Stereochemical assignment of the C23-C35 portion of sphinxolide/reidispongiolide class of natural products by asymmetric synthesis

Article abstract of DOI:10.1016/S0957-4166(03)00372-0

The absolute configuration of the seven stereogenic centers contained in the C23-C35 portion of reidispongiolide A is determined by asymmetric synthesis of the corresponding fragment obtained by ozonolysis of the natural macrolide.

Full text of DOI:10.1016/S0957-4166(03)00372-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1787–1798
Stereochemical assignment of the C23–C35 portion of
sphinxolide/reidispongiolide class of natural products by
asymmetric synthesis
Angela Zampella,a Valentina Sepe,a Rosa D’Orsi,a Giuseppe Bifulco,b Carla Bassarellob and Maria
Valeria D’Auriaa,*
aDipartimento di Chimica delle Sostanze Naturali, Universita` degli Studi di Napoli ‘Federico II’, via D. Montesano 49,
80131 Naples, Italy
bDipartimento di Scienze Farmaceutiche, Universita` degli Studi di Salerno, Via Ponte Don Melillo,
84084 Fisciano (Salerno), Italy
Received 12 February 2003; accepted 6 May 2003
Abstract—The absolute configuration of the seven stereogenic centers contained in the C23–C35 portion of reidispongiolide A is
determined by asymmetric synthesis of the corresponding fragment obtained by ozonolysis of the natural macrolide. © 2003
Elsevier Science Ltd. All rights reserved.
1. Introduction
sphinxolide.11 Further, we have deduced the absolute
stereochemistry of three stereogenic centers contained
in the C17–C22 fragment of reidispongiolide by asym-
metric synthesis of four possible diastereoisomers of the
corresponding degradation fragment.12
The sphinxolides1 and reidispongiolides2 are 26-mem-
bered lactones isolated in our laboratories from two
New Caledonian marine sponges Neosiphonia superstes
and Reidispongia coerulea. They exhibit an extraordi-
nary in vitro activity against various human tumor cell
lines and a potent actin-depolimerizating activity.3
Other related natural products exhibiting the same
mechanism of action include aplyronins,4 scyto-
phycins,5 mycalolides,6 ulapualides,7 halichondramides8
and kabiramides.9 All the aforementioned macrolides of
marine origin display a very similar 11-carbon, stereo-
chemically complex, acyclic side chain with an N-
methyl-N-formylamido end-group that seems to play a
crucial role in determining the mode of action. We have
elucidated the gross structure of members of sphinx-
olides and reidispongiolides by means of spectral data
but the stereochemistry remained unassigned.
Herein, we report the elucidation of the relative and of
the absolute configuration of seven stereogenic centers
contained in the C23–C35 portion of reidispongiolide A
by comparison of the spectral data of synthetic com-
pounds 3 and 4 with those of natural C23–C35 frag-
ment 2 obtained by ozonolysis of reidispongiolide A
(Fig. 1).
The application of the J-based configurational analysis
method to sphinxolide disclosed the 24S*,25S*,26S*,
27S*,28S* relative configuration for the C24–C28 sub-
unit and the 32R*,33R* relative configuration for the
C32–C33 subunit, leaving the total relative configura-
tion and the absolute configuration of the sphinxolide
side chain still undetermined. It is interesting to note
that the relative stereochemistry of C24–C28 and C32–
C33 subunits of the sphinxolide family determined by
Murata’s approach was identical to that established for
the corresponding stereogenic centers in the aplyronine
and scytophycin side chains. However, an unambigous
determination of the relative stereochemistry of the
sphinxolide side chain is necessary because recent
studies13 indicated that, despite the structural similarity,
In the framework of a project devoted to the determi-
nation of the relative and absolute configuration of this
interesting class of natural products, we have recently
applied the J-based configurational analysis method10
and we have assigned the relative configuration of the
C7–C8, C10–C15, C24–C28 and C32–C34 subunits of
* Corresponding author. Tel.: +39-081678527; fax: +39-081678552;
e-mail: madauria@cds.unina.it
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00372-0

1788
A. Zampella et al. / Tetrahedron: Asymmetry 14 (2003) 1787–1798
Figure 1. Structure of reidispongiolide A 1 and of the degradation fragments 2a and 2b.
thestereochemistryofC22–C26regionofmycalolidesand
ulapualides is enantiomeric with that of scytophycins and
aplyronins, while identical in the C30–C33 region.
2. Results and discussion
Our first disconnection, summarized in Scheme 1 involved
cleavage of the C29–C30 bond leaving two subunits 7 and
8 to be coupled through a Horner–Wadsworth–Emmons
coupling procedure. This approach, previously used for
the construction of the side chain of halichondramides14
and scytophycins15 would allow a straightforward access
to both diastereoisomers of the natural fragment 3 and
4 simply using the enantiomeric ketophosphonates 8a and
8b.
Therefore, in order to establish the relative stereochem-
istry between the C24–C28 and the C32–C33 parts in
reidispongiolide 1 and to determine the absolute stereo-
chemistry we have synthetized the two possible
diastereoisomers 3a–b and 4a–b in a stereocontrolled
manner for comparison with the natural fragments 2a and
2b.
Scheme 1.

A. Zampella et al. / Tetrahedron: Asymmetry 14 (2003) 1787–1798
1789
Scheme 2. Reagents and conditions: (a) TDPSCl, DMAP, Et3N (99%); (b) LiBH4, MeOH, 0°C (99%); (c) (COCl)2, DMSO, TEA,
CH2Cl2, −78“0°C (95%); (d) Bu2BOTf, R-4-benzyl-3-propionyloxazolidinone, −78°C, 1 h, then 13, −78“−10°C, 2 h, 98%; (e)
TBSOTf, 2,6-lutidine, CH2Cl2, (97%); (f) LiBH4, MeOH, rt, (75%); (g) (COCl)2, DMSO, TEA, CH2Cl2, −78“0°C, (98%); (h)
tert-BuOK, trans-2-butene, n-BuLi, −78“−45°C, (+)-Ipc2BOMe, BF3·OEt2, aldehyde 16, −78°C, 8 h, NaOH, H2O2, overnight, rt
(70%); (i) MeOTf, di-t-Bu-Pyr, (78%); (j) OsO4, NMO acetone/H2O 3:1, then H5IO6 (97%).
The synthetic strategy for accessing to aldehyde 7 relies
upon Evans’ aldol procedure to introduce C25–C26
stereocenters followed by a Brown’s crotylboronation for
the construction of C27–C28 propionate unit.
Analogously Brown’s crotylboronation was selected as
key synthetic step to access to ketophosphonates 8a–b.
after protection of the OH-function as its TBS ether
followed by removal of the oxazolidinone auxiliary with
LiBH4 in MeOH (73% yield, two steps).
Primary alcohol 15 was submitted to oxidation under
standard Swern condition and the unpurified aldehyde 16
was reacted with (+)-(E)-crotyldiisopinocampheylborane
under Brown’s condition to give a 7:3 diastereomeric
mixture of homoallylic alcohols 17 and 18.
The synthesis of aldehyde 7 commences with addition
under Evans’ condition of the boron enolate derived from
(R)-4-benzyl-3-propionyloxazolidinone to protected
aldehyde 13 easily prepared from commercially available
methyl (2S)-3-hydroxy-2-methylpropionate 9 (Scheme
2).16 The aldol adduct 14 was obtained in 98% yield
(> 97% de)17 and was converted to primary alcohol 15
The stereochemistry of the newly generated stereocenters
in 17 and 18 was determined on the basis of the 13C NMR
analysis of 1,3 diol acetonides 17c and 18c derived from
the 1,3 diols 17b and 18b (Scheme 3). Surprisingly, we
Scheme 3. Reagents and conditions: (a) MeOH/HCl, rt; (b) TDPSCl, Et3N, DMAP, rt; (c) dimethoxypropane dry, p-TsOH (cat.).

1790
A. Zampella et al. / Tetrahedron: Asymmetry 14 (2003) 1787–1798
found that the major distereoisomer 17 has a C25–C27
syn relationship based on the resonances 30.5 and 20.5
observed in the 13C NMR spectrum of the acetonide
17c.
Thus the monoprotected propane diol 2019 was oxidised
to the aldehyde 21. The homoallylic alcohol 22 was
obtained (de >98%, ee 95%) through addition of (−)-
(E)-crotyldiisopinocampheylborane to the above alde-
hyde. The diastereoisomeric purity of 22 was >98% as
Evidently, the existing chirality in the aldehyde 16
played a significant role in the asymmetric induction,
which overrode the induction predicted for the Brown
crotylboronation.18 In spite of the observed undesired
stereochemical outcome, we continued the synthetic
sequence on the minor stereoisomer 18, leaving the
problem of the optimization of this unfavourable step
until after the definition of the absolute stereochemistry
of the C25–C35 region of reidispongiolide A.
1
judged by the H NMR spectra of the isolated homoal-
lylic alcohol, whereas the enantiomeric excess and the
absolute stereochemistry at C33 were determined by the
application of the modified Mosher’s method.
Methylation of the secondary hydroxy group (NaH,
CH3I, 80% yield) followed by oxidative cleavage of the
terminal double bond, gave the aldehyde 24.
