Total synthesis of the cytotoxic threo, trans, threo, trans, threo annonaceous acetogenin asimin and its C-10 epimer: Unambiguous confirmation of absolute stereochemistry

Article abstract of DOI:10.1021/np990132+

A convergent synthesis of asimin (1) and its C-10 epimer 33 is reported. The essential features of this synthesis include (a) the addition of an enantioenriched γ-OMOM allylic indium reagent to a core C-23 aldehyde precursor to install the C-24-C-34 segment with concomitant introduction of the C-24 and C-23 stereocenters; (b) the addition of an enantioenriched γ- OMOM allylic indium reagent to a core C-16 aldehyde to install the C-10-C-15 segment with formation of the C-15 and C-16 stereocenters, (c) the addition of a dialkyl zinc reagent, catalyzed by a Chiral triflamide-Ti(O-i-Pr)₄ complex, to introduce the C-1-C-9 segment with creation of either the 10(R) or 10(S) stereocenters; and (d) aldol condensation of the foregoing C-1-C-34 segment with OTBS-protected lactic aldehyde to incorporate the C-35-C-37 butenolide segment. Removal of the three MOM protecting groups was achieved with aqueous HCl in THF. The 10(R) diastereomer was found to correspond to natural asimin.

Full text of DOI:10.1021/np990132+

J . Nat. Prod. 1999, 62, 1123-1127
1123
Tota l Syn th esis of th e Cytotoxic Th r eo, Tr a n s, Th r eo, Tr a n s, Th r eo
An n on a ceou s Acetogen in Asim in a n d Its C-10 Ep im er : Un a m bigu ou s
Con fir m a tion of Absolu te Ster eoch em istr y
J ames A. Marshall* and Hongjian J iang
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22901
Received March 26, 1999
A convergent synthesis of asimin (1) and its C-10 epimer 33 is reported. The essential features of this
synthesis include (a) the addition of an enantioenriched γ-OMOM allylic indium reagent to a core C-23
aldehyde precursor to install the C-24-C-34 segment with concomitant introduction of the C-24 and
C-23 stereocenters; (b) the addition of an enantioenriched γ-OMOM allylic indium reagent to a core C-16
aldehyde to install the C-10-C-15 segment with formation of the C-15 and C-16 stereocenters, (c) the
addition of a dialkyl zinc reagent, catalyzed by a chiral triflamide-Ti(O-i-Pr)4 complex, to introduce the
C-1-C-9 segment with creation of either the 10(R) or 10(S) stereocenters; and (d) aldol condensation of
the foregoing C-1-C-34 segment with OTBS-protected lactic aldehyde to incorporate the C-35-C-37
butenolide segment. Removal of the three MOM protecting groups was achieved with aqueous HCl in
THF. The 10(R) diastereomer was found to correspond to natural asimin.
The Annonaceous acetogenins comprise a widespread
family of cytotoxic natural products with a remarkable
range of biological activities.1 Their novel and selective
mode of action as inhibitors of oxidative phosphorylation
offers a unique potential for these compounds as anticancer
agents.2 In fact, data from cell-culture bioassays against
human tumor cell lines reveals nearly unbelievable levels
of cytotoxicity, even against cells exhibiting multiple-drug
resistance toward current chemotherapeutic agents.3 For
this reason, and by virtue of their extremely limited
availability, these compounds have been targeted for total
synthesis by a number of research groups.4
reagent prepared by treatment of the (S)-allylic stannane
12 in situ with InCl3 yielded the adduct 13.4c The bis-
tosylate 14 gave rise to the threo, trans, threo, trans, threo
bis-tetrahydrofuran core unit 15 upon stirring with TBAF
in THF. Hydrogenation/hydrogenolysis with H2/Pd-C at
one atmosphere afforded alcohol 16, which was oxidized
to the aldehyde 17 with PCC.11
The C-1-C-9 side chain of asimin was introduced
through addition of the organozinc reagent 18 to aldehyde
17 in the presence of Ti(O-i-Pr)4 and the (S,S)-cyclohex-
anediamine bis-triflamide catalyst 19 (Scheme 2).4c,12 The
resulting adduct, alcohol 20 is presumed to be the 10R
diastereomer based on a wealth of precedent.12 Attempted
assignment of C-10 absolute configuration through analysis
of the 1H NMR spectra of the (R)- and (S)-O-methyl
mandelates was not successful owing to the absence of
diagnostic peaks.13 The MOM ether 21 was condensed with
