The modified Julia olefination in vitamin D2 synthesis

Article abstract of DOI:10.1055/s-1999-3530

A partial synthesis of vitamin D₂ employing fragments derived from a new improved degradation procedure is described. The 7,8-double bond of the vitamin D triene system was synthesised via the modified Julia olefination. The new procedure is more efficient than the classical Julia olefination.

Full text of DOI:10.1055/s-1999-3530

PAPER
1209
The Modified Julia Olefination in Vitamin D2 Synthesis
Paul R. Blakemore,a Philip J. Kocienski,*a Stanislaw Marzcak,b Jerzy Wicha*b
a Chemistry Department, Glasgow University, Glasgow G12 8QQ, UK
Fax +44((141)3306867; E-mail: P.Kocienski@chem.gla.ac.uk
b Institute of Organic Chemistry, Polish Academy of Sciences, ul Kasprzaka 44/52, 01–224 Warsaw, Poland
Received 3 April 1999
lead tetraacetate. The resultant mixture of carbonyl com-
pounds was reduced with sodium borohydride in the pres-
ence of cerium trichloride according to the procedure of
Luche9 to give A-ring dienol 7 (81%) and the Windaus–
Grundmann C19 ketone 6 (83%)10 together with 13% of
the corresponding CD-ring b-hexahydrindanol 8b. In the
original Okamura procedure, the diol cleavage step is fol-
lowed by reduction of the mixture of carbonyl compounds
with sodium bis(2-methoxyethoxy)aluminium hydride
(Red-Al®) to give 8b as the only CD-ring component and
A-ring dienol 7 contaminated with varying amounts of the
alcohol 9. In our modification, the absence of contamina-
tion by 9 and the formation of ketone 6 rather than alcohol
Abstract: A partial synthesis of vitamin D2 employing fragments
derived from a new improved degradation procedure is described.
The 7,8-double bond of the vitamin D triene system was synthesised
via the modified Julia olefination. The new procedure is more effi-
cient than the classical Julia olefination.
Key words: vitamin D, alkene synthesis, sulfone, benzothiazole,
one-pot Julia olefination
The synthesis of vitamin D and its metabolites continues
to attract intense interest owing to their potential for the
treatment of rickets, renal osteodystrophy, osteoporosis,
psoriasis, leukemia, breast and prostate cancer, AIDS, and
1
8b significantly increased the efficiency of the synthesis
(vide infra).
Alzheimer’s disease. Construction of the conjugated
triene system has been a major stimulus to the develop-
ment of new connective olefin syntheses. A conspicuous
example is the Julia olefination which was first developed
as an alternative to the Horner–Wittig reaction to con-
struct the 7,8-double bond in a synthesis of vitamin D4
(the 22,23-dihydro analogue of vitamin D2) in 1979. 2 The
classical Julia olefination has since entered the repertoire
as one of the standard fragment linkage reactions in com-
plex natural product synthesis despite its length (3/4 steps)
and the need for sodium amalgam in the final stage. 3 We
now report the construction of the 7,8-double bond of vi-
tamin D2 (1) using the recently reported one-pot modified
Julia olefination4–6 via union of the benzothiazolyl sulfone
2b and the aldehyde 3 (Scheme 1).
H
H
(a) Pb(OAc)4 (1.2 equiv.)
pyridine (3 equiv.)
CH2Cl2, 0°C
6 (83%)
HO
H
H
O
OH
+
OH
(b) CeCl3•7H2O (2 equiv.)
NaBH4 (1.2 equiv.)
MeOH, 0°C
RO
TBSCl, DMAP
imidazole
CH2Cl2, rt, 89%
4 R = H
7 (81%)
TBSO
5 R = TBS
+
OH
22
H
23
H
H
TBSO
H
OH
8
8β (13%)
9
O
H
H
SO2
7
+
Scheme 2
N
S
1
HO
TBSO
The next step of the synthesis required substitution of the
hydroxy function at C4 of the hexahydroindanol by a 2-
sulfanylbenzothiazole unit. Attempts to accomplish this
task by a Mitsunobu reaction on the axial alcohol 8b gave
mainly recovered starting alcohol together with some
elimination products. We therefore required a synthesis of
the equatorial alcohol 8a for which the ketone was the
most convenient starting material. However, attempts to
prepare 8a by Bouveault-Blanc reduction of ketone 6
(Scheme 3) were complicated by competing base-cataly-
1 Vitamin D2
2β
3
Scheme 1
The requisite fragments for our study were prepared by a
modification of a procedure of Toh and Okamura.7 Thus,
the known vitamin D2 triol 48 (Scheme 2) was converted
to the mono-TBS ether 5 and the vicinal diol cleaved with
Synthesis 1999, No. 7, 1209–1215 ISSN 0039-7881 © Thieme Stuttgart · New York

1210
P. R. Blakemore et al.
PAPER
sed epimerisation of the trans-hydrindanone and subse- Dess-Martin oxidation of the pure A-ring dienol 7
quent reduction of the cis-hydrindanone. However, the (Scheme 5) led to the rapid formation of the dienal 3
epimerisation reaction could be suppressed by conducting which exists in equilibrium with its cyclic tautomer 15.
the reduction in the presence of dried Amberlite IR118 Shortly after isolation, the ratio of 3 to 15 was approxi-
acidic exchange resin to give pure 8a in 81% yield. Mit- mately 8:2 according to 1H NMR spectroscopy of the mix-
sunobu reaction of 8a with 2-sulfanylbenzothiazole now ture and at equilibrium the final ratio is 7:3. Complete
occurred in good yield to afford the corresponding b-thio- separation of these ring-chain tautomers is impossible ow-
ether 10b. Synthesis of the vitamin D2 CD-ring sulfone 2b ing to rapid interconversion and pointless since the pyran
was completed by an extremely sluggish Mo(VI)-cataly- acts as a latent aldehyde equivalent in the Julia olefina-
sed oxidation.
tion.