Methylation of desired homoallylic alcohol 18 under
mild conditions afforded 19 in 78% yield. Quantitative
oxidative cleavage of the terminal double bond com-
pleted the synthesis of the C23–C29 aldehyde 7.
Finally, treatment of 24 with methyl dimethylphospho-
nate in the presence of nBuLi, followed by oxidation of
the resulting alcohol with PDC/DMF then produced
the phosphonate 8a.
The two enantiomeric b-keto phosphonates 8a and 8b,
required for the projected coupling reaction with alde-
hyde 7, were obtained in a straightforward manner
using the seven steps sequence depicted in Scheme 4 for
the preparation of 8a.†
A Wadsworth–Emmons coupling between aldehyde 7
and 8a or 8b using activated barium hydroxide20 in wet
THF as base next gave the E-alkene 5 and 6 in 76 and
78% yield, respectively (Scheme 5). Completion of the
synthesis of the natural fragments 3 and 4 required a
Scheme 4. Reagents and conditions: (a) NaH, Bu4NI, PMBCl, 0°C“rt (70%); (b) (COCl)2, DMSO, TEA, CH2Cl2, −78“0°C,
(99%); (c) tert-BuOK, trans-2-butene, n-BuLi, −78“−45°C, (−)-Ipc2BOMe, BF3·OEt2, aldehyde 21, −78°C, 3 h, NaOH, H2O2,
overnight, rt (70%); (d) NaH, CH3I, THF (80%); (e) OsO4, NMO, acetone/H2O 3:1, then H5IO6 (95%); (f) (MeO)2POCH3, nBuLi,
THF, −78°C (85%); (g) PDC, DMF (65%).
Scheme 5. Reagents and conditions: (a) activated Ba(OH)2, then 7, rt; (b) Pt(C), H2, ethanol; (c) NaBH4, MeOH, rt; (d) DDQ,
CH2Cl2, rt; (e) MeOH/HCl, rt.
† The synthesis of 8b from 10 was carried out under the same conditions except (+)-Ipc2BOMe used instead of (−)-Ipc2BOMe.

A. Zampella et al. / Tetrahedron: Asymmetry 14 (2003) 1787–1798
Table 1. 1H NMR data for compounds 2–4 (CD3OD, 500 MHz)
1791
No.
2aa
2ba
3a
3b
4a
4b
23
3.77 dd (10.3,
5.1)
3.57 dd (10.3,
6.0)
3.77 dd (10.3,
5.1)
3.57 dd (10.3,
6.0)
3.77 dd (10.6,
5.2)
3.57 dd (10.6,
6.0)
3.77 dd (10.3, 4.4)
3.57 dd (10.3, 5.9)
3.77 dd (10.3, 5.1)
3.57 dd (10.3, 6.1)
3.77 dd (10.3, 4.3)
3.57 dd (10.3, 6.0)
24
25
26
1.77 m
3.75 dd
1.88 m
1.77 m
3.75 dd
1.88 m
1.77 m
3.75 dd
1.88 m
1.77 m
3.75 dd
1.88 m
1.77 m
3.75 dd
1.88 m
1.77 m
3.75 dd
1.88 m
27
28
3.14 dd (6.9, 4.3) 3.14 dd (6.9, 4.3) 3.14 dd (7.0, 4.0) 3.14 dd (7.3, 4.4)
3.14 dd (7.7, 5.1)
1.76 m
3.15 dd (6.9, 4.3)
1.76 m
1.76 m
1.76 m
1.76 m
1.76 m
29
30
31
32
1.72 m, 1.14 m
1.60 m, 1.40 m
3.41 m
1.62 m, 1.39 m
1.76 m, 1.53 m
3.47 m
1.72 m, 1.14 m
1.60 m, 1.40 m
3.41 m
1.62 m, 1.39 m
1.76 m, 1.53 m
3.47 ddd (11.0, 8.1, 3.7)
1.97 m
1.78 m, 1.14 m
1.60 m, 1.40 m
3.41 m
1.78 m, 1.19 m
1.81 m, 1.64 m
3.43 m
1.72 m
1.97 m
1.72 m
1.75 m
1.94 m
33
3.74 m
3.63 m
3.74 m
3.63 m
3.70 m
3.63 m
34
35
1.86 m, 1.65 m
3.70 m
1.86 m, 1.65 m
3.70 m
1.86 m, 1.65 m
3.70 m
1.86 m, 1.65 m
3.70 m
1.86 m, 1.70 m
3.70 m
1.78 m, 1.60 m
3.70 m
Me-24
Me-26
Me-28
Me-32
OMe-27
OMe-33
0.87 d (6.6)
0.92 d (6.7)
1.03 d (6.6)
0.92 d (6.7)
3.54 s
0.87 d (6.6)
0.92 d (6.7)
1.03 d (6.6)
0.85 d (6.7)
3.54 s
0.87 d (6.8)
0.92 d (7.0)
1.03 d (6.9)
0.92 d (6.7)
3.54 s
0.87 d (7.3)
0.92 d (6.6)
1.03 d (6.9)
0.85 d (6.6)
3.54 s
0.87 d (6.9)
0.92 d (7.1)
1.03 d (6.9)
0.93 d (7.1)
3.54 s
0.87 d (7.6)
0.92 d (6.9)
1.04 d (6.9)
0.86 d (6.9)
3.55 s
3.42 s
3.36 s
3.42 s
3.36 s
3.41 s
3.38 s
a Assignment was inferred from 2D-COSY experiment
Table 2. 13C NMR data for compounds 2 and 3
four-step sequence involving: a) catalytic hydrogenation
of the double bond (Pt/C, H2); b) NaBH4 reduction of
carbonyl at C31 position; c) oxidative cleavage of
thePMB group; d) complete removal of the silyl pro-
tecting groups.
(CD3OD, 125 MHz)
No.
2aa,b
2ba,b
3b
4b
23
24
25
26
27
28
29
30
31
32
33
34
67.2
39.6
73.7
37.7
91.0
36.6
27.7
33.9
73.1
42.0
81.8
33.6
60.4
13.7
10.0
17.4
10.0
62.1
57.0
67.2
39.6
73.7
37.7
91.0
36.6
27.7
33.2
74.4
41.7
80.7
33.6
60.4
13.7
10.4
17.4
10.7
62.1
57.0
67.2
39.6
73.7
37.7
91.0
36.6
27.7
33.2
74.4
41.7
80.7
33.6
60.4
13.7
10.4
17.4
10.7
62.1
57.0
67.0
39.7
74.3
37.7
90.8
36.8
27.9
33.5
74.6
41.9
80.6
33.8
60.4
13.7
10.4
17.7
10.5
62.1
57.1
NMR data of both epimers at C-31 of the synthetic
triol 3 were superimposable with those of the corre-
sponding fragments derived from the natural reidispon-
giolide, whereas small but significant differences were
observed for some protons in 4 when compared with
the natural fragments 2a and 2b as shown in Tables 1
and 2. In particular, the NMR data of the two C31
epimers of the compound 4 differed in the chemical
shifts for the OMe at C33, for the methyl groups at C28
and C32 and for the resonances of the C30 methylene
protons.
35
Me-24
Me-26
Me-28
Me-32
OMe-27
OMe-33
The absolute configuration of the C23–C35 segment of
reidispongiolides/sphinxolides was then determined
through Mosher’s analysis.‡ The C23,C35-di-Mosher
esters were prepared from the natural fragment 2b.
a Assignment based on analysis of HMQC and HMBC data.
b In the original paper (see ref. 12) the 13C NMR values for natural
fragments 2a and 2b were inferred from HMBC experiments and are
not correct for calibration problems. The revised values are reported
in the table.
1
Importantly, the H NMR spectra of C23,C35-di-(S)-
Mosher ester and C23,C35-di-(R)-Mosher ester were
distinctly different. The synthetic fragment 3 was then
converted to the corresponding C23,C35-di-(S)-Mosher
ester, and its 1H NMR spectrum was found to be
‡ The [h]D value of synthetic fragment was found to be of the same
sign and similar absolute value [synthetic [h]D=+5.0 (c 0.5), natural
[h]D=+3.6 (c 0.4)]. However, we were concerned that the value
might be too small to draw an unambiguous conclusion.
1
superimposable on the H NMR spectrum of the natu-
ral C23,C35-di-(S)-Mosher ester, thereby establishing
the absolute configuration of the C23–C35 portion of

1792
A. Zampella et al. / Tetrahedron: Asymmetry 14 (2003) 1787–1798
Figure 2. The methyl region of 1H NMR (500 MHz, CDCl3) of di-Mosher esters. (a) Di-(R)-Mosher ester derived from the
natural C23–C35 fragment 2b. (b) Di-(S)-Mosher ester derived from the natural C23–C35 fragment 2b. (c) Di-(S)-Mosher ester
derived from the synthetic C23–C35 fragment 3b.
reidispongiolide A to be the same of the synthetic
fragment 3 (Fig. 2).
