Determination of the relative and absolute stereochemistry of fostriecin (CI-920)

Article abstract of DOI:10.1021/jo962166h

The absolute stereochemistry of fostriecin (1, CI-920), a potent antitumor antibiotic presently in Phase I clinical trials at NCI, was determined to be 5R,8R,9R,11R. 2D ¹H-¹H NMR NOE experiments conducted on the cyclic phosphate derivative 2 and acetonide 4 revealed a syn-diol stereochemical relationship between C8 and C9 and an anti-diol stereochemical relationship between C9 and C11, respectively. The 5R absolute configuration assignment was confirmed by synthesis of the degradation product 8 previously disclosed. Additional degradation studies of 1 to provide 7 and chiral-phase HPLC comparison with a sample of known chirality established the absolute stereochemistry of C11 to be R. This, along with the relative stereochemical assignments established the full set of absolute stereochemistry assignments for 1.

Full text of DOI:10.1021/jo962166h

1748
J . Org. Chem. 1997, 62, 1748-1753
Deter m in a tion of th e Rela tive a n d Absolu te Ster eoch em istr y of
F ostr iecin (CI-920)
Dale L. Boger,* Masataka Hikota, and Bryan M. Lewis
Department of Chemistry and The Skaggs Institute of Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La J olla, California 92037
Received November 19, 1996X
The absolute stereochemistry of fostriecin (1, CI-920), a potent antitumor antibiotic presently in
Phase I clinical trials at NCI, was determined to be 5R,8R,9R,11R. 2D 1H-1H NMR NOE
experiments conducted on the cyclic phosphate derivative 2 and acetonide 4 revealed a syn-diol
stereochemical relationship between C8 and C9 and an anti-diol stereochemical relationship between
C9 and C11, respectively. The 5R absolute configuration assignment was confirmed by synthesis
of the degradation product 8 previously disclosed. Additional degradation studies of 1 to provide
7 and chiral-phase HPLC comparison with a sample of known chirality established the absolute
stereochemistry of C11 to be R. This, along with the relative stereochemical assignments established
the full set of absolute stereochemistry assignments for 1.
Fostriecin (1, CI-920)1 is a structurally novel phosphate
ester produced by Streptomyces pulveraceus active in
vitro against leukemia (L1210, IC50 0.46 µM), lung,
breast, and ovarian cancer and displays efficacious in vivo
antitumor activity against L1210 leukemia in mice.2 It
is currently being investigated in phase I clinical trials
at NCI. Fostriecin inhibits DNA topoisomerase II (IC50
40 µM) in vitro3 through a novel, non-DNA-strand cleav-
ing mechanism, but does not induce G2 arrest like other
topoisomerase II inhibitors.4 Instead, it inhibits the
mitotic entry checkpoint,5 potentially through inhibition
of protein phosphatases 1 and 2A (IC50 4 µM and 40 nM,
respectively).6-9 Inhibition of the mitotic entry check-
point and protein phosphatase are novel properties for a
potential clinical antitumor agent. Despite these proper-
F igu r e 1.
Sch em e 1. P r ep a r a tion of th e Cyclic P h osp h a te
Diester
X Abstract published in Advance ACS Abstracts, February 15, 1997.
(1) Tunac, J . B.; Graham, B. D.; Dobson, W. E. J . Antibiot. 1983,
36, 1595. Stampwala, S. S.; Bunge, R. H.; Hurley, T. R.; Willmer, N.
E.; Brankiewicz, A. J .; Steinman, C. E.; Smitka, T. A.; French, J . C. J .
Antibiot. 1983, 36, 1601.
(2) J ackson, R. C.; Fry, D. W.; Boritzki, T. J .; Roberts, B. J .; Hook,
K. E.; Leopold, W. R. Adv. Enzyme Regul. 1985, 23, 193.
(3) Boritzki, T. J .; Wolfard, T. S.; Besserer, J . A.; J ackson, R. C.;
Fry, D. W. Biochem. Pharmacol. 1988, 37, 4063.
(4) Topoisomerase II inhibitors which induce G2 arrest: (a) etopo-
side: Chen, G. L.; Yang, L.; Rowe, T. C.; Halligan, B. D.; Tewey, K.
M.; Liu, L. F. J . Biol. Chem. 1984, 259, 13560. (b) Doxorubicin: Tewey,
K. M.; Rowe, T. C.; Yang, L.; Halligan, B. D.; Liu, L. F. Science 1984,
266, 466. (c) Amsacrine: Nelson, E. M.; Tewey, K. M.; Liu, L. F. Proc.
Natl. Acad. Sci. U.S.A. 1984, 81, 3161.
(5) For a review: Murray, A. W. Nature 1992, 359, 599.
(6) Roberge, M.; Tudan, C.; Hung, S. M. F.; Harder, K. W.; J irik, F.
R.; Anderson, H. Cancer Res. 1994, 54, 6115.
ties and the clinical potential of 1, the complete relative
and absolute stereochemistry of the molecule is un-
known.10,11 Herein, we detail studies that provide the
relative and absolute stereochemistry of fostriecin (Figure
1).
Although the 5R absolute stereochemistry of 1 was
established in the work leading to the basic tenants of
the structure determination,10 the relative and absolute
stereochemistry at C8, C9, and C11 are unknown. The
relative stereochemistry between C8 and C9 was deter-
mined as follows (Scheme 1). The natural product 1 was
converted to the five-membered cyclic phosphodiester 2
(p-bromobenzoyl chloride, pyridine, 0 °C, 70%).12 The
closure to 2 was established by 31P NMR (D2O, 161 MHz,
δ) with the observance of a signal at 14.69 characteristic
of a five-membered (10-15) versus six-membered (-0.5
to -5.0) cyclic phosphodiester.13 Upon examination of
(7) Ho, D. T.; Roberge, M. Carcinogenesis 1996, 17, 967.
(8) For a review of protein serine/threonine phosphatases: Inge-
britsen, T. S.; Cohen, P. Eur. J . Biochem. 1983, 132, 255.
(9) Other inhibitors of protein serine/threonine phosphatases: (a)
okadaic acid: Tachibana, K.; Scheuer, P. J .; Tsukitani, Y.; Kikuchi,
Y.; Van Engen, D.; Clardy, J .; Gopichand, Y.; Schmitz, F. J . J . Am.
Chem. Soc. 1981, 103, 2469. (b) Microcystins: Botes, D.; Tuinman, A.;
Wessels, P.; Viljoen, C.; Kruger, H.; Williams, D. H.; Santikarn, S.;
Smith, R.; Hammond, S. J . Chem. Soc., Perkin Trans. 1 1984, 2311.
Painuly, P.; Perez, R.; Fukai, T.; Shimizu, Y. Tetrahedron Lett. 1988,
29, 11. (c) Calyculin A: Kato, Y.; Fusetani, N.; Matsunaga, S.;
Hashimoto, K.; Fujita, S.; Furuya, T. J . J . Am. Chem. Soc. 1986, 108,
2780. (d) Nodularin: Botes, P. B.; Wessels, P. L.; Kruger, H.; Runnegar,
M. T. C.; Santikarn, S.; Smith, R. J .; Barna, J . C. J .; Williams, D. H.
J . Chem. Soc., Perkin Trans. 1 1985, 2747. Rinehart, K. L.; Harada,
K.; Namikoshi, M.; Chen, C.; Harvis, C.; Munro, M. H. G.; Blunt, J .;
Mulligan, P.; Beasley, V.; Dahlem, A.; Carmichael, W. J . Am. Chem.
