Synthesis of the C21-C34-segment of the aplyronines using the dimer of methylketene

Article abstract of DOI:10.1016/S0040-4020(02)00723-8

This report describes a convergent synthesis of the C₂₁-C₃₄-segment of aplyronine. The starting point for both halves of this segment was the dimer of methylketene, readily available in either enantiomeric form by asymmetric catalysis. Diastereoselective reduction and functional group manipulation afforded the partners for a Wittig coupling reaction. The appropriate choice of oxygen protecting groups allowed the Wittig reaction to proceed, and hydrogenation of the resulting olefin afforded the C₂₁-C₃₄-synthon.

Full text of DOI:10.1016/S0040-4020(02)00723-8

Tetrahedron 58 (2002) 7093–7100
Synthesis of the C21–C34-segment of the aplyronines using the
dimer of methylketene
*
Michael A. Calter and Xin Guo
Department of Chemistry, University of Rochester, Rochester, NY 14627-0216, USA
Received 12 April 2002; accepted 13 May 2002
Abstract—This report describes a convergent synthesis of the C21–C34-segment of aplyronine. The starting point for both halves of this
segment was the dimer of methylketene, readily available in either enantiomeric form by asymmetric catalysis. Diastereoselective reduction
and functional group manipulation afforded the partners for a Wittig coupling reaction. The appropriate choice of oxygen protecting groups
allowed the Wittig reaction to proceed, and hydrogenation of the resulting olefin afforded the C21–C34-synthon. q 2002 Elsevier Science
Ltd. All rights reserved.
1. Introduction
stereochemistry of the numerous chiral centers of the target.
We were interested in discovering a route to these molecules
that would instead take advantage of the efficiency of
asymmetric catalysis. We report here a synthesis of the
C21–C34 segment of aplyronine starting with the dimer of
methylketene, 1, readily available in high enantiomeric
excess using cinchona alkaloid catalysis (Scheme 1).5
The aplyronines are a stereochemically complex family of
polyketide natural products. The three members of this
family share a common carbon skeleton, including a 24-
membered macrolactone, but differ in the position of
various aminoester substitutents.1 The aplyronines exhibit
strong cytoxicity toward a variety of cancer lines.1 This
activity most likely stems from the ability of these
molecules to bind and depolymerize actin filaments
(Fig. 1).2
We based our route to the C21–C34 segment on the easy
availability of the syn,syn-polypropionate diastereomer
from 1 (Scheme 2).6 This diastereomer results from the
aldol reaction of the enolate produced by the opening of 1
with the lithium amide derived from N,O-
dimethylhydroxylamine.
The challenging structures and interesting biological
activity of these molecules have caused several groups to
pursue their synthesis. One total synthesis of a member of
the aplyronine family has appeared,3 along with several
subunit syntheses.4 These syntheses generally rely on chiral
pool synthons or chiral auxiliaries to control the absolute
We envisioned that the syn,syn-aldol reactions of the
enolates derived from 1 and its enantiomer could produce
the stereoarrays present in both halves of the target segment.
Scheme 1.
Figure 1. The aplyronines.
Keywords: methylketene dimer; aplyronine; Wittig reaction.
*
Corresponding author. Tel.: þ1-585-275-1626; fax: þ1-585-473-6889;
e-mail: calter@chem.rochester.edu
Scheme 2.
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00723-8

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Scheme 5. (a) (i) TESCl, imidazole, DMF; (ii) KBEt3H, Et2O, 2788C;
(iii) TBSCl, Et3N, DMF; (iv) DIBAL-H, THF, 2788C; (v) NaBH4, EtOH,
08C; (vi) I2, PPh3, imidazole, CH2Cl2, 08C; (vii) PPh3, i-Pr2NEt, MeCN,
848C.
hyde (Scheme 4). anti-Reduction of 2 to 3,7 followed by
acetonide formation, yielded 4.8 Reduction of 4 to the
aldehyde, followed by immediate further reduction,
afforded primary alcohol 5. We converted this alcohol to
the corresponding iodide 6 using a slight modification of the
conditions reported by Corey.9 We employed CH2Cl2 as a
solvent for this reaction rather than the Et2O/CH3CN
mixture initially reported, as reaction in the latter solvent
mixture led to significant decomposition. Finally, phos-
phonium salt formation yielded 7.10
Scheme 3.
anti-Selective reductions, followed by protection and
refunctionalization, could produce both halves in an
appropriate form for coupling (Scheme 3).
We also prepared an alternative left half synthon with the
C23 and C25-hydroxyls protected with different silyl groups
(Scheme 5, Eq. (1)). We prepared this compound from 2 by
silylation, Cram–Felkin–Nguyen selective reduction,11 and
silylation, followed by a similar sequence to that used to
prepare 7.
2. Results and discussion
2.1. Synthesis of the left half synthon
2.2. Synthesis of the right half synthon
As we were unsure as to the optimal protecting group
scheme for this portion of the molecule, we synthesized left
hand synthons with two different sets of protecting groups.
Synthesis of both versions of the left half began with aldol
adduct 2, available from 1 and b-benzyloxypropionalde-
The route to this synthon began with the aldol adduct
prepared by the reaction of the enolate derived from the
enantiomer of 1 with a-( p-methoxybenzyloxy) acet-
aldehyde (Scheme 6). Although this reaction proceeds in
good overall yield, it afforded the product as an inseparable
mixture of diastereomers in a 6:1 ratio. After silylation of
the mixture, we were still unable to separate the dia-
stereomers. Treatment of this mixture of diastereomers with
KBEt3H reduced the major diastereomer in high diastereo-
selectivity without effecting the minor compound, allowing
us to isolate 8 as a diastereomerically pure compound. We
next chose to protect the C31-hydroxyl as a benzyloxy-
methyl (BOM) ether to afford 9.12
We next homologated 9 to the fully elaborated right hand
synthon (Scheme 7). Reduction to the aldehyde, followed by
Wittig reaction,13 yielded monosubstituted olefin 10.
Hydroboration gave primary alcohol 11,14 which was
silylated to produce 12. Removal of the PMB group to
Scheme 4. (a) (i) LiN(OMe)Me; (ii) b-benyloxypropionaldehyde, THF,
2788C. (b) NaBH(OAc)3, HOAc. (c) Me2C(OMe)2, TsOH, Me2CO. (d) (i)
DIBAL-H, THF, 2788C; (ii) NaBH4, EtOH, 08C. (e) I2, PPh3, imidazole,
CH2Cl2, 08C. (f) PPh3, i-Pr2NEt, MeCN, 848C.
Scheme 6. (a) (i) LiN(OMe)Me; (ii) a-( p-methoxybenzyloxy)
acetaldehyde THF, 2788C. (b) (i) TBSOTf, 2,6-lutidine, CH2Cl2,
2788C; (ii) KBEt3H, Et2O, 2788C. (c) BOMCl, i-Pr2NEt, CH2Cl2.