the TBS ether of (S)-lactic aldehyde 22 to afford, after
treatment with TBAF, the γ-lactone adduct 23 as a mixture
of C35 isomers.4e,14 Exposure of the alcohol 23 to trifluo-
roacetic anhydride and triethylamine led to the butenolide
25 via the unisolated trifluoroacetate 24. Cleavage of the
MOM ethers was effected with aqueous HCl in THF. For
comparison purposes, the triol 1 was converted to the (S)-
MTPA ester 26.8 The 1H NMR spectra of triol 1 and the
(S)-ester 26 were identical to the corresponding spectra of
asimin and its (S)-MTPA ester. The authentic (R)-MTPA
ester showed several small differences in the 1H NMR
spectrum. In addition, the optical rotation of the triol 1 was
in good agreement with the reported value.5
In 1994, McLaughlin and co-workers reported the isola-
tion of three acetogenins, asimin (1), asiminacin (2), and
asiminecin (3), from the stem back of the North American
paw-paw tree, Asimina triloba Dunal,5 which they identi-
fied as structural isomers of asimicin (4), a compound
previously isolated from the same source.6 All three of the
new compounds showed extremely high potency against
human tumor cell lines. The initial report depicted asimin
as the C-10(S) isomer. However, in a subsequent paper the
stereochemistry at C-10 was shown as R.7 In that report,
it was revealed that the assignment of configuration was
based upon chemical shift differences of 0.06 Hz between
1
the protons at C-4 and C-3 in the H NMR spectra of the
tris(2-methoxy-2-trifluoromethyl-2-phenylacetate) (MTPA)
derivatives.8 In view of the rather subtle basis for this
assignment, and because of the high biological profile of
these compounds, we undertook a total synthesis of both
C-10 epimers of asimin along lines previously developed
in our laboratory.4c,9 Our synthesis started with alcohol 5,
which was converted to aldehyde 6 as previously de-
scribed.10 Addition of an allenylindium intermediate, gen-
erated in situ from the (R)-allylic stannane 7 and InCl3, to
aldehyde 6 of >95% ee afforded alcohol 8 (Scheme 1).4c This
alcohol was “protected” as the tosylate derivative 9. Upon
stirring with 5% Pd-C under an atmosphere of hydrogen,
tosylate 9 underwent hydrogenation of the double bond and
concomitant hydrogenolysis of the benzyl ether. The result-
ing alcohol 10 was oxidized with PCC11 to afford aldehyde
11 in high overall yield. Addition of the allylic indium
10(S)-Asimin (33) was prepared from aldehyde 17 by an
identical sequence, except the triflamide 27 of (R,R)-1,2-
cyclohexanediamine was used to catalyze the addition of
the alkylzinc reagent 18 to aldehyde 17 (Scheme 3). The
(S)-MTPA derivative 34 was subtly, but definitely different
from the (S)-MTPA derivative 26 of the 10R alcohol 1. In
addition, the optical rotation was significantly lower for the
10S compound ([R]D +22 for 1 and +16 for 33). Interest-
ingly, the 1H NMR spectrum of the (S)-MTPA derivative
34 was virtually identical to that of the (R)-MTPA deriva-
tive of the 10R alcohol, indicating a pseudoenantiomeric
relationship between these two derivatives. This finding
* To whom correspondence should be addressed: Tel: (804) 977-7377.
Fax: (804) 924-7993. E-mail: jam5x@virginia.edu.
10.1021/np990132+ CCC: $18.00
© 1999 American Chemical Society and American Society of Pharmacognosy
Published on Web 07/31/1999

1124 J ournal of Natural Products, 1999, Vol. 62, No. 8
Marshall and J iang
F igu r e 1. Representative members of the asimicin subgroup of Annonaceous acetogenins.
Sch em e 1
Sch em e 2
Sch em e 3

Absolute Stereochemistry of Asimin and Its C-10 Epimer
J ournal of Natural Products, 1999, Vol. 62, No. 8 1125
is not surprising considering the 1H NMR spectra of the
diastereomeric alcohols 1 and 33 are identical.
(1 H, m), 3.80 (1 H, m), 3.63 (2 H, m), 3.49 (1 H, m), 3.40 (1 H,
m), 3.35 (3 H, s), 2.43 (3 H, s), 1.80-1.15 (26 H, m), 0.86 (21
H, m), 0.04 (6 H, s), 0.02 (6 H, s); 13C NMR (CDCl3, 75 MHz)
δ 144.3, 134.3, 129.6, 127.9, 96.4, 85.8, 78.3, 77.6, 77.2, 76.6,
75.3, 75.0, 63.1, 55.7, 31.9, 31.4, 30.0, 29.6, 29.4, 29.3, 26.6,
26.3, 26.1, 25.8, 25.7, 25.6, 22.7, 21.6, 17.9, 16.9, 15.2, 14.1,
-4.1, -4.2, -4.7.
