Total synthesis and structure confirmation of the annonaceous acetogenins 30(S)-hydroxybullatacin, uvarigrandin A, and 5(R)-uvarigrandin a (narumicin I?)

Article abstract of DOI:10.1021/jo0266137

A synthesis of the bistetrahydrofuran Annonaceous acetogenins 30(S)-hydroxybullatacin, uvarigrandin A, and 5(R)-uvarigrandin A through application of a previously disclosed four-component modular approach is described in which extended core segments are c

Full text of DOI:10.1021/jo0266137

Tota l Syn th esis a n d Str u ctu r e Con fir m a tion of th e An n on a ceou s
Acetogen in s 30(S)-Hyd r oxybu lla ta cin , Uva r igr a n d in A, a n d
5(R)-Uva r igr a n d in A (Na r u m icin I?)
J ames A. Marshall,*,† Arnaud Piettre,† Mikell A. Paige,† and Frederick Valeriote‡
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904,
and The J osephine Ford Cancer Center, Detroit, Michigan 48202
Received October 27, 2002
A synthesis of the bistetrahydrofuran Annonaceous acetogenins 30(S)-hydroxybullatacin, uvari-
grandin A, and 5(R)-uvarigrandin A through application of a previously disclosed four-component
modular approach is described in which extended core segments are coupled to a C4- or C5-hydroxy
butenolide terminus. The butenolide termini segments were prepared from (S)- or (R)-malic acid.
Spectral properties of synthetic 30(S)-hydroxybullatacin and uvarigrandin A, as well as their Mosher
ester derivatives, were in close agreement to the reported values for the natural substances. The
synthetic 5(R)-uvarigrandin A is possibly identical to narumicin I, but subtle differences in the
reported NMR spectra prevented an unambiguous assessment of this point.
Acetogenins of the Annonaceae have proven to be a rich
source of natural products with a wide range of bioac-
tivities.1 In particular, a bistetrahydrofuran subgroup of
this family has been found to inhibit the growth of human
tumor cells at submicromolar levels. A number of these
F IGURE 1. Generic root structure of cytotoxic bistetrahy-
drofuran Annonaceous acetogenins.
compounds are also cytotoxic to tumor cells that have
developed resistance to typical chemotherapeutic agents.2
Despite the abundance of their plant sources the
Not surprisingly, considerable effort has been devoted
Annonaceous acetogenins remain scarce because they are
to the synthesis of Annonaceous acetogenins.5-8 As few
present in minute amounts as complex mixtures of
of these lipophilic compounds are crystalline, structure
isomers that can be separated only with great difficulty.3
analysis has relied mainly upon spectroscopic methods
Important structural features of the most active antitu-
with occasional confirmation through total synthesis. We
mor compounds are depicted in Figure 1. The structures
recently disclosed a modular synthetic approach to the
feature an unbranched chain of 32 carbons attached to
structure types shown in Figure 1.9 This approach
the R-position of a γ-methyl butenolide. Embedded in the
featured highly selective additions of chiral R-oxygenated
allylic stannane and indium reagents such as B and D
(M ) SnBu3 or InBr2) to an acylic core aldehyde precursor
(A then C) followed by core ring closure (E f F ) and
central portion of this chain is a hydrophilic bistetrahy-
drofuran core moiety with two flanking hydroxyl groups.
Of the 64 possible stereoisomers of this core unit only 7
have been found in Nature.4 All of these have the (R)
configuration at C23 and the (S) configuration at C36. A
third hydroxyl group is also present in those compounds
(5) (a) Marshall, J . A.; Hinkle, K. W. J . Org. Chem. 1996, 61, 4247.
(b) Marshall, J . A.; Hinkle, K. W. J . Org. Chem. 1997, 62, 5989. (c)
with the highest activity. This group is typically located
at C4, C10, or C30 and less commonly at C5, C28, or C29.
Marshall, J . A.; Chen, M. J . Org. Chem. 1997, 62, 5996.
(6) (a) Marshall, J . A.; Hinkle, K. W. Tetrahedron Lett. 1998, 39,
1303. (b) Marshall, J . A.; J iang, H. Tetrahedron Lett. 1998, 39, 1493.
(c) Marshall, J . A.; J iang, H. J . Org. Chem. 1998, 63, 7066. (d) Marshall,
J . A.; J iang, H. J . Org. Chem. 1999, 64, 971. (e) Marshall, J . A.; J iang,
H. J . Nat. Prod. 1999, 62, 1123.
† University of Virginia.
‡ The J osephine Ford Cancer Center.
(1) (a) Gu, Z.-M.; Zhao, G.-X.; Oberlies, N. H.; Zeng, L.; McLaughlin,
J . L. In Recent Advances in Phytochemistry; Arnason, J . T., Mata, R.,
Romeo, J . T., Eds.; Plenum Press: New York, 1995; Vol. 29, pp 249-
310. (b) Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He, K.;
McLaughlin, J . L. Nat. Prod. Rep. 1996, 275. (c) Cave´, A.; Figade´re,
B.; Laurens, A.; Cortes, D. In Progress in the Chemistry of Natural
Products; Herz, W., Kirby, G. W., Moore, R. E., Steglish, W., Tamm,
C., Eds.; Springer-Verlag Chemistry: New York, 1997; pp 81-287.
