Total synthesis of the cytotoxic threo, trans, erythro, cis, threo Annonaceous acetogenin trilobin

Article abstract of DOI:10.1021/jo982057y

A synthesis of trilobin, a new stereochemical varient of the adjacent bis-tetrahydrofuran subgroup of the Annonaceous acetogenins, is described. The synthesis involves three stereochemically defining carbon-carbon bond- forming steps. The first of these introduces the C23-C24 stereocenters and the left side chain by means of an S(E),2' addition of the nonracemic 11- carbon γ-oxygenated allylic indium reagent derived from the α-oxygenated allylic stannane 4 to a C24-C16 core aldehyde 3. The second develops the C15- C16 stereocenters and a segment of the right chain through BF₃-promoted S(E)2' addition of the nonracemic 6-carbon γ-oxygenated allylic stannane 11 to the C16-C34 aldehyde 10. The third employs the addition of the dialkylzinc reagent 17 to the C10-C34 aldehyde 15 in the presence of a chiral bis- sulfonamide catalyst to establish the C10 stereocenter while adding the C1- C9 residue of the right chain. The C36 stereocenter and the butenolide are appended through condensation of the C1-C34 ester with the protected (S)- lactaldehyde 23.

Full text of DOI:10.1021/jo982057y

J . Org. Chem. 1999, 64, 971-975
971
Tota l Syn th esis of th e Cytotoxic Th r eo, Tr a n s, Er yth r o, Cis, Th r eo
An n on a ceou s Acetogen in Tr ilobin
J ames A. Marshall* and Hongjian J iang
Department of Chemistry University of Virginia, Charlottesville, Virginia 22901
Received October 13, 1998
A synthesis of trilobin, a new stereochemical varient of the adjacent bis-tetrahydrofuran subgroup
of the Annonaceous acetogenins, is described. The synthesis involves three stereochemically defining
carbon-carbon bond-forming steps. The first of these introduces the C23-C24 stereocenters and
the left side chain by means of an SE2′ addition of the nonracemic 11-carbon γ-oxygenated allylic
indium reagent derived from the R-oxygenated allylic stannane 4 to a C24-C16 core aldehyde 3.
The second develops the C15-C16 stereocenters and a segment of the right chain through BF3-
promoted SE2′ addition of the nonracemic 6-carbon γ-oxygenated allylic stannane 11 to the C16-
C34 aldehyde 10. The third employs the addition of the dialkylzinc reagent 17 to the C10-C34
aldehyde 15 in the presence of a chiral bis-sulfonamide catalyst to establish the C10 stereocenter
while adding the C1-C9 residue of the right chain. The C36 stereocenter and the butenolide are
appended through condensation of the C1-C34 ester with the protected (S)-lactaldehyde 23.
The recently described Annonaceous acetogenins tri-
lobacin and trilobin are the first known members of
adjacent bis-tetrahydrofuran Annonaceous acetogenins
with a threo, trans, erythro, cis, threo backbone (Figure
1).1 We have previously delineated methodology that
could, in principle, be employed for the synthesis of any
possible stereochemical arrangement of this backbone,2
and have applied this methodology to total syntheses of
the threo, trans, threo, trans, threo compounds (+)-
asimicin,3 (+)-asiminecin,4 (+)-asiminocin,4 and the threo,
trans, threo, trans, erythro acetogenin (+)-(30S)-bullanin.5
The high potency of trilobin and trilobacin against human
lung cancer, breast cancer, and colon cancer cell lines (one
million to nearly 10 billion times the cytotoxic potency
of the reference compound, adriamycin),1 coupled with
their unusual backbone stereochemistry and limited
availability,6 stimulated our interest in undertaking a
total synthesis of these natural products.
F igu r e 1. Proposed structures for trilobacin and trilobin.
As a test of the methodology and strategy, we selected
trilobin as our synthetic target. Our proposed route,
outlined in Figure 2, parallels that followed in our recent
synthesis of the nonadjacent bis-tetrahydrofuran squa-
mostatin-D.7 The stereocenters of intermediates B and
C are formed through SE2′ additions of γ-oxygenated
nonracemic allylic indium and tin reagents to aldehydes
A and B. The C10 stereocenter of intermediate D is
introduced by addition of a dialkylzinc reagent catalyzed
F igu r e 2. Proposed synthetic route to trilobin.
by a nonracemic bis-sulfonamide. Introduction of the
butenolide moiety, and the remaining stereocenter, is
achieved through condensation of ester D with a pro-
tected lactic aldehyde.
The starting material for this project, aldehyde 3 of
>95% ee, was prepared as previously described5,8 from
alcohol 1 by a sequence involving (1) ortho ester Claisen
rearrangement, (2) asymmetric dihydroxylation leading
to hydroxy lactone 2 of >95% ee,9 (3) formation of the
(1) (a) Zhao, G.-X.; Gu, Z.-M.; Zeng, L. Chao, J .-F.; Kozlowski, J . F.;
Wood, K. V.; McLaughlin, J . L. Tetrahedron 1995, 51, 7149. (b)
Reviews: Cave´, A.; Figade´re, B.; Laureno, A.; Cortes, D. In Progress
in the Chemistry of Natural Products; Herz, W., Kirby, G.-W., Moore,
R. E., Steglich, W., Tamm, Ch., Eds.; Springer: New York, 1997; Vol.
70, pp 81-288. Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.;
He, K.; McLaughlin, J . L. Nat. Prod. Rep. 1996, 275. (c) For leading
references to recent synthetic efforts in this area, see Hoye, T. R.; Ye,
Z. J . Am. Chem. Soc. 1996, 118, 1801. Yazbec, A.; Sinha, S. C.; Keinan,
E. J . Org. Chem. 1998, 63, 5863.
(2) Marshall, J . A.; Hinkle, K. W. J . Org. Chem. 1996, 61, 4247.
