Alkoxide precoordination to rhodium enables stereodirected catalytic hydrogenation of a dihydrofuranol precursor of the C29-40 F/G sector of pectenotoxin-2

Article abstract of DOI:10.1016/j.tet.2004.06.142

An enantioselective synthesis of the stereochemically fully endowed C(29-40) fragment of pectenotoxin-2 is detailed. The highlight of the synthesis is an alkoxide-directed hydrogenation in which ionic complexation of the deprotonated substrate to [Rh(NBD)(DIPHOS-4)]BF₄, accomplished by the co-addition of an equivalent of sodium hydride in THF, completely deters a kinetic tendency for dehydration and properly sets the critical stereochemistry at C-35. The dual objectives made possible by this catalytic technology are expected to have far-ranging applications. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.06.142

Tetrahedron 60 (2004) 9589–9598
Alkoxide precoordination to rhodium enables stereodirected
catalytic hydrogenation of a dihydrofuranol precursor of the
C29-40 F/G sector of pectenotoxin-2
*
Xiaowen Peng, Dmitriy Bondar and Leo A. Paquette
Evans Chemical Laboratories, The Ohio State University, Columbus, OH 43210 USA
Received 28 April 2004; revised 16 June 2004; accepted 18 June 2004
Available online 25 August 2004
Abstract—An enantioselective synthesis of the stereochemically fully endowed C(29-40) fragment of pectenotoxin-2 is detailed. The
highlight of the synthesis is an alkoxide-directed hydrogenation in which ionic complexation of the deprotonated substrate to
[Rh(NBD)(DIPHOS-4)]BF4, accomplished by the co-addition of an equivalent of sodium hydride in THF, completely deters a kinetic
tendency for dehydration and properly sets the critical stereochemistry at C-35. The dual objectives made possible by this catalytic
technology are expected to have far-ranging applications.
q 2004 Elsevier Ltd. All rights reserved.
Diarrhetic shellfish poisoning (DSP), first formally recog-
nized in northeastern Japan about 30 years ago,1 is now
known to occur worldwide.2 DSP is caused by eating
scallops, mussels, or clams that have ingested toxigenic
dinoflagellates and accumulated the toxins in this manner.
The major symptoms of DSP are gastrointestinal disorders
such as diarrhea, nausea, vomiting and abdominal pain.3
Several dinoflagellate members of the genus Dinophysis
have been identified as the organisms responsible for
transmittal of the toxins to shellfish.1 In 1985, Yasumoto
et al. isolated these substances from the digestive gland of
Patinopecten yessoensis, identified them to constitute a
family of polyether macrolides, and assigned to them the
name pectenotoxins (PTX’s).4 The structures of six of the
10 known PTX’s are illustrated.
The structural variations arise from differences in the
oxidation level of the R group attached to C-18 and the
specific stereochemistry at C-7. The absolute configurations
follow from a combination of X-ray crystallographic and
comparative 1H NMR analyses.4 The hepatotoxic properties
of PTX-1 and PTX-2 have been detailed.5 Beyond this,
PTX-2 exhibits selective nanomolar cytotoxicity against
several human cancer cell lines6 and an impressive capacity
for site-specific interaction with the actin cytoskeleton.7 In
combination with these interesting biological properties are
the exquisitely complex structural features consisting of 19
stereocenters (six are quaternary), a pair of spiroacetals, and
several additional oxygenated rings housed in a 33-carbon
macrolide ring. Not unexpectedly, this formidable synthetic
challenge has attracted the attention of several research
groups. Stereocontrolled routes to the C8–C18,8 C11–C26,9
C31–C40,10 and C29–C40 fragments11 of PTX-2 have been
reported. Particularly noteworthy are the total asymmetric
syntheses of PTX-4 and PTX-8 recently completed by the
Evans group.12
Keywords: Stereodirected hydrogenation; Ionic complexation; Rhodium
catalysis; anti-Aldol; 2-Lithio-4,5-dihydrofuran.
* Corresponding author. Tel.: C1-614-292-2520; fax: C1-614-292-1685;
e-mail: paquette.1@osu.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.142

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X. Peng et al. / Tetrahedron 60 (2004) 9589–9598
Scheme 1.
1. Results and discussion
diastereomer could be separated by careful column
chromatography. The stereochemical assignment to 5 was
consistent with the observed 1H–1H coupling constant
(JHa,HbZ7.2 Hz). Typical values are JZ3.2–6.4 Hz for syn
aldols and 7.2–9.6 Hz for their anti counterparts.13b
From the outset, we envisioned an approach to the F/G
sector of 1 that was to be based on the generation of 2 via
stereocontrolled reduction of the double bond resident in
3.11 This advanced intermediate would in turn be assembled
by the coupling of two simpler fragments as indicated in
Scheme 1. As matters turned out, 3 exhibits a flagrant
tendency to undergo dehydration when subjected to a
variety of hydrogenation conditions. In the final analysis, a
new, ultramild, catalytic protocol capable of circumventing
this problem had to be developed. In the spirit of the present
symposium-in-print, the merits of ionic complexation
involving alkali metal alkoxides and a cationic rhodium
catalyst are established. These conditions were also met
with enhanced p-facial selectivity, thus boosting its overall
value to targeted organic synthesis.
Following conversion to the MOM-protected derivative, the
chiral auxiliary was cleaved with sodium borohydride in
aqueous tetrahydrofuran16 to afford alcohol 6. One-carbon
homologation was brought about by SN2 displacement of
the subsequently introduced tosylate group by cyanide ion.
Dibal-H reduction of nitrile 7 made available the aldehyde,
which was treated with sodium borohydride to gain access
to alcohol 8. Protection of the OH group as a MOM ether
was followed by ozonolytic cleavage of the double bond to
deliver the target aldehyde 10.
At this point, attention was directed to the elaboration of
dihydrofuran 14 (Scheme 3). The ready availability of
enantiomerically pure 11 from D-mannose17 prompted
consideration of its deployment as starting material. In
line with precedent, 11 proved suited to lithiation with tert-
butyllithium at K78 8C.18 The vinyl anion so formed
reacted rapidly (!5 min) with 10 at this temperature to
furnish 12, which was immediately protected19 as its SEM
ether 13. 13C NMR analysis of this intermediate clearly
revealed the presence of two diastereomers which could not
The configurational relationship of the methyl group and
MOM ether at C-37 and C-38 in 3 suggested the application
of an anti-aldol reaction13 involving the Z-enolate of chiral
oxazolidinone 414 in the presence of 2 equiv. of the Lewis
acid dibutylboron triflate.15 With crotonaldehyde as the
reaction partner, the desired product 5 was obtained as a
single diastereomer when the condensation was performed
on small (w200 mg) scale (Scheme 2). As the quantities
were increased, selectivity decreased. The second
Scheme 2.

X. Peng et al. / Tetrahedron 60 (2004) 9589–9598
9591
Scheme 3.
be separated by flash column chromatography. Fortunately,
the diastereomers 14 and 15, obtained in a ratio of 5:1
following selective desilylation with tetrabutylammonium
fluoride at 0 8C, were amenable to purification in this
manner. Although the absolute configuration of C-36 in both
14 and 15 could not be unequivocally ascertained, this issue
was of little consequence since this center has to be oxidized
to the ketone level at one of the final steps of the synthesis.
