Stereocontrolled total synthesis of an annonacin A-type acetogenin: Pseudoannonacin A?

Article abstract of DOI:10.1021/jo9713621

A stereocontrolled first total synthesis of a diastereomer of the presumed mono-tetrahydrofuran type acetogenin annonacin A, starting with enantiomerically pure precursors, is described. The absolute stereochemistry of the C₁₅-C₂₀ segment corresponding to the tetrahydrofuran ring of the natural product was secured by X-ray crystal structure analysis of an advanced intermediate. The synthetic product (a mixture of epimers at C₁₀) had spectroscopic data identical to that of the natural product, but a different optical rotation.

Full text of DOI:10.1021/jo9713621

J . Org. Chem. 1998, 63, 1049-1057
1049
Ster eocon tr olled Tota l Syn th esis of a n An n on a cin A-Typ e
Acetogen in : P seu d oa n n on a cin A?†
Stephen Hanessian* and Teresa Abad Grillo
Department of Chemistry, Universite´ de Montre´al, C.P. 6128, Succursale Centre-ville,
Montre´al, QC, H3C 3J 7, Canada
Received J uly 24, 1997
A stereocontrolled first total synthesis of a diastereomer of the presumed mono-tetrahydrofuran
type acetogenin annonacin A, starting with enantiomerically pure precursors, is described. The
absolute stereochemistry of the C15-C20 segment corresponding to the tetrahydrofuran ring of the
natural product was secured by X-ray crystal structure analysis of an advanced intermediate. The
synthetic product (a mixture of epimers at C10) had spectroscopic data identical to that of the natural
product, but a different optical rotation.
The polyketide-derived fatty acid natural products
belonging to the acetogenin group were isolated from the
Annonaceae family of tropical and subtropical trees.1
They are characterized by the presence of a mono- or bis-
tetrahydrofuran ring(s) as a part of a “central” core unit
of a long-chain hydrocarbon that may also contain
hydroxy groups. Usually the end unit in these intriguing
natural products consists of a butenolide moiety. The
acetogenins exhibit a broad range of potent biological
activities that include antitumor, antiprotozoal, antimi-
crobial, immunosuppressant, antifeedant, and related
effects to mention a few.2 Despite such a plethora of
biological and physiological activities in animals and
insects, only a few structures have been elucidated
beyond doubt through synthesis. Stereochemical assign-
ments have been made by inference to known structures
and by correlating biogenetic patterns and based on
comparisons with material obtained by total synthesis.3
Although, a number of crystalline acetogenins are known,2
no X-ray structures of any of the mono-tetrahydrofuran
types have been determined to the best of our knowledge.
The largest group of annonaceous acetogenins are
characterized by the presence of a secondary hydroxy
group at the R,R′-position of the hydrocarbon chains on
each side of a tetrahydrofuran ring. Although they are
fewer in number compared to the bis-tetrahydrofuran
types,3 they present a major challenge for synthesis in
view of the presence of four stereogenic centers encom-
passing the central tetrahydrofuran ring and its flanking
carbon atoms. In some analogues, the additional hydroxy
groups are present on the hydrocarbon chain between the
F igu r e 1.
tetrahydrofuran ring and the chiral butenolide end group.
The structures of solamin, corrosolone, and annonacin
A are shown in Figure 1 as representative examples of
mono-tetrahydrofuran type acetogenins.
The total synthesis of solamin was reported by Trost,4
Keinan,5 Oritani,6 and their co-workers, utilizing differ-
ent approaches. The synthesis of corossolone, starting
with D-tartaric acid and L-lactic acid as chiral templates,
was described by Wu and co-workers.7 Although frag-
ments of annonacin A have been synthesized,8,9 its total
synthesis has not been achieved to the best of our
knowledge.
† Dedicated to Professor Dieter Seebach on the occasion of his 60th
birthday, wishing him the best in life and in chemistry.
(1) For reviews, see: Rupprecht, Y. K.; Hui, J .-H.; McLaughlin, J .
L. J . Nat. Prod. 1990, 53, 237. Fang, X.-P.; Rieser, M. J .; Gu, Z.-M.;
Zhao, G.-X.; McLaughlin, J . L. Phytochem. Anal. 1993, 4, 27. Zeng
L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He, K.; McLaughlin, J .
L. Nat. Prod. Rep. 1996, 275. Cave´, A.; Frigade`re, B.; Laurens, A.;
Cortes, D. In Progress in the Chemistry of Organic Natural Products:
Acetogenins From Annonaceae; Herz, W., Ed.; Springer-Verlag: New
York, 1997; Vol. 70, pp 81-288.
(2) McLaughlin, J .-L.; Chang, C.; Smith, D. L. In Human Medicinal
Agents from Plants; Kinghorn, A. D., Baladrin, M. F., Eds.; American
Chemical Society: Washington, DC, 1993; Chapter 9, p 117.
(3) For recent reviews, see: Hoppe, R.; Scharf, H. D. Synthesis 1995,
1447. Frigade`re, B. Acc. Chem. Res. 1995, 28, 359. For recent
syntheses of bis-tetrahydrofuran types, see: Marshall, J . A.; Hinkle,
K. W. J . Org. Chem. 1997, 62, 5989. Marshall, J . A.; Chen, M. J . Org.
Chem. 1997, 62, 5996 and references therein.
Annonacin A was isolated from seeds of Annona
squamosa L. and obtained as an amorphous solid, [R]D
+23.8 (CH2Cl2).10 It was characterized spectroscopically,
and the relative configuration of the central tetrahydro-
(4) Trost, B. M.; Shi, Z. J . Am. Chem. Soc. 1994, 116, 7459.
(5) Sinha, S. C.; Keinan, E. J . Am. Chem. Soc. 1993, 115, 4891.
(6) Makabe, H.; Tanaka, A. J .; Oritani, T. Chem. Soc., Perkin Trans.
1 1994, 1975.
(7) Yao, Z.-J .; Wu, Y.-L. J . Org. Chem. 1995, 60, 1170.
(8) Harmange, J .-C.; Cave´, A.; Figade`re, B. Tetrahedron Lett. 1992,
33, 5749.
(9) Hoppe, R.; Flasche, M.; Scharf, H.-D. Tetrahedron Lett. 1994,
35, 2873.
S0022-3263(97)01362-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/27/1998

1050 J . Org. Chem., Vol. 63, No. 4, 1998
Hanessian and Grillo
Sch em e 1
F igu r e 2.
furan ring was assigned as being threo-trans-erythro
(C16R,C19R)
1,2,10 as shown in Figure 1. The configurations
at C4 and C10 remain unknown. Since reference samples
of known absolute (or relative) configuration are not
available, it has not been possible to exclude the erythro-
trans-threo (for C15R,C16S,C19S,C20S) configuration for an-
nonacin A, in which C16 and C19 would be epimeric to
the commonly depicted threo-trans-erythro (C15R f C20S
)
relationship shown in Figure 1.
Stereochemical features have been further complicated
by the absence of a uniform way of depicting the
structural representations of these compounds. Changes
in perspective have often led to confusion in correlations
and in synthesis planning.11
come from L-lactic acid, and intermediate D can be
prepared from D-glutamic acid. In such a strategy, only
the configuration at C10 would remain uncertain, and in
the worst of scenarios, it would consist of a mixture of
epimers in the final product.
We describe in this paper our efforts toward a concise
and stereocontrolled total synthesis of the erythro-trans-
threo (C15R,C16S,C19S,C20S) diastereomer of annonacin A
utilizing the Chiron approach. A disconnective analysis
shown in Figure 2 relates the stereochemistry of C19 and
C4 in the natural product to L-glutamic and D-glutamic
acids, respectively, and C34 to that of L-lactic acid (C33-
C35). The well-known lactone C12 obtained from L-
glutamic acid can be elaborated to a lactone intermediate
B that secures the configuration of the tetrahydrofuran
ring junctions as well as that of C15. Further manipula-
tion and chain elongation at both ends of B produces an
advanced intermediate A, which is then elaborated to the
intended natural product. The C11-C34 subunit would
Resu lts a n d Discu ssion
The synthesis started with the condensation of 2-((tri-
methylsilyl)oxy)furan with the lactol derived from the
lactone 112 (Scheme 1) under Lewis acid catalysis.13,14
This reaction produced a mixture of four diastereomeric
lactone adducts in which the 4S,5S-threo and the 4R,5S-
(13) (a) J efford, C. W.; J aggi, D.; Boukouvalas, J . Tetrahedron Lett.
1987, 28, 4037. (b) Rassu, G.; Spanu, P.; Casiraghi, G.; Pinna, L.
Tetrahedron 1991, 47, 8025 and the references therein.
