An Efficient and Highly Stereocontrolled Route to Bulgecinine Hydrochloride

Article abstract of DOI:10.1021/jo035441q

(-)-Bulgecinine is a nonproteinogenic amino acid component present in bulgecins A, B, and C, antibiotic glycopeptides derived from Pseudomonas acidophila and Pseudomonas mesoacidophila. In combination with β-lactam antibiotics, bulgecins exihibit a unique

Full text of DOI:10.1021/jo035441q

An Efficien t a n d High ly Ster eocon tr olled Rou te to Bu lgecin in e
Hyd r och lor id e
J uhienah K. Khalaf and Apurba Datta*
Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive,
Lawrence, Kansas 66045
adutta@ku.edu
Received October 1, 2003
(-)-Bulgecinine is a nonproteinogenic amino acid component present in bulgecins A, B, and C,
antibiotic glycopeptides derived from Pseudomonas acidophila and Pseudomonas mesoacidophila.
In combination with â-lactam antibiotics, bulgecins exihibit a unique synergistic antibacterial
activity against various Gram-negative microorganisms. Utilizing D-serine as a chiral template
and employing a highly regio- and stereoselective intramolecular amidomercuration-oxidation
protocol in the key pyrrolidine ring forming step, an efficient total synthetic route to enantiopure
bulgecinine is reported herein.
SCHEME 1
In tr od u ction
(2S,4S,5R)-(-)-Bulgecinine (1) is a common constituent
of Pseudomonas sp. derived glycopeptides, bulgecins A,
B, and C.1 Structurally, the aglycon bulgecinine can be
considered to be a proline analogue with additional
hydroxy and hydroxymethylene substituents at the 4-
and 5-positions of the pyrrolidine ring, respectively.
Interestingly, despite lacking antibacterial activity on
their own, bulgecins were found to sensitize various
Gram-negative bacteria toward â-lactam antibiotics,
resulting in more efficient inhibition of bacterial growth
at lowered drug concentrations. This unique synergistic
antibacterial activity and the unusual amino acid core
of bulgecinine have attracted considerable attention as
targets of total synthesis2 and biological studies.1,3 Al-
though several total syntheses of (-)-bulgecinine have
been reported in the literature,2 many of these methods
suffer from lack of efficiency and poor stereoselectivity
in key bond-forming reactions. Consequently, develop-
ment of new strategies and approaches to address the
above challenges continues to be a worthwhile research
goal.
In continuation of our efforts toward stereoselective
synthesis of bioactive molecules, utilizing amino acids as
chiral template,4 we report herein an efficient route to
enantiopure (-)-bulgecinine, starting from the readily
available amino acid D-serine. Our retrosynthetic strat-
egy is outlined in Scheme 1.
The key transformations in the proposed strategy will
involve (i) chelation-controlled reduction of a chiral allylic
ketone intermediate toward stereoselective formation of
the C4 secondary hydroxy group and (ii) an intramolecu-
lar amidomercuration-oxidation protocol to construct the
pivotal pyrrolidine core of the target molecule.
Resu lts a n d Discu ssion
As per a literature procedure, D-serine was converted
to the corresponding N,O-acetonide-protected Weinreb
(2) For earlier syntheses of (-)-bulgecinine, see: (a) Holt, K. A.;
Swift, J . P.; Smith, M. E. B.; Taylor, S. J . C.; McCague, R. Tetrahedron
Lett. 2002, 43, 1545. (b) Krasin˜ski, A.; J urczak, J . Tetrahedron Lett.
2001, 42, 2019. (c) Burk, M. J .; Allen, J . G.; Kiesman, W. F. J . Am.
Chem. Soc. 1998, 120, 657. (d) Maeda, M.; Okazaki, F.; Murayama,
M.; Tachibana, Y.; Aoyagi, Y.; Ohta, A. Chem. Pharm. Bull. 1997, 45,
962. (e) Mazo´n, A.; Na´jera, C.; Ezquerra, J .; Pedregal, C. Tetrahedron
Lett. 1997, 38, 2167. (f) Panday, S. K.; Langlois, N. Synth. Commun.