(3) Marshall, J . A.; Hinkle, K. W. J . Org. Chem. 1997, 62, 5989.
(4) Marshall, J . A.; Chen, M.; J . Org. Chem. 1997, 62, 5996.
(5) Marshall, J . A.; Hinkle, K. W. Tetrahedron Lett. 1998, 39, 1303.
(6) Only 4 mg was obtained in pure form from 200 g of stem bark
extract.1a
(8) Sinha, S. C.; Sinha, A.; Yazbec, A.; Keinan, E. J . Org. Chem.
1996, 61, 7640.
(9) Kolb, H. C.; VanNiewenkze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483. The ee of hydroxy lactone 2 was determined through
1H NMR analysis of the (R)- and (S)-O-methyl mandelates as described
in the Ph.D. Thesis of Kevin Hinkle, University of Virginia, 1998.
Copies of these spectra are included in the Supporting Information.
(7) Marshall, J . A.; J iang, H. J . Org. Chem. 1998, 63, 7066.
10.1021/jo982057y CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/15/1999

972 J . Org. Chem., Vol. 64, No. 3, 1999
Marshall and J iang
Sch em e 1
Sch em e 2
Weinreb amide,10 (4) diol protection as the bis-TBS ether,
and (5) reduction of the Weinreb amide (eq 1). Addition
alcohol 9 in 90% yield. Oxidation to the aldehyde 10 was
effected with the Dess-Martin periodinane reagent13 in
95% yield (eq 1).
Completion of the bis-tetrahydrofuran core was effected
by addition of the (S)-γ-OMOM allylic stannane 1114 to
aldehyde 10 with BF3•OEt2 in CH2Cl2 to afford the syn
adduct 12 in 80% yield. Treatment of this adduct with
Bu4NOH in THF led to the bis-tetrahydrofuran 13 with
the requisite threo, trans, erythro, cis threo core stereo-
chemistry. Again, the 1H NMR spectrum of this cyclic
ether was free of signals that would arise from stereo-
isomeric byproducts. Hydrogenation - hydrogenolysis of
13 over 5% Pd-C gave the saturated alcohol 14 in 86%
yield. Oxidation, as before, with the periodinane reagent13
led to the aldehyde 15 in 86% yield (Scheme 1).
For introduction of the C1-C9 carbon chain of trilobin,
the diorganozinc reagent 17 was required. This interme-
diate was prepared from unsaturated ester 1615 through
boron-zinc exchange of the derived organoborane with
Et2Zn (eq 2).16
Addition of 17 to aldehyde 15 in the presence of the
(S,S)-1,2-diaminocyclohexane-bis-triflamide 18 as a cata-
lyst afforded adduct 19 in 68% yield (Scheme 2).16 The
of the γ-alkoxy allylic indium reagent derived from the
(10) Baska, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977,
17, 4171.
11,12
(R)-R-OMOM allylic stannane 4 and InCl3
afforded
the anti adduct 5 as a single diastereomer in 80% yield.
The derived tosylate 6 cyclized to the cis threo tetrahy-
drofuran 7 upon exposure to TBAF in THF. The 1H NMR
spectrum of this cyclc product was devoid of spurious
signals that would be expected to arise from diastereo-
meric byproducts, thereby confirming the high diastereo-
and enantioselectivity of the stannane addition step
leading to the precursor 6. The tosylate derivative 8 was
hydrogenated with concomitant hydrogenolysis of the
benzyl ether over 5% Pd-C as the catalyst to afford the
(11) Stannane 4 was prepared from (E)-2-undecenal by the sequence
(1) LiSnBu3 then ADD (1,1′-(azodicarbonyl)dipiperidine); (2) (S)-
BINAL-H; (3) MOMCl, i-Pr2NEt.2 For details see the Supporting
Information.
(12) Marshall, J . A.; J iang, H. Tetrahedron Lett. 1998, 39, 1493.
(13) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4156. Meyer,
S. D.; Schreiber, S. L. J . Org. Chem. 1994, 59, 7549.
(14) The R-OMOM precursor of stannane 11 was prepared from (E)-
6-(benzyloxy)-2-hexenal by the sequence of ref 10. Isomerization to the
γ-isomer 11 was effected with BF3•OEt2 in CH2Cl2. For details, see
the Supporting Information.
(15) Liu, S.-H. J . Org. Chem. 1977, 42, 3209.
(16) Lutz, C.; Knochel, P. J . Org. Chem. 1997, 62, 7895.

Total Synthesis of Trilobin
J . Org. Chem., Vol. 64, No. 3, 1999 973
Ta ble 1. En a n tiom er ic Sta bility of Bu ten olid e 29 in
Am in e Solven ts
solvent
T, °C
t, h
29 ee, %a
Et2NH
Et3N
Et2NH
23
23
reflux
16
16
24
80
∼98
0
ee of this adduct was judged to be >95% based on
analysis of the 1H NMR spectra of the (R)- and (S)-O-
methyl mandelates 20 and 21.17 Protection of alcohol 19
as the MOM ether 22 followed by condensation with (S)-
OTBS lactaldehyde 2318 yielded the hydroxy lactone 24
which was dehydrated by treatment with (CF3CO)2O and
Et3N to afford butenolide 25 in 63% overall yield for the
three steps.19
a
Analysis by GC and optical rotation.
but not triethylamine, can indeed effect racemization of
the 4-methylbutenolide moiety.
