Synthesis of the C1-side chain of zaragozic acid D and progress towards a total synthesis

Article abstract of DOI:10.1016/S0040-4020(02)01514-4

A synthesis of a 1,3-dithiane corresponding to the C1-side chain of zaragozic acid D is described. An aldol reaction using an Evans oxazolidinone is the key step in controlling stereochemistry. Metallation of the derived dithiane monosulfoxide and coupling to an aldehyde effected construction of the C1-C7 bond. Subsequent steps are also reported, including acid-mediated ketalization resulting in formation of an advanced synthetic intermediate containing the bicyclic ketal core of the natural product.

Full text of DOI:10.1016/S0040-4020(02)01514-4

Tetrahedron 59 (2003) 367–375
Synthesis of the C1-side chain of zaragozic acid D and progress
towards a total synthesis
a
a,b
Alan Armstrong,a,b Paul A. Barsanti, Toby J. Blench and Ron Ogilviec
,
*
aSchool of Chemistry, University of Nottingham, Nottingham NG7 2RD, UK
bDepartment of Chemistry, Imperial College, South Kensington, London SW7 2AY, UK
cPfizer Global Research and Development, Sandwich, Kent CT13 9NJ, UK
Received 15 August 2002; revised 14 November 2002; accepted 21 November 2002
Abstract—A synthesis of a 1,3-dithiane corresponding to the C1-side chain of zaragozic acid D is described. An aldol reaction using an
Evans oxazolidinone is the key step in controlling stereochemistry. Metallation of the derived dithiane monosulfoxide and coupling to an
aldehyde effected construction of the C1–C7 bond. Subsequent steps are also reported, including acid-mediated ketalization resulting in
formation of an advanced synthetic intermediate containing the bicyclic ketal core of the natural product. q 2003 Elsevier Science Ltd. All
rights reserved.
1. Introduction
configuration of zaragozic acid D, and preliminary studies
that demonstrate that this can be advanced towards the
natural product using our dithiane monoxide coupling
approach.
The zaragozic acids (squalestatins) (Fig. 1) are some of the
most intensely studied synthetic targets of the last ten
years.1 They are potent inhibitors of squalene synthase, and
therefore have potential as cholesterol-lowering drugs. They
also inhibit the enzyme ras-farnesyl protein transferase, an
enzyme of interest in the anti-cancer area. To synthetic
chemists, additional interest is imparted by their complex
and intriguing structure: in particular, the highly substituted
2,8-dioxabicyclo[3.2.1]octane core has stimulated the
development of some highly inventive synthetic strategies.1
We recently reported2 a total synthesis of (þ)-zaragozic
acid C 2 in which a key step was coupling of the
monosulfoxide derived from the dithiane 5 with the
aldehyde 4, obtained by double asymmetric dihydroxylation
of an appropriately functionalised 1,3-diene. We wished to
demonstrate that our strategy could potentially be applied to
other members of the natural product series, and selected
zaragozic acid D 3 as a suitable target. While total syntheses
have been recorded for zaragozic acid A3 (squalestatin S1)
and zaragozic acid C,4 as well as for zaragozic acid H5,5 no
synthetic studies have been reported to date on zaragozic
acid D, which shows the most potent ras-farnesyl protein
transferase inhibition in this natural product series.6 The
stereochemistry of the C1-side chain has not been
unambiguously assigned, although it is reasonable to
assume that the configuration will be the same as in the
analogous stereocentres in 1 and 2. Here we report the first
synthesis of a C1-side chain 6 corresponding to the assumed
2. Results and discussion
As in the synthesis of the zaragozic acid C C1-side chain,2,4a
the key step to establishing the syn-stereochemistry in 6 was
to be an Evans aldol reaction7 between aldehyde 7 and an
enolate bearing an oxazolidinone auxiliary. This was
performed with the valine-derived oxazolidinone 8 in
place of the phenylalanine-derived chiral auxiliary used
Keywords: aldol; acetal; 1,3-dithiane.
*
Corresponding author. Address: Department of Chemistry, Imperial
College, South Kensington, London SW7 2AY, UK. Tel.: þ44-20-
75945876; fax: þ44-20-75945804; e-mail: a.armstrong@ic.ac.uk
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01514-4

368
A. Armstrong et al. / Tetrahedron 59 (2003) 367–375
Figure 1. Representative zaragozic acids (squalestatins).
previously in the literature.2,4a Thus, treatment of 8 with
Bu2BOTf and Et3N at 2788C followed by addition of
aldehyde 7 gave the desired aldol product 9 in 88% yield
and as a single diastereomer. Protection of the free
secondary alcohol in 9 as the TBDPS ether 10 followed
by reductive removal of the auxiliary led to the primary
alcohol 11 (Scheme 1).
higher order cuprate,9 formed from the bromostyrene by
treatment with BuLi and CuCN, also resulted in no
t
reaction. Displacement with lithium phenylacetylide was
also unsuccessful. As an alternative approach, we envisaged
one-carbon homologation to the aldehyde 14 and sub-
sequent olefination as an appropriate route. Tosylate 12 was
converted to nitrile 13, reduction of which (DIBAL-H) and
hydrolysis of the intermediate imine gave the desired
aldehyde 14. Several alternatives were investigated for
olefination of 14. Wittig olefination with benzyltriphenyl-
phosphonium bromide/PhLi in ether gave the desired
product in good yield (97%) but poor stereoselectivity
(1.6:1 E/Z). Julia olefination with benzylphenyl sulfone also
afforded disappointing selectivity (2.6:1 E/Z). Better results
were ultimately achieved using a recently reported10
modification of the Wadsworth–Emmons olefination.
Thus, addition of a mixture of aldehyde 14 and diethyl
The next challenge in the synthesis was to introduce the
E-alkene unit that is unique to the side chain of zaragozic
acid D. Initial attempts focused on introducing this unit
directly. Alcohol 11 was converted to tosylate 12
(Scheme 2). An initial attempt to displace the tosylate
with the magnesio cuprate8 derived from trans-b-bromo-
styrene resulted in no reaction. Another attempt using the
Scheme 1. Reagents and conditions: (a) 8, Bu2BOTf, Et3N, CH2Cl2,
2788C, then 7, 88%; (b) TBDPSCl, imidazole, DMF, 81%; (c) LiBH4,
MeOH, THF, 08C, 62%.
Scheme 2. Reagents and conditions: (a) TsCl, pyridine, CH2Cl2, 89%; (b)
NaCN, DMSO, 608C, 98%; (c) DIBAL-H, CH2Cl2, 2788C, then H3Oþ,
74%; (d) diethyl benzylphosphonate, NaH, 15-C-5, THF, 08C to rt, 77%.

A. Armstrong et al. / Tetrahedron 59 (2003) 367–375
369
Scheme 3. Reagents and conditions: (a) BCl3·SMe2, CH2Cl2, 95%; (b)
Dess–Martin periodinane, CH2Cl2, rt, 94%; (c) propane-1,3-dithiol,
BF3·OEt2, CH2Cl2, 100%; (d) mCPBA, CH2Cl2, 08C, 76%, ca. 5:1 trans/cis.
benzylphosphonate to a slurry of NaH in THF containing
catalytic amounts of 15-crown-5 afforded E-alkene 15 in
good yield (77%), in which the Z-isomer could not be
Scheme 4. Reagents and conditions: (a) 3 equiv. 18, 3.1 equiv. nBuLi, THF,
2788C, then 1 equiv. 4, THF, 2788C; (b) P2I4, Et3N, CH2Cl2; (c) TBAF,
THF, 808C, 12% 20 from 4; (d) Ac2O, cat. DMAP, pyridine, 658C, 69%; (e)
20:10:1 CH2Cl2/TFA/H2O, 78%; (f) BzCl, cat. DMAP, pyridine, 98%.
