A practical synthesis of the F-ring of halichondrin B via ozonolytic desymmetrization of a C2-symmetric dihydroxycyclohexene

Article abstract of DOI:10.1021/jo026302w

C₂-symmetric dihydroxycyclohexene 1 was desymmetrized via a one-pot Criegee ozonolysis/acylation protocol to afford acetal-lactone 2. Installation of the allyl side chain on the convex face of the bicyclic system and subsequent reduction provided the desired tetrahydrofuran 4 with the correct relative and absolute stereochemistries. Simple functional group manipulations led to the desired F-ring module 3 of halichondrin B.

Full text of DOI:10.1021/jo026302w

A P r a ctica l Syn th esis of th e F -Rin g of
Ha lich on d r in B via Ozon olytic
Desym m etr iza tion of a C2-Sym m etr ic
Dih yd r oxycycloh exen e
Lei J iang, J oseph R. Martinelli, and Steven D. Burke*
Department of Chemistry, University of
Wisconsin-Madison, 1101 University Avenue,
Madison, Wisconsin 53706-1396
F IGURE 1. Structure of halichondrin B.
burke@chem.wisc.edu
Received August 9, 2002
SCHEME 1. Mech a n ism for th e P r op osed On e-P ot
Ozon olysis/Ter m in u s Differ en tia tion
Abstr a ct: C2-symmetric dihydroxycyclohexene 1 was de-
symmetrized via a one-pot Criegee ozonolysis/acylation
protocol to afford acetal-lactone 2. Installation of the allyl
side chain on the convex face of the bicyclic system and
subsequent reduction provided the desired tetrahydrofuran
4 with the correct relative and absolute stereochemistries.
Simple functional group manipulations led to the desired
F-ring module 3 of halichondrin B.
Halichondrin B (Figure 1) is the most potent member
of the halichondrin family of anticancer agents isolated
from marine sponges.1 The mechanism of action involves
the binding of the vinca domain of tubulin, resulting in
the inhibition of tubulin polymerization and tubulin
dependent GTP hydrolysis.2 On the basis of its potential
as an antitumor agent, the National Cancer Institute has
recommended halichondrin B for stage A preclinical
trials.2d,3 Synthetically, halichondrin B possesses a num-
ber of interesting structural features including a contigu-
ous C1-C54 carbon chain containing 32 stereocenters,
a unique 2,6,9-trioxatricyclo[3.3.2.03,7]decane “cage” ring
system, and a 22-membered macrolactone with a trans-
2,5-disubstituted THF ring (F-ring). Synthetic efforts
have been devoted to halichondrin B by several groups,4
highlighted by Kishi’s total synthesis.5a We have recently
reported an efficient synthesis of the F-ring module5 of
halichondrin B via a palladium-mediated, ligand-con-
trolled desymmetrization of a C2-symmetric diol diacetate.4i
Herein, we present an alternative, practical route for the
same segment of halichondrin B.
Ozone is a versatile oxidizing agent that has been used
extensively in organic synthesis as a result of the seminal
work of Rudolf Criegee, initiated over 50 years ago.6 In
* To whom correspondence should be addressed.
(1) For isolation, see: (a) Hirata, Y.; D. Pure Appl. Chem. 1986, 58,
701. (b) Pettit, G. R.; Herald, C. L.; Boyd, M. R.; Leet, J . E.; Dufresne,
C.; Doubek, D. L.; Schmidt, J . M.; Cerny, R. L.; Hooper, J . N. A.;
Rutzler, K. C. J . Med. Chem. 1991, 34, 3339. (c) Pettit, G. R.; Ichihara,
Y.; Wurzel, G.; Williams, M. D.; Schmidt, J . M.; Chapuis, J . C. J . Chem.
Soc., Chem. Commun. 1995, 383. (d) Pettit, G. R.; Tan, R.; Gao, F.;
Williams, M. D.; Doubek, D. L.; Boyd, M. R.; Schmidt, J . M.; Chapuis,
J .; Hamel, E.; Bai, R.; Hooper, J . N. A.; Tackett, L. P. J . Org. Chem.
1993, 58, 2538. (e) Pettit, G. R.; Gao, F.; Doubek, D. L.; Boyd, M. R.;
Hamel, E.; Bai, R.; Schmidt, J . M.; Tackett, L. P.; Rutzler, K. C. Gazz.
Chim. Ital. 1993, 123, 371. (f) Litaudon, M.; Hart, J . B.; Blunt, J . W.;
Lake, R. J .; Munro, M. H. G. Tetrahedron Lett. 1994, 35, 9435.
(2) For biological activities, see: (a) Hamel, E. H. Pharmacol. Ther.
