Deprotecting dithiane-containing alkaloids

Full text of DOI:10.1021/jo0157829

6
502
J . Org. Chem. 2001, 66, 6502-6504
Dep r otectin g Dith ia n e-Con ta in in g
Alk a loid s
Sch em e 1
Fraser F. Fleming,* Lee Funk, Ramazan Altundas, and
Yong Tu
Duquesne University, Department of Chemistry &
Biochemistry, Pittsburgh, Pennsylvania 15282-1530
Sch em e 2
flemingf@duq.edu
Received May 22, 2001
Dithianes are unparalleled as lynchpin carbanions1
that directly assemble protected ketones. The unrivaled
2
versatility of dithianes is tempered only by the ultimate
3
unmasking of the dithiane to the corresponding ketone,
a seemingly trivial conversion for which numerous
4
reagents have been developed. Dithiane deprotection is
particularly challenging for dithiane-containing alkaloids
since alkylative, oxidative, and Lewis acidic reagents
exhibit similar affinities toward the alkaloid as for the
dithiane.5
The dithiane-containing quinolizidine 2a is potentially
an excellent alkaloid precursor, being rapidly synthesized
by a unique intramolecular conjugate addition reaction.6
The potential deployment of 2a in alkaloid syntheses
hinges on deprotecting the dithiane in the presence of
the tertiary amine. Of the few reagents developed for
from 8 cleanly affords 3 (33% yield) accompanied by a
polymeric material that presumably arises from self-
condensation of intermediate carbocations. Although the
dithiane was not hydrolyzed,11 valuable insight into the
precise conditions for hydrolysis was obtained. Specifi-
deprotecting dithiane-containing alkaloids, the combina-
7
tion of SbCl
5
-Me
2
S
2
is regarded as being particularly
cally, attempts to protect the amine by precomplexing
mild8 and well suited for dithiane-containing amines.
12
2a with SbCl
3
,
or other transition metals, led to poor
Quinolizidine 2a reacts readily with the SbCl
reagent resulting in a smooth conversion, not to the
anticipated ketone, but rather to the vinyl sulfide 3
5
-Me
2
S
2
mass recovery suggesting that 2a functions as an excel-
lent ligand with a pronounced affinity toward transition
1
3
14
metals! The inability to hydrolyze or couple the vinyl
sulfide 315 further indicated the necessity for deprotecting
under aqueous conditions to preferentially intercept the
sulfonium intermediate 6.
(Scheme 1)!
The mechanistically challenging formation of vinyl
9
sulfide 3 is surprisingly well precedented. SbCl
5
reacts
with MeSSMe to generate SbCl
3
and the powerful thio-
Armed with mechanistic insight the dithiane hydroly-
sis of 2a was pursued in aqueous media. Alkaloid 2a is
methylating10 reagent 4 (Scheme 2) that thiomethylates
the more accessible equatorial sulfur atom. Dissociation
of the resulting sulfonium salt 5 and addition of excess
dimethyl disulfide generates 7 that undergoes sequential
thiomethyl transfers to afford 8. Disulfide elimination
7
1
6
17
readily protonated with aqueous acids (TFA,
2 4
H SO ,
HClO ) forming an ammonium salt without perceptible
4
hydrolysis of 2a . Isolation of the perchlorate salt and
exposure to trimethyloxonium tetrafluoroborate resulted
in the recovery of only a small amount of unreacted 2a ,
despite this procedure successfully cleaving a closely
(
(
1) Smith, Amos B., III; Pitram, Suresh M. Org. Lett. 1999, 1, 2001.
2) (a) Page, P. C. B.; van Niel, M. B.; Prodger, J . C. Tetrahedron
5c
related dithiane-containing alkaloid. Direct alkylative
1
989, 45, 7643. (b) Gr o¨ bel, B.-T.; Seebach, D. Synthesis 1977, 357.
3) Difficulties in unmasking dithianes have often emerged during
(
syntheses with complex intermediates necessitating reagent screening
and, in some cases, indirect transacetalization followed by hydrolysis.
