Dihydroxylation of vinyl sulfones: Stereoselective synthesis of (+)- and (-)-febrifugine and halofuginone

Article abstract of DOI:10.1021/jo902396m

(Chemical Equation Presented) The asymmetric dihydroxylation of amino-functionalized vinyl sulfone 19 has been used for the 3-step preparation of 3-hydroxylpiperidine 24 in 86% enantiomeric excess. This enantiomerically enriched building block was used then to synthesize the naturally occurring antimalarial alkaloid febrifugine 1 and its antiangiogenic analogue, halofuginone 3.

Full text of DOI:10.1021/jo902396m

pubs.acs.org/joc
antimalarial activities for 1 and 2 are surprisingly approximately
Dihydroxylation of Vinyl Sulfones: Stereoselective
Synthesis of (þ)- and (-)-Febrifugine and
Halofuginone
equal.1 The existence of these C-2 isomers and their comparable
biological activities suggest that isomerization via a retro-con-
jugate-conjugate addition sequence may occur in vivo.4
Although these compounds possess interesting biological pro-
files, possibly via a novel mechanism, and have been used
historically as a herbal remedy, they do have serious side effects
(including nausea, vomiting , and liver toxicity) which have
precluded their use as antimalarial drugs.3 The chemical struc-
tures of 1 and 2 were elucidated in 1950s following studies by
Baker and co-workers.5 However, the precise relative and
absolute stereochemistry has historically caused confusion, and
it was as recently as 1999 that the absolute stereochemistry of
these compounds was finally unambiguously determined by
total synthesis.6 Since 1999 these targets have proved popular
and several successful synthetic strategies toward 1and 2, in both
racemic and enantioselective fashion, have been reported.7
Halofuginone 3 (the active component of tempostatin and
stenorol) is an analogue of 1, in which the metabolically vulner-
able aromatic protons have been replaced.3,8 Stenorol has been
used for more than 2 decades as an antiprotozoal agent in the
poultry industry.9 Issues concerning the optimal dose adminis-
tered to chickens led to the discovery that 3 also inhibits type 1
collagen biosynthesis10 and this observation in turn led to the
Noel P. McLaughlin and Paul Evans*
Centre for Synthesis and Chemical Biology, School of
Chemistry and Chemical Biology, University College Dublin,
Dublin 4, Ireland
paul.evans@ucd.ie
Received November 9, 2009
(4) (a) Barringer, D. F., Jr.; Berkelhammer, G.; Carter, S. D.; Goldman,
L.; Lanzilotti, A. E. J. Org. Chem. 1973, 38, 1933. (b) Barringer, D. F., Jr.;
Berkelhammer, G.; Wayne, R. S. J. Org. Chem. 1973, 38, 1937.
(5) Baker, B. R.; Schaub, R. E.; McEvoy, F. J.; Williams, J. H. J. Org.
Chem. 1952, 17, 132 and references cited therein.
(6) Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H.; Kim, H.-S.;
Wataya, Y. J. Org. Chem. 1999, 64, 6833.
The asymmetric dihydroxylation of amino-functionalized
vinyl sulfone 19 has been used for the 3-step preparation of
3-hydroxylpiperidine 24 in 86% enantiomeric excess. This
enantiomerically enriched building block was used then to
synthesize the naturally occurring antimalarial alkaloid feb-
rifugine 1 and its antiangiogenic analogue, halofuginone 3.