Consequently, both intermediates are serviceable. For
convenience, only the pure diastereomer 14, arbitrarily
assigned the b configuration, was utilized almost exclu-
sively in the sequel. This configuration is consonant with
predominant adherence to the Cram chelate transition state
during 1,2-addition to aldehyde 10.
an appreciable amount (46%) of unreacted starting material
was recovered (Scheme 5). A similar reaction performed on
15 but with a solvent change to tetrahydrofuran revealed no
advantageous medium effect. Other than return of 20% of
the reactant, there was produced 50% of 20.
The structural assignment to 17 was facilitated by its
conversion to the p-methoxybenzyl ether 19. NOESY
analysis of this derivative performed in CDCl3 solvent
allowed for clean differentiation of H-34a and H-34b and
the establishment of their spatial relationship to H-33 and
H-35. There was no question that the undesired configur-
ation had been set at C-35. Direct spectral comparison of the
1H NMR spectral features of 17 and 20 confirmed that
neither of the two well-known hydroxyl-directing hydro-
genation catalysts was suited to the task in the present
context. Rather, our results suggest that Hu¨nig’s base found
it possible to coordinate to rhodium with activation of the
catalyst. Subsequent mechanistic events conspired to cause
approach from the less hindered face of the double bond to
be kinetically favored.
The feasibility of this route to 14 set the stage for a
hydroxyl-directed hydrogenation20 to serve as the means for
establishing the third stereogenic center in tetrahydrofuran
ring F. However, the pronounced tendency of 14 to undergo
the elimination of water during attempted saturation had to
be dealt with properly. For example, stirring a 0.07 M
CH2Cl2 solution of the dihydrofuranol with 20 mol%
21
[Rh(NBD)(DIPHOS-4)]BF4 under 800 psi of hydrogen
for 17 h furnished 16 as the major product (Scheme 4). The
The complication prompted a more in-depth investigation
into the phenomenon. In particular, we were attracted to a
1974 report by Thompson and McPherson that described a
significant enhancement in p-facial discrimination with
Wilkinson’s catalyst upon covalent bonding of an alkoxide
to the rhodium center.23 Disappointingly, the subjection of
14 to these conditions resulted in the absence of any
detectable reaction. This observation led to alternative
examination of the merits of ionic complexation between
the alkali metal salts of 14 and 15 and the cationic catalyst
[Rh(NBD)(DIPHOS-4)]BF4. Hydrogenation of the potass-
ium salt of 15 in THF gave rise to a product mixture
entirely comparable response accorded to experiments
involving [Ir(COD)(py)(PCy3)]PF6 (84% of 16) led us to
22
consider the Lewis-acidic nature of these catalysts as a
potential source of the difficulty. Since the rhodium-based
reagent is known to be stable to triethylamine, recourse was
made to the inclusion of 2–3 equiv. of Hu¨nig’s base in the
reaction medium. This tactic did serve successfully to deter
the production of 16. However, the reputed hydroxyl-
directing capability of this rhodium catalyst did not surface.
In the case of 14, 17 and 18 were formed (46% and 3%) and
Scheme 4.

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X. Peng et al. / Tetrahedron 60 (2004) 9589–9598
Scheme 5.
consisting predominantly of 21 (Scheme 6). Comparable
processing of 14 in THF solution containing sodium hydride
gave only 18 (68% at 80% conversion). The optimization
studies that followed demonstrated that excellent reprodu-
cibility and efficiency were attainable with 1.05 equiv. of
NaH in THF when the reaction time was extended to three
days. The adoption of these mild basic reaction conditions is
enthusiastically endorsed in difficult cases such as those
faced here.
To complete our passage to 2, intermediate 22 was
hydrolyzed in aqueous acetic acid to unmask the 1,2-diol,
the subsequent cleavage of which was effected with sodium
periodate on silica gel24 (Scheme 7). The homologation of
aldehyde 23 with phosphonate ester 2425 and subsequent
exposure to DDQ26 gave rise efficiently to 2.
In summary, a means for the concise assembly of the C29–
C40 subunit of pectenotoxin-2 has been defined. The key
Scheme 6.

X. Peng et al. / Tetrahedron 60 (2004) 9589–9598
9593
Scheme 7.
step of the undertaking is an alkoxide-directed hydrogen-
ation. The optimized conditions effectively skirt as well the
tendency of 14 to experience dehydration with formation of
furan 16. The feasibility of this scenario was the centerpiece
of a stereocontrolled 18-step route that provided 2 in 3.2%
overall yield.
combined organic phases were dried and evaporated to
leave a residue, purification of which by flash chromatog-
raphy (silica gel, hexane–EtOAc 9:1) afforded the MOM
ether (1.51 g, 92%) as a white solid, mp 70.5–71.0 8C; IR
(CH2Cl2, cmK1) 1780, 1699; 1H NMR (300 MHz, CDCl3) d
7.36–7.24 (m, 5H), 5.85–5.74 (m, 1H), 5.34–5.25 (m, 1H),
4.77–4.69 (m, 2H), 4.46 (d, JZ6.7 Hz, 1H), 4.32 (dd, JZ
7.2, 7.2 Hz, 1H), 4.21–4.04 (m, 3H), 3.33 (s, 3H), 3.25 (dd,
JZ3.3, 13.4 Hz, 1H), 2.79 (dd, JZ9.1, 13.5 Hz, 1H), 1.76
(dd, JZ1.6, 6.5 Hz, 3H) 1.09 (d, JZ6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 175.8, 153.3, 135.39, 133.0, 129.6,
129.5, 129.0, 128.6, 128.2, 127.4, 93.1, 78.9, 65.7, 55.8,
55.1, 42.0, 37.9, 17.9, 14.2; ES HRMS m/z (MCNa)C calcd
370.1630, obsd 370.1642; [a]2D2ZC1.4 (c 0.20, CHCl3).
2. Experimental.27
2.1. Data for compounds
2.1.1. Aldol product 5. To a solution of 4 (182 mg,
0.78 mmol) in 3 mL of dry ether cooled to 0 8C was added
dibutylboron triflate (0.39 mL, 1.56 mmol) dropwise fol-
lowed by diisopropylethylamine (0.16 mL, 0.90 mmol). The
mixture was stirred at 0 8C for 40 min before being cooled to
K78 8C. A solution of crotonaldehyde (0.081 mL,
0.97 mmol) in 1 mL of ether was introduced dropwise at
K78 8C. The reaction mixture was stirred for 30 min,
diluted with 2 mL of ether, quenched with 1.5 mL of 1 M
tartaric acid solution at K78 8C, and stirred at rt for an
additional 2 h. The separated aqueous phase was extracted
with ether. The combined organic phases were washed with
saturated NaHCO3 solution and cooled to 0 8C prior to the
addition of a solution containing 3:1 MeOH/30% H2O2
(2 mL). The mixture was stirred at rt for 30 min, diluted
with ether, and washed with saturated NaHCO3 solution and
brine prior to drying. The solvent was removed under
vacuum and the residue was purified by flash column
chromatography (silica gel, hexane–EtOAc/7:1) to give 5
(0.146 g, 62%) as a white solid, mp 110.0–111.0 8C; IR
Anal. Calcd for C19H25O5N: C, 65.69, H, 7.25. Found: C,
65.75, H, 7.17.