On the basis of these results, the structure assigned to
asimin (1) by McLaughlin and co-workers through analysis
1
of the MTPA ester H NMR chemical shift differences can
be taken as correct.7 A noteworthy feature of the present
synthesis is the ability to “protect” the alcohol functions of
adduct 8 as the tosylate 9 for later use in the bis-cyclization
reaction 14 f 15.
Ald eh yd e 11. To a mixture of 0.55 g (0.71 mmol) of alcohol
10 and 0.40 g of 4 Å molecular sieves in 6.0 mL of CH2Cl2 at
0 °C was added 0.50 g (2.30 mmol) of PCC. The reaction
mixture was stirred at room temperature for 1 h, diluted with
ether, and filtered through Celite. Solvent was removed under
reduced pressure, and the residue was purified by column
chromatography on Si gel (elution with 10% EtOAc in hexane)
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. NMR spectra were
determined in CDCl3 at 300 MHz (1H NMR) and 75 MHz (13C
NMR). The chemical shifts are expressed in δ values relative
to TMS. FT-IR were taken on an Impact 410 spectrometer.
Optical rotations were measured on a Perkin-Elmer 343
polarimeter. Kieselgel 60F254 plates were employed for TLC
analyses. Si gel (200-400 mesh) was used for column chro-
matography. Reagents prepared according to literature pro-
cedures are footnoted. All other reagents were obtained from
commercial sources. All reactions were performed under N2
in oven-dried flasks. Elemental analyses were carried out by
Atlantic Microlab, Inc. (Norcross, GA).
to afford 0.48 g (89%) of aldehyde 11: [R]25 +22.0 (c 0.62,
D
CHCl3); IR (film) 1728 cm-1; 1H NMR (CDCl3, 300 MHz) δ 9.77
(1 H, s), 7.79 (2 H, d, J ) 8.5 Hz), 7.31 (2 H, d, J ) 8.5 Hz),
4.68 (1 H, d, J ) 6.5 Hz), 4.59 (1 H, d, J ) 6.5 Hz), 4.47 (1 H,
m), 3.81 (1 H, m), 3.49 (1 H, m), 3.42 (1 H, m), 3.36 (3 H, s),
2.45 (2 H, m), 2.42 (3 H, s), 1.91-1.13 (24 H, m), 0.87 (21 H,
m), 0.03 (6 H, s), 0.02 (6 H, s); 13C NMR (CDCl3, 75 MHz) δ
202.3, 144.4, 134.3, 129.7, 127.9, 96.4, 85.7, 78.4, 75.2, 74.2,
55.7, 41.1, 31.9, 31.5, 29.6, 29.4, 29.3, 26.6, 26.0, 25.7, 22.6,
21.5, 17.9, 14.1, -4.1, -4.7, -4.8; anal. C 62.33%, H 10.03%,
calcd for C40H76O8SSi2, C 62.13%, H 9.91%.
Alcoh ol 8. A solution of 1.07 g (4.84 mmol) of InCl3 in 80.0
mL of EtOAc was sonicated for 20 min, and to it was added a
solution of 2.10 g (4.24 mmol) of aldehyde 64c in 2.0 mL of
EtOAc. The mixture was cooled to -78 °C, and to it was added
a solution of 3.43 g (6.81 mmol) of stannane 74c in 2.0 mL of
EtOAc. The reaction mixture was allowed to warm to room
temperature (3 h), quenched with NaHCO3, and extracted with
ether. The ether extracts were washed with brine, dried with
MgSO4, and concentrated under reduced pressure. The crude
product was purified by column chromatography on Si gel
(elution with 10% EtOAc in hexane) to afford 2.50 g (83%) of
Alcoh ol 13. The procedure for alcohol 8 was employed with
0.17 g (0.77 mmol) of InCl3, 0.59 g (0.76 mmol) of aldehyde
11, and 0.65 g (1.21 mmol) of stannane 12 in 8.0 mL of EtOAc.