(7) For recent syntheses of 1 and 2 see: (a) Katoh, M.; Matsune, R.;
Nagase, H.; Honda, T. Tetrahedron Lett. 2004, 45, 6221. (b) Katoh, M.;
Matsune, R.; Honda, T. Heterocycles 2006, 67, 189. (c) Burgess, L. E.; Gross,
E. K. M.; Jurka, J. Tetrahedron Lett. 1996, 37, 3255. (d) Takeuchi, Y.;
Azuma, K.; Takakura, K.; Abe, H.; Harayama, T. Chem. Commun. 2000,
1643. (e) Takeuchi, Y.; Azuma, K.; Takakura, K.; Abe, H.; Kim, H.-S.;
Wataya, Y.; Harayama, T. Tetrahedron 2001, 57, 1213. (f) Takeuchi, Y.;
Oshige, M.; Azuma, K.; Abe, H.; Harayama, T. Chem. Pharm. Bull. 2005, 53,
868. (g) Taniguchi, T.; Ogasawara, K. Org. Lett. 2000, 2, 3193. (h) Ooi, H.;
Urushibara, A.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. Org. Lett. 2001, 3,
953. (i) Huang, P.-Q.; Wei, B.-G.; Ruan, Y.-P. Synlett 2003, 1663. (j) Liu, R.-
C.; Huang, W.; Ma, J.-Y.; Wei, B.-G.; Lin, G.-Q. Tetrahedron Lett. 2009, 50,
4046. (k) Michael, J. P.; de Koning, C. B.; Pienaar, D. P. Synlett 2006, 383. (l)
Wee, A. G. H.; Fan, G.-J. Org. Lett. 2008, 10, 3869. (m) Sukemoto, S.;
Oshige, M.; Sato, M.; Mimura, K.-I.; Nishioka, H.; Abe, H.; Harayama, T.;
Takeuchi, Y. Synthesis 2008, 3081. (n) Sieng, B.; Ventura, O. L.; Bellosta, V.;
Cossy, J. Synlett 2008, 1216. (o) Sudhakar, N.; Srinivasulu, G.; Rao, G. S.;
Rao, B. V. Tetrahedron: Asymmetry 2008, 19, 2153. (p) Wijdeven, M. A.; van
den Berg, R. J. F.; Wijtmans, R.; Botman, P. N. M.; Blaauw, R. H.;
Schoemaker, H. E.; van Delft, F. L.; Rutjes, F. P. J. T. Org. Biomol. Chem.
2009, 7, 2976. (q) Chen, W.; Liebeskind, L. S. J. Am. Chem. Soc. 2009, 131,
12546. (r) Ashoorzadeh, A.; Caprio, V. Synlett 2005, 346. (s) Ashoorzadeh,
A.; Archibald, G.; Caprio, V. Tetrahedron 2009, 65, 4671. (t) Emmanuvel, L.;
Kamble, D. A.; Sudalai, A. Tetrahedron: Asymmetry 2009, 20, 84.
(8) (a) Hirai, S.; Kikuchi, H.; Kim, H.-S.; Begum, K.; Wataya, Y.;
Tasaka, H.; Miyazawa, Y.; Yamamoto, K.; Oshima, Y. J. Med. Chem.
2003, 46, 4351. (b) Zhu, S.; Zhang, Q.; Gudise, C.; Wei, L.; Smith, E.; Zeng,
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Horoiwa, S.; Hirai, S.; Kasahara, R.; Hariguchi, N.; Matsumoto, M.;
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Febrifugine 1 and its isomer isofebrifugine 2 (Figure 1) were
isolated from a Chinese medicinal plant, chang shan (Dichroa
febrifuga), and were later found to be present in a popular garden
plant, hydrangea.1 Decoctions of chang shan have been used for
over 2000 years for the treatment of a variety of aliments
including stomach cancer and malaria.2 More recently it has
been shown that both 1 and 2 exhibit potent antimalarial activity
in their own right in several models of this disease, which has
been estimated to affect between 300 million and 500 million
people each year.2,3 Currently the mode by which these com-
pounds elicit their activity is unknown2 and interestingly, the
(1) (a) Koepfli, J. B.; Mead, J. F.; Brockman, J. A., Jr. J. Am. Chem. Soc.
1947, 69, 1837. (b) Kuehl, F. A., Jr.; Spencer, C. F.; Folkers, K. J. Am. Chem.
Soc. 1948, 70, 2091. (c) Koepfli, J. B.; Mead, J. F.; Brockman, J. A., Jr. J. Am.
Chem. Soc. 1949, 71, 1048. (d) Koepfli, J. B.; Brockman, J. A., Jr.; Moffat, J.
J. Am. Chem. Soc. 1950, 72 3323. (e) Ablondi, F.; Gordon, S.; Morton, J., II;
Williams, J. H. J. Org. Chem. 1952, 17, 14.
(2) (a) Wiesner, J.; Ortmann, R.; Jomaa, H.; Schlitzer, M. Angew. Chem.,
Int. Ed. 2003, 42, 5274. (b) Mital, A. Curr. Med. Chem. 2007, 14, 759.