14.1. (4R,2%R,3%S,4%S)-4-Benzyl-3-(5%-tert-butyldiphenyl-
silyloxy-3%-hydroxy-2%,4%-dimethylpentanoyl)-2-oxazolidi-
none 14
3. Conclusion
Bu2BOTf (13.4 mL, 1 M in CH2Cl2, 13.4 mmol) and
Et3N (2.3 mL, 16.8 mmol) were added to a solution
of (R)-4-benzyl-3-propionyloxazolidinone (3.1 g, 13.4
mmol) in dry dichloromethane (70 mL) at −78°C
under argon and the resulting pale yellow solution
was stirred for 1 h at −78°C and then at 0°C for 30
min before being re-cooled to −78°C. A solution of
the aldehyde 13 (4.0 g, 12.2 mmol) in dry CH2Cl2
was cannulated to the solution which was stirred at
−78°C for 1 h and then warmed to −10°C, stirred for
1 h and then quenched with pH 7 potassium phos-
phate monobasic-sodium hydroxide buffer (14 ml). A
solution of 30% H2O2 in MeOH (1:2, 32 ml) was
added to the mixture that was stirred overnight at
room temperature and concentrated. The residue was
diluted with CH2Cl2 and the resulting layers sepa-
rated. The aqueous phase was extracted with CH2Cl2
(3×50 mL) and the combined organic layers were
washed with saturated aqueous NaHCO3, water, and
brine. The organic phase was then dried (Na2SO4),
concentrated, chromatographed on silica gel (8:2 n-
hexane:ethyl acetate) to give 14 (6.8 g, 98%) as a
colorless oil. [h]D24=−25.3 (c 16, CHCl3); IR (thin
film): 3690, 1790, 1695 cm−1; HR FABMS m/z
560.2812 (M+H)+, calcd for C33H42NO5Si: 560.2832;
1H NMR (500 MHz, CDCl3) l (ppm): 0.91 (3H, d,
J=6.9 Hz, CH3-4%); 1.07 (9H, s, tBu-Si); 1.29 (3H, d,
J=6.7 Hz, CH3-2%); 1.88 (1H, m, H-4%), 2.79 (1H, m,
CH2-Bn); 3.31 (1H, dt, J=2.6 and 12.8 Hz, CH2-Bn);
3.73 (1H, dd, J=6.0 and 10.3 Hz, H-5%a); 3.82 (1H,
dd, J=4.3 and 10.3 Hz, H-5%b); 3.99 (2H, m, H-2%
and H-3%); 4.18 (2H, m, H-5); 4.70 (1H, m, H-4);
7.20–7.44 (11H, m, Ph); 7.65 (4H, m, Ph); 13C NMR
(125 MHz, CDCl3) l (ppm): 9.4, 13.2, 19.3, 26.9
(3C), 37.7, 40.6, 53.4, 55.6, 66.2, 68.4, 75.0, 127.2,
127.7 (4C), 128.9 (2C), 129.4 (2C), 129.7 (2C), 133.2,
135.4 (2C), 135.6 (4C), 153.1, 176.4.
In conclusion, the stereochemistry of the C23–C35
portion of reidispongiolide A was unambiguously
determined as 24S,25S,26S,27S,28S,32R,33R by enan-
tioselective synthesis and Mosher’s analysis.
4. Experimental
NMR spectra were obtained on a Bruker AMX 500
MHz recorded in CDCl3 (lH=7.26 and lC=77.0 ppm)
and CD3OD (lH=3.30 and lC=49.0 ppm). J are in
hertz and chemical shifts (l) are reported in ppm and
referred to CHCl3 and CHD2OD as internal standards.
1
Where H NMR data for a mixture of diasteroisomers
is presented, an asterix (*) follows the assignment of a
resolved resonance that correspond to a proton of the
minor diasteroisomer. Where 13C NMR data for a
mixture of diasteroisomers is presented, resolved reso-
nances that correspond to the minor diasteroisomer are
indicated in brackets. FAB MS spectra were obtained
with glycerol as matrix on a VG Prospec (Fisons) mass
spectrometer. Optical rotations were measured with a
Perkin–Elmer 141 polarimeter operating at 589 nm.
Infrared (IR) spectra were recorded on a Bruker IFS 48
FT-IR apparatus and only selected and characteristic
IR absorption data are provided for each compound.
Methyl (2S)-(+)-3-hydroxy-2-methylpropionate was
purchased from Fluka. Solvents and reagents were used
as supplied from commercial sources with the following
exceptions. Tetrahydrofuran, toluene, dichloromethane
and triethylamine were distilled from calcium hydride
immediately prior to use. All reactions were monitored
by TLC on silica gel plates (Machery, Nagel). Crude
products were purified by column chromatography on
silica gel 70–230 mesh. All reactions were carried out
under argon atmosphere using flame-dried glassware.

A. Zampella et al. / Tetrahedron: Asymmetry 14 (2003) 1787–1798
1793
4.2. (4R,2%R,3%S,4%S)-4-Benzyl-3-(5%-tert-butyldiphenyl-
4.4. (2R,3S,4S)-3-(tert-Butyldimethylsilyloxy)-5-(tert-
butyldiphenylsilyloxy)-2,4-dimethylpentanal 16
silyloxy-3%-tert-butyldimethylsilyloxy-2%,4%-dimethyl-
pentanoyl)-2-oxazolidinone
A solution of DMSO (1.1 mL, 16 mmol) in dry
dichloromethane (50 mL) was cooled at −78°C and
oxalyl chloride (698 mL, 8 mmol) was added dropwise
over 15 min. After 30 min a solution of the alcohol 15
(2.0 g, 4 mmol) in dry CH2Cl2 was added via cannula
and the mixture was stirred at −78°C for 1 h. Et3N (2.8
mL, 20 mmol) was added dropwise and the mixture was
allowed to warm to room temperature. The reaction
was quenched by addition of aqueous NaHSO4 (1 M,
50 mL). The layers were separated and the aqueous
phase was extracted with CH2Cl2 (3×50 mL). The com-
bined organic layers were washed with NaHSO4, water,
saturated aqueous NaHCO3, and brine. The organic
phase was then dried, concentrated to give the corre-
sponding aldehyde 16 (1.95 g, 98%) as a colorless oil
which was used immediately without any further purifi-
cation. HR FABMS m/z 499.3078 (M+H)+, calcd for
2,6-Lutidine (3.5 mL, 24.3 mmol) and TBSOTf (3.0
mL, 12.1 mmol)) were added sequentially to a solu-
tion of the alcohol 14 (3.4 g, 6.1 mmol) in dry
CH2Cl2 at 0°C under argon atmosphere. The mixture
was allowed to warm at room temperature where stir-
ring was continued for 2 h. Saturated NaHCO3 was
added and the organic phase was washed with water,
dried (MgSO4) and then concentrated in vacuo.
Purification by column chromatography on silica gel
using n-hexane:ethyl acetate (98:2) as eluent gave the
silyl ether as a colorless oil (4.0 g, 97% yield). [h]2D4=
−37.3 (c 5, CHCl3); IR (thin film): 1789, 1700, 1200,
1100 cm−1; HR FABMS m/z 674.3679 (M+H)+, calcd
for C39H56NO5Si2: 674.3697; 1H NMR (500 MHz,
CDCl3) l (ppm): −0.1 (3H, s, CH3-Si); 0.03 (3H, s,
CH3-Si); 0.82 (9H, s, tBu-Si); 1.03 (3H, d, J=7.1 Hz,
CH3-4%); 1.04 (9H, s, tBu-Si); 1.20 (3H, d, J=6.7 Hz,
CH3-2%); 1.96 (1H, m, H-4%); 2.72 (1H, m, CH2-Bn);
3.33 (1H, dt, J=2.6 and 12.8 Hz, CH2-Bn); 3.73 (1H,
dd, J=6.0 and 10.3 Hz, H-3%a); 3.95 (2H, H-5%a and
H2%); 4.08 (2H, m, H-5%b and H-5a); 4.18 (1H, m,
H-5b); 4.45 (1H, m, H-4); 7.18–7.41 (11H, m, Ph);
7.64 (4H, m, Ph); 13C NMR (125 MHz, CDCl3) l
(ppm): −4.6, −3.2, 8.2, 13.4, 18.1, 19.2, 25.8 (3C),
26.9 (3C), 37.5, 40.9, 41.9, 55.6, 65.9, 66.1, 73.7,
127.3, 127.7 (4C), 128.9 (2C), 129.4 (2C), 129.5 (2C),
132.9, 135.4 (2C), 135.6 (4C), 152.8, 175.5.
1
C29H47O3Si2: 499.3064; H NMR (500 MHz, CDCl3) l
(ppm): −0.06 (3H, s, CH3-Si); −0.04 (3H, s, CH3-Si);
0.81 (9H, s, tBu-Si); 0.92 (3H, d, J=6.7 Hz, CH3-4);
1.08 (9H, s, tBu-Si); 1.09 (3H, d, J=6.9 Hz, CH3-2),
1.99 (1H, m, H-4); 2.50 (1H, m, H-2); 3.50 (1H, dd,
J=6.8 and 10.3 Hz, H-5a); 3.71 (1H, dd, J=6.0 and
10.3 Hz, H-5b); 4.2 (1H, br dd, J=6.1 Hz); 7.41 (6H,
m, Ph); 7.70 (4H, m, Ph), 9.70 (1H, s, H-1); 13C NMR
(125 MHz, CDCl3): l (ppm): −4.4, −4.2, 8.2, 13.4, 18.1,
19.2, 25.8 (3C), 26.9 (3C), 40.9, 49.6, 65.9, 71.8, 127.4
(4C), 129.5 (2C), 133.9 (2C), 135.9 (4C), 205.0.