The present synthesis of trilobin confirms the assigned
structure and demonstrates the applicability of chiral
oxygenated allylic metal methodology to this subgroup
of interesting natural products. Future studies will be
directed toward other subgroups and analogues of the
most cytotoxic members of the family.
The final stage of the synthesis, deprotection of the
MOM ethers of butenolide 25, was effected in 85% yield
with aqueous HCl in methanol-THF. The resulting
product 26 was identified as (+)-trilobin through com-
1
1
parison of the H and 13C NMR spectra, and the H NMR
spectrum of the (S)-Mosher ester derivative 2720 with
those of the natural product.1a The rotation was some-
what lower than that reported (+22.7 compared to
+33.31a). However, the latter was measured in methanol
at a concentration of 0.15 mg/mL. We employed CH2Cl2
as the solvent for our measurement because of the limited
solubility of the material in methanol and the intrinsic
error associated with the determination of small rota-
tional values of dilute samples.
Exp er im en ta l Section
(9E)-(11R,12S,15S,16S)-19-(Ben zyloxy)-15,16-bis[(ter t-
b u t yld im et h ylsilyl)oxy]-11-(m et h oxym et h oxy)-9-n on a -
d ecen -12-ol (5). A solution of 0.92 g (4.16 mmol) of InCl3 in
80 mL of EtOAc was sonicated for 15 min, and to it was added
a solution of 2.00 g (4.04 mmol) of aldehyde 35 in 1.0 mL of
EtOAc. The mixture was cooled to -78 °C, and a solution of
3.04 g (6.04 mmol) of stannane 4 in 1.0 mL of EtOAc was
added. The reaction mixture was allowed to warm to room
temperature (3 h), quenched with NaHCO3, and extracted with
ether. The extracts were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. Purification
by column chromatography on silica gel (elution with 10%
EtOAc in hexane) afforded 2.24 g (80%) of alcohol 5. [R]D -56.8
A recent report indicated that racemization of the
butenolide moiety of Annonaceous acetogenins was ef-
fected by treatment with Et2NH, implying that these
compounds are configurationally labile under even weakly
basic conditions.21 This report was of some concern to us
as the elimination reaction leading to butenolide 25
employs Et3N as the base and a previous synthesis of
asiminocin and asiminecin involved a Sonogashira cou-
pling of a vinylic iodide and a terminal acetylenic
butenolide in which Et2NH served as the solvent.4 We
therefore conducted a control experiment with butenolide
29 of >98% ee (prepared as detailed in eq 3) to evaluate
(c 1.26, CHCl3); IR (film) 3493, 2925, 2846 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 7.33 (m, 5 H), 5.71 (dt, J ) 8.8, 15.8 Hz,
1 H), 5.40 (dd J ) 8.6, 15.8 Hz, 1 H), 4.73 (d, J ) 6.5 Hz, 1 H),
4.55 (d, J ) 6.5 Hz, 1 H), 4.50 (s, 2 H), 3.91 (m, 1 H), 3.69 (m,
1 H), 3.56 (m, 2 H), 3.47 (t, J ) 6.9 Hz, 2 H), 3.37 (s, 3 H), 2.06
(m, 2 H), 1.21-1.83 (m, 20 H), 0.88 (m, 21 H), 0.04 (m, 12 H);
13C NMR (CDCl3, 75 MHz) δ 137.8, 128.2, 127.5, 127.3, 124.7,
93.3, 80.1, 75.4, 75.2, 73.5, 72.7, 70.7, 55.4, 32.4, 31.8, 29.5,
29.4, 29.2, 29.1, 27.1, 26.7, 26.0, 25.8, 22.6, 18.0, 14.1, -4.1,
-4.2, -4.5, -4.6. Anal. Calcd for C40H76O6Si2: C, 67.74; H,
10.80. Found: C, 67.86; H, 10.79.
(9E )-(11R ,12R ,15S ,16S )-19-(B e n zy lo x y )-11-(m e t h -
oxym eth oxy)-12,15-oxid o-9-n on a d ecen -16-ol (7). To a so-
lution of 2.10 g (2.82 mmol) of alcohol 5 in 2.0 mL of pyridine
was added 3.20 g (16.8 mmol) of TsCl. The reaction mixture
was stirred at room temperature for 12 h, quenched with
water, and extracted with ether. The extracts were washed
with brine, dried over MgSO4, and concentrated under reduced
pressure. To the residue was added 60.0 mL of THF followed
by 17.0 mL (17.0 mmol) of TBAF (1.0 M in THF). The reaction
mixture was heated at 45 °C for 12 h, quenched with water,
and extracted with ether. The ether extracts were washed with
brine, dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude product was purified by column
chromatography on silica gel (elution with 20% EtOAc in
hexane) to afford 1.20 g (92%) of alcohol 7. [R]D -62.2 (c 0.78,
CHCl3); IR (film) 3458, 2916, 2855 cm-1; 1H NMR (CDCl3 300
MHz) δ 7.33 (m, 5 H), 5.70 (dt, J ) 6.9, 15.8 Hz, 1 H), 5.36
(dd, J ) 8.5, 15.5 Hz, 1 H), 4.73 (d, J ) 6.5 Hz, 1 H), 4.55 (d,
J ) 6.5 Hz, 1 H), 4.51 (s, 2 H), 4.04 (m, 1 H), 3.90 (m, 2 H),
3.52 (m, 2 H), 3.40 (m, 1 H), 3.38 (s, 3 H), 2.05 (m, 2 H), 1.18-
its stability toward amine bases. Upon stirring for 16 h
in Et2NH, the ee of 29 fell to 80% as measured by GC
and optical rotation (Table 1). The same experiment with
Et3N as solvent led to negligible loss of ee. In refluxing
Et2NH, racemization of butenolide 29 was complete
within 24 h. We also carried out the coupling of a
terminal alkynyl butenolide with 1-bromopropene (∼1.5:1
E:Z) under the Sonogashira conditions (2 h reaction time
at room temperature).22 The coupling products exhibited
a 10% decrease in ee compared to the starting material.