M. A. Calter, X. Guo / Tetrahedron 58 (2002) 7093–7100
7095
Scheme 7. (a) (i) DIBAL-H, THF, 2788C; (ii) (Ph3PCH3)·Br, NaHMDS,
Et2O, 08C. (b) (i) 9-BBN, THF, 08C; (ii) H2O2, NaOH, THF, 08C.
(c) TBSOTf, 2,6-lutidine, CH2Cl2, 2788. (d) DDQ, CH2Cl2, H2O. (e) Dess–
Martin periodinane, pyridine, CH2Cl2.
give 13,15 followed by Dess–Martin oxidation,16 yielded
aldehyde 14.
Scheme 9. (a) LiHMDS, THF. (b) (i) 1 atm H2, 20% Pd(OH)2/C, EtOH; (ii)
55 psi H2, 5% Rh–Al2O3, EtOAc.
readily to form disubstituted olefin 15. Surprisingly, this
reaction afforded the Z-isomer in high selectivity. Com-
pletion of the side chain synthesis next required hydrogen-
ation of the disubstituted double bond. Hydrogenation at
atmospheric conditions with a variety of catalysts resulted in
the loss of the C21 and C31-hydroxyl protecting groups
without reduction of the double bond. As we needed to
refunctionalize the C21 and C31-hydroxyl groups prior to
coupling, the loss of these protecting groups was not
unwelcome. However, the resulting diol was somewhat
unstable toward desilylation, so we immediately submitted
the unpurified compound to hydrogenation at 55 psi in the
presence of rhodium on alumina to afford saturated diol 16.
The two step hydrogenation sequence was necessary, as
direct hydrogenation of 15 in the presence of Rh/Al2O3 led
to saturation of the aromatic ring of the BOM group.
2.3. Coupling of left and right half synthons
We initially attempted to couple the bis-silyl ether version
of the left hand synthon with aldehyde 14 (Scheme 8). This
reaction did not yield coupled product under conditions
reported for similar Wittig reactions.10,17 Preliminary
experiments revealed that both the bis-silyl ether and 14
would undergo Wittig reaction with unhindered substrates.
Apparently, the combination of the steric bulk of the silyl
protecting groups on both partners prevented the Wittig
reaction from proceeding.
We next pursued the coupling of 14 with the less hindered
ylide precursor 7 (Scheme 9). The reaction with the ylide
generated in the presence of a lithium counterion proceeded
We are currently exploring the refunctionalization of 16 into
a compound suitable for coupling to the remainder of the
target. We anticipate that selective transformation of the
primary hydroxyl at C21 into the nucleophilic component for
an olefination reaction, followed by formation of the C31-
acetate, will afford a coupling partner for the completion of
the aplyronine skeleton.
3. Conclusions
We have developed an efficient synthesis of the C21–C34-
segment of the aplyronines. This synthesis serves to further
demonstrate the utility of the methylketene dimer in
asymmetric polypropionate synthesis, and also illustrates
the effect of oxygen protecting groups on complex Wittig
reactions. Work on refunctionalization of 16 continues, as
does work on the remaining portions of the target.
Scheme 8. (a) LiHMDS, THF, 08C. (b) NaHMDS, THF, 08C.

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M. A. Calter, X. Guo / Tetrahedron 58 (2002) 7093–7100
1
4. Experimental
699 cm21; H NMR (400 MHz, CDCl3) d 7.34–7.25 (m,
5H), 4.50 (s, 2H), 4.18–4.12 (m, 2H), 3.70 (s, 3H), 3.70–
3.60 (m, 2H), 3.24–3.15 (br, 1H), 3.18 (s, 3H), 1.92–1.83
(m, 1H), 1.65–1.55 (m, 2H), 1.21 (d, 3H, J¼7.1 Hz), 0.93
(d, 3H, J¼7.0 Hz); 13C NMR (100 MHz, CDCl3) d 174.6,
138.1, 128.3, 127.6, 127.5, 77.7, 73.1, 70.3, 68.8, 61.5, 53.3,
40.3, 36.7, 34.0, 31.7, 15.3, 11.3. Anal. calcd for
C18H29NO5: C, 63.69; H, 8.61; N, 4.13. Found: C, 63.66;
H, 8.82; N, 3.94.
4.1. General methods and materials
For general experimental details, see previously cited
work.18
4.1.1. (2R,4R,5S )-7-Benzyloxy-5-hydroxy-2,4-dimethyl-
3-oxo-heptanoic acid methoxy-methyl-amide (2). To a
solution of 0.382 mL (0.317 g, 5.20 mmol) of N,O-
dimethylhydoxylamine in THF (10 mL) at 2788C was
added 2.08 mL (5.20 mmol) of 2.5 M n-BuLi in hexane.
After stirring at 2788C for 20 min, the mixture was rapidly
cannulated into a solution of 0.582 g (5.20 mmol) of 1 in
THF (50 mL) at 2788C. Immediately after the cannulation
was completed, a solution of 0.656 g (4.00 mmol) of
b-benzyloxypropionaldehyde in THF (6.0 mL) was added.
The reaction mixture was stirred at 2788C for 40 min. Then
a mixture of 110 mL of CH2Cl2 and 20 mL of aqueous
1.0 M HCl was added at 2788C and the mixture was
allowed to warm to rt over 30 min. The organic layer was
separated and the aqueous layer was washed with CH2Cl2
(2£20 mL). The combined organic layers were dried
4.1.3. [2R(4R,5R,6S )]-2-[6-(2-Benzyloxy-ethyl)-2,2,5-tri-
methyl-[1,3]dioxan-4-yl]-N-methoxy-N-methyl-propion-
amide (4). To a solution of 0.385 g (1.13 mmol) of 3 in
acetone (18 mL) at rt was added 18 mL of 2,2-dimethoxy
propane and 0.024 g (0.14 mmol) of p-toluenesulfonic acid.
After the mixture was stirred for 30 min at rt, saturated
aqueous NaHCO3 (10 mL) and CH2Cl2 (60 mL) were added
and the mixture was stirred for another 30 min. The aqueous
layer was then separated and washed CH2Cl2 (2£20 mL).
