Double intramolecular S(N)' O-cyclization for stereoselective synthesis of bistetrahydrofuran core of acetogenins

Article abstract of DOI:10.1021/jo981771c

A C₂-symmetric bistetrahydrofuran core of acetogenins has been prepared via double intramolecular S(N)' O-cyclization reactions. Approaches using readily prepared both E- and Z-olefin substrates are investigated. The cyclization of E-olefins gave a mixture of two diastereomers with low selectivity, while the corresponding Z-olefins predominantly provided a desired trans,trans-bistetrahydrofuran product. The high diastereoselectivity is presumably controlled by a hydrogen-bonding transition state. An efficient enantioselective synthesis of this C₂-symmetric bistetrahydrofuran is also described. Sharpless asymmetric dihydroxylation was used for this approach.

Full text of DOI:10.1021/jo981771c

J . Org. Chem. 1999, 64, 2259-2263
2259
Dou ble In tr a m olecu la r SN′ O-Cycliza tion for Ster eoselective
Syn th esis of Bistetr a h yd r ofu r a n Cor e of Acetogen in s
Pan Li, J iong Yang, and Kang Zhao*
Department of Chemistry, New York University, New York, New York 10003
Received August 31, 1998
A C2-symmetric bistetrahydrofuran core of acetogenins has been prepared via double intramolecular
SN′ O-cyclization reactions. Approaches using readily prepared both E- and Z-olefin substrates are
investigated. The cyclization of E-olefins gave a mixture of two diastereomers with low selectivity,
while the corresponding Z-olefins predominantly provided a desired trans,trans-bistetrahydrofuran
product. The high diastereoselectivity is presumably controlled by a hydrogen-bonding transition
state. An efficient enantioselective synthesis of this C2-symmetric bistetrahydrofuran is also
described. Sharpless asymmetric dihydroxylation was used for this approach.
In tr od u ction
struction of substituted tetrahydrofurans,6 we were
intrigued with the possibility of using this strategy for
the efficient preparation of bistetrahydrofuran systems
which could be used to synthesize a sufficient amount of
the naturally occurring acetogenins and/or the isomers
with various side chains for the evaluation of biological
activity (SARs).
Over 200 acetogenins have been isolated from the plant
Annonacea and many of them contain one or more 2,5-
disubstituted tetrahydrofuran rings as a core unit. This
acetogenin family exhibits a diverse array of biological
properties: antitumor, antiprotozoal, antifeedant, im-
munosuppressive, pesticidal, anthelminitic, and microbial
activities.1,2 It is believed that the primary mode of action
for these acetogenins is inhibition of the mitochondrial
NADH:ubiquinone oxidoreductase, an essential enzyme
for ATP production.3 The structure-activity relationships
(SARs) of acetogenins suggest that Parviflorin (1) and
the Asimicin subgroup (2-5), both of which are comprised
of a core containing trans,threo,trans-bistetrahydrofuran
moiety, showed promise in the inhibition of oxygen
uptake in mitochondrial assays of rat liver.4 The interest-
ing structural features and biological activity of aceto-
genins have attracted considerable attention. The re-
search groups of Trost,5a Marshall,5b,c,e Hoye,5f,g Sinha,5d,h
and Sasaki5i have all reported elegant syntheses for this
trans,threo,trans-bistetrahydrofuran system. As an ap-
plication of our SN′ O-cyclization strategy for the con-
Resu lts a n d Discu ssion
Retr osyn th etic An a lysis. Our retrosynthetic analy-
sis is outlined in Scheme 1. The hidden symmetry of
(1) See recent reviews: (a) Zheng, L.; Ye, Q.; Oberlies, N. H.; Shi,
G.; Gu, Z.-M.; He, K.; McLaughlin, J . L. Nat. Prod. Rep. 1996, 275,
and references therein. (b) Ramirez, E. A.; Hoye, T. R. Studies in
Natural Products Chemistry, Vol. 17, Structure and Chemistry, Part
D; Atta-ur-Rahman, Ed.; Elsevier: New York, 1995. (c) Gu, Z.; Fang,
X.; Zeng, L.; Wood, K. V.; McLaughlin, J . L. Heterocyles 1993, 36, 2221.
(2) Reviews on syntheses: (a) Hoppe, R.; Scharf, H.-D. Synthesis
1995, 1447. (b) Figadere, B. Acc. Chem. Res. 1995, 28, 359. (c) Koert,
U. Synthesis 1995, 115.
Sch em e 1
(3) (a) Degli Esposti, M.; Ghelli, A.; Ratta, M.; Cortes, D.; Estornell,
E. Biochem. J . 1994, 301, 161. (b) Londershausen, M.; Leicht, W.; Lieb,
F.; Moeschler, H.; Weiss, H. Pestic. Sci. 1991, 33, 427.
(4) (a) Landolt, J . L.; Ahammadsahib, K. I.; Hollingworth, R. M.;
Barr, R.; Crane, F. L.; Buerck, N. L.; McCabe, G. P.; McLaughlin, J .
L. Chem.-Biol. Interact. 1995, 98, 1. (b) Alfonso, D.; J ohnson, H. A.;
Colman-Saizarbitoria, T.; Presley, C. P.; McCabe, G. P.; McLaughlin,
J . L. Nat. Toxins 1996, 4, 181.