1992, 55, 31. (b) Bai, R.; Paull, K. D.; Herald, C. L.; Malspeis, L.; Pettit,
G. R.; Hamel, E. H. J . Biol. Chem. 1991, 266, 15882. (c) Luduena, R.
F.; Roach, M. C.; Prasad, V.; Pettit, G. R. Biochem. Pharmacol. 1993,
45, 421. (d) Pettit, G. R. Pure Appl. Chem. 1994, 66, 2271.
(3) (a) Personal correspondence with Ernest Hamel, M.D., Ph.D.,
Senior Investigator, Laboratory of Molecular Pharmacology, Develop-
mental Therapeutics Program, Division of Cancer Treatment, National
Cancer Institute, NIH. Dr. Hamel informed us that halichondrin B
was effective in vivo against human tumors transplanted into immu-
nodeficient nude mice. (b) Personal correspondence with Michael R.
Boyd, M.D., Ph.D., Chief, Laboratory of Drug Discovery Research and
Development, NCI Cancer Research Center, Frederick, MD. Dr. Boyd
shared with us his data and slides that resulted in the NCI Decision
Network Committee’s selection of halichondrin B for drug development.
(4) For synthetic effort from the Burke group, see: (a) Burke S. D.;
J ung, K. W.; Phillips, J . R.; Perri, R. E. Tetrahedron Lett. 1994, 35,
703. (b) Burke S. D.; J ung, K. W.; Lambert, W. T.; Phillips, J . R.;
Klovning, J . J . J . Org. Chem. 2000, 65, 4070. (c) Burke, S. D.;
Buchanan, J . L.; Rovin, J . D. Tetrahedron Lett. 1991, 32, 3961-3964.
(d) Burke S. D.; Zhang, G.; Buchanan, J . L. Tetrahedron Lett. 1995,
36, 7023. (e) Burke S. D.; Phillips, J . R.; Quinn, K. J .; Zhang, G.; J ung,
K. W.; Buchanan, J . L.; Perri, R. E. In Anti-infectives: Recent Advances
in Chemistry and Structure-Activity Relationships; Bentley, P. H.,
O’Hanlon, P. J ., Eds.; Royal Society of Chemistry: Cambridge, UK,
1997; p 73. (f) Burke S. D.; Quinn, K. J .; Chen, V. J . J . Org. Chem.
1998, 63, 8626. (g) Burke, S. D.; Austad, B. C.; Hart, A. C. J . Org.
Chem. 1998, 63, 6770. (h) Austad, B. C.; Hart, A. C.; Burke, S. D.
Tetrahedron 2002, 58, 2011. (i) J iang, L.; Burke, S. D. Org. Lett. 2002,
4, 3411. For a complete listing of synthetic efforts toward halichondrin
B from other groups, see ref 4i.
(5) For synthetic efforts toward the F-ring module of halichondrin
B, see: (a) Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J .;
J ung, S. H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.; Spero, D. M.; Yoon,
S. K. J . Am. Chem. Soc. 1992, 114, 3162. (b) Horita, K.; Nagasawa,
M.; Hachiya, S.; Yonemitsu, O. Synlett 1994, 40-43. (c) Horita, K.;
Sakurai, Y.; Nagasawa, M.; Yonemitsu, O. Chem. Pharm. Bull. 1997,
45, 1558-1572.
(6) . For reviews, see: (a) Bailey, P. S. Ozonation in Organic
Chemistry; Academic Press: New York, 1978; Vol. 1; 1982; Vol. 2. (b)
Odinokov, V. N.; Tolstikov, G. A. Russ. Chem. Rev. 1981, 50, 636.
(7) Criegee, R.; Banciu, A.; Kaul, H. Chem. Ber. 1975, 108, 1642.
10.1021/jo026302w CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/31/2002
1150
J . Org. Chem. 2003, 68, 1150-1153

SCHEME 2. Retr osyn th etic An a lysis
SCHEME 3
1975, he reported the intramolecular trapping of carbonyl
oxide with a hydroxyl group in a favorable position.7
Later, Schreiber described a modified workup procedure
for the ozonolysis of cyclic alkenes to afford a variety of
open-chain products with differentiated terminal func-
tionality,8 including an acetal-ester. We envisioned that
the application of Schreiber’s protocol to a substrate with
two hydroxyl groups at the appropriate positions would
lead to the formation of a bicyclic acyloxy acetal-lactone.
The proposed mechanism of this transformation is shown
in Scheme 1. Fragmentation of the primary ozonide A
leads to the desymmetrized intermediate B with one
carbonyl terminus and a carbonyl oxide at the other end.
Intramolecular five-membered hemiacetal formation with
the appropriate hydroxyls would be followed by acylation
to give D, and elimination of acetic acid would furnish
the bicyclic acyloxy acetal-lactone 2.
Retrosynthetically (Scheme 2), the F-ring of halichon-
drin B is viewed as a bridge between C1-C13 and C23-
C36 subunits of the molecule. C14 and C22 are envi-
sioned as the points of the attachment via structure 3.