The combined organic layers were dried (Na2SO4) and
concentrated in vacuo to give crude product. Purification by
column chromatography afforded 0.366 g (86%) of 4 as a
colorless oil: [a ]2D3¼21.48 (c 1.19, CHCl3); IR (neat) 2982,
2937, 1661, 1455, 1418, 1381, 1227, 1177, 1135, 1099,
1
(Na2SO4) and concentrated in vacuo. H NMR analysis of
1
the unpurified reaction mixture showed a 15:1 ratio of the
major aldol diastereomer to the minor one. Purification by
flash column chromatography afforded 0.767 mg (57%) of 3
as a pale yellow oil: [a ]D23¼þ8.38 (c 0.99, CHCl3); IR (neat)
3472, 2939, 1711, 1660, 1454, 1383, 1101, 990, 752,
1044, 1028, 991, 964, 880, 821, 739, 699, 603 cm21; H
NMR (400 MHz, CDCl3) d 7.32–7.26 (m, 5H), 4.48 (s, 2H),
4.02 (dt, 1H, J¼10.0, 3.9 Hz), 3.69 (s, 3H), 3.58–3.51 (m,
2H), 3.18 (s, 3H), 3.12–3.05 (br, 1H), 1.73–1.60 (m, 3H),
1.28 (s, 3H), 1.21 (s, 3H), 1.07 (d, 3H, J¼7.0 Hz), 0.89 (d,
3H, J¼6.8 Hz); 13C NMR (100 MHz, CDCl3) d 175.5,
138.3, 128.2, 127.7, 127.5, 100.3, 75.7, 73.1, 66.9, 65.5,
61.2, 40.4, 37.3, 31.9, 30.8, 25.3, 23.3, 13.0, 12.5. Anal.
calcd for C21H33NO5: C, 66.46; H, 8.76; N, 3.69. Found: C,
66.22; H, 8.72; N, 3.74.
1
699 cm21; H NMR (400 MHz, CDCl3) d 7.34–7.26 (m,
5H), 4.45 (s, 2H), 4.10 (dt, 1H, J¼9.4, 3.5 Hz), 3.98 (q, H,
J¼7.2 Hz), 3.69–3.59 (m, 2H), 3.63 (s, 3H), 3.17 (s, 3H),
2.76 (qd, 1H, J¼7.1, 4.2 Hz), 1.81–1.64 (m, 2H), 1.31 (d,
3H, J¼7.1 Hz), 1.13 (d, 3H, J¼7.1 Hz); 13C NMR
(100 MHz, CDCl3) d 210.3, 171.6, 137.9, 128.3, 127.6,
127.5, 73.2, 70.5, 68.7, 61.2, 53.3, 49.2, 49.0, 33.4, 12.9,
11.2. Anal. calcd for C18H27NO5: C, 64.07; H, 8.07; N, 4.15.
Found: C, 63.80; H, 8.01; N, 4.08.
4.1.4. [2S(4S,5R,6S )]-2-[6-(2-Benzyloxy-ethyl)-2,2,5-tri-
methyl-[1,3]dioxan-4-yl]-propan-1-ol (5). To a solution
of 0.623 g (1.65 mmol) of 4 in THF (45 mL) at 2788C was
added 5.0 mL (5.0 mmol) of a 1.0 M solution of DIBAL-H
in hexane. After stirring for 20 h at 2788C, acetone
(7.5 mL) was added and the mixture was stirred for another
30 min at 2788C. The mixture was then poured into 450 mL
of 1:1 mixture of aqueous 0.5 M tartaric acid and hexane at
rt and stirred vigorously for 50 min. The aqueous layer was
separated from the clear organic layer and washed with
hexanes (2£100 mL). The organic layers were combined,
dried (Na2SO4) and concentrated in vacuo to give 0.514 g of
product as a colorless oil, which was used in the following
step without further purification. 1H NMR (400 MHz,
CDCl3) d 9.76 (d, 1H, J¼2.6 Hz), 7.39–7.29 (m, 5H),
4.52 (s, 2H), 4.09 (dt, 1H, J¼9.1, 4.5 Hz), 3.58–3.55 (m,
2H), 3.51–3.46 (m, 1H), 2.48 (qdd, 1H, J¼7.0, 5.5, 2.5 Hz),
1.93–1.88 (m, 1H), 1.73–1.67 (m, 2H), 1.34 (s, 3H), 1.30
(s, 3H), 1.16 (d, 3H, J¼7.1 Hz), 0.91 (d, 3H, J¼6.9 Hz); 13C
NMR (100 MHz, CDCl3) d 204.6, 138.2, 128.3, 127.7,
127.5, 100.7, 76.3, 73.1, 66.8, 65.6, 49.7, 37.5, 30.8, 24.7,
23.3, 12.2, 11.0.
4.1.2. (2R,3R,4R,5S )-7-Benzyloxy-3,5-dihydroxy-2,4-
dimethyl-heptanoic acid methoxy-methyl-amide (3). To
1.88 g (8.85 mmol) of NaBH(OAc)3 in a dry round bottom
flask at rt was added 45 mL of HOAc and the mixture was
stirred at rt for 2.5 h. This clear solution was then cannulated
into 0.595 g (1.77 mmol) of 2 in a dry flask at rt. The
mixture was stirred at rt for 45 min, 25 mL of aqueous 1.0 M
Kþ,Naþ-tartrate was added and the mixture was allowed to
stir for another 30 min at rt. Then, 45 mL of CH2Cl2 was
added while the reaction mixture was still being stirred and
the pH value of the aqueous layer was adjusted to
approximately 7 with saturated aqueous NaHCO3 solution.
The aqueous layer was separated and extracted with CH2Cl2
(2£30 mL). The organic layers were combined and washed
again with saturated aqueous NaHCO3. This aqueous
NaHCO3 layer was washed with CH2Cl2 (2£20 mL) and
the combined organic layers were dried (Na2SO4) and
concentrated in vacuo to give pale yellow oil. This oil was
azeotroped with MeOH (3£15 mL) and HOAc (3£2 drops).
1H NMR analysis of the unpurified reaction mixture showed
a single reduction product. Purification by column chroma-
tography afforded 0.412 g (69%) of 3 as a colorless oil:
[a ]2D3¼217.58 (c 1.47, CHCl3); IR (neat) 3417, 2969, 2938,
1659, 1634, 1495, 1462, 1455, 1391, 1101, 991, 739,
To the unpurified aldehyde from the previous step in EtOH
(45 mL) at 08C was added 0.610 mg (1.61 mmol) of NaBH4.
The reaction mixture was stirred for 40 min at 08C, and then
it was poured into a mixture of aqueous 1.0 M NH4Cl
(20 mL) and CH2Cl2 (40 mL) at rt and stirred for another

M. A. Calter, X. Guo / Tetrahedron 58 (2002) 7093–7100
7097
15 min. The aqueous layer was separated and washed
(2£40 mL). The organic layers were combined, dried
(Na2SO4), and concentrated in vacuo. Purification by flash
column chromatography afforded 0.468 g (88% from 4) of 5
as a colorless oil: [a ]D23¼þ0.38 (c 0.89, CHCl3); IR (neat)
3467, 2965, 2933, 2877, 1496, 1455, 1380, 1221, 1176,
1102, 1018, 992, 883, 750, 698 cm21; 1H NMR (400 MHz,
CDCl3) d 7.35–7.26 (m, 5H), 4.48 (s, 2H), 4.05 (dt, 1H,
J¼9.4, 4.3 Hz), 3.76–3.71 (m, 1H), 3.57–3.51 (m, 3H),
3.25 (dd, 1H, J¼7.3, 6.0 Hz), 1.79–1.62 (m, 4H), 1.32 (s,
3H), 1.28 (s, 3H), 0.98 (d, 3H, J¼7.4 Hz), 0.84 (d, 3H,
J¼6.8 Hz); 13C NMR (100 MHz, CDCl3) d 138.2, 128.7,
127.7, 127.5, 100.6, 80.7, 73.1, 66.8, 66.7, 65.8, 38.8, 38.1,
30.8, 25.2, 23.4, 13.9, 12.5. Anal. calcd for C19H30O4: C,
70.77; H, 9.38. Found: C, 70.55; H, 9.39.