(5) Selected recent syntheses (after 1995): (a) Trost, B. M.; Calkins,
T. L.; Bochet, C. G. Angew. Chem., Int. Ed. Engl. 1997, 36, 2632. (b)
Marshall, J . A.; Chen, M. J . Org. Chem. 1997, 62, 5996. (c) Marshall,
J . A.; Hinkle, K. W. J . Org. Chem. 1997, 62, 5989. (d) Keinan, E.; Sinha,
A.; Yazbak, A.; Sinha, S. C.; Sinha, S. C. Pure Appl. Chem. 1997, 69,
423. (e) Marshall, J . A.; Hinkle, K. W. J . Org. Chem. 1996, 61, 4247.
(f) Hoye, T. R.; Ye, Z. J . Am. Chem. Soc. 1996, 118, 1801. (g) Hoye, T.
R.; Tan, L. Tetrahedron Lett. 1995, 36, 1981. (h) Sinha, S. C.; Sinha-
Bagchi, A.; Yazbak, A.; Keinan, E. Tetrahedron Lett. 1995, 36, 9257.
(i) Naito, H.; Kawahara, E.; Maruta, K.; Maeda, M.; Sasaki, S. J . Org.
Chem. 1995, 60, 4419.
acetogenins (1-5) suggests that they could easily be
prepared from a C2-symmetric bistetrahydrofuran, such
as 6 or 7. Compound 7 could be prepared from the SN′
O-cyclization of compound 8. Once cyclized, the two vinyl
groups on 7 could be exploited to further functionalize
the two side chains. Epoxidation, dihydroxylation, ozo-
(6) Li, P.; Wang, T.; Emge, T.; Zhao, K. J . Am. Chem. Soc. 1998,
120, 7391.
10.1021/jo981771c CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/17/1999

2260 J . Org. Chem., Vol. 64, No. 7, 1999
Li et al.
Sch em e 3
nolysis, and hydroboration can be envisioned as processes
to effect this functionalization. For example, a hydroxyl
group of the side chains, which is adjacent to THF rings,
can be introduced diastereoselectively from the corre-
sponding THF carbaldehyde with a Grignard reagent by
using literature procedures.7
SN′ Cycliza tion of E-Olefin s. Our racemic approach
to the bistetrahydrofuran 7 is illustrated in Scheme 2.
Sch em e 2
derivative 17 in excellent yield (96%). This tetrabromide
was then converted to a propargyl alcohol derivative 18
in 90% yield by reaction with n-BuLi and formaldehyde
at -78 °C in anhydrous THF. Hydrogenation with
Lindlar’s catalyst12 in ethyl acetate gave exclusively
Z-allylic alcohol 19, which was converted to the Z-allylic
dibromide 20 by reaction with Ph3P and CBr4 in anhy-
drous diethyl ether in 77% yield from 18. The key SN′
O-cyclization was carried out following the same condi-
tions as described in Scheme 2. Under these conditions,
the desired trans,trans-bistetrahydrofuran derivative 7
was obtained in 88% yield together with 7% of the
cis,trans-isomer 16. Although it is unclear why a good
selectivity (12.6:1) was observed by using Z-olefin, a rigid
transition state could result from hydrogen bonding
between the two hydroxyl groups under the nonbasic
conditions. The transition state for this cyclization can
be imagined as chelated structures (A-B) (Scheme 4).
The commercially available 1,5-cyclooctadiene (9) served
as the starting material for this synthesis, and the two
double bonds in this compound have proved the possibil-
ity of partial oxidation.8 Treatment of 9 with 1 equiv of
m-chloroperoxybenzoic acid (mCPBA) provided a mono-
epoxide which was subjected to an aqueous LiOH solution
at 100 °C to produce the trans-diol 10 in 74% overall
yield. Protection of the hydroxyl groups with TBSCl and
ozonolysis9 of the remaining double bond provided the
corresponding dialdehyde 12. Reaction of the dialdehyde
with a readily available Wittig reagent in THF at 40 °C
gave the E-alkene (13) exclusively. Compound 13 was
reduced with DIBAL in CH2Cl2 at -78 °C to produce
trans allylic diol 14, which was treated with Ph3P and
CBr4 in diethyl ether to brominate the hydroxyl groups.
The double SN′ O-cyclization was first attempted by
treating compound 15 with HF to deprotect the silyl
groups10 followed by subsequent treatment with base.
Using this scheme, a mixture of two bistetrahydrofurans
(7:16 ) 2:1) was obtained in 69% yield. Another possible
diastereoisomer (cis, cis) was not detected.
Sch em e 4
SN′ Cycliza tion of Z-Olefin s. Scheme 3 illustrates an
alternative approach to bistetrahydrofuran 7 by using
Z-olefin 20. Following the procedure described by Mar-
shall,11 the Z-olefin 20 was obtained from the dialdehyde
12 in four steps. Treatment of dialdehyde 12 with Ph3P
and CBr4 in methylene chloride gave a tetrabromide
Hydrogen bonding between the two OH groups provided
five-membered-ring systems A-B, where nucleophilic
attack of the oxygen atoms to the double bonds forms
rigid cyclic transition states resulting in the stereoselec-
tive SN′ cyclization product. To confirm this hypothesis,
a solution of 21 in THF was heated at 50 °C with no base
present and the monocyclized product 2213 was isolated
in high selectivity (>20:1).