(c) Kumar, V.; Mahajan, A.; Chibale, K. Bioorg. Med. Chem. 2009, 17, 2236.
(3) Jiang, S.; Zeng, Q.; Gettayacamin, M.; Tungtaeng, A.; Wannaying, S.;
Lim, A.; Hansukjariya, P.; Okunji, C. O.; Zhu, S.; Fang, D. Antimicrob.
Agents Chemother. 2005, 49, 1169.
(9) (a) Angel, S.; Weinberg, Z. G.; Polishuk, O.; Heit, M.; Plavnik;
Bartov, I. Poultry Sci. 1985, 64, 294–296. (b) Granot, I.; Bartov, I.; Plavnik,
I.; Wax, E.; Hurwitz, S.; Pines, M. Poultry Sci. 1991, 70, 1559.
(10) Yee, K. O.; Connolly, C. M.; Pines, M.; Lawler, J. Cancer Biology
Therapy 2006, 5, 218.
518 J. Org. Chem. 2010, 75, 518–521
Published on Web 12/09/2009
DOI: 10.1021/jo902396m
r
2009 American Chemical Society

McLaughlin and Evans
JOCNote
SCHEME 2. Vinyl Sulfone Synthesis
FIGURE 1. 2,3-Disubstituted piperidine natural products.
SCHEME 1. Retrosynthetic Analysis of Febrifugine Based on
the Asymmetric Dihydroxylation of Vinyl Sulfones
SCHEME 3. Dihydroxylation of Vinyl Sulfones 16, 18, and 19
may be tuned according to the identity of the stereogenic
allylic subsituent and the reaction conditions.7m
A series of vinyl sulfone dihydroxylation precursors
(of the type 12) were accessed following the sequence of
transformations outlined in Scheme 2. Thus, starting from
either 13 or 20 amino protected vinyl sulfones 16-19 were
obtained in good overall yields following modified literature
procedures.15 Regarding this sequence, it was notable that in
order to perform the oxidation-olefination chemistry the
amino group needed to be carried through to 16 or 17 in their
diprotected form.
The behavior of 16, 18, and 19 under dihydroxylation
conditions was next studied in the context of assembling the
requisite γ-hydroxyl R,β-unsaturated cyclization precursors
of the type 11 (Scheme 3). Treatment of 16 initially with AD-
mix-R and then the crude product with the anion derived
from methyl diethylphosphonoacetate gave E-21 in a dis-
appointing yield and enantiomeric excess even after attempts
to optimize reaction parameters. Undeterred we considered
the same process albeit with monoprotected precursors 18
and 19. In both instances improvements in both chemical
and optical yield were observed with the benzyloxy carba-
mate (Cbz) protected material 19 proving optimal.
identification of 3 as a lead compound for the development of an
antiangiogenic agent for the treatment of various cancers.11
The trans-2-alkyl-3-hydroxylpiperidine substitution pattern
present in febrifugine is also found in several additional natu-
rally occurring compounds. For example, the widely reported
indolizidine alkaloids (-)-swainsonine 4 and (þ)-castanosper-
mine 5 contain the same structural motif and in a wider sense
the piperidine alkaloids pelletierine 6 and coniine 7 (given
above as the unnatural enantiomers) possess the type of
stereogenic 2-propyl substituent exhibited by febrifugine.12
We wished to investigate the preparation of the 2-alkyl-3-
hydroxyl-substituted piperidine motif found in the febrifugine
familyusing ourasymmetric dihydroxylation of vinyl sulfones
(Scheme 1).13 We have recently shown that this reaction
enables the preparation of γ-hydroxyl R,β-unsaturated esters
in good enantiomeric excesses and have used this method to
prepare the quercus (Whiskey) lactone 10 and both (þ)- and
(-)-maritolide. More recently this method has been employed
by Au and Pyne in a formal synthesis of (-)-4.14
Thus, it was envisaged that an acyclic precursor of the type
11, possessing an appropriately protected nitrogen atom,
would afford piperidine 8 in its N-protected form. This
type of intramolecular heteroconjugate addition approach
has been previously studied in the context of febrifugine
synthesis.7f,m-o Notably, within these studies high levels of
trans-stereoselective ring closure have been reported which
With the identification of the favored substrate the two-step
sequence was carried out with diethyl (2-oxopropyl)-
phosphonate. In this case the anticipated γ-hydroxyl R,β-
unsaturated ketone proved to be difficult to isolate and was
consistently contaminated with the ultimately desired piperi-
dine 24 (Scheme 4). Further investigation indicated that the
conversion of the enone into 24 was facile, gradually occurring
(11) de Jonge, M. J. A.; Dumez, H.; Verweij, J.; Yarkoni, S.; Snyder, D.;