See, for example: Nakatsuka, M.; Ragan, J . A.; Sammakia, T.; Smith,
D. B.; Uehling, D. E.; Schreiber, S. L. J . Am. Chem. Soc. 1990, 112,
(11) Similar recalcitrant hydrolyses of vinyl sulfide-containing
alkaloids has been noted: Pearson, W. H.; Bergmeier, S. C.; Williams,
J . P. J . Org. Chem. 1992, 57, 3977.
(12) Treatment of 2a with SbCl prior to the addition of 4 causes
3
complete decomposition indicating that complexation between SbCl
3
and 2a is precluded during the formation of 3.
(13) The use of mercury-based reagents (Corey, E. J .; Erickson, B.
5
583.
4) Protective groups in organic synthesis, 3rd ed.; Greene, T. W.,
Wuts, P. G. M., Eds.; J ohn Wiley & Sons: Chichester, 1999.
5) (a) Forns, P.; Diez, A.; Rubiralta, M. J . Org. Chem. 1996, 61,
882. (b) Tang, C. S. F.; Morrow, C. J .; Rapoport, H. J . Am. Chem.
(
(
W. J . Org. Chem. 1971, 36, 3553) resulted in poor mass recovery
1
2
7
presumably resulting from strong, irreversible complexation with the
amine, dithiane, and nitrile groups that make 2a an excellent metal
ligand! Poor mass recovery is observed during the dehydrogenation of
Soc. 1975, 97, 159. (c) Oishi, T.; Takechi, H.; Kamemoto, K.; Ban, Y.
Tetrahedron Lett. 1974, 11.
(
6) Fleming, F. F.; Hussain, Z.; Weaver, D.; Norman, R. E. J . Org.
2
quinolizidines with Hg(OAc) : Kasymov, T. K.; Ishbaev, A. I.; Aslanov,
K. A.; Sadykov, A. S. Chem. Nat. Compd. 1969, 5, 383.
Chem. 1997, 62, 1305.
(
7) Weiss, R.; Schlierf, C. Synthesis 1976, 323.
(14) The following reagents were screened. (a) TFA: Grayson, J . I.;
Warren, S. J . Chem. Soc., Perkin Trans. 1 1977, 2263 (b) TiCl : Sato,
4
(8) Prato, M.; Quintily, U.; Scorrano, G.; Sturaro, A. Synthesis 1982,
6
1
9
79.
M.; Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1981, 22, 1609.
(c) HCl: Chou, W.-C.; Fang, J .-M. J . Org. Chem. 1996, 61, 1473.
(15) Luh, T.-Y.; Ni, Z.-J . Synthesis 1990, 89.
(16) Grayson, J . I.; Warren, S. J . Chem. Soc., Perkin Trans. 1 1977,
2263.
(9) Kim, J . K.; Pau, J . K.; Caserio, M. C. J . Org. Chem. 1979, 44,
544.
(10) (a) Smallcombe, S. H.; Caserio, M. C. J . Am. Chem. Soc. 1971,
3, 5826. (b) Helmkamp, G. K.; Cassey, H. N.; Olsen, B. A.; Pettitt, D.
J . J . Org. Chem. 1965, 30, 933.
(17) Ho, T.-L.; Ho, H. C.; Wong, C. M. Can. J . Chem. 1973, 51, 153.
1
0.1021/jo0157829 CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/23/2001

Notes
and oxidative hydrolysis (HIO 18
J . Org. Chem., Vol. 66, No. 19, 2001 6503
19
5
or CAN ) of 2a results
Sch em e 3
in poor mass recovery that presumably results from
competitive N-alkylation and oxidation.