The crude product was purified by column chromatography
on Si gel (elution with 15% EtOAc in hexane) to afford 0.67 g
(86%) of alcohol 13: [R]25D -7.1 (c 0.76, CHCl3); IR (film) 3510
1
cm-1; H NMR (CDCl3, 300 MHz) δ 7.78 (2 H, d, J ) 8.5 Hz),
7.32 (7 H, m), 5.74 (1 H, dt, J ) 6.5, 15.0 Hz), 5.41 (1 H, dd,
J ) 8.4, 15.4 Hz), 4.71 (1 H, d, J ) 6.9 Hz), 4.67 (1 H, d, J )
6.9 Hz), 4.57 (1 H, d, J ) 6.9 Hz), 4.55 (1 H, d, J ) 6.9 Hz),
4.50 (2 H, s), 4.47 (3 H, m), 3.92 (1 H, m), 3.78 (1 H, m), 3.61
(1 H, m), 3.49 (3 H, m), 3.41 (1 H, m), 3.37 (3 H, s), 3.35 (3 H,
s), 2.42 (3 H, s), 2.17 (2 H, m), 1.85-1.10 (28 H, m), 0.86(21
H, m), 0.02 (6 H, s), 0.00 (6 H, s); 13C NMR (CDCl3, 75 MHz)
δ 144.2, 139.5, 136.5, 134.4, 129.6, 128.3, 127.8, 127.5, 127.4,
125.7, 96.3, 93.7, 85.7, 80.5, 78.3, 75.5, 75.4, 74.0, 72.8, 69.6,
55.6, 55.4, 31.8, 31.4, 29.8, 29.5, 29.4, 29.2, 29.1, 26.6, 26.2,
25.7, 22.6, 21.5, 17.9, 14.0, -4.1, -4.2, -4.7, -4.8.
alcohol 8: [R]25 -9.7 (c 0.66, CHCl3); IR (film) 3484, 2916
D
cm-1; H NMR (CDCl3, 300 MHz) δ 7.33 (5 H, m), 5.72 (1 H,
1
dt, J ) 6.9, 15.8 Hz), 5.38 (1 H, dd, J ) 9.1, 15.8 Hz), 4.73 (1
H, d, J ) 7.3 Hz), 4.56 (1 H, d, J ) 7.3 Hz), 4.50 (2 H, s), 3.92
(1 H, m), 3.65 (1 H, m), 3.56 (2 H, m), 3.47 (2 H, t, J ) 6.6 Hz),
3.37 (3 H, s), 2.06 (2 H, m), 1.94-1.12 (20 H, m), 0.88 (21 H,
m), 0.05 (6 H, s), 0.04 (6 H, s); 13C NMR (CDCl3, 75 MHz) δ
138.7, 137.5, 128.3, 127.5, 127.4, 124.8, 93.6, 80.4, 75.8, 75.4,
74.2, 72.7, 70.7, 55.4, 32.4, 31.9, 29.9, 29.4, 29.2, 29.1, 27.1,
26.7, 26.6, 25.8, 22.6, 18.0, 14.1, -4.1, -4.6; anal. C 67.57%,
H 10.72%, calcd for C40H76O6Si2, C 67.74%, H 10.80%.
Bis-Tosyla te 14. The procedure described for tosylate 9 was
employed with 0.66 g (0.64 mmol) of alcohol 13, 0.73 g (3.8
mmol) of p-TsCl, and 1.5 mL of pyridine. The crude product
was purified by column chromatography on Si gel (elution with
10% EtOAc in hexane) to afford 0.70 g (93%) of bis-tosylate
Tosyla te 9. To a mixture of 1.00 g (1.41 mmol) of alcohol 8
in 2.0 mL of pyridine was added 1.60 g (8.4 mmol) of p-TsCl.
The reaction mixture was stirred for 12 h, quenched with H2O
and extracted with ether. The ether extracts were washed with
brine, dried over MgSO4, and concentrated under reduced
pressure. The crude product was purified by column chroma-
tography on Si gel (elution with 10% EtOAc in hexane) to
14: [R]25 -5.4 (c 0.47, CHCl3); 1H NMR (CDCl3, 300 MHz) δ
D
7.79 (4 H, d, J ) 8.5 Hz), 7.31 (9 H, m), 5.71 (1 H, dt, J ) 6.5,
15.4 Hz), 5.23 (1 H, dd, J ) 8.4, 15.5 Hz), 4.66 (1 H, d, J ) 6.7
Hz), 4.57 (1 H, d, J ) 6.7 Hz), 4.55 (1 H, d, J ) 6.7 Hz), 4.53
(2 H, m), 4.49 (2 H, s), 4.40 (1 H, d, J ) 6.7 Hz), 4.19 (1 H, m),
3.75 (1 H, m), 3.47 (2 H, t, J ) 6.1 Hz), 3.38 (2 H, m), 3.34 (3
H, s), 3.29 (3 H, s), 2.43 (3 H, s), 2.14 (2 H, m), 1.82-1.14 (28
H, m), 0.85 (21 H, m), 0.00 (12 H, m); 13C NMR (CDCl3, 75
MHz) δ 144.2, 144.1, 138.5, 136.5, 134.6, 134.5, 129.6, 129.5,
128.3, 127.8, 127.5, 127.4, 125.2, 96.3, 93.5, 85.6, 85.4, 78.4,
75.3, 75.2, 72.8, 69.5, 65.8, 55.7, 55.4, 31.9, 31.5, 29.6, 29.4,
29.3, 29.0, 28.9, 27.2, 26.6, 26.3, 25.7, 22.6, 21.6, 17.8, 15.2,
14.1, -4.1, -4.2, -4.7.
