Total synthesis of the Annonaceous acetogenins asiminocin and asiminecin by a bidirectional approach

Article abstract of DOI:10.1021/jo970424k

A total synthesis of the Annonaceous acetogenins asiminocin and asiminecin is described. The approach is bidirectional starting from the (S,S)-tartrate derived dialdehyde 7 and the (R)-α-OSEM stannane 6. Addition of 6 to 7 in the presence of InCl₃ afforded the bis-adduct, anti-diol 8. The derived tosylate 9 was converted to the bis-tetrahydrofuran core unit 10 upon treatment with TBAF. Selective silylation of one of the two equivalent terminal diol groupings led to the OTBS ether alcohol 11. Oxidation to aldehyde 12 and then InCl₃-promoted addition of the (S)-allylic stannane 14 gave the anti adduct 15. Removal of the OH group by reduction of the tosylate 16 with LiBEt₃H yielded the SEM ether 17. Hydrogenation of the three double bonds of 17 followed by cleavage of the terminal silyl ether and oxidation afforded aldehyde 20. Conversion to the vinylic iodide 21 followed by Pd(0)- catalyzed coupling with the (S)-alkynyl butenolide 24 gave the asiminocin derivative 25. Selective hydrogenation of the enyne moiety with diimide and cleavage of the SEM protecting groups completed the synthesis of asiminocin (27). Asiminecin (41) was prepared starting from aldehyde 12 and the OTBS allylic stannane 28. Addition of the latter to the former in the presence of InCl₃ afforded the anti adduct 29 which was protected as the SEM ether 30. Hydrogenation followed by OTBS cleavage with TBAF and selective silylation of the primary alcohol with TBSCl and Et₃N-DMAP led to the secondary alcohol 33. Tosylation and hydrogenolysis with LiEt₃BH removed the C30 OTs group affording the SEM ether 35. The remaining steps were carried out along the lines described for asiminocin via the vinyl iodide 38 which was coupled with acetylenic butenolide 24 to afford enyne 39. Selective reduction with diimide and SEM cleavage completed the synthesis.

Full text of DOI:10.1021/jo970424k

5996
J . Org. Chem. 1997, 62, 5996-6000
Tota l Syn th esis of th e An n on a ceou s Acetogen in s Asim in ocin a n d
Asim in ecin by a Bid ir ection a l Ap p r oa ch
J ames A. Marshall* and Minzhang Chen
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22901
Received March 7, 1997X
A total synthesis of the Annonaceous acetogenins asiminocin and asiminecin is described. The
approach is bidirectional starting from the (S,S)-tartrate derived dialdehyde 7 and the (R)-R-OSEM
stannane 6. Addition of 6 to 7 in the presence of InCl3 afforded the bis-adduct, anti-diol 8. The
derived tosylate 9 was converted to the bis-tetrahydrofuran core unit 10 upon treatment with TBAF.
Selective silylation of one of the two equivalent terminal diol groupings led to the OTBS ether
alcohol 11. Oxidation to aldehyde 12 and then InCl3-promoted addition of the (S)-allylic stannane
14 gave the anti adduct 15. Removal of the OH group by reduction of the tosylate 16 with LiBEt3H
yielded the SEM ether 17. Hydrogenation of the three double bonds of 17 followed by cleavage of
the terminal silyl ether and oxidation afforded aldehyde 20. Conversion to the vinylic iodide 21
followed by Pd(0)-catalyzed coupling with the (S)-alkynyl butenolide 24 gave the asiminocin
derivative 25. Selective hydrogenation of the enyne moiety with diimide and cleavage of the SEM
protecting groups completed the synthesis of asiminocin (27). Asiminecin (41) was prepared starting
from aldehyde 12 and the OTBS allylic stannane 28. Addition of the latter to the former in the
presence of InCl3 afforded the anti adduct 29 which was protected as the SEM ether 30.
Hydrogenation followed by OTBS cleavage with TBAF and selective silylation of the primary alcohol
with TBSCl and Et3N-DMAP led to the secondary alcohol 33. Tosylation and hydrogenolysis with
LiEt3BH removed the C30 OTs group affording the SEM ether 35. The remaining steps were carried
out along the lines described for asiminocin via the vinyl iodide 38 which was coupled with acetylenic
butenolide 24 to afford enyne 39. Selective reduction with diimide and SEM cleavage completed
the synthesis.
Ta ble 1. Com p a r a tive Cytotoxicity of Asim in ocin ,
Asim in ecin , a n d Ad r ia m ycin Aga in st Hu m a n Tu m or Cell
Lin es (ED50 µg/m L2
In the previous paper we described a total synthesis
of the Annonaceous acetogenin asimicin.1 While those
investigations were in progress, McLaughlin and co-
workers published a report on the isolation and structure
elucidation of asiminocin, a C37 acetogenin with nearly
one billion times the cytotoxic potency of a standard
reference, adriamycin, as measured against several hu-
man solid tumor cell lines. A second closely related
isomer, asiminecin, also exhibits impressive antitumor
activity (Table 1).2
R1
R2
A-549a
MCF-7b
HT-29c
asiminocin OH
H
3.1 × 10-12 2.9 × 10-12 <10-12
Asiminocin and asiminecin are members of the asimi-
cin subgroup of Annonaceous acetogenins and, as such,
possess the same basic core bis-tetrahydrofuran th-
reo,trans,threo,trans,threo stereochemistry. In view of
the significant biological activity reported for asiminocin
and the relative scarcity of the natural material,3 we
initiated a total synthesis along the lines described for
asimicin. As will be seen the synthetic route, with minor
modification, can also be used for asiminecin.