2.1.3. MOM ether 6. Sodium borohydride (0.307 g,
8.12 mmol) was added in one portion to a solution of
protected 5 (1.41 g, 4.06 mmol) in 40 mL of THF/H2O (3:1)
at 0 8C. The reaction mixture was stirred overnight. More
NaBH4 was added to allow completion of the reaction. HCl
(1 M) was introduced carefully and the product was
extracted into ether. The combined organic phases were
washed with brine, dried, and freed of solvent. The residue
was purified by flash chromatography (silica gel, hexane–
EtOAc 5:1) to give 6 (0.617 g, 87%) as a colorless oil; IR
(neat, cmK1) 3444, 1670, 1453; 1H NMR (300 MHz,
CDCl3) d 5.71–5.60 (m, 1H), 5.31–5.22 (m, 1H), 4.60
(AB quartet, JZ6.7 Hz, 2H), 3.86 (dd, JZ8.4, 8.4 Hz, 1H),
3.70–3.57 (m, 2H), 3.38 (s, 3H), 2.88 (br s, 1H), 1.86–1.75
(m, 1H), 1.72 (dd, JZ6.5, 1.7 Hz, 3H), 0.85 (d, JZ7.0 Hz,
3H); 13C NMR (75 MHz, CDCl3) d 131.3, 129.4, 93.1, 82.1,
66.9, 55.8, 39.9, 17.8, 13.9; ES HRMS m/z (MCNa)C calcd
197.1148, obsd 197.1148; [a]D 22ZC170 (c 0.82, CHCl3).
1
(CH2Cl2, cmK1) 3486, 1776, 1696; H NMR (300 MHz,
CDCl3) d 7.36–7.23 (m, 5H), 5.86–5.72 (m, 1H), 5.58–5.50
(m, 1H), 4.73–4.66 (m, 1H), 4.24–4.14 (m, 3H), 3.94 (dd,
JZ7.2, 7.2 Hz, 3H), 3.29 (dd, JZ3.2, 13.4 Hz, 1H), 2.78
(dd, JZ9.4, 13.4 Hz, 1H), 1.73 (dt, JZ6.5, 0.7 Hz, 1H),
1.17 (d, JZ6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) d
176.6, 153.6, 135.3, 131.6, 129.6 (2C), 129.2, 129.1 (2C),
127.4, 75.9, 66.1, 55.6, 43.4, 37.9, 17.9, 14.6; ES HRMS m/z
(MCNa)C calcd 326.1368, obsd 326.1363; [a]2D2ZK39.6
(c 0.54, CHCl3).
2.1.4. Nitrile 7. To a solution of 6 in pyridine (5 mL) was
added p-toluenesulfonyl chloride (0.624 g, 3.27 mmol) in
one portion followed by a catalytic amount of DMAP. The
reaction mixture was stirred overnight. Saturated NaHCO3
solution (6 mL) was added and stirring was continued for
45 min. The solution was extracted with EtOAc. The
combined organic phases were washed with 1 M HCl
until TLC indicated that no pyridine remained. The organic
phase was washed with saturated NaHCO3 solution and
brine, dried and freed of solvent under vacuum to provide
the tosylate (0.693 g, 97%) as a pale yellow oil.
Anal. Calcd for C17H21O4N: C, 67.31, H, 6.98. Found: C,
67.18, H, 7.04.
2.1.2. MOM protection of 5. MOMCl (0.889 mL,
11.7 mmol) was added dropwise to a solution of 5 (1.42 g,
4.68 mmol) and diisopropylethylamine (2.45 mL,
14.0 mmol) at K78 8C. The reaction mixture was stirred
at rt overnight, saturated NaHCO3 solution (30 mL) was
added to quench the reaction, and the separated aqueous
phase was extracted with CH2Cl2 (35 mL!2). The
The tosylate was dissolved in 5 mL of DMF. KCN (0.429 g,
6.33 mmol) was introduced. After being stirred at 90 8C
overnight, the reaction mixture was diluted with ether/
petroleum ether (1/1) (100 mL) and washed with saturated

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X. Peng et al. / Tetrahedron 60 (2004) 9589–9598
NaHCO3 solution, water, and brine prior to being freed of
solvent under vacuum. The residue was purified by flash
chromatography (silica gel, hexane–EtOAc 20:1) to furnish
7 (0.297 g, 77%) as a colorless oil; IR (neat, cmK1) 2246,
pale blue color persisted. After an excess amount of
triphenylphosphine was added, the mixture was allowed to
return to rt and stirred for 1 h. The solvent was removed and
the residue was purified by flash chromatography (silica gel,
hexane–EtOAc 6:1) to give 10 (0.055 g, 92%) as a colorless
oil; IR (neat, cmK1) 1732, 1461; 1H NMR (300 MHz,
CDCl3) d 9.62 (d, JZ2.2 Hz, 1H), 4.71 (d, JZ6.8 Hz, 1H),
4.66 (d, JZ6.8 Hz, 1H), 4.57 (s, 2H), 3.74 (dd, JZ5.2,
2.2 Hz, 1H), 3.58–3.50 (m, 2H), 3.39 (s, 3H), 3.32 (s, 3H),
2.22–2.13 (m, 1H), 1.87–1.76 (m, 1H), 1.55–1.38 (m, 1H),
1.01 (d, JZ6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) d
203.4, 97.04, 96.4, 86.2, 65.3, 56.1, 55.3, 32.0, 31.5, 15.8;
ES HRMS m/z (MCOCNa)C calcd 259.1158, obsd
259.1172; [a]2D2ZC43.7 (c 0.75, CHCl3).
1
1460, 1384; H NMR (300 MHz, CDCl3) d 5.72–5.60 (m,
1H), 5.19–5.10 (m, 1H), 4.65 (d, JZ6.8 Hz, 1H), 4.40 (d,
JZ6.8 Hz, 1H), 3.71 (dd, JZ8.2, 8.2 Hz, 1H), 3.31 (s, 3H),
2.52–2.34 (m, 2H), 1.94–1.82 (m, 1H), 1.68 (dd, JZ1.5,
6.5 Hz, 3H), 1.00 (d, JZ6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 132.1, 128.1, 118.9, 93.0, 79.0, 55.6, 35.0, 20.7,
17.7, 15.9; ES HRMS m/z (MCNa)C calcd 206.1157, obsd
206.1151; [a]2D2ZC165.5 (c 0.87, CHCl3).
2.1.5. Alcohol 8. To a solution of 7 (0.350 g, 1.91 mmol) in
5 mL of CH2Cl2 was added DIBAL-H (1 M in hexane,
2.86 mL, 2.86 mmol) dropwise at K78 8C. The reaction
mixture was stirred at this temperature for 2 h before being
transferred via cannula into saturated Rochelle salt (potass-
ium sodium tartrate tetrahydrate) solution (5 mL). The
aqueous phase was extracted with CH2Cl2 (10 mL!2). The
combined organic phases were dried and freed of solvent
under vacuum to furnish the aldehyde.
