantiomeric purity of this material was
determined to be 83.4% (ee) by chiral HPLC analysis (see the
Supporting Information for additional details): Rf ) 0.20 (70%
EtOAc in hexanes); IR (cm-1) 3427 (br), 1731; 1H NMR (CDCl3)
δ 1.76-1.87 (m, 2H), 2.07-2.11 (m, 1H), 2.80-2.89 (m, 2H),
3.46-3.53 (m, 1H), 3.60-3.67 (m, 1H), 3.71-3.77 (m, 1H), 3.96
(s, 3H), 4.64 (d, 1H, J ) 3.2), 5.21 (s, 2H), 6.76 (d, 1H, J )
7.8), 7.12 (s, br, 1H), 7.34-7.43 (m, 5H), 8.22 (s, br, 1H); 13C
NMR (CDCl3) δ 32.3, 33.2, 53.9, 66.9, 67.3, 71.8, 116.0, 120.7,
126.0, 128.5, 128.6, 128.8, 136.0, 151.5, 152.3, 153.5; Anal.
Calcd for C18H22N2O5: C, 62.42; H, 6.40; N, 8.09. Found: C,
62.15; H, 6.47; N, 8.02.
1
Cl2); IR (KBr pellet, cm-1) 2223, 1654; H NMR (DMSO-d6) δ
2.32-2.37 (m, 2H), 2.62 (t, 2H, J ) 7.6), 4.96-5.06 (m, 2H),
5.69-5.83 (m, 1H), 6.23 (d, 1H, J ) 7.3), 8.03 (d, 1H, J ) 7.3),
12.55 (s, br, 1H); 13C NMR (DMSO-d6) δ 31.8, 31.9, 100.0,
104.6, 116.1, 116.7, 136.5, 148.9, 156.7, 160.8; Anal. Calcd for
C
10H10N2O‚0.10H2O: C, 68.24; H, 5.84; N, 15.92. Found: C,
68.07; H, 5.95; N, 15.66.
6-Bu t-3-en yl-2-h ydr oxyn icotin am ide (15). Hydrogen per-
oxide (30 wt % solution in water, 45 mL) was added to a
solution of 14 (12.1 g, 70.2 mmol) in a mixture of EtOH (150
mL) and 10% aqueous NaOH (280 mL) at 23 °C. The reaction
mixture was heated to 50 °C for 18 h and then was cooled to
23 °C, and the volatiles were removed under reduced pressure.
The residue was acidified with 12 M HCl to pH 2-3, and the
resulting precipitate was filtered, washed with water (2 × 50
mL), and air-dried to afford 15 as a yellow solid (13.4 g,
100%): mp ) 195-198 °C; Rf ) 0.24 (10% CH3OH in CH2Cl2);
IR (cm-1) 3329, 3134, 1688, 1642; 1H NMR (DMSO-d6) δ 2.31-
2.38 (m, 2H), 2.64 (t, 2H, J ) 7.6), 4.96-5.05 (m, 2H), 5.71-
5.84 (m, 1H), 6.29 (d, 1H, J ) 7.3), 7.45 (s, br, 1H), 8.21 (d,
1H, J ) 7.3), 9.00 (s, br, 1H), 12.37 (s, br, 1H); 13C NMR
(DMSO-d6) δ 31.4, 32.0, 105.1, 116.0, 117.9, 136.7, 144.3, 154.0,
162.9, 164.8; Anal. Calcd for C10H12N2O2‚0.15H2O: C, 61.61;
H, 6.28; N, 14.37. Found: C, 61.84; H, 6.18; N, 14.11.
6-Bu t-3-en yl-2-h yd r oxyn icotin ic Acid (16). A solution of
15 (13.4 g, 70.1 mmol) in 10% aqueous KOH (350 mL) was
refluxed for 20 h and subsequently cooled to room temperature.
The reaction mixture was acidified with 12 M HCl to pH 2-3,
and the resulting precipitate was filtered, washed with water
(2 × 50 mL), and dried under vacuum to afford 16 as a yellow
solid (12.4 g, 92%): mp ) 151-155 °C; Rf ) 0.20 (10% CH3-
OH in CH2Cl2); IR (cm-1) 2905 (br), 1736, 1652; 1H NMR
(DMSO-d6) δ 2.34-2.29 (m, 2H), 2.73 (t, 2H, J ) 7.6), 4.96-
(3′R)-{6-[4′-(ter t-Bu tyld im eth ylsila n yloxy)-3′-h yd r oxy-
bu tyl]-2-m eth oxyp yr id in -3-yl}ca r ba m ic Acid Ben zyl Es-
ter (19). Triethylamine (1.55 mL, 11.1 mmol, 2.5 equiv), tert-
butyldimethylsilyl chloride (1.07 g, 7.10 mmol, 1.6 equiv), and
4-(dimethylamino)pyridine (0.025 g, 0.20 mmol, 0.045 equiv)
were added sequentially to a solution of 18 (1.54 g, 4.45 mmol,
1 equiv) in CH2Cl2 (50 mL) at 23 °C. The reaction mixture was

746 J . Org. Chem., Vol. 67, No. 3, 2002
Dragovich et al.