Soc. 1988, 110, 8557. (e) Tautomycin: Cheng, X.-C.; Ubukata, M.;
Isono, K. J . Antibiot. 1990, 43, 809. (f) Cantharidine: Li, Y.-M.; Casida,
J . E. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 11867. (g) Motuporin:
Valentekovich, R. J .; Schreiber, S. L. J . Am. Chem. Soc. 1995, 117,
9069.
1
the 2D H-1H ROESY NMR spectrum (D2O, 400 MHz,
δ), NOEs were found between H6,7 (5.93-6.00) and H9
(4.34), as well as between the C8-CH3 (1.40) and H10
(10) Early work assigned the absolute configuration at C5 as R,
see: Hokanson, G. C.; French, J . C. J . Org. Chem. 1985, 50, 462.
(11) J ust, G.; O’Connor, B. Tetrahedron Lett. 1988, 29, 753.
(12) This closure could also be effected by treatment with EDCI or
DCC, but provided 2 with lower purity due to the difficulty of removing
the reaction byproducts. See also: Ozasa, T.; Tanaka, K.; Sasamata,
M.; Kaniwa, H.; Shimizu, M.; Matsumoto, H.; Iwanami, M. J . Antibiot.
1989, 42, 1339.
S0022-3263(96)02166-4 CCC: $14.00 © 1997 American Chemical Society

Relative and Absolute Stereochemistry of Fostriecin (CI-920)
J . Org. Chem., Vol. 62, No. 6, 1997 1749
Sch em e 2. P r ep a r a tion of th e Six-Mem ber ed Rin g
Aceton id e
F igu r e 2.
(1.75-1.90), establishing the cis relationships of the C5-
C8 vinyl side chain with H9 and C8-CH3 with the C9 side
chain on the five-membered cyclic phosphodiester and a
syn-1,2-diol relationship between C8 and C9.
The relative stereochemistry between C9 and C11 was
determined as follows (Scheme 2). The free alcohol 3 was
prepared from 1 (alkaline phosphatase, H2O, 37 °C,
100%) according to the procedure of Hokanson and
French10 and was converted to the acetonide 4 (Me2C-
(OMe)2, p-TsOH, THF, 25 °C, 10-15 min, 40%). The
preferential formation of 4 was anticipated and controlled
by use of short reaction times (10-15 min) favoring the
kinetic six-membered 1,3-diol acetonide.14 The alterna-
tive possibility of five-membered acetonide formation
between C8 and C9 was excluded by the subsequent clean
conversion of 4 to monoacetate 514 (excess Ac2O, Et3N,
CH2Cl2, 25 °C, 2 h) versus a diacetate diagnostic of the
1,2-diol acetonide and ultimately confirmed spectroscopi-
cally. Extending the reaction time to 1 h led to the
generation of small amounts of the five-membered 1,2-
diol acetonide (9%) without improving the conversion to
4 (42%).
F igu r e 3.
Sch em e 3. Degr a d a tion of F ostr iecin
The acetonide methyl groups of 4 (1.35 and 1.39)
displayed similar 13C NMR chemical shifts of 24.49 and
24.89 (CDCl3, 100 MHz, δ) within the range characteristic
of an anti-1,3-diol acetonide (23.96-25.22) and different
from the distinct chemical shifts observed with syn-1,3-
diol acetonides (18.67-19.98 and 29.74-30.16).15 In
one axial methyl group of the acetonide and both H9 and
1
H
11. These cross-peaks were not observed in the 2D H-
1H NOESY NMR spectrum. From these results which
further confirmed the structure of the 1,3- versus 1,2-
acetonide, we assigned the relative stereochemistry of the
C8-C9 and C9-C11 stereocenters of fostriecin as a syn-
1,2 and an anti-1,3-diol relationship, respectively.
This proved to be consistent with the adoption of a
rigid, hydrogen-bonded cyclic structure for 1 and 3 (D2O,
400 MHz) involving the C9 oxygen substituent and the
C11 alcohol which is disrupted upon O-acetylation.10 Our
1
addition, diagnostic cross-peaks observed in the 2D H-
1H NOESY NMR spectrum of 4 were observed between
one acetonide methyl group (1.35) and H9 (3.72) and
between the other acetonide methyl group (1.39) and H11
(4.73) (A, Figure 2). This agrees with the existence of
an anti-1,3-diol derived acetonide adopting a twist boat
conformation. Consistent with this assignment, H9 (J (H10)
1
) 6.3, 9.6 Hz) and H11 (J (H10) ) 6.3, 9.5 Hz) exhibit H
NMR coupling constants expected with the twist boat
conformation and the observed NOEs. Additionally, the
alternative syn-1,3-diol-derived acetonide B would be
supported by the observance of three other diagnostic
NOEs, one between H9 and H11 and those between the
examination of the coupling constants of H9, H10A, H10B
,
and H11 in 3 had provided us with a preliminary assess-
ment of the anti-1,3-diol relationship of C9/C11 adopting
a twist boat for the hydrogen-bonded structure (Figure
3).
The final task was the determination of the absolute
stereochemistry at C11, which when coupled with the
relative stereochemistry detailed above and the prior
work of Hokanson and French assigning the C5 R
configuration,10 would establish the complete absolute
stereochemistry of fostriecin (Scheme 3). The free alcohol
3 was cleanly monosilylated (TBDPSCl, imidazole, DMF,
25 °C, 72%) and subjected to oxidative cleavage of the
(13) Egan, W.; Schneerson, R.; Werner, K. E.; Zon, G. J . Am. Chem.
Soc. 1982, 104, 2898. Broeders, N. L. H. L.; Van der Heiden, A. P.;
Pecters, I.; J anssen, H. M.; Koole, L. H. J . Am. Chem. Soc. 1992, 114,
9624.
(14) Meyers, A. I.; Lawson, J . P. Tetrahedron Lett. 1982, 23, 4883.
For 5: FABHRMS (NBA-NaI) m/ z 455.2056 (M+ + Na+, C24H32O7
requires 455.2046).
(15) Rychnovsky, S. D.; Skalitzky, D. J . Tetrahedron Lett. 1990, 31,
945. Evans, D. A.; Rieger, D. L.; Gage, J . R. Tetrahedron Lett. 1990,
31, 7099.

1750 J . Org. Chem., Vol. 62, No. 6, 1997
Boger et al.