1997, 27, 1373. (g) Fehn, S.; Burger, K. Tetrahedron: Asymmetry 1997,
8, 2001. (h) Graziani, L.; Porzi, G.; Sandri, S. Tetrahedron: Asymmetry
1996, 7, 1341. (i) Yuasa, Y.; Ando, J .; Shibuya, S. J . Chem. Soc., Perkin
Trans. 1 1996, 793. (j) Madau, A.; Porzi, G.; Sandri, S. Tetrahedron:
Asymmetry 1996, 7, 825. (k) Oppolzer, W.; Moretti, R.; Zhou, C. Helv.
Chim. Acta 1994, 77, 2363. (l) Schmeck, C.; Hegedus, L. S. J . Am.
Chem. Soc. 1994, 116, 9927. (m) J ackson, R. F. W.; Rettie, A. B.; Wood,
A.; Wythes, M. J . J . Chem. Soc., Perkin Trans. 1 1994, 1719. (n) Yuasa,
Y.; Ando, J .; Shibuya, S. J . Chem. Soc., Chem. Commun. 1994, 11,
1383. (o) J ackson, R. F. W.; Rettie, A. B. Tetrahedron Lett. 1993, 34,
2985. (p) Hirai, Y.; Terada, T.; Amemiya, Y.; Momose, T. Tetrahedron
Lett. 1992, 33, 7893. (q) Barrett, A. G. M.; Pilipauskas, D. J . Org. Chem.
1991, 56, 2787. (r) Barrett, A. G. M.; Pilipauskas, D. J . Org. Chem.
1990, 55, 5194. (s) Ohta, T.; Hosoi, A.; Nozoe, S. Tetrahedron Lett. 1988,
29, 329. (t) Ofune, Y.; Hori, K.; Sakaitani, M. Tetrahedron Lett. 1986,
27, 6079. (u) Bashyal, B. P.; Chow, H. F.; Fleet, G. W. J . Tetrahedron
1987, 43, 423. (v) Wakamiya, T.; Yamanoi, K.; Nishikawa, M.; Shiba,
T. Tetrahedron Lett. 1985, 26, 4759.
(3) For biological studies, see: (a) van Asselt, E. J .; Kalk, K. H.;
Dijkstra, B. W. Biochemistry 2000, 39, 1924. (b) Thunnissen, A.-M.
W. H.; Rozeboom, H. J .; Kalk, K. H.; Dijkstra, B. W. Biochemistry 1995,
34, 12729. (c) Templin, M. F.; Edwards, D. H.; Hoeltje, J . Y. J . Biol.
Chem. 1992, 267, 20039 and references therein.
(1) (a) Imada, A.; Kintaka, K.; Nakao, M.; Shinagawa, S. J . Antibiot.
1982, 35, 1400. (b) Shinagawa, S.; Kashara, F.; Wada, Y.; Harada, S.
Asai, M. Tetrahedron 1984, 40, 3465. (c) Shinagawa, S.; Maki, M.;
Kintaka, K.; Imada, A.; Asai, M. J . Antibiot. 1985, 38, 17.
(4) (a) Stauffer, C. S.; Datta, A. Tetrahedron 2002, 58, 9765. (b)
Datta, A.; Ravi Kumar, J . S.; Roy, S. Tetrahedron 2001, 57, 1169. (c)
Datta, A.; Veeresa, G. J . Org. Chem. 2000, 65, 7609 and references
therein.
