Transformations of chromanol and tocopherol and synthesis of ascorbate conjugates

Article abstract of DOI:10.1016/j.tet.2010.12.066

α-Tocopherol and as a model compound pentamethylchromanol could be transferred into simple and more complex 5a-ether derivatives including galactopyranose as well as ascorbic acid conjugates. Following elaboration of a glucopyranoside spacer element this could be used for tethering the vitamin E and the vitamin C components to give novel conjugates for subsequent biostudies concerning their proposed synergism of antioxidant properties in tissues.

Full text of DOI:10.1016/j.tet.2010.12.066

Tetrahedron 67 (2011) 1654e1664
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Transformations of chromanol and tocopherol and synthesis of ascorbate
conjugates
y
*
Martina Lahmann , Joachim Thiem
University of Hamburg, Faculty of Science, Department of Chemistry, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 July 2010
Received in revised form 22 December 2010
Accepted 29 December 2010
Available online 8 January 2011
a
-Tocopherol and as a model compound pentamethylchromanol could be transferred into simple and
more complex 5a-ether derivatives including galactopyranose as well as ascorbic acid conjugates. Fol-
lowing elaboration of a glucopyranoside spacer element this could be used for tethering the vitamin E
and the vitamin C components to give novel conjugates for subsequent biostudies concerning their
proposed synergism of antioxidant properties in tissues.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
6-Chromanol
a
-Tocopherol
Ascorbate
Glucopyranoside spacer element
Conjugates
1. Introduction
scale for addition in cosmetics,19e21 including the 6-substituted PEG
ether derivatives.22,23 Since antioxidants are also added to many
Degenerative processes, including aging and age-related dys-
functions are believed to be caused by free radical attack on
a number of essential and sensitive molecules in biopathways. In
healthy organisms free radicals are intercepted by antioxidants at
rates faster than these biomolecules.1e3 One of the most effective
foodstuff and pharmaceuticals this area is objective of continuous
research,24,25 and furtheranextensionto formation ofnovelsynthetic
structures became of interest. Recently, both the synthesis of more
lipophilic ascorbates,26 as well as
a-tocopheryl b-D-glucopyrano-
sides,27,28 analogs therof29 and C-glucopyranosides15 as more hy-
drophilic vitamin E analogs were reported and their properties
studied.
lipid-soluble antioxidant in mammalian blood plasma is
copherol,4,5 a dominant active component of vitamin E.6 In contrast
to -tocopherol active in unpolar moieties, -ascorbic acid, vitamin
a-to-
a
L
In this contribution we wish to disclose our efforts to arrive at
novel tocopheroleascorbate conjugates bridged by saccharide-de-
rived tether structures. Of particular interest were directly linked
C, is the responsible antioxidant in aqueous regions. Consequently,
early on a synergistic system of these two vitamins was postu-
lated.7,8 More recent papers indicate that in vivo the
a
-tocopheryl
radical is indeed quenched by reaction with vitamin C.9,10
Various derivatives of -tocopherol attracted interest, such as
the nicotinic acid ester A,11 the
a
-tocopheroleascorbate structures like 22 as well as saccharide-
spacered structures, such as 47 and 48. In addition and as a model
structure for -tocopherol pentamethylchromanol was studied and
a
a
b
-D
-glucopyranoside B,12 the 60-
carried all through to the corresponding derivatives.
functionalized ascorbate ester component C,13 the uridine-50-
phosphate ester D,14 as well as the C-glucosylated structure E15
(Fig. 1).
2. Results and discussion
This cooperative system of the two vitamins has inspired
In addition to a-tocopherol (all-rac-a-tocopherol) the structurally
less demanding 2,20,5,7,8-pentamethyl-chroman-6-ol (3) could be
employed in these studies since its chemical properties, in particular
the sensitivity to oxidation, are largely similar. In a simple acid-cata-
lyzed condensation of trimethylhydroquinone (1) with isoprene (2)
originally developed by Claisen30 and improved by Smith et al.31 3
could be obtained easily. Mild oxidation with silver nitrate led to
2-(30-hydroxy-30-methyl-but-1-yl)-3,5,6-trimethyl-quinone (4), and
researcher to form and study further conjugates of
a-tocopherol and
L
-ascorbic acid,4,16e18 and also produce some of them on considerable
* Corresponding author. Tel.: þ49 40 42838 4241; fax: þ49 40 42838 4325;
e-mail address: joachim.thiem@chemie.uni-hamburg.de (J. Thiem).
y
Present address: Bangor University, School of Chemistry, Bangor, GwyneddLL57
2UW, UK.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.12.066

M. Lahmann, J. Thiem / Tetrahedron 67 (2011) 1654e1664
1655
CH3
CH3
CH3
CH3
CH3
H3C
O
H3C
RO
O
C16H33
C16H33
HO
O
HO
HO
HO
5
HO
E
O
HO
O
HO
HO
R =
HO
N
A
B
O
N
O
O
NH
O
P
OH
O
HO
n
O
O
O
O
O
HO OH
HO OH
C
D
Fig. 1. Previously reported tocopherol conjugates.
CH3
CH3
CH3
CH3
CH3
H3C
HO
OH
+
H3C
HO
O
H3C
O
O
H2C
H2C
CH3
i
ii
CH3
CH3
CH3
OH
CH3
1
CH3
3
4
2
iii
CH3
CH3
CH3
CH3
CH3
H3C
O
H3C
HO
O
CH3
H3C
HO
O
CH3
CH3
v
iv
CH3
O
O
OR
Cl
5
9
6 R = Me
7 R = Et
8 R = All
vi
ix
CH3
CH3
CH3
CH3
CH3
H3C
R1O
O
CH3
CH3
H3C
O
H3C
O
CH3
CH3
O
O
O
O
+
OR2
OR
10 R1 = Me3CSiMe2, R2 =
11 R1 = Me3CSiMe2, R2 =
12 R1 = Me3CSiMe2, R2 =
vii
Me
viii
H
13 R =
14 R =
x
15
H
Scheme 1. Reagents and conditions: (i) HOAc, ZnCl, H2SO4 (48%) (Ref. 31); (ii) AgNO3 (quant., in situ) (Ref. 33,34); (iii) AcCl (40%) (Ref. 33,34); (iv) ROH, THF, 0e20 ꢀC, NaH, 18 h:
R¼Me/6, R¼Et/7, R¼All/8 (99%); (v) THF, NaH, AllBr, 0e20 ꢀC (60%); (vi) lutidine, Me3CSiMe2OTf, 0e20 ꢀC (quant., in situ); (vii) (Ph3P)3RhCl, DABCO, 2 h, EtOH/H2O reflux,
(79%); (viii) acetone/H2O/HgO, HgCl2, 2 h, reflux (79%); (ix) CH2Cl2, DHP, TsOH, ꢁ10 ꢀC, 3 h (78%); (x) (Ph3P)3RhCl, DABCO, 2 h, EtOH/H2O, reflux then acetone/H2O, HgO/HgCl2, 1.5 h
reflux (23%).

1656
M. Lahmann, J. Thiem / Tetrahedron 67 (2011) 1654e1664
further treatment with acetyl chloride readily gave 6-O-acetyl-5-
chloromethyl-2,20,7,8-tetramethyl-chromon-6-ol (5).32e34 Thus, this
easilyaccessible and highly reactive 5a-chloro derivative can function
asthe starting material forattachmentofavarietyoffunctionalities to
the chromanol system. The 5a-methyl-(6), the 5a-ethyl-(7) as well as
the corresponding 5a-allyl ethers (8) could be obtained facily in high
yield by reaction of 5 with the corresponding sodium alkoxide (cf.
Ref. 33,34). Reaction of 8 with sodium hydride and allylbromide gave
the di-allyl ether derivative 9, and with lutidine as base and tert-
butyldimethylsilyl triflate compound 10 could be obtained. With 1,4-
diazabicyclo[2.2.2.]octane (DABCO) and tris-triphenyl-phosphine-
rhodium (I) chloride the sensitive propenyl ether 11 was isolated,
which on further treatment with mercury (II) salts gave the labile
silylether-protected 5a-hydroxy derivative 12. Transformation of
compound 8 with dihydropyran led to the tetrahydropyranyl de-
rivative13 inhighyield(78%). Thiswasaccompaniedbysome2,20,7,8-
tetramethyl-5,6-dipyranyl-chromane (15) presumably formed via
cycloaddition of an intermediate ortho-quinomethide structure de-
rived from 8.35 De-protection of 13 with Wilkinson catalyst followed
by mercury (II) treatment gave the THP-blocked 5a-hydroxychroman
14 in fair yield (Scheme 1).
high yield. On further reaction of 20 with 2,3-di-O-benzyl-ascor-
bate (21)36 under acid conditions the ether-linked chromanol-6-O-
ascorbate structure 22 was obtained in average yield. In another
experiment the same compound 22 could be prepared from the
di-allyl ether 9 and 21 under similar acid conditions. Apparently,
both chromanol 5a-esters or 5a-ethers are facily cleaved under
mild acid treatment to give the benzylic 5a-carbenium ion, which
will readily accept alcohols to form novel 5a-ether derivatives
(Scheme 2).
Subsequent studies were done in order to transfer some of the
above findings to the tocopherol system and also possibly extend
the functionalization. Following the approach to 5 also the acety-
lated 5a-chloromethyl tocopherol 23 could be obtained by treat-
ment with acetyl chloride.32 Its reaction with sodium azide led to
the 5a-azido derivative 2437 in quantitative yield. Even though 6-
methoxy-5a-amino-methyl chromanol was reported to be reduced
to the 5-amino component by Staudinger reaction38 a correspond-
ing or other reductive approaches did not lead to 5a-amino to-
copherol. Therefore, 23 was transferred in situ into the more
reactive 5a-iodomethyl component, which on treatment with
potassium phthalate gave the phthalimido derivative 25 quantita-
tively. By de-blocking with hydrazine an O/N-acetyl migration
occurred to give the final derivative 26 in 90% yield. Further at-
tempts to reactivate the amino function for extension from a 5a-
aminomethyl group were discontinued at this stage.
It was of interest to link chromanol via a simple spacer function
to ascorbic acid. Thus, the 5a-chloro-chromanol
5 could be
transformed as above with sodium hydride and 1,3-dioxolane-2-
methanol in THF to give the crystalline derivative 16 in over 60%
yield. The corresponding reaction of 5 with 1,3-dioxolane-2-eth-
anol gave amorphous 17 in 79% yield. For both these compounds
the above base-catalyzed allylation led to the allyl ether de-
rivatives 18 and 19, respectively, in about 70% yield. Surprisingly,
both compounds 18 and 19 on short treatment with formic acid at
room temperature led to the formation of the 5a-formate 20 in
In a series of transformation compound 23 could be reacted with
sodium hydroxide to give the 5a-hydroxymethyl compound 27 in
average yield. Treatment with sodium hydride and various alcohols
gave the 5a-alkoxymethyl derivatives in good yield (e.g., 30: 92%
yield). In a corresponding reaction also 1,2,3,4-di-O-isopropylidene-
a-
D
-galactopyranose39 could be attached via its 6-OH-position
CH3
CH3
CH3
CH3
H3C
R1O
O
H3C
HO
O
i
CH3
CH3
OR2
Cl
5
O
16 R1 =H,
R2 =
O
CH3
O
O
ii
ii
CH3
17 R1 = H,
18 R1 =
R2 =
, R2 =
, R2 =
H3C
O
O
iii
O
O
CH3
O
OR
19 R1 =
O
9 R = All
20 R = CHO
CH3
CH3
CH3
HO
HO
H3C
O
O
O
O
iv
BnO OBn
O
O
HO
21
O
22
BnO OBn
Scheme 2. Reagents and conditions: (i) Et2O, 1,3-dioxolane-2-methanol, NaH, 0e20 ꢀC, 2.5 h, 16 (62%); Et2O, 1,3-dioxolane-2-ethanol, NaH, 0e20 ꢀC, 12 h, 17 (79%); (ii) Et2O, AllBr,
NaH, 0e20 ꢀC, 24 h, 18 (62%); 73%); (iii) HCO2H, 20 ꢀC, 20 min, 19 (93%); (iv) toluene, TsOH, 1.5 h reflux, 22 from 20 (40%); 22 from 9 (24%).

