Reactive enols in synthesis 2. Synthesis of (+)-latifolic acid and (+)-latifoline

Article abstract of DOI:10.1021/jo015741c

We describe a short, enantioselective synthesis of the naturally occurring pyrrolizidine alkaloid (+)-latifoline (1) employing a tandem [3,3] sigmatropic rearrangement/[1,2] allyl shift as a key step in constructing (+)-latifolic acid (4).

Full text of DOI:10.1021/jo015741c

J . Org. Chem. 2001, 66, 7025-7029
7025
Rea ctive En ols in Syn th esis 2. Syn th esis of (+)-La tifolic Acid a n d
(+)-La tifolin e
Ioana Drutu, Evan S. Krygowski, and J ohn L. Wood*
Department of Chemistry, Yale University, Sterling Chemistry Laboratory, P.O. Box 208107,
New Haven, Connecticut 06520-8107
john.wood@yale.edu
Received May 9, 2001
We describe a short, enantioselective synthesis of the naturally occurring pyrrolizidine alkaloid
(+)-latifoline (1) employing a tandem [3,3] sigmatropic rearrangement/[1,2] allyl shift as a key step
in constructing (+)-latifolic acid (4).
Sch em e 1. La tifolin e: Retr osyn th etic An a lysis
In tr od u ction
Bifunctional pyrrolizidine alkaloids (e.g., latifoline,
heliosupine, indicine N-oxide, monocrotaline, senecionine,
etc.) are well-known to exhibit interesting biological
properties, including activity against various forms of
leukemia and solid tumors.1 In general, this anti-cancer
activity is attributed to the alkaloid’s capacity to block
DNA replication by either DNA-protein or DNA-inter-
strand cross-linking; however, the structural subtleties
that dictate the mode of action remain enigmatic. Lati-
foline (1), a member of the pyrrolizidine class, was first
isolated in 1962 by Crowley and Culvenor2 from Cyno-
glossum latifolium, an Australian representative of the
Boraginaceae family.
To date, despite extensive synthetic efforts toward a
number of pyrrolizidine alkaloids,3 a synthesis of latifo-
line has yet to be reported. Herein, we describe an
efficient asymmetric synthesis of latifolic acid and its use
in assembling (+)-latifoline.
From a retrosynthetic perspective (Scheme 1), the
availability of angelic acid (2) and retronecine (3) from
commercial sources left assembly of latifolic acid (4)4 as
the primary synthetic challenge in preparing compound
1. To this end, we recognized that 4 could readily arise
from open-chain intermediate 5, which in turn could be
accessed via a tandem [3,3]/[1,2] rearrangement of the
reactive enol (7) produced upon Rh(II)-initiated coupling
of 8 and 9.5
Resu lts a n d Discu ssion
To test the viability of the proposed route, we sought
to prepare the known methyl ester 13a 4 (Scheme 2).
Toward this end, 8a 6 and (()-(9) were subjected to a
rhodium-initiated [3,3] rearrangement that efficiently
delivered R-hydroxy ketone (()-6a as a 6:1 diastereomeric
mixture. Mechanistically, the reaction proceeds initially
to a Z-enol intermediate that then undergoes [3,3]
rearrangement through a chairlike transition state (see
(()-7a in Scheme 1). This scenario, coupled with the
E-geometry of the allylic alcohol, accounts for the relative
configuration of the major product (()-6a , whereas a
boatlike transition state is responsible for the formation
of the minor diastereomer.7
* To whom correspondence should be addressed. Phone: (203) 432-
5991. Fax: (203) 432-6144.
(1) Rajski, S. R.; Williams, R. M. Chem. Rev. 1998, 98, 2723-2795.
(2) Crowley, H. C.; Culvenor, C. C. J . Aust. J . Chem. 1962, 15, 139-
144.
(3) (a) Liu, Z. Y.; Zhao, L. Y. Tetrahedron Lett. 1999, 40, 5593-
5596. (b) Niwa, H.; Ogawa, T.; Okamoto, O.; Yamada, K. Tetrahedron
1992, 48, 10531-48. (c) Niwa, H.; Miyachi, Y.; Okamoto, O.; Uosaki,
Y.; Kuroda, A.; Ishiwata, H.; Yamada, K. Tetrahedron 1992, 48, 393-
412. (d) Nishimura, Y.; Kondo, S.; Umezawa, H. Tetrahedron Lett.