It would therefore appear that exposure to diethylamine,
(22) Sonogashira, K. In Comprehensive Organic Synthesis; Trost,
B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 3, Chapter 2.4.
Butenolide i was prepared as described in ref 4. This experiment was
performed in our laboratory by Dr. Paul Lobben.
(17) 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.
(18) Massad, S. K.; Hawkins, L. D.; Baker, D. C. J . Org. Chem. 1983,
48, 5180.
(19) Yao, Z.-J .; Wu, Y.-L. Tetrahedron Lett. 1994, 35, 157.
(20) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543.
(21) Duret, P.; Figade`re, B.; Hocquemiller, R.; Cave´, A. Tetrahedron
Lett. 1997, 38, 8849.

974 J . Org. Chem., Vol. 64, No. 3, 1999
Marshall and J iang
1.97 (m, 20 H), 0.88 (t, J ) 7.0 Hz, 3 H); 13C NMR (CDCl3, 75
MHz) δ 138.5, 136.6, 128.2, 127.5, 127.3, 126.4, 93.3, 82.6, 81.6,
79.4, 72.7, 70.2, 55.4, 32.2, 31.8, 31.1, 29.3, 29.2, 29.1, 29.0,
28.0, 27.8, 26.1, 22.6, 14.0. Anal. Calcd for C28H46O5: C, 72.69;
H, 10.02. Found: C, 72.67; H, 10.06.
(t, J ) 6.9 Hz, 3 H); 13C NMR (CDCl3, 75 MHz) δ 144.2, 138.5,
136.8, 134.7, 129.5, 128.3, 127.6, 127.5, 127.4, 126.4, 96.7, 93.4,
84.6, 82.3, 80.4, 79.7, 78.7, 77.2, 73.3, 72.8, 69.5, 55.6, 55.5,
31.8, 31.0, 29.8, 29.6, 29.3, 29.1,29.0, 28.4, 27.5, 27.2, 25.3, 22.6,
21.5, 14.1.
Tosyla te 8. A mixture of 0.20 g (0.43 mmol) of alcohol 7
and 0.30 g (1.57 mmol) of TsCl in 0.5 mL of pyridine was
stirred at room temperature for 12 h. The reaction mixture
was quenched with water and extracted with ether. The
extracts were washed with brine, dried over MgSO4, filtered,
and concentrated under reduced pressure. Purification by
column chromatography on silica gel (elution with 15% EtOAc
in hexane) afforded 0.24 g (90%) of tosylate 8. [R]D -21.2 (c
0.66, CHCl3); IR (film) 2925, 2855 cm-1; 1H NMR (CDCl3, 300
MHz) δ 7.80 (d, J ) 8.5 Hz, 2 H), 7.30 (m, 7 H), 5.64 (dd, J )
7.3, 14.6 Hz, 1 H), 5.20 (dd, J ) 6.9, 15.8 Hz, 1 H), 4.70 (d, J
) 6.5 Hz, 1 H), 4.65 (m, 1 H), 4.54 (d, J ) 6.5 Hz, 1 H), 4.44
(s, 2 H), 4.08 (m, 1 H), 3.87 (m, 2 H), 3.39 (t, J ) 6.9 Hz, 2 H),
3.32 (s, 2 H), 2.42 (s, 3 H), 2.01 (m, 2 H), 1.20-1.95 (m, 20 H),
0.88 (t, J ) 6.9 Hz, 3 H); 13C NMR (CDCl3, 75 MHz) δ 144.3,
138.4, 136.6, 134.6, 129.6, 128.3, 127.7, 127.4, 125.8, 93.3, 84.2,
81.9, 79.0, 72.7, 69.6, 55.1, 32.3, 31.8, 29.3, 29.2, 29.1, 29.0,
28.0, 27.4, 27.0, 25.4, 22.6, 21.5, 14.1.
Bis-THF Olefin 13. To a solution of 0.29 g (0.37 mmol) of
alcohol 12 in 10.0 mL of THF was added 1.50 mL (1.50 mmol)
of Bu4NOH (1.0 M in MeOH). The reaction mixture was heated
at 45 °C for 60 min, allowed to cool to room temperature,
quenched with water, and extracted with ether. The ether
extracts were washed with brine, dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude product
was purified by column chromatography on silica gel (elution
with 20% EtOAc in hexane) to afford 0.20 g (88%) of bis-THF
olefin 13. [R]D -9.4 (c 0.67, CHCl3); IR (film) 2925, 2846 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 7.37 (m, 5 H), 5.70 (dt, J ) 8.8,
15.7 Hz, 1 H), 5.31 (dd, J ) 8.8, 15.7 Hz, 1 H), 4.85 (d, J ) 6.9
Hz, 1 H), 4.69 (d, J ) 6.9 Hz, 1 H), 4.66 (d, J ) 6.9 Hz, 1 H),
4.57 (d, J ) 6.9 Hz, 1 H), 4.49 (s, 2 H), 4.00 (m, 1 H), 3.88 (m,
2 H), 3.80 (m, 2 H), 3.46 (d, J ) 6.8 Hz, 2 H), 3.45 (m, 1 H),
3.39 (s, 3 H), 3.37 (s, 3 H), 2.16 (m, 2 H), 1.20-2.10 (m, 28 H),
0.88 (t, J ) 6.9 Hz, 3 H); 13C NMR (CDCl3, 75 MHz) δ 138.5,
135.2, 128.3, 127.5, 127.4, 126.8, 96.6, 93.3, 82.4, 81.7, 81.6,
81.4, 81.3, 80.0, 78.8, 72.8, 69.5, 55.6, 55.1, 31.8, 31.3, 29.7,
29.5, 29.3, 29.1, 28.9, 28.8, 28.6, 28.1. 27.5, 25.3, 22.6, 14.0.