10.1021/jo035441q CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/19/2003
J . Org. Chem. 2004, 69, 387-390
387

Khalaf and Datta
SCHEME 2
SCHEME 3
In light of the above studies, we reasoned that exten-
sion of the above amidomercuration protocol to the
aminodiol derivative 2, containing a δ-alkenyl-carbamate
moiety, could conveniently lead to the corresponding 2,5-
trans-substituted pyrrolidine derivative required for our
present synthesis. To our pleasant surprise, treatment
of 2 with Hg(OAc)2 in refluxing acetonitrile resulted in
the formation of a single product. Subsequent workup
under standard conditions10 and oxidative demercuration
of the organomercury adduct in the presence of molecular
oxygen11 afforded the trisubstituted pyrrolidine deriva-
tive 8 (Scheme 3) in good overall yield. At this stage,
stereochemistry at the newly created center was tenta-
tively assigned on the basis of the expected trans-2,5-
substitution pattern, as precedented for similar cycliza-
tions.8 The structural and stereochemical integrity of
product 8 was further ascertained by NMR (1H and 13C),
mass spectroscopy, and HPLC analysis. Gratifyingly,
conclusive confirmation of the stereochemistry as as-
signed could be obtained from X-ray crystallographic
studies of 9, a downstream product obtained from 8 (vide
infra).
amide derivative 4 (Scheme 2) in 91% overall yield.5
Reaction of the amide 4 with freshly prepared allylmag-
nesium bromide cleanly afforded the corresponding allyl
ketone 5 in quantitative yield. It was, however, observed
that prolonged storage or attempted column chromato-
graphic purification of 5 resulted in partial isomerization
of the terminal olefin to the corresponding R,â-unsatur-
ated ketone derivative. Subsequently, instead of purifica-
tion, the crude ketone 5 was directly subjected to the next
reaction. Thus, the neighboring NCbz group assisted
chelation-controlled reduction4b,6 of the keto carbonyl with
Zn(BH4)2 in the presence of CeCl3‚7H2O resulted in the
required 1,2-anti amino alcohol derivative 6 with excel-
lent stereocontrol (anti/syn > 95/5 by HPLC) and high
overall yield. Deprotection of the N,O-acetonide linkage
of 6 and reprotection of the resulting 1,3-diol 7 unevent-
fully afforded the corresponding O,O-acetonide derivative
2.
Electrophile-initiated cyclization of δ-alkenylamines,
amides, and carbamates has proven to be a useful route
for the formation of a substituted pyrrolidine structural
framework.7 Considerable efforts have been expended to
study the stereochemical aspects of the above type of
cyclization, with particular emphasis on processes leading
to stereoselective formation of either cis- or trans-2,5-
disubstituted pyrrolidines.8 It has thus been found that
mercury(II) ion assisted cyclization of δ-alkenylamine
derivatives leads to the formation of 2,5-substituted
pyrrolidine derivatives with good trans-selectivity.8,9
High stereoselectivity during the above pyrrolidine ring
forming reaction can be rationalized by invoking prefer-
ential formation of a chairlike transition state intermedi-
ate (Figure 1), with energetically favorable equatorial
substituents, leading to the observed product.8h
(5) Collier, P. N.; Campbell, A. D.; Patel, I.; Raynham, T. M.; Taylor,
R. J . K. J . Org. Chem. 2002, 67, 1802.
(6) Campbell, J . E.; Englund, E. E.; Burke, S. D. Org. Lett. 2002, 4,
2273.
F IGURE 1. Energetically favorable chairlike transition state,
leading to the observed stereoselective formation of 8.
(7) (a) Hong, S.; Marks, T. J . J . Am. Chem. Soc. 2002, 124, 7886.
(b) Kim, K. Y.; Livinghouse, T.; Bercaw, J . E. Tetrahedron Lett. 2001,
42, 2933. (c) Robin, S.; Rousseau, G. Tetrahedron 1998, 54, 13681. (d)
J ones, A. D.; Knight, D. W. J . Chem. Soc., Chem. Commun. 1996, 915.
(e) Harding, K. E.; Tiner, T. H. In Comprehensive Organic Synthesis;
Trost, B. M., Ed.; Pergamon Press: New York, 1991; Vol. 4, p 363.