Aldehyde 3 should be readily accessible from 4 via
straightforward transformations. Lactone 5 should be
available from the bicyclic hemiacetal derivative 2 via a
Lewis acid promoted allylation reaction, which was
expected to occur preferentially from the convex face of
the bicyclic ring, thereby providing the desired stereo-
chemistry at C17.
(S,S)-Dihydroxycyclohexene 19 was synthesized from
known (S,S)-4,5-dihydroxy-octa-1,7-diene10 via a ring-
closing metathesis (RCM) reaction with use of Grubbs’
catalyst11 (Scheme 3). Initially, attempted ozonolysis of
the C2-symmetric cyclohexene diol 1 with Schreiber’s
conditions gave a mixture of acyloxy acetal-lactone,
hemiacetal-lactone, and a small amount of bis-hemiac-
etal. Employment of excess acetic anhydride and addition
of DMAP gave a more satisfactory result, allowing the
isolation of the desired acyloxy acetal-lactone 2a ,b in 75%
yield as a separable (4:1) mixture of diastereomers. This
mixture was subjected to Lewis acid promoted allylation
to give an isolable (1:2) mixture of the allylation prod-
ucts.12 NOE experiments on both minor product epi-5 and
major product 5 were performed to identify the desired
product (Figure 2). The Hb of the minor product showed
F IGURE 2. NOE study on compounds epi-5 and 5.
significant NOE when Ha was irradiated, while major
product did not show any enhancement between Ha and
Hb. It is important to note that 5, with electrophilic
functionality at C22, can be viewed as a potential
coupling partner with C23 of the middle fragment of
halichondrin B. Lactone 5 was initially treated with
9-BBN to functionalize the double bond, but lactone
reduction occurred at the same time. To avoid this
complication, lactone 5 was reduced with lithium alumi-
num hydride to provide the corresponding diol 4. Selec-
tive silylation was achieved following Hernandez’s pro-
cedure to give tert-butyldiphenylsilyl (TBDPS) ether 6.13
Subsequent hydroboration of the terminal alkene pro-
(8) Schreiber, S. L.; Claus, R. E.; Reagan, J . Tetrahedron Lett. 1982,
23, 3867.
(9) Suemune, H.; Hasegawa, A.; Sakai, K. Tetrahedron: Asymmetry
1995, 6, 55.
(10) Koert, U.; Stein, M.; Wagner, H. Chem. Eur. J . 1997, 3, 1170.
(11) For a recent review, see: Grubbs, R. H.; Trnka, T. M. Acc. Chem.
Res. 2001, 34, 18.
(12) When the allylation was performed on pure 2b, a 5:1 (5:epi-5)
mixture of diastereomers was obtained, suggesting partial involvement
of an ion pair mechanism rather than solely through the oxonium ion
that would be derived from either substrate diastereomer. Varying the
reaction temperature did not affect stereoselectivity.
J . Org. Chem, Vol. 68, No. 3, 2003 1151

room temperature and stir overnight. It was then quenched with
NaHCO3 and extracted with ethyl acetate (3 × 100 mL). The
combined organics were dried with Na2SO4, filtered, and con-
centrated. FCC (Et2O) furnished 0.52 g (2.85 mmol, 75%) of fused
lactones 2a and 2b (2a /2b ) 4/1) as crystalline solids. 2a : 1H
NMR (CDCl3) δH 6.36 (dd, J ) 6.0, 2.0 Hz, 1H), 5.09 (ddd, J )
6.0, 4.0, 2.0 Hz, 1H), 4.83 (td, J ) 4.0, 2.0 Hz, 1H), 2.75-2.65
(m, 2H), 2.56 (ABMX, J ) 15.5, 7.5, 2.0 Hz, 1H), 2.40 (ABMX,
J ) 15.5, 7.0, 2.0 Hz, 1H), 1.99 (s, 3H); 13C NMR (CDCl3) δC
174.4 (C), 170.0 (C), 98.0 (CH), 82.1 (CH), 78.9 (CH), 39.3 (CH2),
35.4 (CH2), 20.9 (CH3); IR (thin film) 3029, 2988, 2969, 2941,
ceeded uneventfully with disiamyl borane, and oxidative
workup with NaBO3 gave primary alcohol 7. Selective
14
monoacylation of the primary hydroxyl with AcCl/2,6-
lutidiene furnished the secondary alcohol 8. Dess-Martin
periodinane15 oxidation was followed by a one-pot Wittig
methylenation/deacylation reaction giving the primary
alcohol 9.16 Buffered PCC oxidation provided 3, the
desired F-ring segment of halichondrin B, which was
identical with the substance provided via the alternate
sequence.4i
1773, 1725, 1386, 1255, 1190, 1154, 1118, 1012 cm-1; [R]24
D
In summary, a one-pot ozonolysis/acylation desymme-
trization reaction has been employed to provide bicyclic
acyloxy acetal-lactones 2a ,b, which contain a tetrahy-
drofuran nucleus ideally functionalized for conversion in
eight steps to the C14-C22, F-ring segment 3 of hali-
chondrin B. Segment couplings and completion of the
synthesis are underway.