stirred for 19 h at 23 °C and then was partitioned between
0.5 M HCl (150 mL) and a 1:1 mixture of EtOAc and hexanes
(2 × 150 mL). The combined organic layers were dried over
Na2SO4 and were concentrated. Purification of the residue by
flash column chromatography (20% EtOAc in hexanes) pro-
vided 19 (1.69 g, 82%) as a colorless oil: Rf ) 0.32 (20% EtOAc
in hexanes); IR (cm-1) 3436, 1734; 1H NMR (CDCl3) δ 0.07 (s,
6H), 0.90 (s, 9H), 1.72-1.94 (m, 2H), 2.72-2.88 m, 2H), 3.26
(d, 1H, J ) 3.1), 3.50 (dd, 1H, J ) 9.8, 6.9), 3.58-3.63 (m,
1H), 3.65-3.70 (m, 1H), 3.95 (s, 3H), 5.20 (s, 2H), 6.75 (d, 1H,
J ) 8.1), 7.11 (s, br, 1H), 7.33-7.43 (m, 5H), 8.20 (s, br, 1H);
13C NMR (CDCl3) δ -5.2, -5.1, 18.5, 26.1, 32.5, 33.3, 53.7, 67.3,
67.4, 71.6, 115.8, 120.4, 125.7, 128.5, 128.6, 128.8, 136.1, 152.0,
152.3, 153.5; Anal. Calcd for C24H36N2O5Si: C, 62.57; H, 7.88,;
N, 6.08. Found: C, 62.49; H, 7.92; N, 6.09.
66.2, 66.9, 102.3, 122.1, 127.0, 128.1, 128.2, 128.5, 135.9, 142.3,
153.4, 157.3; Anal. Calcd for C17H18N2O4‚0.75H2O: C, 62.28;
H, 5.99; N, 8.54. Found: C, 62.03; H, 5.86; N, 8.46.
(3S)-(3-F or m yl-5-oxo-1,2,3,5-tetr a h yd r oin d olizin -6-yl)-
ca r ba m ic Acid Ben zyl Ester (22). Dimethyl sulfoxide (0.522
mL, 7.36 mmol, 2.6 equiv) was added dropwise to a solution
of oxalyl chloride (0.321 mL, 3.68 mmol, 1.3 equiv) in CH2Cl2
(80 mL) at -78 °C. The reaction mixture was stirred for 20
min at that temperature, and then a solution of 21 (0.890 g,
2.83 mmol, 1 equiv) in CH2Cl2 (20 mL) was added via cannula.
After stirring an additional 20 min at -78 °C, triethylamine
(1.97 mL, 14.15 mmol, 5.0 equiv) was added dropwise. The
reaction mixture was maintained at -78 °C for 1.5 h, and then
acetic acid (15.57 mmol, 0.891 mL, 5.5 equiv) was added. The
reaction mixture was warmed to 0 °C for 5 min and then was
washed with water (50 mL), saturated NaHCO3 (50 mL), and
brine (50 mL). The organic layer was dried over Na2SO4 and
concentrated to afford crude 22 as off-white foam. This
material was utilized without further purification: 1H NMR
(CDCl3) δ 2.38-2.46 (m, 2H), 3.05-3.11 (m, 2H), 5.15-5.25
(m, 3H), 6.22 (d, 1H, J ) 7.8), 7.33-7.44 (m, 5H), 7.72 (s, br,
1H), 8.11 (d, 1H, J ) 7.8), 9.74 (s, 1H).
(3S)-6-(Ben zyloxycar bon ylam in o)-5-oxo-1,2,3,5-tetr ah y-
d r oin d olizin e-3-ca r boxylic Acid (1). A 5% aqueous NaH2-
PO4 solution (5 mL) and a 1.0 M aqueous KMnO4 solution (7
mL) were added sequentially to a solution of crude 22 (1.27
mmol) in t-BuOH (8 mL) at 23 °C. The reaction mixture was
stirred at room temperature for 5 min, and then a saturated
aqueous solution of Na2SO3 (20 mL) was added. The resulting
mixture was stirred at room temperature for 10 min, then was
acidified with 1.0 M HCl to pH 3, and washed with CH2Cl2 (3
× 50 mL). The organic washings were dried over Na2SO4 and
were concentrated. The residue thus obtained was purified by
flash column chromatography (10% CH3OH in CH2Cl2) to give
1 (0.134 g, 30%) as an off-white solid. The enantiomeric purity
of this material was determined to be 60% (ee) by chiral HPLC
analysis (see the Supporting Information for additional de-
tails): mp ) 204-206 °C; Rf ) 0.18 (10% CH3OH in CH2Cl2);
IR (cm-1) 3298, 1722, 1564, 1208; 1H NMR (DMSO-d6) δ 2.17-
2.55 (m, 2H), 2.45-2.59 (m, 2H), 4.98 (dd, 1H, J ) 9.6, 2.7),
5.16 (s, 2H), 6.23 (d, 1H, J ) 7.5), 7.34-7.45 (m, 5H), 7.83 (d,
1H, J ) 7.5), 8.34 (s, 1H); 13C NMR (DMSO-d6) δ 26.2, 29.5,
61.6, 66.0, 99.7, 123.9, 125.7, 127.7, 127.9, 128.4, 136.6, 143.9,
153.4, 155.7, 171.3; Anal. Calcd for C17H16N2O5: C, 62.19; H,
4.91; N, 8.53. Found: C, 62.08; H, 5.00; N, 8.54.