(8) (a) Singh, S.; Chikkanna, D.; Singh, O. V.; Han, H. Synlett 2003,
1279. (b) Takahata, H.; Bandoh, H.; Momose, T. Tetrahedron: Asym-
metry 1991, 2, 351. (c) Takahata, H.; Takehara, H.; Ohkubo, N.;
Momose, T. Tetrahedron: Asymmetry 1990, 1, 561. (d) Tokuda, M.;
Yamada, Y.; Suginome, H. Chem. Lett. 1988, 17, 1289. (e) Kinsman,
R.; Lathbury, D.; Vernon, P.; Gallagher, T. J . Chem. Soc., Chem.
Commun. 1987, 243. (f) Harding, K. E.; Marman, T. H. J . Org. Chem.
1984, 49, 2838. (g) Harding, K. E.; Burks, S. R. J . Org. Chem. 1984,
49, 40. (h) Harding, K. E.; Burks, S. R. J . Org. Chem. 1981, 46, 3920.
The strategically functionalized key pyrrolidine deriva-
tive 8 (Scheme 3) was next subjected to a standard mild
oxidation sequence toward conversion of the free primary
(9) For an example of a similar strategy in piperidine ring formation,
see: Martin, O. R.; Saavedra, O. M.; Xie, F.; Liu, L.; Picasso, S.; Vogel,
P.; Kizu, H.; Asano, N. Bioorg. Med. Chem. 2001, 9, 1269.
(10) Sarraf, S. T.; Leighton, J . L. Org. Lett. 2000, 2, 403.
(11) (a) Doi, Y.; Ishibashi, M.; Kobayashi, J . Tetrahedron 1996, 52,
4573. (b) Hill, C. L.; Whitesides, G. M. J . Am. Chem. Soc. 1974, 96,
870.
388 J . Org. Chem., Vol. 69, No. 2, 2004

Bulgecinine Hydrochloride
to room temperature, the layers were separated, and the
aqueous layer was extracted with EtOAc (2 × 150 mL). The
combined organic extract was washed with brine, dried over
anhydrous Na2SO4, and concentrated in vacuo to give the allyl
ketone 5 as a yellow oil, which was used as such without
further purification: 1H NMR (crude) (400 MHz, CDCl3,
rotameric mixture) δ 1.50-1.74 (4s, 6H), 3.15 and 3.32 (2d, J
) 6.8 Hz, 2H), 3.94-3.97 (m, 1H), 4.14-4.19 (m 1H), 4.47 and
4.49 (2dd, J ) 2.69 and 7.46 Hz, 2H), 5.00-5.19 (m, 4H), 5.73-
5.98 (m, 1H), 7.28-7.36 (m, 5H).
(1S)-1-[(4R)-3-N-Ben zyloxyca r bon yl-2,2-d im et h yl-1,3-
oxa zolid in -4-yl]-bu t-3-en -1-ol (6). To a solution of the allyl
ketone 5 (13 g, 42.9 mmol) in MeOH (300 mL) was added
CeCl3‚7H2O (5.4 g, 104 mmol) in one portion, and the resulting
solution was cooled to -10 °C (NaCl-ice bath) with continuous
stirring. A Zn(BH4)2 solution (0.189 M in Et2O, 550 mL, 104
mmol) was then added dropwise to the reaction mixture (1.5
h), and stirring was continued at the same temperature for
another 1 h. The reaction was quenched by slow addition of
saturated aqueous NaHCO3 solution (100 mL), allowed to
attain room temperature, and then filtered through a sintered
glass funnel. The residual solid was washed thoroughly with
EtOAc, the organic layer was separated from the filtrate, and
the aqueous layer was extracted with EtOAc (3 × 100 mL).
The combined organic extract was washed with brine, dried
over anhydrous Na2SO4, and concentrated under vacuum.
Purification of the crude residue by flash chromatography
(hexane/EtOAc ) 4:1 to 3:1) yielded the amino alcohol 6 as a
colorless oil (12 g, 88%): [R]25D +16.8 (c 1.01, CHCl3); IR (NaCl)
F IGURE 2. Ball and stick model of pyrrolidine 9 (adapted
from the X-ray crystallographic structure).
hydroxy group to carboxylic acid and its subsequent
esterification with diazomethane, to form the fully pro-
tected bulgecinine derivative 9 as a colorless crystalline
solid. The esterification of the intermediate carboxylic
acid in the above sequence was found to facilitate
purification and characterization of the resulting car-
boxylate derivative. X-ray crystallographic analysis of the
ester 9 (Figure 2) also conclusively proved the assigned
structure and absolute configuration across the pyrroli-
dine core.