2.1.8. Coupling of 10 to 11. To a solution of 11 (4.33 g,
14.4 mmol) in 10 mL of THF was added t-BuLi (1.42 M in
pentane, 10.15 mL, 14.4 mmol) dropwise at K78 8C. The
mixture was stirred at K78 8C for 1 h and transferred via
cannula into a solution of 10 (1.38 g, 6.27 mmol) in 15 mL
of THF at K78 8C. After being stirred for 30 min in the
cold, the reaction mixture was quenched with water and
extracted with EtOAc. The combined organic phases were
washed with saturated NaHCO3 solution and brine, dried,
and freed of solvent under vacuum. The residue was purified
by flash chromatography (silica gel, hexane–EtOAc/5:1) to
furnish 12 (1.69 g, 52%) as a colorless oil, which was
The unpurified aldehyde was dissolved in 10 mL of MeOH.
Sodium borohydride (0.088 g, 2.29 mmol) was added in one
portion at 0 8C. The reaction mixture was stirred in the cold
for 30 min. The solvent was removed and the residue was
dissolved in CH2Cl2. The combined organic phases were
washed with 1 M HCl solution, saturated NaHCO3 solution,
and brine, then dried and freed of solvent. The residue was
purified by flash chromatography (silica gel, hexane–
EtOAc/2:1) to give 8 (0.180 g, 61%) as a colorless oil; IR
(neat, cmK1) 3418, 1669, 1453; 1H NMR (300 MHz,
CDCl3) d 5.86–5.55 (m, 1H), 5.30–5.20 (m, 1H), 4.69 (d,
JZ6.7 Hz, 1H), 4.46 (d, JZ6.7 Hz, 1H), 3.75–3.56 (m, 3H),
3.34 (s, 3H), 2.36 (br s, 1H), 1.82–1.67 (m, 5H), 1.46–1.34
(m, 1H), 0.88 (d, JZ6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 130.7, 129.0, 93.2, 81.1, 60.9, 55.6, 35.9, 34.8,
17.8, 16.1; ES HRMS m/z (MCNa)C calcd 211.1305, obsd
211.1319; [a]2D2ZC145 (c 0.50, CHCl3).
immediately subjected to protection; IR (CH2Cl2, cmK1
)
1
3443, 1650, 1472; H NMR (300 MHz, C6D6) d 5.24–5.22
(m, 1H), 4.74–4.69 (m, 1H), 4.61 (dd, JZ6.2, 5.9 Hz, 1H),
4.56–4.49 (m, 3H), 4.48–4.35 (m, 2H), 4.23–4.15 (m, 2H),
3.65–3.51 (m, 2H), 3.22 and 3.21 (s, 3H), 3.17 and 3.08 (s,
3H), 2.33–2.31 (m, 1H), 2.14–1.96 (m, 2H), 1.55–1.28 (m,
2H), 1.50 and 1.47 (s, 3H), 1.34 and 1.33 (s, 3H), 0.98 (d,
JZ6.9 Hz, 3H), 0.95 and 0.90 (s, 3H), 0.07 (s, 3H); 13C
NMR (75 MHz, C6D6) d 163.4, 163.3, 109.4, 109.2, 102.4,
102.1, 100.6, 100.5, 100.4, 99.2, 98.7, 97.0, 89.7, 86.7, 86.6,
86.5, 74.4, 74.3, 74.1, 73.5, 69.0, 67.2, 66.8, 66.7, 66.4,
56.4, 56.1, 55.3, 33.3, 33.0, 32.8, 32.1, 27.3, 26.4, 26.3,
25.9, 25.6, 18.8, 18.7, 17.2, 16.9, K4.0, K4.1, K4.5, K4.7;
ES HRMS m/z (MCNa)C calcd 543.2965, obsd 543.2957.
2.1.6. MOM protection of 8. To a solution of 8 (0.060 g,
0.319 mmol) and diisopropylethylamine (0.139 mL,
0.797 mmol) in 2 mL of CH2Cl2 was added MOMCl
(0.048 mL, 0.637 mmol) dropwise at K78 8C. The reaction
mixture was stirred at rt overnight. Saturated NaHCO3
solution (30 mL) was added and the separated aqueous
phase was extracted with ether. The combined organic
phases were dried and freed of solvent. The residue was
purified by flash chromatography (silica gel, hexane–EtOAc
4.5:1) to afford 9 (0.074 g, quant.) as a pale yellow oil; IR
(CH2Cl2, cmK1) 1450, 1380; 1H NMR (300 MHz, CDCl3) d
5.67–5.55 (m, 1H), 5.30–5.20 (m, 1H), 4.69 (d, JZ6.8 Hz,
1H), 4.59 (d, JZ0.9 Hz, 1H), 4.46 (d, JZ6.7 Hz, 1H), 3.76–
3.72 (m, 1H), 3.62–3.52 (m 2H), 3.33 (s, 3H), 1.92–1.72 (m,
2H), 1.69 (dd, JZ6.4, 1.6 Hz, 3H), 1.39–1.23 (m, 1H), 0.88
(d, JZ6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 130.6,
128.9, 96.4, 93.2, 80.7, 66.0, 55.5, 55.2, 34.6, 32.7, 17.9,
15.4; ES HRMS m/z (MCNa)C calcd 255.1572, obsd
255.1574; [a]2D2ZC112 (c 0.68, CHCl3).
2.1.9. Dihydrofuran 13. To a solution of 12 (1.475 g,
2.83 mmol) and diisopropylethylamine (1.97 mL,
11.3 mmol) in 12 mL of CH2Cl2 was added SEMCl
(1.50 mL, 8.50 mmol) dropwise at 0 8C. The reaction
mixture was stirred at rt overnight, saturated NaHCO3
solution (30 mL) was added, and the separated aqueous
phase was extracted with EtOAc. The combined organic
layers were washed with saturated NaHCO3 solution and
brine, dried, and freed of solvent. The residue was purified
by flash chromatography (silica gel, hexane–EtOAc 15:1) to
afford 13 (1.565 g, 85%) as a pale yellow oil; IR (CH2Cl2,
cmK1) 1658, 1472; 1H NMR (300 MHz, CDCl3) d 5.10 (d,
JZ2.5 Hz, 1H), 4.86–4.82 (m, 1H), 4.73–4.50 (m, 6H),
4.43–4.38 (m, 1H), 4.34–4.23 (m, 2H), 4.10–4.04 (m, 1H),
3.92 (dd, JZ6.4, 8.5 Hz, 1H), 3.73–3.67 (m, 1H), 3.61–3.45
(m, 4H), 3.35 (d, JZ5.7 Hz, 3H), 3.32 (d, JZ1.4 Hz, 3H),
2.00–1.81 (m, 2H), 1.39 (s, 3H), 1.33 (s, 3H), 1.00 (dd, JZ
2.7, 6.7 Hz, 3H), 0.93–0.81 (m, 3H), 0.84 (s, 9H), 0.03 (s,
3H), 0.02 (d, JZ1.6 Hz, 3H), K0.01 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 159.2, 159.1, 108.7, 108.6, 104.1,
103.8, 98.4, 97.4, 96.4, 92.9, 92.8, 85.7, 85.3, 83.1, 82.5,
2.1.7. Aldehyde 10. Ozone was purged through a solution of
9 (0.063 g, 0.27 mmol) in 2 mL of CH2Cl2 at K78 8C until a

X. Peng et al. / Tetrahedron 60 (2004) 9589–9598
9595
73.6, 73.5, 73.3, 73.1, 72.9, 72.5, 66.41, 66.36, 66.3, 66.2,
65.7, 65.6, 56.2, 56.1, 55.1, 31.8, 31.6, 31.3, 31.2, 26.64,
26.56, 25.8, 25.5, 25.4, 18.1, 18.03, 17.98, 16.9, 16.7, K1.3,
K1.4, K4.5, K4.5, K5.0; ES HRMS m/z (MCNa)C calcd
673.3779, obsd 673.3770.