afford 1.14 g (94%) of tosylate 9: [R]25 -13.4 (c 0.50, CHCl3);
D
1H NMR (CDCl3, 300 MHz) δ 7.78 (2 H, d, J ) 8.5 Hz), 7.30 (7
H, m), 5.70 (1 H, dt, J ) 6.1, 15.2 Hz), 5.20 (1 H, dd, J ) 7.6,
15.4 Hz), 4.61 (1 H, d, J ) 6.5 Hz), 4.50 (2 H, s), 4.45 (1 H, d,
J ) 6.5 Hz), 4.44 (1 H, m), 4.25 (1 H, m), 3.43 (4 H, m), 3.32
(3 H, s), 2.38 (3 H, s), 2.00 (2 H, m), 1.87-1.15 (20 H, m), 0.85
(21 H, m), 0.03 (6 H, s), 0.00 (6 H, s); 13C NMR (CDCl3, 75
MHz) δ 144.1, 138.6, 137.3, 134.5, 129.5, 128.3, 127.9, 127.6,
127.4, 124.7, 93.6, 86.0, 77.6, 75.4, 75.0, 72.8, 70.6, 55.4, 32.3,
31.8, 29.4, 29.2, 28.9, 27.0, 26.8, 26.5, 26.4, 26.0, 25.8, 25.7,
22.6, 21.5, 17.9, 14.1, -4.1, -4,6.
Bis-THF Olefin 15. To a solution of 1.10 g (0.93 mmol) of
bis-tosylate 14 in 15.0 mL of THF was added 4.6 mL (4.6
mmol) of TBAF (1.0 M in THF). The reaction mixture was
stirred at 50 °C for 12 h, quenched with H2O, and extracted
with ether. The ether extracts were washed with brine, dried
over MgSO4, and concentrated under reduced pressure. The
crude product was purified by column chromatography on Si
gel (elution with 20% EtOAc in hexane) to afford 0.42 g (75%)
Alcoh ol 10. A mixture of 0.40 g (0.46 mmol) of tosylate 9
and 0.40 g of Pd-C (5%) in 6.0 mL of EtOAc was placed under
one atmosphere of H2 (balloon). The reaction mixture was
stirred for 12 h and filtered through Celite. Solvent was
removed under reduced pressure, and the crude product was
purified by column chromatography on Si gel (elution with 30%
of bis-THF olefin 15: [R]25 -13.3 (c 0.67, CHCl3); IR (film)
D
1
2925, 2855, 1457 cm-1; H NMR (CDCl3, 300 MHz) δ 7.34 (5
EtOAc in hexane) to afford 0.34 g (94%) of alcohol 10: [R]25
H, m), 5.70 (1 H, dt, J ) 6.9, 15.0 Hz), 5.35 (1 H, dd, J ) 8.1,
15.4 Hz), 4.82 (1 H, d, J ) 6.9 Hz), 4.68 (1 H, d, J ) 6.9 Hz),
4.66 (1 H, d, J ) 6.9 Hz), 4.58 (1 H, d, J ) 6.9 Hz), 4.49 (2 H,
s), 4.08-3.87 (6 H, m), 3.46 (2 H, t, J ) 6.5 Hz), 3.39 (3 H, s),
D
+22.0 (c 0.50, CHCl3); IR (film) 3493 cm-1; H NMR (CDCl3,
1
300 MHz) δ 7.78 (2 H, d, J ) 8.5 Hz), 7.31 (2 H, d, J ) 8.5
Hz), 4.68 (1 H, d, J ) 6.5 Hz), 4.58 (1 H, d, J ) 6.5 Hz), 4.46

1126 J ournal of Natural Products, 1999, Vol. 62, No. 8
Marshall and J iang
3.37 (3 H, s), 2.15 (2 H, m), 2.00-1.15 (28 H, m), 0.88 (3 H, t,
J ) 7.2 Hz); 13C NMR (CDCl3, 75 MHz) δ 138.4, 134.8, 128.2,
127.4, 127.0, 96.6, 93.5, 81.6, 81.3, 81.2, 81.0, 79.4, 78.5, 72.8,
69.5, 55.5, 55.1, 31.8, 37.0, 29.7, 29.5, 29.2, 29.1, 28.9, 28.2,
28.0, 27.9, 25.5, 22.6, 14.0; anal. C 71.57%, H 9.85%, calcd for
NH in 0.50 mL of THF at -78 °C was added a solution of 0.031
g (0.04 mmol) of ester 21 in 0.30 mL of THF. The reaction
mixture was stirred at -78 °C for 1 h, and to it was added a
solution of 0.016 g (0.08 mmol) of aldehyde 22 in 0.30 mL of
THF. The reaction mixture was stirred at -78 °C for 1 h,
quenched with NH4Cl, and diluted with ether. The aqueous
