Aspects of stereocontrol in the L-Selectride reduction of 4-acyl-1,3-dioxolane derivatives

Article abstract of DOI:10.1016/j.tet.2010.01.107

The application of L-Selectride, either alone or in combination with ZnCl₂, to aryl ketones 1, 8 and 11 resulted in highly anti-stereoselective reduction. In contrast, lactols 22 and 23 gave a moderate syn-preference using L-Selectride alone an

Full text of DOI:10.1016/j.tet.2010.01.107

Tetrahedron 66 (2010) 2363–2372
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Aspects of stereocontrol in the L-Selectride reduction of 4-acyl-1,3-dioxolane
derivatives
,
a
b
Jeremy Robertson a , William P. Unsworth , Scott G. Lamont
*
a Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
b AstraZeneca Global R&D, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The application of L-Selectride, either alone or in combination with ZnCl2, to aryl ketones 1, 8 and 11
resulted in highly anti-stereoselective reduction. In contrast, lactols 22 and 23 gave a moderate syn-
preference using L-Selectride alone and a high syn-preference in the presence of ZnCl2. Uniquely, high
anti- stereoselectivity was observed in the reduction of o-anisyl lactol 37 with L-Selectride alone, which
was switched to a high syn-preference when ZnCl2 was present.
Received 20 October 2009
Received in revised form
17 December 2009
Accepted 27 January 2010
Available online 4 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Diastereoselective
Ketones
Lactols
Polyols
1. Introduction
O
OH
Ph
OH
Ph
L-Selectride
Ph
Enantiospecific synthesis from the chiral pool is a favourite
strategy for chemists familiar with the idiosyncracies of what may
be polar, multifunctionalised starting materials.1 Synthesis from
carbohydrates must take account of the interplay of many
potentially reactive sites, subtle selectivity differences between
stereoisomers, misunderstandings that arise as a result of parallel
nomenclature systems, and confusing or contradictory literature
results. In this context, we describe our results concerning the
L-Selectride reduction of ketones such as 1 (Scheme 1), in the
presence or absence of ZnCl2, as part of a natural product synthesis.
O
O
O
O
O
O
(+ ZnCl2)
> 20:1 anti:syn
Me Me
1
Me Me
anti-2
Me Me
syn-2
Me
Me
Me
Me
O
O
O
O
O
O
H
H
s-Bu3B–H
Ph
A (→ anti-2)
Ph
B (→ syn-2)
H–Bs-Bu3
Scheme 1. anti-Selective reduction of ketone 1 using L-Selectride with or without
added ZnCl2.
2. Results and discussion
L-Selectride reduction of ketone 1 gave alcohol 2 predominantly
as the anti-isomer regardless of whether or not ZnCl2 was added. This
outcome runs counter to the commonly-reported trend that such
reductions of 1,3-dioxolan-4-yl ketones give moderate to high syn-
selectivity2 and our explanation is as follows: in the reduction of 1,
substrate 1 because the cis-oriented vinyl group impedes hydride
delivery. Reported L-Selectride reductions of 1,3-dioxolan-4-yl ke-
tones concern substrates lacking a cis-disposed substituent at the 5-
position and reduction can proceed through model B.
This explanation does not accommodate Hanessian’s results
addition via ‘steric’ Felkin–Anh model (A) dominates, with
tion by Liþ or ZnCl2 having no qualitative bearing on the outcome (
chelation also favours anti-2). The ( *– *)-dominated Felkin–Anh
model B, which is equivalent to a -chelation model, is disfavoured in
a-chela-
concerning g-lactol reductions that proceed through analogous ke-
a-
tones generated in situ (Scheme 2).3 Thus, lactol 3 was reported to
give alcohol anti-4 using L-Selectride alone (>20:1 dr) with alcohol
syn-4 resulting as a single isomer when ZnCl2 was included. The
authors explained that the anti-isomer resulted from reduction
s
p
b
through model C, the syn-isomer from Cram
Unfortunately, both Newman projections for C and D were mis-
a-chelate model D.
* Corresponding author. Tel.: þ44 1865 275660.
E-mail address: jeremy.robertson@chem.ox.ac.uk (J. Robertson).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.107

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J. Robertson et al. / Tetrahedron 66 (2010) 2363–2372
drawn (they are the wrong enantiomers), which means that their
correct application predicts stereochemical outcomes opposite to
those observed. Whilst the g-alkoxide is implicit in these depictions,
its possible involvement is not mentioned by the authors. Although
the explanations are not valid the authors applied these results in
successful total syntheses4 therefore the outcomes appear reliable.
and whether the vinyl substituent was particularly unusual in
conferring insensitivity towards additives during the reduction
(substrate 11). Under the reduction conditions shown (with or
without ZnCl2, Table 1) the anti-isomers 12 and 13 (Fig. 1) were
produced in a high dr, which only fell off slightly as the temperature
of the reaction was raised (entry 8). The relative unimportance of
solvent choice was established in one case (entry 3).
Ot-Bu
OH
O
OH
O
MIPO
MIPO
MIPO
MIPO
N
Het
Table 1
O
O
O
O
Stereoselective L-Selectride reductionsa of ketones 1, 8 and 11
N
Ot-Bu
L-Selectride
Entry
Substrate
ZnCl2?
Yieldb
(%)
drc
(anti:syn)
Me Me
3
Me Me
L-Selectride,
ZnCl2
1
1
1
1
8
U
d
d
U
d
U
d
d
67
69
71
75
72
83
84
89
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
w10:1
2
3a
4
OH
O
OH
OH
O
OH
Het
Het
O
5
6
8
O
11
11
11
7
anti-4
syn-4
Me Me
from
MHx
Me Me
from
MHx
8a
a
Reactions were run in dichloromethane at ꢀ78 ꢁC except in entries 3 (THF) and 8
(20 ꢁC).
b
Yields refer to isolated yields after chromatography.
c
Estimated by inspection of the 1H NMR spectra of crude products.5
O
O
O
Het
MIPO
MIPO
Het
O
O
O
O
O
OH OMe
OH
Ph
ZnCl2
Me Me
Me Me
TBSO
H–
H–
O
O
O
O
H
H
Me Me
anti-12
Me Me
anti-13
O
Het
O
Het
R
O
R
ZnCl2
O
O
O
Figure 1. Ketone reduction products.
Me
Me
Me
Me
D
C
The stereochemistry of the major anti-isomers 2, 12, and 13 was
established by acetonide hydrolysis and benzylidene acetal
formation to afford dioxanes 17 and 18, and bisacetal 19 (Scheme 4).
In all cases, the assignments were supported by large diaxial
couplings in the 1H NMR spectra (see Experimental section).
Scheme 2. Hanessian’s results and reported stereochemical models for the selective
production of 4 diastereomers. [MIP¼2-methoxy-2-propyl].
We prepared two further substrates, 8 and 11, by standard
methods (Scheme 3) so as to explore whether the presence of an
ortho-alkoxy group could influence the outcome (substrate 8, cf. 3)
OH
OH
R
Ar
anti-2
a or b
Ar
c
Ph
OMe
O
O
R
Ar
O
anti-12
anti-13
MIPO
I
d
a–c
O
O
1
OH OH
Ph
O
O
O
O
R
CH2=CH Ph
CH2=CH 2-MeOC6H4
CH2OH Ph
14
15
16
17 (from 14)
18 (from 15)
Me Me
5
Me Me
6
Ph
O
O
H
O
H
c
Ph
O
O
OMe
O
19
e,f
H
(from 16)
O
O
O
O
Ph
Me Me
7
Me Me
8
Scheme 4. Synthesis of benzylidene acetals 17–19 used to establish anti-stereo-
selective reductions. Reagents: (a) (for 2, 12) concd HCl, MeOH; (b) (for 13) aq AcOH;
(c) PhCH(OMe)2, p-TsOH, CH2Cl2 (54% from 2, 75% from 12).
Ph
OH
O
O
O
O
O
These results gave us confidence that the anti-selective
L-Selectride reduction of substrate 1 was not an isolated case, that
Hanessian’s lactol reduction in the absence of ZnCl2 could also be
accommodated by model A, and therefore that Hanessian’s result in
g
h
TBSO
Ph
O
O
O
O
O
Me Me
Me Me
9
Me Me
10
the presence of ZnCl2 depended on the presence of a free g-alk-
11
oxide. The last conclusion was easily tested by surveying the
reductions of substrate 10 (Scheme 3) and ribonolactone
derivatives 22 and 23 (Scheme 5). The results of this survey are
summarised in Table 2.
Scheme 3. Synthesis of aryl ketone reduction substrates 1, 8 and 11. Reagents: (a) PhLi,
THF (91%); (b) concd H2SO4, MeOH (95%); (c) PPh3, I2, imidazole, toluene (59%); (d) Zn,
aq THF,))) (78%); (e) 2-anisyllithium, ZnCl2, THF (10%); (f) Dess–Martin periodinane,
CH2Cl2 (72%); (g) PhLi, THF (75%); (h) TBSCl, imidazole, DMF (88%).

J. Robertson et al. / Tetrahedron 66 (2010) 2363–2372
2365
Ph
OH
S
O
O
O
RO
PhLi, THF
RO
OH
O
OH
Ph
OH
Ph
O
O
HO
a or b
c
O
O
O
O
syn-25,26
O
O
O
Me Me
Me Me
Me Me
27
Me Me
28
20, R = Bn
22, R = Bn (85%)
23, R = TBS (76%)
d
21, R = TBS
e,f
Scheme 5. Preparation of lactol reduction precursors.
anti-2
syn-2
Scheme 6. (a) H2, Pd/C, MeOH (quant. from 25); (b) TBAF, THF, (57% from 26); (c)
thiocarbonyl diimidazole, THF (58%); (d) P(OMe)3, heat (quant. crude); (e) PPh3, DIAD,
p-NO2C6H4CO2H, C6H6; (f) NaOH, aq MeOH.
Table 2
Stereoselective L-Selectride reductionsa of lactols 10, 22 and 23
Entry
Substrate
ZnCl2?
Yieldb
(%)
drc
(anti:syn)
counterion (Liþ), chelation-control would be more closely balanced
with reduction occurring through an arrangement similar to A
(Scheme 1). The outlier in these reactions, entry 2, could be
1
2
3
4
5
6
7a
10
10
22
22
23
23
23
U
d
U
d
U
d
d
59
87
63
57
64
73
78
1:3
w15:1
w1:15
1:2
w1:15
1:1.5
1:2
explained by
g-chelation strengthened by chelation with the
a-oxygen of the acetonide (G, Fig. 3), and hydride delivery to the
more exposed face of the carbonyl, the endo-face being shielded by
the axial proton, H*. In substrates 22 and 23 such an arrangement
would be disfavoured because the CH2OBn/TBS substituent would
be placed in the axial site occupied by H* in G.7
a
All reactions were run in dichloromethane at ꢀ78 ꢁC with slow warming to
20 ꢁC except in entry 7 (THF).
b
Yields refer to yields of the combined diastereomers after chromatography.
c
Estimated by inspection of the 1H NMR spectra of the product mixtures after
chromatography.5
M
O
O
O
O
Me
Me
O
H
R
O
R
Het
O
With one exception (entry 2), the reductions afforded the syn-
alcohol diastereomers 24–26 (Fig. 2) as major products, with
essentially complete stereoselectivity resulting in the reductions
with added ZnCl2. Omission of ZnCl2 did not result in high anti-
selectivity (cf. Hanessian’s examples), merely a relaxation of the
syn-preference.
O
H
H–Bs-Bu3
Ph
M–H
Me Me
E
F
H
Ph
Ph
O
O
*
*
H
H
H–Bs-Bu3
Li
Li
H
H
OH
O
OH
Ph
OH
O
OH
Ph
O
O
H
H
O
O
H
H
R
R
Me
Me
Me
Me
→ anti-24
O
O
O
O
G
Me Me
Me Me
R
Figure 3. Models for syn-selective reductions of lactols 10, 22 and 23, and anti-se-
lective reduction of lactol 10 in the absence of ZnCl2.
syn-24
syn-25
syn-26
anti-24
anti-25
anti-26
H
CH2OBn
CH2OTBS
Figure 2. Lactol reduction products.