DMP (1.1 eq)
CH2Cl2
OH
O
O
Amberlite®
Na (11 eq)
H
H
rt, 30 min
89%
TBSO
TBSO
TBSO
4
Et2O-EtOH
0°C, 2.5 h
81%
H
7
3
15
H
O
HO
80 after reaction 20
70 at equilibrium 30
6
8α
BTSH, DIAD, PPh3
72%
H
THF, 0°C → rt, 12 h
Scheme 5
H
The synthesis of vitamin D2 was completed (Scheme 6) by
metallation of the sulfone 2b (1 equiv.) with NaHMDS
(1.2 equiv.) at –78 °C followed by addition of the equilib-
rium mixture of aldehyde 3 and its ring tautomer 15 (4:1,
2.8 equiv.) at –100 °C. On gradual warming, the modified
Julia olefination went to completion to give a mixture of
vitamin D2 TBS ether and its 7Z isomer (7E:7Z = 72:28,
ca 70%) along with 16% recovered aldehyde and 18% of
the sulfone 2a. The chromatographically purified mixture
of isomeric vitamin D2 TBS ethers was deprotected with
TBAF in quantitative yield and the isomers separated by
careful chromatograpy to give crystalline vitamin D2 (1)
and its rather unstable 7Z isomer 16. A separate experi-
ment established the configurational instability of the b-
sulfone 2b: treatment of 2b with NaHMDS (6 equiv.) in
Et2O at –78 °C for 1.5 h followed by quenching at low
temperature with MeOH gave epimeric sulfones 2a and
2b in 92% yield with 2a predominating (a:b = 85:15). At-
tempts to improve the efficiency of the coupling by invert-
ing the role of the two fragments were abandoned when a
related study directed towards the synthesis of vitamin D3
(Scheme 7) failed to yield any triene product.
(NH4)6Mo7O24
H2O2, EtOH
H
H
S
SO2
S
rt, 10 d
73%
N
S
N
2β
10β
Scheme 3
In order to quantify the extent of the epimerisation prob-
lem and its suppression by the ion exchange resin, we con-
ducted a similar reduction on Grundmann’s ketone 11 (the
CD fragment of vitamin D3) and the product distribution
of the alcohols ascertained by gas chromatography and of
the ketones by 13C NMR spectroscopy (using the C18 me-
thyl resonance) before complete consumption of ketone
11. The results are summarised in Scheme 4.
In conclusion, the modified Julia olefination presented
here is more convenient and higher yielding than the clas-
sical reaction for the linkage of A-ring and CD-ring vita-
min D fragments first applied to vitamin D4. Furthermore,
a repetition of the synthesis of vitamin D4 with the benefit
of modern separation and analytical techniques11 has re-
vealed that the modified Julia olefination also offers
slightly better stereoselectivity. In any case, stereoselec-
tivity is less important than linkage efficiency since (7Z)-
vitamin D trienes can be photoisomerised into the natural
(7E) isomers.12 Finally, our synthesis of vitamin D2 has
uncovered for the first time some stereochemical limita-
tions to the modified Julia olefination which were not ap-
Scheme 4
Synthesis 1999, No. 7, 1209–1215 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
The Modified Julia Olefination in Vitamin D2 Synthesis
1211
shift in ppm is quoted relative to the residual signals of CHCl3
1
(dH = 7.27 or dC = 77.2). Multiplicities in the H NMR spectra are
described as: s = singlet, d = doublet, t = triplet, q = quartet,
H
H
m = multiplet and br = broad. Coupling constants (J) are reported in
Hz. Numbers in parentheses following the chemical shift in the 13
C
NMR spectra refer to the number of attached hydrogens as revealed
by DEPT experiments employing secondary pulses at 90° and 135°.
Low (LRMS) and high (HRMS) resolution mass spectra were run
on a Jeol JMS700 spectrometer. Ion mass/charge (m/z) ratios are re-
ported as values in atomic mass units followed, in parentheses, by
the peak intensity relative to the base peak (100%).
H
E:Z = 72:28
+
H
Bu4NF (3 eq)
THF, rt, O/N
70% (2 steps)
HO
OH
(7Z)-vitamin D2 (16)
vitamin D2 (1)
(3b,5Z,7R,8a,22E)-3-(tert-Butyldimethylsilyloxy)-9,10-secoer-
gosta-5,10(19),22-triene-7,8-diol (5)
(a) NaHMDS (1.2 eq)
Et2O, –78°C, 1 h
To a stirred suspension of triol 4 (5.0 g, 11.6 mmol),7,8 imidazole
(2.4 g, 35.3 mmol) and 4-(dimethylamino)pyridine (20 mg, 0.16
mmol) in anhyd CH2Cl2 (50 mL) at r.t. under N2 was added drop-
wise over 30 min tert-butylchlorodimethylsilane (1.83 g, 12.2
mmol) in anhyd CH2Cl2 (50 mL) and the resultant mixture stirred
overnight. After this time the organic phase was washed successive-
ly with H2O (2 ¥ 50 mL), brine (50 mL) and then dried (MgSO4)
and concentrated in vacuo. The crude residue was then further puri-
fied via column chromatography (eluting with 20% Et2O in hex-
anes) to yield the monosilylated product 5 (5.60 g, 10.3 mmol, 89%)
as a white powder: mp 128–129 °C (hexanes); [a]D = +76.6
(c = 0.50, CHCl3).
H
TBS-vitamin D2
isomers
2β
+
(b) 3:15 (2.8 eq)
–100°C → rt, O/N
H
BTSO2
2α 18%
Scheme 6
H
S
N
(a) NaHMDS
IR (KBr): n = 3421 (br), 2956 (s), 2860 (s), 1461 (m), 1371 (m),
1254 (m), 1096 (s), 1005 (m), 870 (m), 837 (m), 775 (m) cm–1.
SO2
H
(b) ketone 11
1H NMR (360 MHz, CDCl3): d = 5.52 (1H, dm, J = 9.8 Hz), 5.21
(1H, dd, J = 15.2, 7.1 Hz), 5.14 (1H, dd, J = 15.2, 7.4 Hz), 4.98 (1H,
br s), 4.92 (1H, d, J = 9.8 Hz), 4.88 (1H, br s), 3.72 (1H, tt, J = 9.7,
4.2 Hz), 2.48–2.37 (2H, m), 2.19 (1H, ddd, J = 11.9, 10.0, 1.7 Hz),
2.05–1.90 (3H, m), 1.89–1.40 (10H, m), 1.30–1.08 (5H, m), 0.98
(3H, d, J = 6.6 Hz), 0.91 (3H, d, J = 6.8 Hz), 0.88 (9H, s), 0.86–0.80
(9H, m), 0.07 (3H, s), 0.06 (3H, s).