Asiminocin differs from asimicin in two obvious and
important respectssthe presence of a C30 (S) hydroxyl
substituent and the absence of a C4 hydroxyl substituent.
These differences require a modification of the stannane
reagent and the butenolide coupling strategy used in our
previous route.1 In the present effort we hoped to
incorporate a convergent rather than a linear introduc-
tion of the butenolide terminus. Specifically, the use of
asiminecin
adriamycin
H
OH 3.3 × 10-7 2.7 × 10-9 <10-12
1.8 × 10-2 1.3 × 10-1
3.6 × 10-2
Lung cancer. Breast cancer. c Colon cancer.
a
b
a shorter chain allylic stannane in the bidirectional
addition would enable us to introduce a preformed
butenolide segment through an appropriate coupling
reaction. This strategy would also allow for the introduc-
tion of the C30 (S)-alcohol.
The requisite stannane 6 was prepared from 4-OTBS-,
1-butanol 14 as outlined in eq 1.5 This six-step process
was effected in 30% overall yield and gave material of
1
>95% ee as judged by the H NMR spectra of the (R)-
and (S)-O-methylmandelate derivatives.6
Dialdehyde 77 was treated with the (R)-R-OSEM allylic
stannane 6 in the presence of InCl3 affording the C2
symmetric adduct 8 in 77% yield (eq 2). The derived bis-
X Abstract published in Advance ACS Abstracts, August 1, 1997.
(1) Marshall, J . A.; Hinkle, K. W. J . Org. Chem. 1997, 62, 5989.
(2) Zhao, G.-X.; Chao, J .-F.; Zeng, L.; Rieser, M. J .; McLaughlin, J .
L. Bioorg. Med. Chem. 1996, 4, 25. Zhao, G.-X.; Miesbauer, L. R.;
Smith, D. L.; McLaughlin, J . L. J . Med. Chem. 1994, 37, 1971.
(3) For example, 15 kg of air-dried pulverized stem bark of Asimina
triloba (L.) Dunal afforded only 10 mg of asiminecin after multiple
partition extractions, several column chromatographies, preparative
HPLC, and, finally, preparative TLC fractionation.2
(4) McDougal, P. G.; Rico, J . G.; Oh, Y. I.; Condon, B. D. J . Org.
Chem. 1986, 51, 3388.
(5) Marshall, J . A.; Welmaker, G. S.; Gung, B. W. J . Am. Chem.
Soc. 1991, 113, 647.
(6) Trost, B. M.; Belletire, J . L.; Godleski, S.; McDougal, P. G.;
Balkovec, J . M.; Baldwin, J . J .; Christy, M. E.; Ponticello, G. S.; Varga,
S. L.; Springer, J . D. J . Org. Chem. 1986, 51, 2370.
(7) Marshall, J . A.; Hinkle, K. W. J . Org. Chem. 1996, 61, 4247.
S0022-3263(97)00424-6 CCC: $14.00 © 1997 American Chemical Society

Synthesis of Annonaceous Acetogenins
J . Org. Chem., Vol. 62, No. 17, 1997 5997
Hydrogenation of triene 17 over Rh-Al2O3 afforded the
hexahydro derivative 18. Cleavage of the TBS ether of
18 and oxidation of the alcohol 19 gave aldehyde 20
which was converted to the (E)-vinyl iodide 21 (eq 4).10
tosylate 9, upon mild heating with TBAF in THF, gave
the threo,trans,threo,trans,threo bis-THF diol 10 in 76%
yield. Selective silylation4 followed by Swern oxidation8
yielded the aldehyde 12. The silylation reaction gave
mainly the mono OTBS derivative 11 and recovered diol
10. Only small amounts of the bis-OTBS derivative were
isolated. The three products were easily separated on
silica gel with little loss of material. The apparent rate
difference between mono and bis silylation may result
from internal H-bonding by one of the two equivalent
terminal OH functions.1
An appropriate butenolide coupling partner, 24, for
vinylic iodide 21 was prepared from the (R)-propargylic
alcohol 2211 via the mesylate 23 through Pd(0)-catalyzed
hydrocarbonylation12 and subsequent treatment of the
intermediate allenic acid with catalytic AgNO3 on silica
gel (eq 5).13 The ee of this butenolide was found to be
>95% by HPLC analysis.14 The configuration assign-
ment is made by analogy to previous conversions.12
Pd(0)-catalyzed coupling of vinylic iodide 21 with
alkynylbutenolide 24 afforded the enyne 25 in 96% yield
(eq 6).15 Selective reduction with Wilkinson’s catalyst in
the manner of Hoye and co-workers resulted in ap-
preciable reduction of the butenolide double bond.16 None
of the corresponding reduction product was detected
when a C4 ODPS analogue of 25 was similarly hydro-
genated.17 Thus it would appear that the proximal C4
substituent retards this undesired reduction. The prob-
lem could be circumvented in the case of 25 through use
of diimide, generated in situ from tosylhydrazine.18
Removal of the SEM protecting groups from the
reduced product was effected with PPTS in ethanol.1 The
resulting triol, 27, exhibited 1H and 13C NMR spectra
Completion of the left-hand side chain and installation
of the C30 (S) hydroxyl substituent was effected by means
of the (S)-stannane 14 prepared from enal 13 along the
same lines as 6 (eq 3).5
(10) Takai, K.; Nitta, K.; Utimoto, K. J . Am. Chem. Soc. 1986, 108,
7408. Evans, D. A.; Ng, H. P.; Rieger, D. L. J . Am. Chem. Soc. 1993,
115, 11446.