(2) (a) Oberlies, N. H.; Croy, V. L.; Harrison, M. L.; McLaughlin, J .
L. Cancer Lett. 1997, 115, 73. (b) Oberlies, N. H.; Chang, C.-J .;
McLaughlin, J . L. J . Med. Chem. 1997, 40, 2102.
(3) Zhao, G.-X.; Miesbauer, L. R.; Smith, D. L.; McLaughlin, J . L.
J . Med. Chem. 1994, 37, 1971.
(4) (a) Rupprecht, J . K.; Hui, Y. H.; Mclaughlin, J . L. J . Nat. Prod.
1990, 53, 237. (b) Alzli, F. Q.; Liu, X.-X.; McLaughlin, J . L. J . Nat.
Prod. 1999, 62, 504.
(7) Reviews: (a) Figade´re, B. Acc. Chem. Res. 1995, 28, 359. (b)
Hoppe R.; Scharf, H.-D. Synthesis 1995, 1447. (c) Marshall, J . A.;
Hinkle, K. W.; Hagedorn, C. E. Isr. J . Chem. 1997, 37, 97. (d) Casiraghi,
G.; Zanardi, F.; Battistina, L.; Rassu, G.; Appendino, G. Chemtracts:
Org. Chem. 1998, 11, 803.
(8) (a) Hoye, T. R.; Hanson, P. R.; Kovelesky, A. C.; Ocain, T. D.;
Zhuang, Z. J . Am. Chem. Soc. 1991, 113, 9369. (b) Naito, H.; Kawahara,
E.; Maruta, K.; Naeda, M.; Sasaki, S. J . Org. Chem. 1995, 60, 4419.
(c). Sinha, S.; Sinha, A.; Yazbak, A.; Keinan, E. J . Org. Chem. 1996,
61, 7640. (d) Hoye, T. R.; Ye, Z. J . Am. Chem. Soc. 1996, 118, 1801. (e)
Sinha, S. C.; Sinha, A.; Keinan, E. J . Am. Chem. Soc. 1997, 119, 12014
and references therein. (f) Emde, U.; Koert, U. Tetrahedron Lett. 1999,
40, 5979. (g) Avedission, H.; Sinha, S. C.; Yazbek, A.; Sinha, A.; Neogi,
P.; Sinha, S. C.; Keinan, E. J . Org. Chem. 2000, 65, 6035.
(9) Marshall, J . A.; Piettre, A.; Paige, M. A.; Valeriote, F. J . Org.
Chem. 2003, 68, 1771.
10.1021/jo0266137 CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/08/2003
1780
J . Org. Chem. 2003, 68, 1780-1785

Structure Confirmation of Annonaceous Acetogenins
SCHEME 1 a
a
(a) p-TsNHNH2, NaOAc (66%); (b) BF3‚OEt2, Me2S (74%).
former two were identified as the 32(S) and 31(S)
isomers, respectively, whereas the latter was isolated as
an inseparable 4:1 mixture of (S) and (R) isomers at C30
(see Figure 3). The assignment of the 30(S) configuration
to the major component of this mixture was based on
differences in the chemical shifts of the terminal CH3
signals of the tetra MTPA Mosher ester mixtures (∆ δH
) 0.06 ppm).10,11
F IGURE 2. Modular synthetic approach to bistetrahydrofu-
ran Annonaceous acetogenins.
In our initial application of the aforementioned four-
component modular approach to Annonaceous acetoge-
nins, we prepared a 30(S)-hydroxylated bistetrahydro-
furan, bullanin (Figure 3), from the enyne 1, corresponding
to F in our general approach (Figure 2). The 4(R)-
hydroxylated butenolide segment 2, corresponding to G,
was also prepared and utilized in a synthesis of asimicin
(Figure 3). These two intermediates represent the es-
sential structural features assigned to 30(S)-hydroxybul-
latacin (Figure 3). Accordingly a total synthesis of this
acetogenin would only require coupling of the two seg-
ments followed by hydrogenation and deprotection. In
fact, the union of enyne 1 with the butenolide terminus
2 proceeded efficiently under standard Sonogashira
conditions to afford the dienyne 3 in 69% yield (Scheme
1). As in our previous applications,6 selective hydrogena-
tion of the dienyne function was achieved with diimide
to afford the octahydro product 4. Hydrolysis of the MOM
F IGURE 3. Structures of C4, C5, and C30 hydroxylated
bistetrahydrofuran Annonaceous acetogenins.
ensuing Sonogashira coupling (F + G f H) to append
the butenolide segment (Figure 2). This straightforward
strategy permits the efficient assemblage of the aceto-
genin structure from four basic subunits. By interchang-
ing these subunits a variety of natural acetogenins and
their isomers should be accessible in relatively few steps.
Our initial application of this strategy resulted in
syntheses of the C10 and C4 hydroxylated acetogenins
asimin and asimicin and the two C30 hydroxylated core
isomers asiminocin and bullanin (Figure 3). We now
describe an application of this strategy to the novel C5
hydroxylated acetogenins uvarigrandin A and 5(R)-
uvarigrandin A (narumicin I?) and a C4, C30 tetrahy-
droxy acetogenin, 30(S)-hydroxybullatacin.