M. Lahmann, J. Thiem / Tetrahedron 67 (2011) 1654e1664
1657
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C16H33
H3C
AcO
O
H3C
RO
O
i
Cl
X
24 R = Ac, X = N3
23
O
iii
N
25 R = Ac, X =
ii
O
CH3
CH3
C16H33
H3C
RO
O
26 R = H, X = NHAc
OR
O
27 R = H 28 R = Me
29 R = Et 30 R = All 31 R =
O
O
O
O
Scheme 3. Reagents and conditions: (i) for 24: CH3CN, NaN3, 5 h, reflux (quant.); for 25: NaI, K-phthalimide, DMF, 20 ꢀC, 15 h (98%); (ii) THF, N2H5OH, 12 h, reflux (90%); (iii) THF/
NaH/ROH, Bu4NI, 3 h, reflux, for 27: R¼H (40%); for 28: R¼Me (quant.); for 29: R¼Et (quant.); for 30: R¼All (92%); for 31: R¼diisopropylidene-galactopyranos-6-yl (32%).
(cf. lit.40) to give the first tocopherol sugar ether structure 31
(Scheme 3).
By deacetylation the colourless liquid 3-hydroxy-1,1-dimethoxy-
propane (35) resulted quantitatively (lit.43:different reaction, 23%
In the next section the spacer-functionalized saccharide unit
had to be prepared. Addition of acetic acid to acrolein (32) gave the
very labile 3-acetoxy-propanal (33)41 in low yield. This in turn was
treated with trimethylorthoformate to give 3-acetoxy-1,1-dime-
thoxy-propane (34) (cf. lit.42:different reaction, 4% yield, no data).
yield, no data), which could be used for glycosylation employing a-
acetobromoglucose 3644 under classical KoenigseKnorr conditions
ꢀ
to give the
b
-glucopyranoside 37 in good yield. Its Zemplen
deacetylation gave 38 quantitatively, which was regioselectively
silylated at 6-OH-position with TBDMS chloride to give 39 in situ
and then further tri-allylated to 40 (55% yield over two steps).
Following fluoride-catalyzed cleavage of the silyl-protected spacer-
arm glucopyranoside 41 was ready for condensation with the
chromanol and tocopherol derivatives, respectively (Scheme 4).
Thus, as described above both the acetylated 5a-chloro-chro-
manol 5 as well as 5a-chlorotocopherol 23 were condensed under
NaH-conditions with 41 to give the syrupy adducts 42 as well as 43.
The isolated yields amount to 64% for 42 and 46% for 43, re-
spectively, due to oxidative side reactions during workup. For sta-
bilization the phenolic groups at 6-position was readily allylated to
give the crystalline chromanol-sugar conjugate 44 in 72% yield. A
corresponding reaction with 43 resulted in the syrupy tocopherol
sugar conjugate 45 in 76% yield.
For the final conjugation the 2,3-di-O-allyl ascorbate 46 was
required and formed according to the synthesis of the 2,3-di-O-
benzyl derivative.36 The hygroscopic crystalline compound 46
decomposed readily and was thus obtained in just 23% yield. By
subsequent transacetalization this compound could be attached to
the conjugate 44 via the 5,6-dihydroxy functions to give the target
compound 47 in 93% yield. Due to the new stereogenic acetal centre
two diastereomers were formed in a ratio of about 1:1, and these
could be largely separated and characterized.
i
O
O
AcO
32
33
ii
AcO
iii
OMe
OMe
AcO
AcO
AcO
O
34 R = Ac
35 R = H
AcO
iv
Br
36
R2O
R1O
R1O
O
O
OMe
OMe
R1O
37 R1 = R2 = Ac
v
vi
38 R1 = R2 = H
39 R1 = H, R2 = Me3CSiMe2
The corresponding condensation of the vitamin C derivate 46
with the all-rac-a-tocopherol component 45 resulted in formation
vii
40 R1 =
, R2 = Me3CSiMe2
of the conjugate 48 in 75% yield. Whereas compound 45 as a mix-
ture of eight diastereomers appears homogeneous, the trans-
formation product 48 shows two sets of distereomers in the ratio of
about 1:1, which is apparently due to the dominating influence of
the new stereogenic acetal centre (Scheme 5).
viii
41 R1 =
, R2 = H
Scheme 4. Reagents and conditions: (i) HOAc, 20 ꢀC, 48 h (16%); (ii) CH3C(OCH3)3,
MeOH/H2SO4 (19:1), 20 ꢀC, 2 h (51%); (iii) MeOH, Na2CO3, 20 ꢀC, 18 h (quant.); (iv)
CH2Cl2, Ag2CO3, 20 h, 20 ꢀC (41%); (v) MeOH, NaOMe, 20 ꢀC, 15 h (quant.); (vi) imid-
azole, DMF, ꢁ10 ꢀC, Me3CSiMe2Cl, 1 h (quant., in situ); (vii) THF, AllBr, NaH, 0e20 ꢀC,
24 h (55%); (viii) THF, Bu4NF, 20 ꢀC, 3 h (quant., in situ).
Further reactions will focus on the simultaneous de-blocking of
the six allyl ether functions to generate the polar conjugates, which

1658
M. Lahmann, J. Thiem / Tetrahedron 67 (2011) 1654e1664
4. Experimental
CH3
CH3
R2
HO
AllO
AllO
H3C
R1O
O
O
O
OMe
4.1. General
+
AllO
OMe
TLC was carried out on silica gel (60 GF 254, Merck) and on alu-
minium plates. Detection was by UV-light followed by charring with
sulfuric acid (10%) in ethanol. Preparative column chromatography
was performed on silica gel (60, 230e400 mesh, particle size
Cl
5 R1 = Ac, R2 = CH3
41
23 R1 = Ac, R2 = C16H33
40e63 m
m, Merck), using the flash technique. 1H NMR spectra were
recorded on a Bruker AMX 400 at 400 MHz or a Bruker AMX 500 at
500 MHz 13C NMR spectra were recorded on a Bruker AMX 400 at
100.67 MHz and on a Bruker AMX 500 at 125.77 MHz. NMR assign-
ments were made using standard 1He1H- and 1He13C-COSY experi-
ments. The connectivities of carbon atoms were given by DEPT
experiments. For numbering cf. NMR data of Scheme 6. Mass spectra
were taken on MAT 311A (70 eV) and FAB-MSon VG-AnalyticalVG70-
250S (m-nitrobenzyl alcohol matrix) in positive mode at the given
fragmentor voltage. Melting points were taken on an Olympus BH-
polarising microscope with Mettler FP 82 heating plate and are un-
corrected. Optical rotations were measured at 20 ꢀConaPerkineElmer
model 241 polarimeter using a 1 dm cuvette. Evaporations were car-
ried out at <45 ꢀC under dimished pressure. Elemental analyses were
provided by the Microanalytical Section, Department of Chemistry.
i
CH3
H3C
CH3
R2
O
R1O
O
AllO
AllO
O
O
OMe
OMe
AllO
42 R1 = H, R2 = CH3
44 R1 = All, R2 = CH3
43 R1 = H, R2 = C16H33
45 R1 = All, R2 = C16H33
ii
ii
8a
CH3
4a'
CH3
8a'
CH3
13'
CH3
HO
HO
CH3
8
H3C
AllO
O
7
O
O
8b
4a
2
3
CH3
8'
iii
4'
1'
6
12a'
4
5
AllO OAll
46
b'-Sp
b-Sp
H H
5a
6ab O
O
4
cAllO
O
6aa,6bb
5aa
O
H
O
CH3
2
AllO1
3
O
CH3
R2
H
H
O
O
b
H3C
AllO
O
d
H
4aa
a'-Sp
a-Sp
1aa
2aa
OAll
H
AllO3aa
d
Scheme 6. Description for NMR assignment of compounds.
O
O
AllO
AllO
O
O
4.2. Syntheses
4.2.1. 5-Methyloxymethyl-2,20,7,8-tetramethyl-chroman-6-ol 6. 1H
O
AllO
O
O
AllO
OAll
NMR (400 MHz, CDCl3)
d
¼7.41 (s, 1H, HOeAr); 4.66 (s, 2H, CH2-5a);
3.43 (s, 3H, OMe); 2.62 (m, 2H, CH2-4); 2.15, 2.10 (s, 6H, CH3-7a and
47 R2 = CH3
48 R2 =
-8a); 1.77 (m, 2H, CH2-3); 1.28 (s, 6H, CH3-2a, -2a’). 13C NMR
CH3
(100 MHz, DCDl3)
d
¼147.43, 144.89 (2C, C-6, C-8b); 125.77, 123.09,
(C16H33
)
CH3
CH3
CH3
115.95, 115.16 (4C, C-8, C-7, C-5, C-4a); 72.41 (1C, C-2); 69.83 (1C, C-
5a); 58.10 (3C, OMe); 32.94 (1C, C-3); 26.66 (2C, C-2a, C-2a’); 20.27
(1C, C-4); 11.93, 11.71 (2C, C-7a, -8a).
Scheme 5. Reagents and conditions: (i) for 42: THF, NaH, 0e20 ꢀC, 12 h (64%); for 43:
(46%); (ii) for 44: THF, NaH, AllBr, 0e20 ꢀC, 18 h (72%); for 45: (76%); (iii) n-hexane/
CH2Cl2, TsOH, 1.5 h, reflux; for 47: (93%); for 48: (93%).
4.2.2. 5-Ethyloxymethyl-2,20,7,8-tetramethyl-chroman-6-ol
NMR (400 MHz, CDCl3)
5a); 3.60 (q, 2H, OCH2); 2.60 (m, 2H, CH2-4); 2.15, 2.10 (s, 6H,
7. 1H
d
¼7.72 (s, 1H, HOeAr); 4.70 (s, 2H, CH2-
will be employed for studies concerning the postulated synergism
of vitamins E and C (cf. Ref. 7e10).
CH3-7a and -8a); 1.76 (m, 2H, CH2-3); 1.28 (m, 9H, CH3-2a, -2a’
and CH2CH3). 13C NMR (100 MHz, CDCl3)
d
¼147.01, 144.37 (2C, C-
6 and C-8b); 125.13, 122.64, 115.70, 114.51 (4C, C-8, C-7, C-5, C-
4a); 71.94 (1C, C-2); 67.57, 69.83 (2C, C-5a, OEt); 32.48 (1C, C-3);
26.21 (2C, C-2a, C-2a’); 19.82 (1C, C-4); 14.69 (1C, OEt); 11.93,
11.71 (2C, C-7a, -8a).
3. Conclusion
In this contribution the chemistry of a-tocopherol and its model
compound pentamethylchromanol could be elaborated and
a number of novel phenol-alkyl ethers synthesized including sugar-
attached species. By extension via the reactive 5a-position both
systems could be conjugated to ascorbic acid derivatives directly.
4.2.3. 5-Allyloxymethyl-2,20,7,8-tetramethyl-chroman-6-ol 8. To 6-
O-acetyl-5-chloromethyl-2,20,7,8-tetramethyl-choman-6-ol (5,33,34
1.06 g, 3.6 mmol) and allyl alcohol (0.9 mL, 18 mmol) dissolved in
anhydrous tetrahydrofuran (10 mL) were added sodium hydride
(3.4 g, 85 mmol, 60%) at 0 ꢀC under stirring. The reaction mixture
was stirred for another 18 h gradually warming to room tempera-
ture, and then methanol (20 mL) was added at 0 ꢀC to destroy
Alternatively, after formation of a glucose spacer glycoside a-to-
copherol as well as pentamethylchromanol derivatives and ascor-
bic acid ethers could be condensed to give novel tethered
conjugates ready for further studies.

M. Lahmann, J. Thiem / Tetrahedron 67 (2011) 1654e1664
1659
remaining sodium hydride. The mixture was extracted with
diethylether (50 mL), washed three times with saturated sodium
chloride (20 mL each), dried over MgSO4 and evaporated. The
residue was purified by flash chromatography with ether to give
compound 8 as a colourless wax: 980 mg (90%).
4.2.7. 6-O-tert-butyldimethylsilyl-5-hydroxymethyl-2,20,7,8-tetra-
methyl-chroman-6-ol 12. Compound 11 (58 mg, 0.149 mmol) was
dissolved in a mixture of acetone (18 mL) and water (2 mL) and kept
with HgO (60 mg) and HgCl2 (60 mg) under reflux for 2 h. After
filtration the residue was taken up in ethyl acetate (10 mL), washed
with aqueous KI (50%) and saturated NaCl, dried over MgSO4,
evaporated and purified by flash chromatography (pet. ether/ethyl
acetate 13:2) to give 12: 41.5 mg (79%) as a pale yellow syrup.