It remains to address the question of why Hanessian’s substrates
afford cleanly the anti-isomers in the absence of ZnCl2 whereas
ours do not. Assuming that the 1ꢁ-hydroxy protecting group does
not influence the outcome then the acyl substituent is implicated.
Literature examples of L-Selectride reductions of lactols in this
series are restricted to heteroaryl-derivatives; within these, there
are clear trends. L-Selectride reduction of thiazole derivatives 29–
31 (Fig. 4) shows a clear anti-preference8,2f and the L-Selectride/
ZnCl2 combination returns the syn-reduction products from 32 and
33, in full agreement with Hanessian’s results.9,4 However, it was
reported recently that the 5-bromothiophen-2-yl derivative 34
affords the syn- alcohol using L-Selectride alone and the anti- al-
cohol in the presence of ZnCl2, both in opposition to the trend seen
elsewhere.10 In the same report it was noted that the 3-bromo-
thiophen-2-yl derivatives 35 and 36 failed to react with L-Selec-
tride alone (as also reported for a related thiazolyl derivative)2f but
the usual trend was followed in the presence of ZnCl2 where the
syn-reduction products were obtained.
Stereochemical assignments for the reduction products were
made as follows. First, syn-24 was assigned by comparison of
spectroscopic data with literature data (see Experimental section);
anti-24 was then assigned by default, supported by oxidation
experiments with MnO2, which returned lactol 10 from both 24
isomers. This, and similar MnO2 oxidations of syn-25 and syn-26
(/22 and 23, respectively) also ruled out epimerisation a- to the
intermediate ketone. Finally, syn-25 and syn-26 were correlated
with anti-2 by alcohol deprotection and Corey–Winter elimination
to give syn-2, identical to the product of Mitsunobu inversion of
anti-2 (Scheme 6). The esterification step of the Mitsunobu reaction
gave a ca. 1:1 ratio of syn- and anti- benzoate esters; accordingly,
the hydrolysis afforded a mixture of syn- and anti-2 but this did not
complicate comparison with syn-2 generated from intermediate 28.
The tendency for syn-stereoselective reduction revealed by the
data in Table 2 is opposite to that seen with the ketone substrates 1,
8 and 11. This supports the involvement of the (metallated)
g
-hy-
In view of this background we prepared a final substrate (37,
Scheme 7) differing from lactol 22 merely by the presence of an
ortho-methoxy substituent. Reduction of this compound in the
presence of ZnCl2 gave the expected high syn- selectivity but, in
contrast to the reactions of substrates 22 and 23, reduction with
droxy group in the reductions of lactols 10, 22 and 23. Reduction
from the exo-face of a chelated intermediate (E, Fig. 3) or internal
delivery (F), as suggested by others,6,2a would appear to operate. In
the absence of added ZnCl2, with a less-strongly co-ordinating

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J. Robertson et al. / Tetrahedron 66 (2010) 2363–2372
OH
OH
S
(2.37 g, 91%). A trace quantity of the product of double phenyl ad-
dition was also obtained (data not shown). Rf 0.62 (petrol/ethyl
O
O
TBDPSO
OMe
Me
N
S
N
20
acetate, 2:1); mp 74–76 ꢁC; [
a]
ꢀ26.0 (c 1.0, CH2Cl2); nmax (thin
D
OMe
O
O
O
O
film)/cmꢀ1 3384br, 1450w, 1381m, 1212s, 1160w, 1079s, 872w,
734w, 701w; dH (400 MHz, CDCl3) anomer A: 1.27, 1.41, 1.44 and
1.45 (4ꢂ3H, 4ꢂs, 4ꢂCH3), 3.26 (3H, s, OCH3), 3.68–3.70 (2H, m,
OCH2), 4.56–4.58 (1H, m, CH2CH), 4.66 (1H, d, J 5.6) and 4.94
(1H, dd, J 5.6, 1.5, 2ꢂCH), 5.14 (1H, s, OH), 7.36–7.40 (3H, m) and
7.55–7.65 (2H, m, Ph); dC (100 MHz, CDCl3) anomer A: 24.1 (CH3),
24.3 (CH3), 24.9 (CH3), 26.5 (CH3), 49.2 (OCH3), 62.2 (CH2), 82.4
(CH), 85.0 (CH), 88.5 (CH), 101.1 (C), 107.2 (C), 112.8 (C), 126.9 (CH),
127.6 (CH), 128.2 (CH), 139.0 (C); anomer B: 24.4 (CH3), 24.4 (CH3),
25.1 (CH3), 26.6 (CH3), 48.7 (OCH3), 60.6 (CH2), 81.0 (CH), 81.4 (CH),
86.2 (CH), 100.2 (C), 102.1 (C), 116.1 (C), 125.7 (CH), 126.9 (CH), 128.1
(CH), 142.3 (C); m/z (ESIþ) 361 (MNaþ, 100%), 321 (70), 249 (60);
HRMS (ESIþ) found 361.1618, C18H26NaO6 (MNaþ) requires
361.1622.
NRBoc
Me Me
Me Me
30, R = H; 31, R = Me
29
OMe
N
OH
S
OH
Y
X
O
O
X
Y
TBDPSO
OMe
RO
34
35
36
Br
H
Br Br
H
Br
O
O
O
O
N
Me Me
Me Me
32, R = MIP; 33, R = TBDPS
Figure 4. Reported lactol substrates for L-Selectride reduction.
L-Selectride alone was highly anti-selective, in agreement with
Hanessian’s results.11,12
3.2. (3aR,6R,6aR)-6-Hydroxymethyl-4-methoxy-2,2-dimethyl-
4-phenyltetrahydrofuro[3,4-d][1,3]dioxole
OMe
OH
To
a
solution of (3aR,6R,6aR)-6-(2-methoxypropan-2-ylox-
O
BnO
y)methyl-2,2-dimethyl-4-phenyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol
(722 mg, 2.14 mmol) in methanol (100 mL) was added concentrated
sulfuric acid (58 mL, 1.07 mmol). After stirring for 5 min, the reaction
O
O
Me Me
37
was quenched by the addition of triethylamine (1.49 mL,10.7 mmol)
and the mixture was concentrated in vacuo. The residue was dis-
solved in ethyl acetate (5.0 mL), loaded onto a short plug of silica, and
flushed through with more ethyl acetate (50 mL) to afford the title
L-Selectride
ZnCl2
L-Selectride
compound as a colourless viscous oil with an anomeric ratio >20:1
OH
O
OH OMe
OH
O
OH OMe
20
(569 mg, 95%). Rf 0.35 (petrol/ethyl acetate, 2:1); [
a
]
ꢀ36.7 (c 0.7,
BnO
BnO
D
CH2Cl2); nmax (thin film)/cmꢀ13443br,1450w,1373w,1261m,1212m,
1096s,1027s, 872w, 762w; dH (500 MHz, CDCl3) 1.21 and 1.24 (2ꢂ3H,
2ꢂs, 2ꢂCH3), 3.11 (3H, s, OCH3), 3.21 (1H, dd, J 9.0, 3.2, OH), 3.79 (1H,
ddd, J 12.2, 9.0, 4.7) and 3.85 (1H, app dt, J 12.2, 3.2, CH2), 4.56–4.60
(1H, m, CH2CH), 4.76 (1H, d, J 5.7, CHCHO), 4.96 (1H, d, J 5.7, CHCPh),
7.32 (3H, m) and 7.49 (2H, d, J 7.1, Ph); dC (125 MHz, CDCl3) 24.8 (CH3),
26.0 (CH3), 49.8 (OCH3), 64.3 (CH2), 81.8 (CH), 87.0 (CH), 88.1 (CH),
112.2 (C), 112.4 (C), 127.5 (CH), 128.0 (CH), 128.4 (CH), 136.1 (C); m/z
(ESIþ) 583 (M2Naþ, 20%), 303 (MNaþ, 100), 249 (100); HRMS (ESIþ)
found 303.1206, C15H20NaO5 (MNaþ) requires 303.1203.
O
O
Me Me
Me Me
anti-38 (47%)
syn-38 (69%)
Scheme 7. Stereochemical outcomes in the reduction of o-anisyl lactol 37.
In conclusion, the L-Selectride reduction of 4-aroyl-1,3-dioxo-
lanes and related lactols provides complementary routes to anti-
and syn- benzylic alcohols, respectively. The observed sense of
diastereoselection can be accommodated by a number of models
(A and E–G) but their predictive relevance, particularly in the lactol
reductions, has to be tempered by the possible influence of the acyl
or hemiacetal substituent.
3.3. (3aR,6S,6aS)-6-Iodomethyl-4-methoxy-2,2-dimethyl-4-
phenyltetrahydrofuro[3,4-d][1,3]dioxole (6)
[Note: this compound is unstable when stored neat at rt and was
either used immediately or stored in benzene at ꢀ18 ꢁC].
Procedure A. To a solution of (3aR,6R,6aR)-6-hydroxymethyl-
4-methoxy-2,2-dimethyl-4-phenyltetrahydrofuro[3,4-d][1,3]dioxole
(350 mg, 1.25 mmol) in toluene (15 mL) was added sequentially:
triphenylphosphine (493 mg, 1.87 mmol), imidazole (128 mg,
1.87 mmol) and iodine (477 mg, 1.87 mmol), and the mixture was
stirred at rt for 2 h. The reaction mixture was then washed with aq
Na2S2O3 solution (20 mL, 10%) and the washings extracted with
ethyl acetate (3ꢂ20 mL). The combined organic solutions were
dried over MgSO4, concentrated in vacuo, and the residue purified
by column chromatography (petrol/ethyl acetate, 20:1) to afford
3. Experimental section
Starting materials 5,4b 7,13 9,14 10,15 2016 and 2117 were prepared
following literature procedures.
3.1. (3aR,6R,6aR)-6-(2-Methoxypropan-2-yloxy)methyl-2,2-
dimethyl-4-phenyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol
To a stirred solution of bromobenzene (0.89 mL, 8.46 mmol) in
THF (80 mL) at ꢀ78 ꢁC was added tert-butyllithium (10.4 mL, 1.7 M
solution in hexanes, 17.7 mmol). After stirring for 30 min, a solution
of lactone 5 (2.0 g, 7.69 mmol) in THF (40 mL), cooled to ꢀ78 ꢁC,
was added dropwise via cannula. The mixture was stirred for
90 min at ꢀ78 ꢁC, quenched with brine (40 mL), then allowed to
warm to rt, extracted with ethyl acetate (3ꢂ80 mL) and dried over
MgSO4. Concentration in vacuo and purification by column chro-
matography (petrol/ethyl acetate, 10:1/4:1/0.5:1) afforded the
title compound as a mixture of anomers (A:B, 8:1) as a white solid
the title compound as a white solid with an anomeric ratio >20:1
23
(286 mg, 59%). Rf 0.61 (petrol/ethyl acetate, 10:1); mp 62 ꢁC; [
a]
D
ꢀ59.3 (c 0.3, CDCl3); nmax (thin film)/cmꢀ1 1450w, 1373m, 1262m,
1211w, 1097s, 1021s, 872m, 760w, 700w; dH (500 MHz, CDCl3) 1.26
and 1.33 (2ꢂ3H, 2ꢂs, 2ꢂCH3), 3.06 (3H, s, OCH3), 3.37 (1H, app t,
J 10.0) and 3.45 (1H, dd, J 10.0, 5.7, CH2), 4.61 (1H, dd, J 10.0, 5.7,
CH2CH), 4.76 (1H, d, J 5.7, CHCHO), 4.91 (1H, d, J 5.7, CHCPh),
7.32–7.42 (3H, m) and 7.45–7.50 (2H, m, Ph); dC (125 MHz, CDCl3)
6.9 (CH2), 25.2 (CH3), 26.5 (CH3), 49.6 (OCH3), 84.1 (CH), 87.1 (CH),

J. Robertson et al. / Tetrahedron 66 (2010) 2363–2372
2367
87.8 (CH), 112.3 (C), 113.0 (C), 127.4 (CH), 128.0 (CH), 128.4 (CH),
136.1 (C); m/z (ESIþ) 563 (100%), 413 (MNaþ, 30), 295 (40); HRMS
(ESIþ) found 413.0229, C15H19INaO4 (MNaþ) requires 413.0220.