(14) Koert, U.; Stein, M.; Harms, K. Tetrahedron Lett. 1993, 34,
2299. See also: Frigade`re, B.; Chaboche, C.; Peyrat, J .-F.; Cave´, A.
Tetrahedron Lett. 1993, 34, 8093. Frigade`re, B.; Peyrat, J .-F.; Cave´,
A. J . Org. Chem. 1997, 62, 3428.
(10) Lieb, F.; Nonfon, M.; Wachendorff-Neumann, U.; Wendisch, D.
Planta Med. 1990, 56, 317.
(11) Compare for example the representations of annonacin A and
related analogues in refs 4-9.
(12) Hanessian, S.; Murray, P. J . Tetrahedron 1987, 43, 5055.

Total Synthesis of an Annonacin A-Type Acetogenin
J . Org. Chem., Vol. 63, No. 4, 1998 1051
Sch em e 2
erythro isomers 2 and 3 (1.14:1 ratio) were the major
products which could be separated from the minor
isomers by crystallization or chromatography. The ab-
solute configuration of the threo isomer was determined
unambiguously by a single-crystal X-ray analysis. The
stereochemical identity of the 4R,5S-erythro isomer 3 was
clearly established by a chemical correlation with 2.
Thus, catalytic reduction of 2 gave the saturated lactone
6 whose structure was also confirmed by X-ray analysis
(Scheme 1). Hydrolysis to the lithium salt and careful
acidification, followed by an intramolecular Mitsunobu
inversion by lactone formation,15 gave the 4R,5S-lactone
8 as the predominant product (13:1). Hydrogenation of
3 gave a product identical with that obtained from the
intramolecular inversion sequence starting with 6 of
known absolute configuration. It should be noted that
the isomeric lactones 2 and 3 and their saturated
derivatives 6 and 8 were easily separable by column
chromatography or by fractional crystallization.
With three stereogenic centers corresponding to C15,
C16, and C19 of the intended erythro-trans-threo annonacin
A isomer secured in intermediate 8, we proceeded to
elaborate the chains flanking the tetrahydrofuran unit.
Thus, reduction of 8 with DIBAL-H followed by a Wittig
extension16 led to 9. Hydrogenation afforded the corre-
sponding saturated ester which was protected as the
BOM ether 10 (Scheme 2). Removal of the silyl protect-
ing group, Swern oxidation, and a Grignard reaction with
(15) See, for example: (a) Hanessian, S.; Faucher, A.-M. J . Org.
Chem. 1991, 56, 2947. (b) Melillo, D. G.; Liu, T.; Ryan, K.; Sletzinger,
M.; Shinkai, I. Tetrahedron Lett. 1981, 22, 913. (c) Hughes, D. L. In
Organic Reactions; Paquette, L. A.; et al., Eds.; Wiley: New York, 1992;
Vol. 42, Chapter 2. (d) Mitsunobu, O. Synthesis 1981, 1.
(16) Buchanan, J . G.; Edgar, A. R.; Power, M. J .; Theaker, P. D.
Carbohydr. Res. 1974, 38, C22.

1052 J . Org. Chem., Vol. 63, No. 4, 1998
Hanessian and Grillo
Sch em e 3
dodecylmagnesium bromide led to a 2:1 mixture of
epimeric alcohols 11 and 12 in excellent yield. Upon
deprotection, the minor crystalline erythro alcohol 13 was
assigned the C20R configuration (annonacin A numbering)
as evidenced by single-crystal X-ray analysis. The major
isomer 11 would thus be the required precursor to the
intended target product. A chemical correlation with 12
was possible by an oxidation-reduction sequence. Thus,
oxidation of 12 with TPAP,17 followed by reduction of the
resulting ketone with L-Selectride,18 gave the desired
alcohol 11 as the preponderant product (>24:1). Reduc-
tion with NaBH4 in MeOH gave much lower ratios of the
desired isomer. It is of interest to comment on the
stereochemical outcome of the Grignard reaction. Nor-
mally, R-aldehydo tetrahydrofurans undergo a chelation-
controlled addition by virtue of a favorable coordination
of the organomagnesium reagent with the ring oxygen.19
This should have led to a much higher ratio of 11 as the
major isomer. Evidently, the presence of the R-OBOM
group in the aldehyde derived from 10 interferes with
the anticipated five-membered chelate, thus preventing
a clean enantiofacial attack. Alternative methods using
cuprate reagents (C12H25MgBr/Li2CuCl4 or /CuBr‚SMe2)
derived from the Grignard reagent led to higher ratios
of 11 albeit in lower yields.
With the C10-C32 segment of the intended diastere-
omer of annonacin A in hand, and an absolute stereo-
chemistry secured by X-ray crystal structure analysis,
we proceeded to elaborate the remainder of the right-
hand portion of the advanced intermediate 11 after
protection to the MOM ether 13a (Scheme 2). A sulfone
anion coupling method was adopted as shown in Scheme
3. Thus, the anion of the phenyl sulfone chiron 16,
readily prepared from D-glutamic acid, was condensed20
directly with the ester function in 13a to give the R-keto
sulfone 17. Reductive desulfonylation with Na/Hg,21
followed by reduction of the ketone group in 18 and
protection, afforded the intermediate 19 as an epimeric
mixture at C10 (annonacin A numbering). Unfortunately
attempts to separate the diastereomers at this stage by
derivatization (acetate, benzoate, esters) were unsuccess-
ful. Also, no attempts were made to achieve stereose-
lective reduction of the ketone group in 18.
22 as a microcrystalline solid, mp 100-102 °C, [R]D +2.5.
Due to the unavailability of annonacin A, a comparison
of our synthetic sample with the authentic natural
product was not possible. Table 1 lists comparisons of
1H and 13C NMR data at 400 and 100 MHz, respectively,
which are in excellent agreement with published data
for annonacin A itself.10 Previous 13C NMR correlations
have also been made with synthetic fragments8 and
indicate a distinct difference between the chemical shifts
for a threo-trans-threo pattern as in murisolin and those
found in the proposed threo-trans-erythro (C15 f C20)
configuration for annonacin A, or its erythro-trans-threo
(C15 f C20) diastereovariant.24
It now remained to elaborate the chiral butenolide unit
in order to complete the total synthesis of our intended
target. Previous efforts in the synthesis of acetogenins
have utilized the O-THP derivative of (S)-lactaldehyde
as a source of the butenolide.22 Thus, desilylation of 19
(Scheme 4) and oxidation to the aldehyde followed by a
Wittig extension and reduction gave the saturated ester
20. Condensation of the enolate derived from 20 with
O-THP (S)-lactaldehyde,22 followed by mesylation and
elimination in the presence of DBU, gave the protected
precursor 21.
Finally, treatment with TMS-Br23 at low temperature
smoothly removed the MOM and BOM groups to afford
In view of the stereocontrolled method of synthesis of
our product, we can safely assign the erythro-trans-threo
(C15R,C16S,C19S,C20S) absolute configuration to the tet-
rahydrofuran unit and its flanking R,R′-carbon atoms
bearing the secondary hydroxyl groups. The discrepancy
with the optical rotation value of our synthetic product
(17) Griffith, W. P.; Ley, S. V. Aldrichimica Acta 1990, 23, 13.
(18) Frigade`re, B.; Harmange, J .-C.; Laurens, A.; Cave´, A. Tetra-
hedron Lett. 1991, 32, 7539.
(19) Wolfrom, M. L.; Hanessian, S. J . Org. Chem. 1962, 27, 1800.
(20) See, for example: Bartlett, P. A.; Green, F. R.; Rose, E. H. J .
Am. Chem. Soc. 1978, 100, 4852.
(21) Kocienski, P. J .; Lythgoe, B.; Ruston, S. J . Chem. Soc., Perkin
Trans. 1 1978, 829.
(22) Naito, H.; Kawahara, E.; Maruta, K.; Maeda, M.; Sasaki, S. J .
Org. Chem. 1995, 60, 4419.
(23) Hanessian, S.; Delorme, D.; Dufresne, Y. Tetrahedron Lett.
1984, 25, 2515.
(24) For the determination of absolute configuration of certain
acetogenins, see: Rieser, M. J .; Hui, Y.-H.; Rupprecht, K.; Kozlowski,
J . F.; Wood, K. V.; McLaughlin, J . L.; Hanson, P. R.; Zhuang, Z.; Hoye,
T. R. J . Am. Chem. Soc. 1992, 114, 10203.

Total Synthesis of an Annonacin A-Type Acetogenin
J . Org. Chem., Vol. 63, No. 4, 1998 1053
Sch em e 4
starting with an enantiopure precursor corresponding to
that segment of the molecule. It is doubtful that the
presence of two diastereomers differing in the configu-
ration at C10 only accounts for the discrepancy in the
physical constants reported for annonacin A.10
1
It is possible that coincidentally the H and 13C NMR
chemical shifts of the proposed threo-trans-erythro
(C15R,C16R,C19R,C20S) configuration of annonacin A10 and
those of the synthetic diastereomer 22 are nearly identi-
cal. It is therefore clear that this particular threo-trans-
erythro isomer should be synthesized also before an
unambiguous assignment of absolute stereochemistry to
annonacin A can be made. The unavailability of natural
annonacin A will still present a problem in correlation,
since only an optical rotation value can be compared with
that of a synthetic sample. The unknown absolute
configuration at C4, C10, and C34 in the natural product
only heightens the challenge for the hunt in our labora-
tory and presumably elsewhere also. For the time being
we shall designate the (C15R,C16S,C19S,C20S) erythro-trans-
threo isomer 22 as pseudo-annonacin A.