3462, 1695 cm-1 1H NMR (125.7 MHz, CDCl3, rotameric
;
Finally, a one-pot, simultaneous global deprotection in
refluxing aqueous hydrochloric acid culminated in an
efficient and highly stereoselective total synthesis of the
hydrochloride salt of natural bulgecinine 1 (Scheme 3).12
The spectral and analytical data of 1 were found to be in
mixture) δ 1.27-1.60 (4s, 6H), 2.02-2.40 (m, 2H), 3.14 (br s,
1H, exchangeable with D2O), 3.86-4.23 (m, 4H), 4.99-5.37
(m, 4H), 5.66-6.0 (m, 1H), 7.38 (s, 5H); 13C NMR (125.7 MHz,
CDCl3 rotameric mixture) δ 22.9, 24.5, 26.3, 26.6, 30.8, 37.9,
38.7, 60.6, 62.0, 64.0, 64.3, 66.8, 67.5, 70.9, 71.2, 94.4, 117.5,
117.7, 126.8, 127.2, 128.0, 128.1, 128.3, 128.5, 134.5, 134.9,
135.9, 154.2, 152.5; FABMS calcd for C
good agreement with the assigned structure {[R]25
D
17H23NO4 m/z (M + H)+
+11.71(c 0.65, 1 N HCl); lit.1b [R]D +12.4 (c 0.95 N HCl)}.
In conclusion, starting from D-serine and utilizing a
highly regio- and stereoselective intramolecular ami-
domercuration protocol in the key pyrrolidine ring form-
ing step, we have developed an efficient route to enan-
tiopure natural (-)-bulgecinine. The present synthesis
compares well with the reported methods and offers an
attractive alternative approach to the title compound.
Furthermore, as chiral nonracemic pyrrolidines are com-
mon structural subunits found in many natural and
nonnatural compounds of structural and biomedical
importance, the strategy and the approach described
above can also be easily extended toward accessing
variously functionalized pyrrolidine cores with potential
applications in chemistry and biology.
306.2, found 306.2. HPLC: Iprosil 120-5 Si 5.0 µm, 20% EtOAc/
hexane, 1 mL/min, 254 nm, tR major isomer (anti) ) 17.29 min
(> 95%), tR minor isomer (syn) ) 17.97 min.
(2R,3S)-2-(Ben zyloxyca r bon yl)a m in o-h ex-5-en e-1,3-d i-
ol (7). The amino alcohol 6 (3.0 g, 9.84 mmol) was dissolved
in a mixture of AcOH/H2O (3:1, 30 mL) and stirred at room
temperature overnight. Excess solvent was removed in vacuo,
and the residual product was purified by flash chromatography
(hexane/EtOAc ) 7:3), affording the amino diol 7 as a white
solid (2.4 g, 92%): mp 96-98 °C; [R]25 -12.0 (c 0.83, CHCl3);
D
IR (NaCl) 3305, 1688 cm-1; 1H NMR (500 MHz, CDCl3) δ 2.33-
2.45 (m, 4H, 2H exchangeable with D2O), 3.67-3.68 (m, 1H),
3.79-3.81 (m, 1H), 3.89-3.92 (m, 1H), 4.05-4.08 (m, 1H),
5.12-5.21 (m, 4H), 5.67 (br d, J ) 6.6 Hz, 1H), 5.82-5.94 (m,
1H), 7.34-7.40 (m, 5H); 13C NMR (125.7 MHz, CDCl3) δ 38.8,
54.8, 62.1, 66.9, 72.5, 118.6, 118.8, 128.0, 128.1, 128.5, 133.9,
136.2, 156.4; FABMS calcd for C14H19NO4 m/z (M + H)+ 266.1,
found 266.1.