Sch em e 4. P r ep a r a tion of Meth yl Keton e Der ived
fr om F ostr iecin
ester 10 followed by asymmetric dihydroxylation (3 equiv
of K3Fe(CN)6, 3 equiv of NaHCO3, 3 equiv of K2CO3, 0.05
equiv of (DHQD)2-AQN,21 t-BuOH/H2O 1:1, 0 °C, 48 h,
79%, 88−92% ee) provided the diol 11. Enrichment to
>98% ee was accomplished by one recrystallization
(>50% overall, Et2O)22 and conveniently monitored by 1H
NMR analysis (CDCl3, 400 MHz) of the corresponding
bis-Mosher ester (2.3 equiv of (R)-MTPA-Cl, 3 equiv of
DMAP, THF, 25 °C, 6 h). Subsequent selective protection
of the primary alcohol 11 (1.1 equiv of TBDPSCl, 2.2
equiv of imidazole, DMF, 25 °C, 15 h, 89-92%) cleanly
provided 12 and acid-catalyzed lactonization (4 equiv of
CF3CO2H, 5 equiv of anisole, 25 °C, 0.5 h, 75%) afforded
13. Formation of the R-phenylselenyl lactone 14 (1.1
equiv of LDA; 1.2 equiv of PhSeBr, THF, -78 °C, 1 h,
50%), deprotection of the TBDPS ether (1.9 equiv of Bu4-
NF, 5.8 equiv of HOAc, THF, 25 °C, 3 h, 68%) and
oxidation of 15 to the selenoxide (4 equiv of H2O2, CH2-
Cl2-H2O, 25 °C, 2 h, 85%) followed by elimination
provided the unsaturated lactone alcohol 16, [R]20D +160
(c 0.85, CHCl3), lit.23 [R]26 +175 (c 0.92, CHCl3). The
D
correlation of our synthetic 16 with authentic 1623 of
known absolute configuration established that the Sharp-
less asymmetric dihydroxylation proceeded with the
expected enantioselectivity. Swern oxidation of 16 (10
equiv of (COCl)2, 12 equiv of DMSO, 35 equiv of Et3N,
CH2Cl2, -78 °C) followed by in situ reaction of 17 with
the stabilized Wittig reagent (15 equiv, 0 °C, 30 min, 52%
overall) provided 8 ([R]20D +201 (c 0.110, CHCl3), identical
in all respects with the degradation product 810 ([R]D
+217 (c 1.16, CHCl3) obtained from fostriecin. This latter
correlation confirmed the C5 stereochemical assignment
of Hokanson and French and provided an advanced
synthetic intermediate in our approach to fostriecin.
These and related efforts will be disclosed in due time.
C8,C9-diol (NaIO4, CH3OH-H2O). Immediate reduction
(NaBH4, 65% for two steps) of the resulting aldehyde to
the diol, and its protection as the dibenzoate (BzCl, Et3N,
DMAP, CH2Cl2, 65%) gave 6. The dibenzoate was
subjected to ozonolysis followed by reductive workup (O3,
CH3OH; NaBH4) and benzoylation (BzCl, Et3N, DMAP,
THF, 65%) to yield the tribenzoate 7. This material was
identical (NMR, IR, MS) to the (R)-(+)-tribenzoate 7 and
the (()-tribenzoate prepared from commercially available
R-(+)-1,2,4-butanetriol and (()-1,2,4-butanetriol, respec-
tively, and eluted on an analytical Chiracel OD-H HPLC
column (0.46 × 20 cm, 20% 2-PrOH/hexane, 0.6 mL/min)
with the same retention time as (2R)-7 (11.4 min) versus
(2S)-7 (18.4 min). This, combined with the relative
configuration assignments, provided the complete rela-
tive and absolute stereochemical determination of fos-
triecin as 5R,8R,9R,11R.16
Finally, in conjunction with our synthetic efforts on 1
we have conducted a correlation (Scheme 4) that confirms
the C5 absolute stereochemical assignment of Hokanson
and French.10 The absolute configuration at C5 was
introduced through Sharpless asymmetric dihydroxyla-
tion of a terminal olefin.19 Thus, conversion of hex-5-
enoic acid20 (9) to the corresponding p-methoxybenzyl
Exp er im en ta l Section
(1E,3R,4R,6R,7Z,9Z,11E)-1-[(6R)-2-Oxo-5,6-d ih yd r o-2H-
p yr a n -6-yl]-3,4,6,13-t et r a h yd r oxy-3-m et h yl-1,7,9,11-t r i-
d eca tetr a en e 3,4-Cyclop h osp h a te, Sod iu m Sa lt (2).
A
solution of fostriecin (1, 2 mg, 4.4 mmol) in pyridine (500 µL)
was treated at 0 °C (ice bath) with p-bromobenzoyl chloride
(1.9 mg, 8.5 µmol), and the mixture was allowed to stir for 45
min at 0 °C. The reaction mixture was concentrated and
purified by chromatography on reverse phase silica (0-10%
CH3CN-H2O) to yield 2 (1.34 mg, 1.8 mg theoretical, 70%):
1H NMR (D2O, 400 MHz) δ 7.12 (1H, ddd, J ) 3.1, 5.6, 9.8
Hz), 6.79 (1H, dd, J ) 11.0, 15.3 Hz), 6.64 (1H, t, J ) 11.0
Hz), 6.35 (1H, t, J ) 11.0 Hz), 6.19 (1H, t, J ) 11.0 Hz), 6.08
(1H, dd, J ) 5.9, 15.3 Hz), 6.03 (1H, ddd, J ) 1.2, 2.3, 9.8 Hz),
6.00-5.93 (2H, m), 5.56 (1H, t, 9.4 Hz), 5.12 (1H, ddd, J )
5.3, 5.4, 10.2 Hz), 4.34 (1H, dd, J ) 3.4, 9.3 Hz), 4.18 (2H, d,
J ) 5.9 Hz), 2.65-2.58 (1H, ddd, J ) 5.1, 5.2, 18.8 Hz), 2.56-
2.52 (1H, dddd, J ) 3, 3, 10.7, 18.8 Hz), 1.90-1.75 (2H, m),
1.43 (s, 3H); 13C NMR (D2O, 125 MHz) δ 170.4, 151.8, 137.1,
136.7, 135.7, 133.8, 132.0, 128.7, 127.9, 126.5, 122.2, 87.4, 83.2,
80.9, 66.4, 64.8, 39.6, 31.6, 21.8; 31P NMR (161 MHz, D2O) δ
14.69; IR (neat) νmax 3358, 2920, 1709, 1383, 1247, 1221, 1109,
1054, 972, 942, 876, 820 cm-1; FABHRMS (NBA-NaI) m/ z
435.1197 (M + Na+, C19H25O8P requires 435.1185).
(16) The work is also consistent with and would seem to unambigu-
ously confirm the relative and absolute configuration assignments for
the leustroducsins,17 phoslactomycins,18 and phospholine18 whose
stereochemistry was tentatively assigned based on the chiroptical
properties of Mosher esters of the alcohols. See: Shibata, T.; Kurihara,
S.; Yoda, K.; Haruyama, H. Tetrahedron 1995, 51, 11999.
(17) Leustroducsins: Kohama, T.; Enokita, R.; Okazaki, T.; Miyaoka,
H.; Torikata, A.; Inukai, M.; Kaneko, I.; Kagasaki, T.; Sakaida, Y.;
Satoh, A.; Shiraishi, A. J . Antibiot. 1993, 46, 1503. Kohama, T.;
Nakamura, T.; Kinoshita, T.; Kaneko, I.; Shiraishi, A. J . Antibiot. 1993,
46, 1512.
(19) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483.
(20) Gilman, H.; Kirby, R. H. Org. Synth. 1941, 1, 361.
(21) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996,
35, 448.
(22) The corresponding methyl, tert-butyl, and benzyl esters were
also examined but failed to provide a crystalline diol capable of optical
purity enrichment through recrystallization.