(11) Marshall, J . A.; Xie, S. J . Org. Chem. 1995, 60, 7230.
(12) Marshall, J . A.; Wolf, M. A. J . Org. Chem. 1996, 61, 3238.
(13) Marshall, J . A.; Sehon, C. A. J . Org. Chem. 1995, 60, 5966.
(14) A Chiracel OB-H column was used with 90:10 hexanes-i-PrOH
as the eluting solvent.
(15) Cf. (a) Sonogashira, K. In Comprehensive Organic Synthesis;
Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 3, Chapter 2.4.
(b) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467.
(16) Hoye, T. R.; Hanson, P. R.; Kovelsky, A. C.; Ocain, T. D.; Zhung,
Z. J . Am. Chem. Soc. 1991, 113, 9369.
Treatment of aldehyde 12 with stannane 14 in the
presence of InCl3 afforded the anti adduct 15 in nearly
quantitative yield. The ee of the C29 carbinyl center was
found to be greater than 95% by 1H NMR analysis of the
(R)- and (S)-O-methylmandelates.6 On the basis of this
analysis, and our previous findings, we can surmize that
the center at C30 is (S) and of equally high ee.7 Hydro-
genolysis of the C29 alcohol was effected by reduction of
the tosylate 16 with LiBEt3H.9
(17) Cf. Hoye, T. R.; Tan, L. Tetrahedron Lett. 1995, 36, 1995. Sinha,
S. C.; Sinha, A.; Yazbak, A.; Keinan, E. J . Org. Chem. 1996, 61, 7640.
Hoye, T. R.; Ye, Z. J . Am. Chem. Soc. 1996, 118, 1801.
(18) Hart, D. J .; Hong, W.-P.; Hsu, L.-Y. J . Org. Chem. 1987, 52,
4665.
(8) Omurka, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(9) Brown, H. C.; Kim. S. C.; Krishnamurthy, S. J . Org. Chem. 1980,
45, 1.

5998 J . Org. Chem., Vol. 62, No. 17, 1997
Marshall and Chen
scribed acetylenic butenolide 24,15 and the resulting
enyne 39 was selectively reduced with diimide to the
hexahydro derivative 40. No trace of product resulting
from butenolide reduction could be detected. Removal
of the SEM protecting groups, as before, yielded asimi-
necin (41) (eq 8). The spectral properties of this material
and those of the tris Mosher ester derivative were in
accord with the reported values.2
indentical to those of asiminocin. The optical rotation
was also in accord with the reported value.2
Aldehyde 12 also served as the starting point for a
synthesis of asiminecin. In this case the OTBS stannane
28, prepared as described for the OSEM analogue 14, was
used to introduce the requisite 29(R) stereocenter. The
InCl3-promoted addition afforded the adduct 29 in 81%
yield. Conversion to the SEM ether 30 followed by
hydrogenation led to the hexahydro derivative 31. The
derived diol 32 gave rise to the mono-TBS derivative 33
in 84% yield by treatment with TBSCl and Et3N, DMAP
(eq 7).
The foregoing syntheses of asiminocin and asiminecin,
like our previous synthesis of asimicin,1 follows a bidi-
rectional approach. However by using a shorter chain
allylic stannane in the intial bis-addition, we increase
the flexibility of the route and thereby permit the
introduction of an intact butenolide moiety. In the
present syntheses the selective reduction of side chain
unsaturation is effectively achieved by diimide. This
methodology should find general usage in the synthesis
of Annonaceous acetogenins.17
Exp er im en ta l Section
Diol 8. A suspension of InCl3 (440 mg, 2.0 mmol) in EtOAc
(50 mL) was placed in a sonication bath for 15 min to dissolve
the InCl3. The solution was removed from the bath, and
dialdehyde 7 (402 mg, 1.0 mmol) was added. The resulting
mixture was cooled to -78 °C followed by slow addition of a
solution of stannane 6 (1.65 g, 2.5 mmol) in EtOAc (10 mL)
with stirring. After addition, the reaction mixture was stirred
for 30 min at -78 °C and then allowed to warm to room
temperature and stirred overnight. The reaction was quenched
with saturated NaHCO3. After separation, the aqueous layer
was extracted with Et2O. The combined organic layers were
dried over MgSO4, treated with Et3N (3 mL), and concentrated.
The residue was purified by flash chromatography (10% EtOAc
in hexanes) to give 0.86 g (77%) of diol 8 as a colorless oil:
[R]D -24.5 (c 2.65, CH2Cl2); IR (neat) 3484, 2951, 1248, and
1108 cm-1; 1H NMR δ 5.72 (dt, J ) 15.3 and 6.6 Hz, 2H), 5.41
(dd, J ) 15.3 and 8.7 Hz, 2H), 4.71, 4.65 (ABq, J ) 6.6 Hz,
4H), 3.95 (dd, J ) 8.1 and 3.3 Hz, 2H), 3.76-3.49 (m, 10H),
2.25 (br s, 2H), 2.12 (q, J ) 7.2 Hz, 4H), 1.91-1.20 (m, 12H),
0.96-0.87 (m, 40H), and 0.04-0.02 (m, 42H); 13C NMR δ 136.4,
125.3, 92.1, 80.6, 75.9, 74.3, 65.3, 62.5, 32.3, 29.9, 28.8, 26.8,
25.9, 25.8, 18.1, 18.0, -1.4, -4.1, -4.6, and -5.3. Anal. Calcd
for C56H122O10Si6: C, 59.84; H, 10.94. Found: C, 59.96; H,
10.95.