Exp er im en ta l Section
(4S,5R)-5-(Ben zyloxyca r b on yl)a m in o-2,2-d im et h yl-4-
(2-p r op en yl)-1,3-d ioxa n e (2). The amino diol 7 (1.8 g, 6.79
mmol) was dissolved in a mixture of acetone (45 mL) and 2,2-
dimethoxypropane (14 mL), a catalytic amount of camphor
sulfonic acid (30 mg) was added to it, and the resulting solution
was stirred at room temperature for 2 h. The reaction was
quenched by addition of NEt3 (4.5 mL), and the solvent was
removed in vacuo to give the crude product. Purification by
flash chromatography (hexane/EtOAc ) 3:1) yielded the di-
1-[(4R)-3-N-Ben zyloxyca r bon yl-2,2-d im eth yl-1,3-oxa zo-
lid in -4-yl]-bu t-3-en -1-on e (5). To a cooled (-78 °C) solution
of the D-serine-derived Weinreb amide 45 (28.4 g, 88.2 mmol)
in THF (300 mL) was added dropwise a solution of allylmag-
nesium bromide [prepared from Mg (8.5 g, 354 mmol) and
allylbromide (17 mL, 194 mmol) in Et2O (180 mL)] over a
period of 1.5 h. After completion of the addition, the reaction
was stirred at the same temperature for another 2 h and then
quenched by careful addition of a saturated aqueous solution
of NH4Cl (150 mL). The resulting solution was allowed to come
oxane 2 as a white solid (1.9 g, 92%): mp 56-58 °C; [R]25
D
-28.0 (c 0.95, CHCl3); IR (NaCl) 3314, 1694 cm-1 1H NMR
;
(400 MHz, CDCl3, rotameric mixture) δ 1.41 (s, 3H), 1.45 (s,
3H), 2.21-2.46 (m, 2H), 3.55-3.73 (m, 3H), 3.93-4.00 (m, 2H),
4.68 (br s, 1H), 5.08-5.18 (m, 4H), 5.81-5.91 (m, 1H), 7.35-
7.40 (m, 5H); 13C NMR (100.6 MHz, CDCl3) δ 20.4, 28.4, 37.4,
50.0, 63.6, 67.4, 72.1, 72.6, 99.3, 117.5, 128.6, 128.7, 129.0,
(12) The results of this study have been reported: Khalaf, J . K.;
Datta, A. Stereoselective total synthesis of (-)-bulgecinine. Abstracts
of Papers, 226th National Meeting of the American Chemical Society,
New York, 2003; American Chemical Society: Washington, DC, 2003;
ORGN 611.
J . Org. Chem, Vol. 69, No. 2, 2004 389

Khalaf and Datta
134.4, 136.6, 156.1; FABMS calcd for C17H23NO4 m/z (M + H)+
306.2, found 306.2.
solvent was removed in a vacuum to give a colorless viscous
oil which was used as such for the subsequent esterfication.
(Step 3) [CAUTION: Diazomethane is an explosive and a
highly toxic gas. Explosions may occur if the substance is dry
and undiluted. All operations involving diazomethane should
be carried out in an efficient fumehood following appropriate
precautions]. To an ice-cooled biphasic solution of KOH (5 g)
in H2O (15 mL) and ether (80 mL) was added N-methyl-N′-
nitro-N-nitrosoguanindine (MNNG, 1.5 g) in one lot. The
organic layer turned bright yellow. The ethereal layer was
decanted into an ice-cooled Erlenmeyer flask containing KOH
pellets. The aqueous layer was washed with ether (3 × 25 mL),
and the ethereal layers were combined. The diazomethane
(CH2N2) thus prepared was added to a stirred solution of the
crude acid (0.728 g in 10 mL of ether), as obtained in step 2,
and the mixture was stirred for 30 min. Excess CH2N2 was
removed by bubbling nitrogen into the reaction mixture for
15 min, followed by removal of solvent under vacuum to yield
the crude product. Purification by flash chromatography
(hexane/EtOAc ) 9:1) afforded the pyrrolidine carboxylate 9
as a white crystalline solid (CH2Cl2/hexane) (0.528 g, 71%
overall): mp 97-99 °C; [R]25D -88.9 (c 1.00, CHCl3); IR (NaCl)
(4a R,6S,7a S)-5-N-(Ben zyloxyca r bon yl)-2,2-d im eth yl-6-
h ydr oxym eth yl-h exah ydr o-[1,3]-dioxin o[5,4-b]pyr r ole (8).