1H NMR (400 MHz, CDCl3)
d
¼7.43 (s, 1H, HOeAr); 5.94 (m, 1H,
H-c); 5.31 (m,1H, H-d); 5.25 (m,1H, H-d’); 4.71 (s, 2H, CH2-5a); 4.07
(m, 2H, H-b); 2.61 (m, 2H, CH2-4); 2.15, 2.10 (s, 6H, CH3-7a and -8a);
1.76 (m, 2H, CH2-3); 1.27 (s, 6H, CH3-2a, -2a’). 13C NMR (100 MHz,
1H NMR (400 MHz, CDCl3)
d
¼4.67 (s, 2H, CH2-5a); 2.84 (m, 2H,
CDCl3)
d
¼147.47, 144.88 (2C, C-6 and C-8b); 133.77 (1C, ]CH, C-all-
CH2-4); 2.10, 2.09 (s, 6H, CH3-7a and -8a); 1.79 (m, 2H, CH2-3); 1.31
c); 125.80, 123.13 (2C, C-7, C-8); 118.15 (1C, ]CH2, C-all-d); 116.00,
115.18 (2C, C-5, C-4a); 72.41 (1C, C-2); 71.11, 67.09 (4C, OCH2, C-all-
b and CH2, C-5a); 32.90, 20.25 (2C, CH2, C-3, C-4); 26.65 (2C, CH3, C-
20, C-2a’); 11.94 (2C, CH3, C-7a, 8a).
(s, 6H, CH3-2a, -2a’); 1.05 (s, 9H, t-BueSi); 0.16 (s, 6H, CH3eSi).
4.2.8. 5-Allyloxymethyl-6-O-tetrahydropyranyl-2,20,7,8-tetramethyl-
chroman-6-ol 13. Compound 8 (138 mg, 0.5 mmol) was dissolved
in anhydrous dichloromethane (2 mL), cooled to ꢁ10 ꢀC and treated
4.2.4. 6-O-Allyl-5-allyloxymethyl-2,20,7,8-tetramethyl-chroman-6-ol
9. Under a nitrogen cover compound 8 (980 mg, 3.6 mmol) dis-
solved in anhydrous THF (10 mL) was cooled to 0 ꢀC, treated with
sodium hydride (60%, 3.6 g, 90 mmol) and stirred for 30 min. Then
allylbromide (3.0 mL, 36 mmol) were added and the mixture kept
at room temperature for 18 h. Workup and purification by flash
chromatography (pet. ether/ethyl acetate 7:1) was as for 8 to give
compound 11 as a pale yellow syrup: 600 mg (60%).
with dihydropyran (113 mL, 1.25 mmol) and TsOH (1 mg) for 3 h at
ꢁ10 ꢀC. Then the mixture was warmed to room temperature,
dichloromethane (15 mL) added and the organic phase washed
successively with saturated NaCl and NaHCO3 solution, dried
(MgSO4), evaporated and purified by flash chromatography (pet.
ether/ethyl acetate 9:1) to give 13: 140 mg (78%) as a pale yellow
syrup.
1H NMR (400 MHz, CDCl3)
d
¼5.97 (m, 1H, H-c); 5.30 (m, 1H, H-
1H NMR (40 MHz, CDCl3)
d
¼6.12 (m, 1H, H-c); 5.95 (m, 1H, H-c);
d); 5.17 (m, 1H, H-d’); 4.74 (m, 1H, OCH-THP); 4.71 (d, 1H, CH2-5a);
4.51 (d, 1H, CH2-5a’); 4.12e3.98 (m, 3H, H-b, -b’, OCH2-THP); 3.38
(m, 1H, OCH2-THP); 2.86 (m, 2H, CH2-4); 2.21, 2.12 (s, 6H, CH3-7a
and -8a); 2.06e1.32 (m, 14H, CH2-3, 3ꢂCH2-THP, CH3-2a, -2a’).
As side product 2,20,7,8-tetramethyl-5,6-dipyranyl-chroman
1535 was obtained and characterized.
5.45 (m, 1H, H-d); 5.29 (m, 1H, H-d); 5.25 (m, 1H, H-d’); 5.17 (m, 1H,
H-d’); 4.53 (s, 1H, CH2-5a); 4.26 (dt, 2H, H-b); 4.03 (dt, 2H, H-b’);
2.83 (m, 2H, CH2-4); 2.18, 2.10 (s, 6H, CH3-7a and -8a); 1.78 (m, 2H,
CH2-3); 1.31 (s, 6H, CH3-2a, -2a’). 13C NMR (100 MHz, CDCl3)
d
¼148.85, 147.78 (2C, C-6 and C-8b); 134.71, 133.91 (2C, ]CH, C-all-
c); 127.69, 125.82, 125.25 (3C, C-5, C-7, C-8); 118.18 (1C, C-4a);
116.46, 116.23 (2C, ]CH2, C-all-d); 75.05, 70.94, 63.74 (3C, C-5a,
2ꢂC-all-b); 72.61 (1C, C-2); 32.32, 19.36 (2C, C-3, C-4); 26.51 (2C, C-
20, C-2a’); 12.36, 11.69 (2C, CH3, C-7a, -8a). Anal. Calcd for
C20H28O3(316.4): C, 75.91; H, 8.92. Found: C, 76.11; H, 8.94. EI-MS:
316(Mþ).
1H NMR (400 MHz, CDCl3)
d
¼5.18 (s, 1H, H-c); 3.39 (m, 1H, H-b);
3.64 (m, 1H, H-b’); 2.86e2.38 (m, 4H, CH2-4, 2ꢂCH2-THP);
2.15e2.04 (m, 1H, CH-e); 2.09, 2.04 (s, 6H, CH3-7a and -8a);
1.74e1.51 (m, 6H, CH2-3, 2ꢂCH2); 1.22 (s, 6H, CH3-2a, -2a’). 13C NMR
(100 MHz, CDCl3)
d
¼145.83, 143.41 (2C, C-6 and C-8b); 123.97,
123.20 (2C, C-7, C-8); 115.83, 114.72 (2C, C-5, C-4a); 96.31 (1C, C-a);
72.73 (1C, C-2); 31.89 (1C, C-e); 33.08, 20.33 (2C, C-3, C-4); 27.12,
26.87 (2C, C-20, C-2a’); 26.33, 25.02, 23.65 (3C, CH2, C-c, C-d, C-f);
11.90 (2C, CH3, C-7a, -8a). EI-MS: 302 (Mþ). Anal. Calcd for
C19H26O3(302.4): C, 75.46; H, 8.67. Found: C, 74.77; H, 8.67.
4.2.5. 5-Allyloxymethyl-6-O-tert-butyldimethylsilyl-2,20,7,8-tetra-
methyl-chroman-6-ol 10. A solution of compound
8 (1.28 g,
4.64 mmol) in lutidine (3.3 mL, 27.8 mmol) was cooled to 0 ꢀC and
tert-butyldimethylsilyl triflate (2.1 mL, 9.27 mmol) added drop wise
under stirring. After 3 h at room temperature the silylation reagent
was hydrolysed with water (1 mL), then diluted with ethyl acetate
(20 mL) and the organic phase washed thoroughly with saturated
NaCl, 0.5 N H2SO4 and saturated NaHCO3 then dried (MgSO4) and the
solvents evaporated to give the raw material 10 as an oil.
4.2.9. 5-Hydroxymethyl-6-O-tetrahydropyranyl-2,20,7,8-tetra-
methyl-chroman-6-ol 14. Compound 13 (100 mg, 0.27 mmol) were
dissolved in ethanol (10 mL) and water (1 mL) and refluxed for 2 h
with (Ph3P)3RhCl (18 mg, 0.018 mmol) and DABCO (4 mg,
0.037 mmol). Then the mixture was evaporated, dissolved in ace-
tone (36 mL) and water (4 mL) and refluxed for 90 min with HgO
(110 mg) and HgCl2 (110 mg), filtered over Celite and evaporated.
The residue was dissolved in dichloromethane (10 mL) washed
with aqueous KI (50%), saturated NaCl, dried (MgSo4) and purified
by flash chromatography (pet. ether/ethyl acetate 13:2) to give 14:
20 mg (23%) as a pale yellow syrup.
1H NMR (400 MHz, CDCl3)
5.13 (m, 1H, H-d’); 4.50 (s, 2H, CH2-5a); 3.92 (m, 2H, H-b); 2.81 (m,
2H, CH2-4); 2.09, 2.08 (s, 6H, CH3-7a and -8a); 1.77 (m, 2H, CH2-3);
1.28 (s, 6H, CH3-2a, -2a’); 1.05 (s, 9H, t-BueSi); 0.10 (s, 6H, CH3eSi).
d
¼5.92 (m,1H, H-c); 5.25 (m,1H, H-d);
4.2.6. 6-O-tert-butyldimethylsilyl-5-(1-propenyl)-oxymethyl-
2,20,7,8-tetramethyl-chroman-6-ol 11. The raw material 10 (1.64 g,
4.2 mmol) was dissolved in ethanol (100 mL) and water (10 mL).
Then tris-triphenyl-phosphine-rhodium (I) chloride (260 mg,
0.29 mmol) and 1,4-diazabicyclo [2.2.2] octane (DABCO, 95 mg,
0.94 mmol) were added and the mixture heated under reflux for
2 h. After cooling ethyl acetate (100 mL) was added, the organic
phase dried (MgSO4) and evaporated. Purification was by flash
chromatography (pet. ether/ethyl acetate 13:1) to give compound
11: 1.30 g (79%) as a pale yellow wax.
1H NMR (400 MHz, CDCl3)
d
¼4.84 (dd, 1H, CH2-5a); 4.55 (dd, 1H,
OCHeTHP-1); 4.34 (ddwt, CH2-5b); 4.02 (m, 3H, OCH2eTHP-5a);
3.73 (dd, 1H, 5a-OH); 3.42 (m, 1H, OCH2-THP-5b); 2.98 (m, 2H, CH2-
4a);2.78(m, 2H,CH2-4b);2.14, 2.10(s, 6H,CH3-7aand-8a);1.98e1.49
(m, 6H, 3ꢂCH2-THP); 1.80 (m, 2H, CH2-3); 1.34, 1.27 (s, 6H, CH3-2a,
-2a’). J5a,OH¼2.5, Ja,b¼11.7, J1THP,5aTHP¼2.0, J1THP,5bTHP¼8.6 Hz.13C NMR
(100 MHz, CDCl3)
d
¼148.19,146.39 (2C, C-6 andC-8b);129.80,126.89,
125.43, 117.02 (4C, C-4a, C-5, C-7, C-8); 102.67 (1C, C-THP-1); 72.69
(1C, C-2); 66.04, 55.54 (2C, OCH2, C-THP-5 and CH2, C-5a); 32.28,
30.92, 24.50, 21.54,19.35 (5C, CH2, C-3, C-4, C-THP-2, C-THP-3, C-THP-
4); 27.36, 25.60 (2C, CH3, C-20, C-2a’); 12.97, 11.71 (2C, CH3 C-7a, -8a).
1H NMR (400 MHz, CDCl3)
d
¼6.30 (m, 1H, H-a); 6.02 (m, 1H, H-
A); 4.84 (m, 1H, H-b); 4.79 (s, 2H, CH2-5a-Z); 4.66 (s, 2H, CH2-5a-E);
4.35 (m, 1H, H-B); 2.82 (m, 2H, CH2-4-Z); 2.74 (m, 2H, CH2-4-E);
2.10, 2.09 (s, 2ꢂ6H, CH3-7a and -8a); 1.78 (m, 2H, CH2-3); 1.58 (s,
3H, CH3-Vin); 1.54 (s, 3H, CH3-Vin); 1.30 (s, 2ꢂ6H, CH3-2a, -2a’);
1.05 (s, 2ꢂ9H, t-BueSi); 0.12 (s, 2ꢂ6H, CH3eSi).
4.2.10. 5-[10-(1,3-Dioxolane-2-yl)-methyl-10-oxy]-methyl-2,20,7,8-
tetramethyl-chroman-6-ol 16. Compound 5 (296 mg, 1.0 mmol) and
1,3-dioxolane-2-methanol (hydroxyacetaldehyde ethylene acetal,

1660
M. Lahmann, J. Thiem / Tetrahedron 67 (2011) 1654e1664
150 mg, 1.44 mmol) dissolved in anhydrous diethylether (5 mL)
were treated with sodium hydride (60%, 60 mg, 1.5 mmol) under
nitrogen at 0 ꢀC. After 2.5 h workup as for 8 followed by flash
chromatography (pet. ether/ethyl acetate 5:1) gave 16: 200 mg
(62%) as a yellow solid; mp 63e64 ꢀC.
and evaporated in high vacuum to give 20: 95 mg (93%) as a yellow
syrup.
