Concise formal synthesis of the bryostatin southern hemisphere (C17-C27)

Article abstract of DOI:10.1021/jo0495081

An efficient synthesis of Hale and co-workers' C17-C27 bryostatin southern hemisphere intermediate has been accomplished in six steps and 33% overall yield from (R)-2-(benzyloxy)propanal. The synthesis features a one-pot DIBALH/HWE ester homologation as w

Full text of DOI:10.1021/jo0495081

Con cise F or m a l Syn th esis of th e Br yosta tin
Sou th er n Hem isp h er e (C17-C27)
Eric A. Voight, Paul A. Roethle, and Steven D. Burke*
Department of Chemistry, University of Wisconsin-Madison,
1101 University Avenue, Madison, Wisconsin 53706-1396
burke@chem.wisc.edu
F IGURE 1. Bryostatin 1.
Received March 25, 2004
Abstr a ct: An efficient synthesis of Hale and co-workers’
C17-C27 bryostatin southern hemisphere intermediate has
been accomplished in six steps and 33% overall yield from
(R)-2-(benzyloxy)propanal. The synthesis features a one-pot
DIBALH/HWE ester homologation as well as a novel aceto-
nide rearrangement/glycal formation cascade.
The bryostatins constitute a family of polyacetate-
derived natural products originally isolated from the
bryozoan Bugula neritina by Pettit and co-workers.1
Their potent antineoplastic activity, low toxicity, and
unique mode of action have led to numerous human
clinical trials investigating bryostatin 1 (Figure 1) alone
or in combination with other chemotherapies.2,3 Detailed
studies by Wender have shown that simplified analogues
are capable of maintaining enzyme-binding capability
and even exhibiting increased biological activity.4
The majority of the naturally occurring bryostatins
have the general structure shown in Figure 1, differing
only in the ester functionalities at C7 and C20. Bryostatin
3 contains further oxidation at C22, and bryostatins 10,
11, and 13 are deoxygenated at C20. Total syntheses of
bryostatins 7, 2, and 3 by Masamune,5 Evans,6 and
Yamamura,7 respectively, have provided important bench-
marks for further synthetic efforts toward these impor-
tant targets. However, the lengths of these routes, each
requiring at least 40 linear steps (about 80 total steps),
have encouraged many other groups to explore poten-
tially more practical routes.8 An efficient, highly conver-
F IGURE 2. Bryostatin retrosynthesis.
gent, and relatively brief synthetic route to the bryosta-
tins remains an important goal.
(1) Pettit, G. R.; Herald, C. L.; Doubek, D. L.; Herald, D. L.; Arnold,
E.; Clardy, J . J . Am. Chem. Soc. 1982, 104, 6846.
Our interest in the bryostatins was stimulated by a
realization that the northern hemisphere (C1-C16)
fragment (1, Figure 2) could be obtained via our recently
developed C2-symmetric diene-diol ketalization/ring-clos-
ing metathesis desymmetrization strategy.9 Compound
2, containing the complete northern fragment skeleton,
has indeed been realized in only seven steps from diene
diol 3.10 This account details our completion of a brief
southern hemisphere (C17-C27) formal synthesis, tar-
geting Masamune’s phenyl sulfone 4, which was used to
complete a bryostatin 7 total synthesis.5 Our route
(2) (a) The Bryostatins. Pettit, G. R. In Progress in the Chemistry
of Organic Natural Products; Herz, W., Ed.; Springer-Verlag: New
York, 1991; pp 153-195. (b) Norcross, R. D.; Paterson, I. Chem. Rev.
1995, 95, 2041. (c) Mutter, R.; Wills, M. Bioorg. Med. Chem. 2000, 8,
1841. (d) Hale, K. J .; Hummersone, M. G.; Manaviazar, S.; Frigerio,
M. Nat. Prod. Rep. 2002, 19, 413.
(3) For current information on bryostatin 1 clinical trials, see: http://
www.cancer.gov/search/clinical_trials/
(4) See ref 2d and (a) Wender, P. A.; Baryza, J . L.; Bennett, C. E.;
Bi, C.; Brenner, S. E.; Clarke, M. O.; Horan, J . C.; Kan, C.; Lacoˆte, E.;
Lippa, B.; Nell, P. G.; Turner, T. M. J . Am. Chem. Soc. 2002, 124,
13648. (b) Wender, P. A.; Mayweg, A. V. W.; VanDeusen, C. L. Org.