16.7, 13.0. Anal. calcd for C37H44IO3P: C, 63.98; H, 6.38.
Found: C, 63.81; H, 6.41.
4.1.7. (2S,3S,4R,5S )-5-(tert-Butyl-dimethyl-silanyloxy)-
3-hydroxy-6-(4-methoxy-benzyloxy)-2,4-dimethyl-hexa-
noic acid methoxy-methyl-amide (8). To a solution of
0.257 mL (0.214 g, 3.50 mmol) of N,O-dimethylhydroxyl-
amine in hexane (11 mL) at 2788C was added 1.40 mL
(3.50 mmol) of 2.5 M n-BuLi in hexane. After stirring at
2788C for 20 min, the resulting slurry was rapidly
cannulated into a solution of 0.392 g (3.50 mmol) of ent-1
in CH2Cl2 (35 mL) at 2788C. Immediately after the
cannulation was completed, a solution of 0.360 mg
(2.00 mmol) of a-( p-methoxybenzyloxy)acetaldehyde in
CH2Cl2 (3 mL) at 2788C was cannulated into the solution
from above and the mixture was stirred at 2788C for
40 min. Then pH 7 buffer solution (20 mL of a 1:1 mixture
of concentrated pH 7 buffer and H2O) was added at 2788C
and the mixture was allowed to warm to rt over 30 min. The
organic layer was separated and the aqueous layer was
washed with CH2Cl2 (2£10 mL). The combined organic
layers were dried (Na2SO4) and concentrated in vacuo.
Purification by flash column chromatography afforded
0.538 g (76%) of an inseparable mixture of the two syn-
aldol diastereomers. Major diastereomer: 1H NMR
(400 MHz, CDCl3) d 7.22 (d, 2H, J¼8.6 Hz), 6.86 (d, 2H,
J¼8.6 Hz), 4.46 (d, 1H, J¼11.4 Hz), 4.41 (d, 1H,
J¼11.4 Hz), 4.09 (dt, 1H, J¼6.4, 5.0 Hz), 3.96 (q, 1H,
J¼7.2 Hz), 3.79 (s, 3H), 3.65 (s, 3H), 3.46–3.36 (m, 2H),
3.17 (s, 3H), 2.89 (qd, 1H, J¼7.2, 5.0 Hz), 1.31 (d, 3H,
J¼7.1 Hz), 1.13 (d, 3H, J¼7.2 Hz).
4.1.5. [4S,5R,6R(1R )]-4-(2-Benzyloxy-ethyl)-6-(2-iodo-1-
methyl-ethyl)-2,2,5-trimethyl-[1,3]dioxane (6). To a sol-
ution of 0.184 g (0.572 mmol) of 5 in CH2Cl2 (6 mL) at 08C
was added 0.117 g (1.72 mmol) of imidazole and 0.300 mg
(1.14 mmol) of triphenylphosphine. After these two com-
pounds had completely dissolved, 0.291 g (1.14 mmol) of
iodine was added and the reaction mixture was stirred for
30 min at 08C. The mixture was then warmed to rt and
stirred for 4 h. Aqueous 0.1 M Na2S2O3 (10 mL) and
CH2Cl2 (6 mL) were added and the mixture was stirred
for another 10 min at rt. The organic layer was separated,
washed with saturated aqueous NaHCO3, dried (Na2SO4)
and concentrated in vacuo. Purification by column chroma-
tography afforded 0.241 g (98%) of 6 as a pale yellow oil:
[a]2D3¼215.18 (c 0.91, CHCl3); IR (neat) 3029, 2982, 2933,
2876, 2360, 2341, 1496, 1455, 1380, 1298, 1226, 1176,
1
1132, 1097, 1050, 1016, 991, 736, 698 cm21; H NMR
To a solution of 0.538 g (1.52 mmol) of the mixture of the
aldol diastereomers from the previous reaction in CH2Cl2
(15 mL) at 2788C was added 0.36 mL (0.33 g, 3.1 mmol) of
2,6-lutidine and 0.52 mL (0.60 g, 2.3 mmol) of TBSOTf.
The mixture was stirred for 30 min and then was quenched
at 2788C by the addition of pH 7 buffer solution (10 mL of a
1:1 mixture of concentrated pH 7 buffer and H2O). The
mixture was allowed to warm to rt over 30 min and the
organic layer was separated. The aqueous layer was washed
with CH2Cl2 (2£9 mL) and the combined organic layers
were dried (Na2SO4) and concentrated in vacuo. Purification
by flash column chromatography afforded 0.483 g (68%) of
the silylated aldol products as an inseparable, 6:1 mixture of
diastereomers. Major diastereomer: 1H NMR (400 MHz,
CDCl3) d 7.21 (d, 2H, J¼8.6 Hz), 6.84 (d, 2H, J¼8.6 Hz),
4.41 (d, 1H, J¼11.8 Hz), 4.36 (d, 1H, J¼11.8 Hz), 4.11 (q,
1H, J¼5.6 Hz), 4.02–3.95 (m, 1H), 3.78 (s, 3H), 3.60 (s,
3H), 3.37–3.28 (m, 2H), 3.14 (s, 3H), 3.01–2.93 (m, 1H),
1.32 (d, 3H, J¼7.1 Hz), 1.11 (d, 3H, J¼7.2 Hz), 0.84 (s,
9H), 0.03 (s, 3H), 0.01 (s, 3H).
(400 MHz, CDCl3) d 7.33–7.26 (m, 5H), 4.47 (s, 2H), 3.99
(dt, 1H, J¼9.8, 3.9 Hz), 3.53–3.51 (m, 2H), 3.38–3.29 (m,
2H), 3.05 (t, 1H, J¼7.2 Hz), 1.73–1.58 (m, 3H), 1.50–1.42
(m, 1H), 1.32 (s, 3H), 1.25 (s, 3H), 0.99 (d, 3H, J¼6.7 Hz),
0.86 (d, 3H, J¼6.8 Hz); 13C NMR (100 MHz, CDCl3) d
138.3, 128.3, 127.7, 127.5, 100.4, 77.4, 73.1, 66.9, 65.6,
39.3, 37.5, 30.8, 25.2, 23.7, 16.8, 15.0, 12.8. Anal. calcd for
C19H29IO3: C, 52.78; H, 6.76. Found: C, 53.07; H, 6.76.