1H NMR (400 MHz, CDCl3)
d
¼8.14 (s, 1H, CHO); 6.09 (ddd, 1H,
CH-6c); 5.42 (dd, 1H, CH2-6d); 5.29 (s, 2H, CH2-5a); 5.27 (dd, 1H,
CH2-6d’); 4.24 (d, 2H, CH2-b); 2.73 (m, 2H, CH2-4); 2.19 (s, 6H, CH3-
7a and -8a); 1.79 (m, 2H, CH2-3); 1.32 (s, 6H, CH3-2a, -2a’);
J6d,6d’¼1.3, J6c,d(E)¼17.0, J6c,d(Z)¼10.7, J6b,c¼5.7, J3,4¼6.9 Hz.
1H NMR (400 MHz, CDCl3)
d
¼7.18 (s, 1H, AreOH); 5.10 (t,1H, CH-
5c); 4.78 (s, 2H, CH2-5a); 4.05e3.91 (m, 4H, OCH2edioxolane); 3.63
(d, 2H, CH2-5b); 2.65 (m, 2H, CH2-4); 2.16, 2.10 (s, 6H, CH3-7a and
-8a); 1.76 (m, 2H, CH2-3); 1.28 (s, 6H, CH3-2a, -2a’); J5b,c¼3.6 Hz. EI-
MS: 322 (Mþ). Anal. Calcd for C18H26O5(322.4): C, 67.06; H, 8.13.
Found: C, 67.04; H, 8.32.
4.2.15. 6-O-Allyl-5-(2,3-di-O-benzyl-L-ascorbate-6-oxy)-methyl-
2,20,7,8-tetramethyl-chroman-6-ol 22. (a) Compound 20 (60 mg,
0.2 mmol) and di-O-benzyl-ascorbate 2136 (127 mg, 0.36 mmol)
dissolved in toluene (2 mL) were treated with TsOH (1 mg) and
heated under reflux for 1.5 h. The cold reaction mixture was neu-
tralised with basic ion exchanger (Amberlite IRA-420, OHꢁ), evap-
orated, and the residue purified by flash chromatography (pet.
ether/ethyl acetate 5:1 plus 0.4% triethylamine) to give 22: 49 mg
(40%) as pale yellow oil.
4.2.11. 5-[20-(1,3-Dioxolane-2-yl)-ethyl-10-oxy]-methyl-2,20,7,8-tet-
ramethyl-chroman-6-ol 17. Compound 5 (1.8 g, 6.0 mmol) and 1,3-
dioxolane-2-ethanol (3-hydroxypropionaldehyde ethylene acetal,
743 mg, 6.3 mmol) dissolved in anhydrous diethylether (10 mL)
were treated with sodium hydride (60%, 378 mg, 9.0 mmol) under
nitrogen at 0 ꢀC for 12 h. Workup as for 8 followed by flash chro-
matography purification gave 17: 670 mg, 79% as a yellow amor-
phous solid.
(b) Compound 9 (170 mg, 0.54 mmol) and di-O-benzyl-ascorbate
2136 (250 mg, 0.7 mmol) dissolved in toluene (10 mL) were treated
with TsOH (3 mg) and heated under reflux for 3 h. Workup and pu-
1H NMR (400 MHz, CDCl3)
d
¼7.46 (s, 1H, 6-OH); 4.99 (t, 1H, CH-
rification as in (a) gave 22: 79 mg (24%). [
a
]
20 þ61.0 (c 0.31, CH2Cl2).
D
5d); 4.67 (s, 2H, CH2-5a); 4.01e3.99, 3.89e3.86 (m, 4H, OCH2-
dioxolane); 3.70 (mwt, 2H, CH2-5b); 2.63 (m, 2H, CH2-4); 2.15, 2.10
(s, 6H, CH3-7a and -8a); 2.06e2.01 (m, 2H, CH2-5c); 1.76 (m, 2H,
CH2-3); 1.27 (s, 6H, CH3-2a, -2a’); J5c,d¼4.4 Hz.
1H NMR (500 MHz, CDCl3)
d¼7.41e7.31, 7.17e7.15 (m, 10H, Aryl);
6.07 (m, 1H, CH-all-c); 5.41 (dd, 1H, CH2-all-d); 5.22 (dd, 1H, CH2-aa-
d’); 5.18 (d,1H, CH2eBn); 5.09 (s, 2H, CH2eBn); 5.09 (d,1H, CH2eBn);
4.70 (d,1H, H-4-aa); 4.56 (s, 2H, CH2-5a); 4.21 (d,1H, CH2-b-all); 4.04
(wdt, H-5-aa);3.67(dd,1H, H-6b-aa);3.62(dd,1H,H-6b-aa);2.76(m,
2H, CH2-4); 2.16e2.09 (s, 6H, CH3-7a and -8a); 1.75 (m, 2H, CH2-3);
1.28 (s, 6H, CH3-20, -2a’). J4,5aa¼2.0, J5,6a-aa¼6.1, J5,6b-aa¼6.6,
J6aa,gem¼9.7, Jc,d(E)¼18.1, Jc,d(Z)¼10.7, Jc,b¼5.6, Jd,gem¼1.6, JBn¼11.9 Hz.
4.2.12. 6-O-Allyl-5-[10-(1,3-dioxolane-2-yl)-methyl-10-oxy]-methyl-
2,20,7,8-tetramethyl-chroman-6-ol 18. Compound 16 (1.278 g,
3.97 mmol) and allylbromide (3 mL, 35 mmol) dissolved in anhy-
drous diethylether (30 mL) were treated with sodium hydride (60%,
800 mg, 20 mmol) under nitrogen at 0 ꢀC for 24 h. Workup as for 8
followed by flash chromatography (pet. ether/ethyl acetate 5:1)
gave 18: 200 mg (62%) as yellow syrup.
13CNMR(125MHz,CDCl3)
d¼169.50(1C,C-1-aa);157.26(1C,C-3-aa);
149.17, (1C, C-6); 148.24 (1C, C-8a); 135.97 (1C, CeBn-2aa); 135.34
(1C,CeBn-3aa);133.99(1C, ]CH, C-all-c);129.06(1C,CeBn);128.58,
128.55 (2C, CH, CeBn); 128.24 (1C, C-7); 127.74 (1C, CH, CeBn);
126.70 (1C, C-8); 124.94 (1C, C-4a); 120.91 (1C, C-2-aa); 118.40 (1C, C-
5); 116.84 (1C, ]CH2, C-all-d); 75.44 (1C, OCH2, C-all-b); 75.09 (1C,
CH, C-4-aa); 73.83 (1C, CH2, CeBn); 73.37 (1C, C-2); 73.08 (1C, CH2,
CeBn); 70.07 (1C, CH2, C-6-aa); 68.13 (1C, CH, C-5-aa); 65.25 (1C, CH2,
C-5a);32.57(1C, CH2, C-3);26.87 (CH3 C-20, -2a’);19.76(1C, CH2, C-4);
12.80 (1C, CH3, C-7a); 12.12 (1C, CH3, C-8a). EI-MS: 614 (Mþ).
1H NMR (400 MHz, CDCl3)
d
¼6.16e6.06 (m, 1H, CH-6c); 5.44 (m,
1H, CH2-6d); 5.24 (m, 1H, CH2-6d’); 5.04 (t, 1H, CH-5c); 4.63 (s, 2H,
CH2-5a); 4.24 (m, 2H, CH2-6b); 3.99e3.85 (m, 4H, OCH2-dioxolane);
3.54 (d, 2H, CH2-5b); 2.83 (m, 2H, CH2-4); 2.16, 2.09 (s, 6H, CH3-7a
and -8a); 1.77 (m, 2H, CH2-3); 1.30 (s, 6H, CH3-2a, -2a’); J5c,d¼4.4 Hz.
EI-MS: 362 (Mþ).
4.2.13. 6-O-Allyl-5-[20-(1,3-dioxolane-2-yl)-ethyl-10-oxy]-ethyl-
2,20,7,8-chroman-6-ol 19. Compound 17 (600 mg, 1.78 mmol) and
4.2.16. 6-O-Acetyl-5-azidomethyl-
chloromethyl-
-tocopherol 2333,34 (1.065 g, 2.1 mmol) and sodium
g
-tocopherol 2437. 6-O-Acetyl-5-
g
allylbromide (25
m
L, 2.95 mmol) dissolved in anhydrous THF
azide (270 mg, 4.2 mmol) dissolved in acetonitrile (40 mL) were
heated under reflux for 5 h. The mixture was diluted with
dichloromethane (100 mL) washed with saturated NaCl solution,
dried (MgSO4) and evaporated in vacuum and high vacuum to give
the raw material 24: 1.03 g (99%) as orange syrup. An analytical
sample was purified by flash chromatography (pet. ether/ethyl
(25 mL) were treated with sodium hydride (60%, 120 mg, 30 mmol)
under nitrogen at 0 ꢀC for 24 h. Workup as for 8 followed by flash
chromatography gave 19: 440 mg (73%) as a pale yellow oil.
1H NMR (400 MHz, CDCl3)
d
¼6.11 (ddd, 1H, CH-6c); 5.43 (ddd,
1H, CH2-6d); 5.25 (ddd, 1H, CH2-6d’); 4.96 (t, 1H, CH-5d); 4.52 (s,
2H, CH2-5a); 4.25 (dddwdt, 2H, CH2-6b); 3.96, 3.83 (m, 4H, OCH2-
dioxolane); 3.63 (t, 2H, CH2-5b); 2.81 (m, 2H, CH2-4); 2.16, 2.09 (s,
6H, CH3-7a and -8a); 1.96 (dt, 2H, CH2-5c); 1.78 (m, 2H, CH2-3); 1.30
(s, 6H, CH3-2a, -2a’); J6d,6d’¼1.5, J6d,b¼3.1, J6d,c(Z)¼10.7, J6d,c(E)¼16.8,
acetate 1:1). IR: 1761 (C]O), 2099 (N3)cmꢁ1
.
1H NMR (400 MHz, CDCl3)
d
¼4.19 (s, 2H, CH2-5a); 2.73 (m, 2H,
CH2-4); 2.35 (s, 3H, OAc); 2.12, 2.03 (s, 6H, CH3-7a and -8a);
1.89e1.70 (m, 2H, CH2-3); 1.62e0.99 (m, 24H, CH3-2a, CH-40, -80,
-120, CH2-h10-11i); 0.89e0.80 (m, 12H, CH3-4a’, -8a’, -12a’, -130).
Anal. Calcd for C31H51O3N3 (513.8): C, 72.47; H, 10.00; N, 8.18.
Found: C, 72.76; H, 10.03; N, 8.09.
J6c,b¼5.6, J5b,c¼6.6, J5c,d¼5.1 Hz. 13C NMR (100 MHz, CDCl3)
¼149.18
d
(1C, C-6); 148.20 (1C, C-8a); 134.32, (1C, ]CH, C-all-6c); 128.15 (1C,
C-7); 126.23 (1C, C-8); 124.64 (1C, C-4a); 118.58 (1C, C-5); 116.74
(1C, ]CH2, C-all-6d); 102.51 (1C, CH, C-5d); 75.52 (1C, CH2, C-6b);
73.05 (1C, C2); 65.96 (1C, CH2, C-5b); 64.90, 64.78 (2C, CH2, C-5a
and OCH2-dioxolane); 34.37 (1C, CH2, C-5c); 32.71 (1C, CH2, C-3);
26.94 (2C, CH3, C-20, C-2a’); 19.71 (1C, CH2, C-4); 12.80 (1C, CH3, C-
7a); 12.13 (1C, CH3, C-8a). EI-MS: 376 (Mþ).
4.2.17. 6-O-Acetyl-5-phthalimidomethyl-g-tocopherol
25. Compound 24 (540 mg, 1.07 mmol), sodium iodide (10 mg,
0.07 mmol) and potassium phthalimide (305 mg, 1.64 mmol) were
dissolved in anhydrous dimethylformamide (15 mL) and stirred for
15 h at room temperature. The mixture was diluted with ethyl ac-
etate (50 mL), washed with water (3ꢂ20 mL), dried (MgSO4) and
evaporated to give 25: 650 mg (98%) as colourless solid, which
turned brown in air; mp 78e80 ꢀC.