1
detected by H NMR spectroscopy.
Now that the E-alkene had been installed, all that remained
was to introduce the dithiane unit at the other end of the
molecule. This was done in an efficient four-step process
(Scheme 3). Removal of the benzyl protecting group was
also in THF (Scheme 4). After chromatographic removal of
the excess of unreacted side chain, treatment of the complex
mixture of diastereomeric adducts with 0.55 equiv. of P2I4
in the presence of Et3N12 gave the dithiane as an inseparable
mixture of the two C7 epimers. Removal of the silyl
protecting group on the C40-alcohol by treatment with
TBAF in THF at 808C allowed chromatographic separation.
The more polar of the two diastereomers (12% over 3 steps
from 4) was tentatively assigned as having the desired
C7-configuration 20 by analogy to the relative polarity of
the two corresponding C7-epimers in our zaragozic acid C
work.2 This assumption proved to be correct (vide infra).
The other diastereomer 19 (ca. 17%) could not be isolated
pure since it co-ran with an isomeric material tentatively
assigned as resulting fr0 om acetonide migration. Selective
acetylation of the C4 -hydroxyl in 20 was effected by
exposure to acetic anhydride and DMAP in pyridine at
658C, to give 21 in 69% yield, with no evidence of formation
of the diacylated product.
11
achieved by exposure of 15 to BCl3·SMe2 in CH2Cl2 to
give the primary alcohol 16. Dess–Martin oxidation of 16 to
aldehyde 17 and subsequent dithiane formation with
propane-1,3-dithiol and catalytic BF3·OEt2 gave 6 in
quantitative yield (Scheme 3). Overall, then, an efficient
and stereocontrolled synthesis of the C1-side chain 6 of
zaragozic acid D had been achieved.
2.1. Coupling to the core aldehyde 4
Now that the C1-side chain 6 had been successfully
synthesised, its coupling with the core aldehyde 4 could
be studied. As with the simpler dithiane 5, we experienced
problems in effecting metallation of 6, despite examining a
range of bases, solvents and additives. In line with our
earlier work,2 we therefore elected to oxidise the dithiane 6 to
the monosulfoxide 18 in order to increase the acidity of the
protons a- to sulfur. This was achieved by treatment of 6 with
mCPBA in CH2Cl2 at 08C to give the monosulfoxide 18 (76%)
asamixtureofallfourpossiblediastereomers, whichappeared
as two major separable spots by TLC. In accord with our
findings for the zaragozic acid C side chain,2 we assigned the
minor, less polar spot as the two cis isomers (sulfoxide oxygen
cis with respect to the substituent on the 2-position of the 1,3-
dithiane ring), and the major spot as the trans isomers. The
major, trans isomers were carried through the synthesis.
The stage was now set for the key ketalisation step.
Treatment of 21 with 20:10:1 CH2Cl2/TFA/H2O, the
conditions developed by Evans,4b resulted in the formation
of the desired bicyclic ketal 22 in a good yield (78%)
(Scheme 5). As in our earlier work, this reaction cascade
involved remarkably facile removal of the 1,3-dithiane and
acetonide protecting groups as well as selective ketalisation.
Bis-benzoylation then afforded 23. The assignment of
Aldehyde 4 was synthesised as previously reported.2 The
coupling of the two partners and conversion to the bicyclic
ketal 22 was performed in a manner analogous to our
zaragozic acid C synthesis2 (Scheme 4). Thus, 3 equiv. of
the monosulfoxide 18 in THF were treated with 3.1 equiv.
nBuLi at low temperature to form the corresponding anion,
followed by dropwise addition of 1 equiv. of the aldehyde 4,
Scheme 5. Reagents and conditions: (a) BCl3·SMe2, 24 h, CH2Cl2, 65%.

370
A. Armstrong et al. / Tetrahedron 59 (2003) 367–375
structure to the desired ketal 23 was made by comparison
with the corresponding zaragozic acid C intermediate. The
1H NMR spectrum was very similar to those obtained
previously, and displayed the key coupling between H6 and
H7 of 2–3 Hz which is characteristic for the correct C6/C7
stereochemistry and the correct ketal isomer.
layer chromatography was performed using pre-coated glass-
backed plates (Merck Kiselgel 60 F254) and visualised by
ultra-violet light and potassium permanganate, acidic
ammonium molybdate or anisaldehyde as appropriate.
4.1.1. Preparation of (4S,20R,30R)-3-(7-benzyloxy-30-
hydroxy-20-methylheptanoyl)-4-isopropyl-oxazolidin-2-
one 9. To a solution of 8 (18.5 g, 100 mmol) in CH2Cl2
(260 mL) at 2788C was added Bu2BOTf (105 mL,
105 mmol, 1 M in CH2Cl2, 1.05 equiv.) and Et3N
(15.9 mL, 115 mmol, 1.15 equiv.) dropwise under nitrogen.
The solution was allowed to 08C and stirred for 50 min. The
solution was re-cooled to 2788C and then a solution of
aldehyde 7 (21.2 g, 110 mmol, 1.1 equiv.) in CH2Cl2
(70 mL) at 2788C was added via cannula over 1 h. The
mixture was stirred at 2788C for 1.5 h and then allowed to
come to rt and stirred for a total of 16 h. The reaction was
quenched at 08C with pH 7 phosphate buffer (100 mL) and
MeOH (270 mL). A mixture of 2:1 MeOH/30% H2O2
(270 mL) was added and the solution allowed to come to rt
over 1.5 h. The mixture was poured onto water and the
organics separated. The aqueous was extracted with CH2Cl2
(£2) and the combined organics were dried (MgSO4) and
the solvent removed to yield a pale yellow oil. The crude
mixture was purified by flash chromatography (35–45%
ethyl acetate/petrol) to yield the title compound 9 (33.2 g,
88%) as a colourless oil; [a]2D1¼þ48.9 (c 0.96, CHCl3); nmax
(film) 3524, 2939, 2866, 1778, 1696, 1454, 1386, 1300,
1204, 1105, 990, 738 and 700 cm21; dH (400 MHz, CDCl3)
7.36–7.24 (5H, m, Ph), 4.49 (2H, s, PhCH2O), 4.47–4.43
(1H, m, NCH(iPr)), 4.27 (1H, t, J¼9.0 Hz, one of
CH(iPr)CH2O), 4.20 (1H, dd, J¼3.0, 9.0 Hz, one of
CH(iPr)CH2O), 3.95–3.91 (1H, m, CH2CH(OH)), 3.74
(1H, dq, J¼2.5, 7.0 Hz, CH(CH3)CvO), 3.47 (2H, t,
J¼6.5 Hz, BnOCH2), 3.05 (1H, br s, OH), 2.37–2.29 (1H,
m, CH3CHCH3), 1.68–1.51 (4H, m, BnOCH2CH2CH2-
CH2), 1.46–1.35 (2H, m, BnOCH2CH2CH2CH2), 1.23 (3H,
d, J¼7.0 Hz, CH(CH3)CvO), 0.91 (3H, d, J¼7.0 Hz, one
of CH3CHCH3), 0.87 (3H, d, J¼7.0 Hz, one of CH3-
CHCH3); dC (100 MHz, CDCl3) 177.8 (s), 153.3 (s), 138.6
(s), 128.4 (d), 127.6 (d), 127.5 (d), 72.9 (t), 71.1 (d), 70.2 (t),
63.3 (t), 58.2 (d), 42.0 (d), 33.5 (t), 29.6 (t), 28.3 (d), 22.7 (t),
17.9 (q), 14.7 (q), 10.7 (q); m/z (FABþ) 378 (MþH, 41),
360 (7), 270 (10), 231 (3), 184 (2), 154 (5), 147 (2), 141
(13); observed 378.2288, C21H32NO5 (MþH) requires
378.2280.