1986, 27, 4323-6. (e) Narasaka, K.; Sakakura, T.; Uchimaru, T.;
Guedin-Vuong, D. J . Am. Chem. Soc. 1984, 106, 2954-61.
(4) In an effort to determine the relative stereochemistry of latifolic
acid, Matsumoto accomplished a stereorandom synthesis of all four
possible diastereomers. (a) Matsumoto, T.; Okabe, T.; Fukui, K. Chem.
Lett. 1972, 29-32. (b) Matsumoto, T.; Okabe, T.; Fukui, K. Chem. Lett.
1973, 773-776.
(5) For other uses of reactive enols in synthesis, see: Wood, J . L.;
Holubec, A. A.; Stoltz, B. M.; Weiss, M. M.; Dixon, J . A.; Doan, B. D.;
Shamji, M. F.; Chen, J . M.; Heffron, T. P. J . Am. Chem. Soc. 1999,
121, 6326-6327.
(6) Prepared from the corresponding â-oxobutanoate ester. For a
general procedure, see: Baum, J . S.; Shook, D. A.; Davies, H. M. L.;
Smith, H. D. Synth. Commun. 1987, 17, 1709-1716.
10.1021/jo015741c CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/25/2001

7026 J . Org. Chem., Vol. 66, No. 21, 2001
Drutu et al.
Sch em e 3. Syn th esis of (+)-La tifolic Acid
Sch em e 2. Syn th esis of (()-La tifolic Acid Meth yl
Ester
reduction and reductive ozonolysis of (+)-5b proceeded
smoothly to furnish (+)-12b which, upon exposure to
TPAP,13 gave lactone (+)-13b.14 To our delight, depro-
tection of the benzyl ester under hydrogenolytic condi-
tions produced (+)-latifolic acid (4) in quantitative yield.
The spectroscopic and physical properties of the product
were identical to those reported for natural (+)-latifolic
acid.4,15
With ample quantities of optically active latifolic acid
in hand, we began exploring the double esterification of
(+)-retronecine (3),16 a task that proved to be nontrivial
(Scheme 4). Thus, after considerable experimentation, it
was found that protection of the C9-OH as the corre-
sponding TBS-ether (+)-14 followed by sequential treat-
ment of the remaining alcohol with n-BuLi and excess
angelyl chloride affords angelate (+)-15.
In our efforts to convert (+)-15 to (+)-16, isomerization
of the angelate moiety to the thermodynamically pre-
ferred tiglate proved problematic even under nonbasic
conditions (use of CAN/MeOH led to a 1:1 mixture of
diastereomers). We eventually discovered that when
SiF417 was used as a mild source of fluoride we were able
to isolate (+)-16 in excellent yield without any tiglate
contamination. Poised for the final acylation, difficulties
associated with the lability of (+)-4 toward base and the
sterically congested carboxylic acid moiety proved to be
the next obstacles. We sought to circumvent the steric
hindrance at the sp2 reaction center by converting the
primary allylic alcohol into a good leaving group (-Br, -Cl,
-OMs, Mitsunobu conditions) and using the carboxylate
unit as a nucleophile. Unfortunately, none of these
conditions produced the desired ester. Use of a number
of commonly employed activating agents (DCC, DMAP,
HOBt, PyBop, etc.) led to no reaction, whereas use of base
to activate the primary allylic alcohol promoted decom-
position of latifolic acid. Eventually, it was determined
Exposure of crude (()-6a to BF3‚OEt2 effected a
completely diastereoselective 1,2-allyl shift8 to yield
(()-5a 9 (same 6:1 ratio). The stereochemical outcome of
the reaction is consistent with a syn-periplanar transition
state 10. Unfavorable steric interactions disrupting this
conformation could lead to lower stereoselectivity, as
observed when the methyl ester is replaced with a benzyl
ester (vide infra). Subsequent reduction of (()-5a with
sodium borohydride/zinc chloride followed by reductive
ozonolysis furnished lactols (()-12a .10 Finally, oxidation
of 12a with Celite-supported silver carbonate11 produced
the corresponding lactone (()-13a , which was found to
be spectroscopically in accord with literature values.4
Unfortunately, attempts to advance 13a to 4 via hydroly-
sis of the methyl ester led to complex mixtures.