4.2.14. 6-O-Allyl-5-formyloxymethyl-2,20,7,8-tetramethyl-chroman-
6-ol 20. Compound 18 (120 mg, 0.33 mmol) was dissolved in for-
mic acid (3 mL) and stirred at room temperature for 20 min. The
deep yellow solution was diluted with diethylether (15 mL), suc-
cessively washed with aqueous NaHCO3 and NaCl, dried (Na2SO4)
1H NMR (400 MHz, CDCl3)
4.69 (m, 2H, CH2-5a); 2.30 (s, 3H, OAc); 2.08, 1.92 (s, 6H, CH3-7a
d¼7.80e7.66 (m, 4H, CHePh);

M. Lahmann, J. Thiem / Tetrahedron 67 (2011) 1654e1664
1661
and -8a); 1.92e1.00 (m, 28H, CH2-4, CH2-3, CH3-2a, CH-40, -80, -120,
CH2-h10-110i); 0.88e0.82 (m, 12H, CH3-4a’, -8a’, -12a’, -130). EI-MS:
617 (Mþ), 575 (MþꢁC2H2O).
CH2-h10-110i); 1.24 (t, 3H, OEt); 0.91e0.80 (t, 12H, m, CH3, C-4a’, -8a’,
-12a’, -130). 13C NMR (100 MHz, CDCl3)
d¼146.94,144.23 (2C, C-6 and
C-8b); 125.15, 122.61, 117.39, 115.66, (4C, C-8, C-7, C-5, C-4a); 73.97
(1C, C-2); 67.57, 65.74 (2C, CH2, OEt, C-5a);39.41e36.85 (6C, CH2, C-10,
-30, -50, -70, -90, -110); 32.34, 32.26 (2C, CH, C-40, -80); 30.97 (1C, CH2, C-
3); 27.54 (1C, CH, C-120); 24.36, 24.00 (2C, CH2, C-60, -100),
23.30e22.18 (2C, CH3, C-12a’,-130);20.58e19.24 (4C, CH2, C-20, -4 and
CH3, C-4a’, -8a’); 14.68 (1C, CH3, OEt); 11.45, 11.25 (CH3, C-7a, -8a).
4.2.18. 5-Acetamidomethyl-
g
-tocopherol
26. Compound
25
(116 mg, 0.19 mmol) dissolved in THF (3 mL) was treated with
hydrazine hydrate (0.3 mL, 6.17 mmol) and then heated under
reflux for 12 h. The mixture was evaporated, then water (2 mL) and
dichloromethane (5 mL) added, and the organic phase successively
washed with saturated aqueous NaHCO3 and NaCl, dried (MgSO4)
and evaporated. Purification was by flash chromatography (pet.
ether/ethyl acetate 1:1) gave 26: 83 mg (90%) as colourless oil.
4.2.22. 5-Allyloxymethyl-
g-tocopherol 30. Anhydrous allyl alcohol
(120 L, 1.76 mmol) in anhydrous dimethylacetamide (5 mL) was
m
treated under nitrogen at 0 ꢀC with sodium hydride (80%, 280 mg,
9.33 mmol). Drop wise a solution of compound 2333,34 (200 mg,
0.33 mmol) in dimethylacetamide (5 mL) was added and the
mixture stirred for 1 h at 0 ꢀC. Excess of NaH was destroyed with
methanol, the mixture diluted with ethyl acetate (50 mL) and the
organic phase washed successively with water, 2 N H2SO4 and
saturated NaCl solution. After drying (MgSO4) and evaporation the
residue was purified by flash chromatography (pet. ether/ethyl
acetate 3:1) to give 30: 150 mg (92%) as a yellow oil.
1H NMR (400 MHz, CDCl3)
d
¼8.77 (s, 1H, HOeAr); 6.33 (t, 1H,
NH); 4.37 (d, 2H, CH2-5a); 2.66 (m, 2H, CH2-4); 2.19 (s, 3H, NHAc);
2.10, 1.99 (s, 6H, CH3-7a and -8a); 1.88e1.69 (m, 2H, CH2-3);
1.64e0.99 (m, 24H, CH3-2a, CH-40, -80, -120, CH2-h10-110i);
0.93e0.79 (m, 12H, CH3-4a’, -8a’, -12a’, -130); JNH,CH2¼6.1 Hz. 13C
NMR (100 MHz, CDCl3)
d¼172.50 (1C, C]O, NHAc); 146.64, 145.11
(2C, C-6 and C-8b); 126.43, 124.86, 119.27, 115.81 (4C, C-8, C-7, C-5,
C-4a); 74.48 (1C, C-2); 60.41 (1C, CH2, C-5a); 40.00, 39.40 (2C, CH2,
C-10, -110); 37.49, 37.42, 37.31, 36.34 (4C, CH2, C-30, -50, -70, -90);
32.80, 32.74 (2C, CH C-40, -80); 31.40 (1C, CH2, C-3); 28.00 (1C, C-
120); 24.82, 24.47 (2C, CH2, C-60, -100); 22.81e22.64 (2C, CH3, C-120,
-130); 21.04, 20.39 (2C, CH2, C-20, -40); 19.76, 19.70 (2C, CH3, C-4a’,
-8a’); 12.50, 12.04 (2C, CH3, C-7a,-8b).
1H NMR (400 MHz, CDCl3)
d
¼7.43 (s, 1H, HOeAr); 5.94 (ddd, 1H,
H-c); 5.31 (dd, 1H, H-d); 5.25 (dd, 1H, H-d’); 4.71 (s, 2H, CH2-5a);
4.07 (d, 2H, H-b); 2.59 (m, 2H, CH2-4); 2.15, 2.10 (s, 6H, CH3-7a and
-8a); 1.84e1.69 (m, 2H, CH2-3); 1.63e1.00 (m, 24H, CH3-2a, CH-40,
-80, -120, CH2-h10-110i); 0.87e0.83 (m, 12H, CH3-4a’, -8a’, -12a’, -130).
Jd,d’¼1.5, Jd,c(Z)¼17.3, Jd’,c(E)¼10.5, Jb,c¼5.6 Hz. 13C NMR (100 MHz,
4.2.19. 5-Hydroxymethyl-
g-tocopherol
27. Compound
2333,34
CDCl3)
d
¼146.96 (2C, C-6 and C-8a); 133.34 (1C, CH, C-all-c); 125.37,
(478 mg, 0.94 mmol) was dissolved in oxygen free THF (15 mL)
and added to a degassed mixture of sodium hydroxide solution
(0.25 M,10 mL) and THF (15 mL). Then tetrabutyl ammonium iodide
(10 mg) were added and the mixture refluxed for 3 h. Following
neutralisation with 2 N H2SO4 ethyl acetate (50 mL) was added, the
organic phase washed with saturated NaCl solution, dried (MgSO4),
evaporated and purified by flash chromatography (pet. ether/ethyl
acetate 5:1) to give 27: 170 mg (40%) as a yellow oil.
122.65 (3C, C-5, C-7, C-8); 117.66 (1C, CH2, C-all-d); 114.96 (1C, C-
4a); 74.01 (1C, C-2); 70.67, 66.64 (2C, OCH2, C-all-b and CH2, C-5a);
38.94 (2C, CH2, C-10, -110); 36.95e36.85 (4C, CH2, C-30, -50, -70, -90);
32.34 (2C, CH, C-40, -80); 29.25 (1C, CH2, C-3); 27.54 (1C, CH, C-120);
24.36, 24.00 (2C, CH2, C-60, -100); 22.27, 22.28 (2C, CH3, C-12a’, -130);
20.58, 19.49 (2C, CH2, C-20, -4); 19.30, 19.24 (2C, CH3, C-4a’, -8a’);
11.47, 11.27 (2C, CH3, C-7a, -8a).
1H NMR (400 MHz, CDCl3)
d
¼7.12 (s, 1H HOeAr); 4.84 (s, 2H,
4.2.23. 5-(1,2,3,4-Di-O-isopropylidene-
a
-
D
-galactopyranos-6-oxy)-
-galactopyr-
CH2-5a); 2.60 (m, 2H, CH2-4); 2.16, 2.10 (s, 6H, CH3-7a and -8b);
1.84e1.68 (m, 2H, CH2-3); 1.66e1.00 (m, 24H, CH3-2a, CH-40, -80,
-120, CH2-h10-110i); 0.91e0.79 (m, 12H, CH3-4a’, -8a’, -12a’, -130). 13C
g-tocopherol 31. 1,2,3,4-Di-O-isopropylidene-a-D
anose39 (208 mg, 0.8 mmol) dissolved in anhydrous THF (5 mL)
under nitrogen was treated with NaH (192 mg, 8 mmol) at room
temperature. Then compound 23 (300 mg, 0.5 mmol) dissolved in
anhydrous THF (5 mL) was added drop wise and the reaction kept
for 2.5 h at room temperature under stirring. Excess NaH was
destroyed with methanol, the mixture evaporated, dissolved in
dichloromethane (20 mL) washed with water (2ꢂ10 mL), dried
(MgSO4) and evaporated. Purification was by flash chromatography
(pet. ether/ethyl acetate 5:1) gave 31: 108 mg (32%), pale yellow
NMR (100 MHz, CDCl3)
d
¼146.78, 144.47 (2C, C-6 and C-8a); 125.29,
122.55, 118.41 (3C, C-8, C-7, C-5); 114.77 (1C, C-4a); 74.14 (1C, C-2);
59.54 (1C, CH2, C-5a); 39.43, 38.94 (2C, CH2, C-10,-110); 37 02e36.85
(4C, CH2, C-30, -50, -70, -90); 32.34, 32.27 (2C, CH, C-40, -80); 30.91 (1C,
CH2, C-3); 27.54 (1C, CH, C-120); 24.36, 24.00 (2C, CH2, C-60, -100);
22.27, 22.18 (2C, CH3, C-12a’, -130); 20.60e19.20 (4C, CH2, C-20, -4
and CH3, C-4a’, -8a’); 11.49, 11.27 (CH3, C-7a, -8a). EI-MS: 446 (Mþ),
429 (Mþ-OH), 428 (MþꢁH2O). Anal. Calcd for C29H50O3 (446.7): C,
77.97; H, 11.28; N, 8.18. Found: C, 77.75; H, 11.28.
syrup. [
a
]
20 ꢁ133.3 (c 1.0, CHCl3).
D
1H NMR (400 MHz, CDCl3)
d
¼7.08 (s, 1H, HOeAr); 3.71 (d, 2H,
CH2-5a); 2.60e2.68 (m, CH2-4); 2.10, 2.17 (s, 6H, CH3-7a, -8a);
1.67e1.84 (m, 2H, CH2-3); 1.68e1.00 (m, 24H, CH3-2a, CH-40, -80,
-120, CH2-h10-110i); 0.87e0.83 (m, 12H, CH3-4a’, -8a’, -12a’, -130);
5.55 (d, 1H, H-1); 4.25 (dd, 1H, H-2); 4.60 (dd, 1H, H-3); 4.32 (t, 1H,
H-4); 4.02 (dt, 1H, H-5); 4.75 (dd, 1H, H-6a); 4.68 (dd, 1H, H-6b);
J1,2¼4.6, J2,3¼7.9, J3,4¼2.1, J4,5¼5.1, J5,6a¼4.1, J5,6b¼4.1, J6a,6b¼11.9 Hz.
4.2.20. 5-Methyloxymethyl-
CDCl3)
g
-tocopherol 28. 1H NMR (400 MHz,
¼7.42 (s, 1H, HOeAr); 4.65 (s, 2H, CH2-5a); 3.43 (s, 3H,
d
OCH3); 2.60 (m, 2H, CH2-4); 2.15, 2.10 (s, 6H, CH3-7a and -8a);
1.84e1.68 (m, 2H, CH2-3); 1.66e1.00 (m, 24H, CH3-2a, CH-40, -80,
-120, CH2-h10-110i); 0.87e0.83 (m, 12H, CH3, C-4a’, -8a’, -12a’, -130).
13C NMR (100 MHz, CDCl3)
d
¼147.36, 144.74 (2C, C-6 and C-8b);
125.78, 123.06, 115.92, 115.38 (4C, C-8, C-7, C-5, C-4a); 74.45 (1C, C-
2); 69.82 (1C, CH3, OMe); 58.10 (1C, CH2, C-5a); 39.86e37.30 (6C,
CH2, C-10, -30, -50, -70, -90, -110); 32.80 (2C, CH, C-40, -80); 32.70 (1C,
CH2, C-3); 28.00 (1C, CH, C-120); 24.82, 24.46 (2C, CH2, C-60, -100);
23.75e22.64 (2C, CH3, C-12a’, -130); 21.03e19.66 (4C, CH2, C-20, -4
and CH3, C-4a’, -8a’); 11.93, 11.71 (2C, CH3, C-7a, -8a).