4.1.6. {[2R(4R,5R,6S )]-2-[6-(2-Benzyloxy-ethyl)-2,2,5-
trimethyl-[1,3]dioxan-4-yl]-propyl}-triphenyl-phos-
phonium iodide (7). To a solution of 0.223 g (0.515 mmol)
of 6 in MeCN (15 mL) at rt was added 0.27 mL (0.20 mg,
1.6 mmol) of i-Pr2NEt and 2.04 g (7.79 mmol) of tri-
phenylphosphine. The mixture was heated to 848C and
allowed to reflux for 24 h. After cooling to rt, the solvents
were removed in vacuo. The residue was purified by flash
chromatography to give 0.358 g (100%) of 7 as a pale
yellow foam: [a ]2D3¼þ33.08 (c 0.34, CHCl3); IR (neat)
2919, 1587, 1485, 1455, 1438, 1382, 1231, 1176, 1112, 997,
1
750, 722, 691 cm21; H NMR (400 MHz, CDCl3) d 7.92–
To a solution of 2.1 mL (2.1 mmol) of 1.0 M KBEt3H in
Et2O (9 mL) at 2788C was added a solution of 0.483 g
(1.03 mmol) of the mixture of silylated aldol products from
above in Et2O (4 mL) via a syringe pump over 20 min. After
30 min, pH 7 buffer solution (10 mL) was added at 2788C.
Then the mixture was warmed to rt over 30 min and the
organic layer was separated. The aqueous layer was washed
twice with Et2O (2£8 mL) and the combined organic layers
7.65 (m, 15H), 7.32–7.29 (m, 5H), 4.48 (d, 1H, J¼11.8 Hz),
4.45 (d, 1H, J¼11.8 Hz), 3.98 (dt, 1H, J¼10.2, 3.4 Hz),
3.77–3.50 (m, 4H), 3.33 (dd, 1H, J¼8.9, 6.4 Hz), 2.08–1.94
(m, 1H), 1.69–1.48 (m, 3H), 1.40 (s, 3H), 1.31 (s, 3H), 0.85
(d, 3H, J¼6.8 Hz), 0.73 (d, 3H, J¼6.8 Hz); 13C NMR
(100 MHz, CDCl3) d 138.3, 135.0, 134.9, 133.9, 133.8,
132.0, 131.9, 131.8, 131.8, 130.4, 130.2, 128.4, 128.3,
128.2, 127.7, 127.5, 118.9, 118.0, 100.8, 78.5, 78.4, 73.1,
66.6, 65.3, 38.5, 34.5, 34.5, 30.7, 25.5, 25.4, 24.9, 24.0,
1
were dried (Na2SO4) and concentrated in vacuo. H NMR
analysis of the unpurified reaction mixture indicated the

7098
M. A. Calter, X. Guo / Tetrahedron 58 (2002) 7093–7100
presence of only a single reduction product and unreacted
minor silylated aldol adduct. Purification by flash column
chromatography afforded 0.271 g (29% total from ent-1) of
8 as a single diastereomer (colorless oil): [a ]2D3¼219.98 (c
0.51, CHCl3); IR (neat) 3393, 2929, 2856, 1614, 1586,
1513, 1462, 1417, 1387, 1302, 1251, 1175, 1147, 1079,
To a suspension of 0.230 g (0.645 mmol) of CH3PPh3Br in
Et2O (6.5 mL) at 08C was added 0.56 mL (0.56 mmol) of a
1.0 M solution of NaHMDS in THF. The resulting yellow
suspension was stirred for 4 h at 08C, and then a solution of
the unpurified aldehyde from the previous reaction in Et2O
(2.2 mL) was added dropwise and the mixture was stirred
for another 25 min at 08C. Then H2O (10 mL) was added
and the mixture was warmed to rt for 10 min. The organic
layer was separated and the aqueous layer was washed with
Et2O (2£10 mL). The combined organic layers were dried
(Na2SO4) and concentrated in vacuo. Purification by flash
column chromatography afforded 0.106 g (93% from 9) of
10 as a colorless oil: [a ]2D3¼þ3.358 (c 0.51, CHCl3); IR
(neat) 3068, 2929, 2856, 1613, 1586, 1514, 1462, 1360,
1302, 1249, 1172, 1147, 1039, 913, 836, 777, 735,
1
1041, 993, 952, 838, 778, 739, 705, 673 cm21; H NMR
(400 MHz, CDCl3) d 7.23 (d, 2H, J¼8.6 Hz), 6.85 (d, 2H,
J¼8.6 Hz), 4.45 (d, 1H, J¼11.6 Hz), 4.42 (td, 1H, J¼6.4,
1.5 Hz), 4.35 (d, 1H, J¼11.6 Hz), 3.78 (s, 3H), 3.70 (s, 3H),
3.38–3.32 (m, 3H), 3.16 (s, 3H), 3.20–3.13 (br, 1H), 1.70–
1.62 (m, 1H), 1.31 (d, 3H, J¼7.1 Hz), 0.84 (s, 9H), 0.77 (d,
3H, J¼6.9 Hz), 0.06 (s, 3H), 0.02 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 158.9, 130.4, 129.1, 113.5, 75.7, 72.9,
72.5, 69.6, 61.4, 55.1, 40.2, 35.6, 31.6, 25.8, 18.1, 16.0, 9.8,
24.3, 25.2. Anal. calcd for C24H43NO6Si: C, 61.37; H,
9.23; N, 2.98. Found: C, 61.55; H, 9.41; N, 2.87.