(Step 1) To a stirred solution of the alkenyl carbamate 2 (1.86
g, 6.1 mmol) in CH3CN (50 mL) was added mercuric(II) acetate
(4.86 g, 15.3 mmol), and the mixture was refluxed for 1 h. The
reaction was cooled to room temperature and diluted by
addition of EtOAc (20 mL) and brine (20 mL). The resulting
biphasic mixture was stirred at room temperature for 1.5 h
and filtered to remove the precipitated inorganic byproduct.
The organic layer was separated from the filtrate, the aqueous
layer was extracted with EtOAc (3 × 50 mL), the combined
organic extract was dried over anhydrous Na2SO4, and the
solvent was removed in vacuo to give a white foamy solid,
which was used as such for the subsequent reaction. (Step 2)
Through a well-stirred solution of NaBH4 (0.228 g, 6.0 mmol)
in DMF (125 mL) at room temperature was bubbled oxygen
(O2) gas for 1 h. To this mixture was added dropwise (2 h) a
DMF solution (125 mL) of the white foamy product (2.56 g),
obtained as above, with continuous bubbling of O2. After
stirring for a further 2 h, the reaction mixture was filtered
through Celite, the residue was washed thoroughly with
EtOAc (4 × 75 mL), and the filtrate was concentrated under
vacuum. Purification of the crude residue by flash chroma-
tography (hexane/EtOAc ) 1:1) yielded the bicyclic pyrrolidine
1748, 1712 cm-1 1H NMR (400 MHz, CDCl3, rotameric
;
mixture) δ 1.44, 1.47 and 1.51 (3s, 6H), 1.78-1.82 (dd, J )
2.2 and 11.4 Hz, 1H), 2.56-2.65 (m, 1H), 3.27-3.37 (m, 1H),
3.55 and 3.78 (2s, 3H), 3.72-3.76 (m, 1H), 3.89-4.03 (2t, J )
10.6 Hz, 1H), 4.34-4.38 (dd, J ) 8.8 and 18.0 Hz, 1H), 4.45-
4.48 and 4.74-4.78 (2dd, J ) 4.3 and 10.6 Hz, 1H), 4.96-5.18
(m, 2H), 7.31-7.38 (m, 5H); 13C NMR (100.6 MHz, CDCl3,
rotameric mixture) δ 19.8, 19.9, 29.5, 29.6, 33.2, 33.8, 52.6,
52.9, 56.8, 56.9, 57.2, 66.1, 66.5, 67.5, 68.0, 72.5, 72.8, 100.8,
101.0, 128.5, 128.6, 128.7, 128.7, 128.9, 129.0, 136.2, 136.4,
154.5, 155.4, 172.6, 172.7; FABMS calcd for C18H23NO6 m/z
(M + H)+ 350.1, found 350.1.
8 as a colorless oil (1.27 g, 65% overall): [R]25 - 55.4 (c 1.0,
D
CHCl3); IR (NaCl) 3454, 1699 cm-1; 1H NMR (400 MHz, CDCl3,
rotameric mixture) δ 1.44 (s, 3H), 1.48 (s, 3H), 2.31-2.33 (m,
1H), 3.09-3.11 (m, 1H), 3.67-3.95 (m, 4H), 4.01-4.16 (m, 2H),
4.26-4.35 (d, J ) 6.6 Hz, 1H, exchangeable with D2O), 4.40-
4.47 (m, 1H), 5.13 (br s, 2H), 7.35-7.41 (m, 5H); 13C NMR
(125.7 MHz, CDCl3, rotameric mixture) δ 19.4, 29.1, 31.6, 58.7,
61.4, 66.0, 66.5, 67.8, 72.0, 100.1, 128.1. 128.2, 128.3, 128.4,
128.6, 135.5, 156.6; FABMS calcd for C17H23NO5 m/z (M + H)+
322.6, found 322.1. HPLC: Iprosil, 120-5 Si 5.0 µm, 20%
EtOAc/hexane, 1 mL/min, 254 nm, tR ) 19.63 min.