TBSO
TBSO
17
18
Scheme 7
13C NMR (90 MHz, CDCl3): d = 145.9 (0), 141.8 (0), 135.6 (1),
132.2 (1), 124.8 (1), 111.1 (2), 75.0 (0), 71.4 (1), 70.9 (1), 59.8 (1),
57.5 (1), 47.2 (2), 44.2 (0), 43.0 (1), 40.2 (1), 40.2 (2), 37.6 (2), 36.8
(2), 33.5 (2), 33.3 (1), 27.9 (2), 26.0 (3C, 3), 22.0 (2), 20.8 (3), 20.6
(2), 20.2 (3), 19.8 (3), 18.3 (0), 17.9 (3), 13.2 (3), –4.4 (3), –4.5 (3)
ppm.
parent from earlier successful syntheses of dienes13 and
trienes.14
LRMS (CI mode, NH3): m/z = 562 (15%), 527 (30), 509 (72), 377
(13), 294 (100), 267 (57), 249 (51).
All reactions requiring anhydrous conditions were conducted in
flame-dried apparatus under a static atmosphere of N2. THF and
Et2O were freshly distilled from sodium benzophenone ketyl prior
to use. CH2Cl2 was freshly distilled from CaH2. Preparative chro-
matographic separations were performed on Macherey-Nagel silica
gel 60 (230–400 mesh) and reactions were followed by TLC analy-
sis using Macherey-Nagel silica gel 60 plates with fluorescent indi-
cator (254 nm) and visualised with UV or phosphomolybdic acid.
All commercially available reagents were purchased from Aldrich
and were used as supplied.
Anal. Calcd. for C34H60O3Si (M = 544): C, 74.94; H, 11.10. Found
C, 74.99; H, 10.9.
Oxidative Cleavage of Diol 5
To a stirred solution of the diol 5 (3.0 g, 5.5 mmol) and pyridine
(1.34 mL, 1.31 g, 16.6 mmol) in anhyd CH2Cl2 (25 mL) at 0 °C un-
der N2 was added portionwise Pb(OAc)4 (2.93 g, 6.6 mmol) and the
resultant suspension stirred vigorously for 10 min. The mixture was
then filtered through a Celite pad and the residue washed well (3 ¥ 5
mL CH2Cl2). The filtrate and combined washings were then concen-
trated in vacuo and subsequently dissolved in a solution of ceri-
um(III) chloride heptahydrate (4.11 g, 11.0 mmol) in MeOH (30
mL). The mixture was then cooled to 0 °C, treated with NaBH4
(0.26 g, 6.8 mmol) and stirred for 15 min. H2O (30 mL) and Et2O
(30 mL) were then added and the layers shaken well and then sepa-
rated. The aqueous phase was then further extracted (3 ¥ 10 mL
Et2O) and the combined organic extracts washed with brine (15
mL), dried (MgSO4) and then concentrated in vacuo. The crude res-
idue was then further purified via column chromatography (eluting
with 10–15% Et2O in hexanes) to yield in order of elution: the
Windaus-Grundmann C19 ketone (6, 1.26 g, 4.6 mmol, 83%),15 the
corresponding over-reduced b-alcohol product 8b (0.20 g, 0.72
Mps were recorded using open capillary tubes on a Griffin melting
point apparatus and are uncorrected. Specific optical rotations
([a]D) were measured at ambient temperature (24±3 °C) from
CHCl3 solutions using a 5 mL cell with 1 dm path length. IR spectra
were recorded on a Nicolet Impact 410 FT-IR spectrometer using a
thin film supported between NaCl plates or KBr discs where stated.
Details are reported as nmax in cm–1, followed by an intensity de-
1
scriptor: s = strong, m = medium, w = weak or br = broad. H and
13C NMR spectra were recorded in Fourier transform mode at the
field strength specified or on a Bruker AM360. All spectra were ob-
tained in CDCl3 solution in 5 mm diameter tubes, and the chemical
Synthesis 1999, No. 7, 1209–1215 ISSN 0039-7881 © Thieme Stuttgart · New York

1212
P. R. Blakemore et al.
PAPER
mmol, 13%)16 and the A-ring dienol 7 (1.20 g, 4.5 mmol, 81%)7 all
LRMS (EI+mode): m/z = 278 (22%), 260 (8), 217 (36), 180 (29),
as clear oils.
151 (20), 135 (100), 109 (31), 93 (35).
[1R-[1a,(1R*,2E,4R*),3ab,7aa]]-Octahydro-7a-methyl-1-(1,4,5-
trimethylhex-2-enyl)-1H-inden-4-one (6)
[a]D = –19.1 (c = 1.00, CHCl3).
Anal. Calcd. for C19H34O (M = 278): C, 81.95; H, 12.31. Found C,
81.82; H, 12.22.
IR (film): n = 2958 (s), 1716 (s), 1460 (m), 1372 (m), 972 (m) cm–1.
[1R-[1a,(1R*,2E,4R*),3ab,4a,7aa]]-4-[(Benzothiazol-2-yl)sulfa-
nyl]octahydro-7a-methyl-1-(1,4,5-trimethylhex-2-enyl)-1H-in-
dene (10b)
1H NMR (360 MHz, CDCl3): d = 5.25 (1H, dd, J = 15.3, 7.2 Hz),
5.17 (1H, dd, J = 15.3, 7.9 Hz), 2.46 (1H, ddm, J = 11.0, 7.7 Hz),
2.33–2.17 (2H, m), 2.11–1.42 (12H, m), 1.35–1.30 (1H, m), 1.05
(3H, d, J = 6.7 Hz), 0.92 (3H, d, J = 6.8 Hz), 0.85 (3H, d, J = 6.6
Hz), 0.83 (3H, d, J = 6.7 Hz), 0.66 (3H, s).
13C NMR (90 MHz, CDCl3): d = 212.3 (0), 135.1 (1), 132.7 (1),
62.3 (1), 56.8 (1), 50.0 (0), 43.0 (1), 41.2 (2), 40.1 (1), 39.1 (2), 33.2
(1), 27.9 (2), 24.3 (2), 21.2 (3), 20.1 (3), 19.8 (3), 19.3 (2), 17.8 (3),
12.9 (3) ppm.
To a stirred solution of the a-alcohol 8a (512 mg, 1.84 mmol), 2-
sulfanylbenzothiazole (Aldrich, 460 mg, 2.75 mmol) and PPh3 (814
mg, 3.0 mmol) in anhyd THF (10 mL) under N2 at 0 °C was added
dropwise diisopropyl azodicarboxylate (555 mg, 2.75 mmol) in an-
hyd THF (3 mL). After 1 h the reaction was allowed to warm to r.t.
and stirred for a further 24 h. The solvent was then removed in vac-
uo and the crude residue further purified via column chromatogra-
phy (eluting with 10% Et2O in hexanes) to yield 10b (562 mg, 1.32
mmol, 72%) as a colourless solid: mp 68–70 °C (hexanes);
[a]D = +36.1 (c = 0.40, CHCl3).
