A formal synthesis of pumiliotoxin 251D, via a highly diastereoselective addition of a titanium homoenolate to an L-proline derivative

Full text of DOI:10.1021/jo9820972

1410
J . Org. Chem. 1999, 64, 1410-1411
Sch em e 1
A F or m a l Syn th esis of P u m iliotoxin 251D,
via a High ly Dia ster eoselective Ad d ition of
a Tita n iu m Hom oen ola te to a n L-P r olin e
Der iva tive
Anthony G. M. Barrett* and Federica Damiani
Department of Chemistry, Imperial College of Science,
Technology and Medicine, South Kensington,
London, UK, SW7 2AY
Received October 19, 1998
Pumiliotoxin A, B, and 251D (1), alkaloids isolated
from skin secretion of neotropical dendrobatid frogs, have
shown ability to activate voltage-dependent sodium
channels, therefore displaying in some cases cardiotonic
and myotonic activity.1 Since the natural source of these
alkaloids is limited, they have been subject to consider-
able synthetic investigations including the total synthe-
ses of Overman, Trost, and Gallagher.2,3 Lactam 2 is a
key intermediate in the Gallagher synthesis of pumilio-
toxin 251D and has alternatively been prepared from
L-proline in nine steps with an overall yield of 9%.3,4 Since
the conversion of lactam 2 into pumiliotoxin 251D
required only three steps,3 a concise synthesis of this
compound would be of value in the elaboration of libraries
of analogues. Herein we report a concise, six-step, highly
stereoselective synthesis of lactam 2 from L-proline,
which therefore represents a formal total synthesis of
pumiliotoxin 251D (1).
Sch em e 2
7 in 49% yield as a single diastereoisomer.8 Hydrogena-
tion of 7 in MeOH gave the desired lactam 2 in quantita-
tive yield (Scheme 1). This procedure afforded lactam 2
with complete diastereoselectivity, in 19% overall yield
and in seven steps from L-proline.
Although this method provides a shorter and higher
yielding access to pumiliotoxin 251D (1), it involved an
undesirable sequence of redox steps. Therefore we sought
a more direct approach to ketone 5. Treatment of com-
mercially available Cbz-protected proline methyl ester9
with the Tebbe reagent (10 )10 afforded, after filtration
through a short path of silica gel, a mixture of enol ether
9 and ketone 5. Hydrolysis of this mixture in acetone with
a catalytic amount of 1 M HCl gave ketone 5,6 which was
obtained as a pure compound without chromatography,
in 89% yield over the two steps (Scheme 2). This final
improvement allows the synthesis of lactam 2 in six steps
and in 41% overall yield from L-proline.
Grignard reaction of aldehyde 3 with methylmagne-
sium bromide gave a diastereoisomeric mixture of alco-
hols 4, although some addition of the Grignard reagent
to the carbamate did occur. The best yields of the desired
alcohols 4 were achieved when the reaction was con-
ducted for 1 h at -78 °C using 5 equiv of methylmagne-
sium bromide (61% isolated yield). Alcohols 4 were
oxidized to the ketone 5 (91%) using J ones reagent5 at 0
°C.6 Reaction of the titanium homoenolate 6, prepared
in situ from titanium tetrachloride and 1-ethoxy-1-
(trimethylsilyloxy)cyclopropane following the procedure
of Nakamura and Kuwaijma,7 with ketone 5 gave alcohol
(6) The enantiomeric purity of ketone 5 was determined by chiral
HPLC analysis which showed that no racemization had occurred
[Chiralpak-AD column; eluant 10% EtOH/hexanes]. This system clearly
resolved a racemic modification of the ketone 5.
(7) Nakamura, E.; Oshino, H.; Kuwajima, I. J . Am. Chem. Soc. 1986,
108, 3745.
(1) For recent reviews, see (a) Daly, J . W.; Garraffo, H. M.; Spande,
T. F. The Alkaloids 1993, 43, 185. (b) Daly, J . W.; Spande, T. F. In
Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Wiley: New York, 1986; Vol. 4, Chapter 1.