1
ethers was effected with Me2S and BF3 etherate. The H
and 13C NMR spectra of the tetraol product 5 were in
complete accord with the reported spectra. As an ad-
ditional confirmation of structure and stereochemistry,
the tetra (S)-MTPA ester 6 was prepared.11 The 1H NMR
spectrum of this derivative closely matched the reported
spectrum of the 30(S) isomer. The foregoing synthesis
therefore confirms the assigned structure and stereo-
chemistry of the natural material.
In 1991, Hisham et. al reported studies on the isolation
and structure assignment of two C5 hydroxylated bistet-
rahydrofuran acetogenins, narumicin I and narumicin II
(Figure 3).12 Though inseparable, the two were postulated
as threo, trans, threo, trans, threo and threo, trans, threo,
trans, erythro core stereoisomers on the basis of differ-
McLaughlin and co-workers isolated the novel tetrahy-
droxy threo, trans, threo, trans, erythro (C15 f C24)
bistetrahydrofuran acetogenins 32-hydroxybullatacin, 31-
hydroxybullatacin, and 30-hydroxybullatacin from etha-
nolic extracts of bark from Annona bullata Rich.10 The
(11) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512.
(12) Hisham, A.; Pieters, L. A. C.; Claeys, M.; Van Den Heuvel, H.;
Esmons, E.; Domisse, R.; Vlietinck, A. J . Phytochemistry 1991, 30,
2373.
(10) Gu, Z.-M.; Zeng, L.; Schwedler, J . T.; Wood, K. V.; McLaughlin,
J . L. Phytochemistry 1995, 40, 467.
J . Org. Chem, Vol. 68, No. 5, 2003 1781

Marshall et al.
1
ences in the H and 13C NMR spectra in comparison to
SCHEME 2 a
related known acetogenins such as asimicin and bullanin.
Subsequently Raynaud and co-workers isolated the same
mixture from a different plant source and were able to
separate the two isomeric narumicins by preparative
HPLC.13 They confirmed the assigned core stereochem-
istry, but the relative stereochemistry at C5 and C36
remained undefined along with the absolute stereochem-
istry.
A third C5 hydroxylated bistetrahydrofuran acetoge-
nin, uvarigrandin A, was described in 1997 by Pan and
Yu.14 Through application of Mosher MTPA 1H NMR
analysis, these investigators were able to assign the
relative and absolute stereochemistry as 5(S), 24(S)
threo, trans, threo, trans, threo (Figure 3).
To date C5 hydroxylated acetogenins have received
scant attention. No synthesis has been reported and no
studies on the cytotoxicity of these bistetrahydrofuran
compounds have appeared. For these reasons we decided
to extend our four-component strategy to uvarigrandin
A and its C5(R) epimer. This latter substance could
conceivably be identical to narumicin I. We were also
interested in evaluating the activity of these compounds
against human tumor cells. The antitumor activity of C5
hydroxylated acetogenins has not previously been re-
ported.
a
(a) TBSCl, DMF, Im (93%); (b) DIBAL-H, hexanes, -78 °C
(85%); (c) I2, PPh3, Im, Et2O-MeCN (90%); (d) White’s lactone,
LDA, then iodide 11, THF-HMPA (79%); (e) m-CPBA, then
toluene, reflux (84%); (f) HF‚pyr, THF, 0 °C (75%); (g) Dess-
Martin periodinane, CH2Cl2; (h) CrCl2, CHI3,THF-dioxane (40%,
2-steps); (i) HF‚pyr, THF (92%).
SCHEME 3 a
As part of our earlier studies we prepared the threo,
trans, threo, trans, threo core unit 18. This was coupled
to the C4 hydroxylated butenolide segment 2 to yield a
precursor of asimicin (Figure 3).9 An application of this
strategy to the aforementioned C5 hydroxylated isomers
would require the previously unknown C5 hydroxylated
butenolide segments corresponding to 17 and the C5
diastereoisomer. These were prepared from the two
enantiomers of ester diol 8, which are easily obtained
through selective reduction of (R)- or (S)-dimethyl malate
(Scheme 2).15 The use of these starting materials was
particularly appropriate as we had previously employed
acetonide derivative 7 of diol 8 in our synthesis of the
butenolide segment 2 of asimicin. For the present ap-
plication the bis-TBS ether 9 was reduced to the alcohol
10 and converted to iodide 11, which reacted with the
enolate of “White’s lactone” to afford lactone 12.16 Oxida-
tion to the sulfoxide derivative and thermal elimination
led to butenolide 13, which was selectively desilylated
to the primary alcohol 14. Takai olefination17 of aldehyde
15 afforded the vinyl iodide 16, which was desilylated to
the C5 hydroxy segment 17.
a
(a) TsNHNH2, NaOAc, DME (94%); (b) HCl, THF-MeOH
(86%).
with the reported spectrum of uvarigrandin A. Of equal
importance, the H NMR spectrum of the tri-(R) Mosher
1
ester derivative 22 compared favorably with the reported
spectrum. The most notable comparison features of this
spectrum were diagnostic signals for hydrogens at C3,
C35, C36, and C37 (see Supporting Information).