(7) For a review, see: (a) Reetz, M. T. Angew. Chem., Int. Ed. Engl.
1984, 23, 556. For selected papers, see: (b) Koert, U.; Stein, M.; Harms,
K. Tetrahedron Lett. 1993, 34, 2299. (c) Mead, K.; Macdonald, T. L. J .
Org. Chem. 1985, 50, 422.
(8) Davies, S. G.; Polywka, M. E. C.; Thomas, S. E. Tetrahedron Lett.
1985, 26, 1461.
En a n tioselective Syn th esis of 7. Based on this
strategy, we have designed a route to the enantioselective
(9) (a) Li, P.; Wang, J .; Zhao, K. J . Org. Chem. 1998, 63, 3151. (b)
Schreiber, S. L.; Claus, R. E.; Reagan, J . Tetreahedron Lett. 1982, 23,
3867.
(10) The use of TBAF conditions for removal of TBS converted allyl
bromide groups to the corresponding fluoride, and for the related
transformation conditions, see: Cox, D. P.; Terpinski, J .; Lawrynowicz,
W. J . Org. Chem. 1984, 49, 3216.
(12) (a) Corey, E. J .; De, B. J . Am. Chem. Soc. 1984, 106, 2735. (b)
Lindlar, H. Helv. Chim. Acta 1952, 35, 446.
(13) 1H NMR (200 MHz, CDCl3) for the monocyclized intermediate
22: δ 5.71 (3H, m), 5.16 (2H, m), 4.36 (1H, dt, J ) 7.1, 6.8 Hz), 4.01
(2H, d, J ) 8.0 Hz), 3.88 (1H, m), 3.39 (1H, m), 2.71 (1H, br), 2.30 (2H,
dt, J ) 7.4, 7.1 Hz), 2.04 (2H, m), 1.60 (4H, m). 13C NMR (50 MHz,
CDCl3): δ 139.2, 135.5, 126.5, 115.9, 82.9, 80.7, 73.7, 33.4, 33.2, 29.0,
27.9, 23.7.
(11) Marshall, J . A.; Xie, S. J . Org. Chem. 1995, 60, 7230.

Bistetrahydrofuran Core of Acetogenins
J . Org. Chem., Vol. 64, No. 7, 1999 2261
Exp er im en ta l Section 18
Sch em e 5
1,2-tr a n s-Dih yd r oxy-5-cycloocten e (10). To a solution of
1,5-cyclooctadiene (9) (20 g, 185 mmol) in methylene chloride
(600 mL) was slowly added 3-chloroperoxybenzoic acid (mCP-
BA) (70%, 46 g, 186 mmol) at 10 °C. The reaction mixture was
stirred at room temperature overnight, washed with aqueous
NaHCO3 (200 mL) and 10% NaOH (200 mL), and evaporated
under reduced pressure. The crude product was obtained and
used in the next step without further purification.
To the solution of the resulting monoepoxide (17 g, 137
mmol) in water (450 mL) was added LiOH‚H2O (17 g, 405
mmol) at room temperature. The reaction mixture was re-
fluxed for 14 h, cooled to room temperature, and extracted with
ethyl acetate (4 × 250 mL). The combined organic layers were
dried over MgSO4. Following evaporation under reduced
pressure the crude product was purified by flash silica gel
chromatography (eluting with 50-90% ethyl acetate in petro-
leum ether) to give pure 1,2-trans-dihydroxy-5-cyclooctene (10)
synthesis of 7 as described in Scheme 5. Double alkyla-
tion of tert-butyl acetate with (E)-1,4-dibromo-2-butene
under LDA conditions afforded a diester 23 in 74%
yield.14 Sharpless asymmetric dihydroxylation15 with AD-
mix-â in t-BuOH and H2O introduced the (R,R)-dihy-
droxyl groups on the E-olefin with 89% yield and high
enantiomeric excess (ee > 98%).16 Protection of the diol
with TBS followed by DIBAL reduction provided the
optically active dialdehyde 12 in 40% overall yield.
Following the procedures described in Scheme 3, we
successfully isolated the enantiomeric pure isomer 7.
The relative stereochemistry of compound 7 was es-
tablished by comparison to a known compound 27
(Scheme 6) which was reported by Koert’s group.7b
1
(19 g, 135 mmol, 74% overall) as a colorless liquid. H NMR
(200 MHz, CDCl3): δ 5.58 (2 × 1H, m), 3.64 (2 × 1H, m), 3.19
(2 × 1H, br), 2.33 (2 × 1H, m), 2.10 (2 × 2H, m), 1.57 (2 × 1H,
m). 13C NMR (50 MHz, CDCl3): δ 129.6, 74.3, 34.0, 23.3. MS:
m/e (relative intensity), 142 (3.7, M+), 124 (2.9), 114 (9.2), 96
(22), 81 (41), 54 (94), 39 (100). Anal. Calcd for C8H14O2‚
0.2H2O: C, 65.90; H, 9.95. Found: C, 65.64; H, 9.61.