LRMS (EI+mode): m/z = 276 (100%), 261 (6), 233 (32), 215 (41),
192 (13), 178 (34), 151 (55), 133 (49), 109 (44).
IR (film): n = 2954 (s), 1456 (s), 1428 (m), 992 (s), 754 (s) cm–1.
1H NMR (360 MHz, CDCl3): d = 7.85 (1H, dm, J = 8.1 Hz), 7.74
(1H, dm, J = 7.9 Hz), 7.34 (1H, ddd, J = 8.5, 7.3, 1.3 Hz), 7.30–7.25
(1H, m), 5.24 (1H, dd, J = 15.3, 7.2 Hz), 5.16 (1H, dd, J = 15.3, 8.0
Hz), 4.56 (1H, br s), 2.20 (1H, dm, J = 10.5 Hz), 2.05–1.95 (2H, m),
1.93–1.12 (12H, m), 1.02 (3H, d, J = 6.6 Hz), 0.93 (3H, d, J = 6.9
Hz), 0.91 (3H, s), 0.85 (3H, d, J = 6.7 Hz), 0.84 (3H, d, J = 6.8 Hz).
13C NMR (90 MHz, CDCl3): d = 168.7 (0), 153.4 (0), 135.6 (1),
135.2 (0), 132.3 (1), 126.1 (1), 124.2 (1), 121.5 (1), 121.0 (1), 56.5
(1), 52.5 (1), 48.5 (1), 43.0 (1), 42.8 (0), 40.2 (2), 40.2 (1), 33.5 (2),
33.3 (1), 27.8 (2), 24.5 (2), 21.0 (3), 20.1 (3), 19.8 (3), 18.7 (2), 17.8
(3), 13.8 (3).
(S,Z)-[5-(tert-Butyldimethylsilyloxy)-2-methylenecyclohexy-
lidene]ethanol (7)
[a]D = +44.0 (c = 0.43, CHCl3).
IR (film): n = 3340 (m, br), 2986 (s), 1254 (m), 1094 (s), 1006 (m),
836 (m), 774 (m) cm–1.
1H NMR (360 MHz, CDCl3): d = 5.45 (1H, tm, J = 7.0 Hz), 4.97
(1H, br s), 4.63 (1H, br s), 4.27 (1H, dd, J = 12.5, 7.3 Hz), 4.19 (1H,
ddd, J = 12.4, 6.2, 1.8 Hz), 3.85 (1H, tt, J = 8.6, 4.0 Hz), 2.45–2.35
(2H, m), 2.25–2.17 (1H, m), 2.13–2.03 (1H, m), 1.92–1.84 (1H, m),
1.65–1.54 (1H, m), 0.89 (9H, s), 0.07 (3H, s), 0.06 (3H, s).
13C NMR (90 MHz, CDCl3): d = 145.1 (0), 140.7 (0), 125.1 (1),
112.1 (2), 70.3 (1), 60.0 (2), 46.2 (2), 36.2 (2), 32.5 (2), 26.0 (3),
18.3 (0), –4.5 (3), –4.5 (3).
LRMS (EI+mode): m/z = 427 (45%), 394 (66), 384 (25), 260 (11),
168 (58), 125 (40).
Anal. Calcd. for C26H37NS2 (M = 427): C, 73.01; H, 8.72; N, 3.27.
Found C, 72.97; H, 8.73; N, 3.26.
LRMS (CI mode, NH3): m/z = 286 (100%), 268 (37), 251 (16), 119
(16).
[1R-[1a,(1R*,2E,4R*),3ab,4a,7aa]]-4-[(Benzothiazol-2-yl)sulfo-
nyl]octahydro-7a-methyl-1-(1,4,5-trimethylhex-2-enyl)-1H-in-
dene (2b)
[1R-[1a,(1R*,2E,4R*),3ab,4b,7aa]]-Octahydro-7a-methyl-1-
(1,4,5-trimethylhex-2-enyl)-1H-inden-4-ol (8a)
To a stirred suspension of the Windaus-Grundmann C19 ketone 6
(1.0 g, 3.62 mmol), dried Amberlite® IR118 acidic ion-exchange
resin (5.8 g, commercially supplied grade (Aldrich) dried at 0.1
mmHg, 50 °C, 5 h) and anhyd EtOH (9 mL) in Et2O (36 mL) at 0 °C
under N2 was added portionwise sodium metal (1.38 g, 60 mmol, ca
20 portions) over 2.5 h. After this time H2O (15 mL) was added and
the biphasic mixture filtered to remove the resin beads. The resin
beads were then washed well (3 ¥ 10 mL Et2O) into the filtrate and
the layers separated. The aqueous phase was then extracted (2 ¥ 10
mL Et2O) and the combined organic extracts washed with brine (30
mL), dried (MgSO4) and concentrated in vacuo. The residue was
further purified via column chromatography (eluting with 25%
Et2O in hexanes) to yield the vitamin D2 CD-ring a-alcohol 8a (812
mg, 2.92 mmol, 81%) as a crystalline solid: mp 81–83 °C (hex-
anes); [a]D = –24.4 (c = 0.95, CHCl3).
A stirred solution of the thioether 10b (523 mg, 1.22 mmol) in EtOH
(15 mL) at 0 °C was treated with ammonium heptamolybdate tet-
rahydrate (150 mg, 0.12 mmol) in 30% H2O2 (680 mg, 6.0 mmol)
and the resultant suspension allowed to warm to r.t. over 1 h. After
subsequent stirring at rt for 2 d, TLC analysis indicated the com-
plete consumption of the sulfide and showed the formation of two
diastereomeric sulfoxides. Further Mo catalyst (150 mg, 0.12
mmol) in 30% H2O2 (680 mg, 6.0 mmol) was added and the mixture
stirred at r.t. for a further 6 d. Due to sluggishness of the oxidation
of the sulfoxides to the sulfone, a further two portions of Mo/H2O2
(as before) were added over the next 2 d during which time the re-
action was continously sonicated. After this protracted reaction time
the mixture was diluted with Et2O (50 mL) and H2O (30 mL) and
the layers shaken and then separated. The aqueous layer was then
extracted (4 ¥ 15 mL Et2O) and the combined organic extracts
washed with brine (20 mL), dried (MgSO4) and then concentrated
in vacuo. The residue was then further purified via column chroma-
tography (eluting with 5% Et2O in hexanes) to yield the sulfone 2b
(410 mg, 0.89 mmol, 73%) as fine white needles: mp 135–137 °C
(EtOH); [a]D = –10.4 (c = 0.52, CHCl3).