Procedure B. To a solution of (3aR,6R,6aR)-4-methoxy-2,2-di-
methyl-4-phenyl-6-(p-toluenesulfonyloxy)methyltetrahydrofuro[3,4-
d][1,3]dioxole (see below) (1.43 g, 3.30 mmol) in acetonitrile
(10 mL) was added NaI (977 mg, 6.52 mmol). The reaction mixture
was heated to reflux and stirred for 18 h. After cooling to rt the
solids were removed by filtration, and the solution was concen-
trated in vacuo. The residue was dissolved in ether (50 mL) and
washed sequentially with aq Na2S2O3 solution (20 mL, 10%), water
(20 mL) and brine (20 mL), then dried over MgSO4. Concentration
in vacuo and purification by column chromatography (petrol/ethyl
acetate, 20:1) afforded the title compound (692 mg, 54%). Data as
above.
CHC]O), 7.45 (2H, app t, J 7.6), 7.57 (1H, t, J 7.6) and 7.88 (2H, d, J 7.6,
Ph); dC (125 MHz, CDCl3) 27.4 (CH3), 27.2 (CH3), 79.5 (CH), 80.5 (CH),
110.6 (C), 119.7 (CH2), 128.5 (CH), 128.6 (CH), 133.1 (CH), 133.5 (CH),
135.9 (C), 195.1 (C); m/z (ESIþ) 487 (M2Naþ, 70%), 269 (100), 255
(MNaþ, 90); HRMS (ESIþ) found 255.0992, C14H16NaO3 (MNaþ)
requires 255.0992.
3.6. (4S,5R)-4-[1-(2-Methoxyphenyl)]hydroxymethyl-2,2-
dimethyl-5-vinyl-1,3-dioxolane
To a solution of (4R,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolane-4-
carbaldehyde (7) (240 mg, 1.54 mmol) in THF (10 mL) at ꢀ78 ꢁC
was added a solution of ZnCl2 (2.0 mL, 1 M in ether, 2.0 mmol)
dropwise and the mixture was stirred for 30 min. Meanwhile, to
a
solution of 2-bromoanisole (0.191 mL, 1.54 mmol) in THF
(10 mL) at ꢀ78 ꢁC was added tert-butyllithium (1.99 mL, 1.7 M
solution in hexanes, 3.38 mmol) and the mixture was stirred for
30 min. The resulting organolithium solution was then trans-
ferred into the aldehyde solution at ꢀ78 ꢁC dropwise via cannula,
and stirring was continued at this temperature for 30 min. The
cold bath was then removed and stirring continued for a further
30 min at rt. The reaction was quenched by the addition of aq
NH4Cl solution (5 mL, saturated). The mixture was extracted with
ethyl acetate (3ꢂ10 mL), the extracts dried over MgSO4 and
concentrated in vacuo, and the residue purified by column
chromatography (petrol/ethyl acetate, 7:1) to afford the title
compound as a mixture of diastereomers (A:B, 5:2) and as a pale
yellow oil (42 mg, 10%). Rf 0.28 (petrol/ethyl acetate, 3:1); nmax
(thin film)/cmꢀ1 3745br, 1492m, 1464w, 1379w, 1242s, 1164w,
1097w, 1029s, 928w, 888w, 755m; dH (500 MHz, CDCl3) 1.35 (3H,
s, CH3, B), 1.40 (3H, s, CH3, A), 1.46 (3H, s, CH3, B), 1.61 (3H, s, CH3,
A), 2.81 (1H, d, J 6.7, OH, A), 2.94 (1H, d, J 7.0, OH, B), 3.83 (3H, s,
OCH3, A), 3.88 (3H, s, OCH3, B), 4.50 (1H, dd, J 6.9, 3.9, CHCHOH,
A), 4.53 (1H, dd, J 9.0, 6.2, CHCHOH, B), 4.61–4.66 (1H, m,
CHCH], A), 4.75–4.78 (1H, m, CHCH], B), 4.85 (1H, dd, J 9.0, 7.0,
CHOH, B), 5.03 (1H, dd, J 6.7, 3.9, CHOH, A), 5.27 (1H, app dt,
J 10.2, 1.4,¼CHH0, A), 5.31–5.36 (2H, m, ]CHH0, B and ]CHH0, A),
5.48 (1H, app dt, J 17.2, 1.4, ]CHH0, B), 6.10 (1H, ddd, J 17.7, 10.2,
7.6, CH]CH2, A), 6.21 (1H, ddd, J 17.2, 10.4, 6.9, CH]CH2, B), 6.86
(1H, d, J 8.2, Ar-A), 6.91 (1H, d, J 8.2, Ar-B), 6.95–7.00 (2H, m, Ar-A
and Ar-B), 7.24–7.33 (3H, m, Ar-A and 2ꢂAr-B), 7.41 (1H, dd, J 7.5,
1.5, Ar-A); dC (125 MHz, CDCl3) isomer A: 24.9 (CH3), 27.2 (CH3),
55.3 (OCH3), 66.8 (CH), 79.3 (CH), 80.1 (CH), 108.7 (C), 110.2 (CH),
119.2 (CH2), 120.6 (CH), 127.6 (CH), 128.7 (CH), 129.2 (CH), 133.1
(CH), 156.1 (C); isomer B: 25.5 (CH3), 27.8 (CH3), 55.3 (OCH3), 70.1
(CH), 79.1 (CH), 79.2 (CH), 108.7 (C), 110.7 (CH), 117.7 (CH2), 120.8
(CH), 128.7 (C), 128.9 (CH), 129.2 (CH), 134.1 (CH), 157.1 (C); m/z
(ESIþ) 287 (MNaþ, 100%); HRMS (ESIþ) found 287.1249,
C15H20NaO4 (MNaþ) requires 287.1254.
3.4. (3aR,6R,6aR)-4-Methoxy-2,2-dimethyl-4-phenyl-6-(p-
toluenesulfonyloxy)methyltetrahydrofuro[3,4-d][1,3]dioxole
To
a
stirred solution of (3aR,6R,6aR)-6-(hydroxymethyl)
-4-methoxy-2,2-dimethyl-4-phenyltetrahydrofuro[3,4-d][1,3]dioxole
(1.71 g, 6.11 mmol) in pyridine (3.05 mL) at 0 ꢁC was slowly added p-
toluenesulfonyl chloride (1.28 g. 6.72 mmol) and then DMAP
(75 mg, 0.615 mmol). The reaction mixture was allowed to warm to
rt, stirred for 1 h, and then concentrated in vacuo. The crude product
was then dissolved in dichloromethane (50 mL), washed succes-
sively with hydrochloric acid (20 mL, 1 M), aq NaHCO3 solution
(20 mL, saturated) and brine (20 mL), then dried over MgSO4 and
concentrated in vacuo. Purification by column chromatography
(petrol/ethyl acetate, 7:1)afforded thetitle compoundas awhitesolid
23
(1.57 g, 59%). Rf 0.28 (petrol/ethyl acetate, 5:1); mp 76 ꢁC; [
a]
ꢀ59.3
D
(c 0.3, CDCl3); nmax (thin film)/cmꢀ1 2991w, 1451w, 1361s, 1179m,
1098s,1047w, 969s, 836m, 815m, 764w, 704m, 666m; dH (400 MHz,
CDCl3) 1.21 and 1.28 (2ꢂ3H, 2ꢂs, 2ꢂCH3), 2.47 (3H, s, ArCH3), 2.90
(3H, s, OCH3), 4.16 and 4.21 (2ꢂ1H, 2ꢂdd, J 9.9, 7.2, CH2), 4.48 (1H, td,
J 7.2, 1.3, CHCH2), 4.66 (1H, dd, J 5.8, 1.3, CHCHO), 4.72 (1H, d, J 5.8,
CHCPh), 7.31–7.45 (7H, m, Ph and two of Ts), 7.85 (2H, d, J 8.2, two of
Ts); dC (100 MHz, CDCl3)21.7(CH3), 25.1 (CH3), 26.4(CH3), 49.4 (CH3),
69.5 (CH2), 82.0 (CH), 83.2 (CH), 87.1 (CH), 112.2 (C), 113.1 (C), 127.4
(CH), 128.0 (CH), 128.1 (CH), 128.4 (CH), 130.0 (CH), 132.6 (C), 136.1
(C), 145.2 (C); m/z (ESIþ) 457 (MNaþ, 60%), 403 (MHþꢀMeOH, 100);
HRMS (ESIþ) found 457.1298, C22H26NaO7S (MNaþ) requires
457.1291.
3.5. (4R,5R)-4-Benzoyl-2,2-dimethyl-5-vinyl-1,3-dioxolane (1)
Zinc dust (SigmaAldrich, particle size <10 mm) was activated
and dried immediately prior to use as follows. A suspension of zinc
dust (5.0 g) in hydrochloric acid (50 mL, 1 M) was stirred at rt for
15 min. The zinc was then removed by filtration, washed sequen-
tially with water (2ꢂ50 mL) and ether (2ꢂ50 mL), and dried under
high vacuum with moderate heating (heat gun). Upon cooling,
a sample of this activated zinc (123 mg, 1.88 mmol) was added to
a solution of iodide 6 (75 mg, 0.192 mmol) in THF (1.5 mL) and
water (0.4 mL). The reaction flask was then placed in an ultrasonic
bath for 1 h at 40 ꢁC and the mixture was then filtered through
CeliteÒ, rinsing through with dichloromethane (50 mL). The filtrate
was washed with aq NaHCO3 solution (50 mL, saturated), dried
over MgSO4, concentrated in vacuo, and purified by column chro-
matography (petrol/ethyl acetate, 10:1) to afford the title compound
3.7. (4R,5R)-4-(2-Methoxybenzoyl)-2,2-dimethyl-5-vinyl-1,3-
dioxolane (8)
To a solution of (4S,5R)-4-[1-(2-methoxyphenyl)]hydroxymethyl-
2,2-dimethyl-5-vinyl-1,3-dioxolane
(42 mg,
0.159 mmol)
in
dichloromethane (4.0 mL) at 0 ꢁC was added Dess–Martin period-
inane (101 mg, 0.239 mmol) and the mixture was stirred for 1 h.