4.2.24. 3-Acetoxy-propanal 3341. Acroleine 32 (53 mL, 0.8 mmol)
and acetic acid (47 mL, 0.82 mmol) were mixed with ion exchange
resin IRA-420 (200 ml, acetate form) and kept at room temperature
for 48 h. The ion exchange resin was rinsed with ethyl acetate
(300 mL), the organic phase washed with saturated NaHCO3 solu-
tion (200 mL), NaCl solution (100 ml), dried (Na2SO4) and evapo-
rated. Distillation gave 33: 15.0 g (16%) as a clear colourless oil,
which decomposes within minutes. Bp12:71e72 ꢀC; Ref. 41: 43%,
bp0.5:35e40 ꢀC.
4.2.21. 5-Ethyloxymethyl-
CDCl3)
g
-tocopherol 29. 1H NMR (400 MHz,
¼7.68 (s, 1H, HOeAr); 4.69 (s, 2H, CH2-5a); 3.60 (q, 2H,
d
OCH2); 2.60 (m, 2H, CH2-4); 2.17, 2.10 (s, 6H, CH3-7a and -8a);
1H NMR (400 MHz, CDCl3)
OCH2); 2.70 (dt, 2H, CH2); 1.98 (s, 3H, OAc); J1,2¼1.5, J2,3¼6.1 Hz.
d
¼9.74 (s, 1H, CHO); 4.32 (t, 2H,
1.87e1.69 (m, 2H, CH2-3); 1.61e1.00 (m, 24H, CH3-2a, CH-40, -80, -120,

1662
M. Lahmann, J. Thiem / Tetrahedron 67 (2011) 1654e1664
4.2.25. 3-Acetoxy-1,1-dimethoxy-propane
3442. Compound 33
NaH (60%, 12.0 g, 0.3 mmol), sodium iodide (catalytic amount) and
(14.06 g,121 mmol), trimethylorthoformate (14 mL,127.5 mmol) and
methanol (5 mL) were mixed. Drop wise a mixture (1.4 mL) of
methanol and concentrated H2SO4 (19:1) was added under stirring.
After 2 h the mixture was neutralised with triethylamine, evaporated
andpurifiedbyflash chromatography(pet. ether/ethyl acetate3:1)to
give compound 34: 10.0g (51%)asa colourless liquid;Ref. 42:nodata.
allylbromide (13 mL, 0.15 mmol). After 24 h at room temperature
workup was as for compound 8. The residue was purified by flash
chromatography (pet. ether/ethyl acetate 3:1) to give 40: 2.7 g (55%
20
based on the amount of 38) as colourless syrup. [
a
]
ꢁ1.3 (c 0.15,
D
CH2Cl2).
1H NMR (400 MHz, CDCl3)
d
¼5.94 (m, 3H, CH-all-c); 5.26 (m, 3H,
1H NMR (400 MHz, CDCl3)
d
¼4.48 (t,1H, CH-1);4.11 (t, 2H, CH2-3);
CH2-all-d); 5.15 (m, 3H, CH2-d’-all): 4.53 (t, 1H, CH-c-Sp); 4.37e4.10
(m, 7H, CH2-b-all); 4.24 (d, 1H, H-1b); 3.92 (m, 1H, CH2-a-Sp); 3.84
(dd, 1H, H-6a); 3.78 (dd, 1H, H-6b); 3.59e3.48 (m, 1H, CH2-a’-Sp);
3.40e3.31 (m, 8H, H-3, H-4 and 2ꢂOMe); 3.17 (m, 1H, H-5); 3.13
(dd, 1H, H-2); 1.90 (m, 2H, CH2-b-Sp); 0.89 (s, 9H, t-BueSi); 0.06,
0.05 (s, 6H, MeeSi); J1,2¼7.6, J2,3¼8.6, J5,6a¼2.0, J5,6b¼4.1, J6a,6b¼11.2,
3.31 (s, 6H, 2ꢂOCH3); 2.03 (s, 3H OAc); 1.91 (q, 2H, CH2-2); J1,2¼5.6,
J2,3¼6.6 Hz. EI-MS: 131 (MꢁOCH3), 87 (H3CO]CHeOCH3). Anal.
Calcd for C7H14O4 (162.2): C, 51.70; H, 8.70. Found: C, 51.71; H, 8.73.
4.2.26. 3-Hydroxy-1,1-dimethoxy-propane 3543. Compound 34
(1.05 g, 6.48 mmol) dissolved in anhydrous methanol (5 mL) was
stirred with Na2CO3 (1.13 g, 9.72 mmol) for 18 h at room tempera-
ture. Filtration and evaporation gave the liquid 35: 775 mg (quant.),
which was used without further purification; Ref. 43: no data.
Jb,c-Sp¼5.9 Hz. 13C NMR (100 MHz, CDCl3)
¼134.89, 134.76, 134.61
d
(3C, ]CH, C-al1-c); 116.36, 116.30, 116.16 (3C, ]CH2, C-all-d);
102.81 (1C, C-1); 101.75 (1C, C-c-Sp); 83.80, 75.30 (2C, C-3, C-4);
81.39 (1C, C-2); 74.07 (1C, C-5); 73.27, 73.15 (2C, CH2, C-all-b); 65.16,
(1C, CH2, C-a-Sp); 61.78 (1C, C-6); 52.85, 52.66 (2C, 2ꢂOMe); 32.84
(1C, CH2, C-b-Sp); 25.44 (1C, CH3, C-t-BueSi); 17.89 (1C, t-BueSi);
ꢁ5.90, ꢁ6.01 (2C, CH3, CeMeeSi). EI-MS: 516 (Mþ). Anal. Calcd for
C26H48O8Si(516.7): C, 60.43; H, 9.36. Found: C, 60.43, H, 9.38.
4.2.27. 3,3-Dimethoxypropyl-2,3,4,6-tetra-O-acetyl-
b-D-glucopyr-
anoside 37. 2,3,4,6-Tetra-O-acetyl- -glucopyranosyl bromide
a-D
3644 (2.7 g, 6.6 mmol) and compound 35 (780 mg, 6.5 mmol) dis-
solved in anhydrous dichloromethane (10 mL) were treated under
nitrogen in the dark with silver carbonate (1.9 g, 6.8 mmol) and
stirred for 20 h at room temperature. After filtration over Celite and
washing with dichloromethane (50 mL) the solvents were evapo-
rated and the residue purified by flash chromatography (dichloro-
methane/acetone 15:1) to give 37: 121 g (41%), colourless syrup;
4.2.31. 3,3-Dimethoxypropyl 2,3,4-tri-O-allyl-b-D-glucopyranoside
41. Compound 40 (1.3 g, 2.51 mmol) was dissolved in anhydrous
THF (10 mL), a solution of tetrabutyl ammonium fluoride in THF
(2.7 mL, 1.1 M) added and stirred for 3 h at room temperature. The
raw syrupy material 41 obtained after evaporation was directly
used for the next etherification step.
[
a]
20 ꢁ11.5 (c 2.7, CH2Cl2).
D
1H NMR (400 MHz, CDCl3)
d¼5.20 (t, 1H, H-3); 5.09 (t, 1H, H-4);
4.99 (dd, 1H, H-2); 4.50 (d, 1H, H-1); 4.46 (t, 1H, CH-c-Sp); 4.27 (dd,
1H, H-6a); 4.13 (dd,1H, H-6b); 3.93 (m,1H, CH2-a-Sp); 3.70 (ddd,1H,
H-5); 3.58 (m, 1H, CH2-a’-Sp); 3.33 (s, 3H, OMe); 3.32 (s, 3H, OMe);
2.08, 2.03, 2.01, 1.99 (s, 12H, 4ꢂCH3, OAc); 1.98e1.84 (m, 2H, CH2-b-
Sp); J1,2¼8.1, J2,3¼9.7, J3,4¼9.7, J4,5¼9.7, J5,6a¼4.6, J5,6b¼5.5, J6a,6b¼12.2,
4.2.32. 5-[2,3,4-tri-O-allyl-1-O-(3,3-dimethoxypropyl)-b-D-gluco-
pyranos-6-oxy]-methyl-2,20,7,8-tetramethyl-chroman-6-ol
42. Compound 41 (1.0 g, 2.5 mmol) in anhydrous THF (20 mL) was
treated with sodium hydride (60%, 3.0 g, 75 mmol) for 30 min at
room temperature. Then compound 5 (900 mg, 3.0 mmol) dis-
solved in anhydrous THF (5 mL) was added drop wise and kept for
12 h at room temperature. Workup was as for compound 8 and
flash chromatographic purification (pet. ether/ethyl acetate 2:1)
gave 42: 1.0 g (64%) as a yellow syrup.
Jb,c¼5.9 Hz. 13C NMR (100 MHz, CDCl3)
¼170.22, 169.84, 168.96,
d
168.81(C, C]O, OAc);101.45 (1C,C-c-Sp);100.45(1C, C-1);72.39(1C,
C-3); 71.33 (1C, C-5); 70.87 (1C, C-2); 67.96 (1C, C-4); 65.81 (1C, C-a-
Sp); 61.51 (1C, C-6); 53.07, 52.47 (2C, 2ꢂOMe); 32.47 (1C, C-b-Sp);
20.27, 20.21, 20.16, 20.15 (4C, 4ꢂCH3, OAc). EI-MS: 419 (MþꢁOCH3).
1H NMR (400 MHz, CDCl3)
d¼6.02e5.84 (m, 3H, CH-all-c);
5.33e5.15 (m, 6H, CH2-all-d); 4.78 (d, 1H, CH2-5a); 4.72 (d, 1H, CH2-
5a); 4.58 (t, 1H, CH-c-Sp); 4.41e4.16 (m, 6H, 5ꢂCH2-all-b and H-
1b); 4.07 (m, 2H, CH2-all-b, CH2-a-Sp); 3.83 (dd,1H, H-6a); 3.70 (dd,
1H, H-6b); 3.61 (m, 1H, CH2-a’-Sp); 3.42 (m, 1H, H-5); 3.40 (t, 1H, H-
4); 3.36 (s, 6H, 2ꢂOCH3); 3.28 (t, 1H, H-3); 3.21 (ddwt, 1H, H-2);
2.66 (m, 2H, CH2-4); 2.16, 2.12 (s, 6H, CH3-7a and -8a); 1.96 (m, 2H,
CH2-b-Sp); 1.78 (m, 2H, CH2-3); 1.30 (s, 6H, CH3-2a, -2a’); J1,2¼7.6,
J2,3¼9.5, J3,4¼9.5, J4,5¼4.5, J5,6a¼2.5, J5,6b¼5.7, J6a,6b¼10.7,
J5a,gem¼12.0, Jc,b-Sp¼5.7 Hz.
4.2.28. 3,3-Dimethoxypropyl-b-D-glucopyranoside 38. Compound
37 (4.5 g, 10.0 mmol) dissolved in anhydrous methanol (20 mL) was
deacetylated with NaOMe at pH 8 for 3 h at room temperature.
After neutralisation with Amberlite IR 120Hþ the solution was
evaporated to give 38: 2.8 g (quant.) as colourless syrup; [
(c 1.1, CH2Cl2).
a]
20 ꢁ11.0
D
4.2.29. 3,3-Dimethoxypropyl-6-O-tert-butyldimethylsilyl-b-D-gluco-
pyranoside 39. Imidazol (0.98 g, 14.36 mmol) was dissolved in
anhydrous DMF (10 mL) at ꢁ10 ꢀC and compound 38 (2.7 g,
9.57 mmol) added under stirring. Then tert-butyldimethylsilyl
chloride (1.7 g, 11.50 mmol) was added and the reaction kept under
stirring at ꢁ10 ꢀC for 1 h. Excessive silyl chloride was destroyed
with water the mixture evaporated at 50 ꢀC and the residue dis-
solved in dichloromethane (100 mL). Washing with saturated NaCl
solution, drying (Na2SO4) and evaporation gave 3.9 g of the raw
material 39, which was directly used for the allylation reaction.
4.2.33. 5-[2,3,4-tri-O-allyl-1-O-(3,3-dimethoxypropyl)-
b-D-gluco-
pyranos-6-oxy]-methyl- -tocopherol 43. Compound 41 (1.0 g,
g
2.5 mmol) in anhydrous THF (20 mL) was treated with NaH (60%,
3.0 g, 75 mmol) for 30 min at room temperature. Then compound
23 (1.52 g, 3.0 mmol) in anhydrous THF (5 mL) was added drop wise
and stirring continued for 12 h. Workup was as for compound 8 and
flash chromatographic purification (pet. ether/ethyl acetate 5:1)
gave 43: 950 mg (46%) as a yellow oil.