-142.5° (c 0.88, CHCl3); HRMS (ESI) calculated for C9H14O6Na
(MNaMeOH+) 241.0688, found 241.0689; mp 68-70 °C. 2b: 1H
NMR (CDCl3) δH 6.39 (d, J ) 4.5 Hz, 1H), 5.19 (t, J ) 6.0 Hz,
1H), 5.0 (dt, J ) 6.0, 1.0 Hz, 1H), 2.83 (ABX, J ) 19.0, 6.0 Hz,
1H), 2.73 (ABX, J ) 19.0, 1.0 Hz, 1H), 2.53 (AB, J ) 15.0 Hz,
1H), 2.28 (ABMX, J ) 15.0, 6.0, 4.5 Hz, 1H), 2.02 (s, 3H); 13C
NMR (CDCl3, 75 MHz) δC 173.8 (C), 170.1 (C), 98.3 (CH), 81.7
(CH), 80.0 (CH), 39.1 (CH2), 37.3 (CH2), 21.2 (CH3); IR (KBr
pellet) 3028, 2929, 2899, 1774, 1728, 1380, 1254, 1174, 1062,
1110 cm-1; [R]24D -23.3° (c 0.18, CHCl3); HRMS (ESI) calculated
for C9H14O6Na (MNaMeOH+) 241.0688, found 241.0679; mp 61-
63 °C.
P r ep a r a tion of Com p ou n d 5. To a solution of lactone-
acetates 2a and 2b (0.44 g, 2.4 mmol) in CH3CN (25 mL) at 0
°C was added trimethylallylsilane (0.69 g, 6.0 mmol) followed
by BF3‚Et2O (0.4 g, 2.9 mmol). The reaction mixture was stirred
at 0 °C for 20 min then warmed to room temperature and stirred
Exp er im en ta l Section
Gen er a l P r oced u r es. The solvents used in reactions were
dried prior to use. All other reagents were used as received
without purification. All moisture-sensitive reactions were
performed in flame-dried and/or oven-dried glassware under a
positive pressure of nitrogen unless otherwise noted. Thin-layer
chromatography was carried out with glass TLC plates precoated
with silica gel 60 F254. Flash column chromatography was
accomplished with silica gel 60 (230-400 mesh). High-resolution
mass spectra (HRMS) with electrospray ionization (ESI) were
for an additional 2 h. The reaction was quenched with
a
saturated solution of NH4Cl, extracted with EtOAc (3 × 50 mL).
The combined organics were dried with Na2SO4, filtered, and
concentrated. FCC (50% hexanes/Et2O) furnished 0.36 g (2.14
mmol, 90.0%) of epi-5 and 5 as colorless oils. epi-5: 1H NMR
(CDCl3) δH 5.74 (ddt, J ) 17.0, 11.0, 7.0 Hz, 1H), 5.13-5.03 (m,
2H), 4.99 (ddd, J ) 7.0, 4.0, 2.0 Hz, 1H), 4.51 (app q, J ) 4.0
Hz, 1H), 4.01 (quin, J ) 7.0 Hz, 1H), 2.70 (d, J ) 3.0 Hz, 2H),
measured with
a TOF analyzer. Proton nuclear magnetic
resonance spectra were recorded in deuterated solvents at either
300 or 500 MHz. Carbon nuclear magnetic resonance spectra
were recorded in deuterated solvents at 75 MHz. Infrared
spectra were measured on an FT-IR spectrometer equipped with
a DTGS detector. Optical rotations, for which concentrations (c)
are reported in g/100 mL, were measured on a digital polarim-
eter at room temperature with a Na lamp.
2.45-2.24 (m, 3H), 1.93 (ABMX, J ) 14.0, 8.0, 2.0 Hz, 1H); 13
C
NMR (CDCl3) δC 175.4 (C), 133.7 (CH), 117.8 (CH2), 84.5 (CH),
79.4 (CH), 78.5 (CH), 39.7 (CH2), 37.5 (CH2), 36.4 (CH2); IR (thin
film) 3077, 2978, 2928, 2867, 1780, 1642, 1350, 1157, 1073, 917
P r ep a r a tion of Cycloh ex-4-en e-1,2-d iol (1). To a refluxing
solution of (S,S)-4,5-dihydroxy-octa-1,7-diene10 (0.54 g, 3.8 mmol)
in 330 mL of benzene was added Grubbs’ catalyst (0.16 g, 0.02
mmol) in 50 mL of benzene via syringe pump over a period of 1
h. The solution was stirred at reflux for 4.5 h. After the reaction
mixture was cooled to room temperature, N-methyl morpholine
N-oxide (0.2 g, 1.6 mmol) was added and the reaction mixture
was stirred for an additional 2 h, then, the resulting dark
solution was filtered through a pad of silica gel and the filtrate
was concentrated in vacuo. FCC (50% hexanes/Et2O) furnished
0.36 g (3.16 mmol, 83%) of the cyclic diol 1 as a crystalline solid.