Exp er im en ta l Section
Gen er a l Exp er im en ta l. 1H and 13C spectra were recorded
at 300 and 400 MHz NMR in CDCl3. IR spectra were recorded
as solutions in CHCl3. Optical rotations were recorded at
ambient temperature. Mass spectra were obtained at low and
high resolution. Organic solvents used were dried by standard
methods. Commercially obtained reagents were used without
further purification. All reactions were monitored by TLC with
Merck 60 F254 silica gel coated plates. Flash column chroma-
tography was carried out using 230-400 mesh silica gel at
increased pressure.
Isom er s of 5-(5′-(((ter t-Bu t yld ip h en ylsilyla n yl)oxy)-
m eth yl)tetr a h yd r ofu r -2′-yl)-5H-fu r a n -2-on e (2, 3, 5, a n d
4). A solution of DIBAL-H (45.9 mL, 1 M, 45.9 mmol) in
toluene was added dropwise to a stirring solution of lactone 1
(12.5 g, 35.3 mmol) in toluene (176 mL) at -78 °C. After 1 h
of stirring at -78 °C, methanol was added dropwise at -78
°C and the solution was stirred for 20 min before being allowed
to warm to 0 °C. Ether was added followed by the addition of
water (2 drops). On allowing the solution to warm to rt a
slurry formed which was filtered under reduced pressure and
washed repeatedly with hot EtOAc. The filtrates were col-
lected, concentrated under reduced pressure, and passed
through a short silica plug (hexane:EtOAc 4:1). Removal of
the eluant under reduced pressure gave the product (11.56 g,
92%) as a colorless oil. The resulting lactol (11.5 g, 32.56
mmol) was acetylated by treatment with acetic anhydride (4.3
mL, 45.90 mmol), triethylamine (9.8 mL, 70.6 mmol), and
DMAP (catalytic amount) in CH2Cl2 (150 mL) at rt for 1 h.
After removal of the solvent under reduced pressure, the
remaining oil was rapidly passed through as short silica plug
(hexane:EtOAc 4:1) to afford, after solvent removal, a colorless
oil (12.9 g, 100%).
Ta ble 1. Selected 1H a n d 13C NMR Da ta of An n on a cin
A10 a n d 22
annonacin A
(ref 10)
annonacin A
(ref 10)
22-Hδ
22-Cδ
174.51
1
2
3
4
5
174.68
131.14
37.41
69.77
31.94
37.30
71.69
37.30
33.36
74.36
82.31
83.32
71.62
33.12
131.06
37.18
3.82
3.60
3.84
3.58
69.83; 69.82b
31.81
9
37.18
10
11
14
15
16
19
20
21
32
33
34
35
71.66; 71.63b
37.18
33.29
74.26
82.01
83.16
3.40
3.82
3.82
3.82
3.38
3.84
3.84
3.84
2-((Trimethylsilyl)oxy)furan (8.3 mL, 49.4 mmol) was added
smoothly to a solution of the above product (12.9 g, 32.47
mmol) in CH2Cl2 (120 mL) at -78 °C, followed after 2 min by
the dropwise addition of BF3‚OEt2 (3 mL, 24.7 mmol). The
resultant bright yellow solution was maintained at -78 °C for
1 h after which saturated aqueous NH4Cl was added. The
mixture was allowed to warm to rt whereupon the organic
layer was separated, washed with water and brine, and dried
(Na2SO4). Solvent removal followed by column chromatogra-
phy (hexane:EtOAc 9:1) gave 2 (6.18 g, 40.7%) and 5 (0.86 g,
5.7%) which could be further separated by crystallization and
an inseparable mixture of compounds 3 and 4 (4.56:1, 6.6 g,
43.5%) as a colorless oil. For 2: [R]D -53.6 (c 0.5, CHCl3); IR
71.41; 71.38b
33.15
0.88
7.17
5.02
1.42
0.88
7.18
5.06
1.43
151.93
78.03
19.10
151.75
77.89
19.00
a
b
Data were recorded in CDCl3 at 400 MHz. Split signal.
with that reported for the natural product and its
undescribed physical state including a melting point
remain unresolved issues which are subject to conjecture.
The presence of two epimers differing in configuration
at C10 in the synthetic sample is a minor issue that can
be resolved on the basis of an alternative synthesis
1
(CHCl3) 1765 cm-1; H NMR (400 MHz, CDCl3) δ 7.69-7.65
(m, 4H), 7.42-7.37 (m, 7H), 6.16 (dd, J ) 2.07, 5.7 Hz, 1H),
5.02 (m, 1H), 4.26 (m, 1H), 4.13 (m, 1H), 3.65 (dd, J ) 10.7,

1054 J . Org. Chem., Vol. 63, No. 4, 1998
Hanessian and Grillo
4.5 Hz, 1H), 3.64 (dd, J ) 10.7, 4.5 Hz, 1H), 2.08-1.88 (m,
4H), 1.07 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.8, 153.4,
135.5, 133.5, 129.6, 127.6, 122.5, 84.7, 80.7, 77.8, 66.1, 27.5,
On allowing the solution to warm to rt, a slurry formed which
was filtered under reduce pressure and washed repeatedly
with hot EtOAc. The filtrates were concentrated under
reduced pressure and passed through a short silica plug
(hexane:EtOAc 4:1). Removal of the eluant under reduced
pressure gave the lactol (1.79 g, 94%) as a colorless oil. To a
solution of lactol (1.79 g, 4.2 mmol) in CH2Cl2 (42 mL) was
added a catalytic amount of PhCO2H followed by Ph3PdCHCO2-
Me (1.82 g, 5.46 mmol) in one portion. The reaction mixture
was stirred for 12 h at rt, the solvent was evaporated, and the
residue was purified by column chromatography (hexane:
EtOAc 5:1) to give 9 (1.52 g, 85%) as a colorless oil: [R]D +1.34
t
26.8, 20.9, 19.2; EIMS (m/z) 421 (M - 1), 365, (M - Bu);
HRMS calcd for C25H29O4Si (M - 1) 421.18350, found 421.18450.
5: 1H NMR (400 MHz, CDCl3) δ 7.70-7.65 (m, 4H), 7.42-
7.37 (m, 7H), 6.10 (dd, J ) 5.7, 2.0 Hz, 1H), 5.05 (m, 1H), 4.20
(m, 1H), 4.06 (m, 1H), 3.65 (m, 2H), 2.10-1.70 (m, 4H), 1.04
(s, 9H).
(2S ,2′S ,5′S )-5-(5′-(((t er t -B u t y l-d ip h e n y l-s ily la n y l)-
oxy)m eth yl)tetr a h yd r o[2,2′]bifu r a n yl-5-on e (6). A mix-
ture of 2 (6.18 g, 14.64 mmol) and Pd/C (0.5 g, 5%) in EtOAc
(30 mL) was stirred under 1 atm of pressure of hydrogen for
5 h. Filtration of the mixture through Celite followed by
solvent removal under reduced pressure gave the desired
product 6 (6.20 g, quantitative) as a colorless oil, which
crystallized on standing: mp 76-77 °C; [R]D +4.0 (c 0.075,
1
(c 0.87, CHCl3); IR (CHCl3) 3600-3400, 1728 cm-1; H NMR
(400 MHz, CDCl3) δ 7.72-7.69 (m, 10H), 7.0 (dt, J ) 15.6, 7.1,
6.7 Hz, 1H), 5.87 (d, J ) 15.6 Hz, 1H), 4.15 (m, 1H), 3.85 (m,
1H), 3.71 (s, 3H), 3.67 (dd, J ) 4.6, 2.0 Hz, 2H), 2.57 (brs, OH),
2.45 (m, 1H), 2.28 (m, 1H), 1.55 (m, 2H), 1.08 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 166.9, 148.9, 135.5, 133.5, 129.5, 127.5,
121.1, 82.2, 79.8, 71.1, 66.4, 51.2, 31.0, 28.6, 27.9, 26.8, 26.7,
19.1; EIMS (m/z) 483 (M + 1), 460, 425, 405, 306, 153, (100.0);
HRMS calcd for C28H39O5Si (M + 1) 483.2566, found 483.25510.