IR (KBr): n = 3325 (br s), 2958 (s), 1459 (s), 1368 (m), 1093 (m),
1068 (m), 1031 (m), 1007 (m), 970 (s) cm–1.
1H NMR (360 MHz, CDCl3): d = 5.22 (1H, dd, J = 15.2, 7.1 Hz),
5.16 (1H, dd, J = 15.3, 7.6 Hz), 3.58 (1H, ddd, J = 10.4, 10.4, 4.3
Hz), 2.07–1.94 (2H, m), 1.90–1.05 (14H, m), 1.01 (3H, d, J = 6.6
Hz), 0.92 (3H, d, J = 6.8 Hz), 0.84 (3H, d, J = 6.7 Hz), 0.82 (3H, d,
J = 6.7 Hz), 0.69 (3H, s).
13C NMR (90 MHz, CDCl3): d = 135.8 (1), 132.1 (1), 71.3 (1), 57.5
(1), 56.6 (1), 44.8 (0), 43.0 (1), 40.0 (1), 39.3 (2), 36.1 (2), 33.3 (1),
28.4 (2), 23.6 (2), 22.0 (2), 21.1 (3), 20.1 (3), 19.8 (3), 17.8 (3), 12.4
(3).
IR (KBr): n = 2953 (s), 1470 (m), 1321 (s), 1302 (s), 1151 (m), 1128
(s), 762 (s), 730 (m), 671 (m), 601 (m), 527 (m) cm–1.
1H NMR (360 MHz, CDCl3): d = 8.20 (1H, dm, J = 8.1 Hz), 8.01
(1H, dm, J = 7.8 Hz), 7.63 (1H, tm, J = 7.2 Hz), 7.58 (1H, tm,
J = 7.2 Hz), 5.26 (1H, dd, J = 15.3, 7.4 Hz), 5.16 (1H, dd, J = 15.3,
8.3 Hz), 4.26 (1H, br t, J = 5.4 Hz), 2.34 (1H, qd, J = 12.7, 6.0 Hz),
Synthesis 1999, No. 7, 1209–1215 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
The Modified Julia Olefination in Vitamin D2 Synthesis
1213
2.24–2.00 (4H, m), 1.96–1.62 (4H, m), 1.60–1.43 (4H, m), 1.38–
1.26 (1H, m), 1.20–1.14 (1H, m), 1.14 (3H, s), 1.04 (3H, d, J = 6.6
Hz), 0.93 (3H, d, J = 6.8 Hz), 0.85 (3H, d, J = 6.5 Hz), 0.83 (3H, d,
J = 6.6 Hz).
13C NMR (90 MHz, CDCl3): d = 168.5 (0), 152.9 (0), 137.0 (0),
135.3 (1), 132.5 (1), 127.9 (1), 127.7 (1), 125.5 (1), 122.5 (1), 61.2
(1), 56.1 (1), 52.1 (1), 43.0 (1), 41.3 (0), 40.5 (1), 40.2 (2), 33.2 (1),
27.5 (2), 27.1 (2), 23.9 (2), 21.1 (3), 20.2 (3), 19.8 (3), 18.5 (2), 17.8
(3), 13.1 (3).
centrated in vacuo to yield 111 mg of a crude oil. The residue was
then further purified via column chromatography (eluting with 1–
10% Et2O in hexanes) to yield 57 mg of non-polar material (con-
taining vitamin D2 TBS ethers and pyran 15), recovered aldehyde 3
(13 mg, 0.05 mmol, 16%) and epimeric a-sulfone 2a (9 mg, 0.02
mmol, 18%). A solution of the non-polar material in anhyd THF (2
mL) at r.t. under N2 was then treated with tetrabutylammonium flu-
oride trihydrate (135 mg, 0.43 mmol) and stirred overnight. After
this time the mixture was diluted with Et2O (10 mL) and H2O (10
mL) and the layers shaken and then separated. The aqueous phase
was then extracted (2 ¥ 5 mL Et2O) and the combined organic ex-
tracts washed with brine (5 mL), dried (MgSO4) and then concen-
trated in vacuo. The residue was then further purified via column
chromatography (eluting with 20% Et2O in hexanes) to yield a pure
mixture of natural vitamin D2 (1) and (7Z)-vitamin D2 (16) as a clear
oil (30 mg, 0.076 mmol, 70% (2 steps), 1:16 = 72:28). The vitamin
D2 isomers can be separated by careful chromatography (eluting
with 10–15% Et2O in hexanes); the previously unreported unnatural
isomer 27 shows only limited stability in CDCl3.
LRMS (EI+mode): m/z = 459 (3%), 416 (11), 395 (35), 352 (30),
334 (30), 261 (57), 200 (58), 136 (100).
HRMS (EI+mode): Found M+•, 459.2269. C26H37NO2S2 requires
459.2266.
Anal. Calcd. for C26H37NO2S2 (M = 459): C, 67.93; H, 8.11; N,
3.05. Found C, 67.98; H, 8.12; N, 3.05.
(S,Z)-[5-(tert-Butyldimethylsilyloxy)-2-methylenecyclohexy-
lidene]acetaldehyde (3)
[1R-[1a,(1R*,2E,4R*),3ab,4b,7aa]]-4-(Benzothiazol-2-yl)thiooc-
tahydro-7a-methyl-1-(1,4,5-trimethylhex-2-enyl)-1H-indene
(2a)
To a stirred solution of the A-ring dienol 7 (175 mg, 0.65 mmol) in
anhyd CH2Cl2 (2 mL) at r.t. under N2 was added Dess-Martin
periodinane17 (305 mg, 0.72 mmol). The resultant mixture was then
stirred for 30 min and subsequently diluted with Et2O (10 mL),
poured into sat. Na2S2O3–NaHCO3 (15 mL) and stirred vigorously
for a further 10 min. The layers were then separated and the aqueous
phase extracted (2 ¥ 5 mL Et2O). The combined organic extracts
were then washed with sat. NaHCO3 (10 mL), dried (MgSO4) and
concentrated in vacuo. The residue was then filtered through a short
(4 cm) silica pad (eluting with 7% Et2O in hexanes) to yield a pure
mixture of the aldehyde 318 and its tautomeric pyran 15 (154 mg,
3:15 = 4:1, 0.58 mmol, 89%) as a clear oil. A dynamic equilibrium
exists between the two isomers: CHCl3 solutions of the separated
components both exhibit 3:15 = 7:3 after 36 h at r.t.