1H NMR (CD3OD) δH 5.55-5.52 (m, 2H), 3.63-3.57 (m, 2H),
2.50-2.35 (m, 2H), 2.10-1.95 (m, 2H); 13C NMR (CD3OD) δC
125.3 (2 × CH), 72.4 (2xCH), 34.0 (2 × CH2); IR (KBr pellet)
3346, 3043, 2932, 2898, 2838, 1657, 1441, 1349, 1278, 1056, 680
cm-1; [R]24 -38.6° (c +19.0, CHCl3); HRMS (ESI) calculated
D
for C9H12O3Na (MNa+) 191.0684, found 191.0676. 5: 1H NMR
(CDCl3) δH 5.76 (ddt, J ) 17.0, 10.0, 7.0 Hz, 1H), 5.14-5.05 (m,
3H), 4.80 (ddd, J ) 4.5, 1.5, 1.0 Hz, 1H), 4.14 (d app q, J ) 11.0,
6.0 Hz, 1H), 2.74 (ABX, J ) 18.5, 6.0 Hz, 1H), 2.65 (ABX, J )
18.5 1.0 Hz, 1H), 2.39-2.29 (m, 3H), 1.72 (ABX, J ) 14.0, 10.0,
5.0 Hz, 1H); 13C NMR (CDCl3) δC 176.0 (C), 133.6 (CH), 117.8
(CH2), 84.7 (CH), 77.7 (CH), 77.5 (CH), 38.8 (CH2), 38.2 (CH2),
36.6 (CH2); IR (thin film) 3077, 2978, 2929, 2872, 1772, 1646,
1340, 1176, 1150, 1068, 1034, 901 cm-1; [R]24 +48.4° (c 1.0,
D
CHCl3); HRMS (ESI) calculated for C9H12O3Na (MNa+) 191.0684,
found 191.0694.
P r ep a r a tion of Com p ou n d 6. To a suspension of LAH (200
mg, 4.28 mmol) in 10 mL of THF at 0 °C was added a solution
of lactone 5 (360 mg, 2.14 mmol) in THF (10 mL). The resulting
mixture was stirred for 2 h at which point TLC showed the
reaction was complete. The reaction was cautiously quenched
with saturated NH4Cl. The aqueous layer was extracted with
EtOAc (4 × 40 mL). The combined organics were dried with Na2-
SO4, filtered, and concentrated. FCC (EtOAc) furnished diol 4
cm-1; [R]24 +99.0° (c 1.0, CHCl3); mp reported 100-102 °C,9
D
observed 99-101 °C.
P r ep a r a tion of La cton e-Aceta tes 2a a n d 2b. A solution
of diol 1 (0.44 g, 3.8 mmol) in ethyl acetate (190 mL) at -78 °C
was purged with ozone until the solution turned blue. The
system was then purged with N2 for approximately 10 min or
until the blue color disappeared. To this solution were added
slowly (approximately 30 min each) via syringe pump Ac2O (2.36
g, 23.2 mmol) and Et3N (3.8 g, 38.0 mmol), and stirring was
continued at -78 °C for 10 min prior to the addition of DMAP
(0.2 g, 1.8 mmol). The reaction mixture was allowed to warm to
1
(0.35, g 2.03 mmol, 95%) as a colorless oil. H NMR (CDCl3) δH
5.78 (ddt, J ) 13.5, 10.0, 8.0 Hz, 1H), 5.13-5.02 (m, 2H), 4.36-
4.23 (m, 2H), 3.97 (td, J ) 7.0, 3.0 Hz, 1H), 3.92-3.80 (m, 1H),
3.77-3.67 (m, 1H), 2.65 (br, 1H), 2.53-2.17 (m, 3 H), 2.06
(ABMX, J ) 13.5, 6.0, 1.0 Hz, 1H), 1.99-1.86 (m, 2 H), 1.78
(ABMX, J ) 14.0, 10.0, 5.0 Hz, 1H); 13C NMR (CDCl3) δC 134.4
(CH), 117.2 (CH2), 82.3 (CH), 76.6 (CH), 73.5 (CH), 60.3 (CH2),
40.4 (CH2), 40.1 (CH2), 31.3 (CH2); IR (thin film) 3434, 3077,
(13) Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 20,
99.
(14) Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M. J . Org. Chem.
1989, 54, 5930.
(15) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155. (b)
Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.
(16) Sharma, G. V. M.; Vepachedu, S. R.; Chandrasekhar, S. Synth.