Lett. 2003, 5, 277.
(5) Kageyama, M.; Tamura, T.; Nantz, M. H.; Roberts, J . C.; Somfai,
P.; Whritenour, D. C.; Masamune, S. J . Am. Chem. Soc. 1990, 112,
7407.
(6) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Charette, A. B.;
Prunet, J . A.; Lautens, M. J . Am. Chem. Soc. 1999, 121, 7540.
(7) Ohmori, K.; Ogawa, Y.; Obitsu, T.; Ishikawa, Y.; Nishiyama, S.;
Yamamura, S. Angew. Chem., Int. Ed. 2000, 39, 2290.
(8) (a) See ref 2d. (b) Hale, K. J .; Frigerio, M.; Manaviazar, S. Org.
Lett. 2003, 5, 503.
(9) (a) Burke, S. D.; Mu¨ller, N.; Beaudry, C. M. Org. Lett. 1999, 1,
1827. (b) Burke, S. D.; Voight, E. A. Org. Lett. 2001, 3, 237. (c) Voight,
E. A.; Rein, C.; Burke, S. D. Tetrahedron Lett. 2001, 42, 8747. (d) Keller,
V. A.; Martinelli, J . R.; Strieter, E. R.; Burke, S. D. Org. Lett. 2002, 4,
467. (e) Voight, E. A.; Rein, C.; Burke, S. D. J . Org. Chem. 2002, 67,
8489.
(10) Voight, E. A.; Roethle, P. A.; Burke, S. D. Unpublished results.
10.1021/jo0495081 CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/20/2004
4534
J . Org. Chem. 2004, 69, 4534-4537

SCHEME 1. Syn th esis of Ester 8
SCHEME 2. Syn th esis of â-Ketop h osp h on a te 7
SCHEME 3. Com p letion of th e F or m a l Syn th esis
intersects Hale and co-workers’ intermediate, glycal 5,8b
after only six steps from (R)-2-(benzyloxy)propanal (6),
in favorable comparison to Hale’s route, which required
15 steps from trans-1,4-hexadiene. This strategy was
dependent on a proposed one-pot diisobutylaluminum
hydride (DIBALH)/Horner-Wadsworth-Emmons (HWE)
ester homologation between phosphonate 711 and ester
8. Hydrogenation and a novel acetonide rearrangement/
glycal formation cascade would then yield 5, completing
an expeditious formal synthesis. We hoped to arrive at
â-ketophosphonate 7 and ester 8 via modifications and
improvements of previously reported routes.11,12 If suc-
cessfully executed, the route suggested in Figure 2 would
constitute the shortest (11 step) approach to the com-
pleted southern fragment yet reported.
To begin the synthesis (Scheme 1), the bis(trimethyl-
silyl)enol ether 9 derived from ethyl acetoacetate13 was
added to a cooled (-78 °C) solution of (R)-2-(benzyloxy)-
propanal (6)14 and TiCl2(OiPr)2 according to Evans’
procedure,15 affording â-hydroxy ketone 10 with ∼5:1
diastereoselectivity in 79% yield. An anti-selective reduc-
tion of this mixture using tetramethylammonium tri-
acetoxyborohydride16 over 40 h from -30 to -15 °C
delivered diol 11 in 88% yield, still as a 5:1 ratio of
diastereomers. Although 11 was difficult to purify at this
stage, acetonide formation using 2,2-dimethoxypropane
(DMP) and catalytic p-TSA in acetone facilitated dia-
stereomer separation, providing access to the desired
intermediate 8 in 85% isolated yield as a single dia-
stereomer.12
dation with oxone (2KHSO5‚KHSO4‚K2SO4)11 provided
phenyl sulfone 1419 in quantitative yield without the need
for purification. The known conversion of 14 to 7 was
then carried out as reported11 in preparation for the one-
pot DIBALH/HWE reaction with intermediate 8.