1
CHCl3); IR (CHCl3) 1775 cm-1; H NMR (400 MHz, CDCl3) δ
7.71-7.67 (m, 4H), 7.45-7.36 (m, 6H), 4.47 (m, 1H), 4.13 (m,
1H), 4.05 (m, 1H), 3.68 (dd, J ) 10.7, 4.4 Hz, 1H), 3.64 (dd, J
) 6.5, 4.4 Hz, 1H), 2.69 (m, 1H), 2.43 (m, 1H), 2.24 (m, 2H),
2.07-1.82 (m, 4H), 1.05 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
177.6, 135.5, 135.6, 129.5, 127.5, 127.6, 81.0, 80.9, 80.4, 66.2,
28.0, 27.8, 27.7, 26.7, 24.6, 19.1; EIMS (m/z) 423 (M - 1), 367;
HRMS calcd for C25H31O4Si (M - 1) 423.19916, found 423.19740.
(2R ,2′S ,5′S )-5′-(((t er t -B u t y ld ip h e n y ls ila n y l)o x y )-
m eth yl)tetr a h yd r o[2,2′]bifu r a n yl-5-on e (8). A mixture of
3 and 4 (4.56:1 ratio, 6.60 g, 15.64 mmol) and Pd/C (0.5 g, 5%)
in EtOAc (30 mL) was stirred under 1 atm of pressure of
hydrogen for 5 h. Filtration of the mixture through Celite
followed by solvent removal under reduced pressure gave a
mixture of 8 and its 4S,5R-erythro isomer 7 (6.63 g, quantita-
tive). Column chromatography (10% EtOAc:hexane) gave the
pure trans-erythro compound 8 (5.0 g, 92%) as a colorless oil
and the cis-4S,5R-erythro compound 7 (1.04 g) as a colorless
(2′S,5′S,6R)-6-((Ben zyloxy)m eth oxy)-6-[5′-(((ter t-bu tyl-
d ip h e n ylsila n yl)oxy)m e t h yl)t e t r a h yd r ofu r a n -2′-yl]-
h exa n oic Acid Meth yl Ester (10). A mixture of 10% Pd/C
(0.12 g) and 9 (1.52 g, 3.15 mmol) in EtOAc (3 mL) was stirred
for 5 h at rt. The mixture was filtered through Celite, washed
with EtOAc, and concentrated to afford the product (1.5 g,
quantitative) as a colorless oil: [R]D +33.3 (c 1.68, CHCl3); IR
1
(CHCl3) 1740 cm-1; H NMR (400 MHz, CDCl3) δ 7.70-7.67
(m, 4H), 7.38-7.31 (m, 6H), 4.1 (m, 1H), 3.85 (m, 1H), 3.64
(m, 2H), 3.60 (m, 1H), 3.60 (s, 3H), 2.70 (brs OH), 2.28 (t, J )
7.4 Hz, 2H), 1.98-1.41 (m, 10H), 1.05 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 174.0, 135.5, 133.5, 129.5, 127.5, 85.2, 79.8,
71.1, 66.4, 51.2, 34.0, 33.0, 27.9, 26.8, 26.7, 19.1; EIMS (m/z)
485 (M + 1), 467, 135 (100.0); HRMS calcd for C28H41O5Si (M
+ 1) 485.27234, found 485.27370.
oil: For 8: [R]D -3.9 (c 0.28, CHCl3); IR (CHCl3) 1780 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.76-7.70 (m, 4H), 7.43-7.36
(m, 6H), 4.41 (m, 4H), 4.14 (m, 1H), 3.68 (dd, J ) 10.7, 4.5 Hz,
1H), 3.64 (dd, J ) 10.7, 4.5 Hz, 1H), 2.53 (m, 2H), 2.30 (m,
1H), 2.20-1.80 (m, 3H), 1.73 (m, 1H), 1.06 (s, 9H); 13C MNR
(100 MHz, CDCl3) δ 177.0, 135.5, 133.4, 129.5, 127.5, 81.6,
80.2, 80.1, 66.2, 28.2, 28.0, 27.5, 26.7, 23.8, 19.1; EIMS (m/z)
BOMCl (4.39 mL, 31.5 mmol) was added to a solution of
the above product (1.7 g, 3.51 mmol) and DIPEA (5.5 mL, 31.5
mmol) in CH2Cl2 (35 mL) at 0 °C. The mixture was stirred
for 48 h at 0 °C, quenched with saturated aqueous NH4Cl, and
extracted with CH2Cl2. The organic layer was washed several
times with water and brine and then dried (Na2SO4). Filtra-
tion and evaporation of the solvent afforded the crude mixture
which was chromatographed on a silica gel column (hexane:
EtOAc 6:1) to give 10 (1.37 g, 65%) as a colorless oil: [R]D
t
423 (M - 1), 367 (M - Bu), for 347. For 7: 1H NMR (400
MHz, CDCl3) δ 7.71-7.67 (m, 4H), 7.45-7.36 (m, 6H), 4.48
(m, 1H), 4.11 (m, 1H), 4.05 (m, 1H), 3.68 (dd, J ) 10.7, 4.4 Hz,
1H), 3.64 (dd, J ) 6.5, 4.4 Hz, 1H), 2.70-2.52 (m, 1H), 2.50
(m, 2H), 2.49-2.35 (m, 1H), 1.85 (m, 4H), 1.05 (s, 9H).
In tr a m olecu la r Mitsu n obu Rea ction (8 fr om 6). To a
stirring solution of 6 (100 mg, 0.235 mmol) in THF:H2O (10:1,
11 mL) was added LiOH (13 mg, 0.54 mmol) in one portion at
0 °C. Stirring was continued for 1 h until TLC analysis
indicated the absence of the starting material. Prewashed
Amberlite IR-120 resin (H+) was added to the aqueous phase
until pH ∼4 was attained. The mixture was filtered, and the
aqueous phase was repeatedly extracted with CH2Cl2. The
combined organic phases were dried (Na2SO4), and the solvent
was removed under reduced pressure. The residue was further
dried over P2O5 under reduced pressure for 1 h to afford the
crude ω-hydroxy acid intermediate as a viscous oil (95.5 mg,
0.216 mmol). A solution of Ph3P (170 mg, 0.648 mmol) in THF
(1 mL) was added to a solution of this intermediate in THF
(11.7 mL) at 0 °C followed by the dropwise addition of DEAD
(0.1 mL, 2.97 mmol), and the yellow solution was stirred for a
further 30 min. Evaporation of the solvent followed by column
chromatography (hexane:EtOAc 9:1) gave a 13:1 inseparable
mixture of 8 and 6 (80 mg, 86%).
1
+10.68 (c 0.51, CHCl3); IR (CHCl3) 1740 cm-1; H NMR (400
MHz, CDCl3) δ 7.80-7.76 (m, 4H), 7.48-7.31 (m, 6H), 4.94
(d, J ) 6.88 Hz, 1H), 4.84 (d, J ) 6.88 Hz, 1H), 4.71 (d, J )
11.8 Hz, 1H), 4.66 (d, J ) 11.8 Hz, 1H), 4.14 (m, 1H), 4.06 (m,
1H), 3.70 (m, 1H), 3.69 (m, 2H), 3.68 (s, 3H), 2.33 (t, J ) 7.3
Hz, 2H), 2.15-1.85 (m, 4H), 1.84-1.31 (m, 6H), 1.10 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 174.0, 137.9, 135.6, 133.6, 129.5,
128.3, 127.7, 127.6, 94.6, 81.4, 79.6, 78.7, 69.5, 66.5, 51.4, 33.9,
31.4, 28.2, 26.8, 25.2, 25.1, 19.2; HRMS calcd for C36H49O6-
SiNa 627.31177, found 627.31400.
(1′′S ,2′S ,5′S ,6R )-6-((B e n zy lo x y )m e t h o x y )-6-[5′-(1′′-
h yd r oxyt r id ecyl)t et r a h yd r ofu r a n -2′-yl]h exa n oic Acid
Meth yl Ester (11) a n d Isom er (12). To a solution of 10 (0.87
g, 1.45 mmol) in THF (29 mL) at 0 °C was added a solution of
n-Bu4NF (5.8 mL, 1.0M, 5.8 mmol) in THF, and the mixture
was stirred for 3 h at rt, then quenched with saturated aqueous
NH4Cl, and diluted with ether and the organic layer was
washed with water and brine and dried (Na2SO4). Filtration
and evaporation of the solvent followed by column chroma-
tography gave the expected alcohol (0.5 g, quantitative) as a
colorless oil: [R]D +19 (c 0.105, CHCl3); IR (CHCl3) 3695-3460,
(2′S ,5′S ,6R )-6-[5′-(((t er t -Bu t yld ip h e n ylsila n yl)oxy)-
m eth yl)tetr ah ydr ofu r an -2′-yl]-6-h ydr oxyh ex-2-en oic Acid
Meth yl Ester (9). A solution of DIBAL-H (4.18 mL, 1.5 M,
6.2 mmol) in toluene was added dropwise to a stirring solution
of 8 (1.9 g, 4.48 mmol) in toluene (22 mL) at -78 °C. The
solution was stirred at -78 °C for 1 h. Methanol (6 mL) was
added dropwise at -78 °C, and the solution was stirred for 20
min before being allowed to warm to 0 °C. Ethyl acetate (10
mL) was added followed by the addition of water (2 drops).