Commun. 1990, 20, 3403.
2929, 1635, 1558, 1456, 1339, 1260, 1200, 1063, 999, 914 cm-1
;
[R]24D -8.9° (c 1.3, CHCl3); HRMS (ESI) calculated for C9H16O3-
Na (MNa+)195.0997, found 195.0968.
To a mixture of alcohol 4 (130 mg, 0.75 mmol), DMAP (3.7
mg, 0.03 mmol), and Et3N (83 mg, 0.83 mmol) in CH2Cl2 (7 mL)
1152 J . Org. Chem., Vol. 68, No. 3, 2003

was added TBDPSCl (236 mg, 0.83 mmol). The reaction mixture
was stirred at room temperature overnight, then it was quenched
with H2O and extracted with diethyl ether (3 × 40 mL), and
the combined organics were dried with Na2SO4 and concentrated.
FCC (50% Et2O/hexanes) afforded 262 mg (0.64 mmol, 86%) of
silyl ether 6 as an oil. 1H NMR (CDCl3) δH 7.69-7.63 (m, 4H),
7.56-7.33 (m, 6H), 5.80 (ddt, J ) 17.0, 10.0, 7.0 Hz, 1H), 5.14-
5.02 (m, 2H), 4.43-4.38 (m, 1H), 4.32 (dq, J ) 10.0, 6.0 Hz, 1H),
3.99 (ddd, J ) 10.0, 6.5, 3.0 Hz, 1H), 3.77 (ABMX, J ) 10.0, 4.5,
3.5 Hz, 1H), 3.63 (ABMX, J ) 10.0, 10.0, 3.0 Hz, 1H), 3.31 (br,
1H), 2.42-2.20 (m, 2H), 2.19-2.03 (m, 2H), 1.95-1.74 (m, 2H),
1.06 (s, 9H); 13C NMR (CDCl3) δC 135.5 (4 × CH), 134.5 (CH),
132.6 (C), 132.5 (C), 129.9 (2 × CH), 127.8 (4 × CH), 117.0 (CH2),
82.1 (CH), 76.5 (CH), 73.0 (CH), 61.3 (CH2), 40.2 (CH2), 40.1
(CH2), 31.9 (CH2), 26.7 (3 × CH3), 19.0 (C); IR (thin film) 3448,
3071, 2929, 2857, 1640, 1428, 1082, 1008, 702 cm-1; [R]24D +3.9°
(c 3.5, CHCl3); HRMS (ESI) calculated for C25H34O3SiNa (MNa+)
433.2175, found 433.2158.
P r ep a r a tion of Com p ou n d 7. To a solution of 2-methyl-2-
butene (3.95 mL of 2.0 M, 7.9 mmol) was added 3.95 mL of THF
to dilute the solution to 1.0 M. The resulting solution was cooled
to 0 °C and BH3‚SMe2 (2.0 mL of 2M, 4 mmol) was added. This
mixture was allowed to stir at 0 °C for 1 h, then it was
transferred to a solution of alkene 6 (550 mg, 1.34 mmol) in THF
(10 mL) at 0 °C via cannula. The resulting mixture was allowed
to stir overnight before it was quenched with a saturated solution
of NaBO3. The aqueous layer was extracted with EtOAc (3 × 40
mL). The combined organics were dried with Na2SO4, filtered,
and concentrated. FCC (EtOAc) furnished diol 7 (0.37 g, 0.86
mmol, 65%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δH
7.68-7.60 (m, 4H), 7.48-7.32 (m, 6H), 4.43-4.37 (m, 1H), 4.32-
4.20 (m, 1H), 4.00 (ddd, J ) 10.0, 5.0, 4.0 Hz, 1H), 3.76 (ABMX,
J ) 11.0, 5.0, 4.0 Hz, 1H), 3.70-3.55 (m, 3 H), 3.32 (d, J ) 2
Hz, 1H), 2.62 (t, J ) 5.0 Hz, 1H), 2.20-2.03 (m, 2H), 1.93-1.51
(m, 6H), 1.05 (s, 9H); 13C NMR (CDCl3) δC 135.5 (4 × CH), 132.6
(C), 132.4 (C), 130.0 (2 × CH), 127.9 (4 × CH), 82.1 (CH), 77.4
(CH), 73.0 (CH), 62.9 (CH2), 61.2 (CH2), 41.0 (CH2), 32.9 (CH2),
31.9 (CH2), 29.8 (CH2), 26.8 (3 × CH3), 19.0 (C); IR (thin film)
3399, 3070, 2929, 2857, 1456, 1111, 1008, 701 cm-1; [R]24D -1.7°
(c 1.0, CHCl3); HRMS (ESI) calculated for C25H36O4SiNa (MNa+)
451.2281, found 451.2270.