The C5 epimer, 5(R)-uvarigrandin A (26), of uvari-
grandin A was prepared by a parallel sequence starting
from the bistetrahydrofuran core unit 18 and the buteno-
lide segment 23 (Scheme 4). The latter compound was
synthesized as outlined in Scheme 2 by employing the
Coupling of the bistetrahydrofuran segment 189 and
the hydroxy butenolide 17 by the Sonogashira protocol
proceeded uneventfully to afford the dienyne 19. Selective
reduction with diimide, as previously described, afforded
the bis-MOM-protected acetogenin 20. Hydrolysis of the
MOM ethers was effected with aqueous HCl in metha-
nolic THF to complete the synthesis. The 1H NMR
spectrum of our synthetic triol 21 was in close agreement
1
enantiomer of diol 8. As expected the H NMR spectrum
of triol 26 and the (R)-Mosher triester derivative 27 were
clearly different from those of uvarigrandin A. As noted
above, Raynaud and co-workers suggested that narumi-
cin I is a C5 hydroxylated C37 threo, trans, threo, trans,
threo bistetrahydrofuran acetogenin of unknown config-
uration at C5. Our synthesis confirms the identity of the
5(S) isomer as uvarigrandin A. It can therefore be
concluded than narumicin I must be the 5(R) isomer. We
(13) Raynaud, S.; Fourneau, C.; Hocquemiller, R.; Se´venet, T.; Hadi,
H. A.; Cave´, A. Phytochemistry 1997, 46, 321.
(14) Pan, X. P.; Yu, D. Q. Acta Pharm. Sin. 1997, 32, 286.
(15) Saito, S.; Hasegawa, T.; Inaba, M.; Nishida, R.; Fujii, T.;
Nomizu, S.; Moriwake, T. Chem. Lett. 1984, 1389.
(16) White, J . D.; Somers, T. C.; Reddy, G. N. J . Org. Chem. 1992,
57, 4991.
(17) Takai, K.; Nitta, K.; Utimoto, K. J . Am. Chem. Soc. 1986, 108,
7408.
1782 J . Org. Chem., Vol. 68, No. 5, 2003

Structure Confirmation of Annonaceous Acetogenins
SCHEME 4 a
that will lead to acetogenin structures with no natural
counterparts for systematic structure-activity correla-
tions. Applications along these lines will be reported in
due course.
Exp er im en ta l Section
Meth yl (R)-3,4-Bis(ter t-bu tyldim eth ylsilyloxy)bu tan oate
(9). A solution of diol 8 (4.11 g, 30.6 mmol), TBSCl (13.8 g,
91.5 mmol), and imidazole (12.5 g, 184 mmol) in DMF (60 mL)
was stirred for 15 h and then diluted with ether. The organic
layer was then washed with saturated aqueous NaHCO3,
water, and brine, dried over Na2SO4, filtered, concentrated
under reduced pressure, and chromatographed (ether-petro-
leum ether 1:19) to afford bis-silyl ether 9 (10.4 g, 93%). [R]D
27.3 (c 0.84, CHCl3); IR (film) 1747 cm-1; 1H NMR (300 MHz,
CDCl3) δ 4.15 (1H, m), 3.67 (3H, s), 3.60 (1H, ddd, J ) 9.9,
5.1, 1.2 Hz), 3.44-3.37 (1H, m), 2.65 (1H, ddd, J ) 14.7, 4.5,
1.5 Hz), 2.37 (1H, ddd, J ) 14.8, 8.4, 1.2 Hz), 0.92-0.85 (18H,
m), 0.08-0.05 (12H, m); 13C NMR (75 MHz, CDCl3) δ 172.3,
70.3, 66.9, 51.4, 40.0, 25.9, 25.7, 18.3, 18.0, -4.5, -5.1, -5.4,
-5.4. Anal. Calcd for C17H38O4Si2: C, 56.30; H, 10.56. Found:
C, 56.58; H, 10.64.
a
(a) TsNHNH2, NaOAc, DME; (b) HCl, THF-MeOH (57%, 2
steps).
TABLE 1. Cytotoxicity of An n on a ceou s Acetogen in s
tow a r d H-116 Colon Ca n cer Cells
(R)-3,4-Bis(ter t-bu tyld im eth ylsilyloxy)bu ta n -1-ol (10).
To a stirred solution of ester 9 (10.4 g, 28.7 mmol) in 68 mL of
hexanes, cooled to -78 °C, was added DIBAL-H (72 mL, 1 M
solution in hexanes) over a 40-min period by means of a
syringe pump. Stirring was continued for 30 min, and then
the reaction mixture was poured into 290 mL of saturated
aqueous Rochelle’s salt solution and vigorously stirred at room
temperature overnight. The two layers were separated. The
aqueous layer was extracted with ether, and the combined
organic extracts were washed with brine, dried over Na2SO4,
filtered, concentrated under reduced pressure, and chromato-
graphed (ether-petroleum ether 1:19, 1:9 then 1:5) to afford
alcohol 10 (8.14 g, 85%). [R]D 16.8 (c 0.88, CHCl3); IR (film)
compound
IC50 (g/mL)
IC90 (g/mL)
(30S)-hydroxybullatacina
uvarigrandin Aa
2 × 10-4
2 × 10-1
1.5 × 10-2
3 × 10-1
1.5
2 × 10-4
(5R)-uvarigrandin Aa
5-fluorouracilb
2.5 × 10-4
1.5 × 10-1
a
b
1 g/mL ≈ 1.5 M. 1 g/mL ≈ 7 M.