Anal. Calcd for C36H60O7: C, 71.49; H, 10.00. Found: C, 71.43;
H, 9.96.
Mon o-THF Alcoh ol 9. A mixture of 0.087 g (0.14 mmol)
of tosylate 8 and 0.085 g of 5% Pd-C in 1.0 mL of EtOAc-
EtOH (3:1) was placed under a H2 atmosphere. The reaction
mixture was stirred for 12 h and filtered through Celite. The
solvent was removed under reduced pressure, and the crude
product was purified by column chromatography on silica gel
(elution with 40% EtOAc in hexane) to afford 0.067 g (90%) of
alcohol 9. [R]D +31.4 (c 0.65, CHCl3); IR (film) 3449, 2933, 2855
Bis-THF Alcoh ol 14. A mixture of 0.30 g (0.50 mmol) of
olefin 13 and 0.30 g of 5% Pd-C in 3.0 mL of EtOAc was placed
under a H2 atmosphere. The reaction mixture was stirred for
40 h and filtered through Celite. The solvent was removed
under reduced pressure, and the crude product was purified
by column chromatography on silica gel (elution with 50%
EtOAc in hexane) to afford 0.22 g (86%) of alcohol 14. [R]D
+40.8 (c 0.53, CHCl3); IR (film) 3440, 2925, 2855 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 4.84 (d, J ) 6.9 Hz, 1 H), 4.82 (d, J ) 6.9
Hz, 1 H), 4.68 (d, J ) 1.9 Hz, 1 H), 4.66 (d, J ) 1.9 Hz, 1 H),
3.98 (m, 1 H), 3.88 (m, 1 H), 3.81 (m, 2 H), 3.64 (t, J ) 6.8 Hz,
2 H), 3.46 (m, 2 H), 3.39 (s, 6 H), 1.16-2.10 (m, 34 H), 0.88 (t,
J ) 6.9 Hz, 3 H); 13C NMR (CDCl3, 75 MHz) δ 96.7, 96.6, 82.5,
81.7, 81.5, 81.1, 80.0, 79.6, 62.8, 55.7, 55.6, 32.6, 31.9, 31.3,
31.1, 29.8, 29.6, 29.3, 29.1, 28.4, 28.3, 27.5, 25.8, 25.3, 25.1,
22.6, 14.1.
1
cm-1; H NMR (CDCl3, 300 MHz) δ 7.70 (d, J ) 8.5 Hz, 2 H),
7.31 (d, J ) 8.5 Hz, 2 H), 4.77 (d, J ) 6.5 Hz, 1 H), 4.64 (m, 1
H), 4.61 (d, J ) 6.5 Hz, 1 H), 4.02 (m, 1 H), 3.85 (m, 1 H), 3.56
(t, J ) 6.9 Hz, 2 H), 3.42 (m, 1 H), 3.36 (s, 3 H), 2.43 (s, 3 H),
1.17-1.94 (m, 26 H), 0.88 (t, J ) 7.0 Hz, 3 H); 13C NMR (CDCl3,
75 MHz) δ 144.5, 134.5, 129.6, 127.6, 96.6, 83.9, 82.4, 79.6,
78.7, 62.1, 55.7, 31.9, 31.2, 29.8, 29.6, 29.3, 28.1, 27.7, 27.0,
25.3, 22.6, 21.6, 14.1.
Mon o-THF Ald eh yd e 10. To a solution of 0.105 g (0.20
mmol) of alcohol 9 in 2.0 mL of CH2Cl2 was added 0.130 g (0.31
mmol) of Dess-Martin periodinane.13 The reaction mixture
was stirred for 60 min, quenched with Na2S2O3, and extracted
with ether. The ether extracts were washed with brine, dried
over MgSO4, filtered, and concentrated under reduced pres-
sure. The crude product was purified by column chromatog-
raphy on silica gel (elution with 25% EtOAc in hexane) to
afford 0.101 g (95%) of aldehyde 10. [R]D +17.1 (c 0.55, CHCl3);
IR (film) 2916, 2864, 1719 cm-1; 1H NMR (CDCl3, 300 MHz) δ
9.70 (s, 1 H), 7.80 (d, J ) 8.5 Hz, 2 H), 7.33 (d, J ) 8.5 Hz, 2
H), 4.75 (d, J ) 6.9 Hz, 1 H), 4.67 (m, 1 H), 4.62 (d, J ) 6.9
Hz, 1 H), 3.96 (m, 1 H), 3.84 (m, 1 H), 3.41 (m, 1 H), 3.36 (s,
3 H), 2.57 (t, J ) 7.7 Hz, 2 H), 2.45 (s, 3 H), 1.13-2,14 (m, 24
H), 0.88 (t, J ) 6.9 Hz, 3 H); 13C NMR (CDCl3, 75 MHz) δ
200.7, 144.6, 134.2, 129.7, 127.7, 96.6, 82.7, 82.3, 79.6, 78.9,
55.6, 39.4, 31.8, 31.0, 29.8, 29.6, 29.3, 27.5, 27.1, 25.3, 23.2,
22.6, 21.6, 14.1.