1
1735 cm-1; H NMR (400 MHz, CDCl3) δ 7.33-7.26 (m, 5H),
4.87 (d, J ) 6.88 Hz, 1H), 4.6 (m, 2H), 4.04 (m, 1H), 3.99 (m,
1H), 3.73 (m, 1H), 3.62 (s, 3H), 3.61 (m, 1H), 3.50 (m, 1H),
2.27 (t, J ) 7.4 Hz, 2H), 1.95-1.88 (m, 3H), 1.68-1.30 (m, 7H);
13C NMR (100 MHz, CDCl3) δ 173.9, 137.8, 128.2, 127.6, 127.5,
94.5, 81.2, 79.7, 78.4, 69.5, 64.7, 51.3, 33.8, 31.1, 27.5, 26.6,
25.0, 24.9; EIMS (m/z) 367 (M + 1), 338, 259 (100.0); HRMS
calcd for C20H31O6 (M +1 ) 367.21280, found 367.21207.

Total Synthesis of an Annonacin A-Type Acetogenin
J . Org. Chem., Vol. 63, No. 4, 1998 1055
To a stirred solution of oxalyl chloride (1.89 mL, 0.162 mmol)
in THF (2.95 mL) at -78 °C was added a solution of DMSO
(2.52 mmol, 0.179 mL) in THF (1.26 mL). The solution was
allowed to warm to -35 °C for 3 min and was then recooled to
-78 °C. A solution of the above alcohol (461 mg, 1.26 mmol)
in THF (2.37 mL) was then added to the reaction mixture. The
resulting solution was allowed to warm to -35 °C, and after
15 min it was treated with DIPEA (1.09 mL). The reaction
mixture was allowed to warm to rt, and an ethereal solution
of dodecylmagnesium bromide (7.55 mL, 1.0M, 5.55 mmol) was
then added dropwise to the vigorously stirred mixture at 0
°C. The reaction was quenched with saturated aqueous NH4-
Cl, diluted with ether, and the organic layer was washed with
water and brine and then dried (Na2SO4). Filtration and
evaporation of the solvent afforded the crude mixture, which
was chromatographed on a silica gel column (hexane:EtOAc
9:1), to give the threo isomer 11 (402.0 mg, 60%) and the
erythro isomer 12 (184.0 mg, 27%) as a colorless oils.
Con ver sion of 12 to 11. TPAP (catalytic amount) was
added as a single portion to a stirring mixture of the erythro
alcohol 12 (138 mg, 0.258 mmol), NMO (N-methylmorpholine
N-oxide) (60.5 mg, 0.512 mmol), and powdered 4 Å molecular
sieves in CH2Cl2 (0.5 mL) at rt under argon. After 1 h of
stirring, the reaction mixture was filtered through a pad of
silica (EtOAc) and the solvent was removed under reduced
pressure. L-Selectride (0.3 mL, 0.3 mmol) was added dropwise
to a stirring solution of the freshly prepared ketone in THF
(2.3 mL) at -78 °C. The mixture was stirred at -78 °C for 1
h after which the reaction was quenched by the dropwise
addition of methanol. Removal of the solvent followed by
column chromatography (hexane:EtOAc 6:1) gave 11 (105 mg)
and 12 (4 mg) (76%) as colorless oils. For 11: [R]D +5.56 (c
0.8, CHCl3); IR (CHCl3) 3584, 1735 cm-1; 1H NMR (400 MHz,
C6D6) δ 7.34-7.26 (m, 5H), 4.89 (d, J ) 6.8 Hz, 1H), 4.79 (d,
J ) 6.8 Hz, 1H), 4.65 (d, J ) 11.8 Hz, 1H), 4.61 (d, J ) 11.8
Hz, 1H), 3.98 (m, 1H), 3.76 (m, 1H), 3.64 (s, 3H), 3.35 (m, 1H),
2.34 (d, J ) 3.8 Hz, OH), 2.29 (t, J ) 7.4 Hz, 2H), 1.95-1.91
(m, 3H), 1.65-1.25 (m, 35H), 0.87 (t, J ) 6.7 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 173.8, 137.8, 128.3, 127.6, 127.5, 94.5,
82.7, 81.2, 78.2, 73.9, 69.5, 51.3, 33.8, 33.4, 31.8, 31.2, 29.6,
29.5, 29.4, 29.2, 28.3, 26.9, 25.5, 25.0, 24.9, 22.6, 14.0; EIMS
(m/z) 533 (M + 1), 517, 427 (100.0); HRMS calcd for C32H53O6
(M + 1) 533.38422, found 533.38190.
Hz, 2H), 1.91-1.80 (m, 3H), 1.70-1.25 (m, 29H), 0.87 (t, J )
6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.8, 137.9, 128.2,
127.6, 127.5, 96.5, 94.5, 81.6, 81.2, 79.4, 78.5, 69.5, 55.5, 51.3,
33.8, 31.8, 31.3, 31.2, 29.7, 29.5, 29.4, 29.2, 28.4, 26.6, 25.4,
25.0, 24.9, 22.6, 14.0; EIMS (m/z) 577 (M - 1) 547, 471 (100.0);
HRMS calcd for C34H57O7 (M - 1) 577.41040, found 577.41280.
(6R)-7-((ter t-Bu t yld ip h en ylsila n yl)oxy)-6-(m et h oxy-
m eth oxy)h ep ta n oic Acid Meth yl Ester (15). A solution
of DIBAL-H (17.45 mL, 1.5 M, 26.1 mmol) in toluene was
added dropwise to a stirring solution of lactone 1412 (7.13 g,
20.1 mmol) in toluene (100 mL) at -78 °C. The solution was
stirred at -78 °C for 1 h, after which methanol was added
dropwise at -78 °C and the solution was stirred for 20 min
before being allowed to warm to 0 °C. EtOAc was added
followed by the addition of water (2 drops). A slurry formed
which was filtered under reduced pressure and washed
repeatedly with hot EtOAc. The filtrates were collected,
concentrated under reduced pressure, and passed through a
short silica plug (hexane:EtOAc 4:1). Removal of the eluant
under reduced pressure gave the expected lactol (6.5 g, 93%)
as a colorless oil. To a solution of lactol (0.64 g, 1.8 mmol) in
CH2Cl2 (18 mL) at rt was added a catalytic amount of PhCO2H
followed by Ph3PdCHCO2Me (0.78 g, 2.3 mmol) in one portion.
The reaction mixture was stirred for 12 h at rt, the solvent
was evaporated, and the residue was purified by column
chromatography (hexane:EtOAc 5:1) to give the expected R,â-
unsaturated ester (0.68 g, 92%) as a colorless oil: [R]D + 2 (c
0.45, CHCl3); HRMS calcd for C24H33O4Si (M + 1) 413.21481,
found 413.21310.
A mixture of 10% Pd/C (100 mg) and the above product
(0.686 g, 1.66 mmol) in EtOAc (1.6 mL) was stirred for 2 h at
rt under 1 atm of pressure of hydrogen. The mixture was
filtered through Celite, washed with EtOAc, and concentrated
to afford the product (0.689 g, 100%) as a colorless oil: [R]D
+28 (c 1.05, CHCl3); HRMS calcd for C24H34O4NaSi 437.21240,
found 437.21020.
MOMCl (0.69 mL, 9.12 mmol) was added to a solution of
the above-obtained product (630 mg, 1.52 mmol) and DIPEA
(1.6 mL, 1.52 mmol) in CH2Cl2 (15 mL) at 0 °C, and the
mixture was stirred for 4 h at 0 °C f rt. The reaction mixture
was quenched with saturated aqueous NH4Cl extracted with
CH2Cl2, and the organic layer was processed as usual. Column
chromatography (hexane:EtOAc 9:1) gave 15 (695.0 mg,
quantitative) as a colorless oil: [R]D +23.86 (c 1.06, CHCl3);
(1′′R ,2′S ,5′S ,6R )-6-H y d r o x y -6-[5′-(1′′-h y d r o x y t r i -
d ecyl)tetr a h yd r ofu r a n -2′-yl]h exa n oic Acid Meth yl Ester
(13). A mixture of 12 (10 mg, 0.019 mmol) and Pd(OH)2/C in
dry methanol (1 mL) was stirred under 1 atm of pressure of
hydrogen for 18 h. The resulting mixture was filtered through
a pad of Celite, and the solvent was removed under reduced
pressure to afford 13 (7.1 mg, 91%) as a colorless solid.