were unable to obtain spectra of narumicin I or the MTPA
derivative for comparison with our synthetic 26. While
the tabulated 13C NMR data of the two are quite similar,
slight chemical shift differences at 14.0 vs 14.1, 22.6 vs
22.7, 29.3 vs 29.5, 31.9 vs 31.8, 37.5 vs 37.4, 70.8 vs 70.7,
81.8, vs 81.7, 133.9 vs 134.0, 149.5 vs 149.4, and 176.7
vs 174.1 prevents an unequivocal opinion regarding their
identity. An additional 13 peaks showed exact cor-
respondence between the two samples (less than 37 peaks
are observed owing to overlap of two or more signals; see
Supporting Information for a tabulation). Lacking copies
1
3381 cm-1; H NMR (300 MHz, CDCl3) δ 3.90 (1H, m), 3.83-
3.69 (2H, m), 3.62 (1H, ddd, J ) 9.9, 4.8, 1.5 Hz), 3.52 (1H,
ddd, J ) 9.8, 7.5, 1.2 Hz), 2.70 (1H, t, J ) 5.7 Hz), 1.96-1.83
(1H, m), 1.82-1.69 (1H, m), 0.90 (18H, m), 0.12-0.05 (12H,
m); 13C NMR (75 MHz, CDCl3) δ 72.2, 66.9, 59.7, 36.8, 25.9,
25.8, 18.3, 18.0, -4.5, -5.0, -5.5.
(R)-1,2-Bis(ter t-b u t yld im et h ylsilyloxy)-4-iod ob u t a n e
(11). To a solution of alcohol 10 (3.63 g, 10.8 mmol) in 56 mL
of a 3:1 mixture of ether-CH3CN, cooled to 0 °C, was
successively added PPh3 (3.13 g, 11.9 mmol), imidazole (809
mg, 11.9 mmol), and iodine (3.01 g, 11.9 mmol) by portions.
The reaction mixture was stirred for 1 h 15 min, quenched by
addition of 50 mL of saturated aqueous NaHCO3, and ex-
tracted with ether. The combined organic extracts were washed
with 10% Na2S2O3 and water, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was
triturated with hexanes and filtered to remove Ph3P(O). After
removal of the solvent under reduced pressure, the resulting
1
of the actual H and 13C spectra of narumicin I for peak
height and pattern comparison, we are unable to render
a valid opinion regarding its identity with our 5(R)-
uvarigrandin A (26).
Samples of the three synthesized bistetrahydrofuran
acetogenins were evaluated for cytotoxicity against H-116
human colon cancer cells (Table 1). 5-Fluorouracil, a
current colon cancer drug was also tested against these
tumor cells for comparison.18 The IC50 and IC90 values
for the three acetogenins were comparable to those
previously found for asimicin and asimin and were
considerably lower than those of 5-fluorouracil.
The present investigations extend the scope of our
modular four-component synthesis of Annonaceous ac-
etogenins to C4,C30-dihydroxylated and C5-hydroxylated
bistetrahydrofurans. As illustrated, the approach makes
possible the construction of a variety of stereo and
“remote” hydroxyl isomers in only a few steps through
use of a few common, well-defined segments. Although
not specifically addressed in the present work, combina-
tions of existing or easily prepared segments can be made
product was purified by column chromatography with
a
gradient of hexanes to 97:3 hexanes-Et2O to afford iodide 11
1
(4.30 g, 90%). [R]D 30.8 (c 0.77, CHCl3); H NMR (300 MHz,
CDCl3) δ 3.73 (1H, m), 3.58 (1H, ddd, J ) 9.9, 5.1, 1.2 Hz),
3.42 (1H, ddd, J ) 9.9, 6.6, 1.2 Hz), 3.35-3.17 (2H, m), 2.23-
2.08 (1H, m), 1.94 (1H, m), 0.90 (18H, m), 0.12 (3H, s), 0.09
(3H, s), 0.06 (6H, s); 13C NMR (75 MHz, CDCl3) δ 72.9, 66.8,
38.7, 25.9, 25.9, 18.3, 18.1, 3.0, -4.2, -4.6, -5.3, -5.4. Anal.
Calcd for C16H37IO2Si2: C, 43.23; H, 8.39. Found: C, 43.61;
H, 8.45.
La cton e 12. To a stirred solution of diisopropylamine (1.2
mL, 8.56 mmol) in anhydrous THF (14 mL), cooled to -78°C,
was added dropwise BuLi (3.65 mL, 8.03 mmol). After 20 min,
a solution of “White’s lactone” (1.67 g, 8.03 mmol) in 8.6 mL
of THF was added dropwise. The dry ice-acetone bath was
replaced by an ice bath. After 15 min, a solution of iodide 11
(4.27 g, 9.62 mmol) in 8.6 mL of a 5:1 mixture of THF-HMPA
was added. The reaction mixture was slowly allowed to warm
(18) Blumberg, D.; Ramananthan, R. K. J . Clin. Gastroenterol. 2002,
34, 15.