4.5. (3S,4S,5S,6S,7S)-6-(tert-Butyldimethylsilyloxy)-8-
4.3. (2S,3R,4S)-3-(tert-Butyldimethylsilyloxy)-5-(tert-
butyldiphenylsilyloxy)-2,4-dimethylpentanol 15
(tert-butyldiphenylsilyloxy)-3,5,7-trimethyl-1-octen-4-ol
18
Dry methanol (567 ml, 17.7 mmol) and LiBH4 (8.85
mL, 2 M in THF, 17.7 mmol) were added to a solu-
tion of the previous silyl alcohol (4.0 g, 5.9 mmol) in
dry THF at 0°C under argon and the resulting mix-
ture was stirred for 1 h at 0°C. The mixture was
quenched by addition of NaOH (1 M, 11.8 mL) and
then allowed to warm to room temperature. Ethyl
acetate was added and the separated aqueous phase
was extracted with ethyl acetate (3×30 mL). The com-
bined organic phases were washed with water, dried
(Na2SO4) and concentrated. Purification by silica gel
(n-hexane:ethyl acetate 85:15) gave the alcohol 15 as
a colorless oil (2.2 g, 75%). [h]2D4=+0.6 (c 15, CHCl3);
IR (thin film): 3630, 3520, 1200, 1100 cm−1; HR
To a cloudy solution of potassium tert-butoxide (4.8
mL, 1 M in THF, 4.8 mmol) and trans-2-butene
(excess) in THF (2 mL) at −78°C was added drop-
wise nBuLi (3 mL, 1.6 M in hexane, 4.8 mmol). The
resulting yellow mixture was allowed to stir at −45°C
for 20 min. The reaction mixture was recooled to
−78°C and a solution of (+)-B-methoxydiisopinocam-
pheylborane (1.85 g, 5.8 mmol) in THF (1 mL) was
added. The resulting colorless reaction mixture was
stirred at −78°C for 35 min. BF3·Et2O (715 mL, 5.8
mmol) was added rapidly followed immediately by a
solution of the crude aldehyde 16 (1.04 g, 2.09 mmol)
in THF (2.5 mL). The resulting cloudy reaction was
stirred at −78°C for 4 h. The reaction was quenched
by addition of 3N aqueous NaOH (5 mL) followed
by 30% aqueous H2O2 (5 mL). The reaction mixture
was warmed to 25°C and stirred overnight. The mix-
ture was diluted with ethyl acetate and saturated
aqueous NaCl. The layers were separated and the
aqueous layer was extracted with ethyl acetate (3×30
mL). The combined organic extracts were dried
(MgSO4) and then concentrated in vacuo. Purification
by silica gel (n-hexane:ethyl acetate 994:6) gave the
mixture of homoallylic alcohols 17 and 18 (810 mg,
70%).
FABMS
m/z
501.3232
(M+H)+,
calcd
for
1
C29H49O3Si2: 501.3220; H NMR (500 MHz, CDCl3)
l (ppm): −0.1 (3H, s, CH3-Si); 0.03 (3H, s, CH3-Si);
0.82 (9H, s, tBu-Si); 0.86 (3H, d, J=6.7 Hz, CH3-2),
0.95 (3H, d, J=6.9 Hz, CH3-4), 1.08 (9H, s, tBu-Si);
1.84 (1H, m, H-2); 1.99 (1H, m, H-4); 3.43 (2H, m,
H-1); 3.51 (1H, dd, J=6.0 and 9.5 Hz, H-5a); 3.78
(2H, m, H-5b and H-3); 7.41 (6H, m, Ph); 7.64 (4H,
m, Ph); 13C NMR (125 MHz, CDCl3): l (ppm): −4.4,
−4.2, 11.7, 14.0, 18.2, 19.2, 25.9 (3C), 26.9 (3C), 38.6,
40.4, 66.5, 66.6, 74.2, 127.6 (4C), 129.6 (2C), 133.8
(2C), 135.6 (4C).

1794
A. Zampella et al. / Tetrahedron: Asymmetry 14 (2003) 1787–1798
(1H, m, H-5); 1.87 (1H, m, H-7); 2.46 (1H, m, H-3);
2.93 (1H, dd, J=8.6, 1.7 Hz, H-4); 3.39 (1H, dd,
J=10.3, 7.7 Hz H-8a); 3.41 (3H, s, OCH3); 3.72 (1H,
dd, J=10.3, 6.0 Hz, H-8b); 3.96 (1H, d, J=6.0 Hz,
H-6); 4.99 (1H, s, H-1a); 5.01 (1H, d, J=5.1 Hz, H-1b);
5.88 (1H, m, H-2); 7.39 (6H, m, Ph); 7.67 (4H, m, Ph);
13C NMR (125 MHz, CDCl3): l (ppm): −4.4, −3.6,
11.3, 13.6, 18.0, 18.4, 19.2, 26.1 (3C), 26.9 (3C), 38.6,
39.8, 42.6, 60.3, 66.4, 72.6, 87.2, 114.2, 127.5 (4C),
129.4 (2C), 134.0, 134.1, 135.7 (4C), 140.4.
The mixture was separated by HPLC chromatography
performed on a Macherey-Nagel Nucleosil column (3.9
mm i.d.×30 cm) with a 99.5% hexane/ethyl acetate
solvent as eluent to obtain 600 mg of pure 17 and 220
mg of pure 18.
Data for 17: [h]2D4=−3.8 (c 3, CHCl3); IR (thin film):
3375, 2930, 1640, 1230, 1089 cm−1; HR FABMS m/z
1
555.3695 (M+H)+, calcd for C33H55O3Si2: 555.3690; H
NMR (500 MHz, CDCl3) l (ppm): −0.09 (3H, s, CH3-
Si); 0.01 (3H, s, CH3-Si); 0.93 (9H, s, tBu-Si); 0.99 (6H,
d, J=6.6 Hz, CH3-5 and CH3-7), 1.05 (3H, d, J=6.9
Hz, CH3-3), 1.15 (9H, s, tBu-Si); 1.88 (1H, m, H-7);
2.17 (1H, m, H-5); 2.37 (1H, m, H-3); 3.43 (1H, dd,
J=3.7 and 5.9 Hz, H-4); 3.59 (1H, t, J=9.6 Hz H-8a);
3.81 (1H, dd, J=9.6, 6.6 Hz, H-8b); 3.98 (1H, t, J=4.4
Hz, H-6); 5.12 (1H, s, H-1a); 5.15 (1H, d, J=5.9 Hz,
H-1b); 5.84 (1H, m, H-2); 7.41 (6H, m, Ph); 7.68 (4H,
m, Ph); 13C NMR (125 MHz, CDCl3): l −4.0, −3.7, 9.1,
13.9, 16.8, 18.3, 19.2, 26.2 (3C), 27.0 (3C), 37.5, 40.9,
41.8, 66.2, 76.1, 76.5, 115.6, 127.6 (4C), 129.5 (2C),
133.8 (2C), 135.6 (4C), 141.0.
4.7. (2R,3R,4S,6S,7S)-5-(tert-Butyldimethylsilyloxy)-7-
(tert-butyldiphenylsilyloxy)-3-methoxy-2,4,6-trimethyl-
heptanal 7
To a solution of alkene 19 (120 mg, 0.21 mmol) in
acetone/water (8:1, 2 mL) at room temperature was
added OsO4 (30 ml, 0.0042 mmol) followed, after 10
min, by NMO (30 mg, 0.25 mmol). The mixture was
stirred overnight, and H5IO6 (95 mg, 0.42 mmol) was
added. After 30 min the resulting mixture was extracted
with ethyl acetate and the organic layer was washed
with water, brine, dried (Na2SO4), filtered and concen-
trated to afford aldehyde 7 (116 mg, 97%) that was
used for the next step without further purification. HR
FABMS m/z 571.3650 (M+H)+, calcd for C33H55O4Si2:
Data for 18: [h]2D4=−4.1 (c 7, CHCl3); IR (thin film):
3350, 2950, 1640, 1230, 1100 cm−1; HR FABMS m/z
1
555.3679 (M+H)+, calcd for C33H55O3Si2: 555.3690; H
1
571.3639; H NMR (500 MHz, CDCl3) l (ppm): −0.04
NMR (500 MHz, CDCl3) l (ppm): −0.1 (3H, s, CH3-
Si); 0.02 (3H, s, CH3-Si); 0.77 (9H, s, tBu-Si); 0.78 (3H,
d, J=6.7 Hz, CH3-7), 0.96 (3H, d, J=6.9 Hz, CH3-5),
1.06 (9H, s, tBu-Si); 1.08 (3H, d, J=6.9 Hz, CH3-8),
1.71 (1H, m, H-7); 2.04 (1H, m, H-5); 2.29 (1H, m,
H-3); 3.43 (1H, t, J=8.8 Hz, H-4); 3.76 (2H, m, H-8a
and H-6); 3.87 (1H, dd, J=10.3, 5.1 Hz, H-8b); 5.01
(1H, d, J=10 Hz, H-1a); 5.05 (1H, d, J=4.5 Hz, H-1b);
5.88 (1H, m, H-2); 7.41 (6H, m, Ph); 7.64 (4H, m, Ph);
13C NMR (125 MHz, CDCl3): l (ppm): −4.4, −4.2,
12.4, 15.1, 17.9, 18.1, 19.2, 25.8 (3C), 26.9 (3C), 39.6,
40.3, 40.6, 66.8, 76.6, 77.0, 115.3, 127.5 (4C), 129.5
(2C), 134.6 (2C), 135.6 (4C), 139.0.