The remaining steps of the synthesis parallel those
employed for asiminocin. Thus hydrogenolysis of the
tosylate 34 with LiEt3BH afforded the deoxy derivative
35. Cleavage of the TBS ether followed by Swern
oxidation gave aldehyde 37 in 87% yield. The derived
vinyl iodide 3810 was coupled with the previously de-

Synthesis of Annonaceous Acetogenins
J . Org. Chem., Vol. 62, No. 17, 1997 5999
Bis-Tosyla te 9. To a stirred solution of diol 8 (1.0 g, 0.89
mmol) in pyridine (10 mL) at 0 °C was added p-TsCl (2.4 g, 12
mmol). The resulting mixture was stirred for 30 min and then
warmed to room temperature and stirred for another 18 h.
EtOAc and brine were added. After separation, the aqueous
layer was extracted with EtOAc. The combined organic layers
were dried over MgSO4 and concentrated. The residue was
purified by flash chromatography (10% EtOAc in hexanes) to
give 0.95 g (75%) of bis-tosylate 8 as a colorless oil: [R]D -27.2
(c 1.56, CHCl3); IR (neat) 2951, 2855, 1466, 1370, and 1099
cm-1; 1H NMR δ 7.78 (d, J ) 8.4 Hz, 4H), 7.30 (d, J ) 8.4 Hz,
4H), 5.72 (dt, J ) 15.6 and 6.6 Hz, 2H), 5.24 (dd, J ) 15.6 and
7.8 Hz, 2H), 4.59, 4.51 (ABq, J ) 6.6 Hz, 4H), 4.46 (m, 2H),
4.24 (dd, J ) 7.5 and 3.0 Hz, 2H), 3.71-3.43 (m, 8H), 3.33 (br
d, J ) 9.0 Hz, 2H), 2.42 (s, 6H), 2.09 (m, 4H), 1.72-1.45 (m,
12H), 0.94-0.81 (m, 40H), and 0.04-0.02 (m, 42H); 13C NMR
δ 144.0, 136.5, 134.7, 129.5, 127.9, 125.2, 92.1, 85.5, 77.8, 75.3,
65.1, 62.4, 32.1, 28.7, 27.0, 26.4, 25.9, 25.8, 21.6, 18.3, 17.9,
-1.4, -4.1, -4.7, and -5.3. Anal. Calcd for C70H134O14S2Si6:
C, 58.69; H, 9.43. Found: C, 58.78; H, 9.50.
bis-Tetr a h yd r ofu r a n Diol 10. To a stirred solution of bis-
tosylate 9 (3.60 g, 2.5 mmol) in THF (100 mL) at rt was added
TBAF (1.0 M solution in THF, 20 mL, 20 mmol). The resulting
mixture was heated to 50 °C and stirred for 12 h. After being
cooled to rt, the mixture was concentrated. The residue was
purified by flash chromatography (75% EtOAc in hexanes) to
give 1.2 g (76%) of bis-tetrahydrofuran 10 as a colorless oil:
[R]D -66.2 (c 1.33, CH2Cl2); IR (neat) 3441, 2943, 1449, and
1248 cm-1; 1H NMR δ 5.71 (dt, J ) 15.3 and 6.6 Hz, 2H), 5.41
(dd, J ) 15.3 and 7.8 Hz, 2H), 4.70, 4.66 (ABq, J ) 6.6 Hz,
4H), 4.06-3.92 (m, 6H), 3.77-3.48 (m, 8H), 2.15 (m, 4H), 1.94-
1.60 (m, 12H), 0.92 (m, 4H), and 0.01 (s, 18H); 13C NMR δ
134.7, 127.1, 91.8, 81.4, 81.3, 78.4, 64.8, 61.7, 31.7, 28.6, 27.8,
27.7, 17.9, and -1.6. Anal. Calcd for C32H62O8Si2: C, 60.91;
H, 9.90. Found: C, 60.77; H, 9.87.
to give 0.51 g (85%) of aldehyde 12 as a yellow oil: [R]D -58.0
(c 1.32, CHCl3); IR (neat) 2951, 2887, 1725, and 1253 cm-1
;
1H NMR δ 9.76 (br s, 1H), 5.70 (dt, J ) 15.3 and 6.6 Hz, 2H),
5.43 (dd, J ) 15.3 and 7.8 Hz, 1H), 5.35 (dd, J ) 15.3 and 7.8
Hz, 1H), 4.70, 4.66 (ABq, J ) 6.9 Hz, 2H), 4.67 (s, 2H), 4.06-
3.90 (m, 6H), 3.78-3.48 (m, 6H), 2.53 (m, 2H), 2.39 (m, 2H),
2.10 (m, 2H), 1.90-1.54 (m, 10H), 0.92 (m, 4H), 0.89 (s, 9H),
0.04 (s, 6H), and 0.01 (s, 18H). Anal. Calcd for C42H88O8Si4:
C, 61.41; H, 10.03. Found: C, 61.37; H, 9.95.