Having secured the route in terms of relative stereo-
chemistry we focused our efforts on completing an
enantioselective synthesis of 4. To this end, sequential
treatment of benzyl diazoacetoacetate (8b)6 and (S)-(+)-
(9) (98% ee)7a with Rh2(TFA)4 and BF3‚OEt2 afforded a
4:1 mixture of diastereomeric alcohols 5b in 70% yield
(94% ee)12 (Scheme 3). Subsequent chelation-controlled
(7) For a detailed discussion concerning the mechanism and ste-
reoselectivity of the Rh-initiated Claisen rearrangement, see: (a) Wood,
J . L.; Moniz, G. A.; Pflum, D. A.; Stoltz, B. M.; Holubec, A. A.; Dietrich,
H-J . J . Am. Chem. Soc. 1999, 121, 1748-1749. (b) Wood, J . L.; Moniz,
G. A. Org. Lett 1999, 1, 371-374 and references therein.
(8) Wood, J . L.; Stoltz, B. M.; Dietrich, H-J .; Pflum, D. A.; Petsch,
D. T. J . Am. Chem. Soc. 1997, 119, 9641-9651.
(9) Compound (()-5a has recently been employed by our research
group in the synthesis of (()-K252A analogues. See: Tamaki, K.;
Shotwell, J . B.; White, R. D.; Drutu, I.; Petsch, D.; Nheu, T. V.; He,
H.; Hirokawa, Y.; Maruta, H.; Wood, J . L. Org. Lett. 2001, 3, 1689.
(10) The series of reactions leading to (()-11a was performed on
the 6:1 diastereomeric mixture obtained upon rearrangement of
(()-7a . The minor diastereomer was omitted from the schemes for
clarity; the yields of (()-5a and (()-11a refer to the mixture, all the
other yields reflect the amount of desired diastereomer. The chelation
controlled reduction also furnished a 6:1 mixture of diastereomeric diols
(()-11a , indicating complete stereoselectivity.
(13) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 7, 639-666.
(14) For practical purposes, the reactions leading to 13b were
typically performed on the 4:1 diastereomeric mixture. The yield of
11b refers to the 4:1 mixture, whereas the yield of 13b reflects the
amount of diastereomerically pure lactone obtained by crystallization
of the crude reaction product.
(15) Roitman, J . N. Aust. J . Chem. 1988, 41, 1827-1833.
(16) Sufficient amounts of retronecine (3) were obtained via reduc-
tive cleavage of monocrotaline. For details see, Supporting Information.
(11) McKillop, A.; Young, D. W. Synthesis 1979, 401-422.
(12) The major diastereomer (shown in Scheme 3) can be isolated
by HPLC. The minor diastereomer has the opposite absolute config-
uration at the tertiary hydroxyl (for discussion see ref 7).

Synthesis of (+)-Latifolic Acid and (+)-Latifoline
Sch em e 4. Com p letion of (+)-La tifolin e
J . Org. Chem., Vol. 66, No. 21, 2001 7027
The aqueous layer was extracted with Et2O (3 × 75 mL). The
combined organic extracts were dried over Na2SO4. The solvent
was evaporated under reduced pressure, and the residue was
purified by flash chromatography on silica gel (EtOAc:hexane/
20:80) to furnish 11a (1.2 g, 60% yield, 6:1 diastereomeric
mixture) as a yellow oil. An analytically pure sample of the
major diastereomer was obtained by HPLC on silica gel, using
EtOAc/hexane/17:83: 1H NMR (500 MHz, CDCl3) δ 0.99 (d, J
) 7 Hz, 3H), 1.20 (d, J ) 6 Hz, 3H), 1.67 (d, J ) 5 Hz, 3H),
1.95 (br s, 1H), 2.55 (quintet, J ) 7 Hz, 1H), 3.35 (s, 1H), 3.84
(s, 3H), 3.95 (m, 1H), 5.44-5.51 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 15.25, 17.21, 18.08, 42.34, 52.79, 69.77, 82.68, 126.95,
131.28, 175.73; IR (thin layer, NaCl) 1007 (s), 1083 (s), 1149
(s), 1225 (s), 1730 (s), 2850-3000 (m), 3200-3550 (m) cm-1
HRMS (FAB) m/z 203.1284,calcd for C10H17O4 203.1283.