(3H, s, CH3-Si); 0.05 (3H, s, CH3-Si); 0.70 (3H, d,
J=6.9 Hz, CH3-4); 0.83 (9H, s, tBu-Si); 0.89 (3H, d,
J=6.9 Hz, CH3-6), 1.06 (9H, s, tBu-Si); 1.14 (3H, d,
J=6.9 Hz, CH3-2), 1.89 (2H, m, H-4 and H-6); 2.73
(1H, m, H-2); 3.34 (3H, s, OCH3); 3.43 (2H, m, H-3
and H-7a); 3.69 (1H, dd, J=10.3, 5.2 Hz, H-7b); 4.06
(1H, d, J=6.1 Hz, H-5); 7.37 (6H, m, Ph); 7.67 (4H, m,
Ph); 13C NMR (125 MHz, CDCl3): l (ppm): −3.9, 9.8,
11.3, 13.2, 18.4, 19.2, 26.0 (3C), 26.8 (3C), 37.7, 42.3,
47.8, 58.2, 66.3, 72.0, 84.2, 127.5 (4C), 129.5 (2C), 133.9
(2C), 135.6 (4C), 203.8.
4.8. 3-(4%-Methoxybenzyloxy)propanal 21
4.6. (3S,4S,5S,6S,7S)-4-O-Methyl-6-O-(tert-butyl-
dimethylsilyl)-8-O-(tert-butyldiphenylsilyl)-3,5,7-
trimethyl-1-octen-4,6,8-triol 19
A solution of DMSO (1.7 mL, 24 mmol) in dry
dichloromethane (40 mL) was cooled at −78°C and
oxalyl chloride (2 M in CH2Cl2, 6 mL, 12 mmol) was
added dropwise over 15 min. After 30 min a solution of
the alcohol 20 (1.2 g, 6 mmol) in dry CH2Cl2 was added
via cannula and the mixture was stirred at −78°C for 1
h. Et3N (4.2 mL, 30 mmol) was added dropwise and the
mixture was allowed to warm to room temperature.
The reaction was quenched by addition of aqueous
NaHSO4 (1 M, 40 mL). The layers were separated and
the aqueous phase was extracted with CH2Cl2 (3×40
mL). The combined organic layers were washed with
NaHSO4, water, saturated aqueous NaHCO3, and
brine. The organic phase was then dried, concentrated
to give the corresponding aldehyde 21 (1.15 g, 99%) as
a colorless oil which was used immediately without any
further purification. HR FABMS m/z 195.1040 (M+
H)+, calcd for C11H15O3: 195.1021; 1H NMR (500
MHz, CDCl3) l (ppm): 2.65 (2H, t, J=7.0 Hz, H-2);
3.74 (2H, overlapped, H-3); 3.76 (3H, s, OCH3); 4.45
(2H, s, ArCH2O-); 6.85 (2H, d, J=8.5 Hz, ArH); 7.32
(2H, d, J=8.5 Hz, ArH); 9.73 (1H, s, H-1).
2,6-Di-tert-butylpyridine (1.8 ml, 8.1 mmol) and
methytrifluoromethansulfonate (888 ml, 8.1 mmol) were
added sequentially to a solution of alcohol 18 (150 mg,
0.27 mmol) in CH2Cl2 at 0°C under argon atmosphere.
The mixture was allowed to warm at room temperature
where stirring was continued for 14 h. Saturated
NaHCO3 was added and the organic phase was washed
with water, dried (MgSO4) and then concentrated in
vacuo. Purification by column chromatography on sil-
ica using n-hexane:ethyl acetate (998:2) as eluent gave
the methyl ether 19 (120 mg, 78%) as a colorless oil.
[h]2D4=+10.9 (c 1.4, CHCl3); IR (thin film): 2930, 1640,
1463, 1255, 1094, 835 cm−1; HR FABMS m/z 569.3858
(M+H)+, calcd for C34H57O3Si2: 569.3846; 1H NMR
(500 MHz, CDCl3) l (ppm): −0.05 (3H, s, CH3-Si); 0.04
(3H, s, CH3-Si); 0.74 (3H, d, J=6.9 Hz, CH3-5); 0.82
(9H, s, tBu-Si); 0.89 (3H, d, J=6.9 Hz, CH3-7), 1.05
(9H, s, tBu-Si); 1.11 (3H, d, J=6.9 Hz, CH3-3), 1.70

A. Zampella et al. / Tetrahedron: Asymmetry 14 (2003) 1787–1798
1795
4.9. (3R,4S)-1-(4%-Methoxybenzyloxy)-4-methyl-5-
OCH3); 4.42 (2H, m, ArCH2O-); 5.01 (1H, d, J=4.8
Hz, H-6a); 5.04 (1H, bs, H-6b); 5.78 (1H, m, H-5); 6.88
(2H, d, J=8.7 Hz, ArH); 7.26 (2H, d, J=8.7 Hz, ArH).
13C NMR (125 MHz, CDCl3) l (ppm): 14.5, 31.1, 40.2,
55.2, 58.0, 67.0, 72.6, 81.6, 113.7 (2C), 114.7, 129.2
(2C), 130.1, 140.5, 158.9.
hexen-3-ol 22
To a cloudy solution of potassium tert-butoxide (8.8
mL, 1 M in THF, 8.8 mmol) and trans-2-butene
(excess) in THF (2 mL) at −78°C was added dropwise
nBuLi (5.5 mL, 1.6 M in hexane, 8.8 mmol). The
resulting yellow mixture was allowed to stir at −45°C
for 20 min. The reaction mixture was recooled to −78°C
and a solution of (−)-B-methoxydiisopinocampheylbo-
rane (3.6 g, 11.4 mmol) in THF (1 mL) was added. The
resulting colorless reaction mixture was stirred at
−78°C for 35 min. BF3·Et2O (1.4 mL, 11.33 mmol) was
added rapidly followed immediately by a solution of
the crude aldehyde 21 (1.0 g, 5.2 mmol) in THF (2.5
mL). The resulting cloudy reaction was stirred at −78°C
for 4 h. The reaction was quenched by addition of 3N
aqueous NaOH (30 mL) followed by 30% aqueous
H2O2 (30 mL). The reaction mixture was warmed to
25°C and stirred overnight. The mixture was diluted
with ethyl acetate and saturated aqueous NaCl. The
layers were separated and the aqueous layer was
extracted with ethyl acetate (3×10 mL). The combined
organic extracts were dried (MgSO4) and then concen-
trated in vacuo. Purification by silica gel (n-hex-
ane:ethyl acetate 92:8) gave the homoallylic alcohol 22
(914 mg, 70%). [h]2D4=−0.38 (c 2.6, CHCl3); IR (thin
film): 3455, 2955, 2931, 1613, 1513, 1256, 1089 cm−1;
HR FABMS m/z 251.1630 (M+H)+, calcd for
C15H23O3: 251.1647; 1H NMR (500 MHz, CDCl3) l
(ppm): 1.02 (3H, d, J=6.8 Hz, CH3-4); 1.71 (2H, m,
H-2); 2.22 (1H, m, H-4); 3.65 (3H, m, H-1 and H-3);
3.76 (3H, s, OCH3); 4.45 (2H, s, ArCH2O-); 5.05 (1H,
d, J=4.8 Hz, H-6a); 5.08 (1H, bs, H-6b); 5.80 (1H, m,
H-5); 6.87 (2H, d, J=8.7 Hz, ArH); 7.25 (2H, d, J=8.7
Hz, ArH); 13C NMR (125 MHz, CDCl3) l (ppm): 15.8,
33.5, 44.0, 55.2, 69.0, 73.0, 74.3, 113.7 (2C), 115.4,
129.3 (2C), 130.1, 140.5, 158.9.
1
The characterization data recorded for ent-23 (IR, H
NMR, 13C NMR, HRMS) was identical to that listed
above for enantiomer 23; [h]2D4=−8.8 (c 1.8, CHCl3).
4.11. (2R,3R)-3-Methoxy-5-(4%-methoxybenzyloxy)-2-
methylpentanal 24
To a solution of alkene 23 (520 mg, 2.0 mmol) in
acetone/water (8:1) at room temperature was added
OsO4 (251 mL, 0.04 mmol) followed, after 10 min by
NMO (281 mg, 2.4 mmol). The mixture was stirred
overnight and H5IO6 (912 mg, 4.0 mmol) was added.