J . Org. Chem, Vol. 68, No. 5, 2003 1783

Marshall et al.
to room temperature, stirred for 16 h, diluted with ether,
washed with saturated aqueous NH4Cl, 10% Na2S2O3, water,
and brine, dried over Na2SO4, filtered, concentrated under
reduced pressure, and chromatographed (ether-petroleum
ether 1:19 then 1:9) to afford lactone 12 (3.35 g, 79%) as a
95:5 mixture of diastereoisomers. Major isomer: IR (film) 1771
cm-1; 1H NMR (500 MHz, CDCl3) δ 7.60-7.51 (2H, m), 7.43-
7.29 (3H, m), 4.56-4.42 (1H, m), 3.62 (1H, m), 3.56-3.48 (1H,
m), 3.40-3.31 (1H, m), 2.49 (1H, ddd, J ) 23.2, 12.5, 3.0 Hz),
2.03-1.91 (2H, m), 1.91-1.84 (1H, m), 1.84-1.72 (1H, m),
1.53-1.41 (1H, m), 1.23 (3H, dd, J ) 10.5, 3.5 Hz), 0.93-0.82
(18H, m), 0.07-0.00 (12H, m). Anal. Calcd for C27H48O4SSi2:
C, 61.78; H, 9.22. Found: C, 61.70; H, 9.32.
Vin yl Iod id e 16. To a suspension of CrCl2 (1.09 g, 8.87
mmol) in 4 mL of anhydrous THF was added a solution of the
preceding aldehyde 15 and recrystallized iodoform (986 mg,
2.50 mmol) in 22 mL of dioxane, over a 1-h period by means
of a syringe pump. The reaction mixture was stirred for 16 h
and then quenched by successive addition of 10 mL of Et2O
and 20 mL of water. The two layers were separated. The
aqueous layer was saturated with solid NaCl and extracted
with Et2O. The combined organic extracts were washed with
brine, dried over Na2SO4, filtered, concentrated under reduced
pressure, and chromatographed (ether-petroleum ether 1:19
then 1:3) to afford 211 mg of vinyl iodide 16 (40% for the last
1
two steps). [R]D 41.8 (c 0.95, CHCl3); IR (film) 1754 cm-1; H
NMR (300 MHz, CDCl3) δ 6.98 (1H, d, J ) 1.8 Hz), 6.51 (1H,
ddd, J ) 14.4, 6.0, 2.1 Hz), 6.26 (1H, ddd, J ) 14.5, 2.1, 1.2
Hz), 5.05-4.93 (1H, m), 4.15 (1H, m), 2.41-2.20 (2H, m), 1.79-
1.68 (2H, m), 1.40 (3H, dd, J ) 6.6, 1.8 Hz), 0.88 (9H, s), 0.07-
0.01 (6H, m); 13C NMR (75 MHz, CDCl3) δ 173.5, 149.0, 148.3,
133.8, 77.4, 76.5, 74.4, 34.9, 25.8, 20.7, 19.1, 18.1, -4.6, -4.9.
Bu ten olid e 13. To sulfide 12 (3.34 g, 6.36 mmol) in 32 mL
of anhydrous CH2Cl2 at 0 °C was added portionwise m-CPBA
(1.10 g, 6.37 mmol). After 50 min, an additional amount of
m-CPBA (198 mg, 1.15 mmol) was added. Stirring was
continued for 15 min, and then the reaction mixture was
quenched by addition of 56 mL of a 1:1 mixture of saturated
aqueous NaHCO3 and saturated aqueous Na2S2O3, slowly
allowed to warm to room temperature, stirred for 1 h 45 min,
and extracted with CH2Cl2. The combined organic extracts
were washed with brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure to give 3.50 g of crude
sulfoxide as a thick colorless foam. The crude sulfoxide was
then refluxed in 80 mL of toluene for 1 h. After removal of the
solvent under reduced pressure, the crude product was chro-
matographed (ether-petroleum ether 1:19, 1:9 then 1:5) to
afford butenolide 13 (2.23 g, 84%) contaminated with a small
amount of PhSOH. [R]D 30.5 (c 0.72, CHCl3); IR (film) 1766,
Alcoh ol 17. To a solution of silyl ether 16 (94 mg, 0.224
mmol) in 8.7 mL of anhydrous THF in a Nalgene reaction
vessel was added 0.81 mL of HF-pyridine solution. The
reaction mixture was stirred for 19 h, carefully poured into
80 mL of saturated aqueous NaHCO3, and extracted with
EtOAc. The combined organic extracts were washed with
saturated aqueous CuSO4, water, and brine, dried over Na2-
SO4, filtered, concentrated under reduced pressure, and chro-
matographed (ether-petroleum ether 3:1) to afford alcohol 17
(63 mg, 92%). [R]D 31.6 (c 0.64, CHCl3); IR (film) 3418, 1740
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.06 (1H, d, J ) 1.2 Hz),
1
1656 cm-1; H NMR (500 MHz, CDCl3) δ 6.99 (1H, q, J ) 1.5
6.57 (1H, dd, J ) 14.5, 6.0 Hz), 6.39 (1H, dd, J ) 14.7, 1.2
Hz), 5.07-4.97 (1H, m), 4.13 (1H, m), 2.62 (1H, d, J ) 4.2 Hz),
Hz), 4.99 (1H, m), 3.71 (1H, m), 3.56 (1H, dd, J ) 10.0, 5.5
Hz), 3.42 (1H, dd, J ) 10.2, 6.5 Hz), 2.46-2.23 (2H, m), 1.89-
1.81 (1H, m), 1.68-1.60 (1H, m), 1.41 (3H, d, J ) 6.5 Hz), 0.89
2.49-2.29 (2H, m), 1.78 (2H, m), 1.41 (3H, d, J ) 6.9 Hz); 13
C
NMR (75 MHz, CDCl3) δ 174.0, 150.0, 147.8, 133.3, 77.7, 73.4,
(9H, s), 0.89 (9H, s), 0.06 (6H, s), 0.05 (3H, s), 0.05 (3H, s); 13
C
34.2, 20.9, 19.0.