1H NMR (400 MHz, CDCl3)
d
¼4.53 (t,1H, CH-c-Sp); 4.25 (d,1H, H-
1H NMR (400 MHz, CDCl3)
d
¼5.99e5.81 (m, 3H, m, CH-all-c);
1b); 3.94 (m,1H, CH2-a-Sp); 3.88 (dd,1H, H-6a); 3.83 (dd,1H, H-6b);
3.60 (m,1H, CH2-a’-Sp); 3.38e3.26 (m,10H, H-2, H-3, H-4, H-5 and s,
6H, 2ꢂOMe); 1.91 (m, 2H, CH2-b-Sp); 0.87 (s, 9H, t-BueSi); 0.07 (s,
6H, MeeSi); J1,2¼7.6, J5,6a¼5.1, J5,6b¼5.1, J6a,6b¼10.7, Jb,c-Sp¼5.6 Hz.
5.30e5.12 (m, 6H, CH2-all-d); 4.75 (m, 1H, CH2-5a); 4.69 (m, 1H,
CH2-5a); 4.55 (t, 1H, CH-c-Sp); 4.37e4.09 (m, 7H, 5ꢂCH2-b-all and
H-1b, AreOH); 4.05 (m, 2H,1ꢂCH2-b-all, CH2-a-Sp); 3.81 (m, 1H, H-
6a); 3.67 (m, 1H, H-6b); 3.59 (m, 1H, CH2-a’-Sp); 3.40 (m, 1H, H-5);
3.37 (ddwt, 1H, H-4) 3.33 (s, 6H, 2ꢂOMe); 3.25 (ddwt, 1H, H-3);
3.19 (ddwt, 1H, H-2); 2.62 (m, 2H, CH2-4); 2.13, 2.10 (s, 6H, CH3-7a
and -8b); 1.93 (m, 2H, CH2-b-Sp); 1.74 (m, 2H, CH2-3); 1.58e1.00
(m, 24H, CH3-2a, CH-40, -80, -120, CH2-h10-110i); 0.90e0.81 (m, 12H,
4.2.30. 3,3-Dimethoxypropyl
thylsilyl- -glucopyranoside 40. The raw material 39 (3.8 g,
0.51 mmol) dissolved in anhydrous THF (30 mL) was treated with
2,3,4-tri-O-allyl-6-O-tert-butyldime-
b-D

M. Lahmann, J. Thiem / Tetrahedron 67 (2011) 1654e1664
1663
CH3-4a’, -8a’, -12a’, -130); J1,2¼7.0, J2,3¼9.0, J3,4¼9.0, J4,5¼9.0,
hygroscopic solid; mp 45e47 ꢀC (decomposition); [
CH2Cl2).
1H NMR (CDCl3)
a
]
20 þ31.8 (c 1.2,
D
J5a,gem¼12.0 Hz.
d
¼5.98 (m, 2H, H-c); 5.35 (m, 2H, H-d); 5.30 (m,
4.2.34. 6-O-Allyl-5-[2,3,4-tri-O-allyl-1-O-(3,3-dimethoxypropyl)-
D
b
-
2H, H-d0); 4.95 (m, 2H, H-b); 4.71 (d, 1H, H-4); 4.59 (m, 2H, H-b0);
3.97 (wdt,1H, H-5); 3.85 (dd,1H, H-6a); 3.79 (dd,1H, H-6b); 2.78 (s,
2H, 2ꢂOH); J4,5¼2.6, J5,6a¼5.9, J5,6b¼4.6, J6a,6b¼11.5 Hz. 13C NMR
-glucopyranos-6-oxy]-methyl-2,20,7,8-tetramethyl-chroman-6-ol
44. Compound 42 (900 mg, 1.45 mmol) dissolved in anhydrous THF
(10 mL) was treated with NaH (60%, 650 mg, 16.0 mmol) for 30 min,
and then allylbromide (1.4 mL, 16.0 mmol) was added and the
mixture kept at room temperature for 18 h. Workup as for com-
pound 8 followed by flash chromatographic purification (pet. ether/
(100 MHz, CDCl3)
d
¼169.11 (1C, C]O, C-1); 156.33 (1C, C-3);
132.36, 131.34 (2C, ]CH, C-all-c); 120.81 (1C, C-2); 119.04e118.70
(2C, ]CH2, C-all-d); 75.28 (1C, C-4); 72.32e71.55 (2C, OCH2, C-all-
b); 69.51 (1C, C-5); 62.93 (1C, C-6). EI-MS: 256 (Mþ). Anal. Calcd for
C12H16O8(256.3): C, 56.24; H, 6.29. Found: C, 55.57; H, 6.43.
ethyl acetate 3:1) gave 44: 690 mg (72%) pale rose crystals; mp
20
52e53 ꢀC; [
a
]
D
ꢁ2.5 (c 0.9, CH2Cl2).
1H NMR (CDCl3)
d
¼6.12 (m, 1H, CH-all-c); 5.96 (m, 2H, CH-all-
4.2.37. 6-O-Allyl-5-[2-(5,6-O-metylidene-2,3-di-O-allyl-
L-ascorbyl)-
c); 5.84 (m, 1H, CH-all-c); 5.47 (mc, 1H, CH2-all-d); 5.33e5.11 (m,
7H, CH2-all-d); 4.63 (d, 1H, CH2-5a); 4.55 (d, 1H, CH2-5a); 4.53 (t,
1H, CH-c-Sp); 4.38e4.15 (m, 8H, 7ꢂCH2-all-b, H-1b); 3.96 (m, 2H,
CH2-all-b, CH2-a-Sp); 3.76 (dd, 1H, H-6a); 3.66 (dd, 1H, H-6b); 3.54
(m, 1H, CH2-a’-Sp); 3.40e3.32 (m, 8H, H-3, H-5, 2ꢂOCH3); 3.26 (m,
1H, H-4); 3.17 (dd, 1H, H-2); 2.85 (m, 2H, CH2-4); 2.19, 2.11 (s, 6H,
CH3-7a and -8a); 1.90 (m, 2H, CH2-b-Sp); 1.78 (m, 2H, CH2-3); 1.32
(s, 6H, CH3-2a, -2a’); J1,2¼8.2, J2,3¼9.5, J3,4¼9.5, J4,5¼9.5, J5,6a¼1.9,
J5,6b¼5.0, J6a,6b¼10.7, J5a,gem¼10.1, Jc,b-Sp¼5.7 Hz. 13C NMR
ethyl-2,3,4-tri-O-allyl-
b-D
-glucopyranos-6-oxy]-methyl-2,20,7,8-tet-
ramethyl-chroman-6-ol 47. Compounds 44 (200 mg, 0.3 mmol) and
46 (80 mg, 0.31 mmol) dissolved in a mixture of n-hexane (5 mL)
and dichloromethane (5 mL) were treated with p-TsOH (1 mg) and
heated at a water separator for 1.5 h. After cooling dichloromethane
(30 mL) was added, neutralised with saturated NaHCO3 solution,
washed with NaCl solution, dried (Na2SO4), evaporated and puri-
fied by flash chromatography (pet. ether/ethyl acetate 5:1) to give
47: 238 mg (93%) as a pale rose oil consisting of two diastereomers,
which could be partly separated. Upper diastereomer: 110 mg (43%),
(100 MHz, CDCl3)
d
¼135.66, 135.59, 135.12, 134.73 (4C, ]CH, C-all-
c); 117.33, 117.17, 117.06 (3C, ]CH2, C-all-d); 103.62 (1C, C-c-Sp);
102.49 (1C, C-1); 81.98 (1C, C-3); 78.21 (1C, C-2); 76.82e75.69 (3C,
C-4, C-5, C-all-b); 71.70, 68.11, 67.66 (3C, C-6, C-a-Sp, C-5a); 55.57
(2C, 2ꢂOMe); 35.54, 35.05 (2C, C-b-Sp, CH2-3); 29.50, 29.14 (1C, C-
2a, C-2a’); 22.14 (1C, CH2-4); 14.50 (2C, C-7a, 8a). EI-MS: 660 (Mþ).
Anal. Calcd for C37H56O10(660.8): C, 67.14; H, 8.54. Found: C, 67.14;
H, 8.54.
lower diastereomer: 91 mg (36%), mixed fraction: 37 mg (14%).
20
Upper diastereomer:
(400 MHz, CDCl3)
[a
]
D
þ4.1 (c 0.3, CH2Cl2). 1H NMR
d
¼6.08 (m, 1H, CH-all-c); 5.94 (m, 4H, CH-all-c);
5.81 (m, 1H, CH-all-c); 5.48e5.06 (m, 10H, CH2-d-all); 5.03 (m, 1H,
CH-c-Sp); 4.91 (m, 2H, CH2-d-all); 4.67e4.49 (m, 5H, CH2-b-all, H-
4-aa, CH2-5a); 4.35e4.09 (m, 10H, H-1b, CH2-b-all, H-6a-aa, H-5-
aa); 3.94 (m, 3H, CH2-a-Sp, CH2-b-all, H-6b-aa); 3.72 (m, 1H, H-6a);
3.63 (m, 1H, H-6b); 3.56 (m, 1H, CH2-a’-Sp); 3.33 (m, 2H, H-3, H-5);
3.22 (t, 1H, H-4); 3.14 (t, 1H, H-2); 2.82 (m, 2H, CH2-4); 2.15, 2.08 (s,
6H, CH3-7a and -8a); 1.93 (m, 2H, CH2-b-Sp); 1.74 (m, 2H, CH2-3);
4.2.35. 6-O-Allyl-5-[2,3,4-tri-O-allyl-1-O-(3,3-dimethoxypropyl)-
b-
D
-glucopyranos-6-oxy]-methyl- -tocopherol 45. Compound 43
g
(920 mg, 1.11 mmol) in anhydrous THF (10 mL) was treated with
NaH (60%, 650 mg, 16.0 mmol) for 30 min, and then allylbromide
(2.0 ml, 23.0 mol) was added and the mixture kept at room tem-
perature for 24 h. Workup as for compound 8 and purification by
flash chromatography (pet. ether/ethyl acetate 5:1) gave 45:
730 mg (76%) as a pale yellow oil.
1.29, 1.28 (s, 6H, CH3, 20, -2a’). 13C NMR (100 MHz, CDCl3)
d¼168.15
(1C, C-1-aa); 155.29 (1C, C-3-aa); 148.78 (1C, C-6); 147.77 (1C, C-
8a); 134.90, 134.77, 134.36, 133.92, 132.39, 131.36 (6C, ]CH, C-c-
all); 127.63, 125.86, 125.15 (3C, C-5, C-7, C-8); 120.89 (1C, C-2-aa);
118.86e116.10 (2C, C-4a and ]CH2 C-d-all); 103.37 (1C, C-c-Sp);
102.92 (1C, C-1b); 83.68 (1C, C-3); 81.04 (1C, C-2); 77.35 (1C, C-4);
1H NMR (400 MHz, CDCl3)
d¼6.10 (m, 1H, CH-all-c); 5.92 (m, 2H,
74.99 (1C, CH2 C-b-all); 74.43 (1C, C-4-aa); 74.37e73.05 (2C, CH2 C-
b-all and C-5-aa); 72.93 (1C, C-5); 72.60 (1C, C-2); 72.12, 71.96 (2C,
CH2, C-b-all); 68.89 (1C, C-6); 65.80 (1C, C-6-aa); 64.88 (1C, C-5a);
64.59 (1C, CH2, C-a-Sp); 33.83 (1C, CH2, C-b-Sp); 32.25 (1C, C-3);
26.66, 26.35 (2C, CH3, C-20, -2a’); 19.34 (1C, C-4); 12.34 (1C, CH3, C-
CH-all-c); 5.81 (m, 1H, CH-all-c); 5.44 (m, 1H, CH2-all-d); 5.31e5.08
(m, 7H, CH2-all-d); 4.62e4.68 (m, 3H, CH2-5a, CH-c-Sp); 4.37e4.11
(m, 8H, CH2-b-all, H-1b); 3.99e3.87 (m, 2H, CH2-b-all, CH2-a-Sp);
3.74 (m, 1H, H-6a); 3.64 (m, 1H, H-6b); 3.52 (m, 1H, CH2-a’-Sp);
3.38e3.28 (m, 8H, H-3, H-5, 2ꢂOMe); 3.23 (m, 1H, H-4); 3.15 (t, 1H,
H-2); 2.81 (m, 2H, CH2-4); 2.16, 2.08 (s, 6H, CH3-7a and -8a); 1.88
(m, 2H, CH2-b-Sp); 1.74 (m, 2H, CH2-3); 1.59e0.99 (m, 24H, CH3-2a,
CH-40, -80, -120, CH2-h10-110i); 0.87e0.83 (m, 12H, CH3-4a’, -8a’,
7a); 11.67 (1C, CH3, C-8b).