(18) Phoslactomycins: Fushimi, S.; Nishikawa, S.; Shimazu, A.;
Seto, H. J . Antibiot. 1989, 42, 1019. Fushimi, S.; Furihata, K.; Seto,
H. J . Antibiot. 1989, 42, 1026.
(23) Tsubuki, M.; Kanai, K.; Honda, T. Heterocycles 1993, 35, 281.

Relative and Absolute Stereochemistry of Fostriecin (CI-920)
J . Org. Chem., Vol. 62, No. 6, 1997 1751
1
The 2D H-1H ROESY NMR spectrum (D2O, 400 MHz) of
970, 825, 740, 705 cm-1; FABHRMS (NBA-CsI) m/ z 721.1942
(M + Cs+, C35H44O6Si requires 721.1962).
2 displayed the following diagnostic NOE cross-peaks: H2/H3,
H3/H4, H4/H5, H6,7/H9, H6,7/H15, H6,7/H16, H6,7/H17, H6,7/H19, H9/
(3R,4Z,6Z,8E)-10-[(ter t-Bu t yld ip h en ylsilyl)oxy]-4,6,8-
d eca tr ien e-1,3-d iol. A solution of the TBDPS ether (6.9 mg,
12 µmol) described above in CH3OH (2.0 mL) was treated with
a solution of NaIO4 (100 mg) in H2O (10.0 mL, 385 µL, 18 µmol)
at 25 °C. After 4 h, NaBH4 (5 mg, 0.1 mmol) was added at 0
°C, and the mixture was stirred for 30 min (0 °C) and 3 h (25
°C). The reaction mixture was diluted with CHCl3 (12 mL),
washed with saturated aqueous NaCl (2 mL), dried (Na2SO4),
filtered, and concentrated in vacuo. Chromatography (SiO2,
67% EtOAc-hexane) gave the diol (3.2 mg, 65%) as a colorless
oil: 1H NMR (CD3OD, 500 MHz) δ 7.68-7.65 (4H, m), 7.43-
7.37 (6H, m), 6.79 (1H, dd, J ) 11.5, 15.0 Hz), 6.43 (1H, t, J )
11.5 Hz), 6.28 (1H, t, J ) 11.5 Hz), 6.06 (1H, t, J ) 11.5 Hz),
5.83 (1H, dt, J ) 15.0, 5.0 Hz), 5.44 (1H, dd, J ) 9.0, 11.5 Hz),
4.79-4.74 (1H, m), 4.29 (2H, d, J ) 5.0 Hz), 3.67 (1H, dt, J )
12.5, 6.5 Hz), 3.61 (1H, dt, J ) 12.5, 6.5 Hz), 1.83-1.76 (1H,
m), 1.68-1.61 (1H, rough dq), 1.06 (9H, s); IR (neat) νmax 3345,
2930, 2860, 1470, 1430, 1110, 1060, 700 cm-1; FABHRMS
(NBA-CsI) m/ z 555.1344 (M + Cs+, C26H34O3Si requires
555.1332).
(2E,4Z,6Z,8R)-8,10-Bis(ben zoyloxy)-1-[(ter t-bu tyldiph en -
ylsilyl)oxy]-2,4,6-d eca tr ien e (6). A solution of the diol (2.8
mg, 6.6 µmol) described above in CH2Cl2 (2.0 mL) was treated
with Et3N (36 µL, 0.26 mmol), BzCl (10 µL, 86 µmol) and a
catalytic amount of DMAP, and the mixture was stirred at 25
°C overnight under N2. CH3OH (1.0 mL) was added and after
30 min, the reaction mixture was diluted with EtOAc (10 mL),
washed with saturated aqueous NaHCO3 (2 mL), saturated
aqueous NaCl (2 mL), dried (Na2SO4), filtered, and concen-
trated in vacuo. Chromatography (SiO2, 9% EtOAc-hexane)
afforded 6 (2.9 mg, 4.5 mg theoretical, 65%) as a colorless oil:
1H NMR (CD3CN, 400 MHz) δ 8.10-7.95 (4H, m), 7.70-7.55
(6H, m), 7.50-7.41 (10H, m), 6.80 (1H, m), 6.61 (1H, t, J )
11.5 Hz), 6.43 (1H, t, J ) 11.5 Hz), 6.18-6.09 (2H, m), 5.90
(1H, dt, J ) 15.0, 4.9 Hz), 5.61 (1H, m), 4.45 (1H, ddd, J )
5.1, 7.1, 11.3 Hz), 4.38 (1H, ddd, J ) 5.3, 6.9, 11.3 Hz), 4.32
(2H, d, J ) 4.9 Hz), 2.41-2.30 (1H, m), 2.22-2.13 (1H, m),
1.05 (9H, s); IR (neat) νmax 3070, 2930, 2855, 1720, 1450, 1430,
1315, 1275, 1110, 1070, 1025, 710 cm-1; FABHRMS (NBA-
CsI) m/ z 763.1836 (M + Cs+, C40H42O5Si requires 763.1856).
(2R)-1,2,4-Tr is(Ben zoyloxy)bu ta n e (7). A stream of O3/
O2 was bubbled through a solution of 6 (0.73 mg, 1.16 µmol)
in CH3OH (1.2 mL) at -78 °C for 3 min. After stirring for 15
min, NaBH4 (5 mg, 0.1 mmol) was added, and the mixture was
allowed to warm to 25 °C over 30 min. The reaction mixture
was diluted with EtOAc (10 mL), washed with H2O (2 mL)
and saturated aqueous NaCl (2 mL), dried (Na2SO4), filtered,
and concentrated in vacuo. The residue was dissolved in THF
(0.5 mL), and Et3N (18 µL, 0.13 mmol), BzCl (5.0 µL, 43 µmol),
and a catalytic amount of DMAP were added to the solution
at 25 °C. After stirring for 8 h, H2O (1 mL) was added, and
the reaction mixture was stirred for 30 min. The mixture was
diluted with EtOAc (10 mL), washed with saturated aqueous
NaHCO3 (1 mL) and saturated aqueous NaCl (1 mL), dried
(Na2SO4), filtered, and concentrated in vacuo. PTLC (SiO2,
17% EtOAc-hexane) gave 7 (0.30 mg, 62%) as a colorless oil:
1H NMR (CDCl3, 500 MHz) δ 8.04-7.98 (6H, m), 7.56-7.49
(3H, m), 7.42-7.35 (6H, m), 5.74-5.69 (1H, m), 4.64 (1H, dd,
J ) 3.5, 13.5 Hz), 4.553 (1H, dd, J ) 7.5, 13.5 Hz), 4.548 (1H,
dt, J ) 11.5, 6.0 Hz), 4.45 (1H, ddd, J ) 5.5, 7.5, 11.5 Hz),
2.38-2.27 (2H, m); IR (neat) νmax 1720, 1600, 1450, 1315, 1270,
1175, 1110, 1070, 1025 cm-1; FABHRMS (NBA-NaI) m/ z
441.1334 (M + Na+, C25H22O6 requires 441.1314).
H10, H9/H12, H9/H17, H10/H19, H12/H13, H12/H14, H13/H16, H14/H15
H14/H16
,
.