110.1, 109.9, 108.5, 98.3, 96.3, 92.7, 83.8, 73.0, 71.4, 68.3,
66.1, 65.4, 56.2, 55.2, 31.9, 31.0, 26.5, 26.0, 18.0, 16.8, 0.0
(3C); ES HRMS m/z (MCNa)C calcd 541.2803, obsd
541.2795; [a]2D2ZK33 (c 0.36, CHCl3).
(B) Iridium catalysis. [Ir(COD)(py)(PCy3)]PF6 (3.6 mg,
20 mol%) was added to a solution of 14 (0.012 g,
0.022 mmol) in 1.0 mL of CH2Cl2. The reaction mixture
was placed in a stainless steel reactor, purged three times
with H2 and stirred at 800 psi and rt for 17 h. The solvent
was removed under vacuum. The residue was purified by
flash chromatography (silica gel, 1% Et3N, hexane–EtOAc
5:1) to afford 16 (9.6 mg, 84%) as a colorless oil; IR
(CH2Cl2, cmK1) 1557, 1462; 1H NMR (300 MHz, CDCl3) d
6.31–6.27 (m, 2H), 5.05 (dd, JZ6.8, 6.8 Hz, 1H), 4.77–4.70
(m, 2H), 4.66–4.53 (m, 5H), 4.21 (dd, JZ6.4, 8.2 Hz, 1H),
4.01 (dd, JZ7.3, 8.3 Hz, 1H), 3.75–3.66 (m, 2H), 3.57–3.38
(m, 2H), 3.37 (s, 3H), 3.31 (s, 3H), 1.79–1.59 (m, 2H), 1.46
(s, 3H), 1.42 (s, 3H), 1.44–1.29 (m, 1H), 1.00 (d, JZ6.9 Hz,
3H), 0.93–0.83 (m, 2H), K0.01 (s, 9H); 13C NMR (75 MHz,
CDCl3) d 152.5, 152.3, 110.1, 109.9, 108.5, 98.3, 96.3, 92.7,
83.8, 73.0, 71.4, 68.3, 66.1, 65.4, 56.2, 55.2, 31.9, 31.0,
26.5, 26.0, 18.0, 16.8, 0.0 (3C); ES MS HR m/z (MCNa)C
calcd 541.2803, obsd 541.2795; [a]2D2ZK33 (c 0.36,
CHCl3).
2.1.10. Dihydrofuranyl alcohols 14 and 15. To a solution
of 13 (0.100 g, 0.15 mmol) in 3 mL of THF was added
TBAF (1.0 M in THF, 0.23 mL, 0.23 mmol) at 0 8C. The
reaction mixture was stirred at 0 8C for 1 h before being
diluted with 30 mL of ether. The organic phase was washed
with saturated NaHCO3 solution and brine, dried, and freed
of solvent. The residue was purified by flash chromatog-
raphy (silica gel, 1% Et3N, hexane–EtOAc 1:1) to furnish
the major isomer (assumed to be 14, 0.054 g, 66%) and
minor isomer (assumed to be 15, 0.010 g, 12%) both as
colorless oils.
For 14. IR (neat, cmK1) 3472, 1651, 1455; 1H NMR
(500 MHz, C6D6) d 5.18 (d, JZ2.7 Hz, 1H), 5.11 (d, JZ
6.4 Hz, 1H), 4.79 (d, JZ6.6 Hz, 2H), 4.62–4.58 (m, 4H),
4.44 (s, 2H), 4.25 (t, JZ6.2 Hz, 1H), 4.16–4.09 (m, 2H),
4.20 (dd, JZ2.2, 8.0 Hz, 1H), 3.82–3.77 (m, 1H), 3.58–3.47
(m, 3H), 3.29 (s, 3H), 3.19 (s, 3H), 2.13–2.09 (m, 1H), 1.98–
1.94 (m, 1H), 1.52–1.46 (m, 1H), 1.43 (s, 3H), 1.30 (s, 3H),
1.14 (d, JZ6.8 Hz, 3H), 1.00–0.95 (m, 2H), 0.53 (br s, 1H),
0.02 (s, 9H); 13C NMR (125 MHz, C6D6) d 159.4, 109.1,
105.6, 99.1, 96.4, 92.9, 86.9, 83.5, 75.6, 73.5, 73.1, 66.8,
65.5, 65.4, 56.0, 31.4, 30.4, 27.0, 25.6, 18.3, 17.0, K1.2
(3C); ES HRMS m/z (MCNa)C calcd 559.2909, obsd
559.2876; [a]2D2ZK48.9 (c 0.35, CHCl3).
2.1.12. Hydrogenation of 14 in the presence of Hu¨nig’s
base. [Rh(NBD)(DIPHOS-4)]BF4 (3.0 mg, 20 mol%) was
added to a solution of 14 (12 mg, 0.022 mmol) and i-Pr2NEt
(15 mL, 0.068 mmol) in 1.0 mL of CH2Cl2. The reaction
mixture was placed in a stainless steel reactor, purged three
times with H2, and stirred at 800 psi and rt for 17 h. The
solvent was removed under vacuum. The residue was
purified by flash chromatography (silica gel, 1% Et3N,
hexane–EtOAc 3:1) to afford 17 (5.5 mg, 25%) as a
colorless oil, 14 (5.4 mg, 46%) and 18 (0.4 mg, 3%).
For 15. IR (neat, cmK1) 3457, 1659, 1456; 1H NMR
(500 MHz, C6D6) d 5.25 (d, JZ2.6 Hz, 1H), 4.78 (d, JZ
6.8 Hz, 1H), 4.75 (d, JZ6.5 Hz, 2H), 4.69–4.66 (m, 2H),
4.56–4.52 (m, 4H), 4.24 (t, JZ6.6 Hz, 1H), 4.12–4.09 (m,
2H), 3.91–3.88 (m, 1H), 3.80–3.74 (m, 3H), 3.21 (s, 3H),
3.20 (s, 3H), 2.39–2.29 (m, 1H), 2.28–2.23 (m, 1H), 1.65–
1.59 (m, 1H), 1.43 (s, 3H), 1.30 (s, 3H), 1.11 (d, JZ6.9 Hz,
3H), 1.00–0.92 (m, 3H), 0.01 (s, 9H); 13C NMR (125 MHz,
C6D6) d 161.0, 109.2, 103.9, 97.8, 96.6, 93.7, 86.2, 82.9,
73.6, 73.5, 73.2, 67.0, 66.4, 66.0, 56.0, 55.0, 31.9, 31.6,
27.0, 25.6, 18.3, 17.1, K1.3 (3C); ES HRMS m/z
(MCNa)C calcd 559.2909, obsd 559.2930; [a]2D2ZC42.3
(c 0.31, CHCl3).