ꢀ
Lacombe, D.; Marreaud, S.; Yamaguchi, T.; Punt, C. J. A.; van Oosterom,
A. Eur. J. Cancer 2006, 42, 1768.
ꢀ
(15) (a) Carretero, J. C.; Arrayas, R. G. J. Org. Chem. 1998, 63, 6221–
6223. (b) Xiao, X.; Antony, S.; Kohlhagen, G.; Pommier, Y.; Cushman, M.
Bioorg. Med. Chem. 2004, 12, 5147. (c) Macdonald, S. J. F.; Belton, D. J.;
Buckley, D. M.; Spooner, J. E.; Anson, M. S.; Harrison, L. A.; Mills, K.;
Upton, R. J.; Dowle, M. D.; Smith, R. A.; Molloy, C. R.; Risley, C. J. Med.
Chem. 1998, 41, 3919. (d) Evans, P.; Johnson, P.; Taylor, R. J. K. Eur. J. Org.
Chem. 2006, 1740.
(12) For review literature see: (a) Michael, J. P. Nat. Prod. Rep. 2008, 25,
139. (b) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435. (c) Buffat, M. G. P.
Tetrahedron 2004, 60, 1701 and references cited therein.
(13) Evans, P.; Leffray, M. Tetrahedron 2003, 59, 7973.
(14) Au, C. W. G.; Pyne, S. G. J. Org. Chem. 2006, 71, 7097.
J. Org. Chem. Vol. 75, No. 2, 2010 519

McLaughlin and Evans
JOCNote
SCHEME 4. Synthesis of Piperidine 24 and Hemiaminal 26
SCHEME 5. Conversion of 24 to (þ)-Febrifugine and (þ)-Ha-
dihydroxylation was studied. On treatment of 19 with AD-
mix-R and monitoring the reaction until starting material
was consumed the hemiaminal 26 was isolated in good yield
as predominantly the trans-diastereoisomer (dr 5:1).18 On
subsequent subjection of 26 to either H-W-E olefination or
Wittig conditions, which gave 23, it became evident that the
moderate yields observed for this process partly reflect the
recalcitrance of the hemiaminal 26 to undergo olefination. A
poor yield was observed for the formation of 21 in the above
sequence. In this instance the R-hydroxyl aldehyde inter-
mediate is unable to form a cyclic hemiaminal of the type 26
and we speculate that loss of material stemmed from likely
formation of the water-soluble gem-diol and oligomeric
materials which may not participate in the subsequent
olefination chemistry. In terms of enantiomeric excess it
seems plausible that the in situ formation of 26 also may
serve to protect the potentially epimerizable stereogenic
center. Finally, it has been noted previously that steric effects
often serve to diminish levels of stereoselectivity on asym-
metric dihydroxylation.19 Therefore, we speculate that in
going from 16 to 18 to 19 the increase in enantioselectivity
observed was based on a decrease in size of the alkene
substituent. In relation to this, in our previous study13 n-
alkyl vinyl substituents gave higher levels of enantiomeric
excess (95% ee) than observed in the current work.
Subsequent conversion of 24 into naturally occurring (þ)-
febrifugine 1 was achieved in five steps and was based on the
previously reported regioselective bromination sequence
(Scheme 5).6 The spectroscopic data for synthetic 1 obtained
accordingly, including rotation of plane polarized light, were
in agreement with reported values.6,7p The overall stereo-
selective outcome served to prove that the dihydroxylation of
19 was also consistent with our previous work and Sharpless’
predictive model in which the phenyl sulfonyl substituent
represents the largest group.