The stability of 2a in acid suggested an excellent
procedure20 using bis(trifluoroacetoxy)iodobenzene since
the simultaneous formation of trifluoroacetic acid is
thought to prevent oxidation of the amine by preferential
protonation.21 Extensive optimization experiments re-
vealed precise conditions for the dithiane hydrolysis while
providing mechanistic insight of potentially general
relevance for dithiane hydrolyses, particularly dithiane-
containing alkaloids. Careful monitoring of the reaction
1
by H NMR revealed a rapid initial hydrolysis (<30 min)
Ta ble 1. Hyd r olysis of Dith ia n e-Con ta in in g Alk a loid s
until approximately 20% conversion, followed by a slower,
2
2
constant rate of hydrolysis requiring 5 equiv of bis-
trifluoroacetoxy)iodobenzene. The dramatic rate changes
(
led to an optimized procedure where bis(trifluoroacetoxy)-
iodobenzene is added portionwise to a 1:1 water-aceto-
nitrile solution of the dithiane containing 10 equiv of
trifluoroacetic acid, allowing complete hydrolysis in 4 h
(85% yield).
Purifying the unmasked ketone proved particularly
challenging since the amino ketone 11a decomposes23
during silica gel chromatography and coelutes with the
dithiane oxidation product 1,2-dithiolane-1,1-dioxide 14.24
Isolating spectroscopically pure ketone was achieved
through an efficient nonchromatographic purification
where the acidic, aqueous reaction mixture is first
extracted with hexanes, to remove phenyl iodide, followed
by addition of solid K
,2-dithiolane-1,1-dioxide (14). Subsequent extraction
with CH Cl cleanly provides the ketone 11a in 85% yield.
2 3
CO and ethanethiol to remove the
1
2
2
Presumably, the ethanethiol triggers ring-opening of
dithiolane 1,1-dioxide generating a sulfide that is selec-
tively partitioned into the basic aqueous phase.
Identifying 1,2-dithiolane-1,1-dioxide 14 as the ulti-
mate dithiane fragment provides insight into the hy-
drolysis mechanism (Scheme 3). Presumably protonation
and iodination25 of 2a results in the transient formation
of 9 en route to the sulfonium salt 10 that suffers
hydrolysis to generate ketone 11a and disulfide fragment
1
2. Cyclization of 12 leads to dithiolane 13 whose
formation is implicated by the spectral identification of
the dithiolane dioxide 14. Oxidation of the dithiolane
(
18) Shi, X.-X.; Khanapure, S. P.; Rokach, J . Tetrahedron Lett. 1996,
7, 4331.
19) Ho, T.-L.; Ho, H. C.; Wong, C. M. J . Chem. Soc., Chem.
Commun. 1972, 791.
20) (a) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287. (b) For
3
(
(
an analogous procedure with bis(acetoxy)iodobenzene, see: Shi, X.-
X.; Wu, Q.-Q. Synth. Commun. 2000, 30, 4081.
(21) Bis(trifluoroacetoxy)iodobenzene has been used to unmask
dithiane-containing alkaloids that, in some contexts, may be enhanced
with the modified procedure developed here: (a) Yamada, O.;
Ogasawara, K. Org. Lett. 2000, 2, 2785. (b) Rubiralta, M.; Diez, A.;
Reig, I.; Castells, J .; Bettiol, J . L.; Grierson, D. S.; Husson, H. P.
Heterocycles 1990, 31, 173. (c) Micouin, L.; Diez, A.; Castells, J .; L o´ pez,
D.; Rubiralta, M.; Quirion, J .-C.; Husson, H.-P. Tetrahedron Lett. 1995,
1
3 by bis(trifluoroacetoxy)iodobenzene is presumably
faster than oxidation of the protonated quinolizidine
2a , accounting for the requirement of excess oxidant
(Scheme 3).