(2) For review on total synthesis of pumiliotoxin alkaloids, see
Overman, L. E.; Franklin, S. A. Chem. Rev. 1996, 96, 505-522.
(3) Fox, D. N. A.; Lathbury, D.; Mahon, M. F.; Molloy, K. C.;
Gallagher, T. J . Am. Chem. Soc. 1991, 113, 2652.
(4) Cossy, J .; Cases, M.; Gomez Pardo, D. Synlett 1996, 909.
(5) Paquette, L. A. Encyclopedia of Reagents for Organic Synthesis;
Wiley: New York, 1995; Vol. 2, p 1261.
(8) Analysis of the crude reaction product showed the presence of
only one diastereoisomer.
(9) Compound 8 is also available in two steps from L-proline (95%
yield): (a) Corey, E. J .; Shibata, S.; Bakshi, R. K. J . Org. Chem. 1988,
53, 2861. (b) Nakayama, K.; Thompson, W. J . J . Am. Chem. Soc. 1990,
112, 6936.
(10) Pine, S. H.; Shen, G. S.; Hoang, H. Synthesis 1991, 165.
10.1021/jo9820972 CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/22/1999

Notes
J . Org. Chem., Vol. 64, No. 4, 1999 1411
washed with saturated aqueous NaHCO3 (10 mL) and brine,
dried (Na2SO4), and concentrated in vacuo. Chromatography
(hexanes:Et2O 3:2) gave ester 7 (237 mg, 49%): [RD]27 ) -49.9°
(c ) 1.1, CHCl3), IR (neat) 3364, 2977, 2940, 2896, 1732, 1671
Exp er im en ta l Section
Gen er a l. Solvents were dried by distillation under N2, from
sodium benzophenone ketyl (THF, Et2O) or CaH2 (CH2Cl2).
Hexanes refers to the petroleum fraction bp 40-60 °C. All other
reagents were used as commercially supplied. Air- and/or
moisture-sensitive reactions were performed in oven-dried (110
°C) glassware under N2. TLC was carried out on E. Merck
precoated silica gel 60 F254 plates. Chromatography refers to
flash chromatography on E. Merck silica gel 60, 40-60 µm.
(2S)-Ben zyl 2-(1-Hyd r oxyeth yl)-1-p yr r olid in eca r boxyl-
a te (4). MeMgBr in Et2O (3 M; 2.1 mL, 6.57 mmol, 5 equiv) was
added to freshly prepared aldehyde 311 (350 mg, 1.3 mmol) in
dry THF (4 mL). The reaction mixture was stirred at -78 °C
for 1 h, warmed to 0 °C over 30 min, and quenched with
saturated NaHCO3. The aqueous layer was extracted with Et2O
(3 × 30 mL), and the combined organic phases were washed with
brine and dried (Na2SO4). Filtration, evaporation, and chroma-
tography (hexanes:Et2O 1:1) gave alcohol 4 (197 mg, 61%) as a
mixture of two diastereoisomers: IR (neat) 3427, 2973, 2934,
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.3-7.4 (m, 5 H), 5.17 (s, 2
H), 4.14 (q, 2 H, J ) 7.1 Hz), 3.9-4.0 (m, 1 H), 3.7-3.8 (m, 1 H),
3.2-3.3 (m, 1 H), 2.5-2.6 (m, 2 H), 2.07-2.11 (m, 1 H), 1.84-
1.90 (m, 1 H), 1.6-1.81 (m, 4 H), 1.27 (t, 3 H, J ) 7.1 Hz), 1.06
(s, 3 H); 13C NMR (75 MHz, CDCl3) δ 174.4, 158.4, 136.3, 128.6,
128.2, 128.0, 74.8, 67.7, 66.8, 60.3, 48.2, 35.1, 28.6, 28.5, 24.4,
21.2, 14.2; HRMS (CI) [M + H+] calcd 350.1967, found 350.1953.
Anal. Calcd for C19H27NO5: C, 65.31; H, 7.79; N, 4.01. Found:
C, 65.59; H, 7.84; N, 4.00.