NMR (125 MHz, CDCl3) δ 173.5, 148.6, 134.2, 77.3, 72.2, 66.9,
31.7, 25.8, 25.7, 25.6, 20.7, 19.0, 18.2, 17.9, -4.4, -4.9, -5.5,
-5.5.
En yn e 24. To a solution of vinyl iodide 23 (41 mg, 0.135
mmol), Pd(PPh3)2Cl2 (9.9 mg, 0.014 mmol), and CuI (7.9 mg,
0.041 mmol) in 2.6 mL of Et3N, stirred at room temperature
for 30 min, was added dropwise a solution of alkyne 18 (78
mg, 0.149 mmol) in 2.0 mL of Et3N. After 3.5 h, the reaction
mixture was concentrated under reduced pressure, and the
resultant brown residue was purified by column chromatog-
raphy (silica gel treated with 2.5% of Et3N, ether-petroleum
ether 1:5, 1:2, 4:1 then ether) to afford enyne 24 (83 mg, 87%).
[R]D -1.2 (c 0.80, CHCl3); IR (film) 3456, 1758 cm-1; 1H NMR
(500 MHz, CDCl3) δ 7.03 (1H, d, J ) 1.5 Hz), 6.03 (1H, dd, J
) 16.0, 6.0 Hz), 5.73-5.64 (2H, m), 5.38 (1H, dd, J ) 16.0, 8.0
Hz), 5.01 (1H, m), 4.81 (1H, d, J ) 6.5 Hz), 4.69 (1H, d, J )
6.0 Hz), 4.66 (1H, d, J ) 6.5 Hz), 4.58 (1H, d, J ) 6.5 Hz),
4.16 (1H, m), 4.02 (1H, m), 4.01-3.96 (1H, m), 3.93 (3H, m),
3.46 (1H, m), 3.38 (3H, s), 3.37 (3H, s), 2.46-2.33 (2H, m), 2.29
(2H, td, J ) 7.0, 2.0 Hz), 2.16 (2H, q, J ) 7.0 Hz), 2.11 (1H, d,
J ) 4.0 Hz), 1.92 (4H, m), 1.84-1.57 (9H, m), 1.53-1.38 (6H,
m), 1.40 (3H, d, J ) 6.5 Hz), 1.38-1.21 (16H, m), 0.87 (3H, t,
J ) 7.0 Hz); 13C NMR (75 MHz, CDCl3) δ 173.8, 149.5, 143.4,
134.3, 133.5, 127.5, 110.8, 96.6, 93.6, 90.9, 81.6, 81.4, 81.3, 81.1,
79.5, 78.5, 77.5, 71.1, 55.6, 55.1, 34.6, 31.8, 31.3, 31.1, 29.7,
29.5, 29.2, 28.2, 28.1, 28.0, 27.0, 25.5, 22.6, 21.1, 19.0, 18.7,
14.0. Anal. Calcd for C41H66O9: C, 70.05; H, 9.46. Found: C,
69.96; H, 9.53.
5(R)-Uva r igr a n d in A (26). To a refluxing solution of enyne
24 (75 mg, 0.107 mmol) and p-toluenesulfonylhydrazide (1.34
g, 7.19 mmol) in 16 mL of DME was added a solution of sodium
acetate (729 mg, 8.87 mmol) in 20 mL of water over a 4-h
period via a syringe pump. After cooling to room temperature,
the reaction mixture was poured into water and extracted with
EtOAc. The combined organic extracts were washed with
water and brine, dried over Na2SO4, filtered, concentrated
under reduced pressure, and purified by column chromatog-
raphy (ether-petroleum ether 1:1, 4:1 then ether) to afford
59 mg of 5(R)-uvarigrandin A MOM ether (25) contaminated
by some residual tosyl hydrazide.