1H NMR (360 MHz, CDCl3): d = 8.24 (1H, dm, J = 7.7 Hz), 8.02
(1H, dm, J = 7.1 Hz), 7.65 (1H, td, J = 7.2, 1.4 Hz), 7.60 (1H, td,
J = 1.3 Hz), 5.21 (1H, dd, J = 15.2, 7.1 Hz), 5.14 (1H, dd, J = 15.2,
7.7 Hz), 3.67 (1H, td, J = 11.7, 3.4 Hz), 2.07–1.89 (3H, m), 1.84
(1H, sextet, J = 6.7 Hz), 1.76–1.65 (3H, m), 1.62–1.52 (3H, m),
1.50–1.13 (5H, m), 1.01 (3H, d, J = 6.6 Hz), 0.90 (3H, d, J = 6.8
Hz), 0.83 (3H, d, J = 6.5 Hz), 0.81 (3H, d, J = 6.5 Hz), 0.75 (3H, s).
Vitamin D2 (1)
Mp 109–110 °C (MeOH–H2O). (lit. 19 118 °C). NMR data is in
complete agreement with that previously reported.20,21
(7Z)-Vitamin D2 (16)
(S,Z)-[5-(tert-Butyldimethylsilyloxy)-2-methylenecyclohexy-
lidene]acetaldehyde (3)
The stereochemistry of 16 was assigned by analogy with other re-
ported (7Z)-vitamin D congeners.12,22
1H NMR (360 MHz, CDCl3): d = 9.81 (1H, d, J = 8.0 Hz), 5.89 (1H,
dm, J = 8.0 Hz), 5.21 (1H, m), 5.00 (1H, m), 4.06 (1H, tt, J = 6.8,
3.4 Hz), 2.60–2.54 (2H, m), 2.42 (1H, dd, J = 13.3, 6.9 Hz), 2.25
(1H, ddd, J = 12.4, 7.7, 4.6 Hz), 1.95–1.86 (1H, m), 1.80–1.70 (1H,
m), 0.87 (9H, s), 0.07 (6H, s).
1H NMR (360 MHz, CDCl3): d = 6.36 (1H, d, J = 11.6 Hz), 6.23
(1H, d, J = 11.6 Hz), 5.28–5.15 (2H, m), 5.09 (1H, m), 4.85 (1H,
m), 3.82 (1H, tt, J = 9.1, 4.1 Hz), 2.52 (1H, dd, J = 12.3, 3.2 Hz),
2.38 (1H, dt, J = 13.9, 5.0 Hz), 2.30–1.20 (20H, m), 1.03 (3H, d,
J = 6.6 Hz), 0.93 (3H, d, J = 6.5 Hz), 0.85 (3H, d, J = 6.4 Hz), 0.83
(3H, d, J = 6.1 Hz), 0.66 (3H, s).
13C NMR (90 MHz, CDCl3): d = 144.4 (0), 141.7 (0), 136.0 (0),
135.8 (1), 132.2 (1), 123.5 (1), 121.8 (1), 113.3 (2), 70.2 (1), 56.3
(1), 55.1 (1), 46.7 (0), 46.6 (2), 43.0 (1), 40.8 (2), 40.5 (1), 39.1 (2),
35.9 (2), 33.3 (1), 32.7 (2), 28.5 (2), 26.5 (2), 24.3 (2), 21.6 (3), 20.2
(3), 19.8 (3), 17.8 (3), 13.1 (3).
13C NMR (90 MHz, CDCl3): d = 192.8 (0), 163.2 (0), 144.0 (0),
128.5 (1), 116.8 (2), 69.5 (1), 46.3 (2), 35.4 (2), 31.5 (2), 25.9 (3C,
3), 18.2 (0), –4.5 (3), –4.6 (3).
(S)-3,4-Dehydro-6-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahy-
droisochroman (15)
1H NMR (360 MHz, CDCl3): (selected) d = 6.36 (1H, d, J = 5.5
Hz), 5.02 (1H, d, J = 5.7 Hz), 4.43 (2H, m), 3.91 (1H, dddd,
J = 11.2, 8.1, 5.1, 3.4 Hz) +other signals.
Scheme 8 depicts the synthesis of sulfone 17.
13C NMR (MHz, CDCl3): d = 143.2 (1), 123.0 (0), 119.4 (0), 105.9
(1), 68.3 (2), 68.1 (1), 36.8 (2), 31.6 (2), 26.1 (3C, 3), 25.3 (2), 18.4
(0), –4.5 (3), –4.6 (3).
OH
SBT
BTSH, DIAD, Ph3P
THF, rt, 12 h
89%
BT = 2-benzothiazolyl
Vitamin D2 (1)
TBSO
TBSO
To a stirred solution of the b-sulfone 2b (50 mg, 0.11 mmol) in an-
hyd Et2O (4 ml) at –78 °C under N2 was added dropwise a solution
of sodium hexamethyldisilazide (65 ml, 2.0 M in THF, 0.13 mmol)
and the resultant yellow solution stirred for 1 h. After this time the
mixture was cooled to –100 °C and a solution of the freshly pre-
pared aldehyde–pyran mixture (3:15 ~ 4:1, 80 mg, 0.31 mmol) in
anhyd Et2O (2 mL) added dropwise. The reaction was then allowed
to warm steadily to r.t. over the next 1.5 h and then stirred overnight.
After this time the mixture was diluted with Et2O (10 mL) and H2O
(10 mL) and the layers shaken and then separated. The aqueous
phase was then extracted (2 ¥ 5 mL Et2O) and the combined organic
extracts washed with brine (10 mL), dried (MgSO4) and then con-
19
7
(NH4)6Mo7O24, 30% H2O2
EtOH, 0°C, 2 h; rt, 4 h
SO2BT
SOBT
SO2BT
+
+
TBSO
TBSO
TBSO
21 (54%)
17 (21%)
20 (13%)
Scheme 8
Synthesis 1999, No. 7, 1209–1215 ISSN 0039-7881 © Thieme Stuttgart · New York

1214
P. R. Blakemore et al.
PAPER
(Z,S)-2-[2-[5-(tert-Butyldimethylsilyloxy)-2-methylenecyclo-
hexylidene]ethylsulfanyl]benzothiazole (19)
(S,Z)-4-[(Benzothiazol-2-yl)sulfonyl]methyl-1-[(1,1-dimethyl-
ethyl)dimethylsilyl]oxy-3-vinylcyclohex-3-ene (20)
To a stirred solution of the A-ring dienol 7 (540 mg, 2.0 mmol),
PPh3 (630 mg, 2.4 mmol) and 2-sulfanylbenzothiazole (550 mg, 3.3
mmol) in anhyd THF (10 mL) at r.t. under N2 was added dropwise
neat diisopropyl azodicarboxylate (0.48 g, 2.4 mmol). The resultant
solution was stirred for 12 h and then concentrated in vacuo. The
crude residue was further purified via column chromatography
(eluting with 5% Et2O in hexanes) to yield the sulfide 19 (747 mg,
1.79 mmol, 89%) as a clear oil: [a]D = +36.9 (c = 1.04, CHCl3).