(5S,6S)-5-Hyd r oxy-5-m eth yl-1-a za bicyclo[4.3.0]n on a n -2-
on e (2). To ester 7 (155 mg, 0.44 mmol) in MeOH (100 mL) was
added 10% Pd/C (100 mg), and the mixture was evacuated and
stirred under H2 (1 atm) overnight. The solution was filtered
through Celite and concentrated in vacuo to give 2 (75 mg,
100%), as a pure compound. Recrystallization from hexanes/Et2O
gave 2: mp 89-91 °C; [RD]29 ) -53.0° (c ) 0.97, CHCl3); IR
2883, 1680, 1696 cm-1 1H NMR (400 MHz, CDCl3) δ 7.3-7.4
;
1
(neat) 3328, 2971, 2952, 2928, 2884, 1616 cm-1; H NMR (400
(m, 5 H), 5.16 (d, 1 H, J ) 12.6 Hz), 5.13 (d, 1 H, J ) 12.4 Hz),
4.0 (s, 1 H), 3.77-3.82 (m, 1 H), 3.70-3.74 (m, 1 H), 3.57-3.63
(m, 1 H), 3.3-3.4 (m, 1H), 1.94-2.02 (m, 1 H), 1.72-1.90 (m, 2
H), 1.61-1.69 (m, 1 H), 1.16; 1.10 (2d, 3 H, J ) 5.9 Hz, J ) 6.4
Hz, ratio ) 2:1); 13C NMR (100 MHz, CDCl3) δ major diastereo-
isomer: 158.1, 136.4, 128.5, 128.1, 127.9, 72.0, 67.4, 64.9, 47.3,
28.8, 24.1, 20.8, minor diastereoisomer: 158.1, 136.6, 128.5,
128.1, 127.9, 69.4, 67.2, 64.0, 47.9, 27.6, 24.1, 17.6; HRMS (CI)
MHz, CDCl3) δ 3.45 (dd, 2 H, J ) 4.4, 9.3 Hz), 3.30 (dd, 1 H, J
) 5.5, 10.3 Hz), 2.94 (s, 1 H), 2.49 (ddd, 1 H, J ) 18.7, 11.4, 7.8
Hz), 2.32 (dd, 1 H, J ) 18.1, 7.4 Hz), 1.6-2.2 (m, 6 H), 1.25 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 169.2, 67.3, 66.3, 45.7, 34.9,
28.1, 26.4, 26.2, 21.9; HRMS (CI) [M + H+] calcd 170.1181, found
170.1176. All data were identical with those reported.3
(2S)-Ben zyl 2-(1-Met h oxy-1-p r op en yl)p yr r olid in eca r -
boxyla te (9). To ester 8 (224 mg, 0.85 mmol) in dry THF (2.5
mL) at 0 °C was added Tebbe reagent 10 in PhMe (0.5 M, 1.7
mL) (Aldrich). The mixture was allowed to warm to room
temperature and, after 30 min, Et2O (10 mL) was added,
followed by the slow addition of aqueous NaOH (0.1 M) while
stirring the mixture. After gas evolution ceased, the mixture was
dried (Na2SO4) and filtered through Celite. Evaporation and
chromatography (hexanes:Et2O 7:3-1:1) gave enol ether 9 (175
mg, 79%) and ketone 5 (36 mg, 17%). Data for enol ether 9: 1H
NMR (300 MHz, CDCl3) δ 7.3-7.4 (m, 5 H), 5.1-5.2 (m, 2 H),
4.3-4.4 (m, 1 H), 3.9-4.0 (m, 2 H), 3.4-3.6 (m, 5 H), 1.8-2.1
(m, 4 H); HRMS (CI) [M + H+] calcd 262.1443, found 262.1443.
This crude mixture was used directly in the next step, and no
further characterization was possible to obtain on the unstable
9, which easily hydrolyzed to ketone 5.
(2S)-Ben zyl 2-Acetyl-1-p yr r olid in eca r boxyla te (5). Aque-
ous 1 M HCl (5 drops) was added to 9 (175 mg, 0.67 mmol) in
Me2CO (30 mL). After 30 min, saturated NaHCO3 was added to
reach neutral pH, and the solution was evaporated and the
residue extracted with EtOAc (3 × 20 mL). The organic layer
was washed with brine and dried (Na2SO4). Evaporation of the
solvent gave ketone 5 (151 mg, 91%) which by NMR was pure
enough for the next step: [RD]27 ) -43° (c ) 1, CHCl3), all data
was identical with previous sample.