Ester 8 was reduced with DIBALH (1.1 equiv) at -78
°C in toluene (Scheme 3). In a separate flask, â-keto-
phosphonate 7 (1.2 equiv) was deprotonated with sodium
hydride in THF, and the resulting anion was added via
cannula to the first flask. After warming to room tem-
perature, R,â-unsaturated ketone 15 was obtained in 74%
yield from 8. Hydrogenation of the double bond in 15 was
accompanied by hydrogenolysis of the benzyl ether,
yielding hydroxyketone 16. Varying amounts of five-
membered ring acetonide (17) were always observed in
this reaction, presumably due to the more thermody-
namically stable nature of this ring in comparison with
Although a preparation of â-ketophosphonate 7 has
been reported previously,11 we sought an abbreviated
route, which is detailed in Scheme 2. Commercially
available methyl 2,2-dimethyl-3-hydroxypropionate (12)
was converted to phenyl sulfide 1317 in 67% yield using
tributylphosphine, phenyl disulfide, and pyridine.18 Oxi-
(11) Hale, K. J .; Frigerio, M.; Manaviazar, S. Org. Lett. 2001, 3, 3791.
(12) Baxter, J .; Mata, E. G.; Thomas, E. J . Tetrahedron 1998, 54,
14359. This three-step sequence is closely related to a strategy reported
by Thomas and co-workers; however, a completed southern hemisphere
synthesis was not realized by this route.
(13) (a) Brownbridge, P.; Chan, T. H.; Brook, M. A.; Kang, G. J . Can.
J . Chem. 1983, 61, 688. (b) Molander, G. A.; Cameron, K. O. J . Am.
Chem. Soc. 1993, 115, 830.
(14) Prepared via a modification of Heathcock’s procedure: Takai,
K.; Heathcock, C. H. J . Org. Chem. 1985, 50, 3247. See Supporting
Information for details.
(15) Evans, D. A.; Ripin, D. H. B.; Halstead, D. P.; Campos, K. R. J .
Am. Chem. Soc. 1999, 121, 6816.
(17) Gracia, J .; Thomas, E. J . J . Chem. Soc., Perkin Trans. 1 1998,
2865.
(18) Shibuya, H.; Tsujii, S.; Yamamoto, Y.; Miura, H.; Kitagawa, I.
Chem. Pharm. Bull. 1984, 32, 3417.
(16) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J . Am. Chem.
Soc. 1988, 110, 3560.
(19) See ref 11 and Parham, W. E.; McKown, W. D.; Nelson, V.;
Kajigaeshi, S.; Ishikawa, N. J . Org. Chem. 1973, 38, 1361.
J . Org. Chem, Vol. 69, No. 13, 2004 4535

the six-membered ring acetonide.20 Therefore, instead of
separating 16 and 17, the crude mixture, after filtration
of the hydrogenation catalyst and concentration, was
dissolved in benzene (PhH) and treated with 5 mol %
camphorsulfonic acid (CSA) in the presence of DMP as a
dehydrating agent.21 After 5 h at room temperature, the
desired glycal (5) was obtained in 75% overall yield for
NaHCO3 (3 × 20 mL), dried (Na2SO4), and concentrated.
Purification by FCC (40-70% Et2O/hexanes) gave diol 11 (1.04
g, 88%) as a clear semisolid with one minor diastereomer (from
starting material mixture, dr ∼5:1). For the major diastereo-
mer: 1H NMR (CDCl3) δ 7.2-7.4 (m, 5H), 4.68 (d, J ) 11.5 Hz,
1H), 4.45 (d, J ) 11.5 Hz, 1H), 4.4-4.2 (m, 1H), 4.17 (q, J ) 7
Hz, 2H), 3.9-3.7 (m, 1H), 3.46 (apquint, J ) 6.5 Hz, 1H), 3.44
(d, J ) 4 Hz, 1H), 2.83 (d, J ) 3 Hz, 1H), 2.52 (d, J ) 6.5 Hz,
2H), 1.8-1.5 (m, 2H), 1.27 (t, J ) 7 Hz, 3H), 1.21 (d, J ) 6 Hz,
3H); 13C (CDCl3) δ 172.8 (C), 138.4 (C), 128.7 (CH), 128.0 (CH
× 2), 127.9 (CH × 2), 78.5 (CH), 72.3 (CH), 71.2 (CH2), 65.7 (CH),
60.8 (CH2), 41.9 (CH2), 38.8 (CH2), 15.6 (CH3), 14.4 (CH3); IR
(thin film) 3446, 2978, 2924, 1733 cm-1; [R]24D -35 (c 1.0, CHCl3);
HRMS (FAB) calcd for C16H24O5Na (M + Na+) 319.1521, found
319.1526.