Completion of a total synthesis would require conversion of
the three benzyloxy groups in 23 to the triacid unit of the
natural product. In our zaragozic acid C work,2 the triple
deprotection of the three benzyl ethers was achieved by
hydrogenolysis. However, the presence of the alkene in the
C1 side chain was likely to preclude this for 23, so Lewis
acid methods were examined. Pleasingly, good results were
obtained by reaction with a large excess of BCl3·SMe2 for
24 h, leading to formation of the desired alcohol 24 in 65%
1
yield (Scheme 5). The H NMR spectrum clearly showed
that the alkene in the C1 side chain remained intact. While
24 has not been progressed any further towards the natural
product 1, we have therefore demonstrated that the side
chain alkene will withstand most of the important synthetic
transformations that are required for a total synthesis. Triple
oxidation of the alcohols to the acid level and, after suitable
protecting group manipulation, selective attachment of the
C6 acyl side chain has good precedent in our earlier work.2
3. Conclusions
We have accomplished a synthesis of the dithiane 6 which
corresponds to the C1-side chain of zaragozic acid D. We
have also demonstrated that this dithiane is compatible with
many of the key synthetic steps needed to complete a total
synthesis of the natural product, and have successfully
prepared an advanced synthetic intermediate.
4. Experimental
4.1. General procedures
1H and 13C NMR spectra were recorded on a Bruker AM
400, Bruker DRX 400, Bruker DRX 500 or JEOL GX-270
NMR spectrometer using residual protic solvent (CHCl3,
dH¼7.26 ppm), tetramethylsilane (dH¼0 ppm) or CDCl3
(dC¼77.0 ppm, t) as internal reference. The multiplicities in
13C spectra were determined by DEPT experiments.
Infrared spectra were run on a Perkin–Elmer 1605 FT-IR
or a Mattson Satellite FT-IR machine from 4000–
600 cm21. Mass spectra were recorded under the conditions
stated on either a VG Autospec or a VG 70E. Microanalyses
were performed at the University of Nottingham. Optical
rotations were measured on either a JASCO DIP 370 digital
or an Optical Activity Polarimeter. Melting points were
measured on Laboratory Devices Mel-Temp II and are
uncorrected. Column chromatography was performed on
Merck Kiselgel 60 (230–400 mesh). Diethyl ether and
tetrahydrofuran solvents were distilled from sodium-benzo-
phenone ketyl; dichloromethane from calcium hydride and
dimethyl formamide from anhydrous magnesium sulfate.
Petrol refers to petroleum ether of boiling range 40–608C
which was distilled prior to use. All other reagents were
used as purchased unless stated otherwise. Analytical thin
4.1.2. Preparation of (4S,20R,30R) 3-[7-benzyloxy-30-(tert-
butyldiphenylsilanyloxy)-20-methylheptanoyl]-4-isopro-
pyloxazolidin-2-one 10. To a solution of alcohol 9 (47.1 g,
125 mmol) in DMF (80 mL) was added imidazole (25.5 g,
375 mmol) and TBDPSCl (52 mL, 200 mmol, 1.6 equiv.)
under nitrogen. The solution was stirred for 23 h and then
poured onto saturated aqueous NH4Cl. The mixture was
extracted with ether (£3) and the combined organics were
washed successively with 2 M HCl (£1), water (£1), brine
(£1), dried (MgSO4) and the solvent removed to yield a
cloudy yellow oil. The crude mixture was purified by flash
chromatography (10–20–50% ether/hexane) to yield the
title compound (62 g, 81%) as a colourless oil; [a]2D1¼þ27.9
(c 0.86, CHCl3); nmax (film) 2933, 1778, 1704, 1589, 1454,
1428, 1384, 1300, 1203, 1105, 822, 739, 702 and 613 cm21
dH (400 MHz, CDCl3) 7.68–7.64 (4H, m, Ph), 7.45–7.26
;

A. Armstrong et al. / Tetrahedron 59 (2003) 367–375
371
(11H, m, Ph), 4.42 (2H, s, PhCH2O), 4.18–4.14 (2H, m,
CH2CH(OSi)CH(CH3) and NCH(iPr)), 4.08 (1H, dd, J¼2.0,
9.0 Hz, one of CH(iPr)CH2O), 3.93 (1H, t, J¼9.0 Hz, one of
CH(iPr)CH2O), 3.87 (1H, m, CH(OSi)CH(CH3)), 3.28 (2H,
t, J¼6.5 Hz, BnOCH2), 2.41–2.37 (1H, m, CH3CHCH3),
1.55–1.46 (2H, m, BnOCH2CH2CH2CH2), 1.39–1.32 (2H,
m, BnOCH2CH2), 1.28–1.19 (2H, m, BnOCH2CH2CH2-
CH2), 1.27 (3H, d, J¼70.0 Hz, CH(OSi)CH(CH3)), 1.07
(1H, m), 3.62–3.58 (1H, m, CH2CH(OSi)CH(CH3)), 3.16–
3.08 (2H, m), 2.36 (3H, s, SO2ArCH3), 1.88–1.81 (1H, m,
CH2CH(OSi)CH(CH3)), 1.40–0.84 (15H, m, includes 0.87
(9H, s, tBu), 0.81 (3H, d, J¼6.9 Hz, CH(OSi)CH(CH3)); dC
(100 MHz, CDCl3) 145.1 (s), 139.1 (s), 136.5 (d), 135.0 (s),
134.0 (s), 133.7 (s), 130.4 (d), 130.3 (d), 130.1 (d), 128.9
(d), 128.5 (d), 128.2 (d), 128.2 (d), 128.1 (d), 128.0 (d), 77.8
(d), 73.9 (d), 13.8 (t), 73.4 (t), 70.5 (t), 34.1 (t), 29.9 (t), 27.6
(q), 22.8 (t), 22.2 (q), 20.0 (s), 10.9 (q); m/z (þFAB) 643
(M2H)þ, 473, 443, 419, 389, 353, 333, 293, 273, 217, 197,
183, 135, 121, 109, 91, 71; found: C, 70.8; H, 7.6.
C38H48O5SSi requires C, 70.8; H, 7.5%.
t
(9H, s, Bu), 0.88 (3H, d, J¼7.0 Hz, one of CH3CHCH3),
0.83 (3H, d, J¼7.0 Hz, one of CH3CHCH3); dC (100 MHz,
CDCl3) 174.8 (s), 153.6 (s), 138.7 (s), 136.1 (d), 136.0 (d),
134.6 (s), 133.8 (s), 129.6 (d), 129.5 (d), 128.3 (d), 127.6
(d), 127.5 (d), 127.4 (d), 127.4 (d), 73.5 (d), 72.8 (t), 70.1 (t),
63.0 (t), 58.8 (d), 42.3 (d), 35.0 (t), 29.6 (t), 28.0 (d), 27.0
(q), 21.4 (t), 19.5 (s), 18.1 (q), 14.5 (q), 11.0 (q); m/z
(FABþ) 616 (Mþ, 6), 558 (28), 538 (17), 390 (7), 360 (18),
346 (7), 323 (7), 289 (3), 261 (6), 252 (3); observed
615.3385, C37H49NO5Si (Mþ) requires 615.3380.