Alcoh ol 15. The procedure for diol 8 was followed with 0.30
g (1.4 mmol) of InCl3 in 25 mL of EtOAc, 0.50 g (0.67 mmol) of
aldehyde 12, and 1.0 g (2.0 mmol) of stannane 14 in 10 mL of
EtOAc. After extraction and removal of solvent, the residue
was purified by flash chromatography (20% EtOAc in hexanes)
to give 0.65 g (100%) of alcohol 15 as a colorless oil: [R]D -17.2
(c 1.44, CHCl3); IR (neat) 3476, 2943, 1248, and 1029 cm-1
;
1H NMR δ 5.82-5.65 (m, 3H), 5.41-5.31 (m, 3H), 4.72-4.63
(m, 6H), 4.06-3.91 (m, 7H), 3.78-3.48 (m, 7H), 3.60 (t, J )
6.6 Hz, 2H), 2.31-1.50 (m, 18H), 1.00 (t, J ) 7.2 Hz, 3H), 0.97-
0.86 (m, 6H), 0.89 (s, 9H), 0.04 (s, 6H), 0.02 (s, 9H), and 0.01
(s, 18H); 13C NMR δ 138.8, 135.1, 135.0, 127.0, 126.9, 124.2,
92.1, 91.9, 81.50, 81.46, 81.3, 80.7, 78.7, 78.6, 72.9, 65.3, 65.4,
62.5, 32.3, 31.8, 28.8, 28.7, 28.0, 27.8, 26.0, 25.4, 18.3, 18.1,
13.5, -1.4, and -5.3. Anal. Calcd for C49H98O10Si4: C, 61.33;
H, 10.29. Found: C, 61.33; H, 10.36.
Tosyla te 16. The procedure described for bis-tosylate 9 was
employed with 0.54 g (0.56 mmol) of alcohol 15 in 10 mL of
pyridine and 1.0 g (5.2 mmol) of p-TsCl. After extraction and
removal of solvent the residue was purified by flash chroma-
tography (15% EtOAc in hexanes) to give 0.57 g (90%) of
1
tosylate 16 as a colorless oil: [R]D -19.9 (c 1.63, CHCl3); H
NMR δ 7.79 (d, J ) 8.1 Hz, 2H), 7.31 (d, J ) 8.1 Hz, 2H),
5.75-5.64 (m, 2H), 5.59 (dt, J ) 15.3 and 6.6 Hz, 1H), 5.35
(dd, J ) 15.3 and 7.8 Hz, 1H), 5.28 (dd, J ) 15.3 and 7.8 Hz,
1H), 5.16 (dd, J ) 15.3 and 7.8 Hz, 1H), 4.70, 4.67 (ABq, J )
6.6 Hz, 2H), 4.65 (s, 2H), 4.56, 4.46 (ABq, J ) 6.9 Hz, 2H),
4.52 (m, 1H), 4.13 (dd, J ) 7.5 and 3.0 Hz, 1H), 4.07-3.90 (m,
6H), 3.79-3.40 (m, 6H), 3.60 (t, J ) 6.9 Hz, 2H), 2.44 (s, 3H),
2.13-1.54 (m, 18H), 0.96 (t, J ) 7.5 Hz, 3H), 0.95-0.85 (m,
6H), 0.89 (s, 9H), 0.04 (s, 6H), and 0.01 (s, 27H). Anal. Calcd
for C56H104O12SSi4: C, 60.39; H, 9.41. Found: C, 60.29; H,
9.35.
Mon o-TBS Eth er Alcoh ol 11. To a solution of diol 10 (290
mg, 0.46 mmol) in THF (10 mL) at rt was added NaH (95%;
20 mg, 0.79 mmol). The resulting mixture was stirred for 30
min, and TBSCl (85 mg, 0.56 mmol) was added. The reaction
mixture was stirred for another 40 min. The reaction was
quenched with saturated NaHCO3, and Et2O was added. After
separation, the aqueous layer was extracted with Et2O. The
combined organic layers were dried over MgSO4 and concen-
trated. The residue was purified by flash chromatography
(10% EtOAc in hexanes first, then 30% EtOAc in hexanes, then
75% EtOAc in hexanes) to give 130 mg (38%) of OTBS ether
11 along with 5% of the bis-OTBS derivative and 150 mg (52%)
of recovered diol 10. 11: [R]D -53.6 (c 1.76, CH2Cl2); IR (neat)
3484, 2951, 1466, and 1248 cm-1; 1H NMR δ 5.71 (dt, J ) 15.3
and 6.6 Hz, 1H), 5.70 (dt, J ) 15.3 and 6.6 Hz, 1H), 5.40 (dd,
J ) 15.3 and 7.8 Hz, 1H), 5.35 (dd, J ) 15.3 and 7.8 Hz, 1H),
4.70, 4.66 (ABq, J ) 6.9 Hz, 4H), 4.07-3.93 (m, 6H), 3.78-
3.48 (m, 8H), 2.12 (m, 4H), 1.94-1.54 (m, 12H), 0.92 (m, 4H),
0.89 (s, 9H), 0.04 (s, 6H), and 0.01 (s, 18H); 13C NMR δ 135.0,
134.6, 127.3, 126.8, 91.9, 91.8, 81.3, 81.3, 81.3, 78.6, 78.5, 64.8,
64.8, 62.5, 62.1, 32.2, 31.9, 28.7, 28.6, 27.9, 27.8, 25.9, 18.4,
18.0, -1.5, and -5.3. Anal. Calcd for C36H76O8Si3: C, 61.24;
H, 10.28. Found: C, 61.30; H, 10.25.