1
the two steps.22 The H and 13C NMR data for 5 matched
that reported by Hale and co-workers,8b and X-ray
crystallographic analysis of recrystallized 5 (Et2O/hex-
anes) confirmed this structural assignment.23
In conclusion, a convenient and highly convergent
formal synthesis of the bryostatin southern hemisphere
(4, Figure 2) has been carried out in six steps and 33%
overall yield from (R)-2-(benzyloxy)propanal. This ac-
complishment brings a practical route to natural and
nonnatural bryostatins closer within reach. Efforts to-
ward the bryostatin northern hemisphere (1, Figure 2)
from intermediate 2 continue and will be reported in due
course.
P r ep a r a tion of Aceton id e 8. Diol 11 (1.01 g, 3.40 mmol)
was dissolved in 2:1 acetone/DMP (33 mL), and p-TSA‚H2O (65
mg, 0.34 mmol) was added. After 30 min at room temperature,
the clear reaction mixture was quenched with Et3N (3.4 mL)
and concentrated. Purification by FCC (10-15% Et2O/hexanes)
gave acetonide 8 (975 mg, 85%) as a clear oil: 1H NMR (CDCl3)
δ 7.4-7.2 (m, 5H), 4.63 (ABq, J AB ) 11.5, ∆νAB ) 7 Hz, 2H),
4.26 (dddd, J ) 10, 8, 6, 5.5 Hz, 1H), 4.15 (ABX3, J AB ) 11 Hz,
J AX ) J BX ) 7 Hz, ∆νAB ) 6 Hz, 2H), 3.88 (dt, J ) 10, 6.5 Hz,
1H) 3.54 (apquint, J ) 6.5 Hz, 1H), 2.52 (ABX, J AB ) 15.5 Hz,
J AX ) 8 Hz, 1H), 2.44 (ABX, J AB ) 15.5 Hz, J BX ) 5.5 Hz, 1H),
1.86 (ddd, J ) 12.5, 10, 6 Hz, 1H), 1.50 (ddd, J ) 12.5, 10, 6.5
Hz, 1H), 1.38 (s, 3H), 1.36 (s, 3H), 1.26 (t, J ) 7 Hz, 3H), 1.15
(d, J ) 6.5 Hz, 3H); 13C NMR (CDCl3) δ 170.9 (C), 139.1 (C),
128.3 (CH × 2), 127.7 (CH × 2), 127.5 (CH), 100.8 (C), 76.3 (CH),
71.8 (CH2), 69.9 (CH), 63.8 (CH), 60.5 (CH2), 40.9 (CH2), 33.6
(CH2), 24.8 (CH3), 24.4 (CH3), 15.3 (CH3), 14.3 (CH3); IR (thin
Exp er im en ta l Section
P r ep a r a tion of â-Hyd r oxy Keton e 10. A solution of Ti-
(OiPr)4 (1.83 mL, 6.19 mmol) in CH2Cl2 (25 mL) was cooled to 0
°C, and TiCl4 (0.646 mL, 5.89 mmol) was added. After 15 min,
cooling to -78 °C was followed by addition of a cooled (-78 °C)
solution of (R)-2-(benzyloxy)propanal (6, 1.24 g, 7.55 mmol) in
CH2Cl2 (6 mL) via cannula. The resulting yellow solution was
stirred 15 min before a cooled (-78 °C) solution of bis(trimeth-
ylsilyl)enol ether 9 (3.73 g, 13.6 mmol) in CH2Cl2 (6 mL) was
added over 10 min via cannula. The yellow-orange reaction
mixture was stirred for 20 min at -78 °C, followed by warming
to 0 °C and addition of pH 7 phosphate buffer (70 mL). CH2Cl2
(30 mL) was added, the layers were separated, and the aqueous
layer was extracted with CH2Cl2 (3 × 50 mL). The combined
organic layers were dried (Na2SO4), concentrated, and purified
via FCC (10-12% acetone/hexanes) to give â-hydroxy ketone 10
(1.75 g, 79%) as a slightly yellow oil in ∼5:1 dr. For the major
diastereomer: 1H NMR (CDCl3) δ 7.4-7.2 (m, 5H), 4.66 (d, J )
11.5 Hz, 1H), 4.44 (d, J ) 11.5 Hz, 1H), 4.19 (q, J ) 7 Hz, 2H),
4.04 (tdd, J ) 6.5, 5, 4.5 Hz, 1H), 3.51 (qd, J ) 6.5, 5 Hz, 1H),
3.49 (s, 2H), 2.74 (d, J ) 4.5 Hz, 1H), 2.73 (d, J ) 6.5 Hz, 2H),
1.27 (t, J ) 7 Hz, 3H), 1.22 (d, J ) 6.5 Hz, 3H); 13C NMR (CDCl3)
δ 202.6 (C), 167.1 (C), 138.2 (C), 128.4 (CH × 2), 127.8 (CH ×
2), 127.7 (CH), 76.6 (CH), 70.9 (CH2), 70.3 (CH), 61.3 (CH2), 49.9
(CH2), 45.7 (CH2), 14.9 (CH3), 14.1 (CH3); IR (thin film) 3499,
film) 2986, 2936, 1737 cm-1; [R]24 +40 (c 1.1, CHCl3); HRMS
D
(FAB) calcd for C19H28O5Na (M + Na+) 359.1834, found 359.1837.