1
For 17. H NMR (300 MHz, C6D6) d 4.87 (d, JZ6.0 Hz,
1H), 4.78 (d, JZ6.9 Hz, 2H), 4.60 (q, JZ6.1 Hz, 1H), 4.56
(d, JZ6.5 Hz, 1H), 4.49 (d, JZ1.5 Hz, 2H), 4.24–4.18 (m,
2H), 4.14–4.10 (m, 1H), 4.05–4.00 (m, 2H), 3.75 (dd, JZ
16.8 Hz, JZ8.2 Hz, 1H), 3.64 (dd, JZ17.5 Hz, JZ8.7 Hz,
1H), 3.54–3.24 (m, 5H), 3.22 (s, 3H), 3.19 (s, 3H), 2.00–
1.77 (m, 5H), 1.46 (s, 3H), 1.36 (s, 3H), 1.04 (d, JZ6.8 Hz,
3H), 0.95–0.87 (m, 2H), 0.01 (s, 9H); 13C NMR (75 MHz,
C6D6) d 109.4, 97.3, 97.1, 85.2, 83.8, 79.8, 78.9, 74.3, 71.8,
68.4, 67.1, 66.3, 56.3, 55.3, 45.7, 35.9, 32.4, 31.8, 27.5,
26.1, 18.6, 17.7, K0.9 (3C).
2.1.11. Formation of furan 16. (A) Rhodium catalysis.
[Rh(NBD)(DIPHOS-4)]BF4 (14 mg, 20 mol%) was added
to a solution of 14 (0.054 g, 0.101 mmol) in 1.5 mL of
CH2Cl2. The reaction mixture was placed in a stainless steel
reactor, purged three times with H2, and stirred at 800 psi
and rt for 17 h. The spent catalysis was filtered and washed
with EtOAc. The solvent was removed under vacuum. The
residue was purified by flash column chromatography (silica
gel, 1% Et3N, hexane–EtOAc 5:1) to afford 16 (29 mg,
54%) as a colorless oil; IR (CH2Cl2, cmK1) 1557, 1462; 1H
NMR (300 MHz, CDCl3) d 6.31–6.27 (m, 2H), 5.05 (dd, JZ
6.8, 6.8 Hz, 1H), 4.77–4.70 (m, 2H), 4.66–4.53 (m, 5H),
4.21 (dd, JZ6.4, 8.2 Hz, 1H), 4.01 (dd, JZ7.3, 8.3 Hz, 1H),
3.75–3.66 (m, 2H), 3.57–3.38 (m, 2H), 3.37 (s, 3H), 3.31 (s,
3H), 1.79–1.59 (m, 2H), 1.46 (s, 3H), 1.42 (s, 3H), 1.44–
1.29 (m, 1H), 1.00 (d, JZ6.9 Hz, 3H), 0.93–0.83 (m, 2H),
K0.01 (s, 9H); 13C NMR (75 MHz, CDCl3) d 152.5, 152.3,
2.1.13. Formation of PMB ether 19. A suspension of 17
(16 mg, 0.030 mmol) and NaH (60% in mineral oil, 36 mg,
0.15 mmol) in 1 mL of DMF was stirred at rt for 1 h before
p-methoxybenzyl bromide (0.018 g, 0.089 mmol) was
added. The reaction mixture was stirred at rt for 4 h and
quenched with saturated NaHCO3 solution (3 mL). The
solution was extracted with ether/pet ether (1/1, 50 mL),
washed with brine, dried, and freed of solvent. The residue
was purified by flash chromatography (silica gel, hexane–
EtOAc 4:1) to furnish 19 (16 mg, 82%) as a pale yellowish
oil; 1H NMR (300 MHz, CDCl3) d 7.26–7.23 (m, 2H), 6.87–
6.84 (m, 2H), 4.83 (d, JZ6.9 Hz, 1H), 4.76 (d, JZ6.6 Hz,
1H), 4.71 (d, JZ6.9 Hz, 1H), 4.66 (d, JZ6.6 Hz, 1H), 4.61–
4.50 (m, 3H), 4.40–4.31 (m, 2H), 4.13–4.09 (m, 1H), 4.06–

9596
X. Peng et al. / Tetrahedron 60 (2004) 9589–9598
3.90 (m, 3H), 3.86–3.83 (m, 1H), 3.80 (s, 3H), 3.78–3.76
(m, 1H), 3.66–3.41 (m, 5H), 3.40 (s, 3H), 3.39 (s, 3H), 2.34–
2.26 (m, 1H), 2.17–2.06 (m, 1H), 1.98–1.85 (m, 2H), 1.30
(s, 3H), 1.37 (s, 3H), 0.97 (d, JZ6.8 Hz, 3H), 0.92–0.89 (m,
2H), 0.01 (s, 9H); 13C NMR (75 MHz, CDCl3) d 159.2,
130.6, 129.1 (2C), 113.8 (2C), 108.6, 98.5, 96.5, 96.4, 83.2,
83.0, 79.9, 78.6, 78.5, 73.9, 70.8, 67.0, 66.3, 65.8, 56.4,
55.4, 55.2, 33.6, 32.0, 31.9, 26.8, 25.8, 18.2, 16.7, K1.3
(3C).
0.093 mmol) in the same solvent (0.50 mL). The contents
of the vial were stirred for 10 min before a solution of
[Rh(NBD)(DIPHOS-4)]BF4 (13.5 mg, 20 mol%) in deoxy-
genated THF (1.5 mL) was quickly introduced. The vial was
placed in a stainless steel reactor, flushed with argon, and
pressurized to 800–900 psi of hydrogen. After 3 days of
stirring, the pressure was released and the reaction mixture
was subjected directly to chromatography on silica gel
(elution with 2:1 hexane/ethyl acetate) to afford 18 as a
colorless oil (34 mg, 68%) and recovered 14 (10 mg, 20%).
2.1.14. Hydrogenation of 15 in the presence of Hu¨nig’s
base. [Rh(NBD)(DIPHOS-4)]BF4 (4 mg, 20 mol%) was
added to a solution of 14 (15 mg, 0.028 mmol) and i-Pr2NEt
(12 mL, 0.084 mmol) in 1.5 mL of THF. The reaction
mixture was placed in a stainless steel reactor, purged three
times with H2 and stirred at 800 psi and rt for 18 h. The
solvent was removed under vacuum. The residue was
purified by flash chromatography (silica gel, 1% Et3N,
hexane–EtOAc 3:1) to afford 20 (7.5 mg, 50%) as a
colorless oil and 15 (3 mg, 20%).