(R)-6-[(1E,3R,4R,6R,7Z,9Z,11E)-3,4,6,13-Tetr a h yd r oxy-
4,6-O-isop r op ylid en e-3-m eth yl-1,7,9,11-tr id eca tetr a en -1-
yl]-5,6-d ih yd r o-2H-p yr a n -2-on e (4). A suspension of 3 (1.0
mg, 2.9 µmol) in THF (1.0 mL) was treated with 2,2-dimeth-
oxypropane (15 µL, 0.12 mmol), followed by a catalytic amount
of anhydrous p-TsOH at 25 °C. After 10 min of stirring, 3
drops of Et3N was added, and the mixture was concentrated
in vacuo. PTLC (SiO2, 50% EtOAc-hexane) gave 4 (0.4 mg,
1.1 mg theoretical, 40%) as a colorless oil: 1H NMR (CDCl3,
600 MHz) δ 6.87 (1H, ddd, J ) 3.1, 5.4, 12.7 Hz, H3), 6.71 (1H,
dd, J ) 11.4, 15.2 Hz, H16), 6.52 (1H, t, J ) 11.4 Hz, H13), 6.20
(1H, t, J ) 11.4 Hz, H14), 6.09 (1H, t, J ) 11.4 Hz, H15), 6.05
(1H, d, J ) 12.7 Hz, H2), 5.96-5.85 (3H, m, H6, H7 and H17),
5.51 (1H, rough dd, H12), 4.96 (1H, dt, J ) 10.3, 4.7 Hz, H5),
4.75-4.70 (1H, m, H11), 4.24 (2H, br s, H18), 3.72 (1H, dd, J )
6.3, 9.6 Hz, H9), 2.50-2.38 (2H, m, H4), 2.30 (1H, s, C8-OH),
1.99 (1H, ddd, J ) 6.3, 9.6, 12.9 Hz, H10), 1.64 (1H, ddd, J )
6.3, 9.5, 12.9 Hz, H10), 1.39 (3H, s, acetonide CH3), 1.35 (3H,
s, acetonide CH3), 1.21 (3H, s, CH3); 13C NMR (CDCl3, 125
MHz) δ 163.9, 144.5, 138.0, 134.5, 131.8, 130.4, 126.1, 125.7,
124.9, 123.9, 121.7, 100.8, 77.3, 73.6, 71.7, 63.6, 63.3, 33.2, 29.9,
24.9, 24.5, 22.3; IR (neat) νmax 3440, 2985, 2930, 1715, 1380,
1225, 1060, 1020 cm-1; FABHRMS (NBA-NaI) m/ z 413.1952
(M + Na+, C22H30O6 requires 413.1940).
The 2D 1H-1H NOESY NMR spectrum (CDCl3, 600 MHz)
of 4 displayed the following diagnostic NOE cross-peaks: H2/
H3, H3/H4, H4/H5, H4/H6, H5/H6, H7/H9, H7/H19, H9/H10, H9/H19
H9/acetonide methyl (δ 1.35), H10/H11, H10/H12, H10/H19, H11
H14, H11/acetonide methyl (δ 1.39), H12/H13, H13/H14, H13/H16
,
/
,
H14/H15, H15/H17, H16/H18, H17/H18
.
The 2D 1H-1H COSY (CDCl3, 600 MHz) of 4 displayed the
following diagnostic cross-peaks: H2 (δ 6.05)/H3 (δ 6.87), H3
(δ 6.87)/H4 (δ 2.38-2.50), H4 (δ 2.38-2.50)/H5 (δ 4.96), H5 (δ
4.96)/H6 (δ 5.85-5.89), H9 (δ 3.72)/H10 (δ 1.64 and 1.99), H10
(δ 1.64 and 1.99)/H11 (δ 4.70-4.75), H11 (δ 4.70-4.75)/H12 (δ
5.51), H12 (δ 5.51)/H13 (δ 6.52), H13 (δ 6.52)/H14 (δ 6.20), H14 (δ
6.20)/H15 (δ 6.09), H15 (δ 6.09)/H16 (δ 6.71), H16 (δ 6.71)/H17 (δ
6.90-6.96), H17 (δ 6.90-6.96)/H18 (δ 4.24).
Alternatively, a suspension of 3 (4.9 mg, 14 µmol) in THF
(1.0 mL) was treated with 2,2-dimethoxypropane (30 µL, 0.24
mmol), followed by catalytic anhydrous p-TsOH at 25 °C. After
1 h, 3 drops of Et3N were added and the mixture was
concentrated in vacuo. PTLC (SiO2, 33% EtOAc-hexane,
elution 2×) gave 4 (2.3 mg, 42%), the corresponding primary
alcohol acetal (1.2 mg, 19%), the five-membered ring 1,2-diol
acetonide (0.48 mg, 8.8%), and its corresponding primary
alcohol acetal (0.30 mg, 4.6%), as colorless oils.25
(R)-6-[(1E,3R,4R,6R,7Z,9Z,11E)-13-[ter t-Bu tyld ip h en yl-
silyl)oxy]-3,4,6-t r ih yd r oxy-3-m et h yl-1,7,9,11-t r id eca t et -
r a en -1-yl]-5,6-d ih yd r o-2H-p yr a n -2-on e. A solution of 3 (6.3
mg, 18 µmol) in DMF (0.5 mL) was treated with imidazole (3.7
mg, 54 µmol) and TBDPSCl (7.0 µL, 27 µmol), and the mixture
was stirred at 25 °C for 30 min. This sequence was repeated
twice. The reaction mixture was diluted with EtOAc (3 mL),
washed successively with H2O (3 × 1 mL) and saturated
aqueous NaCl (1 mL), dried (Na2SO4), filtered, and concen-
trated in vacuo. Chromatography (SiO2, 50% EtOAc-hexane)
provided the TBDPS ether (7.6 mg, 10.6 mg theoretical, 72%)
as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.70-7.65 (4H,
m), 7.45-7.32 (6H, m), 6.87 (1H, ddd, J ) 3.1, 5.3, 9.7 Hz),
6.77 (1H, m), 6.45 (1H, t, J ) 11.5 Hz), 6.20 (1H, t, J ) 11.5
Hz), 6.08 (1H, t, J ) 11.5 Hz), 6.03 (1H, d, J ) 9.7 Hz), 5.93
(1H, d, J ) 15.7 Hz), 5.88 (1H, dd, J ) 4.8, 15.7 Hz), 5.84 (1H,
m), 5.58 (1H, t), 5.00-4.92 (2H, m), 4.28 (2H, d, J ) 3.7 Hz),
3.82 (1H, dd, J ) 6.2, 6.7 Hz), 3.00 (1H, br s), 2.55-2.35 (2H,
m), 1.80-1.55 (4H, m), 1.25 (3H, s), 1.06 (9H, s); IR (neat) νmax
3410, 2930, 2855, 1710, 1665, 1430, 1385, 1250, 1110, 1060,
Chiral phase HPLC analysis on an analytical Chiralcel
OD-H column (0.46 × 20 cm, 20% 2-PrOH/hexane, 0.6 mL/
min) revealed that 7 (tR ) 11.4 min) derived from 1 eluted
with the same retention time as authentic (2R)-7, tR ) 11.4
min, and not (2S)-7, tR ) 18.4 min (R ) 1.61).