;
P r ep a r a tion of La ctol 12a . A cooled (-78 °C) solution of
11a (0.7 g, 3.46 mmol) in CH2Cl2 (10 mL) was treated with
ozone (9 mL/min) until the solution turned slightly blue (about
5 min). The solution was purged with N2 until the blue color
disappeared, and then dimethyl sulfide (5 mL) was added. The
cold bath was removed, and the solution was stirred at room
temperature for 1 h. Evaporation of solvent under a nitrogen
stream, followed by flash chromatography on silica gel (EtOAc/
hexane 20:80), afforded 12a (0.58 g, 90% yield, 1:1 mixture of
diastereomers) as a white solid: mp 90-91 °C; 1H NMR (500
MHz, CDCl3) δ 1.05 (d, J ) 7 Hz, 3H), 1.08 (d, J ) 7 Hz, 3H),
1.16 (d, J ) 6 Hz, 3H), 1.21 (d, J ) 6 Hz, 3H), 2.45 (quintet,
J ) 7 Hz, 1H), 2.61 (quintet, J ) 7 Hz, 1H), 3.25 (br s, 1H),
3.55 (br s, 1H), 3.90 (s, 3H), 3.93 (s, 3H), 3.98 (q, J ) 6 Hz,
1H), 4.32 (q, J ) 6 Hz, 1H), 5.24 (d, J ) 6 Hz, 1H), 5.30 (m,
1H); 13C NMR (125 MHz, CDCl3) δ 8.05, 9.90, 14.27, 15.21,
47.68, 51.38, 52.76, 53.21, 79.03, 81.33, 85.02, 85.47, 98.61,
102.78, 173.06, 173.96; IR (thin film, NaCl plate) 1065 (s), 1142
that lengthy exposure of (+)-16 to the preformed latifolic
acid imidazolide (17)18 was a suitable method for effecting
the desired coupling and afforded latifoline in reasonable
yield (45%) as a white crystalline solid.19 The synthetic
material was identical in all respects to naturally occur-
ring (+)-latifoline.
In summary, we accomplished an efficient, enantiose-
lective synthesis of (+)-latifoline (seven steps for the
longest linear sequence, 14% overall yield starting from
benzyl diazoacetoacetate, 21% overall yield starting from
retronecine).
(s), 1231 (s), 1727 (s), 2800-3000 (m), 3200-3600 (m) cm-1
;
HRMS (FAB) m/z 213.0740, calcd for C8H14O5Na 213.0738 (M+-
Na).
P r ep a r a tion of La tifolic Acid Meth yl Ester (13a ). A
solution of lactol 12a (100 mg, 0.52 mmol) in benzene (4 mL)
was added to a dry round-bottom flask containing AgCO3/
Celite (50wt %, 500 mg, 0.9 mmol). The flask was submerged
in a preheated oil bath, and the mixture was brought to reflux
for 2 h. An additional portion of AgCO3/Celite (500 mg) was
added, and the mixure was refluxed for another 30 min. Upon
complete consumption of starting material (TLC), the reaction
mixture was filtered through a pad of Celite, the solvent
evaporated, and the residue purified by flash chromatography
on silica gel (EtOAc/hexane 20:80) to yield 13a (40 mg, 40%
yield) as white needles. The physical and spectroscopic data
for this synthetic material were in perfect agreement with data
reported for racemic latifolic acid methyl ester.4
P r ep a r a tion of Ter tia r y Alcoh ol 5b. To a solution of
benzyl 2-azo-3-oxobutanoate (6.10 g, 27.98 mmol) and (S)-(E)-
3-penten-2-ol (2.89 g, 33.57 mmol) in CH2Cl2 (150 mL) was
added Rh2(TFA)4 (65 mg, 0.1 mmol). The mixture was im-
mersed in a preheated oil bath, and after 5 h at reflux, the
reaction was judged complete by TLC. After the mixture was
cooled to room temperature, the solvent was evaporated under
reduced pressure and the residue dissolved in benzene (150
mL). The resultant solution was cooled to 0 °C and treated
with BF3‚OEt2 (4.12 mL, 33.57 mmol). After 2 h, the reaction
was quenched with saturated NaHCO3 (15 mL). The layers
were separated, and the aqueous layer was extracted with CH2-