3
8
6, 1693. (d) L o´ pez, I.; Diez, A.; Rubiralta, M. Tetrahedron 1996, 52,
581. (e) Forns, P.; Diez, A.; Rubiralta, M.; Solans, X.; Font-Bardia,
The optimized bis(trifluoroacetoxy)iodobenzene-medi-
M. Tetrahedron 1996, 52, 3563. (f) Reference 5a.
ated hydrolysis and purification effectively unmasks a
variety of dithiane-containing alkaloids (Table 1). The
efficacy is underscored by the lability of several 3-oxopi-
peridines that are cleanly obtained with the nonchro-
matographic purification and yet are unstable to silica
gel chromatography (Table 1, entries 1-3). The array of
dithianes presented in Table 1 demonstrates that the
deprotection is successful with relatively complex quino-
lizidines, several of which are advanced synthetic inter-
(
22) Use of excess periodane was also reported in a related procedure
20b
using bis(acetoxy)iodobenzene.
(23) Although efforts to identify the fate of the amino ketones has
been unsuccessful, related indolizidines are known to suffer hydride
migration affording iminium ion intermediates that, in this case, could
be potentially deleterious: Razavi, H.; Polt, R. J . Org. Chem. 2000,
6
5, 5693.
24) Repetitive chromatography provided a pure sample of 14 that
(
1
exhibited a H NMR spectrum identical to that previously reported:
Sheu, C.; Foote, C. S.; Gu, C.-L. J . Am. Chem. Soc. 1992, 114, 3015.
(25) Moriarty, R. M.; Vaid, R. K. Synthesis 1990, 431.

6
504 J . Org. Chem., Vol. 66, No. 19, 2001
Notes
2249, 1719 cm-1; 1H NMR δ 1.53 (tt, J ) 13.3, 4.2 Hz, 2H), 1.59-
mediates. The oxidative cleavage accommodates nitrile,
R-aminonitrile, amide, imide, lactam, and ester function-
ality providing the corresponding ketones in 69-97%
yield. The dithiane hydrolysis is apparently retarded by
proximal electron-withdrawing groups since the nitrile
1
.69 (m, 2H), 1.91-2.75 (m, 7H), 2.98-3.01 (m, 2H), 3.34-3.35
(
1
m, 1H); 13C NMR δ 21.9, 23.0, 27.1, 28.2, 38.7, 53.9, 56.2, 71.3,
20.0, 203.7.
(
()-Meth yl 4-[N-[((1S)-9-Oxo-1,2,3,6,7,8,9a -h ep ta h yd r o-
qu in olizin yl)m eth yl]ca r ba m oyl]bu ta n oa te (11b). The gen-
2
a is hydrolyzed more slowly than 2b and 2c and
eral procedure was employed with a CH CN/H O solution (10
3
2
requires a greater excess of the oxidant. Presumably, the
strong inductive electron withdrawal from the nitrile
decreases the nucleophilicity of the neighboring dithiane
group that competes less effectively for the oxidant than
the dithiolane 13.
Dithianes are exceptional reagents whose use in syn-
thesis is tempered only by deprotection to the corre-
sponding ketone. Deprotection of several dithiane-
containing alkaloids provides insight into the hydrolysis
mechanism with bis(trifluoroacetoxy)iodobenzene that is
potentially of general relevance for sensitive dithiane-
containing intermediates. The nonchromatographic pu-
rification cleanly generates the corresponding ketoam-
ines, providing an ideal dithiane hydrolysis procedure for
labile alkaloids.
mL, 1:1) of 2b (150.8 mg, 0.38 mmol), trifluoroacetic acid (430
mg, 3.8 mmol), and [bis(trifluoroacetoxy)iodo]benzene (160.4 mg,
0
.37 mmol; 245.1 mg, 0.57 mmol) added initially and at 0.5 h,
respectively, to provide 107.6 mg (92%) of 11b as an oil: IR (film)
-1
1
3
2
307, 1726, 1649 cm
; H NMR δ 1.05-1.10 (m, 1H), 1.51-
.69 (m, 13H), 2.78-3.08 (m, 4H), 3.32-3.45 (m, 2H), 3.67 (s,
1
3
3H), 3.68-3.95 (m, 2H), 5.99 (s, 1H); C NMR δ 20.9, 23.9, 24.9,
25.5, 28.5, 33.2, 35.5, 40.3, 42.8, 51.5, 54.8, 55.5, 73.0, 172.2,
1
73.6, 208.3.