After 30 min the resulting mixture was extracted with
ethyl acetate and the organic layer was washed with
water, brine, dried (Na2SO4), filtered and concentrated
to afford aldehyde 24 (505 mg, 95%) that was used for
the next step without further purification. HR FABMS
m/z 267.1575 (M+H)+, calculated for C15H23O4:
1
267.1596; H NMR (500 MHz, CDCl3) l (ppm): 1.09
(3H, d, J=6.9 Hz, CH3-2); 1.78 (2H, m, H-4); 2.64 (1H,
m, H-2); 3.35 (3H, s, OCH3); 3.54 (2H, m, H-3 and
H-5b); 3.67 (1H, m, H-5a); 3.80 (3H, s, OCH3); 4.42
(2H, m, ArCH2O-); 6.88 (2H, d, J=8.7 Hz, ArH); 7.25
(2H, d, J=8.7 Hz, ArH); 9.71 (1H, s, H-1); 13C NMR
(125 MHz, CDCl3) l (ppm): 9.7, 31.5, 49.7, 55.2, 57.8,
65.9, 72.7, 78.7, 113.8 (2C), 129.3 (2C), 130.4, 159.2,
204.0.
1
The characterization data recorded for ent-24 (IR, H
NMR, 13C NMR, HRMS) was identical to that listed
above for enantiomer 24.
1
The characterization data recorded for ent-22 (IR, H
4.12. Dimethyl (3S,4R)-2-hydroxy-4-methoxy-6-(4%-
methoxybenzyloxy)-3-methylhexyl phosphonate
NMR, 13C NMR, HRMS) was identical to that listed
above for enantiomer 22; [h]2D4=+0.5 (c 2.0, CHCl3).
A solution of n-butyllithium (3.04 mL, 2.5 M in hex-
ane, 7.6 mmol) was added dropwise over 5 min to a
stirred solution of dimethyl methylphosphonate (864
mL, 7.98 mmol) in dry THF at −78°C under nitrogen
and the resulting solution was stirred for 0.5 h at
−78°C. A solution of the aldehyde 24 (500 mg, 1.9
mmol) in dry THF was added dropwise over 20 mins
and the mixture was stirred for an additional hour. It
was then quenched with aqueous saturated NaHCO3
solution and allowed to come to room temperature.
The mixture was extracted with ethyl acetate (3×50 ml)
and the combined organic extracts were dried (Na2SO4)
and then concentrated in vacuo. Purification by silica
gel (n-hexane:ethyl acetate 2:8) gave the hydroxyphos-
phonate (617 mg, 85%, 65:35 diasteromeric mixture) as
a colorless oil. HR FABMS m/z 391.1901 (M+H)+,
4.10. (3R,4S)-1-O-(4%-Methoxybenzyl)-3-O-methyl-4-
methyl-5-hexen-1,3-diol 23
Sodium hydride (1.28 g, 60% suspension in oil, 32
mmol) was added in one portion to a stirred solution of
the alcohol 22 (800 mg, 3.2 mmol) in THF dry at 0°C
under nitrogen. The mixture was stirred at 0°C for 5
min and then methyl iodide (4 ml, 64 mmol) was added
in one portion. The resulting mixture was left at room
temperature for 2 h and then quenched with MeOH,
diluted with water and extracted with ethyl acetate. The
combined organic extracts were dried (MgSO4) and
then concentrated in vacuum. Purification by silica gel
(n-hexane:ethyl acetate 99:1) gave 23 (676 mg, 80%).
[h]2D4=+5.6 (c 3, CHCl3); IR (thin film): 3031, 1612,
1513 cm−1; HR FABMS m/z 265.1825 (M+H)+, calcd
1
calcd for C18H32O7P: 391.1886; H NMR (500 MHz,
1
for C16H25O3: 265.1804; H NMR (500 MHz, CDCl3) l
CD3OD) l (ppm): 0.92–0.86* (d’s, J=6.9 Hz, CH3-3);
1.69–1.63* (1H, m, H-1a); 1.76 (1H, m, H-5a); 1.93–
1.86* (1H, m, H-1b); 2.04 (2H, m, H-3 and H-5b);
3.36–3.32* (s’s, OCH3); 3.58–3.50* (3H, m, H-4 and
(ppm): 1.01 (3H, d, J=6.9 Hz, CH3-4); 1.69 (2H, m,
H-2); 2.44 (1H, m, H-4); 3.25 (1H, m, H-1); 3.34 (3H, s,
OCH3-4); 3.53 (2H, m, H-1 and H-3); 3.80 (3H, s,

1796
A. Zampella et al. / Tetrahedron: Asymmetry 14 (2003) 1787–1798
H-6); 3.75–3.72 (s’s CH3O-P); 3.76–3.78 (s’s CH3O-P);
3.80 (3H, s, OCH3); 4.21–4.22* (1H, m, H-2); 4.45 (2H,
m, ArCH2O-); 6.91 (2H, d, J=8.7 Hz, ArH); 7.28 (2H,
d, J=8.7 Hz, ArH); 13C NMR (125 MHz, CD3OD) l
(ppm): 9.6 (10.8), 31.2 (31.0), 32.0 (32.1), 42.8 (42.9),
52.9, 53.2, 55.7, 58.0 (57.9), 67.2, 67.4, (67.9), 76.3, 81.6
(80.1), 114.7 (2C), 130.4 (130.5) (2C), 131.7, 160.7.
(ppm): −0.01 (3H, s, CH3-Si); 0.02 (3H, s, CH3-Si); 0.73
(3H, d, J=6.8 Hz, CH3), 0.77 (9H, s, tBu-Si); 0.84 (3H,
d, J=7.1 Hz, CH3), 1.02 (3H, d, J=6.9 Hz, CH3); 1.06
(9H, s, tBu-Si); 1.15 (3H, d, J=6.9 Hz, CH3), 1.67 (2H,
m); 1.71 (1H, m); 1.76 (1H, m); 1.85 (2H, m); 2.65 (1H,
m); 3.06 (1H, d, J=8.1 Hz); 3.13 (1H, t, J=8.0 Hz);
3.27 (3H, s, OCH3); 3.31 (3H, s, OCH3); 3.38 (1H, m);
3.54 (2H, m); 3.62 (2H, m); 3.80 (3H, s, OCH3); 3.92
(1H, m); 4.42 (2H, m); 6.14 (1H, d, J=15.6 Hz); 6.86
(2H, d, J=8.7 Hz), 6.94 (1H, dd, J=15.6, 6.1 Hz); 7.24
(2H, d, J=8.7 Hz); 7.40 (6H, m, Ph); 7.65 (4H, m, Ph);
13C NMR (125 MHz, CDCl3): l (ppm): −3.9, −3.6,
11.5, 12.3, 13.7, 17.0, 18.4, 19.2, 26.1 (3C), 26.9 (3C),
29.7, 31.3, 38.3, 38.7, 42.2, 46.9, 55.2, 58.1, 60.2, 66.2,
66.3, 72.4, 72.5, 79.8, 86.8, 113.7 (2C), 127.6 (6C), 129.5
(2C), 129.6 (2C), 130.7, 133.9 (3C), 135.6 (4C), 149.4,
159.2, 202.4.
The characterization data recorded for ent-hydroxy-
1
phosphonate (IR, H NMR, 13C NMR, HRMS) was
identical to that listed above 3S,4R hydroxy-
phosphonate.
4.13. Dimethyl (3R,4R)-4-methoxy-6-(4%-methoxybenzyl-
oxy)-3-methyl-2-oxohexyl phosphonate 8a
Pyridinium dichromate (2.0 g, 5.2 mmol) was added in
one portion to a solution of the hydroxyphosphonate
(500 mg, 1.3 mmol) in dry DMF and the resulting
solution was stirred at room temperature under nitro-
gen for 5 h. The mixture was diluted with water and
then extracted with ether. The combined ether extracts
were washed with water and brine, then dried (Na2SO4)
and evaporated to dryness in vacuo to leave 8a as a
colorless oil (328 mg, 65%). [h]2D4=−1.7 (c 4.5, CHCl3);
HR FABMS m/z 389.1740 (M+H)+, calcd for
4.15. (3S,4S,8S,9S,10S,11S,12S)-11-(tert-Butyldimethyl-
silyloxy)-13-(tert-butyldiphenylsilyloxy)-3,9-dimethoxy-
1-(4%-methoxybenzyloxy)-4,8,10,12-tetramethyl-6-
tridecen-5-one 6
A solution of the ketophosphonate 8b (23.3 mg, 0.06
mmol) in dry THF was stirred in the presence of
activated barium hydroxide octahydrate (10 mg. 0.054
mmol) at room temperature for 30 min, and then a
solution of the aldehyde 7 (20 mg, 0.035 mmol) in 40:1
THF/water was added. The inhomogeneous mixture
was stirred vigorously at room temperature for 3.5 h
and then diluted with dichloromethane. The organic
extract was washed with saturated NaHCO3 and brine
and then dried (Na2SO4) and concentrated in vacuo.