1
697 cm21; H NMR (400 MHz, CDCl3) d 7.32–7.25 (m,
5H), 7.22 (d, 2H, J¼8.6 Hz), 6.84 (d, 2H, J¼8.7 Hz), 5.93–
5.84 (m, 1H), 5.02 (br, 1H), 4.99 (br, 1H), 4.82 (d, 1H,
J¼6.7 Hz), 4.80 (d, 1H, J¼6.7 Hz), 4.69 (d, 1H,
J¼11.9 Hz), 4.58 (d, 1H, J¼11.9 Hz), 4.44 (d, 1H,
J¼11.6 Hz), 4.35 (d, 1H, J¼11.6 Hz), 4.16 (td, 1H,
J¼5.8, 2.0 Hz), 3.78 (s, 3H), 3.40–3.30 (m, 3H), 2.53–
2.45 (m, 1H), 1.80–1.73 (m, 1H), 1.10 (d, 3H, J¼7.2 Hz),
0.84 (s, 9H), 0.77 (d, 3H, J¼7.2 Hz), 0.01 (s, 3H), 20.02 (s,
3H); 13C NMR (100 MHz, CDCl3) d 158.9, 140.2, 138.0,
130.3, 129.1, 128.2, 127.6, 127.4, 114.3, 113.5, 96.7, 85.7,
73.6, 72.5, 70.7, 69.8, 55.1, 39.8, 39.6, 25.9, 18.3, 17.9,
10.0, 23.8, 25.0. Anal. calcd for C31H48O5Si: C, 70.41; H,
9.15. Found: C, 70.55; H, 9.27.
4.1.8. (2S,3S,4R,5S )-3-Benzyloxymethoxy-5-(tert-butyl-
dimethyl-silanyloxy)-6-(4-methoxy-benzyloxy)-2,4-
dimethyl-hexanoic acid methoxy-methyl-amide (9). To a
solution of 0.166 g (0.354 mmol) of 8 in CH2Cl2 (3.5 mL) at
rt was added 0.68 mL (0.50 g, 3.9 mmol) of i-Pr2NEt and
0.53 mL (0.55 g, 3.5 mmol) of BOMCl. The mixture was
stirred for eight days, and then quenched by the addition of
aqueous 1.0 M HCl (5 mL), H2O (2 mL) and CH2Cl2
(4 mL) at rt. The mixture was stirred for 10 min and the
organic layer was separated. The aqueous layer was washed
twice with CH2Cl2 (2£10 mL) and the combined organic
layers were washed with H2O, dried (Na2SO4) and
concentrated in vacuo. Purification by flash column
chromatography afforded 0.153 g (74%) of 9 as a colorless
oil: [a ]2D3¼þ15.78 (c 0.62, CHCl3); IR (neat) 2930, 1660,
1613, 1514, 1463, 1386, 1302, 1249, 1036, 836, 776,
4.1.10. (3R,4R,5R,6S )-4-Benzyloxymethoxy-6-(tert-
butyl-dimethyl-silanyloxy)-7-(4-methoxy-benzyloxy)-
3,5-dimethyl-heptan-1-ol (11). To a solution of 119 mg
(0.225 mmol) of 10 in THF (4.5 mL) at rt was added 1.2 mL
(0.58 mmol) of 0.5 M solution of 9-BBN in THF. After
stirring for 7 h, the mixture was cooled to 08C and 0.58 mL
(0.58 mmol) of aqueous 1.0 M NaOH was added, followed
by 0.197 g (1.74 mmol) of a 30% aqueous solution of H2O2.
The mixture was then stirred for 1 h at 08C and Et2O
(120 mL) was added. The mixture was washed with H2O,
then brine and dried (Na2SO4) and concentrated in vacuo.
Purification by flash column chromatography afforded
0.121 g (98%) of 11 as a colorless oil: [a]2D3¼þ10.08 (c
0.51, CHCl3); IR (neat) 3426, 2929, 1628, 1586, 1514,
1462, 1360, 1302, 1249, 1173, 1039, 836, 777, 736,
1
698 cm21; H NMR (400 MHz, CDCl3) d 7.30–7.29 (m,
5H), 7.23 (d, 2H, J¼8.6 Hz), 6.83 (d, 2H, J¼8.6 Hz), 4.77
(d, 1H, J¼6.6 Hz), 4.72 (d, 1H, J¼6.6 Hz), 4.54 (s, 2H),
4.44 (d, 1H, J¼11.6 Hz), 4.38 (d, 1H, J¼11.6 Hz), 4.00 (dt,
1H, J¼5.4, 4.7 Hz), 3.83 (dd, 1H, J¼7.9, 4.4 Hz), 3.79 (s,
3H), 3.63 (s, 3H), 3.50–3.42 (m, 3H), 3.14 (s, 3H), 2.07–
1.99 (m, 1H), 1.10 (d, 3H, J¼6.9 Hz), 0.93 (d, 3H,
J¼7.1 Hz), 0.85 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 176.0, 158.9, 138.0, 130.4,
129.1, 128.2, 127.6, 127.3, 113.5, 96.4, 83.4, 73.2, 72.7,
72.3, 69.9, 61.1, 55.1, 38.8, 38.1, 32.0, 25.8, 18.1, 13.5,
12.4, 24.1, 24.8. Anal. calcd for C32H51NO7Si: C, 65.16;
H, 8.71; N, 2.37. Found: C, 65.33; H, 8.87; N, 2.14.
1
698 cm21; H NMR (400 MHz, CDCl3) d 7.32–7.31 (m,
5H), 7.22 (d, 2H, J¼8.7 Hz), 6.84 (d, 2H, J¼8.6 Hz), 4.82
(br, 2H), 4.67 (d, 1H, J¼11.9 Hz), 4.59 (d, 1H, J¼11.9 Hz),
4.44 (d, 1H, J¼11.6 Hz), 4.35 (d, 1H, J¼11.5 Hz), 4.17 (td,
1H, J¼5.8, 1.5 Hz), 3.78 (s, 3H), 3.75–3.69 (m, 1H), 3.60–
3.54 (m, 1H), 3.40–3.31 (m, 3H), 1.97–1.84 (m, 2H), 1.68–
1.53 (m, 2H), 1.03 (d, 3H, J¼7.2 Hz), 0.83 (s, 9H), 0.77 (d,
3H, J¼6.8 Hz), 0.00 (s, 3H), 20.03 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 158.9, 137.7, 130.3, 129.1, 128.2,
127.7, 127.4, 113.5, 96.9, 86.7, 73.6, 72.6, 70.5, 70.0, 60.1,
55.1, 39.1, 33.1, 31.5, 25.9, 18.2, 17.3, 10.0, 23.8, 25.0.
Anal. calcd for C31H50O6Si: C, 68.09; H, 9.22. Found: C,
68.37; H, 9.28.
4.1.9. [(1S,2R,3R,4R )-3-Benzyloxymethoxy-1-(4-meth-
oxy-benzyloxymethyl)-2,4-dimethyl-hex-5-enyloxy]-tert-
butyl-dimethyl-silane (10). To a solution of 0.127 g
(0.215 mmol) of 9 in THF (2.2 mL) at 2788C was added
0.75 mL (0.75 mmol) of 1.0 M solution of DIBAL-H in
hexane. The mixture was stirred for 30 min at 2788C and
then quenched by addition of acetone (1.8 mL). The mixture
was stirred at 2788C for another 30 min and then poured
into 60 mL of a 1:1 mixture of aqueous 0.5 M tartaric acid
and hexane at rt. This mixture was stirred vigorously for
45 min and the organic layer was separated. The aqueous
layer was washed with hexane (2£15 mL) and the combined
organic layers were dried (Na2SO4) and concentrated in
vacuo. The unpurified reaction mixture was used directly in
the next step.