(R)- a n d (()-1,2,4-Tr is(ben zoyloxy)bu ta n e (7). A stirred
solution of (R)- or (()-1,2,4-butanetriol (25.0 mg, 0.236 mmol)
in THF (3.0 mL) was treated with Et3N (656 µL, 4.71 mmol),
BzCl (328 µL, 2.83 mmol), and a catalytic amount of DMAP,
and the mixture was stirred at 25 °C overnight. H2O (1.0 mL)
was added and after 2 h, the reaction mixture was diluted with
(24) Taylor, R. J . K.; Wiggins, K.; Robinson, D. H. Synthesis 1990,
589.
(25) Characterization is provided in the Supporting Information.

1752 J . Org. Chem., Vol. 62, No. 6, 1997
Boger et al.
EtOAc (20 mL), washed with saturated aqueous NaHCO3 (5
mL) and saturated aqueous NaCl (5 mL), dried (Na2SO4),
filtered, and concentrated in vacuo. Chromatography (SiO2,
10% EtOAc-hexane) afforded (R)- or (()-7 (98.8 mg, 98.7 mg
theoretical, 100%) as a colorless oil: both compounds displayed
identical 1H NMR (CDCl3, 500 MHz) and IR (neat) with 7
derived from 1; FABHRMS (NBA-NaI) m/ z 441.1325 (M +
er ester of 11). A solution of 11 (5.8 mg, 21.6 µmol) and
DMAP (7.9 mg, 64.9 µmol) in THF (108 µL, 0.2 M) was treated
with (R)-Mosher’s chloride ((R)-MTPA-Cl, 12.6 mg, 49.8 µmol,
9.4 µL) at 25 °C, and the reaction mixture was stirred for 4 h.
The reaction solvent was removed in vacuo. Chromatography
(SiO2, 0.5 × 5 cm, 25-50% EtOAc-hexane gradient elution)
afforded the bis-Mosher ester of 11 (6.0 mg, 15.1 mg theoreti-
cal, 40%): Rf 0.4 (25% EtOAc-hexane); 1H NMR (CDCl3, 400
MHz) δ 7.48 (2H, d, J ) 7.7 Hz), 7.43 (2H, d, J ) 7.1 Hz),
7.40-7.31 (6H, m), 7.28 (2H, d, J ) 8.7 Hz), 6.88 (2H, d, J )
8.7 Hz), 5.31-5.30 (1H, m), 5.04 (2H, s), 4.53 (1H, dd, J ) 2.9,
12.4 Hz), 4.24 (2H, dd, J ) 5.1, 12.4 Hz), 3.80 (3H, s), 3.43
(3H, d, J ) 1.1 Hz), 3.41 (3H, d, J ) 1.0 Hz), 2.29 (2H, t, J )
6.9 Hz), 1.73-1.57 (m, 4H); 19F NMR (CDCl3, 376 MHz) δ
-68.10, -68.13; 19F NMR for racemic material (CDCl3, 376
MHz) δ -67.70, -67.93, -68.10, -68.13; FABHRMS (NBA-
CsI) m/ z 833.1169 (M + Cs+, C34H34F6O9 requires 833.1161).
(4-Meth oxyp h en yl)m eth yl (R)-6-[(ter t-Bu tyld ip h en yl-
silyl)oxy]-5-h yd r oxyh exa n oa te (12). A solution of 11 (500
mg, 1.86 mmol) in DMF (3.7 mL, 0.5 M) was treated sequen-
tially with imidazole (279 mg, 4.1 mmol) and TBDPSCl (564
mg, 2.05 mmol, 534 µL), and the mixture was stirred at 25 °C
under Ar for 15 h. The reaction mixture was poured into H2O
(40 mL) and extracted with Et2O (3 × 50 mL). The combined
organic layers were washed with H2O (50 mL), dried (MgSO4),
and filtered, and the solvent was removed in vacuo. Chroma-
tography (SiO2, 2 × 10 cm, 10-25% EtOAc-hexane gradient
elution) afforded 12 (840 mg, 941 mg theoretical, 89%) as a
Na+, C25H22O6 requires 441.1314); (R)-1,2,4-butanetriol [R]20
D
+49.6 (c 0.500, CHCl3).
(4-Meth oxyp h en yl)m eth yl Hex-5-en oa te (10). Meth od
A. A suspension of hex-5-enoic acid (9,20 38.00 g, 0.333 mol),
4-methoxybenzyl chloride (57.38 g, 0.366 mol), and NaHCO3
(55.96 g, 0.666 mol) in DMF (190 mL) was stirred at 45 °C for
2 days. Additional 4-methoxybenzyl chloride (5.21 g, 0.0333
mol) was added, and stirring was continued for another 1 day.
The reaction mixture was cooled to 25 °C, diluted with EtOAc
(300 mL), washed with H2O (2×100 mL) and saturated
aqueous NaCl (100 mL), dried (Na2SO4), filtered, and concen-
trated in vacuo. Chromatography (SiO2, 0-5% EtOAc-hexane
gradient elution) afforded 10 (69.55 g, 89%) as a clear colorless
oil.
Meth od B. A solution of hex-5-enoic acid (9,20 11.4 g, 0.1
mol) in CH2Cl2 (250 mL, 0.4 M) was treated sequentially with
saturated aqueous NaHCO3 (167 mL), Bu4NI (48.0 g, 0.13 mol),
and 4-methoxybenzyl chloride (18.8 g, 0.12 mol), and the
mixture was stirred at 25 °C for 28 h. The layers were
separated, and the aqueous layer was extracted with CH2Cl2
(4 × 50 mL). The organic layers were combined, dried
(MgSO4), filtered, and concentrated in vacuo giving a white
solid. This material was triturated with hexanes and filtered,
washing the solid with hexanes (4 × 50 mL). The filtrate was
concentrated in vacuo. Chromatography (SiO2, 3.5 × 15 cm,
0-10% EtOAc-hexane gradient elution) afforded 10 (11.5 g,
22.1 g theoretical, 52%) as a clear oil: Rf 0.45 (10% EtOAc-
hexane); 1H NMR (CDCl3, 250 MHz) δ 7.28 (2H, d, J ) 8.6
Hz), 6.87 (2H, d, J ) 8.6 Hz), 5.74 (1H, dddd, J ) 6.8, 6.8,
10.2, 17.2 Hz), 5.03 (3H, m), 4.97-4.92 (1H, m), 3.79 (3H, s),
2.32 (2H, t, J ) 7.5 Hz), 2.06 (2H, q, J ) 7.2 Hz), 1.71 (2H, p,
J ) 7.5 Hz); 13C NMR (CDCl3, 100 MHz) δ 173.4, 159.5, 137.6,
130.0, 128.1, 115.3, 113.9, 65.9, 55.2, 33.6, 33.1, 24.0; IR (neat)
νmax 2943, 1733, 1610, 1512, 1246, 1164 cm-1; FABHRMS
(NBA-NaI) m/ z 257.1159 (M + Na+, C14H18O3 requires
257.1154).