IR (film): n = 2929 (s), 2856 (s), 1472 (s), 1334 (s), 1252 (s), 1152
(s), 1097 (s), 1006 (m), 882 (m), 837 (s), 763 (s), 729 (m) cm–1.
1H NMR (360 MHz, CDCl3): d = 8.23 (1H, dm, J = 7.9 Hz), 7.99
(1H, dm, J = 8.4 Hz), 7.64 (1H, ddd, J = 8.2, 7.2, 1.4 Hz), 7.59 (1H,
ddd, J = 8.1, 7.2, 1.3 Hz), 6.50 (1H, dd, J = 17.1, 10.9 Hz), 5.01
(1H, d, J = 16.4 Hz), 4.79 (1H, d, J = 11.1 Hz), 4.42 (1H, d, J = 14.2
Hz), 4.33 (1H, d, J = 14.0 Hz), 3.97–3.90 (1H, m), 2.59–2.34 (3H,
m), 2.07 (1H, ddm, J = 17.2, 7.0 Hz), 1.84–1.75 (1H, m), 1.68–1.58
(1H, m), 0.89 (9H, s), 0.07 (3H, s), 0.06 (3H, s).
13C NMR (90 MHz, CDCl3): d = 165.4 (0), 153.0 (0), 137.7 (0),
136.7 (0), 133.1 (1), 128.1 (1), 127.8 (1), 125.6 (1), 122.3 (1), 121.9
(0), 114.8 (2), 67.1 (1), 58.8 (2), 35.3 (2), 31.5 (2), 30.1 (2), 26.0
(3C, 3), 18.3 (0), –4.4 (3), –4.5 (3).
IR (film): n = 2934 (s), 2855 (s), 1460 (s), 1428 (s), 1252 (m), 1092
(s), 997 (s), 902 (m), 869 (m), 836 (s), 774 (s), 755 (s), 726 (m) cm–1.
1H NMR (360 MHz, CDCl3): d = 7.88 (1H, dm, J = 8.2 Hz), 7.76
(1H, dm, J = 8.0 Hz), 7.42 (1H, ddd, J = 8.4, 7.3, 1.2 Hz), 7.30 (1H,
ddd, J = 8.1, 7.0, 1.2 Hz), 5.51 (1H, tm, J = 7.8 Hz), 5.06 (1H, br s),
4.87 (1H, br s), 4.19 (1H, dd, J = 12.8, 7.9 Hz), 4.11 (1H, ddd,
J = 12.8, 7.6, 1.1 Hz), 3.83 (1H, tt, J = 8.2, 3.7 Hz), 2.50–2.38 (2H,
m), 2.22 (1H, dd, J = 12.9, 8.1 Hz), 2.11 (1H, dddm, J = 14.4, 8.4,
4.4 Hz), 1.90–1.82 (1H, m), 1.62 (1H, dddd, J = 12.9, 9.8, 8.2, 4.6
Hz), 0.87 (9H, s), 0.04 (6H, s).
13C NMR (90 MHz, CDCl3): d = 167.1 (0), 153.5 (0), 145.1 (0),
142.9 (0), 135.5 (0), 126.2 (1), 124.3 (1), 121.7 (1), 121.1 (1), 119.0
(1), 112.1 (2), 70.1 (1), 46.3 (2), 36.2 (2), 32.6 (2), 32.5 (2), 26.0
(3C, 3), 18.3 (0), –4.5 (3), –4.5 (3).
LRMS (CI mode, isobutane): m/z = 450 (100%), 136 (16).
(S,Z)-4-[(Benzothiazol-2-yl)sulfinyl]methyl-1-[(1,1-dimethyl-
ethyl)dimethylsilyl]oxy-3-vinylcyclohex-3-ene (21)
IR (film): n = 2928 (s), 2856 (s), 1472 (m), 1252 (s), 1007 (s), 1004
(m), 881 (m), 836 (s), 774 (m), 760 (m) cm–1.
1H NMR (360 MHz, CDCl3, isomeric mixture - * denotes a resolved
signal arising from a single isomer): d = 8.06 (1H, dm, J = 8.2 Hz),
7.99 (1H, dm, J = 8.1 Hz), 7.56 (1H, ddd, J = 8.4, 7.3, 1.3 Hz),
7.51–7.45 (1H, m), 6.65 (1H, dd, J = 17.1, 11.0 Hz), 5.15 (1H, d,
J = 17.1 Hz), 4.96 (1H, d, J = 11.0 Hz), 4.17 (1H*, d, J = 13.1 Hz),
4.09 (1H*, d, J = 13.0 Hz), 4.03 (1H*, d, J = 13.1 Hz), 3.96 (1H*, d,
J = 12.8 Hz), 3.99–3.90 (1H, m), 2.52–2.20 (3H, m), 2.19–2.08
(1H, m), 1.85–1.74 (1H, m), 1.68–1.56 (1H, m), 0.89 (9H*, s), 0.88
(9H*, s), 0.07 (3H, s), 0.07 (3H, s).
LRMS (EI+mode): m/z = 417 (37%), 370 (25), 285 (17), 252 (17),
224 (26), 193 (17), 149 (18), 119 (100), 91 (52), 73 (64).
HRMS (EI+mode): Found M+•, 417.1619. C22H31NOS2Si requires
417.1616.
13C NMR (90 MHz, CDCl3, isomeric mixture - † denotes signals
common to both isomers): d = 177.6† (0), 153.9† (0), 136.1 (0),
136.0 (0), 135.4 (0), 135.4 (0), 133.4 (1), 133.3 (1), 127.0† (1),
126.3† (1), 124.5 (0), 124.3 (0), 124.1 (1), 124.0 (1), 122.4 (1),
122.4 (1), 114.4 (2), 114.3 (2), 67.4 (1), 67.2 (1), 61.9 (2), 61.8 (2),
35.1† (2), 31.6 (2), 31.4 (2), 31.0 (2), 30.6 (2), 26.0† (3C, 3), 18.3†
(0), –4.5† (3), –4.5† (3).