()-1-[((1S)-9-Oxo-1,2,3,6,7,8,9a -h e p t a h yd r oq u in olizi-
n yl)m eth yl]p ip er id in e-2,6-d ion e (11c). The general proce-
dure was employed with a CH CN/H O solution (10 mL, 1:1) of
c (50.3 mg, 0.136 mmol), trifluoroacetic acid (160 mg, 1.40
(
3
2
2
mmol), and [bis(trifluoroacetoxy)iodo]benzene (57.6 mg, 0.13
mmol; 86 mg, 0.20 mmol) added initially and at 0.5 h, respec-
tively, to provide 39.7 mg (96%) of 11c as an oil: IR (film) 1724,
1
1
6
(
674; H NMR δ 1.00 (ddd, J ) 25, 12, 5 Hz, 1H), 1.48-2.08 (m,
H), 2.19 (td, J ) 11, 4 Hz, 2H), 2.25-2.71 (m, 9H), 2.81-2.96
m, 2H), 3.65 (dd, J ) 13.5, 4.5 Hz, 1H), 3.79 (dd, J ) 13.5, 7.7
Exp er im en ta l Section 26
Hz, 1H); 13C NMR δ 16.8, 23.7, 26.4, 27.4, 32.1, 32.7, 40.5, 43.0,
5
5.4, 55.5, 73.7, 173.2, 207.4.
-Aza -9-p r op yl-1,5-d ith ia sp ir o[5.5]u n d eca n e (2d ). Neat
,3-propanedithiol (650 mg, 6.0 mmol) and ethereal BF ‚OEt
Cl solution (10
mL) of 11d (282 mg, 2 mmol). After 16 h, ice-cold aqueous NaOH
5% v/v, 30 mL) was added, the aqueous phase was extracted
with EtOAc (3 × ∼30 mL), and the combined organic extracts
were dried (MgSO ). Concentration of the resulting crude
(
()-(1S )-9-Me t h ylt h io-1,2,3,6,7,9a -h e xa h yd r oq u in oli-
zin eca r bon itr ile (3). SbCl (0.21 mL, 1.67 mmol) was added
to a room-temperature CH Cl solution (15 mL) of Me (0.15
mL, 1.70 mmol). After 5 min, the mixture was cooled to -78 °C
9
5
1
(
3
2
2
2
2 2
S
0.3 mL) were added to a room-temperature CH
2
2
6
2 2
and a CH Cl solution (2 mL) of 2a (172 mg, 0.83 mmol) was
(
added over 5 min. The cooling bath was removed, and after 3 h
at ambient temperature aqueous NaOH (5%, 20 mL) was added.
4
The aqueous phase was extracted with CH
2
Cl
2
(4 × 20 mL), the
material and purification by radial chromatography (hexane/
EtOAc 95:5-70:30) provided 298 mg (65%) of 11d as an oil: IR
extracts were dried (MgSO ) and concentrated, and the resultant
4
crude material was purified by radial chromatography (1 mm
-
1 1
(
1
(
2
film) 2809, 2772 cm ; H NMR δ 0.89 (t, J ) 7 Hz, 3H), 1.43-
plate, 1:19-3:10 EtOAc/hexanes) to afford 49.2 mg (33%) of 3
.56 (m, 2H), 1.95-2.03 (m, 2H), 2.10-2.14 (m, 4H), 2.29-2.35
-
1
1
as a colorless oil: IR (film) 3040, 2238, 1630 cm
; H NMR
13
m, 2H), 2.53-2.57 (m, 4H), 2.79-2.83 (m, 4H); C NMR δ 11.9.