20
Lower diastereomer: [
(400 MHz, CDCl3)
a
]
þ15.3 (c 2.5, CH2Cl2). 1H NMR
D
d
¼6.09 (m, 1H, CH-all-c); 5.93 (m, 4H, CH-all-
c); 5.80 (m, 1H, CH-all-c); 5.47e5.06 (m, 10H, CH2-d-all); 5.03 (t,
1H, CH-c-Sp); 4.92 (m, 2H, CH2-d-all); 4.66e4.50 (m, 5H, H-4-aa,
CH2-b-all h2Hi, CH2-5a); 4.34e4.18 (m, 10H, H-1b, H-5-aa, CH2-b-
all h8Hi); 4.12 (m, 1H, CH2-b-all); 4.06 (dd, 1H, H-6a-aa); 3.94 (m,
3H, H-6b-aa, CH2-a-Sp, CH2-b-all); 3.72 (m, 1H, H-6a); 3.64 (m,
1H, H-6b); 3.57 (m, 1H, CH2-a’-Sp); 3.33 (m, 2H, H-3, H-5); 3.23
(t, 1H, H-4); 3.13 (t, 1H, H-2); 2.83 (m, 2H, CH2-4); 2.16, 2.08 (s,
6H, CH3-7a and -8a); 1.97 (m, 1H, CH2-b-Sp); 1.88 (mc, 1H, CH2-b-
Sp); 1.75 (m, 2H, CH2-3); 1.29, 1.28 (s, 6H, CH3, 20, -2a’); J1,2¼8.2,
J2,3¼8.8, J3,4¼9.1, J4,5¼9.5, J5,6b¼5.1, J6a,6b¼10.7, J5,6a-aa¼4.7, J6a,b-
-12a’, -130); J1,2¼8.1 Hz. 13C NMR (100 MHz, CDCl3)
¼148.73 (2C, C-
d
6, C-8a); 134.84, 134.67, 134.30, 133.94 (4C, ]CH C-all-c); 127.64,
125.90, 125.09, 118.34 (4C, C-4a, C-5, C-7, C-8); 116.47, 116.32, 116.21
(3C, ]CH2 C-all-d); 102.80, 101.65 (2C, C-1, C-c-Sp); 83.74, 81.16,
77.39, (3C, C-2, C-3, C-4); 74.99e73.14 (4C, C-2, C-5, C-6, C-all-b);
65.30, 64.90 (2C, C-a-Sp, C-5a); 52.70 (2C, CH3, 2ꢂOMe); 38.93,
37.03, 36.99, 36.86, 32.73 (8C, C-b-Sp, CH2-3, C-10, -30, -50, -70, -90,
-110); 32.36, 27.54 (3C, C-40, -80, -120); 24.38, 24.03 (2C, C-60, -100);
23.56e22.2 (3C, CH3, C-2a,-12a’, -130); 20.57 (1C, CH2-4); 13.32,
19.24 (2C, CH3, C-4a’, -8a’); 18.99 (1C, C-20); 12.34, 11.67 (2C, CH3, C-
7a, -8a). EI-MS: 871 (Mþ).
¼8.5, Jb,c-Sp¼5.4 Hz. 13C NMR (CDCl3)
¼168.22 (1C, C-1-aa);
d
aa
155.10 (1C, C-3-aa); 148.78 (1C, C-6); 147.78 (1C, C-8a);
134.89e131.41 (6C, ]CH, C-c-al1); 127.62, 125.82, 125.14 (3C, C-5,
C-7, C-8); 121.16 (1C, C-2-aa); 118.88e116.11 (12C, ]CH2, C-d-
all); 118.20 (1C, C-4a); 102.83 (2H, C-c-Sp and C-1b); 83.69 (1H,
C-3); 81.15 (1C, C-2); 77.33 (1C, C-4); 74.99 (1C, CH2, C-b-all);
74.46 (1C, C-4-aa); 74.37e71.96 (12C, CH2, C-b-all, C-5-aa and CH,
C-5); 72.60 (1C, C-2); 68.78 (1C, C-6); 65.42 (1C, C-6-aa); 64.94
(1C, C-5a); 64.86 (1C, C-a-Sp); 33.65 (1C, C-b-Sp); 32.25 (1C, C-3);
4.2.36. 2,3-Di-O-allyl- -ascorbic acid 46. L-Ascorbic acid (3.0 g,
L
17.0 mmol) and allylbromide (3.03 mL. 36 mmol) dissolved in an-
hydrous dimethylformamide (10 mL) were treated with sodium
hydride (60%, 1.44 g 36.0 mmol) for 3 h at room temperature.
Workup as for compound 8 was followed by chromatography
(diethylether) to give 46: 1.0 g (23%) as a pale yellow waxy

1664
M. Lahmann, J. Thiem / Tetrahedron 67 (2011) 1654e1664
3. part
Vol. 300.
B Methods Enzymol.; Packer, L., Ed.; Academic: San Diego, 1999;
26.68, 26.34 (2C, CH3, C-2, -2a’); 19.34 (1C, C-4); 12.35 (1C, CH3,
C-7a); 11.67 (1C, CH3, C-8b).
4. Herschberger, L. A.; Tappel, A. L. Lipids 1982, 17, 686e691.
5. Iwatsuki, M.; Komuro, E.; Niki, E. Bull. Chem. Soc. Jpn. 1995, 68, 620e624.
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1173e1183.
10. Amorati, R.; Ferroni, F.; Pedulli, G. F.; Valgimigli, L. J. Org. Chem. 2003, 68,
9654e9658.
11. Nakamura, T.; Kijima, S. Ger. Offen. 1974, 2331058; Chem. Abstr. 1974, 80,
P82664h.
4.2.38. 6-O-Allyl-5-[2-(5,6-O-methylidene-2,3-di-O-allyl-
L
-as-
-to-
corbyl)-ethyl-2,3,4-tri-O-allyl- -glucopyranos-6-oxy]-methyl-
b
-D
g
copherol 48. Compounds 45 (208 mg, 0.24 mmol) and 46 (67 mg,
0.26 mmol) dissolved in a mixture of n-hexane (5 mL) and
dichloromethane (5 mL) were treated with p-TsOH (1 mg) and
heated in a water separator for 1 h. Workup as for compound 47
was followed by flash chromatographic purification (pet. ether/
ethyl acetate 5:1) to give 48: 190 mg (75%) as a colourless oil
consisting of two diastereomers, which could be partly separated.
Upper set of diastereomers: 57 mg (22.5%), lower set of diastereomers:
55 mg (22%), mixed fraction: 78 mg (30.5%).
12. Schneider, G.; Thiem, J.; Lahmann, M. (Beiersdorf AG), EP 0726273A1, 1996;
Chem. Abstr. 1996, 125, 196234w.
13. Arakawa, S.; Ogawa, S.; Arakawa, E.; Sato, H. Jpn. Kokai Tokkyo Koho, JP
62,187,470, 1986; Chem. Abstr. 1988, 109, P73692f.
14. Ogata, K. (Senju Pharmaceutical), Eur. Pat. Appl. EP 226753, 1987; Chem. Abstr.
1987, 107, P218015h.
1H NMR (400 MHz, CDCl3)
CH-all-c); 5.79 (m,1H, CH-all-c); 5.47e5.06 (m,12H, CH2-all-d); 5.03
(t, 1H, CH-c-Sp), 4.92 (m, 2H, CH2- -all); 4.66e4.47 (m, 5H, H-4-aa,
CH2-b-all, CH2-5a); 4.35e4.17 (m, 7H, H-1 , H-5-aa, CH2-b-all); 4.17
d¼6.09 (m, 1H, CH-all-c); 5.93 (m, 4H,
15. Praly, J.-P.; He, L.; Quin, B. B.; Tanoh, M.; Chen, G.-R. Tetrahedron Lett. 2005, 46,
7081e7085.
16. Packer, J. E.; Slater, T. F.; Willson, R. L. Nature 1979, 278, 737e738.
17. Doba, T.; Burton, G. W.; Ingold, K. U. Biochim. Biophys. Acta 1985, 835,
298e303.
D
b
(m,1H, CH2-b-all); 4.05 (dd,1H, H-6a-aa); 3.94 (m, 3H, H-6b-aa, CH2-
a-Sp, CH2-b-all); 3.76 (m, 1H, H-6a); 3.65 (m, 1H, H-6b); 3.66 (m, 1H,
CH2-a’-Sp); 3.33 (m, 2H, H-3, H-5); 3.24 (t,1H, H-4); 3.13 (t,1H, H-2);
2.80 (m, 2H, CH2-4); 2.16, 2.08 (s, 6H, CH3-7a and -8a); 1.98 (m, 1H,
CH2-b-Sp);1.88 (m,1H, CH2-b-Sp);1.75 (m, 2H, CH2-3);1.63e1.01 (m,
24H, CH3-2a, CH-40, -80, -120, CH2-h10-110i); 0.89e0.81 (m, 12H, CH3-
18. Scarpa, M.; Rigo, A.; Maiorino, M.; Ursini, F.; Gregolin, G. Biochim. Biophys. Acta
1984, 801, 215e319.
19. Ogata, K.; Yamamoto, K.; Tsuruoka, H. Iyakuhin Kenkyu 1990, 21, 222e228;
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20. Kuribayashi, Y.; Yoshida, K.; Sakaue, T.; Okumura, A. Drug Res. 1992, 42,
1072e1074.
21. Morizaki, K.; Fukuota, T.; Sasaki, M.; Jpn. Kokai Tokkyo Koho, JP 05,331,166;
Chem. Abstr. 1994, 121, P109569k.
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Chem. Abstr. 1994, 120, P37812p.
4a’, -8a’, -12a’, -130). 13C NMR (100 MHz, CDCl3)
d¼168.09 (1C, C-1-
aa); 155.10 (1C, C-3-aa); 148.86 (1C, C-6); 147.54 (1C, C-8a);
134.89e131.41 (6C, ]CH, C-c-al1); 127.61, 125.85,125.01 (3C, C-5, C-
7, C-8);121.16(1C,C-2-aa);118.88e116.09(6C, ]CH2, C-d-all);118.20
23. Kim, Y. D.; Kim, C. K.; Lee, C. N.; Ha, J. Cosmet. Toiletries 1993, 108, 63e78.
24. Huassain, H. H.; Babic, G.; Durst, T.; Wright, J. S.; Flueraru, M.; Chichisau, A.;
Chepelev, L. L. J. Org. Chem. 2003, 68, 7023e7032.
(1C, C-4a); 102.84 (2C, CH, C-c-Sp and C-1b); 83.69 (1C, C-3); 81.15
€
25. Adelwohrer, C.; Rosenau, T.; Kosma, P. Tetrahedron 2003, 59, 8177e8182.
26. Tai, A.; Goto, S.; Ishiguro, Y.; Suzuki, K.; Nitoda, T.; Yamamoto, I. Bioorg. Med.
(1C, C-2); 77.34 (1C, C-4); 74.99 (1C, C-b-all); 74.62 (1C, C-4-aa);
74.46e71.93 (8C, C-b-all, C-5-aa and C-5, C-2); 68.08 (1C, C-6); 65.41
(1C, C-6-aa); 64.96 (2C, C-5a and C-a-Sp); 38.94 (2C, CH2 C-10, -110);
38.96e36.86(4C, CH2, C-30, -50, -70, -90);33.64 (1C, CH2, C-b-Sp);32.35
(2C, CH, C-40, -80); 29.25 (1C, C-3); 27.54 (1C, CH, C-120); 24.37, 24.02
(2C, CH2, C-60, -100); 23.55, 23.35 (2C, CH3, C-12a’, -130); 22.28 (1C, C-
2a); 19.31, 19.24 (2C, CH3, C-4a’, -8a’); 19.01 (2C, CH2, C-20 and C-4);
12.33 (1C, CH3, C-7a); 11.66 (1C, CH3, C-8b). FAB-MS: 1062.8 (MꢁH)þ.
Chem. Lett. 2004, 14, 623e627.
27. Lahmann, M.; Thiem, J. Carbohydr. Res. 1997, 299, 23e31.
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Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.12.066.
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