P r ep a r a tion of Su lfid e 13. Methyl 2,2-dimethyl-3-hydroxy-
propionate (6.40 mL, 50.0 mmol), pyridine (100 mL), phenyl
disulfide (12.0 g, 55.0 mmol), and tributylphosphine (15.0 mL,
60.0 mmol) were heated to 60 °C and stirred 20 h. After cooling
to room temperature, Et2O (200 mL) was added and the mixture
was washed with 1N HCl (3 × 100 mL), saturated aq NaHCO3
(2 × 100 mL), dried (Na2SO4), and concentrated. Purification
by FCC (0-10% Et2O/hexanes × 2) gave phenyl sulfide 13 (7.47
g, 67%) as a clear oil. Characterization data were consistent with
the previously reported data.17
P r ep a r a tion of Su lfon e 14. To a vigorously stirred solution
of sulfide 13 (7.47 g, 33.3 mmol) in THF (22 mL), MeOH (22
mL), and H2O (22 mL) at 0 °C was added oxone (57.3 g, 93.2
mmol) portionwise. After 5 min at 0 °C, the white suspension
was warmed to room temperature and stirred for 30 min. The
reaction was poured into H2O (500 mL) and extracted with CH2-
Cl2 (3 × 150 mL), and the combined organic layers were dried
(Na2SO4) and concentrated to give sulfone 14 (8.54 g, >99%) as
a white solid. Characterization data were consistent with the
previously reported data.19
P r ep a r a tion of â-Ketop h osp h on a te 7. Methyl dimethyl
phosphonate (1.37 mL, 12.3 mmol) and THF (12 mL) were cooled
to -78 °C, and n-BuLi (2.5 M in hexanes, 4.92 mL, 12.3 mmol)
was added. After 15 min, ester 14 (1.26 g, 4.92 mmol) in THF (4
mL) was added dropwise via cannula, and the reaction warmed
to room temperature and stirred for 4 h. The reaction mixture
was poured into saturated aqueous NH4Cl (80 mL), extracted
with Et2O (3 × 50 mL) and EtOAc (50 mL), dried (Na2SO4), and
concentrated. Purification by FCC (80-100% EtOAc/hexanes)
gave â-ketophosphonate 7 (1.12 g, 65%) as a clear, viscous oil:
1H NMR (CDCl3) δ 8.0-7.8 (m, 2H), 7.7-7.5 (m, 3H), 3.82 (d, J
) 11 Hz, 6H), 3.49 (s, 2H), 3.38 (d, J ) 21.5 Hz, 2H), 1.49 (s,
6H); 13C (CDCl3) δ 204.9 (C, d, J PC ) 7 Hz), 141.0 (C), 133.7
3030, 2979, 1742, 1712 cm-1; [R]24 -14 (c 1.3, CHCl3); HRMS
D
(FAB) calcd for C16H22O5Na (M + Na+) 317.1365, found 317.1379.