tr a n s-1,2-Bis(ter t -b u t yld im et h ylsilyl)oxy-5-cyclooc-
ten e (11). To a solution of trans-1,2-dihydroxy-5-cyclooctene
(10) (13.0 g, 91.4 mmol) in anhydrous DMF (150 mL) was
added tert-butyldimethylsilyl chloride (TBSCl) (41.0 g, 272.1
mmol) at 0 °C followed by addition of imidazole (37.0 g, 543.3
mmol). The reaction mixture was stirred at 0 °C for 4 h and
maintained at room temperature overnight. The product was
extracted with diethyl ether (3 × 100 mL), and the combined
extracts were washed with water (3 × 100 mL) and dried over
MgSO4. After removal of solvents under reduced pressure, the
crude trans-1,2-bis(tert-butyldimethylsilyl)oxy-5-cyclooctene
(11) was purified by silica gel flash column chromatography
(eluting with pure petroleum ether) (33.5 g, 90.4 mmol, 99%).
1H NMR (200 MHz, CDCl3): δ 5.60 (2 × 1H, m), 3.92 (2 × 1H,
m), 2.32 (2 × 1H, m), 2.08 (2 × 2H, m), 1.64 (2 × 1H, m), 0.90
(2 × 9H, s), 0.048 (2 × 3H, s), 0.027 (2 × 3H, s). 13C NMR (50
MHz, CDCl3): δ 130.3, 74.4, 33.8, 26.5, 22.7, 18.7, -3.97,
-4.17. MS: m/e (relative intensity), 370 (0.004, M+), 313 (1.2),
181 (4), 147 (45), 73 (100). Anal. Calcd for C20H42O2Si2: C,
64.80; H, 11.42. Found: C, 64.84; H, 11.47.
Sch em e 6
Ozonolysis9 of 7 gave a dialdehyde which was trans-
formed to alcohol 26 by reduction with sodium borohy-
dride. TBDPS protection of the dihydroxyl groups on 26
provided 27. The 1H and 13C NMR data we obtained
matched the reported data.
4,5-Bis(ter t-bu tyldim eth ylsilyl)oxyoctadialdeh yde (12).
A solution of 1,2-bis(tert-butyldimethylsilyl)oxy-5-cyclooctene
(11) (4.4 g, 11.9 mmol) in methanol (50 mL) and methylene
chloride (50 mL) was ozonized at -78 °C. After 40 min, the
solution turned blue to indicate the completed ozonolysis
(excess ozone was removed by bubbling argon into the solu-
tion). To this mixture was added triphenyl phosphine (5.0 g,
19.1 mmol), and the mixture was stirred at room temperature
for 5 h. After removal of solvents by evaporation, the residue
was dissolved in pure petroleum ether to filter off the byprod-
uct triphenylphosphine oxide. The filtrate was evaporated, and
the crude product was purified by flash silica gel chromatog-
raphy (eluting with 10% ethyl acetate in petroleum ether) to
give 4,5-bis(tert-butyldimethylsilyl)oxyoctadialdehyde (12) (4.5
Con clu sion
We have developed a convenient synthesis of the C2-
symmetric bistetrahydrofuran core of acetogenins via our
previously reported SN′ O-cyclization strategy. The req-
uisite starting materials for the desired cyclization reac-
tions can be easily prepared in both racemic and enan-
tiomerically pure forms. The double SN′ intramolecular
cyclization products were achieved with high stereose-
lectivity. The newly formed terminal double bonds can
serve as functional groups for the stepwise elaboration
to secondary hydroxyl derivatives.17
1
g, 11.2 mmol, 94%) as a white solid, mp 58-60 °C. H NMR
(200 MHz, CDCl3): δ 9.77 (2 × 1H, t, J ) 1.6 Hz), 3.61 (2 ×
1H, m), 2.48 (2 × 2H, m), 2.00 (2 × 1H, m), 1.65 (2 × 1H, m),
0.88 (2 × 9H, s), 0.05 (2 × 6H, s). 13C NMR (50 MHz, CDCl3):
δ 202.6, 74.7, 41.6, 26.4, 23.3, 18.5, -3.46, -4.09.
(14) Sisido, K.; Sei, K.; Nozaki, H. J . Org. Chem. 1962, 27, 2681.
(15) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G.
A.; Hartung, J .; J eong, K. S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-
M.; Xu, D.; Zhang, X.-L. J . Org. Chem. 1992, 57, 2768. (b) Becker, H.;
King, S. B.; Taniguchi, M.; Vanhessche, K. P. M.; Sharpless, K. B. J .
Org. Chem. 1995, 60, 3940.
(16) The ee of asymmetric dihydroxylation was determined by HPLC
analysis on the Mosher’s ester of 24 according to the reported
procedures. Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95,
512.
Dieth yl 6,7-Bis(ter t-bu tyld im eth ylsilyl)oxy-2(E),10(E)-
d od eca d ien ed ioa te (13). To a solution of 4,5-bis(tert-butyl-
dimethylsilyl)oxyoctadialdehyde (12) (14 g, 34.8 mmol) in dry
THF (170 mL) was added carbethoxymethylene triphenylphos-
phorane (Ph3PdCHCOOEt) (30 g, 86.2 mmol). The mixture
(18) For general experimental details, see: (a) Li, P.; Gi, H.-J .; Sun,
L.; Zhao, K. J . Org. Chem. 1998, 63, 366. (b) Xiang, Y.; Gi, H.-J .; Niu,
D.; Schinazi, R. F.; Zhao, K. J . Org. Chem. 1997, 62, 7430. (c) Gi, H.-
J .; Xiang, Y.; Schinazi, R. F.; Zhao, K. J . Org. Chem. 1997, 62, 88.