Cl2 (3 × 30 mL). After the combined organic extracts were
dried over Na2SO4, the solvent was evaporated and the residue
chromatographed on silica gel using EtOAc/hexane 5:95 as
eluent to yield 5b (5.37 g, 70% yield, 4:1 mixture of diastere-
omers) as a yellow oil. The major diastereomer was isolated
in analytically pure form by HPLC, using EtOAc/hexane 10:
90 as eluent: 1H NMR (500 MHz, CDCl3) δ 0.89 (d, J ) 7 Hz,
3H), 1.53 (d, J ) 7 Hz, 3H), 2.29 (s, 3H), 3.17 (quintet, J ) 7
Hz, 1H), 4.08 (s, 1H), 5.16 (d, J ) 12 Hz, 1H), 5.20. d (12, 1H),
5.31 (m, 1H), 5.44 (m, 1H), 7.35 (m, 5H); 13C NMR (125 MHz,
CDCl3) δ 14.63, 18.01, 25.65, 42.82, 68.20, 87.72, 127.92,
128.61, 128.67, 127.70, 129.83, 134.94, 170.38, 205.28; IR (thin
film, NaCl plate) 1147 (s), 1194 (s), 1237 (s), 1264 (s), 1720
Exp er im en ta l Section
Unless otherwise stated, reactions were performed in flame-
dried glassware under a nitrogen atmosphere using freshly
distilled solvents. Diethyl ether (Et2O) and tetrahydrofuran
(THF) were distilled from sodium/benzophenone. Methylene
chloride (CH2Cl2), benzene (PhH), and triethylamine (Et3N)
were distilled from calcium hydride. All other commercially
obtained reagents were used as received. All reactions were
magnetically stirred and monitored by thin-layer chromatog-
raphy (TLC) using E. Merck silica gel 60 F254 precoated plates
(0.25 mm). Flash chromatography was performed with the
indicated solvent system using Silicycle 0.040-0.060 mm silica
gel. Concentration refers to the removal of solvent with a
rotary evaporator at normal aspirator pressure followed by
further evacuation with a two-stage mechanical pump. All
melting points are uncorrected. Infrared spectra were recorded
on Brucker Avance DPX-500 and Brucker Avance DPX-400
spectrometers. High-resolution mass spectra were performed
at the University of Illinois Mass Spectroscopy Center. Normal-
phase high-performance liquid chromatography (HPLC) was
performed on a Waters model 510 system using a Rainin
Microsorb 80-199-C5 column. Optical rotations were deter-
mined on a Perkin-Elmer model 341 polarimeter.
P r ep a r a tion of Diol 11a . To 0.37 g (10 mmol) of NaBH4
in a dry round-bottom flask immersed in an ice bath was added
a 1 M ZnCl2/Et2O solution (10 mL, 10 mmol) followed by a
solution of 5a (2.0 g, 10 mmol) in THF (20 mL). After 20 min,
the reaction was quenched by slow addition of water (50 mL).
(17) Corey, E. J .; Yi, K. Y. Tetrahedron Lett. 1992, 33, 2289-2290.
(18) Hoskins, W. M.; Crout, D. H. G. J . Chem. Soc., Perkin Trans.
1 1977, 538-544.
(19) Attempts to effect the angelate esterification at the C7-OH with
the C9-OH latifolate ester in place failed; the harsh conditions required
to activate the unusually hindered secondary hydroxyl group invariably
led to decomposition.

7028 J . Org. Chem., Vol. 66, No. 21, 2001
Drutu et al.
(s), 2850-3050 (m), 3400-3450 (m) cm-1; HRMS (FAB) m/z
1748 (s), 2900-3400 (m) cm-1; HRMS (FAB) m/z 175.0606,
calcd for C7H11O5 175.0606 (M+H); [R]20 ) +84.4° (c 2.7,
277.1441, calcd for C16H21O4 277.1439 (M+H); [R]20 ) +13.1°
D
D
acetone).
(c 1.6, CDCl3). Enantiomeric excess was determined to be 94%
by integration of the NMR signals for the major and minor
enantiomers using europium tris[3-(heptafluoropropylhy-
droxymethylene)-(+)-camphorate as a chiral shift reagent.