layer was extracted with ether, and the combined extracts
were dried over MgSO4. Solvent was removed under reduced
pressure, and to the residue was added 1.0 mL of THF followed
by 0.15 mL (0.15 mmol) of TBAF (1.0 M in THF). The reaction
mixture was stirred for 1 h, quenched with H2O, and extracted
with ether. The extracts were dried over MgSO4 and concen-
trated under reduced pressure. The crude product was purified
by column chromatography on Si gel (elution with 40% EtOAc
in hexane) to afford 0.022 g (69%) of lactone 23: IR (film) 3432,
1771 cm-1; 1H NMR (CDCl3, 300 MHz) δ 4.82 (2 H, d, J ) 6.9
Hz), 4.66 (2 H, d, J ) 6.9 Hz), 4.63 (2 H, s), 4.18 (1 H, m), 4.00
(2 H, m), 3.91 (2 H, m), 3.48 (3 H, m), 3.39 (6 H, s), 3.37 (3 H,
s), 2.56 (1 H, m), 2.00-1.14 (51 H, m,), 0.88 (3 H, t, J ) 7.2
Hz).
C
36H60O7, C 71.49%, H 10.00%.
Bis-THF Alcoh ol 16. The procedure described for alcohol
10 was employed with 0.41 g (0.68 mmol) of olefin 15 and 0.41
g of Pd-C (5%) in 5.0 mL of EtOAc. The product was purified
by column chromatography on Si gel (elution with 40% EtOAc
in hexane) to afford 0.28 g (80%) of bis-THF alcohol 16: IR
(film) 3475 cm-1; 1H NMR (CDCl3, 300 MHz) δ 4.84 (1 H, d, J
) 6.9 Hz), 4.82 (1 H, d, J ) 6.9 Hz), 4.67 (2 H, d, J ) 6.9 Hz),
4.07-3.83 (4 H, m), 3.64 (2 H, m), 3.48 (2 H, m), 3.39 (3 H, s),
3.37 (3 H, s), 2.00-1.16 (34 H, m), 0.87 (3 H, t, J ) 7.2 Hz).
Bis-THF Ald eh yd e 17. To a mixture of 0.023 g (0.04 mmol)
of alcohol 16 and 0.020 g of 4 Å molecular sieves in 1.0 mL of
CH2Cl2 at 0 °C was added 0.020 g (0.09 mmol) of PCC. The
reaction mixture was stirred at room temperature for 1 h,
quenched with ether, and filtered through Celite. Solvent was
removed under reduced pressure, and the residue was purified
by column chromatography on Si gel (elution with 25% EtOAc
in hexane) to afford 0.020 g (87%) of bis-THF aldehyde 17:
Bu ten olid e 25. To a mixture of 0.019 g (0.02 mmol) of
alcohol 23 and 0.10 mL (0.2 mmol) of Et3N in 2.0 mL of CH2-
Cl2 at 0 °C was added 0.02 mL (0.08 mmol) of (CF3CO)2O. The
reaction mixture was stirred at room temperature for 20 h,
quenched with NaHCO3, and extracted with ether. The
extracts were dried over MgSO4 and concentrated under
reduced pressure. The crude product was purified by column
chromatography on Si gel (elution with 20% EtOAc in hexane)
[R]25 +42.8 (c 0.96, CHCl3); IR (film) 1728 cm-1 1H NMR
;
D
(CDCl3, 300 MHz) δ 9.76 (1 H, s), 4.82 (1 H, d, J ) 6.9 Hz),
4.81 (1 H, d, J ) 6.9 Hz), 4.67 (1 H, d, J ) 6.9 Hz), 4.65 (1 H,
d, J ) 6.9 Hz), 4.00 (2 H, m), 3.91 (2 H, m), 3.48 (2 H, m), 3.39
(3 H, s), 3.38 (3 H, s), 2.44 (2 H, dt, J ) 1.5, 7.3 Hz), 2.00-
1.16 (32 H, m), 0.87 (3 H, t, J ) 7.2 Hz); 13C NMR (CDCl3, 75
MHz) δ 202.4, 96.7, 96.6, 81.7, 81.5, 81.3, 81.2, 81.1, 79.4, 79.2,
55.6, 43.7, 31.8, 31.1, 30.8, 29.7, 29.5, 29.2, 28.2, 25.5, 25.1,
22.6, 22.1, 14.0; anal. C 67.44%, H 10.79%, calcd for C29H54O7,
C 67.67% H 10.57%.