(17) McDougal, P. G.; Rico, J . G.; Oh, Y.-I.; Condon, B. D. J . Org.
Chem. 1986, 51, 3388.

2262 J . Org. Chem., Vol. 64, No. 7, 1999
Li et al.
1
was stirred at 40 °C for 6 h. After removal of solvents by
evaporation, the residue was dissolved in pure petroleum ether
to filter off the byproduct triphenylphosphine oxide. The
filtrate was evaporated, and the crude product was purified
by flash silica gel chromatography (eluting with 5% ethyl
acetate in petroleum ether) to give diethyl 6,7-bis(tert-butyl-
dimethylsilyl)oxy-2(E),10(E)-dodecadienedioate (13) (17.4 g,
32.1 mmol, 92%) as a colorless oil. 1H NMR (200 MHz,
CDCl3): δ 6.97 (2 × 1H, dt, J ) 15.8, 7.0 Hz), 5.82 (2 × 1H, d,
J ) 15.7 Hz), 4.19 (2 × 2H, q, J ) 7.2 Hz), 3.56 (2 × 1H, m),
2.37 (2 × 1H, m), 2.13 (2 × 1H, m), 1.79 (2 × 1H, m), 1.45 (2
× 1H, m), 1.29 (2 × 3H, t, J ) 7.1 Hz), 0.88 (2 × 9H, s), 0.055
(2 × 3H, s), 0.045 (2 × 3H, s). 13C NMR (50 MHz, CDCl3): δ
166.9, 149.4, 121.9, 75.0, 60.6, 29.8, 29.3, 26.4, 18.6, 14.9,
-3.39, -3.97. HRMS: calcd, for C28H55O6Si2 (MH+) 543.3537;
found, 543.3549.
oil. For minor product 16, H NMR (200 MHz, CDCl3): δ 5.85
(2H, m), 5.13 (4H, m), 4.42 (1H, m), 4.32 (1H, m), 3.97 (1H,
m), 3.88 (1H, m), 2.18-1.60 (8H, m). 13C NMR (50 MHz,
CDCl3): δ 139.8, 139.7, 115.6, 115.4, 82.5, 82.4, 81.9, 81.3, 33.1,
32.4, 29.0, 28.4. For major product 7, 1H NMR (200 MHz,
CDCl3): δ 5.84 (2 × 1H, ddd, J ) 6.4, 10.2, 17.0 Hz), 5.19 (2
× 1H, dt, J ) 1.6, 17.0 Hz), 5.05 (2 × 1H, dt, J ) 1.6, 10.3
Hz), 4.23 (2 × 1H, m), 3.98 (2 × 1H, m), 2.05 (2 × 2H, m), 1.68
(2 × 2H, m). 13C NMR (50 MHz, CDCl3): δ 139.8, 115.5, 82.0,
81.0, 33.1, 29.0. HRMS: calcd, for C12H18O2 194.1306; found,
194.1304.
5,6-Bis(ter t-bu tyldim eth ylsilyl)oxy-1,1,10,10-tetr abr om o-
1,9-d eca d ien e (17). To a solution of triphenyl phosphine (23.4
g, 89.2 mmol) in anhydrous methylene chloride (60 mL) was
added CBr4 (15.0 g, 45.2 mmol) in portions at 0 °C over 20
min. The reaction mixture was stirred at room temperature
for 30 min, cooled to 0 °C, and added to a solution of 4,5-bis-
(tert-butyldimethylsilyl)oxyoctadialdehyde (12) (4.5 g, 11.2
mmol) in methylene chloride (5 mL). After stirring at room
temperature overnight, most of the solvent was removed by
evaporation. Petroleum ether (60 mL) was added to precipitate
out the byproducts, which were filtered off through Celite. The
filtrate was concentrated under reduced pressure. The crude
residue was subjected to silica gel flash column chromatogra-
phy (eluting with petroleum ether) to give 5,6-bis(tert-bu-
tyldimethylsilyl)oxy-1,1,10,10-tetrabromo-1,9-decadiene (17)
6,7-Bis(ter t-bu tyld im eth ylsilyl)oxy-2(E),10(E)-d od eca -
d ien e-1,12-d iol (14). To a solution of diethyl 6,7-bis(tert-
butyldimethylsilyl)oxy-2(E),10(E)-dodecadienedioate (13) (17
g, 31 mmol) in dry methylene chloride (160 mL) was added
dropwise a solution of DIBAL-H in cyclohexane (1.0 M, 180
mL, 180 mmol) at -78 °C. The reaction mixture was stirred
for 3 h and then quenched with 10% NaOH solution (100 mL).