(m, 1H), 4.18 (dd, J ) 8.0, 5.5 Hz, 1H), 4.14-4.03 (m, 2H), 3.86-
3.70 (m, 2H), 2.61 (ABX, J ) 18.0, 7.0 Hz, 1H), 2.21 (ABMX,
J ) 18.0, 7.0, 1.0 Hz, 1H), 2.03 (s, 3H), 1.96-1.59 (m, 6H), 1.01
(s, 9H); 13C NMR (CDCl3, 75 MHz) δC 216.4 (C), 171.0 (C), 135.5
(4 × CH), 133.6 (C), 133.5 (C), 129.6 (2 × CH), 127.6 (4 × CH),
76.0 (CH), 74.8 (CH), 64.0 (CH2), 59.6 (CH2), 42.4 (CH2), 33.4
(CH2), 32.0 (CH2), 26.8 (3 × CH3), 24.8 (CH2), 20.9 (CH3), 19.2
(C); IR (thin film) 3070, 2955, 2857, 1744, 1739, 1472, 1428, 1363,
1239, 1182, 1111, 703 cm-1; [R]24D -19.6° (c 1.9, CHCl3); HRMS
(ESI) calculated for C27H38O5SiNa (MNa+) 493.2396, found
493.2386.
A suspension of methyltriphenylphosphonium bromide (90
mg, 0.25 mmol) in dry THF (1 mL) was treated with n-BuLi (0.1
mL, 0.25 mmol, 2.5 M solution in hexane) under N2 at 0 °C. The
resulting yellow solution was allowed to stir at room temperature
for 30 min, then it was cooled to -78 °C. A solution of the ketone
from above (28 mg, 0.06 mmol) in dry THF (0.5 mL) was added
slowly and the reaction mixture was stirred at -78 °C for 2 h
before it was allowed to warm to room temperature. Stirring
was continued for 4 h before quenching with saturated aqueous
NH4Cl. The aqueous layer was extracted with Et2O three times,
and the combined organics were dried (MgSO4) and concen-
trated. Purification by FCC (70% Et2O/hexanes) gave pure 9 (20
1
mg, 0.048 mmol, 84%). H NMR (CDCl3) δH 7.70-7.63 (m, 4H),
7.45-7.31 (m, 6H), 4.94 (q, J ) 3.0 Hz, 1H), 4.80 (q, J ) 3.0 Hz,
1H), 4.66-4.58 (m, 1H), 3.95 (quin, J ) 8.5 Hz, 1H), 3.87-3.71
(m, 2H), 3.62 (t, J ) 6.0 Hz, 2H), 2.62 (ABM app X3, J ) 18.5,
6.0, 2.0 Hz, 1H), 2.31-2.18 (m, 2H), 1.90-1.51 (m, 6H), 1.04 (s,
9H); 13C NMR (CDCl3) δC 151.5 (C), 135.6 (4 × CH), 134.0 (C),
133.9 (C), 129.5 (2 × CH), 127.6 (4 × CH), 104.8 (CH2), 76.8
(CH), 76.6 (CH), 62.8 (CH2), 60.7 (CH2), 38.9 (CH2), 38.2 (CH2),
32.0 (CH2), 29.6 (CH2), 26.9 (3× CH3), 19.2 (C); IR (thin film)
3478, 3152, 2946, 2909, 2865, 1466, 1439, 1390, 1365.0, 1248,
1196, 1110, 1049, 699 cm-1; [R]24 -22.9° (c 1.2, CHCl3) HRMS
D
(ESI) calculated for C26H36O3SiNa (MNa+) 447.2331, found
447.2310.