After this time the reaction mixture was allowed to warm to rt and
stirred for a further 4 h, concentrated in vacuo, and purified by col-
umn chromatography (petrol/ethyl acetate, 6:1), to afford the title
(1) as a colourless viscous oil (35 mg, 79%). Rf 0.28 (petrol/ethyl
compound (8) as a colourless oil (30 mg, 72%). Rf 0.51 (petrol/ethyl
23
23
acetate, 10:1); [
a]
þ23.7 (c 0.6, CHCl3); nmax (thin film)/cmꢀ1
acetate, 2:1); [
a
]
D
þ46 (c 0.3, CHCl3); nmax (thin film)/cmꢀ1 2986w,
D
1697s, 1598w, 1449w, 1381m, 1216s, 1163w, 1100m, 1047m, 875w,
693m; dH (400MHz, CDCl3) 1.49 and 1.70 (2ꢂ3H, 2ꢂs, 2ꢂCH3), 4.98
(1H, app t, J 7.7, CHCH]), 5.02 (1H, d, J 10.1) and 5.20 (1H, d, J 17.1,
]CH2), 5.57 (1H, ddd, J 17.1, 10.1, 7.7, CH]CH2), 5.60 (1H, d, J 7.7,
1683s, 1598m, 1485m, 1467w, 1438w, 1379w, 1286m, 1245s, 1208m,
1090m, 1019m, 878w; dH (500 MHz, CDCl3) 1.47 and 1.68 (2ꢂ3H,
2ꢂs, 2ꢂCH3), 3.92 (3H, s, OCH3), 4.95 (1H, app t, J 7.5, CHCH]), 5.00
(1H, d, J 10.3) and 5.21 (1H, d, J 16.9,]CH2), 5.61 (1H, ddd, J 16.9,10.3,

2368
J. Robertson et al. / Tetrahedron 66 (2010) 2363–2372
7.5, CH]CH2), 5.71 (1H, d, J 7.5, CHC]O), 6.94 (1H, d, J 8.4), 7.02
(1H, t, J 7.9), 7.49 (1H, ddd, J 8.4, 7.9,1.8) and 7.84 (1H, dd, J 7.9,1.8, Ar);
dC (125 MHz, CDCl3) 25.5 (CH3), 27.1 (CH3), 55.4 (OCH3), 79.1 (CH),
83.2 (CH),110.1 (C),111.4 (CH),118.6 (CH2),121.0 (CH),126.1 (C),131.2
(CH), 133.8 (CH), 134.5 (CH), 158.5 (C), 195.9 (C); m/z (ESIþ) 547
(M2Naþ, 10%), 326 (80), 285 (MNaþ, 20); HRMS (ESIþ) found
285.1084, C15H18NaO4 (MNaþ) requires 285.1097.
3.10. (3aR,6R,6aR)-6-(tert-Butyldimethylsilyloxy)methyl-2,2-
dimethyl-4-phenyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol (23)18
To a stirred solution of phenyllithium (1.01 mL, 1.8 M in dibutyl
ether, 1.82 mmol) in THF (20 mL) at ꢀ78 ꢁC was added a solution of
lactone 21 (458 mg, 1.52 mmol) in THF (5.0 mL) dropwise via can-
nula. The mixture was stirred for 90 min at ꢀ78 ꢁC, quenched with
brine (10 mL), allowed to warm to rt, then extracted with ethyl
acetate (3ꢂ20 mL), and dried over MgSO4. The solution was con-
centrated in vacuo and purified by column chromatography (petrol/
ethyl acetate, 20:1) to afford the lactol (23) as a mixture of anomers
(A:B, 4:1) and as a colourless oil (490 mg, 85%). Rf 0.40 (petrol/ethyl
3.8. (4R,5R)-4-Benzoyl-5-(tert-butyldimethylsilyloxy)methyl-
2,2-dimethyl-1,3-dioxolane (11)
To a solution of lactol 10 (196 mg, 0.831 mmol) in DMF
(1.0 mL) at 0 ꢁC were added imidazole (283 mg, 4.16 mmol) and
tert-butyldimethylsilyl chloride (313 mg, 2.08 mmol). The re-
action mixture was warmed to rt and stirred for 18 h. Water
(5.0 mL) was added, the mixture extracted with ether
(3ꢂ5.0 mL), and the combined organic portions dried over
MgSO4. The residue was purified by column chromatography
25
23
acetate, 10:1); [
a]
ꢀ37.6 (c 1.4, CHCl3), lit.18a
[
a]
ꢀ20.0 (c 1.5,
D
D
EtOH); nmax (thin film)/cmꢀ1 3387br, 1451w, 1373m, 1257s, 1162w,
1076s, 837s, 779m, 669m, 666w; dH (400 MHz, CDCl3) 0.10 and 0.11
(2ꢂ3H, 2ꢂs, SiMe2, B), 0.18 and 0.20 (2ꢂ3H, 2ꢂs, SiMe2, A), 0.92
(9H, s, t-Bu, B), 0.98 (9H, s, t-Bu, A), 1.27 (3H, s, CH3, A), 1.41 (6H, s,
CH3, A and CH3, B), 1.69 (3H, s, CH3, B), 3.84–3.95 (4H, m, CH2, A and
B), 4.30–4.33 (1H, m, CHCH2, B), 4.48–4.52 (1H, m, CHCH2, A), 4.60
(1H, d, J 7.2, CHCPh, B), 4.65 (1H, d, J 5.7, CHCPh, A), 4.90 (1H, dd, J
7.2, 4.2, CHCHO, B), 4.92–4.96 (1H, m, CHCHO, A), 5.30 (1H, s, OH, B),
5.32 (1H, s, OH, A), 7.30–7.40 (6H, m) and 7.58–7.66 (4H, m, 2ꢂPh, A
and B); dC (100 MHz, CDCl3) anomer A: ꢀ5.6 (SiCH3), ꢀ5.6 (SiCH3),
18.3 (C), 24.9 (CH3), 25.9 (CH3), 26.4 (CH3), 64.9 (CH2), 81.9 (CH),
86.2 (CH), 88.8 (CH), 106.9 (C), 112.7 (C), 127.0 (CH),127.5 (CH), 128.1
(CH), 138.9 (C); m/z (ESIþ) 783 (M2Naþ, 40%), 778 (M2NHþ4 , 90), 444
(40), 403 (MNaþ, 20), 363 (100); HRMS (ESIþ) found 403.1900,
C20H32NaO5Si (MNaþ) requires 403.1911.
(petrol/ether, 10:1) to afford the title compound (11) as a col-
23
ourless oil (257 mg, 88%). Rf 0.27 (petrol/ether, 5:1); [
a
]
þ9.1
D
(c 0.9, CHCl3); nmax (thin film)/cmꢀ1 2930m, 1699s, 1471w, 1381w,
1254m, 1104s, 837s, 780m; dH (400 MHz, CDCl3) ꢀ0.25 and ꢀ0.21
(2ꢂ3H, 2ꢂs, SiMe2), 0.65 (9H, s, t-Bu), 1.45 and 1.62 (2ꢂ3H, 2ꢂs,
2ꢂCH3), 3.55 (1H, dd, J 10.4, 4.4) and 3.62 (1H, dd, J 10.4, 7.4,
CH2), 4.63 (1H, ddd, J 7.4, 6.8, 4.4, CHCH2), 5.53 (1H, d, J 6.8,
CHC]O), 7.43–7.47 (2H, m), 7.53–7.57 (1H, m) and 7.95–7.98 (2H,
m, Ph); dC (125 MHz, CDCl3) ꢀ5.9 (CH3), ꢀ5.9 (CH3), 18.2 (C), 25.5
(CH3), 25.6 (CH3), 27.5 (CH3), 61.8 (CH2), 78.7 (CH), 78.9 (CH),
109.7 (C), 128.3 (CH), 128.4 (CH), 133.1 (CH), 136.3 (C), 193.8 (C);
m/z (ESIþ) 723 (M2Naþ, 30%), 718 (M2NH4þ, 40), 373 (MNaþ, 60),
351 (MNHþ4 , 100), 219 (50); HRMS (ESIþ) found 373.1799,
C19H30NaO4Si (MNaþ) requires 373.1806.
3.11. General procedure for L-Selectride and L-Selectride/
ZnCl2 reductions of ketones (1), (8) and (11) and lactols (10),
(22) and (23)
A solution of ZnCl2 (0.39 mL, 1.0 M solution in ether, 0.39 mmol)
was added dropwise to a solution of ketone 1, 8 or 11 or lactol 10, 22
or 23 (0.29 mmol) in dichloromethane (11 mL) at ꢀ78 ꢁC. After
stirring for 30 min, L-Selectride (1.0 mL, 1 M solution in THF,
1.0 mmol) was then added dropwise and stirring continued at the
same temperature for 90 min.y For the reduction of ketones 1, 8 and
11 the reaction was quenched at this point, see below; for the re-
duction of lactols 10, 22 and 23 the mixture was allowed to warm
slowly to rt and stirred for 18 h prior to quenching. In both cases,
the reaction was quenched by the careful sequential addition of
methanol (0.25 mL), water (0.125 mL), aq H2O2 solution (0.125 mL,
30%) and aq NaOH solution (0.125 mL, 6.0 M). Stirring was contin-
ued while the mixture warmed to rt (for the ketones). The mixture
was then diluted with water (5.0 mL), extracted with dichloro-
methane (3ꢂ15 mL), and the extracts washed successively with aq
NaHCO3 solution (10 mL, saturated), aq Na2CO3 solution (10 mL,
saturated) and brine (10 mL). The organic solution was dried over
MgSO4, concentrated in vacuo and purified by column chroma-
tography to provide pure products (2, 12, 13, and 24–26).
3.9. (3aR,6R,6aR)-6-Benzyloxymethyl-2,2-dimethyl-4-
phenyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol (22)
To a stirred solution of phenyllithium (2.47 mL, 1.80 M in
dibutyl ether, 4.44 mmol) in THF (50 mL) at ꢀ78 ꢁC was added
a solution of lactone 20 (1.03 g, 3.70 mmol) in THF (10 mL)
dropwise via cannula. The mixture was stirred for 90 min at
ꢀ78 ꢁC, quenched with brine (25 mL), allowed to warm to rt,
then extracted with ethyl acetate (3ꢂ50 mL), and dried over
MgSO4. The solution was concentrated in vacuo and purified by
column chromatography (petrol/ethyl acetate, 8:1) to afford the
lactol (22) as a mixture of anomers (A:B, 5:1) and as a colourless
22
oil (998 mg, 76%). Rf 0.48 (petrol/ethyl acetate, 4:1); [
a
]
ꢀ35.0
D
(c 0.6, CHCl3); nmax (thin film)/cmꢀ1 3386br, 3032w, 2987w,
2938m, 1452m, 1374s, 1211s, 1077s, 912w, 872m, 735m, 699s;
dH (400 MHz, CDCl3) isomer A: 1.26 and 1.40 (2ꢂ3H, 2ꢂs, 2ꢂCH3),
3.73 (1H, dd, J 10.2, 3.3) and 3.78 (1H, dd, J 10.2, 3.1, CH2CH),
4.54–4.57 (1H, m, CH2CH), 4.62 (1H, d, J 11.8, CHH0Ph), 4.65 (1H,
d, J 5.8, CHCPh), 4.71 (1H, d, J 11.8, CHH0Ph), 4.97 (1H, dd, J 5.8, 1.5,
CHCHO), 5.06 (1H, s, OH), 7.30–7.42 (8H, m) and 7.57–7.65 (2H,
m, 2ꢂPh); isomer B (selected data): 1.40 and 1.70 (2ꢂ3H, 2ꢂs,
2ꢂCH3), 4.42–4.45 (1H, m, CHCH2), 4.87 (1H, dd, J 7.3, 4.4,
CHCHO); dC (100 MHz, CDCl3) isomer A: 24.8 (CH3), 26.4 (CH3),
71.3 (CH2), 74.0 (CH2), 82.3 (CH), 84.7 (CH), 88.5 (CH), 107.3 (C),
112.7 (C), 127.0 (CH), 127.6 (CH), 128.1 (CH), 128.2 (CH), 128.4
(CH), 128.7 (CH), 136.4 (C), 139.0 (C); isomer B: 25.0 (CH3) 25.6
(CH3), 69.6 (CH2), 73.6 (CH2), 81.0 (CH), 81.4 (CH), 86.2 (CH),
102.2 (C), 116.2 (C), 125.7 (CH), 127.5 (CH), 127.7 (CH), 128.2 (CH),
128.3 (CH), 128.4 (CH), 138.0 (C), 142.2 (C); m/z (ESIþ) 735
(M2Naþ, 90%), 730 (M2NHþ4 , 100), 379 (MNaþ, 60), 339 (100);
HRMS (ESIþ) found 379.1516, C21H24NaO5 (MNaþ) requires
379.1516.