Alcoh ol 12. To a mixture of 0.28 g (0.53 mmol) of mono-
THF aldehyde 10 and 0.29 g (0.58 mmol) of stannane 1114 in
3.0 mL of CH2Cl2 at -78 °C was slowly added 0.08 mL (0.60
mmol) of BF3•OEt2. The reaction mixture was stirred at -78
°C for 30 min, quenched with NaHCO3, diluted with ether and
allowed to warm to room temperature. The aqueous layer was
extracted with ether and the combined ether extracts were
washed with brine, dried over MgSO4 and concentrated under
reduced pressure. The crude product was purified by column
chromatography on silica gel (elution with 30% EtOAc in
hexane) to afford 0.31 g (80%) of alcohol 12. [R]D -11.2 (c 0.55,
CHCl3); IR (film) 3501, 2925, 2855 cm-1; 1H NMR (CDCl3, 300
MHz) δ 7.80 (d, J ) 8.5 Hz, 2 H), 7.31 (m, 7 H), 5.70 (dt, J )
8.8, 15.7 Hz, 1 H), 5.24 (dd, J ) 8.8, 15.8 Hz, 1 H), 4.77 (d, J
) 6.9 Hz, 1 H), 4.69 (d, J ) 6.9 Hz, 1 H), 4.66 (m, 1 H), 4.62
(d, J ) 6.9 Hz, 1 H), 4.50 (m, 3 H), 4.00 (m, 1 H), 3.83 (m, 1
H), 3.73 (m, 1 H), 3.48 (t, J ) 6.7 Hz, 2 H), 3.41 (m, 2 H), 3.36
(s, 6 H), 2.42 (s, 3 H), 2.17 (m, 2 H), 1.19-2.11 (m, 28 H), 0.88
Bis-THF Ald eh yd e 15. To a solution of 0.147 g (0.28 mmol)
of alcohol 14 in 2.0 mL of CH2Cl2 was added 0.160 g (0.37
mmol) of Dess-Martin periodinane.13 The reaction mixture
was stirred for 60 min, quenched with Na2S2O3, and extracted
with ether. The ether extracts were washed with brine, dried
over MgSO4, filtered, and concentrated under reduced pres-
sure. Purification by column chromatography on silica gel
(elution with 20% EtOAc in hexane) afforded 0.126 g (86%) of
aldehyde 15. [R]D +46.9 (c 0.63, CHCl3); IR (film) 2916, 2846,
1
1728 cm-1; H NMR (CDCl3, 300 MHz) δ 9.77 (t, J ) 1.9 Hz,
1 H), 4.84 (d, J ) 6.9 Hz, 1 H), 4.81 (d, J ) 6.9 Hz, 1 H), 4.66
(d, J ) 6.9 Hz, 2 H), 3.98 (m, 1 H), 3.88 (m, 1 H), 3.81 (m, 2
H), 3.46 (m, 2 H), 3.39 (s, 3 H), 3.38 (s, 3 H), 2.44 (dt, J ) 1.9,
7.3 Hz, 2 H), 1.20-2.10 (m, 32 H), 0.88 (t, J ) 6.9 Hz, 3 H);
13C NMR (CDCl3, 75 MHz) δ 202.3, 96.7, 96.5, 82.4, 81.8, 81.6,
81.1, 79.9, 79.3, 55.6, 43.7, 31.8, 31.3, 30.8, 29.7, 29.5, 29.2,
28.9, 28.4, 28.2, 27.4, 25.2, 25.0, 22.6, 22.1, 14.0. Anal. Calcd
for C29H54O7: C, 67.67; H, 10.57. Found: C, 67.89; H, 10.51.
Alcoh ol 19. To 0.30 g (1.62 mmol) of ethyl 8-nonenoate 1615
was slowly added 0.20 mL (0.76 mmol) of Et2BH (3.8 M in
ether) at -10 °C. The reaction mixture was allowed to warm
to room temperature and stirred for 2 h. Solvent and other
volatiles were removed under reduced pressure (0.05 mmHg,
30 min) to afford the hydroboration product. To this organo-
borane was added 0.25 mL (2.34 mmol) of Et2Zn at 0 °C. The
reaction mixture was stirred for 30 min, and the excess Et2Zn
and Et3B were removed under vacuum (0.05 mmHg, 3 h). The
resulting dialkylzinc was diluted with 0.5 mL of ether. A
mixture of 0.007 g (0.01 mmol) of (1S,2S)-1,2-bis-(trifluo-
romethanesulfonamido)cyclohexane 18 and 0.08 mL (0.28
mmol) of Ti(O-i-Pr)4 in 0.5 mL of ether was stirred at room
temperature for 10 min and cooled to -60 °C. To it was added

Total Synthesis of Trilobin
J . Org. Chem., Vol. 64, No. 3, 1999 975
the dialkylzinc solution, and the mixture was warmed to -20
°C. After 20 min, a solution of 0.040 g (0.08 mmol) of aldehyde
15 in 0.5 mL of ether was added. The reaction mixture was
stirred at -20 °C for 16 h, quenched with 1.0 M HCl, and
extracted with ether. The extracts were washed with brine,
dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude product was purified by column chroma-
tography on silica gel (elution with 30% EtOAc in hexane) to
afford 0.037 g (68%) of alcohol 19. [R]D +33.7 (c 0.3 CHCl3);
IR (film) 3458, 2916, 2855 cm-1; 1H NMR (CDCl3, 300 MHz) δ
4.84 (d, J ) 6.9 Hz, 1 H), 4.81 (d, J ) 6.9 Hz, 1 H), 4.66 (d, J
) 6.9 Hz, 2 H), 4.11 (q, J ) 7.3 Hz, 2 H), 3.98 (m, 1 H), 3.87
(m, 1 H), 3.80 (m, 2 H), 3.57 (m, 1 H), 3.44 (m, 2 H), 3.38 (s, 6
H), 2.28 (t, J ) 7.7 Hz, 2 H), 1.13-2.10 (m, 51 H), 0.88 (t, J )
6.9 Hz, 3 H); 13C NMR (CDCl3, 300 MHz) δ 173.8, 96.6, 82.4,
81.8, 81.7, 81.5, 81.1, 80.0, 79.6, 79.5, 71.8, 60.1, 55.6, 37.4,
37.3, 36.6, 36.5, 34.3, 31.8, 31.3, 31.2, 31.1, 29.7, 29.5, 29.3,
29.2, 29.1, 29.0, 28.4, 28.3, 27.5, 25.7, 25.6, 25.5, 25.3, 24.9,
22.6, 14.2, 14.0. Anal. Calcd for C40H76O9: C, 68.53; H, 10.93.