P r ep a r a tion of Diol 11. Me4NHB(OAc)3 (10.9 g, 40.0 mmol)
was dissolved in CH3CN (41 mL) at room temperature, and
AcOH (13 mL) was added slowly. After 20 min, cooling to -40
°C was followed by addition of â-hydroxy ketone 10 (1.18 g, 4.00
mmol) in CH3CN (13 mL) via cannula. The clear solution was
stirred at -30 °C for 24 h and -15 °C for 16 h and then poured
into saturated Rochelle’s salt (50 mL) and EtOAc (100 mL). The
aqueous phase was extracted with EtOAc (2 × 50 mL), and the
combined organic layers were washed with saturated aqueous
(20) See, for example: (a) Tius, M. A.; Fauq, A. H. J . Am. Chem.
Soc. 1986, 108, 1035. (b) Toshima, H.; Yoshida, S.; Suzuki, T.;
Nishiyama, S.; Yamamura, S. Tetrahedron Lett. 1989, 30, 6721. (c)
Sa´nches-Sancho, F.; Valverde, S.; Herrado´n, B. Tetrahedron: Asym-
metry 1996, 7, 3209. (d) Solladie´, G.; Colobert, F.; Denni, D. Tetrahe-
dron: Asymmetry 1998, 9, 3081.
(21) The reaction could also be carried out under Dean-Stark
conditions without DMP; however, the yield was lowered to 56% as a
result of acetonide hydrolysis side reactions.
(CH), 129.3 (CH × 2), 127.5 (CH × 2), 65.2 (CH2), 53.1 (CH3
×
2, d, J PC ) 6 Hz), 47.5 (C, d, J PC ) 4 Hz), 36.1 (CH2, d, J PC
)
134 Hz), 24.8 (CH3 × 2); IR (thin film) 3065, 2956, 1710 cm-1
;
HRMS (FAB) calcd for C14H21O6PSNa (M + Na+) 371.0694,
found 371.0689.
(22) Purified 16 (69% from 15) could be converted to 5 in 84% yield;
however, the overall yield from 15 was higher when 16 was not
isolated.
P r ep a r a tion of En on e 15. A solution of â-ketophosphonate
7 (575 mg, 1.65 mmol) in THF (8 mL) was cooled to 0 °C, and
(23) See Supporting Information for X-ray crystallographic data.
4536 J . Org. Chem., Vol. 69, No. 13, 2004

NaH (42 mg, 1.7 mmol) was added. The reaction was warmed
to room temperature and stirred for 25 min, becoming a yellow
solution. In a separate flask, ester 8 (428 mg, 1.27 mmol) and
PhCH3 (13 mL) were cooled to -78 °C, and DIBALH (1.5 M in
PhCH3, 1.02 mL, 1.53 mmol) was added slowly down the side of
the flask. After 20 min, the phosphonate anion was added slowly
down the side of the flask via cannula. The reaction was warmed
to room temperature and stirred for 7 h, during which time a
white precipitate was observed. Saturated aqueous Rochelle’s
salt (10 mL) was added carefully, stirring was continued for 10
min, and CH2Cl2 (50 mL) and H2O (50 mL) were added. The
layers were separated, and the aqueous layer was extracted with
CH2Cl2 (3 × 30 mL). The combined organic layers were dried
(Na2SO4) and concentrated. Purification by FCC (30-40% Et2O/
hexanes) gave enone 15 (482 mg, 74%) as a clear, viscous oil:
1H NMR (CDCl3) δ 8.0-7.8 (m, 2H), 7.7-7.5 (m, 3H), 7.4-7.2
(m, 5H), 6.96 (dt, J ) 15.5, 7 Hz, 2H), 6.60 (dt, J ) 15.5, 1.5 Hz,
2H), 4.63 (ABq, J AB ) 12 Hz, ∆νAB ) 9.5 Hz, 2H), 3.91 (ddt, J )
9.5, 7.5, 6 Hz, 1H), 3.88 (dt, J ) 9.5, 6 Hz, 1H), 3.52 (apquint, J
) 6 Hz, 1H), 3.49 (s, 2H), 2.6-2.2 (m, 2H), 1.82 (ddd, J ) 12.5,
9.5, 6 Hz, 1H), 1.49 (ddd, J ) 12.5, 9.5, 6 Hz, 1H), 1.46 (s, 3H),