3.12. (4S,5R,10S)-2,2-Dimethyl-4-(1-phenyl)hydroxymethyl-5-
vinyl-1,3-dioxolane [anti-(2)]
Prepared from ketone 1 as a white waxy solid (in the presence of
ZnCl2: 111 mg, 67% on a 0.708 mmol scale; no ZnCl2: 41 mg, 69% on
a 0.254 mmol scale). Rf 0.35 (petrol/ethyl acetate, 3:1); mp 51 ꢁC;
y
For the reductions performed in the absence of ZnCl2, the reactions were
initiated by the dropwise addition of L-Selectride (1.0 mL, 1 M solution in THF,
1.0 mmol) to a solution of ketone 1, 8 or 11 or lactol 10, 22 or 23 (0.29 mmol) in
dichloromethane (11 mL) at ꢀ78 ꢁC. Otherwise, the reductions followed the above
procedure.

J. Robertson et al. / Tetrahedron 66 (2010) 2363–2372
2369
23
[
a]
ꢀ17.0 (c 0.2, CHCl3); nmax (thin film)/cmꢀ1 3398br, 1381w,
CHCHPh), 4.79 (1H, d, J 5.2, CHPh), 7.30–7.44 (5H, m, Ph); dC
(125 MHz, CDCl3) 25.1 (CH3), 27.4 (CH3), 61.1 (CH2), 71.8 (CH), 77.3
(CH), 80.2 (CH), 108.7 (C), 127.1 (CH), 128.4 (CH), 128.7 (CH), 140.2
(C); m/z (ESIþ) 499 (M2Naþ, 100%), 302 (70), 261 (MNaþ, 60), 221
D
1262m, 1218s, 1165m, 1074w, 1047s, 1024s, 921m, 879m, 804w,
752m, 699s; dH (500 MHz, CDCl3) 1.32 and 1.48 (2ꢂ3H, 2ꢂs,
2ꢂCH3), 2.03 (1H, d, J 3.2, OH), 4.31 (1H, dd, J 8.7, 6.1, CHCHOH), 4.69
(1H, dd, J 8.7, 3.2, CHOH), 4.76 (1H, dd, J 7.0, 6.1, CHCH]), 5.36 (1H,
d, J 10.4) and 5.50 (1H, d, J 17.3, ]CH2), 6.16 (1H, ddd, J 17.4,10.4, 7.0,
CH]CH2), 7.30–7.42 (5H, m, Ph); dC (125 MHz, CDCl3) 25.2 (CH3),
27.8 (CH3), 72.4 (CH), 78.9 (CH), 80.8 (CH), 108.9 (C), 118.4 (CH2),
127.0 (CH), 128.0 (CH), 128.2 (CH), 134.2 (CH), 141.2 (C); m/z (ESIþ)
257 (MNaþ, 100%); HRMS (ESIþ) found 257.1148, C14H18NaO3
(MNaþ) requires 257.1148.
(40); HRMS (ESIþ) found 261.1096, C13H18NaO4 (MNaþ) requires
25
261.1097. Data for anti-24: Rf 0.46 (ethyl acetate); [
a
]
ꢀ15.8 (c
D
0.4, CHCl3); nmax (thin film)/cmꢀ1 3383br, 1455w, 1381m, 1219s,
1166m, 1050s, 864w, 762w, 700w; dH (400 MHz, CDCl3) 1.30 and
1.44 (2ꢂ3H, 2ꢂs, 2ꢂCH3), 3.12 (2H, br s, 2ꢂOH), 3.85 (1H, dd, J
11.5, 4.0) and 3.96 (1H, dd, J 11.5, 7.1, CH2), 4.32 (2H, m, CHCHCH2),
4.82 (1H, d, J 8.5, CHPh), 7.30–7.44 (5H, m, Ph); dC (100 MHz,
CDCl3) 25.2 (CH3), 27.8 (CH3), 60.9 (CH2), 72.4 (CH), 77.5 (CH), 80.0
(CH), 108.5 (C), 126.9 (CH), 128.2 (CH), 128.5 (CH), 141.2 (C); m/z
(ESIþ) 499 (M2Naþ, 60%), 337 (70), 302 (100), 261 (MNaþ, 50), 235
(40), 221 (40); HRMS (ESIþ) found 261.1097, C13H18NaO4 (MNaþ)
requires 261.1097.
3.13. (4S,5R,10S)-2,2-Dimethyl-4-[1-(2-methoxyphenyl)]-
hydroxymethyl-5-vinyl-1,3-dioxolane anti-(12)
Prepared from ketone 8 as a colourless oil (in the presence of
ZnCl2: 9.5 mg, 75% on a 0.048 mmol scale; no ZnCl2: 13 mg, 72% on
25
a 0.068 mmol scale). Rf 0.69 (petrol/ethyl acetate, 1:1); [
a]
ꢀ7.0
D
(c 0.3, CHCl3); nmax (thin film)/cmꢀ1 3453br, 2986m, 2937m,
1602w, 1494m, 1464w, 1380w, 1244s, 1166w, 1031s, 927w, 896w,
755m; dH (500 MHz, CDCl3) 1.35 and 1.46 (2ꢂ3H, 2ꢂs, 2ꢂCH3),
2.90 (1H, d, J 7.0, OH), 3.88 (3H, s, OCH3), 4.53 (1H, dd, J 9.0, 6.2,
CHCHOH), 4.75–4.78 (1H, m, CHCH]), 4.85 (1H, dd, J 9.0, 7.0,
CHOH), 5.34 (1H, app dt, J 10.4, 1.4) and 5.48 (1H, app dt, J 17.2, 1.4,
]CH2), 6.21 (1H, ddd, J 17.2, 10.4, 6.9, CH]CH2), 6.91 (1H, d, J 8.2),
6.98 (1H, app td, J 7.6, 0.9) and 7.26–7.32 (2H, m, Ar); dC (125 MHz,
CDCl3) 25.5 (CH3), 27.8 (CH3), 55.3 (CH3), 70.1 (CH), 79.1 (CH), 79.2
(CH), 108.7 (C), 110.7 (CH), 117.7 (CH2), 120.8 (CH), 128.7 (C), 128.9
(CH), 129.2 (CH), 134.1 (CH), 157.1 (C); m/z (ESIþ) 257 (MNaþ,
100%); HRMS (ESIþ) found 287.1250, C15H20NaO4 (MNaþ) requires
287.1254.
3.16. (4S,5R,10S)-5-Hydroxymethyl-2,2-dimethyl-4-
(1-phenyl)hydroxymethyl-1,3-dioxolane [anti-(24)]
Prepared from lactol 10 in the absence of ZnCl2, following col-
umn chromatography (petrol/ethyl acetate, 4:1/2:1), as a colour-
less oil (127 mg, 78% on a 0.68 mmol scale); a mixed fraction
(18 mg, 11%) was also obtained that contained a small amount of
epimer syn-24. Data as above.
3.17. (4S,5R,10R,100R)-5-(1-Benzyloxymethyl)hydroxymethyl-
2,2-dimethyl-4-(1-phenyl)hydroxymethyl-1,3-dioxolane
[syn-(25)]
3.14. (4S,5R,10S)-5-(tert-Butyldimethylsilyloxy)methyl-2,2-
dimethyl-4-(1-phenyl)hydroxymethyl-1,3-dioxolane
[anti-(13)]
Prepared from lactol 22, in the presence of ZnCl2, as a colour-
less oil (130 mg, 63% on a 0.58 mmol scale) following column
chromatography (petrol/ethyl acetate, 10:1/6:1/2:1). Rf 0.16
22
(petrol/ethyl acetate, 4:1); [
a
]
ꢀ26.5 (c 0.4, CHCl3); nmax (thin
D
Prepared from ketone 11 as a colourless oil (in the presence
of ZnCl2: 61 mg, 83% on a 0.209 mmol scale; no ZnCl2: 73 mg,
84% on a 0.246 mmol scale). Rf 0.24 (petrol/ether, 5:1); [a]
D
film)/cmꢀ1 3425br, 2934w, 1454m, 1380m, 1214s, 1064s, 884w,
700 m; dH (400 MHz, CDCl3) 1.34 and 1.54 (2ꢂ3H, 2ꢂs, 2ꢂCH3),
2.74 (1H, d, J 4.7, CH(OH)Ph), 3.00 (1H, d, J 7.1, CH(OH)CH2), 3.62
(1H, dd, J 9.6, 6.2) and 3.79 (1H, d, J 9.6, 2.8, CH2OBn), 4.19 (1H, dd,
J 6.3, 2.5, CHCH(OH)CH2), 4.29–4.34 (1H, m, CHCH2), 4.42 (1H, dd, J
6.3, 2.2, CHCHPh), 5.14–5.17 (1H, m, CHPh), 7.25–7.43 (10H, m,
2ꢂPh); dC (125 MHz, CDCl3) 24.8 (CH3), 27.0 (CH3), 68.7 (CH), 70.7
(CH), 71.8 (CH2), 76.4 (CH2), 76.9 (CH), 80.3 (CH), 108.6 (C), 126.5
(CH), 127.5 (CH), 127.8 (CH), 127.8 (CH), 128.3 (CH), 128.5 (CH),
137.9 (C), 142.4 (C); m/z (ESIþ) 739 (M2Naþ, 100%), 734 (M2NHþ4 ,
80), 717 (M2Hþ, 30), 381 (MNaþ, 80), 376 (MNHþ4 , 40), 283 (50),
233 (30); HRMS (ESIþ) found 381.1670, C21H26NaO5 (MNaþ) re-
quires 381.1672.
23
ꢀ7.8 (c 0.9, CHCl3); nmax (thin film)/cmꢀ1 3444br, 2932m,
2859w, 1472w, 1380w, 1253m, 1220m, 1076s, 838s, 781w; dH
(400 MHz, CDCl3) 0.18 and 0.18 (2ꢂ3H, 2ꢂs, SiMe2), 0.95 (9H, s,
t-Bu), 1.26 and 1.39 (2ꢂ3H, 2ꢂs, 2ꢂCH3), 3.72 (1H, dd, J 10.3, 3.3)
and 3.62 (1H, app t, J 10.3 CH2), 4.32–4.39 (2H, m, CHCHCH2),
4.55 (1H, d, J 3.1, OH), 4.82 (1H, dd, J 9.0, 3.1, CHPh), 7.31 (1H, d, J
7.3), 7.38 (2H, t, J 7.3) and 7.48 (2H, d, J 7.3, Ph); dC (125 MHz,
CDCl3) ꢀ5.6 (CH3), ꢀ5.6 (CH3), 18.2 (C), 25.2 (CH3), 25.8 (CH3),
28.1 (CH3), 62.0 (CH2), 71.5 (CH), 77.3 (CH), 81.3 (CH), 108.7 (C),
127.0 (CH), 127.7 (CH), 128.2 (CH), 141.2 (C); m/z (ESIþ) 727
(M2Naþ, 90%), 705 (M2Hþ, 40), 375 (MNaþ, 80), 335 (100), 295
(70), 277 (40); HRMS (ESIþ) found 375.1959, C19H32NaO4Si
(MNaþ) requires 375.1962.
3.18. (4S,5R,10R,100R)- and (4S,5R,10R,100S)-5-(1-Benzyloxy-
methyl)hydroxymethyl-2,2-dimethyl-4-(1-phenyl)-
hydroxymethyl-1,3-dioxolane [syn- and anti-(25)]
3.15. (4S,5R,10R)-5-Hydroxymethyl-2,2-dimethyl-4-
(1-phenyl)hydroxymethyl-1,3-dioxolane [syn-(24)]6b
Prepared from lactol 22, in the absence of ZnCl2, as a colourless
oil and as a 2:1 syn-: anti- mixture (117 mg, 57% on a 0.576 mmol
scale) following column chromatography (petrol/ethyl acetate,
6:1/2:1). Selected data for anti-25: dH (400 MHz, CDCl3) 1.24 and
1.36 (2ꢂ3H, 2ꢂs, 2ꢂCH3), 3.64 (1H, dd, J 9.8, 6.9) and 3.85 (1H, d, J
9.8, 2.7, CH2OBn), 4.17–4.35 (3H, CHCHCHCH2, overlapping with
resonances from syn-25), 4.64 (2H, s, CH2Ph), 4.82 (1H, d, J 9.5,
CHPh), 7.25–7.43 (10H, m, 2ꢂPh); dC (125 MHz, CDCl3) 25.3 (CH3),
28.0 (CH3), 68.6 (CH), 71.5 (CH), 71.8 (CH2), 73.5 (CH2), 77.5 (CH),
81.1 (CH), 108.9 (C), 127.2 (CH), 127.8 (CH), 127.9 (CH), 127.9 (CH),
128.3 (CH), 128.5 (CH), 137.2 (C), 141.2 (C).