to afford 0.017 g (90%) of butenolide 25: IR (film) 1754 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 6.98 (1 H, s), 4.99 (1 H, m), 4.82
(2 H, d, J ) 6.9 Hz), 4.66 (2 H, d, J ) 6.9 Hz), 4.63 (2 H, s),
4.00 (2 H, m), 3.90 (2 H, m), 3.48 (3 H, m), 3.39 (6 H, s), 3.37
(3 H, s), 2.26 (2 H, t, J ) 7.5 Hz), 2.00-1.12 (46 H, m), 1.40 (3
H, d, J ) 6.9 Hz), 0.88 (3 H, t, J ) 7.2 Hz).
Hyd r oxy Ester 20. The previously described procedure4c
was employed with 0.66 g (0.13 mmol) of aldehyde 17 resulting
Asim in (1). A mixture of 0.014 g (0.02 mmol) of butenolide
25 in 1.50 mL of 6 M HCl-THF-MeOH (1:2:2) was stirred
for 12 h, quenched with H2O, and extracted with ether. The
ether extracts were dried over MgSO4 and concentrated under
reduced pressure. The crude product was purified by column
chromatography on Si gel (elution with 80% of EtOAc in
in 0.045 g (50%) of alcohol 20: [R]25 +26.7 (c 0.38, CHCl3);
D
IR (film) 3501, 1736 cm-1; H NMR (CDCl3, 300 MHz) δ 4.82
1
(1 H, d, J ) 6.9 Hz), 4.81 (1 H, d, J ) 6.9 Hz), 4.67 (2 H, d, J
) 6.9 Hz), 4.12 (2 H, q, J ) 7.0 Hz), 4.00 (2 H, m), 3.91 (2 H,
m), 3.57 (1 H, m), 3.47 (2 H, m), 3.39 (6 H, s), 2.28 (2 H, t, J
) 7.3 Hz), 2.00-1.17 (51 H, m), 0.88 (3 H, t, J ) 7.2 Hz); 13C
NMR (CDCl3, 75 MHz) δ 173.8, 96.6, 81.7, 81.6, 81.1, 79.4,
79.3, 71.7, 60.0, 55.6, 37.4, 37.3, 36.5, 34.3, 31.8, 31.1, 31.0,
30.0, 29.7, 29.5, 29.3, 29.2, 29.1, 29.0, 28.2, 25.7, 25.6, 25.5,
24.9, 22.6, 14.2, 14.0; anal. C 68.63%, H 10.94%, calcd for
hexane) to afford 0.010 g (90%) of asimin (1): [R]25 +22.0 (c
D
0.45, CHCl3), lit.5 +26.0 (c 0.10, CHCl3); IR (film) 3459, 1745
1
cm-1; H NMR (CDCl3, 300 MHz) δ 6.98 (1 H, s), 4.99 (1 H,
m), 3.86 (4 H, m), 3.58 (1 H, m), 3.39 (2 H, m), 2.26 (2 H, t, J
) 7.6 Hz), 2.12-1.07 (46 H, m), 1.40 (3 H, d, J ) 6.9 Hz), 0.87
(3 H, t, J ) 7.3 Hz); 13C NMR (CDCl3, 75 MHz) δ 173.8, 148.8,
134.3, 83.2, 83.0, 81.8, 74.1, 74.0, 71.8, 37.4, 33.4, 33.3, 31.9,
29.7, 29.6, 29.5, 29.3, 29.2, 29.1, 29.0, 28.0, 27.4, 25.7, 25.6,
25.1, 22.7, 19.2, 14.1.
C
40H76O9, C 68.53%, H 10.93%.