Tr ien e 17. To a stirred solution of tosylate 16 (0.55 g, 0.49
mmol) in THF (5 mL) under Ar was added LiBEt3H (1.0 M in
THF, 5.0 mL, 5.0 mmol). The resulting solution was stirred
at 40 °C for 24 h. The reaction was quenched with saturated
NH4Cl, and Et2O was added. After separation, the aqueous
layer was extracted with Et2O. The combined organic layers
were dried over MgSO4 and concentrated. The residue was
purified by flash chromatography (10% EtOAc in hexanes, then
20% EtOAc in hexanes) to give 0.38 g (81%) of hydrogenolysis
product 17, along with 50 mg (11%) of alcohol 15: [R]D -23.8
1
(c 1.31, CHCl3); H NMR δ 5.75-5.61 (m, 3H), 5.39-5.29 (m,
2H), 5.23 (ddd, J ) 15.3, 8.1, and 1.5 Hz, 1H), 4.70, 4.66 (ABq,
J ) 6.9 Hz, 2H), 4.70, 4.65 (ABq, J ) 6.9 Hz, 2H), 4.70, 4.57
(ABq, J ) 6.9 Hz, 2H), 4.06-3.90 (m, 7H), 3.79-3.46 (m, 6H),
3.60 (t, J ) 6.6 Hz, 2H), 2.13-1.23 (m, 20H), 0.99 (t, J ) 7.5
Hz, 3H), 0.96-0.85 (m, 6H), 0.89 (s, 9H), 0.04 (s, 6H), 0.02 (s,
9H), and 0.01 (s, 18H). Anal. Calcd for C49H98O9Si4: C, 62.37;
H, 10.47. Found: C, 62.47; H, 10.33.
1
Da ta for bis-OTBS: [R]D -50.7 (c 1.21, CHCl3); H NMR
δ 5.70 (dt, J ) 15.3 and 6.6 Hz, 2H), 5.35 (dd, J ) 15.3 and
7.8 Hz, 2H), 4.70, 4.66 (ABq, J ) 6.9 Hz, 4H), 4.06-3.93 (m,
6H), 3.79-3.48 (m, 8H), 2.10 (m, 4H), 1.96-1.54 (m, 12H), 0.92
(m, 4H), 0.89 (s, 18H), 0.04 (s, 12H), and 0.01 (s, 18H). Anal.
Calcd for C42H90O8Si4: C, 61.48; H, 10.55. Found: C, 61.57;
H, 10.61.
TBS Eth er 18. In a 25-mL round bottom flask was placed
triene 17 (0.36 g, 0.38 mmol), EtOAc (15 mL), and 5% Rh/
Al2O3 (103 mg, 0.05 mmol). The reaction atmosphere was
flushed first with Ar and then with H2, and then a ballon
containing H2 was affixed to the flask. After being stirred for
12 h, the reaction mixture was filtered through a Celite bed
and the filtrate was concentrated. The residue was purified
by flash chromatography (10% EtOAc in hexanes) to yield 0.34
g (94%) of hydrogenated product 18 as a colorless oil: [R]D
+29.1 (c 1.50, CHCl3); 1H NMR δ 4.84, 4.71 (ABq, J ) 6.9 Hz,
4H), 4.68 (s, 2H), 4.09 (dt, J ) 8.1 and 5.7 Hz, 2H), 3.90 (m,
2H), 3.72-3.45 (m, 11H), 1.99-1.23 (m, 32H), 0.97-0.87
(m, 9H), 0.88 (s, 9H), 0.04 (s, 6H), and 0.01 (m, 27H); 13C NMR
δ 94.9, 93.5, 81.7, 81.2, 79.3, 77.2, 65.2, 64.9, 63.2, 34.3,
34.2, 32.9, 31.1, 30.2, 28.1, 27.5, 26.0, 25.9, 25.8, 25.6, 25.3,
22.9, 18.3, 18.1, 14.0, -1.4, and -5.3. Anal. Calcd for
C49H104O9Si4: C, 61.97; H, 11.04. Found: C, 62.07; H, 11.14.
Ald eh yd e 12. To a stirred solution of oxalyl chloride (0.44
mL, 5.0 mmol) in CH2Cl2 (50 mL) at -78 °C was slowly added
DMSO (0.71 mL, 10 mmol). The resulting mixture was stirred
for 20 min. A solution of alcohol 11 (0.60 g, 0.81 mmol) in
CH2Cl2 (10 mL) was then added. The mixture was stirred for
1 h, followed by addition of Et3N (2.8 mL). After being stirred
for an additional 5 min at -78 °C, the reaction mixture was
slowly warmed to rt. The reaction was quenched with
saturated NH4Cl, and H2O was added. After separation, the
aqueous layer was extracted with Et2O. The combined organic
layers were dried over MgSO4 and concentrated. The residue
was purified by flash chromatography (20% EtOAc in hexanes)

6000 J . Org. Chem., Vol. 62, No. 17, 1997
Marshall and Chen
Alcoh ol 19. To a stirred solution of TBS ether 18 (0.32 g,
0.34 mmol) in THF (10 mL) was added TBAF (1.0 M solution
in THF; 1.5 mL, 1.5 mmol). The reaction mixture was stirred
at rt for 12 h and then concentrated. The residue was purified
by flash chromatography (30% EtOAc in hexanes) to give 0.28
g (100%) of alcohol 19 as a colorless oil: [R]D +31.1 (c 1.30,
CHCl3); IR (neat) 3484, 2943, and 1055 cm-1; 1H NMR δ 4.84,
4.71 (ABq, J ) 6.9 Hz, 2H), 4.83, 4.71 (ABq, J ) 6.9 Hz, 2H),
4.68 (s, 2H), 4.00 (m, 2H), 3.90 (m, 2H), 3.72-3.39 (m, 11H),
1.95-1.30 (m, 32H), 0.97-0.87 (m, 9H), and 0.01 (m, 27H);
13C NMR δ 94.7, 93.3, 81.6, 81.5, 81.1, 79.3, 79.1, 77.1, 65.1,
65.07, 64.9, 62.6, 34.2, 34.0, 32.6, 31.0, 30.9, 30.1, 28.1, 28.0,
27.4, 25.8, 25.7, 25.4, 25.2, 22.8, 18.0, 14.0, and -1.5. Anal.