Recrystallization (ether-diisopropyl ether) gave colorless plates
that were used for X-ray analysis: mp 50-51 °C; [R]D -8.1 (c
0.27, CHCl3); IR (CHCl3) 1735 cm-1; 1H NMR (400 MHz, C6D6)
δ 3.93-3.89 (m, 2H), 3.81-3.77 (m, 2H), 3.67 (s, 3H), 2.33 (d,
J ) 7.4 Hz, 2H), 2.05-1.95 (brs, 2¥OH), 1.91-1.85 (m, 4H),
1.71-1.50 (m, 6H), 1.43-1.26 (m, 25H), 0.87 (t, J ) 6.7 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 174.0, 82.9, 82.8, 71.8, 71.6,
51.4, 33.8, 33.2, 32.4, 31.9, 31.8, 29.6, 29.5 (×2), 29.3, 28.5,
25.9, 25.4, 25.2, 25.1, 24.8, 22.6, 14.0; HRMS calcd for C24H47O5
(M + 1) 415.3423, found 415.3401.
IR (CHCl3) 1740 cm-1 1H NMR (400 MHz, CDCl3) δ 7.75-
;
7.30 (m, 10H), 4.77 (d, J ) 6.8 Hz, 1H), 4.64 (d, J ) 6.8 Hz,
1H), 3.71-3.60 (m, 3H), 3.67 (s, 3H), 3.36 (s, 3H), 2.32 (t, J )
7.5 Hz, 2H), 1.70-1.20 (m, 6H), 1.07 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 174.0, 135.6, 135.5, 133.4, 129.6, 127.6, 96.1,
77.6, 66.2, 55.4, 51.4, 33.9, 31.3, 26.7, 24.9, 24.8, 19.1; EIMS
(m/z) 481 (M + Na), 457 (M - 1); HRMS calcd for C26H38O5-
NaSi 481.23862, found 481.23700.
(2R )-((7-(B e n ze n e s u lfo n y l)-2-(m e t h o x y m e t h o x y )-
h ep tyl)oxy)ter t-bu tyl-d ip h en ylsila n e (16). To a solution
of 15 (695.0 mg, 1.5 mmol) in THF (15 mL) at 0 °C was added
LiAlH4 (86.5 mg, 2.25 mmol) in one portion. The reaction
mixture was stirred at this temperature for 1 h, EtOAc (5 mL)
was added dropwise, and the reaction was allowed to warm
to rt. Water (10 mL) was added, and the organic layer was
extracted with EtOAc, dried (Na2SO4), and concentrated.
Filtration and evaporation of the solvent afforded the crude
mixture, which was purified by column chromatography (hex-
ane:EtOAc 1:1) to give the corresponding alcohol (543.0 mg,
83%) as a colorless oil: [R]D +26.13 (c 0.62, CHCl3); EIMS (m/
z) 453 (M + Na), 431 (M + 1); HRMS calcd for C25H39O4Si (M
+ 1) 431.26050, found 431.26175.
To a stirred solution of diphenyl disulfide (358 mg, 1.64
mmol) and tri-n-butylphosphine (0.4 mL, 1.64 mmol) in CH2-
Cl2 (12 mL) was added the above product (544.0 mg, 1.26
mmol) in CH2Cl2. The mixture reaction was stirred for 12 h
at rt and then quenched with saturated aqueous NH4Cl and
diluted with CH2Cl2. The organic layer was washed with
water and brine and dried (Na2SO4). Filtration and evapora-
tion of the solvent followed by column chromatography (hex-
ane:EtOAc 9:1) afforded the corresponding phenylthio deriva-
(1′′S,2′S,5′S,6R)-6-((Ben zyloxy)m eth oxy)-6-[5′-(1′′-(m eth -
oxym eth oxy)tr idecyl)tetr ah ydr ofu r an -2′-yl]h exan oic Acid
Meth yl Ester (13a ). MOMCl (0.4 mL, 5.33 mmol) was added
to a solution of 11 (190 mg, 0.35 mmol) and DIPEA (1.24 mL,
7.11 mmol) in CH2Cl2 (5 mL) at 0 °C, and the mixture was
stirred for 12 h at 4 °C. The reaction mixture was quenched
with saturated aqueous NH4Cl and extracted with CH2Cl2, and
the organic layer was washed with water and brine and dried
(Na2SO4). Filtration and evaporation of the solvent followed
by column chromatography (hexane:EtOAc 9:1) gave 13a (181
mg, 88%) as a colorless oil: [R]D -3.9 (c 0.71, CHCl3); IR
1
(CHCl3) 1740 cm-1; H NMR (400 MHz, CDCl3) δ 7.33-7.26
(m, 5H), 4.89 (d, J ) 6.8 Hz, 1H), 4.80 (d, J ) 6.8 Hz, 1H),
4.78 (d, J ) 6.7 Hz, 1H), 4.64 (m, 3H), 3.95 (m, 2H), 3.70 (m,
1H), 3.63 (s, 3H), 3.37 (m, 1H), 3.30 (s, 3H), 2.27 (t, J ) 7.5

1056 J . Org. Chem., Vol. 63, No. 4, 1998
Hanessian and Grillo
tive (627.0 mg, 95%) as a colorless oil: [R]D +22.7 (c 0.185,
CHCl3); HRMS calcd for C31H41O3SiS (M + 1) 521.25220, found
521.25458.
- MOMO), 777 (M - 3MOMO); HRMS calcd for C58H92O9SiNa
983.640834, found 983.6351.
(1′′S,2R,2′S,5′S,8R,S,13R)-{13-((Ben zyloxy)m et h oxy)-
2,8-b is(m e t h oxym e t h oxy)-13-[[5′-(1′′-(m e t h oxym e t h -
oxy)t r id ecyl)t et r a h yd r ofu r a n -2′-yl]t r id ecyl]oxy}-ter t-
bu tyld ip h en ylsila n e (19). To a solution of 18 (212.0 mg,
0.22 mmol) in THF (2 mL) at 0 °C was added LiAlH4 (25 mg,
0.66 mmol) in one portion. The reaction was stirred at this
temperature for 30 min, EtOAc was added dropwise, and the
reaction was allowed to warm to rt. Water (5 mL) was added,
and the organic layer was extracted with EtOAc (3 × 10 mL),
dried (Na2SO4), and concentrated. Filtration and evaporation
of the solvent afforded the crude mixture, which was purified
by column chromatography (hexane:EtOAc 6:4) to give a
mixture of C-10 alcohols (178 mg, 84%) as a colorless oil.
MOMCl (209.6 mL, 2.76 mmol) and DIPEA (0.64 mL, 3.68
mmol) in CH2Cl2 (2.62 mL) were added to the above solution
at 0 °C, and the mixture was stirred for 4 h at 4 °C. The
reaction mixture was quenched with saturated aqueous NH4-
Cl and then extracted with CH2Cl2. The organic layer was
washed with water and brine and dried (Na2SO4). Filtration
and evaporation of the solvent followed by column chroma-
tography (hexane:EtOAc 8:2) gave 19 (186.0 mg, 100%) as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.70-7.76 (m, 4H),
7.45-7.25 (m, 11H), 4.92 (d, J ) 6.8 Hz, 1H), 4.83 (d, J ) 6.7
Hz, 1H), 4.81 (d, J ) 6.8 Hz, 1H), 4.78 (d, J ) 6.7 Hz, 1H),
4.69-4.61 (m, 6H), 4.03-3.95 (m, 2H), 3.79 (m, 1H), 3.70-
3.61 (m, 3H), 3.53-3.44 (m, 2H), 3.39 (s, 3H), 3.36 (s, 3H), 3.35
(s, 3H), 1.96-1.78 (m, 3H), 1.68-1.27 (m, 41H), 1.06 (s, 9H),
0.89 (t, J ) 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 137.9,
135.5, 133.4, 129.5, 128.2, 127.5 (×2), 127.4, 96.5, 96.0, 95.2,
94.5, 81.6, 81.2, 79.4, 78.6, 77.7, 77.3, 69.4, 66.3, 55.6, 55.3,
34.3, 34.2, 31.8, 31.7, 31.2, 29.9, 29.8, 29.7, 29.6, 29.5, 29.2,
26.7, 25.8, 25.5, 15.5, 25.4, 25.3, 25.2, 22.6, 19.1, 14.0; EIMS
(m/z) 1029 (M + Na), 823 (M - 3MOMO); HRMS calcd for
To a solution of the sulfide (206.0 mg, 0.39 mmol) in CH2-
Cl2 (13 mL) was added NaHCO3 (331.0 mg, 3.9 mmol) followed
by 70-75% m-CPBA (204.0 mg, 1.18 mmol) at 0 °C. The
reaction mixture was stirred for 1 h, saturated aqueous
NaHCO3 was added, and the organic layer was washed with
water, brine, and dried (Na2SO4). Filtration and evaporation
of the solvent followed by column chromatography (hexane:
EtOAc 9:1) afforded 16 (627.0 mg, 95%) as a colorless oil: [R]D
1
+20.38 (c 0.52, CHCl3); IR (CHCl3) 1310 cm-1; H NMR (400
MHz, CDCl3) δ 7.93-7.89 (m, 2H), 7.68-7.35 (m, 13H), 4.75
(d, J ) 6.8 Hz, 1H), 4.60 (d, J ) 6.8 Hz, 1H), 3.66-3.55 (m,
3H), 3.32 (s, 3H), 3.07 (m, 2H), 1.66 (m, 2H), 1.66 (m, 2H),
1.48-1.06 (m, 6H), 1.05 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
139.0, 135.5, 133.5, 133.3, 129.6, 129.3, 128.5, 127.9, 127.6,
96.0, 77.5, 66.1, 56.2, 55.4, 31.3, 28.3, 26.7, 24.7, 22.6, 19.1;
EIMS (m/z) 523 (M - OMe), 493 (M - MOMO), 435 (M - OMe
-
tBu); HRMS calcd for C31H42O5SiSNa 577.24200, found
577.24293.