(4-Meth oxyph en yl)m eth yl (R)-5,6-Dih ydr oxyh exan oate
(11). A solution of K3Fe(CN)6 (19.76 g, 60 mmol), K2CO3 (8.3
g, 60 mmol), NaHCO3 (5.04 g, 60 mmol), and (DHQD)2-AQN
(857 mg, 1 mmol) in t-BuOH (100 mL) and H2O (100 mL) was
stirred at 25 °C, warmed slightly to dissolve the materials,
and recooled to 25 °C. The mixture was treated with K2OsO2-
(OH)2 (134 mg, 0.4 mmol) and immediately cooled to 0 °C.
When precipitates appeared, 10 (4.68 g, 20 mmol) was added
at once, and the reaction mixture was stirred at 0 °C for 48 h.
Solid Na2SO3 (16 g) was added slowly over 10 min at 0 °C.
The mixture was warmed to 25 °C and stirred for 45 min. The
mixture was extracted with EtOAc (3 × 100 mL). The
combined organic layers were dried (MgSO4) and filtered, and
the solvent was removed in vacuo. Chromatography (SiO2, 3.5
× 15 cm, EtOAc) afforded 11 (3.95 g, 5.00 g theoretical, 79%)
as a white solid which was 88% ee as determined by prepara-
tion of the bis-(R)-Mosher ester described below. One recrys-
tallization (Et2O) provided enantiomerically pure (>98% ee)
11 (2.55 g, 5.00 g theoretical, 51%) as a white solid: Rf 0.5
(EtOAc); mp 57-59 °C (white plates, Et2O); [R]22D +2.1 (c 0.06,
CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.29 (2H, d, J ) 8.6 Hz),
6.89 (2H, d, J ) 8.6 Hz), 5.05 (2H, s), 3.81 (3H, s), 3.72-3.66
(1H, m), 3.65-3.60 (1H, m), 3.46-3.40 (1H, m), 2.39 (2H, dt,
J ) 3.0, 7.3 Hz), 2.24 (1H, d, J ) 4.3 Hz, CHOH), 1.89 (1H, t,
J ) 5.7 Hz, CH2OH), 1.84-1.66 (2H, m), 1.48-1.43 (2H, m);
13C NMR (CDCl3, 100 MHz) δ 173.7, 159.6, 130.1, 128.0, 113.9,
71.6, 66.6, 66.1, 55.3, 34.0, 32.3, 20.7; IR (neat) νmax 3372, 2933,
2871, 1728, 1610, 1518, 1463, 1254 cm-1; FABHRMS (NBA-
NaI) m/ z 291.1212 (M + Na+, C14H20O5 requires 291.1208).
Anal. Calcd for C14H20O5: C, 62.67; H, 7.51. Found: C, 62.78;
H, 7.39.
clear oil: Rf 0.5 (25% EtOAc-hexane); [R]22 -0.92 (c 2.1,
D
CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.72-7.67 (4H, m), 7.48-
7.39 (6H, m), 7.30 (2H, d, J ) 8.6 Hz), 6.89 (2H, ddd, J ) 2.9,
2.9, 8.6 Hz), 5.06 (2H, s), 3.80 (3H, s), 3.77-3.72 (1H, m), 3.67
(1H, dd, J ) 3.5, 10.1 Hz), 3.51 (1H, dd, J ) 7.4, 10.1 Hz),
2.54 (1H, br s), 2.36 (2H, t, J ) 7.4 Hz), 1.85-1.67 (2H, m),
1.48-1.41 (2H, m), 1.10 (9H, s); 13C NMR (CDCl3, 100 MHz) δ
173.3, 159.5, 135.5, 133.0, 130.0, 129.8, 128.1, 127.7, 113.8,
71.4, 67.8, 65.8, 55.1, 34.1, 31.9, 26.8, 20.9, 19.1; IR (neat) νmax
3503, 3070, 2931, 2857, 1734, 1612, 1516, 1428, 1248, 1112
cm-1; FABHRMS (NBA-CsI) m/ z 639.1546 (M + Cs+, C30H38O5-
Si requires 639.1543).
(R)-6-[[(ter t-Bu tyld ip h en ylsilyl)oxy]m eth yl]-3,4,5,6-tet-
r a h yd r o-2H-p yr a n -2-on e (13). A solution of 12 (100 mg,
0.198 mmol) in anisole (107 mg, 107 µL, 1.9 M) was treated
with CF3CO2H (90 mg, 80 µL), and the mixture was stirred at
25 °C for 30 min. The CF3
CO2H was evaporated under a N2
stream (30 min) and in vacuo (30 min). Chromatography
(SiO2, 2.5 × 15 cm, 10-25% EtOAc-hexane gradient elution)
afforded 13 (55.0 mg, 72.9 mg theoretical, 75%) identical in
all respects with authentic racemic material:24
Rf 0.5 (25%
EtOAc-hexane); [R]22D -12.5 (c 1.6, CHCl3); 1H NMR (CDCl3,
250 MHz) δ 7.70-7.60 (6H, m), 7.50-7.35 (9H, m), 4.45-4.35
(1H, dddd, J ) 4.7, 4.8, 5.1, 9.4 Hz), 3.90-3.70 (2H, m), 2.70-
2.40 (2H, m), 2.05-1.70 (4H, m), 1.05 (9H, s); 13
C NMR (CDCl3,
100 MHz) δ 171.2, 135.5, 132.9, 129.8, 127.7, 80.2, 65.6, 26.8,
24.4, 19.2, 18.3; IR (neat) νmax 3070, 2930, 2857, 1737, 1241,
1108 cm-1; FABHRMS (NBA-NaI) m/ z 391.1696 (M + Na+,
C22H28O3Si requires 391.1705).
(3RS,6R)-6-[[(ter t-Bu tylph en ylsilyl)oxy]m eth yl]-3-(ph en -
ylselen yl)-3,4,5,6-tetr a h yd r o-2H-p yr a n -2-on e (14). A solu-
tion of 13 (350 mg, 0.95 mmol) in THF (3 mL) was added slowly
to a solution of freshly prepared LDA (1.05 mmol, 3.0 mL THF)
at -78 °C, and the mixture was stirred at -78 °C for 1 h.