(3S)-[3-(ter t-Bu tyld im eth ylsila n yloxym eth yl)-5-m eth -
oxy-2,3-d ih yd r o-1H-in d olizin -6-yl]ca r ba m ic Acid Ben zyl
Ester Tr ifu or om eth a n esu lfon ic Acid Sa lt (20). 2,6-Luti-
dine (0.216 mL, 1.85 mmol, 3.0 equiv) and trifluoromethane-
sulfonic anhydride (0.109 mL, 0.648 mmol, 1.05 equiv) were
added sequentially to a solution of 19 (0.285 g, 0.619 mmol, 1
equiv) in CH2Cl2 (30 mL) at -78 °C. The colorless reaction
mixture was stirred at -78 °C for 45 min, warmed to 23 °C
for an additional 15 min, and then was partitioned between
0.5 M HCl (100 mL) and EtOAc (150 mL). The organic layer
was dried over Na2SO4 and was concentrated. The residue thus
obtained was purified by flash column chromatography (5%
CH3OH in CH2Cl2) to give 20 (0.275 g, 75%) as a colorless oil:
1
Rf ) 0.28 (10% CH3OH in CH2Cl2); H NMR (CDCl3) δ -0.14
(s, 3H), -0.01 (s, 3H), 0.74 (s, 9H), 2.35-2.42 (m, 1H), 2.74-
2.89 (m, 1H), 3.30-3.56 (m, 2H), 3.89 (dd, 1H, J ) 11.3, 1.9),
4.13 (dd, 1H, J ) 11.3, 2.8), 4.34 (s, 3H), 5.23 (s, 2H), 5.36-
5.39 (m, 1H), 7.31-7.43 (m, 6H), 8.07 (s, br, 1H), 8.57 (d, 1H,
J ) 8.4); HRMS Calcd for C24H35N2O4Si [M+] 443.2366, found
443.2376.
(3S)-(3-Hydr oxym eth yl-5-oxo-1,2,3,5-tetr ah ydr oin doliz-
in -6-yl)ca r ba m ic Acid Ben zyl Ester (21). 2,6-Lutidine (2.43
mL, 20.84 mmol, 4.0 equiv) and trifluoromethanesulfonic
anhydride (1.31 mL, 7.82 mmol, 1.5 equiv) were added
sequentially to a solution of 19 (2.40 g, 5.21 mmol, 1 equiv) in
CH2Cl2 (100 mL) at -78 °C. The colorless reaction mixture
was stirred at -78 °C for 45 min, warmed to 23 °C for an
additional 15 min, and then partitioned between 0.5 M HCl
(150 mL) and CH2Cl2 (2 × 150 mL). The organic layers were
dried over Na2SO4 and were concentrated. The residue thus
obtained was dissolved in THF (120 mL) at 23 °C and
tetrabutylammonium fluoride (15.63 mL of a 1.0 M solution
in THF, 15.63 mmol, 3.0 equiv) was added. The reaction
mixture was stirred at that temperature for 1 h and then was
partitioned between 0.5 M HCl (150 mL) and EtOAc (2 × 150
mL). The organic layers were dried over Na2SO4 and were
concentrated. The residue thus obtained was purified by flash
column chromatography (80% EtOAc in hexanes) to give 21
(0.953 g, 58%) as a colorless oil: Rf ) 0.36 (10% CH3OH in
Ack n ow led gm en t. We would like to thank David
Stirling and Christine Albizati for performing the HPLC
analyses, Dr. Theodore J ohnson for helping to optimize
the transformation of 22 to 1, as well as William
Romines, Dr. Siegfried Reich, and Prof. Larry Overman
for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: Procedures for the
preparation of racemic mixtures of compounds 18 and 1 and
conditions for HPLC analyses of these mixtures. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
CH2Cl2); IR (cm-1) 3379 (br), 1727, 1649; H NMR (CDCl3) δ
1.86-1.97 (m, 1H), 2.29-2.41 (m, 1H), 2.90-3.15 (m, 2H),
3.80-3.93 (m, 2H), 4.78-4.86 (m, 1H), 5.11-5.15 (m, 1H), 5.20
(s, 2H), 6.20 (d, 1H, J ) 7.5), 7.30-7.41 (m, 5H), 7.75 (s, br,
1H), 8.07 (d, 1H, J ) 7.5); 13C NMR (CDCl3) δ 25.5, 29.4, 65.3,
J O010712N