4.1.5. Preparation of (3R,4R)-8-(benzyloxy)-4-(tert-
butyldiphenylsilyloxy)-3-methyloctanitrile 13. To a sol-
ution of tosylate 12 (51.8 g, 80 mmol) in DMSO (320 mL)
was added NaCN (4.72 g, 96 mmol, 1.2 equiv.) under
nitrogen. The mixture was stirred at 608C for 20 h, allowed
to come to rt, poured onto water and then extracted with
ether (£4). The combined organics were washed with brine
(£1), dried (MgSO4) and the solvent removed to yield a
colourless oil. The crude mixture was purified by flash
chromatography (20–25% ether/petrol) to yield the nitrile
13 (39.3 g, 98%) as a colourless oil; [a]2D2¼28.76 (c 1.37,
CHCl3); nmax (film) 3070, 2932, 2858, 2246, 1589, 1454,
1428, 1387, 1361, 1189, 1110, 1027, 822, 741, 703 and
614 cm21; dH (400 MHz, CDCl3) 7.69–7.66 (4H, m, Ph),
7.47–7.26 (11H, m, Ph), 4.41 (2H, s, PhCH2O), 3.69 (1H,
dt, J¼2.5, 6.5 Hz, CH2CH(OSi)CH(CH3)), 3.26 (2H, app.
dt, J¼1.5, 6.5 Hz, BnOCH2), 2.43 (1H, dd, J¼5.8,
16.6 Hz, one of CH(CH3)CH2CN), 2.27 (1H, dd, J¼8.9,
16.6 Hz, one of CH(CH3)CH2CN), 2.02–1.95 (1H, m,
CH(OSi)CH(CH3)CH2), 1.50–1.31 (4H, m, BnOCH2CH2-
CH2CH2), 1.18–1.08 (2H, m, BnOCH2CH2CH2CH2), 1.06
(9H, s, tBu), 1.03 (3H, d, J¼7.0 Hz, CH(OSi)CH(CH3)); dC
(100 MHz, CDCl3) 138.5 (s), 135.9 (d), 135.8 (d), 134.1 (s),
133.3 (s), 129.9 (d), 129.7 (d), 128.3 (d), 127.8 (d), 127.6
(d), 127.5 (d), 119.6 (s), 75.1 (d), 72.8 (t), 69.9 (t), 35.2 (d),
33.1 (t), 29.4 (t), 27.1 (q), 22.3 (t), 21.1 (t), 19.5 (s), 13.4 (q);
m/z (FABþ) 500 (MþH, 10), 442 (4), 364 (5), 274 (46), 254
(7), 244 (5), 199 (14); observed 500.2995, C32H42NO2Si
(MþH) requires 500.2984.
4.1.3. Preparation of (2R,3R)-7-(benzyloxy)-3-(tert-
butyldiphenylsilyloxy)-2-methylheptanol 11.4a To a sol-
ution of 10 (32 g, 52 mmol) in THF (220 mL) at 08C was
added MeOH (8.1 mL, 208 mmol, 4 equiv.) then LiBH4
(104 mL, 208 mmol, 2 M in THF, 4 equiv.) dropwise over
40 min. The solution was allowed to come to rt and then
stirred for 30 min. A further 8.1 mL of MeOH was added
and the solution stirred for 30 min. Another 8.1 mL of
MeOH was added, the solution stirred for 10 min and then
poured onto saturated aqueous Rochelle’s salt (250 mL).
Sufficient 2 M HCl was added to dissolve the salts, the
mixture was extracted with ether (£3). The combined
organics were washed with water (£1), brine (£1), dried
(MgSO4) and the solvent removed to yield a colourless oil.
The crude mixture was purified by flash chromatography
(35% ether/hexane) to yield the alcohol 11 (30.4 g, 62%) as
a colourless oil; dH (400 MHz, CDCl3) 7.72 (4H, m, Ph),
7.45–7.25 (11H, m, Ph), 4.39 (2H, s, CH2OCH2Ph), 3.85–
3.79 (1H, m, CH2CH(OSi)CH(CH3)), 3.65 (1H, t,
J¼9.2 Hz, OH), 3.56–3.43 (1H, m), 3.30–3.17 (2H, m),
1.95–1.82 (2H, m), 1.60–1.07 (15H, m, includes 1.05 (9H,
t
s, Bu)). 0.83 (3H, d, J¼6.9 Hz, CH(OSi)CH(CH3)). Data
consistent with those reported in the literature.4a
4.1.4. Preparation of (2R,3R)-7-(benzyloxy)-3-(tert-
butyldiphenylsilyloxy)-2-methylheptanol p-toluenesulfo-
nate 12. To a stirred solution of alcohol 11 (68 mg,
0.14 mmol) in CH2Cl2 (0.3 mL) was added p-toluenesulfo-
nyl chloride (40 mg, 0.21 mmol), followed by pyridine
(34 mL, 0.42 mmol). After one day, the mixture was
partitioned between 2 M HCl (1 mL) and CH2C12 (5 mL).
The organics were separated and the aqueous layer extracted
with CH2Cl2 (3£5 mL). The organics were combined and
washed with 30% aqueous CuSO4 solution (1£10 mL), H2O
(3£10 mL), saturated brine (3£10 mL), then dried
(MgSO4), filtered and evaporated under reduced pressure.
The residual yellow oil was purified by flash chromato-
graphy (30% ether/petrol) to give the tosylate 12 (80 mg,
89%) as a clear oil, [a]2D1¼25.6 (c 0.93 in CHCl3); nmax
(film) 3068, 2931, 2857, 1598, 1495, 1455, 1428, 1363,
4.1.6. Preparation of (3R,4R)-8-(benzyloxy)-4-(tert-
butyldiphenylsilyloxy)-3-methyloctanal 14. To a solution
of 13 (19.7 g, 39 mmol) in CH2Cl2 (390 mL) at 2788C was
added DIBAL-H (46.8 mL, 46.8 mmol, 1 M in CH2Cl2,
1.2 equiv.) dropwise under nitrogen over 35 min. The
reaction was stirred for 1 h and then quenched with
MeOH (15 mL). The mixture was allowed to come to rt,
saturated aqueous NH4Cl (ca. 100 mL) was added and the
mixture stirred vigorously for 20 min. 5% H2SO4 (10 mL)
and then the mixture was extracted with CH2Cl2 (£2). The
combined organics were washed with brine (£1), dried
(MgSO4) and the solvent removed to yield a yellow oil. The
crude mixture was purified by flash chromatography (25%
ether/petrol) to yield the aldehyde 14 (14.5 g, 74%) as a
colourless oil; [a]D21¼227.6 (c 0.58, CHCl3); nmax 3070,
2933, 2858, 2715, 1961, 1892, 1824, 1725, 1589, 1455,
1189, 1177, 1110, 1044, 968, 816, 741, 703 and 666 cm21
;
1427, 1382, 1362, 1110, 1043, 822, 740, 703 and 613 cm21
;
dH (400 MHz, CDCl3) 7.66 (2H, d, J¼8.3 Hz, Ar), 7.53–
7.50 (4H, m, Ar), 7.39–7.17 (13H, m, Ar), 4.30 (2H, s,
CH2OCH2Ph), 3.98 (1H, dd, J¼9.3, 6.4 Hz), 3.90–3.84
dH (400 MHz, CDCl3) 9.58 (1H, s, CHO), 7.68–7.66 (4H,
m, Ph), 7.45–7.26 (11H, m, Ph), 4.43 (2H, s, PhCH2O), 3.65
(1H, dt, J¼2.3, 6.0 Hz, CH2CH(OSi)CH(CH3)), 3.28 (2H,

372
A. Armstrong et al. / Tetrahedron 59 (2003) 367–375
app. dt, J¼2.5, 6.5 Hz, BnOCH2), 2.60 (1H, d, J¼13.0 Hz,
one of CH(CH3)CH2CHO), 2.30–2.18 (2H, m, one of
CH(CH3)CH2CHO and CH(CH3)CH2CHO), 1.48–1.32
(4H, m, BnOCH2CH2CH2CH2), 1.29–1.12 (2H, m,
give the alcohol 16 (45 mg, 95%) as a clear oil,
[a]3D1¼þ38.5 (c 1.96 in CHCl3); nmax (film) 3353, 3069,
3024, 2932, 2857, 1472, 1457, 1427, 1388, 1361, 1110,
1049, 965, 821, 740, 702, 665 and 612 cm21; dH (500 MHz,
CDCl3) 7.73–7.70 (4H, m, Ph), 7.45–7.41 (2H, m, Ph),
7.38–7.23 (8H, m, Ph), 7.22–7.19 (1H, m, Ph), 6.30 (1H,
d, J¼15.8 Hz, CH2CHvCHPh), 6.10–6.03 (1H, m, CH2-
CHvCHPh), 3.71 (1H, dt, J¼6.3, 2.7 Hz, CH2-
CH(OSi)CH(CH3), 3.41 (2H, dt, J¼1.1, 6.6 Hz,
CH2CH2OH), 2.52–2.46 (1H, m, CH2CHvCHPh), 2.12–
2.05 (1H, m, CH2CHvCHPh), 1.75–1.70 (1H, m), 1.51–
1.36 (2H, m), 1.31–1.22 (2H, m), 1.21–1.08 (11H, m,
includes 1.10 (9H, s, tBu)), 0.92 (3H, d, J¼6.8 Hz,
CH(OSi)CH(CH3); dC (125 MHz, CDCl3) 137.8, 136.1,
136.0, 134.8, 134.3, 130.9, 130.1, 129.5, 129.4, 128.4,
127.5, 127.3, 126.8, 125.9, 76.2, 62.7, 37.9, 36.5, 33.3, 32.5,
27.1, 22.1, 19.6, 14.0; m/z (þFAB) 509 (MþNa), 413, 301,
241, 197, 173, 137, 115, 91; found: C, 79.3; H, 8.9.