Purification by silica gel (n-hexane:ethyl acetate 98:2)
gave the compound 6 as a colorless oil (22.7 mg, 78%);
IR (thin film): 2930, 1695, 1615, 1230, 1089, 834 cm−1.
HR FABMS m/z 833.5218 (M+H)+, calcd for
1
C18H30O7P: 389.1729; H NMR (500 MHz, CDCl3) l
(ppm): 0.98 (3H, d, J=6.9 Hz, CH3-3); 1.65 (1H, m,
H-5a), 1.78 (1H, m, H-5b), 3.00 (2H, m, H-1a and H-3),
3.20 (1H, m, H-1b), 3.25 (3H, s, OCH3), 3.26 (1H, m,
H-6a), 3.45 (2H, m, H-4 and H-6b), 3.68–3.69, 3.70–
3.72 (6H, CH3O-P), 3.80 (3H, s, OCH3), 4.38 (2H, m,
ArCH2O-), 6.78 (2H, d, J=8.7 Hz, ArH), 7.22 (2H, d,
J=8.7 Hz, ArH); 13C NMR (125 MHz, CDCl3) l
(ppm): 11.8, 31.2, 41.5, 50.3, 52.2, 52.9, 57.8, 60.3, 65.9,
72.7, 80.3, 113.7 (2C), 129.1 (2C), 131.4, 159.2, 204.9.
The characterization data recorded for 8b (IR, 1H
NMR, 13C NMR, HRMS) was identical to that listed
above for enantiomer 8a; [h]2D4=+1.4 (c 5.0, CHCl3).
C49H77O7Si2: 832.5208; H NMR (500 MHz, CDCl3) l
1
(ppm): −0.01 (3H, s, CH3-Si); 0.02 (3H, s, CH3-Si); 0.74
(3H, d, J=6.7 Hz, CH3), 0.77 (9H, s, tBu-Si); 0.84 (3H,
d, J=6.9 Hz, CH3), 1.06 (9H, s, tBu-Si); 1.01 (3H, d,
J=6.9 Hz, CH3), 1.16 (3H, d, J=7.1 Hz, CH3), 1.66
(2H, m); 1.70 (1H, m); 1.76 (1H, m); 1.87 (2H, m); 2.66
(1H, m); 3.06 (1H, d, J=8.2 Hz); 3.12 (1H, t, J=7.8
Hz); 3.27 (3H, s, OCH3); 3.32 (3H, s, OCH3); 3.38 (1H,
m); 3.54 (2H, m); 3.63 (2H, m); 3.80 (3H, s, OCH3);
3.91 (1H, m); 4.42 (2H, m); 6.13 (1H, d, J=15.4 Hz);
6.86 (2H, d, J=8.8 Hz), 6.94 (1H, dd, J=15.4, 5.8 Hz);
7.24 (2H, d, J=8.8 Hz); 7.41 (6H, m, Ph); 7.64 (4H, m,
Ph); 13C NMR (125 MHz, CDCl3): l (ppm): −3.9, −3.6,
11.7, 12.4, 13.7, 17.7, 18.4, 19.2, 26.1 (3C), 26.8 (3C),
29.7, 31.3, 38.5, 38.6, 42.2, 47.8, 55.2, 58.1, 60.2, 65.4,
66.2, 72.4, 72.5, 79.8, 86.9, 113.8 (2C), 127.9 (4C), 129.1
(2C), 129.3 (2C), 129.5 (2C), 130.6, 133.9 (3C), 135.7
(4C), 151.9, 159.1, 202.3.
4.14. (3R,4R,8S,9S,10S,11S,12S)-11-(tert-Butyldimethyl-
silyloxy)-13-(tert-butyldiphenylsilyloxy)-3,9-dimethoxy-
1-(4%-methoxybenzyloxy)-4,8,10,12-tetramethyl-6-
tridecen-5-one 5
A solution of the ketophosphonate 8a (23.3 mg, 0.06
mmol) in dry THF was stirred in the presence of
activated barium hydroxide octahydrate (10 mg, 0.054
mmol) at room temperature for 30 min, and then a
solution of the aldehyde 7 (20 mg, 0.035 mmol) in 40:1
THF/water was added. The inhomogeneous mixture
was stirred vigorously at room temperature for 3.5 h
and then diluted with dichloromethane. The organic
extract was washed with saturated NaHCO3 and brine
and then dried (Na2SO4) and concentrated in vacuo.
Purification by silica gel (n-hexane:ethyl acetate 98:2)
gave the compound 5 as a colorless oil (22.1 mg, 76%);
IR (thin film): 2930, 1693, 1620, 1230, 1089, 834 cm−1;
HR FABMS m/z 833.5220 (M+H)+, calcd for
4.16. (2S,3S,4R,5S,6S,10S,11R)-5,11-Dimethoxy-
2,4,6,10-tetramethyltridecane-1,3,9,13-tetraol 3
Enone 5 was subjected to the following four step
sequence:
1
C49H77O7Si2: 832.5208; H NMR (500 MHz, CDCl3) l

A. Zampella et al. / Tetrahedron: Asymmetry 14 (2003) 1787–1798
1797
(a) 10 mg sample was dissolved in ethanol and
4.18. General procedure to prepare MTPA ester
hydrogenated in the presence of Pt/C catalyst (2 mg)
for 2 h. The mixture was filtered through Celite and
the filtrate was concentrated in vacuo to leave the
ketone as a liquid (9.0 mg, 90%).
(b) NaBH4 was added in one portion to a stirred
solution of this latter in MeOH at room tempera-
ture. The mixture was stirred for 1 h and then was
concentrated in vacuo and then diluted with NH4Cl
and ethyl acetate. The aqueous phase was extracted
with ethyl acetate and then the combined organic
extracts were washed with brine, dried (Na2SO4) and
concentrated in vacuo to leave 8.2 mg of pure alco-
hol (90%).
(c) To a solution of the alcohol in CH2Cl2 and MS
was added DDQ. The reaction was stirred at 25°C
overnight and then filtered through Celite and the
filtrate was washed with aqueous NaOH (1N, 20
mL) and brine and then dried (Na2SO4) and concen-
trated in vacuo (6.6 mg, 95%).
0.5–1.0 mg sample was dissolved in freshly distilled
CH2Cl2 and treated with triethylamine (10 mL), (−)- or
(+)-a-methoxy-a-(trifluoromethyl)phenylacetyl chloride
(MTPA-Cl) (5 mL) and a catalytic amount of 4-
(dimethylamino)pyridine. The mixture was left to
stand at room temperature for 12 h, with the resulting
mixture purified by silica gel column.
1
[(S)-MTPA ester of 22]: [h]2D4=−22 (c 10, CHCl3); H
NMR (500 MHz, CDCl3) l (ppm): 0.91 (3H, d, J=6.9
Hz, CH3-4); 1.87 (2H, m, H-2); 2.47 (1H, m, H-4);
3.39–3.29 (2H, m, H-1); 3.50 (3H, s, OCH3); 3.78 (3H,
s, OCH3); 4.37 (2H, s, ArCH2O-); 5.02 (1H, d, J=5.1
Hz, H-6b); 5.04 (1H, bs, H-6a); 5.27 (1H, m, H-3);
5.67 (1H, m, H-5); 6.88 (2H, d, J=8.6 Hz, ArH); 7.25
(2H, d, J=8.6 Hz, ArH); 7.38–7.53 (5H, m, ArH).
1
[(R)-MTPA ester of 22]: [h]2D4=+13 (c 13, CHCl3); H
NMR (500 MHz, CDCl3) l (ppm): 1.01 (3H, d, J=7.0
Hz, CH3-4); 1.82 (2H, m, H-2); 2.51 (1H, m, H-4);
3.30–3.25 (2H, m, H-1); 3.50 (3H, s, OCH3); 3.78 (3H,
s, OCH3); 4.31 (2H, s, ArCH2O-); 5.04 (1H, d, J=4.8
Hz, H-6b); 5.07 (1H, bs, H-6a); 5.27 (1H, m, H-3);
5.71 (1H, m, H-5); 6.88 (2H, d, J=8.7 Hz, ArH); 7.25
(2H, d, J=8.7 Hz, ArH); 7.38–7.53 (5H, m, ArH).
(d) A solution of HCl in MeOH (2N, 5 mL) was
added to a solution of the silyl alcohol in methanol
(1 mL) at room temperature. The reaction was
stirred for 2 h and Ag2CO3 was added. The mixture
was treated with a stream of N2 to eliminate the
CO2, and concentrated in vacuo to obtain 3.3 mg
(98%) of mixture of C31 epimers of compound 3.
The residue was purified by HPLC (water:methanol
55:45) on a m-Bondapak C-18 (3.9 mm×30 cm) to
afford the two epimers at C-31 of tetrol 3: 3a (0.8
mg, tR 6.9 mim) and 3b (2 mg, tR 9.6 min).