0.0, 25.7, 25.9, 37.4, 48.3, 49.0, 60.4,
-P r op ylp ip er id in -4-on e (11d ). The general procedure was
employed with a CH CN/H O solution (15 mL, 9:1) of 2d (144
mg, 0.64 mmol), trifluoroacetic acid (732 mg, 6.4 mmol), and [bis-
trifluoroacetoxy)iodo]benzene (412 mg, 0.96 mmol) to provide,
2
7
(CS
2
)
δ 1.84-1.96 (m, 4H), 2.21-3.24 (m, 7H), 2.57 (s, 3H),
13
3
1
.50-3.52 (m, 1H), 5.90 (d, J ) 6.2 Hz, 1H); C NMR (CS
2
) δ
1
5.9, 22.9, 27.1, 28.7, 32.2, 51.4, 56.2, 65.2, 117.9, 122.5, 133.2;
3
2
MS m/e 209 (M + H).
Gen er a l Hyd r olysis P r oced u r e. Solid [bis(trifluoroacetoxy)-
iodo]benzene (1 equiv) was added to a room-temperature
(
after radial chromatography (60:40-20:80 hexane/EtOAc), 63.7
mg (71%) of 20 that exhibited spectral data identical to that of
a commercial sample.
CH
3 2
CN/H O solution (1:1) of the dithiane (1 equiv) and trifluo-
roacetic acid (10 equiv). After 0.5 h, additional solid [bis-
(
trifluoroacetoxy)iodo]benzene (1.5-2.3 equiv) was added with
5
-Oxo-1-(4-oxop en tyl)p yr r olid in e-2-ca r bon itr ile (11e).
the reaction being terminated 2.5 h later. The resultant mixture
The general procedure was employed with a CH CN/H O solu-
3
2
was extracted with hexane (3 × ∼15 mL), the aqueous phase
tion (10 mL, 9:1) of 2e (57.1 mg, 0.14 mmol) and [bis(trifluoro-
acetoxy)iodo]benzene (61.9 mg, 0.14 mmol; 92.9 mg, 0.22 mmol)
added initially and at 0.5 h, respectively, to provide, after
filtration through silica gel (1:9 hexane/EtOAc) 26.6 mg (92%)
2 3
was neutralized with solid K CO (until basic to litmus paper),
and then neat EtSH (1 mL) was added following by stirring for
min. The resulting solution was diluted with saturated,
aqueous NaHCO and extracted with CH Cl2. The combined
) and concentrated to afford
5
3
2
-
1
1
of 11e as an oil: IR (film) 2244, 1709 cm ; H NMR δ 1.70-
organic extracts were dried (MgSO
spectroscopically pure ketone.
4
1
6
2
.97 (m, 2H), 2.11 (s, 3H), 2.28-2.58 (m, 6H), 3.12 (dt, J ) 14,
13
Hz, 1H), 3.63-3.73 (m, 1H), 4.51-4.55 (m, 1H); C NMR δ
(
()-(1S)-9-Oxo-1,2,3,6,7,8,9a -h ep ta h yd r oqu in olizin eca r -
bon itr ile (11a ). The general procedure was employed with a
CH CN/H O solution (30 mL, 1:1) of 2a (200 mg, 0.75 mmol),
0.5, 23.4, 28.9, 29.9, 40.5, 41.2, 47.8, 117.6, 174.0, 207.8.
3
2
Ack n ow led gm en t . Financial support from the
J ohnson and J ohnson Focused Giving Program is grate-
fully acknowledged.
trifluoroacetic acid (830 mg, 7.3 mmol), and [bis(trifluoroace-
toxy)iodo]benzene (316 mg, 0.73 mmol; 722 mg, 1.68 mmol; 316
mg, 0.73 mmol) added initially and at 0.5 and 2.5 h intervals,
respectively, to provide 113.7 mg (85%) of 11a : IR (film) 2758,
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13
C
(
26) For general experimental procedures see ref 6. Bis(trifluoro-
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
acetoxy)iodobenzene from Aldrich was used without purification.
27) The 1H and C NMR spectra in CS
13
(
2
were referenced to the
proton and carbon residual signals of the external reference C
6
D
6
.
J O0157829