After stirring at room temperature for 40 min, the mixture
was extracted with methylene chloride (3 × 100 mL). The
combined extracts were dried over MgSO4 and concentrated
under reduced pressure. The crude residue was subjected to
silica gel flash column chromatography (eluting with 70% ethyl
acetate in petroleum ether) to give 6,7-bis(tert-butyldimeth-
ylsilyl)oxy-2(E),10(E)-dodecadiene-1,12-diol (14) (11 g, 24 mmol,
1
(7.7 g, 10.8 mmol, 96%) as an oil. H NMR (200 MHz, CDCl3):
δ 6.41 (2 × 1H, t, J ) 7.2 Hz), 3.54 (2 × 1H, m), 2.23 (2 × 1H,
m), 2.03 (2 × 1H, m), 1.75 (2 × 1H, m), 1.37 (2 × 1H, m), 0.90
(2 × 9H, s), 0.08 (2 × 3H, s), 0.07 (2 × 3H, s). 13C NMR (50
MHz, CDCl3): δ 139.0, 89.5, 75.2, 31.0, 29.0, 26.4, 18.6, -3.37,
-3.99.
1
78%) as a colorless oil. H NMR (200 MHz, CDCl3): δ 5.67 (2
× 2H, m), 4.08 (2 × 2H, d, J ) 4.4 Hz), 3.54 (2 × 1H, m), 2.20
(2 × 1H, m), 1.98 (2 × 1H, m), 1.71 (2 × 1H, m), 1.39 (2 × 1H,
m), 1.34 (2 × 1H, bs), 0.89 (2 × 9H, s), 0.056 (2 × 3H, s), 0.041
(2 × 3H, s). 13C NMR (50 MHz, CDCl3): δ 133.9, 129.5, 75.2,
64.4, 30.4, 29.8, 26.4, 18.6, -3.38, -3.88. HRMS: calcd, for
6,7-Bis(ter t-bu tyld im eth ylsilyl)oxy-2,10-d od eca d iyn e-
1,12-d iol (18). To a solution of 5,6-bis(tert-butyldimethylsilyl)-
oxy-1,1,10,10-tetrabromo-1,9-decadiene (17) (7.7 g, 10.8 mmol)
in anhydrous THF (110 mL) was slowly added a solution of
n-BuLi in hexanes (1.4 M, 32 mL, 44.8 mmol) at -78 °C. After
stirring for 1 h, the solution was allowed to warm to room
temperature over 35 min and then cooled to -78 °C, at which
time, dry paraformaldehyde (1.3 g, 43.3 mmol) was added. The
mixture was warmed to room temperature gradually over 1
h, stirred overnight, and quenched with aqueous NH4Cl
solution (100 mL). After extraction by ethyl acetate (3 × 100
mL), the combined extracts were dried over MgSO4 and
evaporated. Chromatography of the residue on silica gel
(eluting with 6% ethyl acetate in petroleum ether) gave 6,7-
bis(tert-butyldimethylsilyl)oxy-2,10-dodecadiyne-1,12-diol (18)
C
C
24H51O4Si2 (MH+) 459.3326; found, 459.3337. Anal. Calcd for
24H50O4Si2‚0.2H2O: C, 62.34; H, 10.99. Found: C, 62.39; H,
11.03.
6,7-Bis(ter t-bu tyld im eth ylsilyl)oxy-1,12-d ibr om o-2(E),-
10(E)-d od eca d ien e (15). To a solution of 6,7-bis(tert-butyl-
dimethylsilyl)oxy-2(E),10(E)-dodecadiene-1,12-diol (14) (6.5 g,
14.2 mmol) in anhydrous diethyl ether (140 mL) was added
triphenyl phosphine (15 g, 57.2 mmol) in one portion. The
reaction mixture was stirred for 10 min until all the PPh3 was
dissolved. Carbon tetrabromide (19.0 g, 57.3 mmol) was then
added. After stirring at room temperature for 6 h, the
precipitate was filtered off through Celite. The filtrate was
concentrated under reduced pressure. The crude residue was
subjected to silica gel flash column chromatography (eluting
with 1% ethyl acetate in petroleum ether) to give 6,7-bis(tert-
butyldimethylsilyl)oxy-1,12-dibromo-2(E),10(E)-dodecadiene (15)
(7.4 g, 12.6 mmol, 89%) as a pale yellow oil. 1H NMR (200 MHz,
CDCl3): δ 5.74 (2 × 2H, m), 3.95 (2 × 2H, d, J ) 6.4 Hz), 3.54
(2 × 1H, m), 2.23 (2 × 1H, m), 2.01 (2 × 1H, m), 1.71 (2 × 1H,
m), 1.41 (2 × 1H, m), 0.89 (2 × 9H, s), 0.061 (2 × 3H, s), 0.051
(2 × 3H, s). 13C NMR (50 MHz, CDCl3): δ 137.0, 126.9, 75.0,
33.9, 30.0, 29.6, 26.5, 18.6, -3.34, -3.85. HRMS: calcd, for
1
(4.4 g, 9.7 mmol, 90%) as a colorless oil. H NMR (200 MHz,
CDCl3): δ 4.23 (2 × 2H, t, J ) 2.1 Hz), 3.76 (2 × 1H, m), 2.28
(2 × 2H, m), 1.85 (2 × 1H, m), 1.54 (2 × 1H, br), 1.45 (2 × 1H,
m), 0.90 (2 × 9H, s), 0.09 (2 × 6H, s). 13C NMR (50 MHz,
CDCl3): δ 86.9, 79.3, 73.7, 51.9, 29.5, 26.4, 18.6, 16.2, -3.47,
-4.08.