4.1.11. 1-[(2S,3R,4R,5R )-4-Benzyloxymethoxy-2,7-bis-
(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-heptyloxy-
methyl]-4-methoxy-benzene (12). To a solution of 0.110 g
(0.201 mmol) of 11 in CH2Cl2 (5 mL) at 2788C was added

M. A. Calter, X. Guo / Tetrahedron 58 (2002) 7093–7100
7099
0.05 mL (0.04 g, 0.4 mmol) of 2,6-lutidine and 0.07 mL
(0.08 g, 0.3 mmol) of TBSOTf. The mixture was stirred for
1 h at 2788C and then brine (10 mL) was added. The
mixture was warmed to rt over 30 min and the organic layer
was separated. The aqueous layer was washed with CH2Cl2
(2£10 mL) and the combined organic layers were dried
(Na2SO4) and concentrated in vacuo. Purification by flash
column chromatography afforded 0.133 g (100%) of 12 as a
colorless oil: [a ]2D3¼þ5.908 (c 0.58, CHCl3); IR (neat)
2955, 2856, 1613, 1514, 1463, 1387, 1360, 1302, 1250,
1099, 1041, 835, 776, 734, 697 cm21; 1H NMR (400 MHz,
CDCl3) d 7.32–7.28 (m, 5H), 7.22 (d, 2H, J¼8.6 Hz), 6.84
(d, 2H, J¼8.6 Hz), 4.81 (d, 1H, J¼6.6 Hz), 4.78 (d, 1H,
J¼6.5 Hz), 4.65 (d, 1H, J¼11.9 Hz), 4.58 (d, 1H,
J¼11.9 Hz), 4.45 (d, 1H, J¼11.6 Hz), 4.35 (d, 1H,
J¼11.6 Hz), 4.18 (td, 1H, J¼5.9, 1.7 Hz), 3.78 (s, 3H),
3.71–3.66 (m, 1H), 3.60–3.54 (m, 1H), 3.39–3.31 (m, 3H),
1.88–1.67 (m, 3H), 1.34–1.23 (m, 1H), 0.99 (d, 3H,
J¼6.8 Hz), 0.87 (s, 9H), 0.83 (s, 9H), 0.77 (d, 3H,
J¼7.2 Hz), 0.02 (s, 6H), 0.01 (s, 3H), 20.03 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 158.9, 138.0, 130.4, 129.1,
128.2, 127.6, 127.3, 113.5, 96.9, 87.1, 73.6, 72.5, 70.6, 69.7,
61.2, 55.1, 39.0, 33.1, 30.8, 25.9, 25.8, 18.2, 18.1, 17.5, 9.8,
23.9, 25.0, 25.4, 25.5. Anal. calcd for C37H64O6Si2: C,
67.22; H, 9.76. Found: C, 67.39; H, 9.77.
layer was washed with Et2O (2£35 mL). The combined
organic layers were dried (Na2SO4) and the solvents were
removed in vacuo. Purification by flash column chromato-
graphy afforded 0.0963 g (97%) of 14 as a colorless oil: 1H
NMR (400 MHz, CDCl3) d 9.56 (d, 1H, J¼1.1 Hz), 7.50–
7.24 (m, 5H), 4.76 (d, 1H, J¼6.8 Hz), 7.73 (d, 1H,
J¼6.7 Hz), 4.62 (d, 1H, J¼11.8 Hz), 4.58 (d, 1H,
J¼11.8 Hz), 4.31 (dd, 1H, J¼2.7, 1.2 Hz), 3.71–3.66 (m,
1H), 3.60–3.54 (m, 1H), 3.31 (dd, 1H, J¼8.6, 2.6 Hz),
2.24–2.16 (m, 1H), 2.00–1.91 (m, 1H), 1.77–1.68 (m, 1H),
1.34–1.26 (m, 1H), 1.00 (d, 3H, J¼6.8 Hz), 0.89 (s, 9H),
0.86 (s, 9H), 0.83 (d, 3H, J¼6.8 Hz), 0.02 (s, 6H), 0.00 (s,
3H), 20.01 (s, 3H). This aldehyde was then azeotroped
three times with toluene, dried in vacuo for 3 h and used
immediately in the coupling reaction.
4.1.14. [4S,5R,6S(1S,2Z,4R,5R,6R,7R )]-4-(2-Benzyloxy-
ethyl)-6-[6-benzyloxymethoxy-4,9-bis-(tert-butyl-
dimethyl-silanyloxy)-1,5,7-trimethyl-non-2-enyl]-2,2,5-
trimethyl-[1,3]dioxane (15). To a solution of 0.53 mL
(0.41 g, 2.5 mmol) of hexamethyldisilazane in THF
(1.5 mL) at 08C was added 1.0 mL (2.5 mmol) of a 2.5 M
solution of n-BuLi in hexane. This LiHMDS solution was
stirred at 08C for 15 min and used directly in the next
reaction. Directly prior to reaction, 0.225 g (0.324 mmol) of
7 was azeotroped with toluene (3£5 mL). To this compound
in THF (5.5 mL) at 08C was added 0.41 mL (0.35 mmol) of
the LiHMDS solution prepared above. The dark orange
mixture was warmed to rt and stirred 40 min. At this time, a
solution of 0.0963 g (0.179 mmol) of 14 in THF (1.0 mL)
was added. The mixture was stirred for 2 h at rt. And then
aqueous 1.0 M NH4Cl (8 mL) was added and the mixture
was extracted with Et2O (40 mL). The separated aqueous
layer was washed with Et2O (2£10 mL) and the combined
organic layers were dried (Na2SO4) and concentrated in
vacuo. Purification by flash column chromatography
afforded 0.120 g (81%) of 15 as a pale yellow oil:
[a ]2D3¼þ40.68 (c 0.55, CHCl3); IR (neat) 2956, 1462,
1380, 1251, 1098, 1044, 835, 775, 734, 697 cm21; 1H NMR
(400 MHz, CDCl3) d 7.32–7.24 (m, 10H), 5.56 (dd, 1H,
J¼11.6, 8.8 Hz), 5.34 (t, 1H, J¼11.0 Hz), 4.83–4.77 (m,
3H), 4.68 (d, 1H, J¼12.0 Hz), 4.57 (d, 1H, J¼12.0 Hz), 4.47
(s, 2H), 3.94–3.90 (m, 1H), 3.67–3.62 (m, 1H), 3.57–3.50
(m, 3H), 3.33 (brd, 1H, J¼8.9 Hz), 3.13 (dd, 1H, J¼8.1,
3.4 Hz), 2.69–2.62 (m, 1H), 1.91–1.84 (m, 1H), 1.68–1.47
(m, 5H), 1.33–1.22 (m, 1H), 1.28 (s, 3H), 1.26 (s, 3H), 0.99
(d, 3H, J¼6.9 Hz), 0.98 (d, 3H, J¼6.9 Hz), 0.86 (s, 9H),
0.85 (s, 9H), 0.81 (d, 3H, J¼6.9 Hz), 0.80 (d, 3H,
J¼6.9 Hz), 0.01 (s, 6H), 20.01 (s, 3H), 20.02 (s, 3H);
13C NMR (100 MHz, CDCl3) d 138.3, 138.1, 134.0, 130.0,
128.2, 128.1, 127.7, 127.5, 127.4, 127.3, 100.3, 97.2, 87.2,
78.0, 73.1, 69.7, 67.5, 67.1, 65.8, 61.1, 43.9, 36.9, 34.3,
32.7, 30.8, 30.6, 25.8, 24.7, 23.3, 18.1, 17.3, 17.2, 11.9, 9.2,
23.4, 24.9, 25.4, 25.5. Anal. calcd for C48H82O7Si2: C,
69.68; H, 9.99. Found: C, 69.89; H, 10.12.