1
For 18. IR (CH2Cl2, cmK1) 3450, 1370, 1249; H NMR
(500 MHz, CDCl3) d 4.87 (d, JZ7.0 Hz, 1H), 4.78 (d, JZ
7.0 Hz, 1H), 4.74 (d, JZ6.7 Hz, 1H), 4.64 (d, JZ6.7 Hz,
1H), 4.62–4.58 (m, 2H), 4.50 (m, 1H), 4.45–4.41 (m, 1H),
4.26–4.22 (m, 1H), 4.14–4.11 (m, 1H), 3.93 (dd, JZ5.0,
8.5 Hz, 1H), 3.84 (dd, JZ3.5, 8.5 Hz, 1H), 3.67–3.46 (m,
6H), 3.40 (s, 3H), 3.35 (s, 3H), 2.22 (br s, 1H), 2.09–2.04
(m, 2H), 1.97–1.94 (m, 1H), 1.87–1.83 (m, 1H), 1.45–1.35
(m, 1H), 1.41 (s, 3H), 1.35 (s, 3H), 1.02 (d, JZ6.8 Hz, 3H),
0.95–0.87 (m, 2H), 0.01 (s, 9H); 13C NMR (12 MHz,
CDCl3) d 109.4, 98.3, 96.6, 96.4, 83.9, 83.7, 80.1, 78.8,
74.2, 72.9, 68.1, 66.2, 66.0, 56.3, 55.3, 37.4, 31.8, 31.6,
27.0, 25.4, 18.3, 16.9, K1.3 (3C); ES MS HR m/z
(MCNa)C calcd 561.3071, obsd 561.3080; [a]2D2ZC14.5
(c 0.20, CHCl3).
1
For 20. H NMR (500 MHz, CDCl3) d 4.83 (d, JZ6.5 Hz,
1H), 4.81 (d, JZ6.5 Hz, 1H), 4.78 (d, JZ6.5 Hz, 1H), 4.62–
4.58 (m, 3H), 4.37–4.34 (m, 1H), 4.33–4.25 (m, 2H), 4.11–
4.08 (m, 1H), 3.98–3.95 (m, 1H), 3.81–3.75 (m, 1H), 3.65–
3.52 (m, 6H), 3.40 (s, 3H), 3.35 (s, 3H), 2.37–2.31 (m, 1H),
2.04–1.92 (m, 3H), 1.47–1.39 (m, 1H), 1.41 (s, 3H), 1.36 (s,
3H), 1.05 (d, JZ6.8 Hz, 3H), 0.95–0.87 (m, 2H), 0.02 (s,
9H); 13C NMR (125 MHz, CDCl3) d 109.4, 98.3, 96.6, 96.4,
83.9, 83.7, 80.1, 78.8, 74.2, 72.9, 68.1, 66.2, 66.0, 56.3,
55.3, 37.4, 31.8, 31.6, 27.0, 25.4, 18.3, 16.9, K1.3 (3C).
2.1.17. Formation of PMB ether 22. A suspension of 21
(0.007 g, 0.013 mmol) and NaH (60% in mineral oil,
0.010 g, 0.26 mmol) in 1 mL of DMF was stirred at rt for
1 h before p-methoxybenzyl bromide (0.013 g, 0.065 mmol)
was added. The reaction mixture was stirred at rt for 4 h and
quenched with saturated NaHCO3 solution (3 mL). The
solution was extracted with ether/petroleum ether (1/1,
50 mL), washed with brine, dried and freed of solvent. The
residue was purified by flash chromatography (silica gel,
hexane–EtOAc 4:1) to furnish 22 (0.008 g, 93%) as a
yellowish oil; IR (neat, cmK1) 1613, 1514, 1458; 1H NMR
(500 MHz, CDCl3) d 7.28–7.26 (m, 2H), 6.88–6.85 (m, 2H),
4.91 (d, JZ7.0 Hz, 1H), 4.76 (d, JZ7.0 Hz, 1H), 4.73 (d,
JZ6.8 Hz, 1H), 4.64 (d, JZ6.8 Hz, 1H), 4.60–4.55 (m, 3H),
4.48 (d, JZ11.5 Hz, 1H), 4.37–4.31 (m, 2H), 4.13 (t, JZ
5.4 Hz, 1H), 4.06 (dd, JZ6.3, 8.4 Hz, 1H), 3.96–3.91 (m,
2H), 3.80 (s, 3H), 3.67–3.50 (m, 5H), 3.43 (t, JZ5.4 Hz,
1H), 3.38 (s, 3H), 3.33 (s, 3H), 2.22 (dd, JZ5.9, 13.1 Hz,
1H), 2.99–1.94 (m, 1H), 1.89–1.82 (m, 2H), 1.44–1.35 (m,
1H), 1.39 (s, 3H), 1.37 (s, 3H), 1.00 (d, JZ6.8 Hz, 3H), 0.91
(dd, JZ7.6, 9.5 Hz, 2H), 0.01 (s, 9H); 13C NMR (125 MHz,
CDCl3) d 159.1, 130.6, 129.0 (2C), 113.7 (2C), 108.6, 98.3,
96.4, 96.2, 84.1, 83.2, 80.0, 78.9, 78.8, 73.9, 71.1, 67.2,
66.1, 65.9, 56.2, 55.3, 55.1, 34.5, 31.7, 31.5, 26.7, 25.7,
18.2, 16.7, K1.4 (3C); ES HRMS m/z (MCNa)C calcd
681.3641, obsd 681.3662; [a]2D2ZK11.6 (c 0.26, CHCl3).
2.1.15. Hydrogenation of 15 in the presence of potassium
hydride. To a slurry of potassium hydride (3.9 mg of 30%
in oil, 0.029 mmol) in deoxygenated THF (0.50 mL) was
added a solution of 15 (15 mg, 0.028 mmol) in the same
solvent (0.50 mL). The contents of the vial were stirred for
10 min before a solution of [Rh(NBD)(DIPHOS-4)]BF4
(4 mg, 20 mol%) in deoxygenated THF (0.5 mL) was
quickly introduced. The vial was placed in a stainless
steel reactor, flushed with argon, and pressurized to 800–
900 psi of hydrogen. After overnight stirring (17 h), the
pressure was released and the reaction mixture was
subjected directly to chromatography on silica gel (elution
with 2:1 hexanes–ethyl acetate) to afford 21 (8 mg, 53%),
starting material 15 (1.5 mg, 10%) and small amount of 20.
1
For 21. H NMR (300 MHz, C6D6) d 4.81 (d, JZ3.1 Hz,
1H), 4.80 (d, JZ6.6 Hz, 1H), 4.80–4.68 (m, 2H), 4.54 (d,
JZ6.6 Hz, 1H), 4.54–4.52 (m, 1H), 4.52 (d, JZ2.0 Hz, 1H),
4.40–4.31 (m, 2H), 4.20–4.15 (m, 1H), 4.08–4.02 (m, 2H),
3.85 (dd, JZ3.3, 8.2 Hz, 1H), 3.78–3.66 (m, 2H), 3.65–3.50
(m, 4H), 3.26 (s, 3H), 3.20 (s, 3H), 2.33–1.87 (m, 3H), 1.83
(br s, 1H), 1.54–1.31 (m, 1H), 1.38 (s, 3H), 1.24 (s, 3H),
1.03–0.93 (m, 5H), 0.01 (s, 9H); 13C NMR (75 MHz, C6D6)
d 109.3, 97.3, 97.2, 85.2, 83.8, 79.5, 78.9, 74.2, 71.8, 68.4,
67.1, 66.0, 56.3, 55.5, 45.7, 35.5, 32.2, 32.0, 27.5, 26.1,
18.4, 17.7, K0.9 (3C).