P r ep a r a tion of (+)-14. To a suspension of (+)-retronecine
(0.5 g, 3.22 mmol) in CH2Cl2 (20 mL) was added TBSCl (0.8 g,
5 mmol), followed by imidazole (0.4 g, 5.8 mmol). The reaction
mixture was stirred at room temperature for 1 h and then
quenched with saturated NaHCO3 (25 mL). The biphasic
mixture was extracted with Et2O (4 × 100 mL), and the
combined organic extracts were dried over Na2SO4 and evapo-
rated. The residue was purified by flash chromatography
(EtOAc/MeOH 95:5 f 70:30) to yield 14 (695 mg, 80% yield)
as a white crystalline solid. The physical and spectral proper-
ties of the material matched literature data for (+)-9-TBS
retronecine.3e
P r ep a r a tion of Diol 11b. To a cooled (-30 °C) suspension
of NaBH4 (0.8 g, 21.62 mmol) in THF (20 mL) was added a 1
M solution of ZnCl2/Et2O (19.45 mL, 19.45 mmol), followed by
a solution of 5b (5.37 g, 19.45 mmol, 4:1 diastereomeric
mixture) in THF (100 mL). The mixture was allowed to warm
to -15 °C, and stirring was continued for 30 min. After this
time, TLC showed complete consumption of starting material
and the reaction was quenched by adding 1 N HCl until
foaming stopped. The biphasic mixture was extracted with
three portions of CH2Cl2 (100 mL, 50 mL, 50 mL). The
combined organic extracts were washed with brine and dried
over Na2SO4, and the solvent was removed in vacuo. Purifica-
tion of the residue by flash chromatography on silica gel, using
EtOAc/hexane 10:90 f 80:20, gave 11b (3.96 g, 75% yield, 4:1
mixture of diastereomers). An analytically pure sample of the
major diastereomer was obtained by HPLC on silica gel, using
EtOAc/hexane 20:80 as eluent: 1H NMR (500 MHz, CDCl3) δ
0.97 (d, J ) 7 Hz, 3H), 1.18 (d, J ) 6.5 Hz, 3H), 1.59 (d, J )
5 Hz, 3H), 1.95 (d, J ) 11 Hz, 1H), 2.57 (quintet, J ) 4 Hz,
1H), 3.35 (s, 1H), 3.97 (m, 1H), 5.23 (d, J ) 12 Hz, 1H), 5.27
(d, J ) 12 Hz, 1H), 5.41 (m, 2H), 7.39 (m, 5H); 13C NMR (125
MHz, CDCl3) δ 15.01, 17.25, 18.06, 42.18, 67.90, 69.76, 82.47,
126.96, 128.65, 128.71, 128.74, 131.16, 135.00, 175.12; IR (thin
film, NaCl plate) 1005 (s), 1082 (s), 1147 (s), 1216 (s), 1727
(s), 2900-3000 (m), 3300-3600 (m) cm-1; HRMS (FAB) m/z
P r ep a r a tion of 15. To prepare angelyl chloride, a suspen-
sion of potassium angelate (725 mg, 5.25 mmol) in ether (20
mL) was treated with a drop of DMF and oxalyl chloride (0.5
mL, 5.25 mmol). The mixture was stirred vigorously at room
temperature until the evolution of gas ceased (about 5 h). The
mixture was filtered and kept under nitrogen. In a separate
flask, a solution of (+)-14 (500 mg, 1.85 mmol) in THF (20
mL) was cooled to 0 °C. To the cooled solution was added
dropwise 1.7 M n-BuLi in hexane (1.2 mL, 2.00 mmol). After
the solution was stirred for 10 min, the solution of angelyl
chloride was added very slowly until thin-layer chromatogra-
phy showed no further advancement of the reaction (8 mL,
ca. 2.1 mmol). The resultant solution was treated again with
n-BuLi (0.2 mL, 0.34 mmol), followed by 3 mL of the angeloyl
chloride solution (ca 0.8 mmol). This process was repeated
three times, until TLC showed complete consumption of
starting material. The reaction was then adsorbed onto 2 g of
silica gel and purified by flash chromatography, using a
gradient eluent (EtOAc/MeOH 97.5:2.5 f 90:10) to furnish
(+)-15 (390 mg, 60% yield) as a light brown oil: 1H NMR (500
MHz, CDCl3) δ 0.03 (d, J ) 4 Hz, 6H), 0.885 (s, 9H), 1.81
(quintet, J ) 1.5 Hz, 3H), 1.95 (dd, J ) 7, 1.5 Hz, 3H), 2.1 (m,
2H), 2.65 (m, 1H), 3.35 (m, 2H), 3.95 (d, J ) 14 Hz, 1H), 4.13
(d, J ) 14 Hz, 1H), 4.17 (d, J ) 14 Hz, 1H), 4.31 (br s, 1H),
5.38 (br s, 1H), 5.64 (br s, 1H), 6.07 (q, J ) 4 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ -5.46, 15.82, 18.35, 20.62, 25.91,
34.79, 53.96, 60.53, 62.86, 73.57, 75.66, 122.98, 127.80, 138.74,
138.91, 166.94; IR (thin film, NaCl plate) 838 (s), 1083 (s), 1159
(s), 1231 (s), 1715 (s), 2855 (s), 2928 (s), 2953 (s) cm-1; HRMS
(FAB) m/z 352.2307, calcd for C19H34NO3Si 352.2308 (M+H);
265.1597, calcd for C16H23O4 269.1596 (M+H)]; [R]20 ) -7° (c
D
0.4, CDCl3).