Prepared from lactol 10 in the presence of ZnCl2, following
column chromatography (petrol/ethyl acetate, 4:1/2:1), as a col-
ourless oil (71 mg, 44% on a 0.68 mmol scale) as well as a small
amount of the epimer anti-24 (24 mg, 15%). Data for syn-24: Rf
25
0.38 (ethyl acetate); [
a]
ꢀ36.5 (c 0.4, CHCl3), lit.6b
[
a
]
D
ꢀ43.0
D
(c 1.05, CHCl3); nmax (thin film)/cmꢀ1 3418br, 1496w, 1455w,
1381m, 1217s, 1164m, 1042s, 860w, 739w, 702m; dH (500 MHz,
CDCl3) 1.41 and 1.59 (2ꢂ3H, 2ꢂs, 2ꢂCH3), 2.29 and 3.12 (2ꢂ1H,
2ꢂbr s, 2ꢂOH), 3.68 (1H, dd, J 11.8, 3.8) and 3.76 (1H, dd, J 11.8, 5.8,
CH2), 4.19 (1H, ddd, J 6.8, 5.8, 3.8, CHCH2), 4.46 (1H, dd, J 6.8, 5.2,

2370
J. Robertson et al. / Tetrahedron 66 (2010) 2363–2372
3.19. (4S,5R,10R,100R)-5-(1-tert-Butyldimethylsilyloxy)-
hydroxymethyl-2,2-dimethyl-4-(1-phenyl)-
hydroxymethyl-1,3-dioxolane [syn-(26)]
5.37 (1H, dt, J 10.6, 1.1) and 5.55 (1H, J 17.2, 1.1, ]CH2), 5.85 (1H, s,
H-2), 6.06 (1H, ddd, J 17.2, 10.6, 6.2, CH]CH2), 7.34–7.44 (6H, m),
7.51–7.55 (2H, m) and 7.58–7.62 (2H, m, Ph); dC (100 MHz, CDCl3)
71.1 (CH), 82.1 (CH), 83.5 (CH), 100.9 (CH), 118.8 (CH2), 126.4 (CH),
127.5 (CH), 128.4 (CH), 128.6 (CH), 128.6 (CH), 129.0 (CH), 134.6
(CH), 137.6 (C), 138.2 (C); m/z (ESIþ) 305 (MNaþ, 100%); HRMS (ESIþ)
found 305.1141, C18H18NaO3 (MNaþ) requires 305.1148.
Prepared from lactol 23, in the presence of ZnCl2, as a colourless
oil (135 mg, 64% on a 0.554 mmol scale) following column chro-
matography (petrol/ethyl acetate, 10:1). Rf 0.16 (petrol/ethyl
25
acetate, 10:1); [
a
]
ꢀ33.6 (c 0.7, CHCl3); nmax (thin film)/cmꢀ1
D
3454br, 2930m,1463w,1381w,1255s,1214m, 875s, 837m, 700w; dH
(400 MHz, CDCl3) 0.11 (6H, s, SiMe2), 0.93 (9H, s, t-Bu), 1.34 and 1.56
(2ꢂ3H, 2ꢂs, 2ꢂCH3), 2.75 (1H, d, J 4.3) and 3.00 (1H, d, J 7.3, 2ꢂOH),
3.74 (1H, dd, J 9.7, 4.2) and 3.88 (1H, d, J 9.7, 2.5, CH2), 4.12–4.19 (2H,
m, CHCH2 and CHCHPh), 4.42–4.45 (1H, m, CHCHCH2), 5.17–5.19
(1H, m, CHPh), 7.25–7.30 (1H, m), 7.34–7.39 (2H, m) and 7.42–7.46
(2H, m, Ph); dC (125 MHz, CDCl3) ꢀ5.5 (CH3), ꢀ5.4 (CH3), 18.3 (C),
24.6 (CH3), 25.9 (CH3), 27.0 (CH3), 64.4 (CH2), 69.4 (CH), 70.4 (CH),
76.4 (CH), 80.4 (CH), 108.6 (C), 126.5 (CH), 127.4 (CH), 128.3 (CH),
142.4 (C); m/z (ESIþ) 787 (M2Naþ, 100%), 782 (M2NHþ4 , 80), 765
(M2Hþ, 60), 405 (MNaþ, 30), 325 (80), 243 (50); HRMS (ESIþ) found
405.2064, C20H34NaO5Si (MNaþ) requires 405.2068.
3.23. (2R,4S,5R,6R)-4-(2-Methoxyphenyl)-2-phenyl-6-vinyl-
1,3-dioxan-5-ol (18)
Prepared from alcohol anti-12, the title compound (18) was
obtained as a colourless oil (16 mg, 75% on a 0.068 mmol scale)
following column chromatography (petrol/ethyl acetate, 5:1). Rf
25
0.26 (petrol/ethyl acetate, 4:1); [
a]
þ45.7 (c 0.7, CHCl3); nmax (thin
D
film)/cmꢀ1 3474br,1603w, 1495m, 1463w, 1395w, 1288w, 1249s,
1072s, 1028s, 925w, 757m, 701m; dH (500 MHz, CDCl3) 2.51 (1H, d, J
3.6, OH), 3.48–3.54 (1H, m, H-5), 3.91 (3H, s, OCH3), 4.25–4.30 (1H,
m, H-6), 5.20 (1H, d, J 9.1, H-4), 5.35 (1H, dt, J 10.7, 1.4) and 5.55 (1H,
dt, J 17.3, 1.4, ]CH2), 5.84 (1H, s, H-2), 6.09 (1H, ddd, J 17.3, 10.7, 6.0,
CH]CH2), 6.95 (1H, d, J 8.4), 7.06 (1H, td, J 7.5, 0.8), 7.30–7.40 (4H,
m) and 7.57–7.63 (3H, m, Ph and Ar); dC (125 MHz, CDCl3) 55.8
(CH3), 72.4 (CH), 76.2 (CH), 82.5 (CH), 101.0 (CH), 110.6 (CH), 118.2
(CH2), 121.6 (CH), 126.4 (CH), 127.2 (CH), 127.8 (C), 128.2 (CH), 128.9
(CH), 129.0 (CH), 134.7 (CH), 137.7 (C), 156.4 (C); m/z (ESIþ) 647
(M2Naþ, 100%), 376 (80), 335 (MNaþ, 30); HRMS (ESIþ) found
335.1251, C19H20NaO4 (MNaþ) requires 335.1254.
3.20. (4S,5R,10R,100R)- and (4S,5R,10R,100S)-5-(1-tert-
Butyldimethylsilyloxy)hydroxymethyl-2,2-dimethyl-4-(1-
phenyl)hydroxymethyl-1,3-dioxolane [syn- and anti-(26)]
Prepared from lactol 23, in the absence of ZnCl2, as a colourless
oil and as a 6:4 syn-: anti- mixture (135 mg, 73% on a 0.484 mmol
scale) following column chromatography (petrol/ethyl acetate,
10:1). Selected data for anti-26: dH (400 MHz, CDCl3) 0.14 (6H, s,
SiMe2), 0.95 (9H, s, t-Bu), 1.24 and 1.38 (2ꢂ3H, 2ꢂs, 2ꢂCH3), 3.47–
3.51 (1H, m, OH), 3.72 (1H, dd, J 10.0, 6.9) and 3.95 (1H, d, J 10.0, 3.2,
CH2), 3.99–4.05 (1H, m, CHCH2), 4.18 (1H, dd, J 9.7, 5.3, CHCHCH2),
4.33 (1H, dd, J 9.5, 5.3, CHCHPh), 4.58–4.61 (1H, m, OH), 4.85 (1H, d,
J 9.5, CHPh), 7.26–7.50 (5H, m, Ph); dC (125 MHz, CDCl3) ꢀ5.4 (CH3),
ꢀ5.3 (CH3), 18.3 (C), 25.3 (CH3), 25.9 (CH3), 28.0 (CH3), 64.4 (CH2),
69.4 (CH), 71.6 (CH), 77.4 (CH), 81.3 (CH), 108.8 (C), 127.2 (CH), 127.8
(CH), 128.2 (CH), 141.3 (C).
3.24. (2S,4S,4aS,6R,8aR)-2,4,6-Triphenyltetrahydro-
[1,3]dioxino[5,4-d][1,3]dioxine (19)
Ph
6
O
O
H
8
8a
Hα
Hβ
Ph
4a
2
4
O
H
O
Ph
3.21. General procedure for acetonide cleavage and
benzylidene acetal formation from reduction
products anti-(2) and anti-(12)
A solution of anti-13 (22 mg, 0.063 mmol) in aqueous
acetic acid (0.5 mL, 80%) was stirred at rt for 18 h. The solvents
were removed in vacuo and the residue, the crude tetraol 16, was
dissolved in dichloromethane (1.0 mL). The reaction then pro-
ceeded according to the general procedure for generation of
benzylidene acetals 17 and 18. The final product, a complex
mixture of benzylidene isomers, was purified by column chro-
matography to give a sample (5 mg) of the title compound (19),
a pale yellow oil, that was contaminated with some residual
benzaldehyde dimethyl acetal, but which provided clear 1H NMR
data. Rf 0.69 (petrol/ether, 10:1); dH (500 MHz, CDCl3) 3.80 (1H,
To a solution of alcohol anti-2 or anti-12 (1.0 mmol) in meth-
anol (25 mL) at rt was added hydrochloric acid (20 mL, 37% solu-
tion, 0.22 mmol) and the mixture was stirred for 1 h.
Triethylamine (0.139 mL, 1.0 mmol) was then added and the
reaction mixture concentrated in vacuo. The crude triol (14 or 15)
was then dissolved in dichloromethane (25 mL) and benzaldehyde
dimethyl acetal (1.50 mL, 10.0 mmol) and p-toluenesulfonic acid
(172 mg, 1.0 mmol; the monohydrate was heated at reflux in
toluene for 2 h with Dean–Stark attachment then concentrated in
vacuo to give ‘anhydrous’ reagent) were added, and the reaction
stirred at rt for 18 h. Triethylamine (0.139 mL, 1.0 mmol) was
added, the reaction was concentrated in vacuo, and the residue
was purified by column chromatography to afforded the desired
benzylidene acetal (17 or 18).
app t, J 9.2, H-4a), 3.94 (1H, app t, J 10.3, H-8
J 10.3, 9.2, 4.7, H-8a), 4.45 (1H, dd, J 10.3, 4.7, H-8
a
), 4.14 (1H, ddd,
), 4.95 (1H, d,
b
J 9.2, H-4), 5.56 and 5.95 (2ꢂ1H, 2ꢂs, H-2 and H-6), 7.30–7.62
(15H, m, 3ꢂPh).
3.25. (4S,5R,10R,100R)-5-(1,2-Dihydroxyethyl)-2,2-dimethyl-4-
3.22. (2R,4S,5R,6R)-2,4-Diphenyl-6-vinyl-1,3-dioxan-5-ol (17)
(1-phenyl)hydroxymethyl-1,3-dioxolane (27)
Prepared from alcohol anti-2, the title compound (17) was
obtained as a white solid (26 mg, 54% on a 0.17 mmol scale) fol-
From syn-25. Palladium on carbon (3.2 mg, 10%) was added to
a solution of diol syn-25 (32 mg, 0.089 mmol) in methanol (2.5 mL).