2.1.18. Selective deprotection of 22. A solution of 22
(0.008 g, 0.012 mmol) in 2 mL of AcOH–H2O (2:1) was
stirred at rt for 4.5 h. Saturated NaHCO3 solution (10 mL)
was carefully introduced, the solution was extracted with
ether (50 mL), and the combined organic phases were
washed with saturated NaHCO3 solution and brine, dried,
and freed of solvent. The residue was purified by flash
chromatography (silica gel, hexane–EtOAc 1:2) to afford
the diol (0.008 g, quant. yield) as a colorless oil; IR (neat,
2.1.16. Hydrogenation of 14 in the presence of sodium
hydride. To a slurry of sodium hydride (3.9 mg of 60% in
oil, 0.098 mmol, 1.05 equiv.) in deoxygenated THF
(0.50 mL) was added
a solution of 14 (50 mg,

X. Peng et al. / Tetrahedron 60 (2004) 9589–9598
9597
1
cmK1) 3321, 1516, 1249; H NMR (500 MHz, CDCl3) d
2.1.21. Hydroxy ketone 2. To a solution of 25 (0.058 g,
0.092 mmol) in 5.7 mL of CH2Cl2/H2O (18:1) was added
DDQ (0.031 g, 0.139 mmol). The reaction mixture was
stirred at rt for 1.5 h, quenched with saturated NaHCO3
solution, and extracted with EtOAc. The combined organic
phases were washed with brine, dried, and freed of solvent.
The residue was purified by flash chromatography (silica
gel, hexane–EtOAc 1.5:1) to furnish 2 (0.046 g, 97%) as a
7.26–7.24 (m, 2H), 6.90–6.87 (m, 2H), 4.90 (d, JZ6.9 Hz,
1H), 4.77 (d, JZ6.9 Hz, 1H), 4.74 (d, JZ6.7 Hz, 1H), 4.63
(dd, JZ6.6, 17.8 Hz, 1H), 4.59 (d, JZ6.5 Hz, 1H), 4.41–
4.36 (m, 2H), 4.30 (t, JZ3.9 Hz, 1H), 3.95–3.90 (m, 2H),
3.81 (s, 3H), 3.79–3.77 (m, 1H), 3.69–3.59 (m, 5H), 3.56–
3.51 (m, 1H), 3.46 (t, JZ5.3 Hz, 1H), 3.39 (s, 3H), 3.35 (s,
3H), 2.30–2.26 (m, 1H), 1.99–1.89 (m, 2H), 1.88–1.83 (m,
1H), 1.45–1.39 (m, 1H), 1.01 (d, JZ6.8 Hz, 3H), 0.94–0.91
(m, 2H), 0.02 (s, 9H); 13C NMR (125 MHz, CDCl3) d 159.9,
130.0, 129.7 (2C), 114.5 (2C), 98.7, 96.9, 96.6, 84.3, 81.9,
80.0, 79.7, 79.1, 71.4, 70.6, 66.5, 66.4, 65.3, 56.7, 55.7,
55.6, 34.2, 32.1, 31.9, 18.6, 17.1, K1.0 (3C); ES HRMS m/z
(MCNa)C calcd 641.3328, obsd 641.3356; [a]2D2ZK27.5
(c 0.12, CHCl3).
1
colorless oil; IR (CH2Cl2, cmK1) 3438, 1677, 1250; H
NMR (300 MHz, CDCl3) d 6.78 (dd, JZ4.8, 16.0 Hz, 1H),
6.47 (dd, JZ1.6, 16.0 Hz, 1H), 4.87 (d, JZ6.9 Hz, 1H),
4.79 (d, JZ6.9 Hz, 1H), 4.75 (d, JZ6.6 Hz, 1H), 4.64 (d,
JZ6.6 Hz, 1H), 4.62–4.57 (m, 3H), 4.55–4.48 (m, 1H),
4.45–4.43 (m, 1H), 3.69–3.49 (m, 6H), 3.40 (s, 3H), 3.35 (s,
3H), 2.28 (s, 3H), 2.27–2.11 (m, 2H), 2.02–1.97 (m, 1H),
1.87–1.75 (m, 2H), 1.47–1.25 (m, 1H), 1.04 (d, JZ6.8 Hz,
3H), 0.95–0.89 (m, 2H), 0.01 (s, 9H); 13C NMR (75 MHz,
CDCl3) d 198.3, 142.5, 131.9, 98.4, 96.6, 96.5, 84.1, 82.4,
80.4, 78.2, 74.2, 66.2, 66.1, 56.3, 55.3, 37.9, 31.7, 31.4,
27.6, 18.3, 17.0, K1.3 (3C); ES HRMS m/z (MCNa)C
calcd 529.2803, obsd 529.2791; [a]2D2ZK2.4 (c 0.17,
CHCl3).
2.1.19. Aldehyde 23. An excess amount (ca. 20 mg) of
silica gel-supported NaIO4 was added to a solution of the
above diol (0.008 g, 0.013 mmol) in 1 mL of CH2Cl2. The
suspension was stirred at rt for 1 h. The solid was removed
by filtration and the solvent was removed under vacuum to
furnish 23 (0.008 g, quant.) as a yellowish oil; IR (neat,
1
cmK1): 1732, 1613, 1586; H NMR (300 MHz, C6D6), d
9.80 (d, JZ1.9 Hz, 1H), 7.14–7.09 (m, 2H), 6.79–6.74 (m,
2H), 4.88 (s, 2H), 4.83–4.77 (m, 2H), 4.59 (d, JZ6.5 Hz,
1H), 4.51 (dd, JZ6.4, 9.0 Hz, 2H), 4.29–4.22 (m, 3H), 4.15
(d, JZ11.2 Hz, 1H), 3.79–3.67 (m, 2H), 3.64–3.50 (m, 3H),
3.29 (s, 3H), 3.23 (s, 3H), 3.20 (s, 3H), 2.24–2.19 (m, 1H),
2.13–1.99 (m, 2H), 1.90–1.82 (m, 1H), 1.56–1.48 (m, 1H),
1.15 (d, JZ6.8 Hz, 3H), 1.00–0.89 (m, 3H), 0.01 (s, 9H);
13C NMR (75 MHz, C6D6), d 201.3, 160.2, 130.3, 129.6
(2C), 114.5 (2C), 98.7, 97.0, 96.9, 86.8, 84.6, 82.1, 81.0,
80.7, 71.7, 66.4, 66.2, 56.2, 55.2, 55.0, 35.0, 32.3, 32.2,
18.6, 17.8, K1.0 (3C); ESHR MS m/z (MCNa)C calcd
609.3065, obsd 609.3022; [a]2D2ZK21.6 (c 0.19, CHCl3).
Acknowledgements
This research was financed in part by unrestricted grants
from the Eli Lilly Company and Aventis Pharmaceuticals,
Inc.
References and notes
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2.1.20. Chain extension of 23. Diethyl(2-oxopropyl)phos-
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1
1633, 1614; H NMR (300 MHz, CDCl3) d 7.21–7.17 (m,
2H), 6.88–6.78 (m, 3H), 6.25 (dd, JZ1.4, 16.1 Hz, 1H),
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80.4, 78.5, 71.4, 66.2, 66.1, 56.4, 55.4, 55.3, 34.6, 31.7,
31.5, 29.8, 27.2, 18.3, 17.1, K1.3 (3C); ES HRMS m/z
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