It is notable that samples obtained following this sequence
were obtained with minimal quantities of (þ)-isofebrifugine
2. However, care needed to be taken in terms of the length of
exposure of 28 to the acidic conditions required for depro-
tection, and it was also noted that after prolonged storage of
samples of (þ)-1 in CDCl3 significant interconversion of (þ)-
1 into (þ)-2 was observed.4 This sequence presumably occurs
via an R,β-unsaturated ketone; however, an intermediate
resembling this was never detected. Following an identical
lofuginone
in CDCl3 at rt for example. To maximize the efficiency of this
process it was discovered that treatment of the crude material
following Horner-Wadsworth-Emmons olefination with
BF3 OEt2 (0.5 equiv)7f,m gave the desired material 24 in
3
reasonable yield and 86% enantiomeric excess.
As previously reported,7f,m we observed that the forma-
tion of 24 occurred with high diastereoselectivity. Careful
inspection of the proton NMR spectrum obtained for the
crude material failed to indicate signals attributable to the
cis-diastereoisomer, or its hemiketal.16 Also worthy of men-
tion was that the corresponding cyclization of the less
reactive γ-hydroxyl R,β-unsaturated esters 22 and 23 was
not observed under identical conditions. The stereochemical
outcome of this cyclization is consistent with a Felkin-Ahn-
type transition state in which the reactive conformer, afford-
ing trans-24, resembles 25a as opposed to 25b (Scheme 4).17
The use of AD-mix-β gave ent-24 in comparable yield and
enantiomeric excess from vinyl sulfone 19 and the assign-
ment of absolute stereochemistry of compounds 21-24 was
made on the basis of previous work13 and the later conver-
sion of 24 into (þ)-febrifugine (Scheme 5). Deprotection of
24 and ent-24 (not shown) following hydrogenation gave the
novel pelletierine analogues 8.
In an attempt to explain the effect vinyl sulfone structure
had on the outcome of reaction in terms of yield
and enantioselectivity the crude product resulting from
(16) For a report that cis-24 undergoes conversion to the corresponding
2,5-disubstituted furan under Lewis acidic conditions see: Takeuchi, Y.;
Azuma, K.; Abe, H.; Harayama, T. Heterocycles 2000, 53, 2247.
(17) For representative references concerning the diastereoselective reac-
tion of allylic systems see: (a) Gung, B. W.; Francis, M. B. J. Org. Chem.
1993, 58, 6177. (b) Gung, B. W.; Francis, M. B. Tetrahedron Lett. 1995, 36,
2579. (c) Evans, D. A.; Kaldor, S. W. J. Org. Chem. 1990, 55, 1698. (d) Houk,
K. N.; Paddon-Row, M. N.; Rondan, N. G.; Wu, Y.-D.; Brown, F. K.;
Spellmeyer, D. C.; Metz, J. T.; Li, Y.; Loncharich, J. Science 1986, 231, 1108.
(18) Stereochemistry assigned based on data reported for cis-25: Okitsu,
O.; Suzuki, R.; Kobayashi, S. J. Org. Chem. 2001, 66, 809.
(19) Kolb, H. C.; VanNiewenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483.
520 J. Org. Chem. Vol. 75, No. 2, 2010

McLaughlin and Evans
JOCNote
sequence of reactions ent-24 was converted into (-)-1 with
comparable yields (not shown). Similarly, by using 7-bromo-
6-chloro-4-hydroxyquinazoline20 (þ)- and (-)-halofuginone
3 were obtained. Concerning the conversion of 29 into (þ)-3
a crude yield of 71% was initially isolated; however, follow-
ing purification by flash column chromatography a low yield
(17%) of purified material was isolated.
In summary, using the asymmetric dihydroxylation of an
amino-functionalized vinyl sulfone 19 naturally occurring
febrifugine was accessed in 12 linear steps in 12% overall
yield in 86% ee. An identical sequence was employed to
access both enantiomerically enriched forms of halofuginone.
Our original objective was to reduce the length of this synthetic
route utilizing phosphonates already bearing either the quina-
zolinone heterocycle or a leaving group.7n This would remove
the requirement for the bromination-alkylation chemistry
depicted in Scheme 5. However, our initial attempts to achieve
this were unsuccessful and future work will involve further
investigation of this convergent approach.