(1R ,1′′S ,2′S ,5′S ,7R ,S ,12R )-7-(B e n z e n e s u lfo n y l-1-
((ben zyloxy)m eth oxy)-13-((ter t-bu tyldiph en ylsilan yl)oxy)-
12-(m e t h oxym e t h oxy)-1-[5′-(1′′-(m e t h oxym e t h oxy)t r i-
d ecyl)tetr a h yd r ofu r a n -2′-yl]tr id eca n -6-on e (17). To a
solution of 16 (97.4 mg, 0.17 mmol) in THF (0.32 mL) was
added a solution of n-BuLi in hexanes (134.8 mL, 2.5 M, 0.337
mmol) dropwise at 0 °C. The solution was stirred at this
temperature for 15 min, and then was added to a solution of
13a (46 mg, 79.5 mmol) in THF (0.23 mL) at -40 °C. The
mixture was stirred for 1 h at -40 °C f 0 °C and then
quenched with saturated aqueous NH4Cl and diluted with
ether. The organic layer was washed with water and brine
and dried (Na2SO4). Filtration and evaporation of the solvent
afforded the crude mixture, which was chromatographed on a
silica gel column (hexane:EtOAc 9:1) to give 17 (58.0 mg, 66%)
C
60H98O10SiNa 1029.68274, found 1029.67800.
1
as a colorless oil: IR (CHCl3) 1730, 1315 cm-1; H NMR (400
(1′′S,2′S,4R,5′S,8R,S,15R)-15-((Ben zyloxy)m eth oxy)-4,-
MHz, CDCl3) δ 7.75 (m, 2H), 7.65 (m, 4H), 7.53 (t, J ) 8.0 Hz,
2H), 4.91 (d, J ) 6.8 Hz, 1H), 4.82 (d, J ) 6.8 Hz, 1H), 4.80 (d,
J ) 6.8 Hz, 1H), 4.72 (dd, J ) 6.8, 1 Hz, 1H), 4.65 (m, 3H),
4.58 (d, J ) 6.8 Hz, 1H), 3.98 (m, 3H), 3.65 (m, 1H), 3.58 (m,
3H), 3.48 (m, 3H), 3.39 (s, 3H), 3.31 (s, 3H), 2.85 (m, 1H), 2.55
(m, 2H), 2.29 (m, 1H), 1.94-0.89 (m, 43H); 13C NMR (100 MHz,
CDCl3) δ 202.0 (×2), 137.9, 136.4, 136.3, 135.5 (×3), 135.4 (×2),
134.1, 133.3 (×2), 129.6 (×2), 129.3, 128.9, 128.3 (×2), 127.7,
127.6, 127.5, 96.6, 96.1 (×2), 94.6 (×2), 81.7, 81.2, 79.5, 78.5
(×2), 77.5, 77.4, 77.3, 76.9, 76.6, 74.9 (×2), 69.5 (×2), 66.1,
55.6, 55.4, 44.9, 31.8 (×3), 31.4, 31.2, 31.1, 29.7, 29.5 (×4), 29.2
(×2), 28.5, 26.9, 26.7, 26.6 (×2), 25.4, 24.8 (×2), 23.1, 22.5,
20.9, 19.0, 14.1, 14.0; EIMS (m/z) 1123 (M + Na); HRMS calcd
for C64H96O11SiSNa 1123.634035, found 1123.641.
(1R,1′′S,2′S,5′S,12R)-1-((Ben zyloxym et h oxy)-13-((ter t-
b u t yld ip h en ylsila n yl)oxy)-12-(m et h oxym et h oxy)-1-[5′-
(1′′-(m e t h o x y m e t h o x y )t r id e c y l)t e t r a h y d r o fu r a n -2′-
yl]tr id eca n -6-on e (18). To a solution of 17 (279.0 mg, 0.25
mmol) in dry MeOH (5 mL) at 0 °C was added Na2HPO4 (144.0
mg, 1.01 mmol) followed by an Na-Hg amalgam (2.80 g). The
suspension was stirred for 3 h at 0 °C and then diluted with
saturated aqueous NH4Cl and ether. The organic layer was
washed with water and brine and then dried (Na2SO4).
Filtration and solvent removal afforded the crude mixture,
which was purified by column chromatography (hexane:EtOAc
8:2) to give 18 (230.0 mg, 94%) as a colorless oil: [R]D +8 (c
1.4, CHCl3); IR (CHCl3) 1710 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.69 (m, 4H), 7.44-7.29 (m, 11H), 4.92 (d, J ) 6.8 Hz, 1H),
4.83 (d, J ) 6.6 Hz, 1H), 4.81 (d, J ) 6.0 Hz, 1H), 4.78 (d, J )
6.8 Hz, 1H), 4.70-4.60 (m, 4H), 3.99 (m, 2H), 3.78 (m, 1H),
3.65 (m, 3H), 3.47 (m, 1H), 3.40 (s, 3H); 3.36 (s, 3H), 2.35 (t, J
) 7.1 Hz, 4H), 1.93 (m, 3H), 1.59-1.24 (m, 40H), 1.06 (s, 9H),
0.89 (t, J ) 6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 210.9,
137.9, 135.6, 135.5 (×4), 133.4, 129.6 (×2), 128.3 (×2), 127.6
(×5), 127.5 (×2), 96.5, 96.0, 94.6, 81.7, 81.2, 79.5, 78.5, 77.7,
77.2, 69.5, 66.3, 55.6 (×2), 55.4 (×2), 42.6, 42.5, 31.8, 31.5, 31.2,
29.7, 29.6 (×3), 29.5, 29.3 (×2), 28.5, 26.7, 26.6, 25.4, 25.2, 25.1,
23.8, 23.6, 22.6, 19.1, 14.0; EIMS (m/z) 983 (M + Na), 899 (M
10-b is (m e t h o x y m e t h o x y )-15-[5′-(1′′-(m e t h o x y m e t h -
oxy)tr id ecyl)tetr a h yd r ofu r a n -2′-yl]p en ta d eca n oic Acid
Meth yl Ester (20). To a solution of 19 (192.0 mg, 0.19 mmol)
in THF (3.8 mL) at 0 °C was added a solution of n-Bu4NF (0.57
mL, 1.0M, 0.57 mmol) in THF, and the mixture was stirred
for 3 h at rt and then quenched with saturated aqueous NH4-
Cl and diluted with ether, and the organic layer was washed
with water and brine and dried (Na2SO4). Filtration and
evaporation of the solvent followed by column chromatography
(hexane:EtOAc 1:1) gave the corresponding alcohol (139.0 mg,
95%) as a colorless oil: HRMS calcd for C44H80O10Na 791.5694,
found 791.5685.
Solid TPAP (5 mol %) was added in one portion to a stirred
mixture of the above product (31.4 mg, 0.04 mmol), followed
by N-methylmorpholine N-oxide (7.18 mg, 0.06 mmol) and
powdered 4 Å molecular sieves (500 mg/mmol) in CH2Cl2 (0.5
mL) at rt under argon. After 1 h the reaction mixture was
filtered through a pad of silica (EtOAc), the filtrate was
evaporated, and the residue was used in the next step without
further purification.
To a solution of the above aldehyde (18 mg, 0.023 mmol) in
CH2Cl2 (0.2 mL) at rt was added Ph3PdCHCO2Me (10.2 mg,
0.03 mmol). The reaction mixture was stirred for 5 h at rt.
Evaporation of the solvent followed by column chromatography
(hexane:EtOAc 4:1) gave the Wittig adduct (18.8 mg, 97%) as
a colorless oil: HRMS calcd for C47H82O11Na 845.57550, found
845.57710.
To a stirred solution of the above product (61.0 mg, 0.074
mmol) and NiCl2‚6H2O (catalytic amount) in MeOH (0.7 mL)
at 0 °C was added NaBH4 (5.6 mg, 0.148 mmol) in one portion.