Calcd for C43H90O9Si3: C, 61.82; H, 10.86. Found: C, 61.77;
H, 10.79.
24 as a light yellow oil: [R]D +43.4 (c 1.72, CHCl3); IR (neat)
2934, 1754, and 1090 cm-1 1H NMR δ 7.02 (br s, 1H), 5.00
;
(dq, J ) 6.9 and 1.2 Hz, 1H), 2.29 (t, J ) 6.9 Hz, 2H), 2.22 (dt,
J ) 6.9 and 2.4 Hz, 2H), 1.95 (t, J ) 2.4 Hz, 1H), 1.74-1.51
(m, 4H), and 1.40 (d, J ) 6.9 Hz, 3H). Anal. Calcd for
C11H14O2: C, 74.13; H, 7.92. Found: C, 74.09; H, 7.99.
En yn e 25. To a stirred solution of iodide 21 (95 mg, 0.10
mmol) in Et2NH (5 mL) under Ar were added (PPh3)2PdCl2 (7
mg, 0.010 mmol), CuI (6 mg, 0.030 mmol), and butenolide 24
(mg, mmol). The resulting mixture was stirred for 2 h and
concentrated. The residue was purified by column chroma-
tography (20% EtOAc in hexanes) to give 96 mg (96%) of enyne
25 as a yellow oil: [R]D +31.7 (c 1.33, CHCl3); IR (neat) 2934,
1
1763, and 1029 cm-1; H NMR δ 7.02 (m, 1H), 6.04 (dt, J )
15.9 and 6.9 Hz, 1H), 5.44 (dt, J ) 15.9 and 1.5 Hz, 1H), 5.00
(m, 1H), 4.85, 4.71 (ABq, J ) 6.9 Hz, 2H), 4.84, 4.71 (ABq, J
) 6.9 Hz, 2H), 4.68 (s, 2H), 4.00 (m, 2H), 3.91 (m, 2H), 3.72-
3.46 (m, 9H), 2.35-2.27 (m, 4H), 2.09-1.25 (m, 36H), 1.41 (d,
J ) 6.9 Hz, 3H), 0.98-0.88 (m, 9H), and 0.01 (m, 27H). Anal.
Calcd for C55H102O10Si3: C, 65.56; H, 10.20. Found: C, 65.30;
H, 10.10.
Ald eh yd e 20. The procedure for aldehyde 12 was followed
with oxalyl chloride (0.11 mL, 1.3 mmol) in CH2Cl2 (10 mL),
DMSO (0.18 mL, 2.5 mmol), and alcohol 19 (0.27 g, 0.32 mmol)
in CH2Cl2 (2 mL). The product was purified by flash chroma-
tography (15% EtOAc in hexanes) to give 0.25 g (93%) of
aldehyde 20 as a colorless oil: [R]D +33.1 (c 1.35, CHCl3); IR
1
(neat) 2951, 1728, and 1038 cm-1; H NMR δ 9.76 (t, J ) 1.5
Asim in ocin (27). To a stirred solution of 94 mg (0.093
mmol) of enyne 25 and 1.2 g (6.4 mmol) of p-toluenesulfonyl
hydrazide in 10 mL of dimethoxyethane at reflux was added
a solution of 0.60 g (7.3 mmol) of NaOAc in 10 mL of H2O over
a 4-h period. The mixture was then cooled to rt, poured into
H2O, and extracted with CH2Cl2. The combined organic layers
were dried over MgSO4 and concentrated. The residue was
purified by column chromatography (20% EtOAc in hexanes)
to give 80 mg (85%) of hexahydro product 26 as a colorless oil:
[R]D +29.2 (c 1.21, CHCl3); IR (neat) 2925, 1763, and 1064
Hz, 1H), 4.84, 4.71 (ABq, J ) 6.9 Hz, 2H), 4.83, 4.71 (ABq, J
) 6.9 Hz, 2H), 4.68 (s, 2H), 4.00 (m, 2H), 3.90 (m, 2H), 3.72-
3.47 (m, 9H), 2.42 (dt, J ) 7.5 and 1.5 Hz, 2H), 1.96-1.30 (m,
30H), 0.96-0.87 (m, 9H), and 0.01 (m, 27H); 13C NMR δ 202.3,
94.9, 94.8, 93.4, 81.7, 81.4, 81.2, 79.3, 79.0, 77.1, 65.2, 65.1,
64.9, 43.8, 34.3, 34.0, 31.0, 30.8, 30.1, 28.1, 28.09, 28.0, 27.5,
25.7, 25.3, 22.8, 22.2, 18.0, 14.0, and -1.5. Anal. Calcd for
C43H88O9Si3: C, 61.97; H, 10.64. Found: C, 62.06; H, 10.60.