(2S,4S,5R)-Bu lgecin in e Hyd r och lor id e (1). The fully
protected N-Cbz-bulgecinine methyl ester acetonide (9) (0.070
g, 0.2 mmol) was taken in 6 N HCl (7 mL) and refluxed for 5
h. The reaction mixture was cooled to room temperature and
extracted once with 10 mL of CH2Cl2 to remove any organic
soluble impurities. The aqueous layer was then concentrated
in a rotary evaporator to remove the volatiles and the excess
solvent. The residual oily product was kept under high vacuum
overnight, affording bulgecinine hydrochloride (1) as a light
Meth yl (4a R,6S,7a S)-5-N-(Ben zyloxyca r bon yl)-2,2-d i-
m eth yl-h exah ydr o-[1,3]-dioxin o[5,4-b]pyr r ol-6-car boxylate
(9). (Step 1) Dess-Martin periodinane (1.11 g, 2.59 mmol)
dissolved in CH2Cl2 (10 mL) was added to an ice-cooled solution
of the pyrrolidino methanol 8 (0.694 g, 2.16 mmol) in CH2Cl2
(22 mL), and the reaction mixture was stirred at the same
temperature for another 30 min. The reaction was then
allowed to attain room temperature and stirred for another 2
h. The reaction was quenched by addition of a solution of 60
mL of saturated NaHCO3 containing 3 g of Na2S2O3. The layers
were separated, the aqueous layer was extracted with EtOAc
(3 × 100 mL), and the combined organic extract was washed
sequentially with 50 mL each of saturated aqueous NaHCO3,
H2O, and brine. Drying over anhydrous Na2SO4 and removal
of solvent under vacuum resulted in a colorless oily residue,
which was used directly for the subsequent reaction. (Step 2)
The product (0.683 g) as obtained above was dissolved in tert-
butyl alcohol (67 mL) followed by addition of a solution of
2-methyl-2-butene (48 mL, 95.0 mmol, 2 M in THF). To the
resulting mixture at room temperature was added dropwise a
solution of NaClO2 (1.76 g, 19.44 mmol) and NaH2PO4 (1.81
g, 15.12 mmol) in H2O (27 mL). The reaction mixture was
stirred at room temperature for 30 min and partitioned with
20 mL of H2O, and the layers were separated. The aqueous
layer was extracted with EtOAc (3 × 60 mL). The combined
organic extract was dried over anhydrous Na2SO4, and the
yellow viscous solid (0.037 g, 94%): [R]25 +11.71(c 0.65, 1 N
D
1
HCl) {lit.1b [R]D + 12.4 (c 0.95 N HCl)}; H NMR (400 MHz,
D2O) δ 2.15-2.23 (m, 1H), 2.48-2.58 (m, 1H), 3.57-3.80 (m,
3H), 4.27-4.32 (m, 1H), 4.40-4.48 (m, 1H); 13C NMR (100.6
MHz, D2O) δ 36.5, 58.4, 58.6, 68.0, 70.8, 172.0; FABMS calcd
for C6H12ClNO4 m/z (M + H)+ 198.62, found 162.1 (MH+
HCl).
-
Ack n ow led gm en t. We thank the University of
Kansas, Center for Research (KUCR) for funding this
research.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal details and copies of 1H and 13C NMR spectra for com-
pounds 1, 2, and 5-9 and the X-ray crystallographic details
for compound 9 in CIF format. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O035441Q
390 J . Org. Chem., Vol. 69, No. 2, 2004