[(S)-MTPA ester of 3b]: [h]2D4=−14.0 (c 0.6, CHCl3);
HR FABMS m/z 712.3405 (M+H)+, calcd for
1
C35H50F6O8: 712.3410; H NMR (500 MHz, CDCl3) l
(ppm): 0.67 (3H, d, J=6.6 Hz); 0.80 (3H, d, J=7.1
Hz); 0.84 (3H, d, J=6.6 Hz); 1.00 (3H, d, J=6.6 Hz);
1.43 (1H, m); 1.63 (2H, m); 1.73 (1H, m); 1.82 (3H,
m); 1.94 (2H, m); 2.14 (1H, m,); 2.80 (1H, dd, J=8.8,
2.2 Hz); 3.12 (1H, m); 3.23 (3H, s); 3.40 (3H, s); 3.48
(3H, s); 3.54 (3H, s); 3.63 (d, J=10.3 Hz); 4.29 (2H,
m); 4.43 (2H, m); 5.17 (1H, m); 7.40 (5H, m, ArH);
7.51 (5H, m, ArH).
Compound 3a: [h]D24=+3.3 (c 0.3, CHCl3); HR
FABMS m/z 365.2912 (M+H)+, calcd for C19H41O6:
365.2903; 1H NMR (500 MHz, CD3OD) l (ppm):
Table 1.
Compound 3b: [h]D24=+5.0 (c 0.5, CHCl3); HR
FABMS m/z 365.2908 (M+H)+, calcd for C19H41O6:
365.2903; 1H NMR (500 MHz, CD3OD) l (ppm):
Table 1; 13C NMR (125 MHz, CD3OD): Table 2.
[(S)-MTPA ester of 2b]: [h]2D4=−14.4 (c 0.6, CHCl3);
HR FABMS m/z 712.3420 (M+H)+, calcd for
1
C35H50F6O8: 712.3410; H NMR (500 MHz, CDCl3) l
(ppm): 0.67 (3H, d, J=6.6 Hz); 0.80 (3H, d, J=7.3
Hz); 0.84 (3H, d, J=6.6 Hz); 1.00 (3H, d, J=6.6 Hz);
1.44 (1H, m); 1.61 (2H, m); 1.73 (1H, m); 1.82 (3H,
m); 1.94 (2H, m); 2.13 (1H, m); 2.80 (1H, dd, J=8.8,
2.2 Hz); 3.13 (1H, m); 3.23 (3H, s); 3.41 (3H, s); 3.48
(3H, s); 3.54 (3H, s); 3.63 (d, J=9.6 Hz); 4.29 (2H,
m); 4.43 (2H, m); 5.17 (1H, m); 7.40 (5H, m, ArH);
7.52 (5H, m, ArH).
4.17. (2S,3S,4R,5S,6S,10R,11S)-5,11-Dimethoxy-
2,4,6,10-tetramethyltridecane-1,3,9,13-tetraol 4
The synthesis of tetrol 4 from enone 6 was carried out
under the same conditions used to obtain tetrol 3. The
residue was purified by HPLC (water:methanol 52:48)
on a C-18 column LUNA (3 m, 250×4.6 mm) to afford
the two epimers at C-31 of tetrol 4: 4a (0.5 mg, tR 15
min), 4b (1.7 mg, tR 25.5 min)
[(R)-MTPA ester of 2b]: [h]2D4=−10 (c 0.1, CHCl3);
HR FABMS m/z 712.3415 (M+H)+, calcd for
1
C35H50F6O8: 712.3410; H NMR (500 MHz, CDCl3) l
Compound 4a: [h]D24=+16.7 (c 0.3, CHCl3); HR
FABMS m/z 365.2907 (M+H)+, calcd for C19H41O6:
365.2903; 1H NMR (500 MHz, CD3OD) l (ppm):
Table 1.
(ppm): 0.71 (3H, d, J=6.6 Hz); 0.76 (3H, d, J=6.6
Hz); 0.83 (3H, d, J=7.2 Hz); 1.02 (3H, d, J=6.6 Hz);
1.48 (1H, m); 1.66 (2H, m); 1.71 (1H, m); 1.81 (3H,
m); 1.93 (2H, m); 2.11 (1H, m), 2.85 (1H, dd, J=8.1,
2.2 Hz); 3.12 (1H, m); 3.18 (3H, s); 3.42 (3H, s); 3.51
(3H, s); 3.54 (3H, s); 3.71 (d, J=9.6 Hz); 4.30 (1H,
m); 4.36 (1H, m); 4.43 (1H, dd, J=10.3, 5.1 Hz); 4.48
(1H, dd, J=10.3, 2.9 Hz); 5.13 (1H, m); 7.39 (5H, m,
ArH); 7.52 (5H, m, ArH).
Compound 4b: [h]D24=−3.0 (c 0.6, CHCl3); HR
FABMS m/z 365.2908 (M+H)+, calcd for C19H41O6:
365.2903; 1H NMR (500 MHz, CD3OD) l (ppm):
Table 1; 13C NMR (125 MHz, CD3OD): Table 2.

1798
A. Zampella et al. / Tetrahedron: Asymmetry 14 (2003) 1787–1798
10. Matsumori, N.; Kaneno, D.; Murata, M.; Nakamura, H.;
References
Tachibana, K. J. Org. Chem. 1999, 64, 866–876.
11. Bassarello, C.; Bifulco, G.; Zampella, A.; D’Auria, M.
V.; Riccio, R.; Gomez-Paloma, L. Eur. J. Org. Chem.
2001, 39–44.
12. Zampella, A.; Bifulco, G.; Bassarello, C.; Gomez Paloma,
L.; D’Auria, M. V. Eur. J. Org. Chem. 2002, 785–790.
13. Matsunaga, S.; Liu, P.; Celatka, C. C.; Panek, J. S.;
Fusetani, N. J. Am. Chem. Soc. 1999, 121, 5605–5606.
14. Kiefel, M. J.; Maddock, J.; Pattenden, G. Tetrahedron
Lett. 1992, 33, 3227–3230.
1. (a) Guella, G.; Mancini, I.; Chiasera, G.; Pietra, F. Helv.
Chim. Acta 1989, 72, 237–246; (b) D’Auria, M. V.;
Gomez-Paloma, L.; Minale, L.; Zampella, A.; Verbist, J.
F.; Roussakis, C.; Debitus, C. Tetrahedron 1993, 49,
8645–8657.
2. (a) D’Auria, M. V.; Gomez-Paloma, L.; Minale, L.;
Zampella, A.; Verbist, J. F.; Roussakis, C.; Debitus, C;
Patissou, J. Tetrahedron 1994, 50, 4829–4834; (b) Car-
bonelli, S.; Zampella, A.; Randazzo, A.; Debitus, C.;
Gomez-Paloma, L. Tetrahedron 1999, 55, 14665–14674.
3. Zhang, X.; Minale, L.; Zampella, A.; Smith, C. D. Can-
cer Res. 1997, 57, 3751–3758.
15. Paterson, I.; Yeung, K.-S. Tetrahedron Lett. 1993, 34,
5347–5350.
16. Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem.
Soc. 1990, 112, 6348–6359.
4. Yamada, K.; Oijka, M.; Ishigaki, T.; Yoshida, Y.; Eki-
moto, H.; Arakawa, M. J. J. Am. Chem. Soc. 1993, 115,
11020–11021.
17. The diastereomeric purity of aldol adduct 14 was judged
by the NMR spectra and the configuration was assigned
on the basis of literature precedent, see: Smith, A. B., III;
Beauchamp, T. J.; LaMarche, M. J.; Kaufman, M. D.;
Qiu, Y.; Arimoto, H.; Jones, D. R.; Kobayashi, K. J.
Am. Chem. Soc. 2000, 122, 8654–8664.
18. The extraordinary level of substrate control exhibited by
aldehyde 16 in the reaction with (E)-crotylboronates is
quite surprising and deserves further investigation; see:
Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem.
Soc. 1990, 112, 6348–6359.
5. Ishibashi, M.; Moore, R. E.; Patterson, G. M. L.; Xu, C.;
Clardy, J. J. Org. Chem. 1986, 51, 5300–5306.
6. (a) Fusetani, N.; Yasumuro, K.; Matsunaga, S.; Hashi-
moto, K. Tetrahedron Lett. 1989, 30, 2809–2812; (b)
Phuwapraisirisan, P.; Matsunaga, S.; van Soest, R. W.
M.; Fusetani, N. J. Nat. Prod. 2002, 65, 942–943.
7. Roesener, J. A.; Scheuer, P. J. J. Am. Chem. Soc. 1986,
108, 846–847.
8. (a) Kernan, M. R.; Faulkner, D. J. Tetrahedron Lett.
1987, 28, 2809–2812; (b) Kernan, M. R.; Molinski, T. F.;
Faulkner, D. J. J. Org. Chem. 1988, 53, 5014–5020.
9. Matsunaga, S.; Fusetani, N.; Hashimoto, K.; Kosei, K.;
Noma, M. J. Am. Chem. Soc. 1986, 108, 847–849.
19. Urbanek, R. A.; Sabes, S. F.; Forsyth, C. J. J. Am.
Chem. Soc. 1998, 120, 2523–2533.
20. Alvarez-Ibarra, C.; Arias, S.; Ban˜o´n, G.; Ferna´nez, M. J.;
Rodr´ıguez, M.; Sinisterra, V. J. Chem. Commun. 1987,
1509–1511.