The reaction mixture was stirred at 0 °C for 5 min and then
filtered through Celite. The filtrate was evaporated, water was
added to the residue, and the aqueous phase was extracted
several times with ether and dried (Na2SO4). Removal of the
solvent followed by column chromatography (hexane:EtOAc
4:1) afforded 20 (60.0 mg, 97%) as a colorless oil: IR (CHCl3):
1
1738 cm-1; H NMR (400 MHz, CDCl3) δ 7.35-7.27 (m, 5H),
4.91 (d, J ) 6.8 Hz, 1H), 4.81 (d, J ) 6.8 Hz, 1H), 4.80 (d, J )

Total Synthesis of an Annonacin A-Type Acetogenin
J . Org. Chem., Vol. 63, No. 4, 1998 1057
6.8 Hz, 1H), 4.64 (m, 7H), 3.97 (m, 2H), 3.76 (m, 1H), 3.67 (s,
3H), 3.50 (m, 3H), 3.39 (s, 3H), 3.37 (s, 3H), 3.36 (s, 3H), 2.40
(m, 2H), 1.95-1.26 (m, 46H), 0.88 (t, J ) 6.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 174.0, 138.0, 128.2, 127.6, 127.4, 96.6,
95.4, 95.3, 94.6, 81.6, 81.3, 79.5, 78.6, 77.4, 76.4, 69.5, 55.6,
55.5, 55.4, 51.4, 34.2, 34.1, 31.8 (×2), 31.3, 29.9, 29.8, 29.7,
29.6, 29.5 (×3), 29.2 (×2), 28.5, 26.5, 25.8, 25.4, 25.2, 22.6, 14.0;
EIMS (m/z) 847 (M + Na), 641 (M - 3MOMO); HRMS calcd
for C47H84O11Na 847.59113, found 847.58855.
1.41 (d, J ) 6.8 Hz, 3H), 0.88 (t, J ) 7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 173.8, 151.3, 138.0, 130.5, 128.3 (×2),
127.7, 127.5, 96.6, 95.6, 95.3, 94.6, 81.7, 81.3, 79.5, 78.6, 77.4,
77.3, 75.5, 69.5, 55.6 (×2), 55.4, 34.3, 34.2, 31.8 (×2), 31.3, 29.9,
29.8, 29.7, 29.6 (×2), 29.5, 29.3, 28.5, 26.5, 25.8, 25.5, 25.2,
22.6, 19.0, 14.1; EIMS (m/z) 871 (M + Na), 787 (M - MOMO),
665 (M - 3MOMO); HRMS calcd for C49H84O11Na 871.59113,
found 871.59260.
(1′′′S,2′R,2′′S,5S,5′′S,8R,S,13′R)-5-Meth yl-3-{2′,8′,13′-tr i-
h yd r oxy-13′-[5′′-(1′′′-h yd r oxyt r id ecyl)t et r a h yd r ofu r a n -
2′′-yl]tr id ecyl}-5H-fu r a n -2-on e (22). To a solution of 21
(34.0 mg, 0.04 mmol) in CH2Cl2 (1 mL) at -78 °C was added
TMSBr21 (52.9 mL, 0.4 mmol), and the mixture was allowed
to warm to -30 °C over 2 h. The reaction mixture was diluted
with EtOAc (10 mL), washed with a saturated NaHCO3
solution and then brine, and dried (Na2SO4). Removal of the
solvent followed by column chromatography (EtOAc) afforded
22 (20.0 mg, 83%) as a white solid: mp 100-102 °C; [R]D +2.5
(1′′′S ,2′R ,2′′S ,5S ,5′′S ,8R ,S ,13′R )-3-{13′-((B e n z y l-
oxy)m eth oxy)-2′,8′-bis(m eth oxym eth oxy)-13′-[5′′-(1′′′-(m eth -
oxym eth oxy)tr id ecyl)tetr a h yd r ofu r a n -2′′-yl]tr id ecyl}-5-
m eth yl-5H-fu r a n -2-on e (21). A solution of n-BuLi (78.0 mL,
2.5 M in hexane, 0.195 mmol) was added to a solution of
DIPEA (35.06 mL, 0.257 mmol) in anhydrous THF (0.5 mL)
at -78 °C, and the mixture was stirred for 15 min at -78 °C.
A solution of 20 (100 mg, 0.121 mmol) in THF (0.6 mL) was
added to the above mixture. After 30 min, a solution of
O-THP-(S)-lactaldehyde (38.0 mg, 0.24 mmol) in THF (0.3 mL)
was introduced and the reaction mixture was stirred for 25
min at -78 °C before being quenched with saturated aqueous
NH4Cl solution and extracted with ether. The organic layer
was washed with water and brine and dried (Na2SO4).
Evaporation of the solvents afforded the crude mixture which
after column chromatography (hexane:EtOAc 9:1) gave the
product (92.7 mg, 78%) as a mixture of diastereomers (1H NMR
analysis). The mixture was treated with CSA (catalytic
amount in 10 mL of methanol:water 9:1) for 4 h at rt and was
then diluted with ether, washed with a saturated NaHCO3
solution and brine, dried (Na2SO4), and evaporated. To a
solution of the crude product (64.2 mg, 0.074 mmol) in CH2-
Cl2 (0.7 mL) was added TEA (30.9 mL, 0.221 mmol) followed
by MsCl (17.2 mL, 0.22 mmol) at 0 °C, and the mixture was
allowed to warm to rt over 2 h. The reaction mixture was
diluted with ether, washed with a saturated NaHCO3 solution
and brine, dried (Na2SO4), and evaporated. Finally, DBU
(30.16 mL, 0.2 mmol) was added to a solution of the crude
product (95.2 mg, 0.10 mmol) in CH2Cl2 (1 mL) at 0 °C and
the mixture was stirred at this temperature for 30 min. The
reaction was quenched with saturated aqueous NH4Cl, and
the organic layers were extracted with CH2Cl2, washed with
water and brine, and dried (Na2SO4). Solvent removal followed
by column chromatography (hexane:EtOAc 4:1) afforded 21
(34.0 mg, 49%, for three steps) as a colorless oil: IR (CHCl3)
1
(c 0.2, CH2Cl2); IR (CHCl3) 3450-3750, 1755 cm-1; H NMR
(400 MHZ, CDCl3) δ 7.18 (d, J ) 1.3 Hz, 1H), 5.06 (dq, J )
6.8, 1.4 Hz, 1H), 3.84 (m, 4H), 3.58 (m, 1H), 3.38 (m, 1H), 2.52
(ddt, J ) 15.1, 3.4, 1.7 Hz, 1H), 2.39 (dd, J ) 15.1, 8.2 Hz,
1H), 2.03-1.81 (m, 4H), 1.68-1.21 (m, 37H), 1.43 (d, J ) 6.8
Hz, 3H), 0.88 (t, J ) 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 174.5, 151.7, 131.1, 83.1, 82.0, 77.9, 74.2, 71.7, 71.6, 71.4
(×2), 69.8 (×2), 37.2 (×3), 33.3, 33.1, 32.3, 31.8, 29.6, 29.5 (×2),
29.5 (×5), 29.4, 29.2, 29.1, 28.5, 25.9, 25.8, 25.5 (×2), 25.4 (×2),
25.2, 22.6, 19.0, 14.0; EIMS (m/z) 619 (M + Na), 597 (M + 1),
578 (M - H2O); HRMS calcd for C35H64O7Na 619.45496, found
619.45340.
Ack n ow led gm en t. We thank NATO and the Ca-
nary Islands Government for fellowship support to Dr.
T.A.G. and to Dr. G. A. McNaughton-Smith for useful
discussions. Partial financial assistance by NSERC
through the Medicinal Chemistry Chair Program is
gratefully acknowledged. We also thank Dr. M. Simard
for the X-ray crystallographic analysis and Dr. F. Lieb
(Bayer, Leverkusen, Germany) for informing us of the
unavailability of annonacin A.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for intermediates and X-ray ORTEP diagrams for
compound 6 and 13a (28 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
1
1540 cm-1; H NMR (400 MHz, CDCl3) δ 7.35-7.27 (m, 5H),
7.16 (d, J ) 1.4 Hz, 1H), 5.02 (dq, J ) 6.8, 1.5 Hz, 1H), 4.90
(d, J ) 6.8 Hz, 1H), 4.81 (d, J ) 6.8 Hz, 1H), 4.80 (d, J ) 6.8
Hz, 1H), 4.68-4.60 (m, 7H), 3.99 (m, 2H), 3.83-3.76 (m, 2H),
3.50-3.44 (m, 2H), 3.38 (s, 3H), 3.36 (s, 3H), 3.34 (s, 3H), 2.49
(d, J ) 5.8 Hz, 2H), 1.94-1.87 (m, 3H), 1.67-1.25 (m, 38H),
J O9713621