Found: C, 68.29; H, 10.86.
reaction mixture was stirred for 1 h, quenched with NH4Cl,
and diluted with ether. The aqueous layer was extracted with
ether, and the combined extracts were washed with brine,
dried over MgSO4, and concentrated under reduced pressure.
To the residue was added 1.0 mL of THF followed by 0.2 mL
(0.20 mmol) of TBAF (1.0 M in THF). The reaction mixture
was stirred for 30 min, quenched with water, and extracted
with ether. The extracts were washed with brine, dried over
MgSO4, and concentrated under reduced pressure. Purification
by column chromatography on silica gel (elution with 50%
EtOAc in hexane) afforded 0.022 g (73%) of alcohol 24. IR (film)
1
3432, 2925, 2855 cm-1; H NMR (CDCl3, 300 MHz) δ 4.84 (J
) 6.9 Hz, 1 H), 4.81 (d, J ) 6.9 Hz, 1 H), 4.66 (d, J ) 6.9 Hz,
2 H), 4.63 (s, 2 H), 4.20 (m, 1 H), 3.97 (m, 1 H), 3.86 (m, 1 H),
3.79 (m, 2 H), 3.52 (m, 1 H), 3.44 (m, 2 H), 3.39 (s, 6 H), 3.36
(s, 3 H), 2.56 (m, 1 H), 1.42 (d, J ) 7.0 Hz, 3 H), 1.14-2.09 (m,
48 H), 0.88 (t, J ) 6.9 Hz, 3 H).
MOM-P r otected Tr ilobin 25. To a mixture of 0.02 g (0.026
mmol) of alcohol 24 and 0.035 mL (2.60 mmol) of Et3N in 1.0
mL of CH2Cl2 at 0 °C was added 0.02 mL (0.14 mmol) of (CF3-
CO)2O. The reaction mixture was stirred at room temperature
for 20 h, quenched with NaHCO3, and extracted with ether.
The extracts were washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The crude product was
purified by column chromatography on silica gel (elution with
20% EtOAc in hexane) to afford 0.017 g (87%) of butenolide
25. 1H NMR (CDCl3, 300 MHz) δ 6.98 (s, 1 H), 4.84 (d, J ) 6.9
Hz, 1 H), 4,81 (d, J ) 6.9 Hz, 1 H), 4.66 (d, J ) 6.9 Hz, 2 H),
4.63 (s, 2 H), 3.98 (m, 1 H), 3.88 (m, 1 H), 3.80 (m, 2 H), 3.52
(m, 1 H), 3.45 (m, 2 H), 3.39 (s, 6 H), 3.36 (s, 3 H), 2.26 (t, J )
8.1 Hz, 2 H), 1.42 (d, J ) 7.0 Hz, 3 H), 1.19-2.09 (m, 46 H),
0.88 (t, J ) 6.9 Hz, 3 H).