The flask was briefly evacuated and filled with Ar (ꢂ3) then evac-
uated and filled with H2 (ꢂ3) and stirring continued at rt for 2 h.
The H2 atmosphere was replaced with Ar (three evacuation/filling
cycles) and the reaction mixture filtered through CeliteÒ and con-
centrated in vacuo to afford triol 27 as a colourless oil (24 mg,100%).
lowing column chromatography (petrol/ethyl acetate, 10:1/4:1).
23
Rf 0.28 (petrol/ethyl acetate, 4:1); mp 86 ꢁC; [
a
]
þ48.0 (c 0.1,
D
CHCl3); nmax (thin film)/cmꢀ1 3396br, 1455w, 1069m, 1028s, 759m,
700s; dH (400 MHz, CDCl3) 1.72–1.75 (1H, br m, OH), 3.50 (1H, app
td, J 9.0, 3.5, H-5), 4.24–4.29 (1H, m, H-6), 4.62 (1H, d, J 9.0, H-4),

J. Robertson et al. / Tetrahedron 66 (2010) 2363–2372
2371
25
Rf 0.15 (ethyl acetate); [
a]
ꢀ31.0 (c 0.4, CHCl3); nmax (thin film)/
(CH), 79.0 (CH), 109.4 (C), 118.6 (CH2), 123.6 (CH), 127.8 (CH), 128.5
(CH),128.7 (CH),130.9 (CH),132.4 (CH),135.3 (C),136.6 (C),150.6 (C),
162.9 (C); syn- isomer: 25.4 (CH3), 27.5 (CH3), 75.9 (CH), 78.4 (CH),
79.7 (CH), 109.4 (C), 119.3 (CH2), 123.5 (CH), 128.0 (CH), 128.5 (CH),
128.8 (CH),130.7 (CH),132.6 (CH),135.8 (C),137.4 (C),150.5 (C),163.8
(C). A sample of this crude mixture (8.0 mg) was dissolved in
methanol (0.1 mL) and added dropwise at rt to a stirred solution of
NaOH (1.0 mg, 0.025 mmol) in methanol (0.6 mL). After 1 h the
mixture was diluted with ether (2.0 mL), washed with brine (1.0 mL)
and then concentrated in vacuo to afford a mixture of alcohols anti-2
and syn-2 (55:45 ratio). The product was sufficiently pure for NMR
analysis to enable full correlation of resonances with those of
authentic material synthesised by the routes described above. NMR
data for syn-2: dH (500 MHz, CDCl3) 1.42 and 1.61 (2ꢂ3H, 2ꢂs,
2ꢂCH3), 2.75 (1H, d, J 4.6, OH), 4.42 (1H, dd, J 6.6, 5.5, CHCHOH),
4.54–4.51 (1H, m, CHCH]), 4.64–4.66 (1H, m, CHOH), 5.27 (1H, ddd,
J 10.2,1.4,1.2) and 5.30 (1H, dt, J 17.4,1.4, ]CH2), 5.97 (1H, ddd, J 17.4,
10.2, 7.4, CH]CH2), 7.30–7.39 (5H, m, Ph); dC (125 MHz, CDCl3) 25.1
(CH3), 27.5 (CH3), 72.2 (CH), 78.9 (CH), 81.4 (CH), 108.9 (C), 119.2
(]CH2), 127.3 (CH), 128.0 (CH), 128.4 (CH), 133.7 (]CH), 140.4 (C).
D
cmꢀ1 3385br, 1495w, 1455m, 1382s, 1260s, 1216s, 1164w, 1064s,
886w; dH (400 MHz, CDCl3) 1.34 and 1.53 (2ꢂ3H, 2ꢂs, 2ꢂCH3), 2.60
(1H, br s, OH), 3.00 (2H, br s, 2ꢂOH), 3.65–3.70 (1H, m) and 3.87
(1H, br d, J 10.7, CH2), 4.09–4.14 (2H, m, CHCH2 and CHCHPh), 4.39–
4.43 (1H, m, CHCHCH2), 5.03–5.12 (1H, m, CHPh), 7.27–7.45 (5H, m,
Ph); dC (125 MHz, CDCl3) 25.0 (CH3), 27.3 (CH3), 64.7 (CH2), 69.7
(CH), 70.7 (CH), 77.2 (CH), 80.0 (CH), 108.7 (C), 126.6 (CH), 127.9
(CH), 128.5 (CH), 141.6 (C); m/z (ESIþ) 559 (M2Naþ, 100%), 332 (80),
291 (MNaþ, 30), 193 (40); HRMS (ESIþ) found 291.1200, C14H20NaO5
(MNaþ) requires 291.1203.
From syn-26. To a stirred solution of diol syn-26 (116 mg,
0.303 mmol) in THF (1.5 mL) at rt was added dropwise TBAF
(0.33 mL, 1.0 M solution in THF, 0.33 mmol). After 10 min the
solution was diluted with ether (10 mL), washed with aq NH4Cl
solution (5.0 mL, saturated), dried over MgSO4, and the residue was
purified by column chromatography (solvent system) to afforded
triol 27 as a colourless oil (46 mg, 57%). Data as above.
3.26. (4R,40R,50S)-20,20-Dimethyl-50-[(1R)-(phenyl)]hydroxy-
methyl-4,40-bi(1,3-dioxolane)-2-thione (28)
3.28. (3aR,6R,6aR)-6-Benzyloxymethyl-2,2-dimethyl-4-(2-
methoxyphenyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-ol (37)
To a solution of triol 27 (33 mg, 0.123 mmol) in THF (1.0 mL) at rt
was added thiocarbonyl diimidazole (22 mg, 0.123 mmol) and the
mixture was stirred for 24 h then concentrated in vacuo. The residue
waspurifiedbycolumnchromatography (petrol/ethyl acetate, 3:1)to
To a solution of 2-bromoanisole (0.495 mL, 3.97 mmol) in THF
(38 mL) at ꢀ78 ꢁC was added tert-butyllithium (5.14 mL, 1.7 M
solution in hexanes, 8.74 mmol) and the solution was stirred for
30 min. The resulting organolithium solution was then transferred
dropwise by cannula into a solution of lactone 20 (920 mg,
3.31 mmol) in THF (19 mL) at ꢀ78 ꢁC, and stirring continued at this
temperature for 90 min. The reaction was then quenched by the
addition of brine (10 mL), allowed to warm to rt and then extracted
with ethyl acetate (3ꢂ20 mL). The combined organic extracts were
dried over MgSO4 and concentrated in vacuo. Purification by
column chromatography (petrol/ethyl acetate, 10:1) afforded the
title compound (37) as a pale yellow oil, comprising a mixture of
afford the title compound (28) as a pale yellow oil (22 mg, 58%). Rf 0.51
25
(petrol/ethyl acetate, 1:1); [
a
]
ꢀ42 (c 0.25, CHCl3); nmax (thin film)/
D
cmꢀ1 3420br, 2931w, 1471w, 1294s, 1164m, 957m, 859w, 702w; dH
(400 MHz, CDCl3) 1.37 and1.56 (2ꢂ3H, 2ꢂs, 2ꢂCH3), 2.54 (1H, d, J 8.4,
OH), 4.46 (1H, dd, J 7.1, 6.0, CHCHCH2), 4.57 (1H, dd, J 7.1, 1.8, CHCHPh),
4.76 (2H, app d, J 7.3, CH2), 4.91 (1H, dd, J 8.4,1.8, CHPh), 5.40 (1H, app
td, J 7.3, 6.0, CHCH2), 7.33–7.44 (5H, m, Ph); dC (125 MHz, CDCl3) 24.3
(CH3), 26.4(CH3), 70.5(CH), 71.5(CH2), 76.3(CH), 79.0(CH), 80.0(CH),
109.8 (C), 126.5 (CH), 128.3 (CH), 128.7 (CH), 140.6 (C), 191.5 (C); m/z
(ESIþ) 953 (M3Naþ, 40%), 948 (M3NH4þ, 20), 643 (M2Naþ, 50), 638
(M2NHþ4 ,100), 311 (MHþ, 80), 279 (40); HRMS (ESIþ) found 333.0768,
C15H18NaO5S (MNaþ) requires 333.0767.
anomers (A:B, 2:1) as a pale yellow oil (614 mg, 48%). Rf 0.40
20
(petrol/ethyl acetate, 5:1); [
a]
ꢀ32 (c 0.7, CHCl3); nmax (thin film)/
D
cmꢀ1 3411br, 1603w, 1492m, 1464w, 1372w, 1245s, 1211m, 1079s,
1028s, 873w, 755m, 699w; dH (400 MHz, CDCl3) 1.23 and 1.27
(2ꢂ3H, 2ꢂs, 2ꢂCH3, A), 1.42 and 1.68 (2ꢂ3H, 2ꢂs, 2ꢂCH3, B), 3.64–
3.75 (4H, m, CH2OBn, A & B), 3.78 (3H, s, OCH3, B), 3.91 (3H, s, OCH3,
A), 4.40–4.44 (1H, m, CHCH2, B), 4.45–4.50 (1H, m, CHCH2, A), 4.58
(2H, s, CH2Ph, B), 4.62 and 4.67 (2ꢂ1H, 2ꢂd, J 12.0, CH2Ph, A), 4.77
(2H, m, OH, A, and CHCHCH2, B), 4.86 (1H, br s, OH, B), 4.89–4.92
(2H, m, CHCHCH2, A, and CHC(OH)Ar, B), 5.00 (1H, d, J 5.7, CHC(O-
H)Ar, A), 6.88–6.99 (4H, m, Ar, both), 7.27–7.39 (12H, m, Ar, both),
7.69 (1H, dd, J 7.6, 1.6, CHC(OMe), A), 7.75 (1H, dd, J 7.7, 1.6,
CHC(OMe), B); dC (100 MHz, CDCl3) anomer A: 25.7 (CH3), 26.6
(CH3), 56.1 (CH3), 71.4 (CH2), 73.6 (CH2), 82.6 (CH), 84.4 (CH), 87.6
(CH), 111.4 (CH), 112.4 (CH), 120.4 (CH), 137.3 (C), 156.1 (C); anomer
B: 25.2 (CH3), 26.8 (CH3), 55.4 (CH3), 69.6 (CH2), 73.4 (CH2), 81.1
(CH), 82.1 (CH), 84.9 (CH), 111.3 (CH), 115.4 (CH), 120.3 (CH), 138.1
(C), 156.6 (C); additional resonances at 101.6 (2ꢂC), 106.9 (2ꢂC),
127.3 (CH), 127.6 (2ꢂCH), 127.7 (CH), 128.0 (2ꢂCH), 128.3 (CH),
128.5 (CH), 129.5 (CH) and 129.8 (CH) were not attributed to
individual anomers; m/z (ESIþ) 795 (M2Naþ, 100%), 790 (M2NHþ4 ,
100), 445 (M$CH3CN$NHþ4 , 100), 409 (MNaþ, 80), 369 (90); HRMS
(ESIþ) found 409.1615, C22H26NaO6 (MNaþ) requires 409.1622.