6,7-Bis(ter t-bu tyld im eth ylsilyl)oxy-2(Z),10(Z)-d od eca -
d ien e-1,12-d iol (19). A solution of 6,7-bis(tert-butyldimeth-
ylsilyl)oxy-2,10-dodecadiyne-1,12-diol (18) (2.0 g, 4.4 mmol) in
a flask with ethyl acetate (22 mL), quinoline (0.5 mL, 4.2
mmol), and Lindlar’s catalyst (200 mg, 10% w/w) was stirred
under an atmosphere of H2. After consumption of 1 molar equiv
of H2 the mixture was filtered through Celite to remove the
catalyst. The filtrate was evaporated and purified by silica gel
flash column chromatography (eluting with 15% ethyl acetate
in petroleum ether) to give 6,7-bis(tert-butyldimethylsilyl)oxy-
2(Z),10(Z)-dodecadiene-1,12-diol (19) (2.0 g, 4.3 mmol, 99%)
as an oil. 1H NMR (200 MHz, CDCl3): δ 5.55 (2 × 2H, m),
4.18 (2 × 2H, d, J ) 5.2 Hz), 3.54 (2 × 1H, m), 2.22 (2 × 1H,
m), 1.97 (2 × 1H, m), 1.77 (2 × 1H, br), 1.65 (2 × 1H, m), 1.32
(2 × 1H, m), 0.88 (2 × 9H, s), 0.05 (2 × 6H, s). 13C NMR (50
MHz, CDCl3): δ 133.1, 129.2, 75.4, 59.1, 31.1, 26.4, 25.3, 18.6,
-3.40, -3.95. Anal. Calcd for C24H50O4Si2‚0.2H2O: C, 62.34;
H, 10.99. Found: C, 62.33; H, 11.08.
C
24H47Br2O2Si2 (M+ - H) 581.1481; found, 581.1490. Anal.
Calcd for C24H48Br2O2Si2: C, 49.31; H, 8.28; Br, 27.34. Found:
C, 49.29; H, 8.27; Br, 27.32.
3,6:7,10-Diep oxy-1,11-d od eca d ien e (7 a n d 16). To a
solution of 6,7-bis(tert-butyldimethylsilyl)oxy-1,12-dibromo-
2(E),10(E)-dodecadiene (15) (4 g, 6.8 mmol) in acetonitrile (68
mL) was added HF (48%, 1.2 mL, 33 mmol). The mixture was
stirred at room temperature for 2 h. Excess HF was removed
by aspirator, and the mixture was heated at 50 °C overnight
to complete the monocyclization. Following addition of NaH-
CO3, the mixture was stirred at room temperature for 2 h and
extracted with ethyl acetate. The combined extracts were dried
over MgSO4 and concentrated under reduced pressure. The
crude residue (7:16 ) 2:1 by GC/MS) was subjected to silica
gel flash column chromatography (eluting with 10% ethyl
acetate in petroleum ether) to give 3,6:7,10-diepoxy-1,11-
dodecadiene (7 + 16) (820 mg, 3.2 mmol, 69%) as a colorless
6,7-Bis(ter t-bu tyld im eth ylsilyl)oxy-1,12-d ibr om o-2(Z),-
10(Z)-d od eca d ien e (20). To a solution of 6,7-bis(tert-bu-
tyldimethylsilyl)oxy-2(Z),10(Z)-dodecadiene-1,12-diol (19) (2.0
g, 4.3 mmol) in anhydrous diethyl ether (50 mL) was added

Bistetrahydrofuran Core of Acetogenins
J . Org. Chem., Vol. 64, No. 7, 1999 2263
triphenyl phosphine (4.6 g, 17.5 mmol) in one portion. The
reaction mixture was stirred for 10 min until all the PPh3 was
dissolved. Carbon tetrabromide (5.8 g, 17.5 mmol) was then
added. After stirring at room temperature for 6 h, the
precipitate was filtered off through Celite. The filtrate was
concentrated under reduced pressure. The crude residue was
subjected to silica gel flash column chromatography (eluting
with 2% ethyl acetate in petroleum ether) to give 6,7-bis(tert-
butyldimethylsilyl)oxy-1,12-dibromo-2(Z),10(Z)-dodecadiene (20)
(2.0 g, 3.4 mmol, 79%) as a pale yellow oil. 1H NMR (200 MHz,
CDCl3): δ 5.67 (2 × 2H, m), 3.98 (2 × 2H, d, J ) 7.7 Hz), 3.58
(2 × 1H, m), 2.30 (2 × 1H, m), 2.05 (2 × 1H, m), 1.71 (2 × 1H,
m), 1.40 (2 × 1H, m), 0.90 (2 × 9H, s), 0.07 (2 × 6H, s). 13C
NMR (50 MHz, CDCl3): δ 136.2, 125.9, 75.4, 30.5, 27.6, 26.5,
24.8, 18.6, -3.32, -3.90. HRMS: calcd for C24H47Br2O2Si2 (M+
- H) 581.1481; found, 581.1465. Anal. Calcd for C24H48Br2O2-
Si2: C, 49.31; H, 8.28; Br, 27.34. Found: C, 49.38; H, 8.33;
Br, 27.28.