PhSeBr (269 mg, 1.14 mmol) in THF (2 mL) was added, and
the solution was stirred at -78 °C for 5 h. The reaction
mixture was poured into saturated aqueous NaHCO3 (50 mL)
and extracted with EtOAc (3 × 25 mL). The combined organic
layers were washed with H2O (2 × 20 mL) and saturated
aqueous NaCl (20 mL), dried (MgSO4), and concentrated in
vacuo. Chromatography (SiO2, 2.5 × 15 cm, 10-50% CH2Cl2-
benzene) provided 14 (249 mg, 498 mg theoretical, 50%) as a
2:1 mixture of diastereomers: 83 mg of the less polar isomer;
Rf 0.29 (50% CH2Cl2-benzene); 1H NMR (CDCl3, 250 MHz) δ
7.70-7.62 (6H, m), 7.45-7.32 (9H, m), 4.47 (1H, dddd, J )
4.4, 4.6, 4.6, 9.1 Hz), 3.97 (1H, t, J ) 7.4 Hz), 3.75 (2H, d, J )
6.3 Hz), 2.42-2.28 (1H, m), 2.10-1.95 (2H, m), 1.85-1.75 (1H,
m), 1.05 (9H, s); 13C NMR (CDCl3, 100 MHz) δ 170.1, 135.8,
(4-Meth oxyp h en yl)m eth yl (R)-5,6-Bis[[(S)-r-m eth oxy-
r-(tr iflu or om eth yl)ph en yl]acetoxy]h exan oate (bis-Mosh -

Relative and Absolute Stereochemistry of Fostriecin (CI-920)
J . Org. Chem., Vol. 62, No. 6, 1997 1753
135.6, 135.5, 133.0, 132.8, 129.9, 129.3, 128.9, 127.8, 79.5, 65.4,
26.8, 26.2, 24.0; IR (neat) νmax 3052, 2929, 2856, 1732, 1428,
1244, 1113 cm-1; FABHRMS (NBA-NaI) m/ z 525.1379 (M +
H+, C28H32O3SeSi requires 525.1364); and 166 mg of the more
polar isomer; Rf 0.2 (50% CH2Cl2-benzene); 1H NMR (CDCl3,
250 MHz) δ 7.70-7.65 (6H, m), 7.45-7.30 (9H, m), 4.45-4.35
(1H, dddd, J ) 5.0, 5.0, 8.8, 10.4 Hz), 4.03 (1H, t, J ) 4.5 Hz),
3.76 (2H, d, J ) 5.0 Hz), 2.30-2.10 (3H, m), 1.92-1.82 (1H,
m), 1.10 (9H, s); 13C NMR (CDCl3, 100 MHz) δ 170.4, 135.7,
135.6, 135.5, 133.1, 132.9, 129.8, 129.3, 128.7, 127.8, 80.8, 65.5,
39.8, 26.8, 26.6; IR (neat) νmax 3070, 2929, 2856, 1731, 1427,
1240, 1113 cm-1; FABHRMS (NBA-NaI) m/ z 525.1380 (M +
H+, C28H32O3SeSi requires 525.1364).
(3RS,6R)-6-(Hyd r oxym eth yl)-3-(p h en ylselen yl)-3,4,5,6-
tetr a h yd r o-2H-p yr a n -2-on e (15). A solution of 14 (98 mg,
0.187 mmol) in THF (5.0 mL) was treated with HOAc (62 µL,
1.1 mmol) and Bu4NF hydrate (91 mg), and the mixture was
stirred at 25 °C for 3 h. The reaction mixture was diluted with
EtOAc (20 mL), washed with H2O (10 mL), saturated aqueous
NaHCO3 (10 mL), and saturated aqueous NaCl (10 mL), dried
(Na2SO4), filtered, and concentrated in vacuo. Chromatogra-
phy (SiO2, 50% EtOAc-hexane) provided 15 (36.2 mg, 53.2
mg theoretical, 68%) as a colorless oil: 1H NMR (CDCl3, 400
MHz) δ 7.67-7.61 (2H, m), 7.37-7.27 (3H, m), 4.52-4.46 (0.5
H, m), 4.46-4.39 (0.5 H, m), 4.02 (0.5 H, ddd, J ) 1.0, 4.1, 5.2
Hz), 3.95 (0.5 H, t, J ) 7.2 Hz), 3.75 (1H, br d, J ) 12.2 Hz),
3.62 (1H, ddd, J ) 2.3, 5.4, 12.2 Hz), 2.38-1.67 (5H, m); IR
(neat) νmax 3400, 2930, 1720, 1440, 1250, 1190, 1060, 1020,
740, 690 cm-1; FABHRMS (NBA-NaI) m/ z 287.0180 (M +
H+, C12H14O3Se requires 287.0186).
(R)-6-(Hydr oxym eth yl)-5,6-dih ydr o-2H-pyr an -2-on e (16).
A stirred solution of 15 (45.4 mg, 0.159 mmol) in CH2Cl2 (5.0
mL) and H2O (100 µL) was treated with 35% H2O2 (30.9 µL,
0.318 mmol). After 1 h at 25 °C, the mixture was treated with
additional 35% H2O2 (30.9 µL, 0.318 mmol) and stirred for 1
h. The organic phase was separated, and the aqueous layer
was extracted with CHCl3 (3 × 15 mL). The organic phase
and the extracts were combined, dried (Na2SO4), filtered, and
concentrated. Chromatography (SiO2, 50% EtOAc-hexane)
provided 16 (17.4 mg, 20.5 mg theoretical, 85%) as a colorless
oil: [R]20D +160 (c 0.850, CHCl3) lit. [R]26D + 175 (c 0.92, CHCl3)
identical in all respects (NMR, IR, MS) with authentic mate-
rial.23
(R)-6-[(E)-3-Oxo-1-bu ten -1-yl]-5,6-d ih yd r o-2H-p yr a n -2-
on e (8). A solution of oxalyl chloride (28 µL, 0.32 mmol) in
CH2Cl2 (0.5 mL) was treated with DMSO (27 µL, 0.38 mmol)
at -78 °C under Ar, and the mixture was stirred for 15 min.
A solution of 16 (4.0 mg, 32 µmol) in CH2Cl2 (0.5 mL) was
added to the solution, and the mixture was stirred for 15 min.
Et3N (156 µL, 1.12 mmol) was added to the mixture, and
stirring was continued for 10 min at -78 °C and 5 min at 0
°C. The reaction mixture was treated with 1-(triphenylphos-
phoranylidene)-2-propanone at 0 °C for 30 min and passed
through a plug of SiO2 (50% EtOAc-hexane). The material
obtained was further purified by PTLC (SiO2, 60% EtOAc-
hexane) to give 8 (2.7 mg, 5.2 mg theoretical, 52%) as a
colorless oil: [R]20 +201 (c 0.110, CHCl3), lit.10 [R]D +216.8 (c
D
1.16, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 6.90 (1H, ddd, J )
3.0, 6.0, 10.0 Hz), 6.74 (1H, dd, J ) 4.5, 16.0 Hz), 6.43 (1H,
dd, J ) 1.5, 16.0 Hz), 6.08 (1H, ddd, J ) 1.0, 2.5, 10.0 Hz),
5.12 (1H, dddd, J ) 1.5, 4.0, 4.5, 11.0 Hz), 2.56 (1H, dddd, J
) 1.0, 4.0, 6.0, 18.5 Hz), 2.44 (1H, dddd, J ) 2.5, 3.0, 11.0,
18.5 Hz), 2.28 (3H, s); 13C NMR (CDCl3, 125 MHz) δ 197.5,
163.0, 144.1, 140.7, 130.5, 121.7, 75.6, 29.0, 28.0; IR (neat) νmax
2920, 1720, 1700, 1675, 1360, 1240, 1090, 1060, 805 cm-1
;
FABHRMS (NBA-NaI) m/ z 189.0532 (M + Na+, C9H10O3
requires 189.0528).
Ack n ow led gm en t. We gratefully acknowledge the
financial support of the National Institutes of Health
(CA 42056), The Skaggs Institute for Chemical Biology,
and the sabbatical leave of M.H. from Tanabe Seiyaku
Co., Ltd. (1996-1997). We thank Warner-Lambert/
Parke-Davis for a sample of fostriecin with which this
work was conducted, and we thank the Sharpless group
for the (DHQD)2-AQN ligand and the use of a Chiralcel
OD-H analytical HPLC column.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
characterized compounds are provided (20 pages). This mate-
rial is contained in libraries on microfiche, immediately follows
this article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O962166H