C32H42O2Si requires C, 79.0; H, 8.7%.
t
BnOCH2CH2CH2CH2), 1.07 (9H, s, Bu), 0.87 (3H, d,
J¼5.5 Hz, CH(OSi)CH(CH3); dC (100 MHz, CDCl3) 202.8
(d), 138.6 (s), 136.0 (d), 134.8 (s), 134.4 (s), 133.9 (s), 129.7
(d), 129.6 (d), 128.3 (d), 127.6 (d), 127.5 (d), 127.4 (d), 76.3
(d), 72.8 (t), 70.1 (t), 47.2 (t), 33.0 (t), 32.4 (d), 29.6 (t), 27.1
(q), 22.6 (t), 19.5 (s), 14.5 (q); m/z (CI, NH4) 520 (MþNH4,
100), 503 (MþH, 34), 274 (11), 264 (52), 256 (2), 247 (62)
216 (6), 196 (7); observed 503.2985, C32H43O3Si (MþH)
requires 503.2981.
4.1.7. Preparation of (5R,6R,8E)-O-benzyl-5-(tert-butyl-
diphenylsilyloxy)-6-methyl-9-phenylnon-8-enol 15. To a
cooled (08C), stirred slurry of NaH (142 mg at 95%,
5.61 mmol) in THF (5 m1) containing 15-crown-5
(0.2 mL, 0.56 mmol) was added a pre-mixed solution of
aldehyde 14 (1.41 g, 2.81 mmol) and diethyl benzyl-
phosphonate (0.88 mL, 4.21 mmol) in THF (15 mL). The
reaction was allowed to warm to rt and stirred for a further
1 h 20 min. The contents were then poured into 2 M NaOH
(10 mL) and extracted with CH2Cl2 (4£10 mL). The
organics were combined and washed with H2O
(1£10 mL), saturated aqueous brine (3£10 mL), then dried
(MgSO4), filtered and evaporated under reduced pressure.
The residual yellow oil was purified by flash chromato-
graphy (20% ether/petrol) to give the alkene 15 (1.69 g,
77%) as a clear oil, [a]2D9¼þ29.0 (c 0.94, CHCl3); nmax
(film) 3068, 3026, 2931, 2856, 1589, 1495, 1472, 1454,
1427, 1379, 1361, 1307, 1259, 1189, 1110, 1072, 1028, 966,
939, 821, 740, 702 and 666 cm21; dH (270 MHz, CDCl3)
7.71–7.50 (4H, m, Ph), 7.42–7.18 (16H, m, Ph), 6.27 (1H,
d, J¼15.8 Hz, CH2CHvCHPh), 6.10–5.95 (1H, m, CH2-
CHvCHPh), 4.40 (2H, s, PhCH2OCH2), 3.70–3.61 (1H, m,
CH2CH(OSi)CH(CH3)), 3.26 (2H, t, J¼6.5 Hz, PhCH2-
OCH2), 2.50–2.38 (1H, m, CH2CHvCHPh), 2.12–1.98
(1H, m, CH2CHvCHPh), 1.80–1.60 (1H, m,
CH(OSi)CH(CH3)CH2), 1.53–1.00 (15H, m, includes 1.06
(9H, s, tBu)), 0.87 (3H, d, J¼6.9 Hz, CH(OSi)CH(CH3)); dC
(67.5 MHz, CDCl3) 138.9 (s), 138.1 (s), 136.3 (d), 135.1 (s),
134.6 (s), 131.1 (d), 130.4 (d), 129.7 (d), 129.6 (d), 128.6
(d), 128.5 (d), 127.8 (d), 127.7 (d), 127.6 (d), 127.0 (d),
126.1 (d), 76.5 (d), 73.0 (t), 70.4 (t), 38.0 (d), 36.7 (t), 33.6
(t), 29.8 (t), 27.4 (q), 22.8 (t), 19.8 (s), 14.2 (q); m/z (þFAB)
577 (MþH), 549, 399, 369, 351, 281, 221, 199, 183, 137,
117, 91; found: C, 81.4; H, 8.6. C39H48O2Si requires C,
81.2; H, 8.4%.
4.1.9. Preparation of (5R,6R,8E)-5-(tert-butyldiphenyl-
silyloxy)-6-methyl-9-phenylnon-8-enal 17. To a stirred
solution of alcohol 16 (105 mg, 0.22 mmol) in CH2Cl2
(2.1 mL) was added Dess–Martin periodinane reagent
(110 mg, 0.26 mmol). After 5 min ‘wet’ CH2Cl2 (0.5 mL)
was added and after 15 min the reaction was concentrated in
vacuo before the addition of a 1:1 solution of saturated
aqueous NaHCO3/1 M Na2S2O3 (25 mL) and ether (25 mL),
then stirred for 25 min. The organics were separated and the
aqueous extracted with ether (3£20 mL). The organics were
combined and washed with H2O (1£25 mL), saturated
aqueous brine (3£25 mL), then dried (MgSO4), filtered and
evaporated under reduced pressure. The residual yellow oil
was purified by flash chromatography (50% ether/petrol) to
give the aldehyde 17 (98 mg, 94%) as a clear oil,
[a]2D7¼þ38.2 (c 0.86 in CHCl3); nmax (film) 3070, 3024,
2931, 2856, 2715, 1725, 1589, 1494, 1472, 1461, 1427,
1388, 1361, 1187, 1110, 1072, 966, 938, 821, 740, 702 and
665 cm21; dH (500 MHz, CDCl3) 9.53 (1H, t, J¼1.4 Hz,
CHO), 7.70–7.67 (4H, m, SiPh), 7.47–7.04 (11H, m, Ph),
6.28 (1H, d, J¼15.8 Hz, CH2CHvCHPh), 6.06–6.00
(1H, m, CH2CHvCHPh), 3.70–3.63 (1H, m, CH2-
CH(OSi)CH(CH3), 2.52–2.45 (1H, m), 2.13–2.01 (3H,
m), 1.80–1.67 (1H, m), 1.48–1.33 (4H, m), 1.07 (9H, s,
tBu), 0.88 (3H, d, J¼6.8 Hz, CH(OSi)CH(CH3)); dC
(125 MHz, CDCl3) 202.3, 137.8, 136.1, 136.0, 131.1,
129.8, 130.0, 129.5, 128.4, 127.5, 127.5, 125.9, 109.6,
75.9, 38.0, 32.9, 27.1, 18.5, 14.1; m/z (þFAB) 485 (MþH),
427 (M2tBu), 339, 221, 199, 183, 165, 145, 129, 123, 117,
105; observed: MþH, 485.2891. C32H41O2Si requires
MþH, 485.2876.