Di-ter t-bu tyl tr a n s-4-Octen ed ioa te (23). To a solution of
diisopropylamine (6.6 mL, 47 mmol) in anhydrous THF at -78
°C (80 mL) was slowly added a solution of n-butyllithium in
hexanes (1.4 M, 32 mL, 45 mmol), and the mixture was stirred
for 40 min. To the above mixture was added tert-butyl acetate
(5.8 mL, 43 mmol), and the reaction mixture was stirred for
another 40 min. After HMPA (8.2 mL, 47 mmol) was added,
the reaction was warmed to -60 °C and a solution of trans-
1,4-dibromo-2-butene (5.5 g, 26 mmol) in THF (20 mL) was
added. The resulting mixture was stirred at -40 °C for 1 h,
quenched with 2 N HCl solution, and extracted with ethyl
acetate. The combined extracts were washed with brine and
dried over MgSO4. Removal of all the solvents under reduced
pressure gave crude di-tert-butyl trans-4-octenedioate (23) (4.5
g, 16 mmol, 74%). 1H NMR (200 MHz, CDCl3): δ 5.42 (2 ×
1H, br), 2.22 (2 × 4H, s), 1.41 (2 × 9H, s). 13C NMR (50 MHz,
CDCl3): δ 172.8, 129.8, 80.6, 36.0, 28.7, 28.6.
(4.4 g, 13.8 mmol, 89%, ee > 98%). 1H NMR (200 MHz,
CDCl3): δ 3.40 (2 × 1H, m), 3.01 (2 × 1H, d, J ) 5.0 Hz), 2.40
(2 × 2H, t, J ) 7.2 Hz), 1.77 (2 × 2H, m), 1.43 (2 × 9H, s). 13C
NMR (50 MHz, CDCl3): δ 174.1, 81.1, 74.3, 32.5, 29.2, 28.7.
Di-ter t-bu tyl 4(R),5(R)-Bis(ter t-bu tyld im eth ylsilyl)oxy-
octa n ed ioa te (25). Di-tert-butyl 4(R),5(R)-bis(tert-butyldi-
methylsilyl)oxyoctanedioate (25) was prepared (75% yield)
from di-tert-butyl 4(R),5(R)-dihydroxyoctane dioate (24) accord-
ing to the similar procedures as described for the preparation
of compound 11, white solid, mp 101-103 °C. [R]25 ) +64.9°
D
(c ) 1.1, ethanol). 1H NMR (200 MHz, CDCl3): δ 3.55 (2 ×
1H, m), 2.37-1.82 (2 × 3H, m), 1.55 (2 × 1H, m), 1.40 (2 ×
9H, s), 0.86 (2 × 9H, s), 0.027 (2 × 6H, s). 13C NMR (50 MHz,
CDCl3): δ 173.3, 80.3, 74.8, 33.1, 28.7, 26.4, 18.5, -3.53, -4.10.
4(R),5(R)-Bis(ter t-b u t yld im et h ylsilyl)oxyoct a d ia ld e-
h yd e [(+)-12]. To a solution of di-tert-butyl 4(R),5(R)-bis(tert-
butyldimethylsilyl)oxyoctanedioate (25) (4.9 g, 9.0 mmol) in
anhydrous CH2Cl2 (100 mL) was added DIBAL (1.0 M, 27 mL,
27.0 mmol) at -78 °C. The reaction mixture was stirred at
-78 °C for 15 min, quenched with aqueous NaOH solution,
and extracted with CH2Cl2 (3 × 100 mL). The combined
extracts were dried over MgSO4. After removal of solvents
under reduced pressure, the crude 4(R),5(R)-bis(tert-butyldi-
methylsilyl)oxyoctadialdehyde [(+)-12] was purified by silica
gel flash column chromatography (52%), white solid, mp 58-
60 °C.
3(R),6(R):7(R),10(R)-Diep oxy-1,11-d od eca d ien e [(-)-7]:
[R]25 ) - 22.9° (c ) 2.0, CH2Cl2).
D
Ack n ow led gm en t. We thank the American Cancer
Society, the NSF Faculty Early Career Development
Program, and the donors of the Petroleum Research
Fund, administered by the American Chemical Society,
for support of this work. P.L. acknowledges the New
York University Dean’s Dissertation Fellowship. J .Y.
acknowledges the New York University MacCracken
Fellowship.
Di-ter t-bu tyl 4(R),5(R)-Dih yd r oxyocta n ed ioa te (24). To
a solution of di-tert-butyl trans-4-octenedioate (23) (4.4 g, 15.5
mmol) in tert-butyl alcohol (75 mL) and water (75 mL) was
added AD-mix-â (32 g, 22.8 mmol) at 0 °C. The reaction
mixture was stirred at 0 °C for 30 min and maintained at room
temperature overnight. After workup with NaHCO3 and ethyl
acetate, the combined solvents were removed under reduced
pressure. The crude di-tert-butyl 4(R),5(R)-dihydroxyoctanedio-
ate (24) was purified by silica gel flash column chromatography
Su p p or tin g In for m a tion Ava ila ble: A synthetic proce-
dure for compound 27 and 300 MHz 1H and 13C NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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