Vin yl Iod id e 21. To a stirred suspension of CrCl2 (0.25 g,
1.9 mmol) in THF (6 mL) was added a solution of aldehyde 20
(0.23 g, 0.28 mmol) and iodoform (0.25g, 0.63 mmol) in 1,4-
dioxane (4 mL). The resulting mixture was stirred for 12 h,
and Et2O and H2O were added. After separation, the aqueous
layer was extracted with Et2O. The combined organic layers
were washed with Na2S2O3, dried over MgSO4, and concen-
trated. The residue was purified by flash chromatography (5%
of EtOAc in hexanes, then 10% EtOAc in hexanes) to give 0.18
g (69%) of vinyl iodide 21 as a yellow oil: [R]D +27.8 (c 1.63,
CHCl3); 1H NMR δ 6.47 (dt, J ) 14.1 and 7.5 Hz, 1H), 5.95 (d,
J ) 14.1 Hz, 1H), 4.82, 4.68 (ABq, J ) 6.9 Hz, 2H), 4.81, 4.68
(ABq, J ) 6.9 Hz, 2H), 4.66 (s, 2H), 3.97 (m, 2H), 3.88 (m,
2H), 3.69-3.44 (m, 9H), 2.10-1.23 (m, 32H), 0.96-0.85 (m,
9H), and -0.01 (s, 27H); 13C NMR δ 146.4, 94.8, 93.4, 81.7,
81.5, 81.2, 79.3, 79.1, 77.1, 74.4, 65.2, 65.1, 64.9, 35.9, 34.3,
34.0, 31.1, 30.8, 30.1, 28.5, 28.1, 28.0, 27.5, 25.7, 25.3, 25.0,
22.8, 18.0, 14.0, and -1.5. Anal. Calcd for C44H89IO8Si3: C,
55.20; H, 9.37. Found: C, 55.37; H, 9.44.
1
cm-1; H NMR δ 6.98 (m, 1H), 4.99 (m, 1H), 4.85, 4.71 (ABq,
J ) 6.9 Hz, 2H), 4.84, 4.71 (ABq, J ) 6.9 Hz, 2H), 4.68 (s,
2H), 4.00 (m, 2H), 3.91 (m, 2H), 3.74-3.46 (m, 9H), 2.26 (br t,
J ) 6.9 Hz, 2H), 1.96-1.25 (m, 49H), 0.97-0.86 (m, 9H), and
0.01 (m, 27H).
A solution of 76 mg (0.075 mmol) of the above product, PPTS
(250 mg, 1.0 mmol), and EtOH (10 mL) was stirred at 75 °C
for 16 h, cooled to rt, and concentrated under reduced pressure.
The residue was purified by flash chromatography (2% MeOH
in 7:3 EtOAc:hexanes) to give 38 mg (82%) of asiminocin (27)
as a colorless oil: [R]D +19 (c 0.82, CHCl3) (lit.2 +26, but
measured on a 1-mg sample in 1 mL of solvent); IR (neat) 3439,
2927, 2853, and 1747 cm-1 1H NMR δ 6.98 (q, J ) 1.5 Hz,
;
1H), 4.99 (m, 1H), 3.84 (m, 4H), 3.57 (m, 1H), 3.38 (m, 2H),
2.25 (tt, J ) 7.6 and 1.5 Hz, 2H), 1.97-1.25 (m, 46H), 1.39 (d,
J ) 6.9 Hz, 3H), and 0.90 (t, J ) 6.9 Hz, 3H); 13C NMR δ 173.9,
148.8, 134.3, 83.2, 83.1, 81.8, 77.4, 74.0, 73.9, 71.9, 37.3, 37.1,
33.4, 33.3, 29.7, 29.6, 29.5, 29.3, 29.1, 29.0, 28.3, 27.8, 27.4,
25.6, 25.5, 25.4, 25.1, 22.7, 19.2, and 14.1.
Bu ten olid e 24. To a stirred solution of alcohol 22 (0.33 g,
2.2 mmol) in CH2Cl2 (30 mL) at -78 °C under N2 was added
Et3N (0.75 mL, 5.4 mmol), followed by MsCl (0.30 mL, 3.9
mmol). The reaction mixture was stirred at -78 °C for 1.5 h,
and a solution of saturated NaHCO3 was added. The mixture
was then warmed to rt, and Et2O was added. After separation,
the aqueous layer was extracted with EtOAc. The combined
organic layers were washed with brine, dried over MgSO4, and
concentrated to give the crude mesylate 23 as a brown oil.
In a round bottom flask under Ar were placed Pd2(dba)3 (8
mg, 0.009 mmol), PPh3 (16 mg, 0.061 mmol), and THF (15 mL).
The flask was then flushed with CO, and the mixture was
stirred for 5 min. The resulting solution was transfered to a
Parr reactor containing a mixture of crude mesylate obtained
above, H2O (1.5 mL), and THF (20 mL). The Parr reactor was
charged with 200 psi of CO gas. After being stirred for 1 h,
the reaction mixture was washed with brine. The aqueous
layer was extracted with EtOAc (15 mL). The combined
organic layers were dried over MgSO4 and filtered.
Ack n ow led gm en t. This research was supported by
Research Grants GM 39998 from the National Institutes
of General Medical Sciences and CHE 9220166 from the
National Science Foundation. We thank Professor J .
L. McLaughlin for the NMR spectra of asiminocin and
asiminecin.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for compounds 2-6, 14, 22, and 29-41; 1H NMR
spectra for compounds 2, 3, 4, 6, 6 (S)-mandelate, 6 (R)-
mandelate, 10, 14, 14 (S)-mandelate, 14 (R)-mandelate, 25,
26, asiminocin (27), authentic asiminocin, 28, 29, 32, 40,
asiminecin (41), 41 (S)-MPTA ester, 41(R)-MPTA ester, and
authentic asiminecin; 13C NMR spectra of 10, asiminocin (27),
authentic asiminocin, asiminecin (41) and authentic asimine-
cin (36 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.
To the above filtrate was added 10% AgNO3/silica gel (0.75
g, 0.44 mmol). The resulting mixture was stirred in the dark
for 12 h. The solid was removed by filtration. The filtrate
was concentrated and purified by flash chromatography (15%
EtOAc in hexanes) to give 0.34 g (87% overall) of butenolide
J O970424K