Ma n d ela tes 20, 21. To a mixture of 5.0 mg (0.007 mmol)
of alcohol 19 and 3.0 mg (0.018 mmol) of (R)-R-methoxy-
phenylacetic acid in 0.5 mL of CH2Cl2 was added 3.7 mg (0.018
mmol) of DCC followed by 1.0 mg of DMAP. The reaction
mixture was stirred for 30 min, and the solvent was removed
under reduced pressure. To the residue was added ether, and
the mixture was filtered through Celite. Solvent was removed
under reduced pressure, and the crude product was purified
by column chromatography on silica gel (elution with 20%
EtOAc in hexane) to afford 5.7 mg (95%) of (R)-m a n d ela te
20: 1H NMR (CDCl3, 300 MHz) δ 4.88 (m, 1 H), 4.85 (d, J )
6.9 Hz, 1 H), 4.78 (d, J ) 6.5 Hz, 1 H), 4.67 (d, J ) 6.5 Hz, 1
H), 4.62 (d, J ) 6.9 Hz, 1 H), 4.13 (q, J ) 7.2 Hz, 2 H), 3.90
(m, 2 H), 3.80 (m, 2 H), 3.30-3.50 (m, 2 H), 3.41 (s, 3 H), 3.39
(s, 3 H), 3.36 (s, 3 H), 2.28 (t, J ) 7.6 Hz, 2 H), 1.00-2.09 (m,
Tr ilobin (26). A solution of 0.013 g (0.02 mmol) of MOM-
protected trilobin 25 in 1.5 mL of 6 N HCl-THF-MeOH
(1:2:2) was stirred at room temperature for 12 h. The reaction
was quenched with water and extracted with ether. The
extracts were dried over MgSO4, filtered, and concentrated
under reduced pressure. Purification by column chromatog-
raphy on silica gel (elution with 80% EtOAc in hexane)
afforded 0.009 g (85%) of trilobin (26). [R]D +22.7 (c 0.15, CH2-
1
51 H), 0.88 (t, J ) 6.9 Hz, 3 H). (S)-Ma n d ela te 21: H NMR
(CDCl3, 300 MHz) δ 4.89 (m, 1 H), 4.85 (d, J ) 6.9 Hz, 1 H),
4.81 (d, J ) 6.5 Hz, 1 H), 4.67 (d, J ) 6.9 Hz, 1 H), 4.65 (d, J
) 6.5 Hz, 1 H), 4.13 (q, J ) 7.2 Hz, 2 H), 3.96 (m, 1 H), 3.88
(m, 1 H), 3.80 (m, 2 H), 3.35-3.50 (m, 2 H), 3.41 (s, 3 H), 3.39
(s, 3 H), 3.38 (s, 3 H), 2.27 (t, J ) 7.6 Hz, 2 H), 1.00-2.10 (m,
51 H), 0.88 (t, J ) 6.9 Hz, 3 H). Note: The italic data are
diagnostic for each diastereomer.
1
Cl2); lit.1a [R]D +33.3 (c 0.015, MeOH); H NMR (CDCl3, 300
MHz) δ 6.99 (s, 1 H), 5.00 (m, 1 H), 4.07 (m, 1 H), 3.96 (m, 1
H), 3.83 (m, 2 H), 3.59 (m, 1 H), 3.38 (m, 2 H), 2.27 (t, J ) 7.4
Hz, 2 H), 1.42 (d, J ) 7.0 Hz, 3 H), 1.12-2.16 (m, 46 H), 0.88
(t, J ) 6.9 Hz, 3 H); 13C NMR (CDCl3, 75 MHz) δ 173.8, 148.9,
134.3, 83.2, 82.6, 81.6, 81.0, 74.5, 73.8, 71.9, 37.4, 34.3, 33.5,
31.9, 29.7, 29.6, 29.5, 29.3, 29.2, 29.1, 28.9, 28.2, 28.1, 27.4,
27.1, 25.8, 25.7, 25.6, 25.2, 22.7, 19.2, 14.1. Tr i-(S)-Mosh er
Ester : 1H NMR (CDCl3, 300 MHz) δ 6.98 (s, 1 H), 5.05 (m, 3
H), 5.00 (m, 1 H), 3.96 (m, 1 H), 3.92 (m, 1 H), 3.71 (m, 1 H),
3.63 (m, 1 H), 2.26 (t, J ) 7.4 Hz, 2 H), 1.40 (d, J ) 7.0 Hz, 3
H), 1.20-2.00 (m, 46 H), 0.88 (t, J ) 7.0 Hz, 3 H).
Bis-THF Ester 22. To a mixture of 0.034 g (0.05 mmol) of
alcohol 19 and 0.30 mL (1.72 mmol) of i-Pr2NEt in 1.0 mL of
CH2Cl2 at 0 °C was added 0.10 mL (1.24 mmol) of MOMCl.
The reaction mixture was stirred for 12 h, quenched with
water, and extracted with ether. The ether extracts were
washed with brine, dried over MgSO4, filtered, and concen-
trated under reduced pressure. Purification by column chro-
matography on silica gel (elution with 20% EtOAc in hexane)
afforded 0.032 g (90%) of bis-THF ester 22. IR (film) 2942,
1
2855, 1728 cm-1; H NMR (CDCl3, 300 MHz) δ 4.84 (d, J )
6.9 Hz, 1 H), 4.81 (d, J ) 6.8 Hz, 1 H), 4.66 (d, J ) 6.9 Hz, 2
H), 4.63 (s, 2 H), 4.11 (q, J ) 7.3 Hz, 2 H), 3.97 (m, 1 H), 3.86
(m, 3 H), 3.79 (m, 2 H), 3.50 (m, 1 H), 3.45 (m, 2 H), 3,39 (s, 6
H), 3.36 (s, 3 H), 2.28 (t, J ) 7.6 Hz, 2 H), 1.13-2.09 (m, 51
H), 0.88 (t, J ) 6.9 Hz, 3 H).
Alcoh ol 24. To a solution of 0.037 mL (0.20 mmol) of
diisopropylamine in 0.5 mL of THF at 0 °C was added 0.07
mL (0.18 mmol) of BuLi (2.5 M in hexane). The reaction
mixture was stirred at 0 °C for 10 min and cooled to -78 °C.
To it was added a solution of 0.029 g (0.04 mmol) of ester 22
in 0.5 mL of THF. After 60 min, a solution of 0.015 g (0.08
mmol) of aldehyde 2318 in 0.5 mL of THF was added. The
Ack n ow led gm en t . This investigation was sup-
ported by research grant R0l GM 56769 from the
National Institute of General Medical Sciences. We
thank Professor J erry McLaughlin for comparison spec-
tra.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the synthesis of stannanes 4 and 11; 1H NMR
spectra for all key intermediates. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O982057Y