Alcoh ol 14. To a solution of bis-silyl ether 13 (157 mg, 0.379
mmol) in 3.8 mL of anhydrous THF at 0 °C in a Nalgene
reaction vessel was added 40 µL of HF-pyridine solution. The
reaction mixture was stirred for 7 h, quenched by addition of
4 mL of saturated aqueous NaHCO3, diluted with EtOAc,
washed with water, saturated aqueous CuSO4, and brine, dried
over Na2SO4, filtered, concentrated under reduced pressure,
and chromatographed (ether-petroleum ether 1:9 then 3:1)
to afford 71 mg of alcohol 14 (62% yield, 75% based on
recovered starting material). [R]D 16.8 (c 0.88, CHCl3); IR (film)
3457, 1748, 1650 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.01 (1H,
q, J ) 1.5 Hz), 5.00 (1H, m), 3.79 (1H, m), 3.63-3.56 (1H, m),
3.54-3.46 (1H, m), 2.42-2.20 (2H, m), 1.90 (1H, bs), 1.82-
1.73 (2H, m), 1.40 (3H, d, J ) 6.6 Hz), 0.90 (9H, s), 0.09 (6H,
s); 13C NMR (75 MHz, CDCl3) δ 173.6, 149.0, 133.8, 77.5, 72.0,
65.9, 31.4, 25.7, 21.1, 19.1, 18.0, -4.6, -4.6. Anal. Calcd for
C
15H28O4Si: C, 59.96; H, 9.39. Found: C, 59.81; H, 9.53.
Ald eh yd e 15. To a solution of alcohol 14 (376 mg, 1.25
mmol) in 20 mL of anhydrous CH2Cl2 at 0 °C was added Dess-
Martin periodinane (586 mg, 1.38 mmol), and the reaction
mixture was allowed to warm to room temperature. After
stirring for 3, 3.5, and 4 h, 300, 618, and 308 mg of Dess-
Martin periodinane were added, respectively, until the reaction
was judged complete by TLC. The reaction mixture was then
quenched by addition of saturated aqueous Na2S2O3, stirred
until a clear solution was obtained, and extracted with CH2-
Cl2. The combined organic extracts were washed with brine,
dried over Na2SO4, filtered, and concentrated under reduced
pressure to give 412 mg of crude aldehyde 15, which was used
without further purification. IR (film) 3086, 2717, 1759, 1653
1
cm-1; H NMR (300 MHz, CDCl3) δ 9.63 (1H, d, J ) 1.5 Hz),
7.03 (1H, q, J ) 1.5 Hz), 5.01 (1H, qd, J ) 7.8, 1.5 Hz), 4.04
(1H, m), 2.39 (2H, td, J ) 8.4, 1.2 Hz), 2.03-1.83 (2H, m), 1.41
(3H, d, J ) 6.9 Hz), 0.98-0.85 (9H, m), 0.14-0.04 (6H, m).
1784 J . Org. Chem., Vol. 68, No. 5, 2003

Structure Confirmation of Annonaceous Acetogenins
The preceding bis-MOM ether 25 was stirred at room
temperature for 12 h in 10.5 mL of a mixture of 6 M HCl-
THF-MeOH (1:2:2), poured into 60 mL of water, and extracted
with EtOAc. The combined organic extracts were washed with
brine, dried over Na2SO4, filtered, concentrated under reduced
pressure, and purified by column chromatography (EtOAc-
petroleum ether 70:30 with 1% then 2% MeOH) to give 28 mg
of 5(R)-uvarigrandin A (26) (57% yield for the last two steps).
CDCl3) δ 7.63 (3H, m), 7.57-7.53 (2H, m), 7.43-7.39 (3H, m),
7.39-7.35 (5H, m), 7.03 (1H, d, J ) 1.5 Hz), 5.10 (1H, m),
5.06-4.97 (3H, m), 4.00 (2H, q, J ) 7.0 Hz), 3.93 (2H, m), 3.61
(6H, s), 3.55 (3H, s), 2.38-2.25 (2H, m), 2.01-1.98 (6H, m),
1.98-1.79 (2H, m), 1.65-1.53 (11H, m), 1.48 (4H, m), 1.41 (3H,
d, J ) 7.0 Hz), 1.33-1.09 (30H, m), 0.89 (3H, t, J ) 7.0 Hz).
Ack n ow led gm en t. Funding was provided by re-
search grant R01GM CA56769 from the National In-
stitutes of General Medical Sciences.
1
[R]D 11.5 (c 0.54, CHCl3); H NMR (500 MHz, CDCl3) δ 7.03
(1H, m), 5.00 (1H, m), 3.86 (2H, m), 3.82 (2H, m), 3.58 (1H,
m), 3.38 (2H, m), 2.55 (2H, d, J ) 4.0 Hz), 2.49-2.33 (2H, m),
2.13 (1H, m), 2.02-1.92 (4H, m), 1.88 (1H, bs), 1.75-1.67 (6H,
m), 1.54-1.20 (40H, m), 1.40 (3H, d, J ) 7.0 Hz), 0.87 (3H, t,
J ) 7.0 Hz); 13C NMR (125 MHz, CDCl3) δ 174.1, 149.4, 134.0,
83.1, 81.7, 77.5, 74.0, 70.7, 37.4, 35.3, 33.4, 31.8, 29.7, 29.6,
29.5, 29.3, 28.9, 28.3, 25.6, 22.6, 21.4, 19.1, 14.0.
Su p p or tin g In for m a tion Ava ila ble: Additional experi-
mental procedures, 1H NMR spectra of key intermediates, and
selected 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
Tr i-(R)-Mosh er Ester of 5(R)-Uva r igr a n d in A 27. The
reported procedure was employed.18 1H NMR (500 MHz,
J O0266137
J . Org. Chem, Vol. 68, No. 5, 2003 1785