4.1.12. (2S,3R,4R,5R )-4-Benzyloxymethoxy-2,7-bis-(tert-
butyl-dimethyl-silanyloxy)-3,5-dimethyl-heptan-1-ol
(13). To a solution of 0.122 g (0.185 mmol) of 12 in CH2Cl2
(5 mL) and H2O (0.3 mL) at rt was added 0.0557 g
(0.245 mmol) of DDQ. After the mixture was stirred for
2 h at rt, saturated aqueous NaHCO3 (12 mL) and CH2Cl2
(3 mL) were added and the mixture was stirred for another
10 min. The organic layer was separated and the aqueous
layer was washed with CH2Cl2 (2£10 mL). The combined
organic layers were washed with saturated aqueous
NaHCO3, dried (Na2SO4) and concentrated in vacuo.
Purification by flash column chromatography afforded
0.0989 g (99%) of 13 as a colorless oil: [a]2D3¼25.08 (c
0.76, CHCl3); IR (neat) 3457, 2955, 2857, 1472, 1387,
1361, 1255, 1098, 1042, 939, 906, 835, 776, 734, 697 cm21
;
1H NMR (400 MHz, CDCl3) d 7.33–7.26 (m, 5H), 4.80 (d,
1H, J¼6.8 Hz), 4.78 (d, 1H, J¼6.8 Hz), 4.64 (d, 1H,
J¼12.0 Hz), 4.60 (d, 1H, J¼11.9 Hz), 3.98 (td, 1H, J¼5.3,
3.3 Hz), 3.7–3.66 (m, 1H), 3.61–3.50 (m, 3H), 3.32 (dd,
1H, J¼7.9, 3.0 Hz), 1.94–1.83 (m, 2H), 1.80–1.72 (m, 1H),
1.32–1.24 (m, 1H), 0.97 (d, 3H, J¼6.9 Hz), 0.87 (s, 18H),
0.86 (d, 3H, J¼7.3 Hz), 0.05 (s, 3H), 0.02 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 137.8, 128.2, 127.7, 127.5, 96.5, 87.3,
72.9, 69.9, 66.0, 61.1, 38.5, 33.5, 31.2, 25.8, 18.1, 17.4,
11.4, 24.2, 24.6, 25.4, 25.5. Anal. calcd for C29H56O5Si2:
C, 64.39; H, 10.43. Found: C, 64.57; H, 10.45.
4.1.13. (2S,3R,4R,5R )-4-Benzyloxymethoxy-2,7-bis-(tert-
butyl-dimethyl-silanyloxy)-3,5-dimethyl-heptanal (14).
To a solution of 0.100 g (0.185 mmol) of 13 in CH2Cl2
(4 mL) at rt were added 0.15 mL (0.15 g, 1.9 mmol) of
pyridine and 0.0978 g (0.230 mmol) of the Dess–Martin
periodinane. The mixture was stirred at rt for 45 min and
Et2O (40 mL) was then added. The mixture was poured into
a 1:1 mixture of aqueous 0.1 M Na2S2O3 and saturated
aqueous NaHCO3 (40 mL) and was stirred for another
20 min. The organic layer was separated and the aqueous
4.1.15. [4S,5R,6S(1S,4R,5R,6R,7R )]-4-(2-Benzyloxy-
ethyl)-6-[6-benzyloxymethoxy-4,9-bis-(tert-butyl-
dimethyl-silanyloxy)-1,5,7-trimethyl-nonyl]-2,2,5-tri-
methyl-[1,3]dioxane (16). To a solution of 0.0341 g
(0.0413 mmol) 15 in EtOH (12 mL) at rt was added
0.0095 g of 20% Pd(OH)2/C. The reaction flask was then
connected to a H2 balloon and the mixture was stirred for

7100
M. A. Calter, X. Guo / Tetrahedron 58 (2002) 7093–7100
2. Suenaga, K.; Kamei, N.; Okugawa, Y.; Takagi, M.; Akao, A.;
Kigoshi, H.; Yamada, K. Bioorg. Med. Chem. Lett. 1997, 7,
269–274.
10 h at rt. The mixture was then filtered through celite with
EtOAc and the filtrate was concentrated in vacuo. The
residue was dissolved in EtOAc (10 mL) and transferred
into a large test tube into which 0.0536 g of 5% Rh/Al2O3
and then several glass beads were added. The tube was then
placed inside a high pressure vial packed with glass wool.
The vial was then connected to a Parr hydrogenation
apparatus and pressurized with 55 psi of H2. After the
mixture was shaken for 48 h, the mixture was filtered
through a column of celite with EtOAc and the filtrate was
concentrated in vacuo. The residue was purified by flash
column chromatography to give 0.0221 g (87%) of 16 as a
colorless oil: [a ]2D3¼21.28 (c 1.07, CHCl3); IR (neat) 3419,
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1
2931, 1463, 1380, 1255, 1094, 836, 776 cm21; H NMR
(400 MHz, CDCl3) d 4.13 (br, 1H), 4.03 (ddd, 1H, J¼11.0,
4.0, 2.5 Hz), 3.82–3.73 (m, 4H), 3.66–3.60 (m, 1H), 3.56
(dd, 1H, J¼9.5, 1.5 Hz), 3.12 (dd, 1H, J¼7.0, 5.2 Hz), 2.51
(br, 1H), 1.94–1.38 (m, 12H), 1.36 (s, 3H), 1.33 (s, 3H),
1.03 (d, 3H, J¼6.9 Hz), 0.97 (d, 3H, J¼6.8 Hz), 0.92 (s,
9H), 0.91 (s, 9H), 0.90 (d, 3H, J¼5.0 Hz), 0.79 (d, 3H,
J¼7.0 Hz), 0.14 (s, 3H), 0.11 (s, 3H), 0.07 (s, 6H); 13C
NMR (100 MHz, CDCl3) d 100.3, 78.6, 77.9, 70.1, 62.6,
61.2, 39.8, 37.4, 37.3, 32.7, 31.6, 31.4, 29.1, 29.0, 25.9,
25.8, 25.6, 23.4, 18.3, 17.9, 17.0, 16.1, 13.2, 13.0, 24.3,
24.7, 25.3, 25.4. Anal. calcd for C33H70O6Si2: C, 64.02;
H, 11.40. Found: C, 64.33; H, 11.38.
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Acknowledgments
We thank the NIH (R29 AI42042) for support of this work.
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