P r ep a r a tion of (+)-La tifolic Acid Ben zyl Ester (13b).
A cooled (-78 °C) solution of 11b (3.0 g, 10.79 mmol, 4:1
mixture of diastereomers) in CH2Cl2 (10 mL) was treated with
ozone (9 mL/min) until the solution turned slightly blue (about
5 min). The solution was purged with N2 until the blue color
disappeared, and then 5 mL of dimethyl sulfide was added.
The cold bath was removed, and the solution was stirred at
room temperature for 1 h. The solvent was evaporated under
a nitrogen stream and the residue taken in CH2Cl2 (10 mL).
After being cooled to 0 °C, the solution was treated with 3 Å
molecular sieves (2.0 g), N-methylmorpholine N-oxide (5.0 g,
42.66 mmol), and TPAP (200 mg, 0.56 mmol). The reaction
was slightly exothermic and was judged complete by TLC after
30 min. The solvent was evaporated and the crude residue
washed with water (3 × 100 mL) to remove the dimethyl
sulfone formed in the oxidation. Flash chromatography on
silica gel (CH2Cl2 as eluent) followed by recrystallization from
Et2O/hexane afforded a single diastereomeric product as long
[R]20 ) +17.5° (c 3.0, CDCl3).
D
P r ep a r a tion of (+)-16. A solution of (+)-15 (150 mg, 0.43
mmol) in anhydrous CH3CN (20 mL) was prepared in a dry
round-bottom flask. A balloon filled with SiF4 was attached,
and the solution was stirred until complete consumption of
starting material was observed by TLC (45 min). The SiF4
balloon was removed, and N2 was bubbled through the solution
for 5 min. The reaction was quenched by adding water (0.5
mL), and the solvent was evaporated in vacuo. The product
was purified by flash chromatography on silica gel, using a
gradient eluent (EtOAc f EtOAc/MeOH f MeOH) to yield
16 (90 mg, 90% yield) as a pale tan crystalline solid. The
spectroscopic and physical properties match the published data
for naturally occurring (+)-7-angelylretronecine: 1H NMR (500
MHz, CDCl3) δ 1.75 (quintet, J ) 1.5 Hz, 3H), 1.90 (dd, J )
13, 3.2, 5 Hz, 3H), 2.05 (m, 2H), 2.61 (q, J ) 9 Hz, 1H), 3.2-
3.3 (m, 2H), 3.83 (d, J ) 14 Hz, 1H), 4.00 (d, J ) 13 Hz, 1H),
4.13 (d, J ) 14 Hz, 1H), 4.29 (s, 1H), 4.81 (br s, 1H), 5.36 (br
s, 1H), 5.55 (br s, 1H), 6.01 (qd, J ) 13, 1.5 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 15.65, 20.47, 34.55, 53.51, 59.75, 63.07,
73.70, 75.46, 123.90, 127.60, 138.66, 139.51, 166.97; IR (thin
film, NaCl plate) 1056, 1161, 1232, 1713, 2830-2930, 3050-
3150 cm-1; HRMS (FAB) m/z 238.1443, calcd for C13H20NO3
1
white needles (1.7 g, 60% yield from 11b): mp 72-73 °C; H
NMR (400 MHz, CDCl3) δ 1.08 (d, J ) 7 Hz, 3H), 1.23 (d, J )
7 Hz, 3H,), 2.93 (q, J ) 7 Hz, 1H), 3.76 (s, 1H), 4.39 (q, J ) 7
Hz, 1H), 5.33 (s, 2H), 7.37 (m, 5H); 13C NMR (125 MHz, CDCl3)
δ 8.12, 13.34, 45.50, 68.67, 79.51, 83.16, 128.83, 128.86, 129.10,
133.83, 171.65, 174.44; IR (thin film, NaCl) 1073 (s), 1143 (s),
1216 (s), 1738 (s), 1787 (s), 2900-3050 (w), 3350-3550 (m)
cm-1; HRMS (FAB) m/z 265.1076, calcd for C14H17O5 265.1075
(M+H)]; [R]20 ) +79° (c 0.75, CDCl3).