1.45 (s, 3H), 1.37 (s, 6H), 1.15 (d, J ) 6 Hz, 3H); 13C (CDCl3) δ
200.6 (C), 145.3 (CH), 141.7 (C), 139.2 (C), 133.7 (CH), 129.4
(CH × 2), 128.5 (CH × 2), 127.90 (CH × 2), 127.86 (CH × 2),
127.6 (CH), 125.2 (CH), 100.8 (C), 76.4 (CH), 71.9 (CH2), 70.1
(CH), 65.8 (CH), 64.1 (CH2), 46.1 (C), 38.8 (CH2), 34.0 (CH2),
25.1 (CH3), 24.8 (CH3 × 2), 24.7 (CH3), 15.5 (CH3); IR (thin film)
extracted with CH2Cl2 (3 × 20 mL), dried (Na2SO4), and
concentrated. Purification by FCC (20-25% Et2O/hexanes) gave
glycal 5 (151 mg, 75%) as a white solid. A sample was recrystal-
lized from Et2O/hexanes for X-ray crystallographic analysis (see
Supporting Information): 1H NMR (C6D6) δ 7.9-7.8 (m, 2H),
7.0-6.9 (m, 3H), 4.46 (brt, J ) 3.5, 1H), 3.74 (ddd, J ) 10, 8.5,
2 Hz, 1H), 3.67 (tdd, J ) 10, 3.5, 2.5 Hz, 1H), 3.53 (dq, J ) 8.5,
6 Hz, 1H), 3.29 (d, J ) 14 Hz, 1H), 3.16 (d, J ) 14 Hz, 1H),
1.8-1.6 (m, 2H), 1.45 (ddd, J ) 14, 9.5, 2.5 Hz, 1H), 1.42 (s,
3H), 1.39 (s, 3H), 1.4-1.2 (m, 3H), 1.35 (s, 3H), 1.28 (s, 3H),
1.2-1.0 (m, 1H), 1.09 (d, J ) 6 Hz, 3H); 3.91 (s, 3H), 3.89 (s,
3H), 2.73 (ddd, J ) 18, 2.5, 2 Hz, 1H), 2.47 (ddd, J ) 18, 4, 2
Hz, 1H); 13C NMR (C6D6) δ 156.5 (C), 143.0 (C), 133.0 (CH), 129.1
(CH), 128.9 (CH), 128.7 (CH), 128.3 (C), 108.4 (C), 95.1 (CH),
79.4 (CH), 77.6 (CH), 72.9 (CH), 64.2 (CH2), 38.9 (CH2), 38.7
(CH2), 28.2 (CH2), 28.02 (CH3), 27.96 (CH3), 27.3 (CH3), 26.2
(CH3), 20.7 (CH2), 17.6 (CH3); IR (thin film) 2981, 2930 cm-1
;
[R]24 +40 (c 1.0, CHCl3); mp 84-87 °C; HRMS (FAB) calcd for
D
C22H32O5SNa (M + Na+) 431.1868, found 431.1869.
Ack n ow led gm en t. We thank the NIH [Grants
CA74394 and GM069352 (S.D.B.) and CBI Training
Grant 5 T32 GM08505 (E.A.V.)] and the Abbott Labo-
ratories Fellowship in Synthetic Organic Chemistry
(E.A.V.) for generous support of this research. The NIH
(1 S10 RR0 8389-01) and NSF (CHE-9208463) are
acknowledged for their support of the NMR facilities of
the University of Wisconsin-Madison Department of
Chemistry. We also thank Dr. Ilia Guzei for X-ray
crystallographic analysis.
2982, 2934, 1691, 1625 cm-1; [R]24 +35 (c 1.0, CHCl3); HRMS
D
(FAB) calcd for C29H38O6SNa (M + Na+) 537.2287, found
537.2266.
P r ep a r a tion of Com p ou n d Glyca l 5. Enone 15 (252 mg,
0.490 mmol) was dissolved in EtOAc (5 mL), and Pd-C (10%,
245 mg) was added. After stirring under an atmosphere of H2
overnight at room temperature, the catalyst was filtered and
the filtrate was concentrated, giving crude 16 (containing some
17 by TLC), which was dissolved in PhH (3.7 mL) and DMP (1.2
mL). Camphorsulfonic acid (6 mg, 0.03 mmol) was added, and
the reaction was stirred for 5 h at room temperature. Saturated
aqueous NaHCO3 (10 mL) was added, and the mixture was
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedure for (R)-2-(benzyloxy)propanal (6), 1H and 13C NMR
spectra for 5 and 7-15, and X-ray crystallographic data for 5.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O0495081
J . Org. Chem, Vol. 69, No. 13, 2004 4537