3.27. (4S,5R,10R)-2,2-Dimethyl-4-(1-phenyl)hydroxymethyl-5-
vinyl-1,3-dioxolane [syn-(2)]
A solution of thionocarbonate 28 (15 mg, 0.048 mmol) in tri-
methylphosphite (1.0 mL) was heated at reflux for 72 h and then
cooled and concentrated in vacuo. The product was sufficiently pure
for NMR confirmation that the anti- diastereomer of alcohol 2 was
not present and the structure of syn-2 was assigned both on this
basis and on the basis of the following Mitsunobu sequence from
anti-2. To a solution of alcohol anti-2 (39 mg, 0.167 mmol) in ben-
zene (2.0 mL) at rt was added triphenylphosphine (66 mg,
0.251 mmol) followed by p-nitrobenzoic acid (42 mg, 0.251 mmol)
and then diisopropyl azodicarboxylate (49.4 mL, 0.251 mmol) drop-
wise. Stirring was continued for 18 h then the mixture was con-
centrated in vacuo and the residue purified by column
chromatography (petrol/ethyl acetate, 5:1) to afford a mixture of p-
nitrobenzoate esters (55:45, anti-: syn-) (19 mg, 34%) as a colourless
oil. dH (500 MHz, CDCl3) 1.36 (3H, s, CH3, anti), 1.44 (3H, s, CH3, syn),
1.49 (3H, s, CH3, anti), 1.66 (3H, s, CH3, syn), 4.62–4.70 (3H, m,
CHCHCHPh, anti, CHCHPh, syn), 4.83 (1H, dd, J 7.4, 5.5, CHCH], syn),
5.11 (1H, d, J 10.4, ]CHH0, syn), 5.18 (1H, d, J 10.6, ]CHH0, anti), 5.25
(1H, d, J 17.0, ]CHH0, syn), 5.37 (1H, d, J 17.0, ]CHH0, anti), 5.79 (1H,
ddd, J 17.0, 10.6, 6.8, CH], anti), 5.89 (1H, d, J 9.0, CHPh, anti) over-
lapping 5.90 (1H, ddd, J 17.0, 10.4, 7.4, CH], syn), 5.95 (1H, d, J 5.2,
CHPh, syn), 7.31–7.40 (6H, m) and 7.44–7.50 (4H, m, PhCH, syn and
anti), 8.15–8.18 (4H, m) and 8.25–8.31 (4H, m, ArCO, syn and anti); dC
(125 MHz, CDCl3) anti- isomer: 25.3 (CH3), 27.8 (CH3), 74.9 (CH), 78.8
3.29. (4S,5R,10R,100R)-5-(1-Benzyloxymethyl)hydroxymethyl-
2,2-dimethyl-4-[1-(2-methoxyphenyl)]hydroxymethyl-1,3-
dioxolane [syn-(38)]
Prepared from lactol 37, following the general procedure for
L-Selectride reduction in the presence of ZnCl2, with the

2372
J. Robertson et al. / Tetrahedron 66 (2010) 2363–2372
following modification. After the addition of aq H2O2 and aq
NaOH the mixture was allowed to stir for 1 h before continuing
the work-up. The product (syn-38) was obtained as a colourless
oil (29 mg, 69% on a 0.109 mmol scale) following column chro-
Acknowledgements
We thank the EPSRC and AstraZeneca for a studentship
(for W.P.U.) and Drs. Tim Claridge and Barbara Odell, University
of Oxford, for supporting NMR studies.
matography (petrol/ethyl acetate, 10:1/4:1). Rf 0.19 (petrol/
22
ethyl acetate, 2:1); [
a
]
ꢀ31 (c 0.6, CHCl3); nmax (thin film)/cmꢀ1
D
3344br, 1603w, 1492m, 1457m, 1379m, 1241s, 1065s, 753w, 699w;
dH (400 MHz, CDCl3) 1.33 and 1.55 (2ꢂ3H, 2ꢂs, 2ꢂCH3), 3.66 (1H,
dd, J 9.6, 6.2) and 3.79 (1H, d, J 9.6, 2.9, CH2OBn), 3.82 (3H, s,
OCH3), 4.21 (1H, dd, J 8.6, 6.3, CHCHCH2), 4.38 (1H, ddd, J 8.6, 6.2,
2.9, CHCH2), 4.45 (1H, dd, J 6.3, 1.6, CHCHAr), 4.62 (2H, s, CH2Ph),
5.52–5.53 (1H, m, CHAr), 6.87 (1H, d, J 8.3), 6.97–7.02 (1H, m),
7.25–7.40 (6H, m) and 7.47 (1H, dd, J 7.6, 1.4, Ph and Ar); dC
(100 MHz, CDCl3) 24.9 (CH3), 27.0 (CH3), 55.4 (CH3), 65.6 (2ꢂCH),
71.9 (CH2), 73.4 (CH2), 76.9 (CH), 78.8 (CH), 108.4 (C), 110.3 (CH),
120.6 (CH), 127.3 (CH), 127.7 (CH), 127.8 (CH), 128.4 (2ꢂCH), 130.2
(C), 138.0 (C), 155.9 (C); m/z (ESIþ) 799 (M2Naþ, 100%), 794
(M2NHþ4 , 90), 777 (M2Hþ, 50), 447 (M$CH3CN$NHþ4 , 100), 411
(MNaþ, 70); HRMS (ESIþ) found 411.1779, C22H28NaO6 (MNaþ)
requires 411.1778.
References and notes
1. Hanessian, S. Total Synthesis of Natural Products: The ‘Chiron’ Approach; Perga-
mon: Oxford, 1983.
2. For example: (a) Mead, K.; Macdonald, T. L. J. Org. Chem. 1985, 50, 422–424; (b)
Chikashita, H.; Nikaya, T.; Uemura, H.; Itoh, K. Bull. Chem. Soc. Jpn. 1989, 62,
2121–2123; (c) Jackson, R. F. W.; Rettie, A. B. Tetrahedron Lett. 1993, 34, 2985–
2986; (d) Jackson, R. F. W.; Rettie, A. B.; Wood, A.; Wythes, M. J. J. Chem. Soc.,
Perkin Trans. 1 1994, 1719–1726; (e) Handa, S.; Hawes, J. E.; Pryce, R. J. Synth.
Commun. 1995, 25, 2837–2845; (f) Jeoffreys, G. R.; Ung, A. T.; Pyne, S. G.;
Skelton, B. W.; White, A. H. J. Chem. Soc., Perkin Trans. 1 1999, 2281–2291.
3. Hanessian, S.; Machaalani, R. Tetrahedron Lett. 2003, 44, 8321–8323.
4. (a) Hanessian, S.; Marcotte, S.; Machaalani, R.; Huang, G. Org. Lett. 2003, 5,
4277–4280; (b) Hanessian, S.; Marcotte, S.; Machaalani, R.; Huang, G.; Pierron,
J.; Loiseleur, O. Tetrahedron 2006, 62, 5201–5214.
5. 1H NMR analysis of the crude reduction product mixtures was possible for the
ketone substrates but not for the lactol substrates. In the latter, the free alcohols
were released from boron-containing residues only during column chroma-
tography and, for these, ratios are quoted based on yields of isolated products.
6. For example: (a) Munier, P.; Krusinski, A.; Picq, D.; Anker, D. Tetrahedron 1995, 51,
1229–1244; (b) Jiang, S.; Singh, G.; Wightman, R. H. Chem. Lett. 1996, 67–68; (c)
Munier, P.;Giudicelli, M.-B.;Picq, D.;Anker, D.J.Carbohydr. Chem.1996,15, 739–762.
7. Cf. Mekki, B.; Singh, G.; Wightman, R. H. Tetrahedron Lett. 1991, 32, 5143–5146.
8. (a) Ung, A. T.; Pyne, S. G. Tetrahedron: Asymmetry 1998, 9, 1395–1407; (b)
Navarre, J.-M.; Guianvarc’h, D.; Farese-Di Giorgio, A.; Condom, R.; Benhida, R.
Tetrahedron Lett. 2003, 44, 2199–2202. Ref. 8b represents another potential
source of stereochemical confusion because the Felkin–Anh explanation pre-
sented in Scheme 3 of that paper predicts the opposite outcome (S) to that
(‘3a,bR’) which it is supposed to model.
3.30. (4S,5R,10R,100S)-5-(1-Benzyloxymethyl)hydroxymethyl-
2,2-dimethyl-4-[1-(2-methoxyphenyl)]hydroxymethyl-1,3-
dioxolane [anti-(38)]
Prepared from lactol 37, following the general procedure
for L-Selectride reduction in the absence of ZnCl2, with the
following modification. The product was purified by chroma-
tography on basic alumina (petrol/ethyl acetate, 4:1/1:1) rather
than on silica. The product (anti-38) was obtained as a colourless
9. Chang, Y.-C.; Herath, J.; Wang, T. H.-H.; Chow, C. S. Bioorg. Med. Chem. 2008, 16,
2676–2686.
10. Peyron, C.; Navarre, J. M.; Dubreuil, D.; Vierling, P.; Benhida, R. Tetrahedron Lett.
2008, 49, 6171–6174.
oil (38 mg, 47% on a 0.207 mmol scale). Rf 0.18 (petrol/ethyl
21
ꢀ20 (c 0.3, CHCl3); nmax (thin film)/cmꢀ1
11. The stereochemical assignment in this particular case was made by comparison
of the 1H NMR data of the reduced products with those of earlier reduction
products. In particular it was noted that the CHAr resonance usually appeared
as a slightly broadened singlet (i.e., unresolved multiplet) in the syn- isomers
and as a clear doublet (J 8.5–9.5 Hz) for the anti-isomers.
12. It was found that the crude product mixture in reductions of substrate 37
contained large amounts of what appeared to be a boron-containing complex
of the product(s) that was not rapidly oxidised. For this reason, the oxidation
during the work-up was allowed to proceed for 1 h, rather than a few minutes;
even so, in the ZnCl2-free case the unidentified ‘complex’ was still present and
could only be removed (although not isolated) when chromatography was
performed on basic alumina.
13. Paquette, L. A.; Bailey, S. J. Org. Chem. 1995, 60, 7849–7856.
14. Commercially available from Aldrich Chemical Company.
15. McCartney, J. L.; Meta, C. T.; Cicchillo, R. M.; Bernardina, M. D.; Wagner, T. R.;
Norris, P. J. Org. Chem. 2003, 68, 10152–10155.
16. Marquez, V. E.; Lim, M.-I.; Tseng, C. K.-H.; Markovac, A.; Priest, M. A.; Khan, M.
S.; Kaskar, B. J. Org. Chem. 1988, 53, 5709–5714.
acetate, 2:1); [
a
]
D
3385br, 1602w, 1495m, 1455w, 1369w, 1246s, 1071s, 916w,
754m, 699w; dH (500 MHz, CDCl3) 1.27 and 1.34 (2ꢂ3H, 2ꢂs,
2ꢂCH3), 3.68 (1H, dd, J 9.8, 6.3) and 3.85–3.88 (1H, m, CH2OBn)
overlaying 3.86 (3H, s, OCH3), 4.22–4.27 (1H, m, CHCH2), 4.32
(1H, dd, J 9.6, 5.2, CHCHCH2), 4.57 (1H, dd, J 9.8, 5.2, CHCHAr),
4.63 and 4.67 (2ꢂ1H, 2ꢂd, J 12.1, CH2Ph), 5.10 (1H, d, J 9.8, CHAr),
6.92 (1H, d, J 8.2), 6.99 (1H, app t, J 7.4) and 7.27–7.40 (7H, m,
Ph and Ar); dC (100 MHz, CDCl3) 25.4 (CH3), 27.7 (CH3), 55.4
(CH3), 68.7 (CH), 68.8 (CH), 71.9 (CH2), 73.5 (CH2), 77.7 (CH),
79.1 (CH), 108.6 (C), 110.9 (CH), 120.9 (CH), 127.6 (CH), 127.7 (CH),
128.4 (CH), 128.6 (C), 129.1 (CH), 129.2 (CH), 138.2 (C), 157.2
(C); m/z (ESIþ) 799 (M2Naþ, 100%), 794 (M2NH4þ, 30), 777 (M2Hþ,
10), 490 (90), 447 (M$CH3CN$NHþ4 , 60), 411 (MNaþ, 30);
HRMS (ESIþ) found 411.1777, C22H28NaO6 (MNaþ) requires
411.1778.
17. Cheng, J. C.-Y.; Hacksell, U.; Daves, G. D., Jr. J. Org. Chem. 1985, 50, 2778–2780.
18. (a) Wilcox, C. S.; Cowart, M. D. Carbohydr. Res. 1987, 171, 141–160; (b) Czernecki,
S.; Ville, G. J. Org. Chem. 1989, 54, 610–612.