4.1.8. Preparation of (5R,6R,8E)-5-(tert-butyldiphenyl-
silyloxy)-6-methyl-9-phenylnon-8-enol 16. To a stirred
solution of 15 (56 mg, 0.10 mmol) in CH2Cl2 (1.0 mL) was
added boron trichloride–dimethyl sulfide complex (315 mL,
2 M solution in CH2Cl2, 0.63 mmol) dropwise over 4 min.
After 1.5 h the mixture was quenched by addition of
saturated aqueous NaHCO3 (5 mL) and diluted with CH2Cl2
(5.0 mL). The organics were separated and the aqueous
layer extracted with CH2C12 (4£5.0 mL). The organics
were combined and washed with H2O (1£10 mL), saturated
aqueous brine (3£10 mL), then dried (MgSO4), filtered and
evaporated under reduced pressure. The residual yellow oil
was purified by flash chromatography (50% ether/petrol) to
4.1.10. Preparation of (40R,50R,70E)-2-[40-(tert-butyl-
diphenylsilyloxy)-50-methyl-80-phenyl-oct-70-en-10-yl]-
1,3-dithiane 6. To a stirred solution of aldehyde 17 (76 mg,
0.16 mmol) in CH2Cl2 (2.0 mL) was added 1,3-propane-
dithiol (16 mL, 0.16 mmol) followed by boron trifluoride
etherate (4 mL, 0.03 mmol). After 12 h, the reaction was
concentrated in vacuo. The residual yellow oil was purified
by flash chromatography (10% ether/petrol) to give the
dithiane 6 (90 mg, 100%) as a clear oil, [a]2D5¼þ24.2 (c 1.6
in CHCl3); nmax (film) 3069, 3023, 2931, 2895, 2856, 1588,
1493, 1474, 1461, 1426, 1380, 1360, 1275, 1110, 1072,

A. Armstrong et al. / Tetrahedron 59 (2003) 367–375
373
1051, 1026, 966, 821, 740, 702 and 612 cm21; dH
(500 MHz, CDCl3) 7.70–7.67 (4H, m, Ph), 7.46–7.40
(2H, m, Ph), 7.39–7.32 (4H, m, Ph), 7.31–7.25 (4H, m, Ph),
7.21–7.16 (1H, m, Ph), 6.27 (1H, d, J¼15.8 Hz, CH2-
CHvCHPh), 6.08–5.95 (1H, m, CH2CHvCHPh), 3.79
(1H, t, J¼7.0 Hz, CH2SCHSCH2) 3.70–3.64 (1H, m,
CH2CH(OSi)CH(CH3), 2.83–2.72 (4H, m), 2.47–2.38
(1H, m, CH2CHvCHPh), 2.11–2.02 (2H, m), 1.87–1.77
(1H, m), 1.73–1.63 (1H, m), 1.52–1.41 (3H, m), 1.40–1.20
(3H, m), 1.08 (9H, s, tBu), 0.89 (3H, d, J¼6.8 Hz,
CH(OSi)CH(CH3); dC (125 MHz, CDCl3) 137.8 (s), 136.0
(d), 134.8 (s), 130.9 (s), 130.0 (d), 129.5 (s), 129.4 (d), 128.4
(d), 127.5 (d), 127.4 (d), 126.7 (d), 125.9 (d), 76.0 (d), 47.3
(d), 37.6 (d), 36.6 (t), 35.2 (t), 33.2 (t), 30.3 (t), 27.2 (q), 26.0
(t), 22.9 (t), 19.5 (s), 13.8 (q); m/z (þFAB) 573 (M2H)þ,
517 (M2tBu), 319, 281, 221, 199, 135, 117, 91, 73;
observed: Mþ2tBu, 517.2101. C31H37OSiS2 requires
Mþ2tBu, 517.2055.
CH2Cl2 (40 mL), in the dark, was added Et3N (365 mL,
2.5 mmol, 1 equiv.) under nitrogen, followed by the coupled
product (2.95 g, 2.5 mmol) in CH2Cl2 (40 mL) via cannula
over 10 min. The reaction was stirred at rt for 30 min,
quenched with saturated aqueous Na2S2O3 and extracted
with CH2Cl2 (£3). The combined organics were washed
with brine (£1), dried (MgSO4) and the solvent removed to
yield a yellow oil. The crude material was purified by flash
chromatography (40% ether/petrol) to yield a pale yellow
oil (2.04 g).
To this mixture of alcohols (2.04 g, 1.75 mmol) in THF
(44 mL) was added TBAF (8.75 mL, 8.75 mmol, 1 M in
THF, 5 equiv.) under nitrogen. The solution was stirred at
808C for 25 h, allowed to come to rt, quenched with water
and then extracted with ether (£3). The combined organics
were washed with brine (£1), dried (MgSO4) and the
solvent removed to yield a brown oil. The crude mixture
was purified by flash chromatography (50% ether/petrol) to
yield 20 (194 mg, 12% over three steps) as an orange foam.
The other diastereomer 19 could not be isolated pure since it
co-ran with an isomeric material tentatively assigned as
resulting from acetonide migration. Data for 20: Rf 0.2 (50%
ether/petrol); nmax (film) 3466, 2861, 1599 cm21; dH
(500 MHz, CDCl3) 7.70–7.17 (20H, m, Ph), 6.40 (1H, d,
J¼15.8 Hz, CH2CHvCHPh), 6.24–6.17 (1H, m, CH2-
CHvCHPh), 4.94 (1H, d, J¼6.5 Hz), 4.77 (1H, d,
J¼7.3 Hz), 4.66 (1H, d, J¼12.5 Hz), 4.56–4.41 (5H, m),
4.16 (1H, br d, J¼10.9 Hz), 3.90–3.55 (7H, m), 3.05 (1H,
m), 2.83 (1H, m), 2.71 (1H, m), 2.57 (1H, m), 2.39–2.30
(2H, m), 2.12 (1H, m), 1.88–1.20 (18H, m), 0.92 (3H, d,
J¼6.8 Hz); dC (125 MHz, CDCl3) 138.6, 138.1, 137.9,
137.6, 131.2, 129.4, 128.5, 128.2, 128.0, 128.0, 127.8,
127.6, 127.5, 127.4, 126.9, 126.0, 110.2, 108.9, 86.4, 81.1,
75.6, 74.2, 73.9 (d), 73.5 (d), 73.0 (d), 71.3 (d), 69.1 (d),
66.1, 59.4, 38.5, 37.3 (d), 35.0 (d), 34.9, 28.3, 27.2, 26.1,
26.0, 25.7 (d), 24.3 (d), 21.3 (d), 13.7.