D
P r ep a r a tion of (+)-La tifolic Acid (4). To a solution of
(+)-latifolic acid benzyl ester (13b) (0.8 g, 3.03 mmol) in EtOAc
(100 mL) was added Pd/C (5wt %) (40 mg). The mixture was
vigorously stirred under an H2 atmosphere (balloon) for 3 h.
Filtration through a pad of Celite (under N2) and concentration
of the filtrate produced analytically pure (+)-latifolic acid (0.5
g, quantitative yield) as a white crystalline solid. The physical
and spectroscopic properties were in good agreement with
published values for (+)-latifolic acid: 1H NMR (500 MHz,
acetone-d6) δ 1.15 (d, J ) 7 Hz, 3H), 1.34 (d, J ) 7 Hz, 3H),
2.99 (q, J ) 7 Hz, 1H), 4.40 (q, J ) 7 Hz, 1H); 13C NMR (125
MHz, acetone-d6) δ 8.80, 13.97, 46.31, 80.27, 83.92, 172.32,
175.13; IR (thin film, NaCl plate) 1072 (s), 1141 (s), 1201 (s),
228.1443 (M+H); [R]20 ) +53.5° (c 0.77 mg/mL, CDCl3).
D
P r ep a r a tion of (+)-La tifolin e (1). A solution of (+)-
latifolic acid (35 mg, 0.2 mmol) in acetone (0.5 mL) was treated
with carbonyldiimidazole (33 mg, 0.2 mmol). After 5 min, the
solvent was evaporated under vacuum and the residue dis-
solved in chloroform (2 mL). This solution was added in four
portions, over 20 h, to a solution of 16 (47 mg, 0.2 mmol) in

Synthesis of (+)-Latifolic Acid and (+)-Latifoline
J . Org. Chem., Vol. 66, No. 21, 2001 7029
chloroform (3 mL). After the last addition, the mixture was
stirred for an additional 5 h and then diluted to 8 mL with
chloroform. The solution was washed with saturated aqueous
CuSO4, saturated NaHCO3, and brine. After the solution was
dried over 4 Å molecular sieves, the solvent was removed in
vacuo. Preparative thin-layer chromatography (silica gel,
MeOH) produced pure (+)-latifoline (35 mg, 45% yield) as a
white crystalline solid: mp 101 °C; 1H NMR (500 MHz, CDCl3)
δ 1.19 (d, J ) 7.2 Hz, 3H), 1.27 (d, J ) 6.7 Hz, 3H), 1.80
(quintet, J ) 1.6 Hz, 3H), 1.95 (dq, J ) 6.4, 1.6 Hz, 3H), 2.12
(m, 2H), 2.66-2.71 (m, 1H), 2.96 (q, J ) 1.72 Hz, 1H), 3.33-
3.4 (m, 2H), 3.95 (d, J ) 15 Hz, 1H), 4.3 (br s, 1H), 4.40 (q, J
) 6.4 Hz, 1H), 4.72 (d, J ) 14 Hz, 1H), 4.87 (d, J ) 14 Hz,
2850-2980 (m) cm-1; HRMS (FAB) m/z 394.1866, calcd for
C
20H28NO7 394.1865 (M+H); [R]D ) +54.2° (c 0.5, CDCl3).
Ack n ow led gm en t. We acknowledge the support of
this work by Bristol-Myers Squibb, Eli Lilly, Glaxo-
Wellcome, Merck, Pfizer, Yamanouchi, and Zeneca
through their Faculty Awards Programs and the Cam-
ille and Henry Dreyfus Foundation for a Teacher-
Scholar Award. We thank Dr. J . Roitman from the
USDA Agricultural Research Service for his generous
donation of natural (+)-latifoline.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedure for preparing retronecine from commercially available
1H), 5.42 (br s, 1H), 5.83 (br s, 1H), 6.08 (q, J ) 6 Hz, 1H); 13
C
1
monocrotaline, as well as copies of the H NMR spectra. This
NMR (125 MHz, CDCl3) δ 8.38, 13.53, 15.83, 20.60, 34.56,
45.52, 53.96, 63.12, 63.69, 73.68, 76.02, 79.51, 83.39, 127.56,
128.76, 131.95, 139.04, 167.02, 171.39, 174.47; IR (thin film,
NaCl plate) 1147 (s), 1231 (s), 1712 (s), 1747 (s), 1784 (s),
material is available free of charge via the Internet at
http://pubs.acs.org.
J O015741C