2.00 equiv) for 30 min. The crude aldehyde in dry THF (10 mL)
was added and the reaction was stirred for 15 h. Diethyl ether
(40 mL) was added to dilute the reaction mixture, which was
then washed with a saturated solution of NH4Cl (2 ꢀ 40 mL)
and brine (40 mL). The combined organic extracts were dried
over MgSO4. Filtration followed by solvent evaporation under
reduced pressure afforded the crude product. At rt a solution of
the crude olefin in acetonitrile (20 mL) was treated with boron
trifluoride diethyl etherate (0.12 mL, 0.97 mmol, 0.49 equiv) and
the mixture was stirred at rt for 10 min. The reaction mixture was
washed with a saturated solution of NaHCO3 (2 ꢀ 30 mL) and
brine (30 mL). The combined organic extracts were dried over
MgSO4. Filtration followed by solvent evaporation under
reduced pressure afforded the crude product. Purification by
flash column chromatography (c-Hex-EtOAc; 1:1) gave com-
pound 24 (310 mg, 53% over 3 steps) as a colorless oil. Rf 0.15
(c-Hex-EtOAc; 1:1); [R]25D -18.4 (c 1.00, CHCl3); νmax (neat/
cm-1) 3599, 3046, 2973, 2950, 1698, 1439, 1355, 1278, 1137, 983,
688; HRMS calcd for C16H21NO4Na 314.1368, found 314.1369
(þ0.2 ppm); δH (400 MHz, CDCl3) 1.41-1.43 (1H, m),
1.67-1.75 (1H, m), 1.78-1.87 (1H, m), 1.89-1.92 (1H, m),
2.15 (3H, s), 2.65 (2H, d, J = 7.5 Hz), 2.86 (1H, t, J = 14.0 Hz),
3.81 (1H, br s), 4.06-4.07 (1H, m), 4.74 (1H, t, J = 7.5 Hz), 5.13
(2H, s), 7.28-7.34 (5H, m) ppm; δC (100 MHz, CDCl3) 19.1,
26.0, 30.1, 39.7, 43.9, 54.3, 67.1, 67.5, 128.0, 128.1, 128.6, 136.8,
156.4, 206.3 ppm; HPLC analysis (IA column), heptane-EtOH
70:30 (1.0 cm3/min): (2R,3S) tr = 8.62 min, (2S,3R) tr = 10.53
min; 86% ee. Anal. Calcd for C16H21NO4: C, 65.96; H, 7.27; N,
4.81. Found: C, 65.78; H, 7.24; N, 4.72.
Experimental Section
(2R,3S)-3-Hydroxy-2-(2-oxopropyl)piperidine-1-carboxylic
Acid Benzyl Ester 24. A solution of 19 (719 mg, 2.00 mmol, 1.00
equiv) in t-BuOH (10 mL) and H2O (10 mL) was treated with
sodium bicarbonate (504 mg, 6.00 mmol, 3.00 equiv) and
methane sulfonamide (190 mg, 2.00 mmol, 1.00 equiv). AD
mix-R (8.00 g) was added and the resulting mixture was stirred
for 22 h. Dichloromethane (30 mL) and H2O (30 mL) were
added and the mixture was partitioned for 30 min. The resulting
aqueous layer was further extracted with dichloromethane (3 ꢀ
40 mL). The combined organic layers were washed with brine
(40 mL) and dried over MgSO4. Filtration followed by solvent
evaporation under reduced pressure afforded the crude aldehyde.
At 0 °C a solution of diethyl (2-oxopropyl)phosphonate (778 mg,
4.01 mmol, 2.00 equiv) in dry THF (30 mL) was treated with
60% (w/w) sodium hydride in mineral oil (160 mg, 4.00 mmol,
Acknowledgment. We would like to acknowledge finan-
cial support from the University College Dublin and Done-
gal County Council. Additionally Dr. Jenny Rickerby is
thanked for Chiral HPLC measurements and Drs. Yannick
Ortin and Jimmy Muldoon for NMR experiments.
Supporting Information Available: Experimental details and
copies of proton, carbon NMR spectra. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(20) Obtained from Credimate Trading Ltd.: http://www.credimate.com.
J. Org. Chem. Vol. 75, No. 2, 2010 521