4.1.11. Preparation of dithiane monoxide 18. To a
solution of dithiane 6 (57 mg, 0.1 mmol) in CH2Cl2
(700 mL) at 08C was added mCPBA (217 mL, 0.1 mmol,
0.46 M in CH2Cl2, 1 equiv.). The solution was stirred for
5 min, quenched with saturated aqueous Na2SO3 and the
mixture was extracted with CH2Cl2 (£4). The combined
organics were dried (MgSO4) and the solvent removed to
yield a colourless oil. The crude mixture was purified by
flash chromatography (90% ethyl acetate/petrol–ethyl
acetate) to yield the dithiane monoxide 18 (45 mg, 76%)
as a 5:1 mixture of the trans and cis pairs of diastereomers.
These could be separated by further chromatography (trans:
26 mg, 44%; cis: 6 mg, 10%), both as white foams, which
1
gave complex H NMR spectra indicating the presence of
mixtures of diastereomers. Data for 18 trans: Rf 0.2
(EtOAc); [a]2D2¼þ24.2 (c 0.98, CHCl3); nmax (CHCl3
solution) 2932, 2858, 1599, 1461, 1382, 1110, 1028, 967
and 612 cm21; m/z (ESþ) 613 (MþNa, 100); observed
613.2545, C35H46O2S2SiNa requires 613.2606. Data for 18
cis: Rf 0.29 (EtOAc); [a]2D7.5¼þ15.8 (c 0.92, CHCl3); nmax
(CHCl3 solution) 2933, 2859, 1599, 1462, 1382, 1362, 1111,
1052, 999, 967, 902 and 612 cm21; m/z (ESþ) 613 (MþNa,
100); observed 613.2563, C35H46O2S2SiNa requires
613.2606.
To a solution of 20 (17 mg, 0.018 mmol) in pyridine
(1.3 mL) was added DMAP (1 mg, catalytic amount)
followed by Ac2O (12 mL, 0.126 mmol, 7 equiv.). The
reaction was stirred at 608C for 3 h, allowed to come to rt,
quenched with water and then extracted with ether (£3). The
combined organics were washed successively with saturated
aqueous CuSO4 (£3), brine (£1), dried (MgSO4) and
solvent removed to yield a yellow oil. The crude mixture
was purified by flash chromatography (50% ether/petrol) to
yield 21 (12 mg, 69%) as a yellow oil. Rf 0.36 (50%
ether/petrol); dH (500 MHz, CDCl3) 7.41–7.19 (20H, m,
Ph), 6.41 (1H, d, J¼15.8 Hz, CH2CHvCHPh), 6.25–6.17
(1H, m, CH2CHvCHPh), 4.98–4.94 (2H, m), 4.82 (1H, d,
J¼8.1 Hz), 4.72–4.17 (7H, m), 4.19 (1H, d, J¼10.9 Hz),
3.96–3.79 (4H, m), 3.59 (1H, d, J¼10.9 Hz), 3.07 (1H, m),
2.61–2.32 (5H, m), 2.09 (3H, s), 2.07–1.23 (16H, m), 0.97
(3H, d, J¼6.8 Hz).
4.1.12. Preparation of (1S,3R,4S,5R,6R,7R,40R,50R,70E)-
1-[40-acetoxy-50-methyl-80-phenyl-oct-70-en-10-yl]-3,4,5-
tris-benzyloxymethyl-4,6,7-trihydroxy-2,8-dioxabicy-
clo[3.2.1]octane 22. To a solution of 18 trans (3.19 g,
5.4 mmol, 3 equiv.) in THF (15 mL) at 2788C was added
nBuLi (2.48 mL, 5.94 mmol, 2.4 M in hexanes, 3.1 equiv.)
dropwise under nitrogen. The solution was stirred for
15 min, then aldehyde 3 (1.0 g, 1.8 mmol) was added via
cannula over 10 min. The mixture was stirred for 1 h,
quenched with water and then allowed to come to rt.
Saturated aqueous NH4Cl was added and the mixture was
extracted with ether (£3). The combined organics were
washed with brine (£1), dried (MgSO4) and the solvent
removed to yield a yellow oil. The crude mixture was
purified by flash chromatography (60% ethyl acetate/
petrol–ethyl acetate) to remove unreacted side chain,
yielding the adducts (2.95 g) as a yellow oil.
To a solution of 21 (128 mg, 0.13 mmol) in CH2Cl2 (3 mL)
was added water (150 mL) and TFA (1.5 mL) under
nitrogen. The solution was stirred at rt for 2 h, quenched
with saturated aqueous NaHCO3 and then extracted with
CH2Cl2 (£2). The combined organics were dried (MgSO4)
and the solvent removed to yield a yellow oil. The crude
material was purified by flash chromatography (70%
To a solution of P2I4 (825 mg, 1.38 mmol, 0.55 equiv.) in

374
A. Armstrong et al. / Tetrahedron 59 (2003) 367–375
ether/petrol–ether) to yield bicyclic ketal 22 (79 mg, 78%)
as a colourless oil; [a]2D2¼þ10.91 (c 0.25, CHCl3); nmax
3436, 3062, 3029, 2925, 2876, 1732, 1495, 1454, 1369,
1244, 1207, 1075, 909, 740 and 699 cm21; dH (500 MHz,
CDCl3) 7.34–7.24 (17H, m, Ph), 7.21–7.16 (3H, m, Ph),
6.37 (1H, d, J¼16.0 Hz, CHvCHPh) 6.19–6.13 (1H, m,
CHvCHPh), 4.91–4.87 (1H, m, H40), 4.78 (1H, d,
J¼2.5 Hz, H6), 4.54 (1H, d, J¼12 Hz, one of OCH2Ph),
4.51 (1H, d, J¼12 Hz, one of OCH2Ph), 4.48 (1H, d,
J¼12.0 Hz, one of OCH2Ph), 4.45 (1H, d, J¼12.0 Hz, one
of OCH2Ph), 4.41–4.39 (1H, m, H3), 4.31 (2H, s, OCH2Ph),
4.00 (1H, d, J¼2.5 Hz, H7), 3.92 (1H, d, J¼10.0 Hz, one of
CH2OBn), 3.79 (1H, dd, J¼3.5, 11.0 Hz, one of CH2OBn),
3.61–3.58 (3H, m, three of CH2OBn), 3.47 (1H, d,
J¼10 Hz, one of CH2OBn), 3.47 (1H, br s, OH), 3.34
(1H, br s, OH), 2.32–2.27 (1H, m, one of H60), 2.03–1.97
(1H, m, one of H60), 2.03 (3H, s, OCOCH3), 1.85–1.80
(2H,m, CH2), 1.74–1.69 (1H, m, CH(CH3)), 1.55–1.48
(2H, m, CH2), 1.33–1.28 (2H, m, CH2), 0.92 (3H, d,
J¼7.0 Hz, CH(CH3)); dC (125 MHz, CDCl3) 171.0 (s),
138.1 (s), 137.6 (s), 136.8 (s), 131.5 (d), 128.6 (d), 128.5 (d),
128.3 (d), 128.2 (d), 127.9 (d), 127.7 (d), 127.6 (d), 126.9
(d), 126.0 (d), 105.2 (s), 105.1 (s), 86.8 (s), 83.6 (d), 79.4
(d), 79.3 (d), 73.9 (t), 73.5 (t), 73.2 (t), 73.0 (d), 70.9 (d),
69.5 (t), 69.4 (t), 68.4 (t), 36.7 (t), 36.5 (d), 35.3 (t), 31.2 (t),
21.2 (q), 19.2 (t), 14.2 (q); m/z (FABþ) 781 (MþH, 5), 721
(1), 531 (2), 461 (1), 391 (2), 355 (2); observed 781.3950,
C47H51O10 (MþH) requires 781.3952.