(R)-Ma n d ela te: 1H NMR (CDCl3, 300 MHz) δ 7.40 (5 H,
m), 4.89 (1 H, m), 4.82 (1 H, d, J ) 6.9 Hz), 4.78 (1 H, d, J )
6.9 Hz), 4.73 (1 H, s), 4.67 (1 H, d, J ) 6.9 Hz), 4.61 (1 H, d,
J ) 6.9 Hz), 4.12 (2 H, q, J ) 7.5 Hz), 3.94 (5 H, m), 3.47 (1 H,
m), 3.41 (3 H, s), 3.39 (3 H, s), 3.36 (3 H, s), 2.28 (2 H, t, J )
7.7 Hz), 2.00-1.00 (49 H, m), 0.88 (3 H, t, J ) 7.2 Hz).
(S)-Ma n d ela te: 1H NMR (CDCl3, 300 MHz) δ 7.39 (5 H,
m), 4.89 (1 H, m), 4.82 (1 H, d, J ) 6.9 Hz), 4.82 (1 H, d, J )
6.9 Hz), 4.81 (1 H, d, J ) 6.9 Hz), 4.73 (1 H, s), 4.67 (1 H, d,
J ) 6.9 Hz), 4.65 (1 H, d, J ) 6.9 Hz), 4.13 (2 H, q, J ) 7.5
Hz), 3.99 (2 H, m), 3.91 (2 H, m), 3.46 (2 H, m), 3.41 (3 H, s),
3.39 (3 H, s), 3.38 (3 H, s), 2.27 (2 H, t, J ) 7.7 Hz), 2.00-0.96
(49 H, m), 0.88 (3 H, t, J ) 7.2 Hz).
Tr i-(S)-Mosh er Ester (26). 1H NMR (CDCl3, 300 MHz)
(diagnostic peaks are italicized) δ 5.00 (4 H, m), 3.94 (2 H, m),
3.78 (2 H, m), 3.54 (6 H, s), 3.52 (3 H, s), 2.26 (2 H, t, J ) 7.7
Hz), 2.00-1.00 (46 H, m), 1.40 (3 H, d, J ) 6.5 Hz), 0.88 (3 H,
t, J ) 6.5 Hz).
Ack n ow led gm en t. This research was supported by Re-
search Grant R01 GM56769 from the Institutes of General
Medical Sciences (NIH). We are indebted to Professor J . L.
McLaughlin for supplying spectral data for asimin and its
derivatives and for a copy of relevant sections of the Ph.D.
Thesis of G.-X. Zhao.
MOM Eth er 21. To a mixture of 0.036 g (0.05 mmol) of
alcohol 20 and 0.10 mL (0.4 mmol) of i-Pr2NEt in 0.50 mL of
CH2Cl2 at 0 °C was added 0.02 mL (0.2 mmol) of MOMCl. The
reaction mixture was stirred for 12 h, quenched with H2O, and
extracted with ether. The ether extracts were washed with
brine, dried over MgSO4, and concentrated under reduced
pressure. The crude product was purified by column chroma-
tography on Si gel (elution with 20% EtOAc in hexane) to
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for all new
compounds and experimental procedures for 17-34. This information
is available free of charge on the World Wide Web at http://pubs.acs.org.
Refer en ces a n d Notes
afford 0.033 g (87%) of MOM ether 21: [R]25 +33.5 (c 0.25,
D
(1) Reviews: (a) Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He,
K.; McLaughlin, J . L. Nat. Prod. Rep. 1996, 275-306. (b) Cave´, A.;
Figade´re, B.; Laurens, A.; Cortes, D. In Progress in the Chemistry of
Organic Natural Products, Herz, W., Kirby, G.-W., Moore, R. E.,
Steglich, W., Tamm, C., Eds.; Springer: New York, 1997; Vol. 70, pp
81-288. (c) Gu, Z.-M.; Zhao, G.-X. Oberlies, N. H.; Zeng, L.;
McLaughlin, J . L. Recent Advances in Phytochemistry; Arnason, J .
T., Mata, R., Romeo, J . T., Eds.; Plenum Press: New York, 1995; Vol.
29, pp 249-310.
CHCl3); IR (film) 1728 cm-1; 1H NMR (CDCl3, 300 MHz) δ 4.82
(2 H, d, J ) 6.9 Hz), 4.66 (2 H, d, J ) 6.9 Hz), 4.64 (2 H, s),
4.12 (2 H, q, J ) 6.9 Hz), 4.00 (2 H, m), 3.91 (2 H, m), 3.48 (3
H, m), 3.39 (6 H, s), 3.37 (3 H, s), 2.28 (2 H, t, J ) 7.2 Hz),
2.00-1.15 (51 H, m), 0.88 (2 H, t, J ) 7.2 Hz).
La cton e 23. To LDA prepared from 0.07 mL (0.18 mmol)
of BuLi (2.5 M in hexane) and 0.03 mL (0.22 mmol) of i-Pr2-

Absolute Stereochemistry of Asimin and Its C-10 Epimer
J ournal of Natural Products, 1999, Vol. 62, No. 8 1127
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NP990132+