[M + H+] calcd 250.1443, found 250.1426. Anal. Calcd for C14H19
-
NO3: C, 67.45; H, 7.68; N, 5.62. Found: C, 67.50; H, 7.81; N,
5.58.
(2S)-Ben zyl 2-Acetyl-1-p yr r olid in eca r boxyla te (5). J ones
reagent was added dropwise to alcohol 4 (640 mg, 2.57 mmol)
in Me2CO (100 mL) at 0 °C to a permanent orange end-point.
The reaction mixture was stirred for 30 min at room temperature
when 2-propanol (50 mL) was added at 0 °C and stirring
continued for 15 min. Filtration through a short plug of silica
gave ketone 5 (580 mg, 91%) which by 1H NMR resulted to be
pure enough for the next step: [RD]27 ) -42.2° (c ) 1, CHCl3);
IR (neat) 3033, 2956, 2926, 2884, 2855, 1705 cm-1; 1H NMR (500
MHz, C6D6, 95 °C) δ 7.0-7.2 (m, 5 H), 5.09 (d, 1 H, J ) 12.5
Hz), 5.05 (d, 1 H, J ) 12.5 Hz), 4.13 (br. s, 1 H), 3.31 (br. s, 2 H),
1.79 (s, 3 H), 1.51-1.6 (m, 1 H), 1.39-1.46 (m, 2 H), 1.2-1.3
(m, 1 H); 13C NMR (75 MHz, CDCl3) δ mixture of rotamers 207.8,
207.5, 155.0, 154.4, 136.6, 136.3, 128.6, 128.5, 128.1, 128.0, 127.8,
67.15, 67.03, 65.5, 65.4, 47.2, 46.7, 30.3, 29.7, 24.3, 23.6; HRMS
(CI) [M + H+] calcd 248.1287, found 248.1278. Anal. Calcd for
C
14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found: C, 67.87; H, 6.81;
N, 5.61.
(4S)-Eth yl 4-[1-[(Ben zyloxy)ca r bon yl]-2S-p yr r olid in yl]-
4-h yd r oxyp en t a n oa t e (7). 1-Ethoxy-1-(trimethylsilyloxy)-
cyclopropane (8.5 mmol, 1.7 mL) was added at 21 °C over 20 s
to TiCl4 in CH2Cl2 (1 M, 8.5 mL, 8.5 mmol). The homoenolate
(8.5 mmol) was diluted with dry CH2Cl2 (8 mL) at -78 °C, and
ketone 5 (340 mg; 1.38 mol) was added. After 1 h, the reaction
mixture was allowed to warm to 0 °C and then slowly to room-
temperature overnight. The mixture was poured into water and
extracted with Et2O (3 × 10 mL), and the organic phase was
Ack n ow led gm en t. We thank Zeneca, Chiroscience,
the EPSRC, and the DTI for generous support under
the Link Asymmetric Scheme; Glaxo-Wellcome Re-
search Ltd for the most generous endowment (to
A.G.M.B.); the Wolfson Foundation for establishing the
Wolfson Centre for Organic Chemistry in Medical
Science at Imperial College; and George A. O’Doherty,
Oswy Pereira, and D. Christopher Braddock for helpful
discussions.
(11) Aldehyde 3 has been synthesized in a three-step sequence from
L-proline via LiAlH4 reduction (85%), Cbz protection (87%), and Swern
oxidation (95%): (a) Enders, D.; Eichenauer, H. Angew. Chem., Int.
Ed. Engl. 1976, 15, 549. (b) St-Denis, Y.; Chan, T.-H. J . Org. Chem.
1992, 57, 3078. (c) Shi, X.; Attygalle, A. B.; Xu, S.-C.; Ahmad, V. U.;
Meinwald, J . Tetrahedron 1996, 52, 6859.
J O9820972