4.1.13. Preparation of (1S,3R,4S,5R,6R,7R,40R,50R,70E)-
1-[40-acetoxy-50-methyl-80-phenyl-oct-70-en-10-yl]-6,7-
bisbenzoyloxy-3,4,5-tris-benzyloxymethyl-4-hydroxy-
2,8-dioxabicyclo[3.2.1]octane 23. To a solution of 22
(25 mg, 0.032 mmol) in pyridine (640 mL) was added
DMAP (ca. 1 mg, catalytic amount) and benzoyl chloride
(15 mL, 0.128 mmol, 4 equiv.) under nitrogen. The solution
was stirred at rt for 30 h, quenched with water and then
extracted with CH2Cl2 (£2). The combined organics were
washed with saturated aqueous CuSO4 (£2), 2 M H2SO4
(£1), water (£1), dried (MgSO4) and the solvent removed to
yield a white solid. The crude material was purified by flash
chromatography (50% ether/petrol) to yield bisbenzoate 23
(31 mg, 98%) as a white foam; [a]2D3¼þ22.6 (c 0.62,
CHCl3); nmax 3451, 3063, 3029, 2962, 2928, 2877, 1702,
1693, 1602, 1452, 1370, 1302, 1113, 1026, 967, 752 and
712 cm21; dH (400 MHz, CDCl3) 8.10–8.04 (4H, m, Ph),
7.62–7.58 (1H, m, Ph), 7.55–7.50 (1H, m, Ph), 7.48–7.45
(2H, m, Ph), 7.33–7.12 (20H, m, Ph), 7.10–7.07 (2H, m,
Ph), 6.44 (1H, d, J¼2.5 Hz, H6), 6.34 (1H, d, J¼16.0 Hz,
CHvCHPh), 6.16–6.08 (1H, m, CHvCHPh), 5.52 (1H, d,
J¼2.5 Hz, H7), 4.90–4.87 (1H, m, H40), 4.78–4.75 (1H, m,
H3), 4.63 (1H, d, J¼12.0 Hz, one of OCH2Ph), 4.54 (1H, d,
J¼12.0 Hz, one of OCH2Ph), 4.47 (1H, d, J¼12.0 Hz, one
of OCH2Ph), 4.34 (2H, app t, J¼12.0 Hz, OCH2Ph), 4.21
(1H, d, J¼12.0 Hz, one of OCH2Ph), 4.10 (1H, d,
J¼6.0 Hz), 3.95–3.91 (2H, m), 3.78–3.70 (3H, m), 3.61
(1H, d, J¼10.0 Hz), 2.31–2.25 (1H, m, one of H60), 2.00–
1.92 (4H, m, inc. OCOCH3 and one of H60), 1.84–1.77 (1H,
m, CH(CH3)), 1.69–1.55 (4H, m, 2£CH2), 1.35–1.30 (2H,
m, CH2), 0.89 (3H, d, J¼7.0 Hz, CH(CH3)); dC (100 MHz,
CDCl3) 170.9 (s), 165.3 (s), 164.9 (s), 138.4 (s) 137.6 (s),
136.8 (s), 133.3 (d), 133.2 (d), 131.4 (d), 130.1 (d), 129.9
(d), 129.6 (s), 129.3 (s), 128.8 (d), 128.5 (d), 128.3 (d),
128.2 (d), 127.9 (d), 127.8 (d), 127.6 (d), 127.4 (d), 126.9
(d), 126.0 (d), 105.1 (s), 105.0 (s), 85.7 (s), 80.9 (d), 78.2
(d), 76.8 (d), 74.2 (d), 74.1 (t), 73.4 (t), 73.2 (t), 71.9 (s),
69.9 (t), 69.7 (t), 69.3 (t), 36.6 (t), 36.5 (d), 35.9 (s), 35.7 (t),
31.0 (t), 21.1 (q), 19.1 (t), 14.2 (q); m/z (FABþ) 989 (Mþ,
1.5), 971 (0.1), 929 (0.1), 911 (0.1), 531 (0.1), 399 (3), 307
(2); observed 989.4428, C61H65O12 (Mþ) requires
989.4476.
4.1.14. Preparation of (1S,3R,4S,5R,6R,7R,40R,50R,70E)-
1-[40-acetoxy-50-methyl-80-phenyl-oct-70-en-10-yl]-6,7-
bis-benzoyloxy-4-hydroxy-3,4,5-trihydroxymethyl-2,8-
dioxabicyclo[3.2.1]octane 24. To a solution of 23 (32 mg,
0.03 mmol) in CH2Cl2 (1 mL) was added BCl3·SMe2
(250 mL, 0.5 mmol, 2 M in CH2Cl2, 17 equiv.) under
nitrogen. The solution was stirred at rt for 21 h, quenched
with saturated aqueous NaHCO3 and then extracted with
CH2Cl2 (£2). The combined organics were washed with
brine (£1), dried (MgSO4) and the solvent removed to yield
a brown oil. The crude material was purified by flash
chromatography (ethyl acetate) to yield the tetraol 24
(14 mg, 65%) as a colourless oil, [a]2D3¼þ35.7 (c 0.28,
CHCl3); dH (400 MHz, CDCl3) 8.09 (2H, dd, J¼1.0, 8.0 Hz,
Ph), 8.03 (2H, dd, J¼1.0, 8.0 Hz), 7.62–7.57 (2H, m, Ph),
7.49–7.44 (4H, m, Ph), 7.34–7.27 (4H, m, Ph), 7.23–7.17
(1H, m, Ph), 6.35 (1H, d, J¼16.0 Hz, CHvCHPh), 6.17–
6.09 (1H, m, CHvCHPh), 5.95 (1H, d, J¼3.0 Hz, H6), 5.60
(1H, d, J¼3.0 Hz, H7), 4.93–4.89 (1H, m, H40), 4.27–4.22
(1H, m, H3), 4.01–3.86 (6H, m, 3£CH2OH), 3.36 (1H, br s,
18 OH), 3.26 (1H, br s, 18 OH), 3.17 (1H, br s, 18 OH), 2.71
(1H, br s, 38 OH), 2.30–2.22 (1H, m, one of H60), 2.03 (3H,
s, OCOCH3), 1.99–1.93 (1H, m, one of H60), 1.83–1.74
(1H, m, CH(CH3)), 1.71–1.45 (4H, m, 2£CH2), 1.33–1.19
(2H, m, CH2), 0.92 (3H, d, J¼7.0 Hz, CH(CH3)); dC
(100 MHz, CDCl3) 171.2 (s), 166.2 (s), 165.2 (s), 137.5 (s),
133.7 (d), 133.6 (d), 131.5 (d), 130.3 (d), 129.9 (d), 129.4
(d), 129.0 (s), 128.8 (s), 128.7 (d), 128.6 (d), 128.5 (d),
128.3 (d), 127.4 (d), 127.3 (d), 127.0 (d), 126.6 (d), 126.0
(d), 104.8 (s), 104.7 (s), 86.2 (s), 80.7 (d), 77.8 (d), 77.6 (d),
77.2 (d), 77.0 (d), 76.6 (d), 74.2 (d), 73.9 (d), 72.5 (s), 72.4
(s), 61.8 (t), 61.5 (t), 60.2 (t), 36.7 (t), 36.6 (d), 35.2 (t), 31.0
(t), 29.7 (t), 22.7 (q), 18.9 (t), 14.1 (q); m/z (FABþ) 741
(MþNa, 1), 719 (MþH, 1.5), 663 (1), 647 (1), 558 (1.5),
538 (1.5), 399 (2.5), 366 (2).
Acknowledgements
We thank the EPSRC (Quota studentship to PAB and
GR/L37588) and Pfizer (CASE award to TJB) for their
support of this work. We are grateful to Pfizer, Merck Sharp
and Dohme, AstraZeneca and Bristol-Myers Squibb for
unrestricted support.
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