Oxidation of Thioether 19
A stirred solution of the thioether 19 (200 mg, 0.48 mmol) in EtOH
(5 mL) at 0 °C was treated with ammonium heptamolybdate tet-
rahydrate (150 mg, 0.12 mmol) in 30% H2O2 (230 mg, 2.0 mmol).
The resulting yellow suspension was allowed to stir for 2 h at 0 °C
and then for a further 4 h at r.t. The mixture was then diluted with
H2O (10 mL) and extracted (4 ¥ 10 mL Et2O). The combined organ-
ic extracts were then dried (MgSO4) and concentrated in vacuo. The
residue was then further purified via column chromatography (elut-
ing with 10–25% Et2O in hexanes) to yield in order of elution: the
sulfone 17 (44 mg, 0.10 mmol, 21%), the isomeric sulfone 20 (28
mg, 0.06 mmol, 13%) and its parent sulfoxides 21 (113 mg, 0.26
mmol, 54%, dr = 1:1) all as clear oils.
LRMS (CI mode, isobutane): m/z = 434 (100%), 251 (20), 184 (20),
119 (39).
Acknowledgement
We thank the EPSRC; the Committee of Scientific Research, Repu-
blic of Poland (grant No. 3T09A 007 10, travel grant No. WAR/
992/067); the British Council and Rhône-Poulenc Rorer for a CASE
studentship (PRB).
(Z,S)-2-[2-[5-(tert-Butyldimethylsilyloxy)-2-methylenecyclo-
hexylidene]ethylsulfanyl]benzothiazole (17)
[a]D = +9.2 (c = 0.48, CHCl3).
IR (film): n = 2930 (s), 2856 (s), 1472 (m), 1332 (s), 1252 (m), 1149
(s), 1091 (s), 868 (m), 837 (m), 763 (m) cm–1.
1H NMR (360 MHz, CDCl3): d = 8.23 (1H, dm, J = 7.6 Hz), 8.02
(1H, dm, J = 7.6 Hz), 7.65 (1H, ddd, J = 7.2, 7.2, 1.4 Hz), 7.60 (1H,
ddd, J = 7.3, 7.3, 1.3 Hz), 5.35 (1H, t, J = 7.6 Hz), 4.99 (1H, br s),
4.83 (1H, m), 4.57 (1H, dd, J = 14.2, 8.9 Hz), 4.28 (1H, ddd,
J = 13.0, 6.2, 1.2 Hz), 3.55 (1H, tt, J = 8.8, 3.8 Hz), 2.42 (1H, dd,
J = 12.9, 3.9 Hz), 2.25 (1H, dt, J = 12.1, 4.4 Hz), 2.23–2.16 (1H,
m), 1.77–1.67 (2H, m), 1.55–1.46 (1H, m), 0.84 (9H, s), 0.00 (3H,
s), –0.01 (3H, s).
13C NMR (90 MHz, CDCl3): d = 166.0 (0), 152.9 (0), 149.0 (0),
144.5 (0), 137.0 (0), 128.2 (1), 127.8 (1), 125.6 (1), 122.5 (1), 112.8
(2), 108.9 (1), 70.3 (1), 55.4 (2), 46.8 (2), 36.1 (2), 32.3 (2), 26.0
(3C, 3), 18.3 (0), –4.6 (3), –4.6 (3).
References
(1) Okamura, W. H.; Zhu, G. Chem. Rev. 1995, 95, 1877.
(2) Kocienski, P. J.; Lythgoe, B.; Ruston, S. J. Chem. Soc., Perkin
Trans. I 1979, 1290.
(3) Kocienski, P. J. Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 6, p 975–
1010.
(4) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron
Lett. 1991, 32, 1175.
(5) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Bull. Soc.
Chim. Fr. 1993, 130, 336.
(6) Baudin, J. B.; Hareau, G.; Julia, S. A.; Lorne, R.; Ruel, O.
Bull. Soc. Chim. Fr. 1993, 130, 856.
(7) Toh, H. T.; Okamura, W. H. J. Org. Chem. 1983, 48, 1414.
(8) Wang, Y.; Ting, H.-S.; Huang, J.-J.; Chow, Y.-C.; Huang, Y.-
T. Acta Chim. Sin. 1958, 24, 126.
LRMS (CI mode, isobutane): m/z = 450 (100%), 136 (26).
HRMS (CI mode): Found (M+H)+, 450.1595. C22H32NO3S2Si re-
quires 450.1593.
Synthesis 1999, No. 7, 1209–1215 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
The Modified Julia Olefination in Vitamin D2 Synthesis
1215
(9) Luche, J.-L.; Rodriguez-Hahn, L.; Crabbe, P. J. Chem. Soc.,
Chem. Comm. 1978, 601.
(10) Kocienski, P.; Lythgoe, B.; Roberts, D. A. J. Chem. Soc.,
Perkin Trans. 1 1978, 834.
(11) Blakemore, P. R.; Grzywacz, P.; Kocienski, P. J.; Marczak, S.;
Wicha, J. manuscript in preparation.
(12) Van Alstyne, E. M.; Norman, A. W.; Okamura, W. H. J. Am.
Chem. Soc. 1994, 116, 6207.
(13) Smith, N. D.; Kocienski, P. J.; Street, S. D. A. Synthesis 1996,
652.
(14) Bellingham, R.; Jarowicki, K.; Kocienski, P.; Martin, V.
Synthesis 1996, 285.
(17) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
(18) Nemoto, H.; Kurobe, H.; Fukumoto, K.; Kametani, T. J. Org.
Chem. 1986, 51, 5311.
(19) Windaus, A.; Dithmar, K.; Fernholz, E. Justus Liebigs Ann.
Chem. 1932, 493, 259.
(20) Mizhiritskii, M. D.; Konstantinovskii, L. E.; Vishkautsan, R.
Tetrahedron 1996, 52, 1239.
(21) Mahé, C.; Patin, H.; Van Hulle, M.-T.; Barton, D. H. R. J.
Chem. Soc., Perkin Trans. I 1981, 2504.
(22) Maestro, M. A.; Sardina, F. J.; Castedo, L.; Mouriño, A. J.
Org. Chem. 1991, 56, 3582.
(15) Windaus, A.; Grundmann, W. Annalen 1936, 524, 295.
(16) Barrett, A. G. M.; Barton, D. H. R.; Russell, R. A.;
Widdowson, D. A. J. Chem. Soc., Chem. Comm. 1975, 102.
Article Identifier:
1437-210X,E;1999,0,07,1209,1215,ftx,en;Z03399SS.pdf
Synthesis 1999, No. 7, 1209–1215 ISSN 0039-7881 © Thieme Stuttgart · New York