P r ep a r a tion of Ald eh yd e 3. To a suspension of PCC (21.6
mg, 0.08 mmol) and sodium acetate (21.6 mg) in 1 mL of CH2-
Cl2 was added a solution of alcohol 9 (17 mg, 0.04 mmol) in 0.5
mL of CH2Cl2. The resulting mixture was stirred for an ad-
ditional 3 h then diluted with diethyl ether and filtered through
a pad of silica gel. FCC (30% hexanes/Et2O) furnished 15 mg
(0.036 mmol, 89%) of 3 as a colorless oil. 1H NMR (CDCl3, 300
MHz) δH 9.74 (t, J ) 1.5 Hz, 1H), 7.69-7.60 (m, 4H), 7.44-7.31
(m, 6H), 4.93 (q, J ) 2.0 Hz, 1H), 4.81 (q, J ) 2.0 Hz, 1H), 4.60-
4.51 (m, 1H), 3.94 (quin, J ) 6.5 Hz, 1H), 3.82-3.70 (m, 2H),
2.64 (ABM app X3, J ) 16.0, 7.0, 2.0 Hz, 1H), 2.53 (ABM2X, J )
17.5, 7.0, 1.5 Hz, 1H), 2.45 (ABM2X, J ) 17.5, 7.0, 1.5 Hz, 1H),
2.23 (ABXM2R, J ) 16.0, 7.0, 2.0, 1.0 Hz, 1H), 1.80 (t, J ) 7.0
Hz, 2H), 1.80-1.68 (m, 2H), 1.04 (s, 9H); 13C NMR (CDCl3, 75
MHz) δC 202.0 (CH), 151.3 (C), 135.6 (4 × CH), 133.9 (2 × C),
129.5 (2 × CH), 127.6 (4 × CH), 105.0 (CH2), 76.5 (CH), 76.0
(CH), 60.7 (CH2), 40.4 (CH2), 38.5 (CH2), 38.2 (CH2), 27.5 (CH2),
26.8 (3 × CH3), 19.2 (C); IR (thin film) 3070, 2949, 2930, 2856,
1725, 1428, 1110, 1083 cm-1; [R]24D -55.0 ° (c 0.5, CHCl3); HRMS
(ESI) calculated for C26H34O3SiNa (M + Na+) 445.2175, found
445.2179. These data matched those of 3 prepared by an
alternate route.4i
P r ep a r a tion of Com p ou n d 8. To a solution of diol 7 (0.19
g 0.44 mmol) in dry CH2Cl2 (5 mL) was added collidine (235 mg,
2.2 mmol). The mixture was cooled to 0 °C, followed by the
addition of a solution of acetyl chloride (36.3 mg, 0.46 mmol) in
CH2Cl2 (1 mL) via syringe pump over a period of 10 min. After
being stirred at this temperature for 2 h, the reaction mixture
was allowed to warm to 7 °C and stirred overnight. The reaction
was quenched with 5% HCl(aq) and EtOAc. The aqueous phase
was extracted with EtOAc (3 × 15 mL). The combined organic
layers were dried with Na2SO4 and concentrated. FCC (50%
Et2O/hexanes) gave pure acetate 8 (174 mg, 0.37 mmol, 84%)
as a colorless oil. 1H NMR (CDCl3) δH 7.68-7.59 (m, 4H), 7.46-
7.34 (m, 6H), 4.39 (m, 1H), 4.23 (d app q, J ) 7.0, 2.5 Hz, 1H),
4.07 (t, J ) 6.5 Hz, 2H), 3.97 (ddd, 9.0, 5.0, 3.0 Hz, 1H), 3.77
(ABX2, J ) 10.0, 4.0 Hz, 1H), 3.62 (ABMX, J ) 10.0, 10.0, 2.5
Hz, 1H), 3.29 (br, 1H), 2.19-2.04 (m, 2H), 2.02 (s, 3H), 1.92-
1.24 (m, 6H), 1.09 (s, 9H); 13C NMR (CDCl3) δC 171.1 (C), 135.5
(4 × CH), 132.6 (C), 132.4 (C), 129.9 (2 × CH), 127.8 (4 × CH),
81.8 (CH), 76.7 (CH), 73.0 (CH), 64.4 (CH2), 61.3 (CH2), 40.8
(CH2), 32.3 (CH2), 31.9 (CH2), 26.7 (3 × CH3), 25.3 (CH2), 20.9
(CH3), 18.9 (C); IR (thin film) 3455, 3061, 2945, 2908, 2868, 1727,
Ack n ow led gm en t. William D. Thomas is acknowl-
edged for running the NOE experiment. We thank the
NIH [Grant CA74394 (S.D.B.)] for generous support of
this research. The NIH (1 S10 RR08389-01) and NSF
(CHE-9208463) are acknowledged for their support of
the NMR facilities of the University of Wisconsin-
Madison Department of Chemistry.
1464, 1439, 1367, 1349, 1225, 1109, 815, 702 cm-1; [R]24 -1.1°
D
(c 2.4, CHCl3); HRMS (ESI) calculated for C27H38O5SiNa (MNa+)
493.2396, found 493.2386.
P r ep a r a tion of Com p ou n d 9. To a solution of alcohol 8 (90
mg, 0.19 mmol) in dry CH2Cl2 (3 mL) was added 1,1,1-triacetoxy-
1,1-dihydro-1,2-benziodoxol-3(1H)-one (180 mg, 0.4 mmol) at
room temperature. The solution was stirred for 3 h until TLC
showed completion of the reaction. It was diluted with Et2O,
filtered through a short pad of silica gel, and concentrated.
Purification by FCC (50% Et2O/hexanes) gave the corresponding
Su p p or tin g In for m a tion Ava ila ble: Spectra (1H NMR,
13C NMR) for compounds 1-9. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
ketone (84 mg, 0.18 mmol, 95%) as a clear oil. H NMR (CDCl3,
300 MHz) δH 7.68-7.63 (m, 4H), 7.45-7.33 (m, 6H), 4.34-4.24
J O026302W
J . Org. Chem, Vol. 68, No. 3, 2003 1153