Short synthesis of a benzyl ether-protected building block for the synthesis of carbocyclic galactopyranose mimics

Article abstract of DOI:10.1016/j.carres.2010.03.030

A versatile intermediate for the synthesis of galactose-mimicking carbasugars was synthesised from tetrabenzyl galactose in five steps and 30% overall yield. The reaction sequence uses an l-proline-mediated aldol reaction as key step. The reaction sequence was run on several grams of material.

Full text of DOI:10.1016/j.carres.2010.03.030

Carbohydrate Research 345 (2010) 1056–1060
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
Short synthesis of a benzyl ether protected building block for the synthesis
of carbocyclic galactopyranose mimics
*
Ian Cumpstey
Department of Organic Chemistry, The Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
A versatile intermediate for the synthesis of galactose-mimicking carbasugars was synthesised from
Received 1 February 2010
Received in revised form 18 March 2010
Accepted 23 March 2010
tetrabenzyl galactose in five steps and 30% overall yield. The reaction sequence uses an
ated aldol reaction as key step. The reaction sequence was run on several grams of material.
Ó 2010 Elsevier Ltd. All rights reserved.
L-proline medi-
Available online 27 March 2010
Keywords:
Aldol
Carbasugar
Valienol
Carbocyclisation
Galactose
A relatively small number of methods for the synthesis of carba-
galactopyranosyl pseudodisaccharides by direct coupling between
carbasugar and carbohydrate exist.1 To investigate such coupling
methods, a quantity of a suitable carbasugar precursor was re-
quired. The derivative 1 shown in Figure 1 is such a precursor.
It has the advantage of differential protection at C-1, which
should allow regiospecific modification at this position. Unsatu-
ration at C-5@C-5a renders C-1 allylic, leading to enhanced
electrophilic reactivity; the unsaturation could be removed by
diastereoselective reduction to give the galacto carbasugar or left
in place for epi-valienamine derivatives. Coupling reactions using
related carbocyclic C-1 electrophiles have been achieved with
amine nucleophiles by palladium catalysis2–4 or direct displace-
ment,5,6 and with thiol nucleophiles on saturated7 or unsatu-
rated8 systems.
Shing has recently described high-yielding carbocyclisations of
carbohydrate-derived diketones bearing cyclic acetal protection
by intramolecular aldol reaction.3 Dehydration and reduction to
the valienol have been described on the glucose-derived com-
pound.12,4 The aldol approach is reminiscent of the biosynthesis
of valienamine, in which sedoheptulose-7-phosphate cyclises to
give 2,5-bis-epi-valiolone.13
The foremost problem that must be overcome in the aldol reac-
tion is one of regioselectivity (Scheme 1). Attack by a C-1a nucleo-
phile on the C-5 ketone gives the required regioisomer 6; attack by
a C-6 nucleophile on the C-1 ketone gives the wrong regioisomer 7.
Diastereoselectivity should also be considered. The required regio-
isomer 6 contains one new stereogenic centre formed during the
reaction (C-5), but as this chiral information is lost during a subse-
quent dehydration to the a,b-unsaturated ketone, a high diastereo-
This compound 1 and its C-1 epimer 2 have been synthesised
before from galactose; by Whalen and Halcomb,8 using a Nozaki–
Hiyama–Kishi cyclisation to close the ring between C-5 and C-5a,
by Wang and Bennet,9 using ring-closing metathesis to cyclise be-
tween C-5 and C-5a and by Kim and co-workers,10 using Vasella’s11
ring-closing metathesis strategy to cyclise between C-1 and C-5a,
followed by palladium-catalysed (3,3)-sigmatropic rearrangement.
A related PMB ether-protected compound has also been synthes-
ised,8 and the benzyl ether to acetate protecting group swap has
been demonstrated at the carbasugar level on a C-5@C-5a unsatu-
rated C-1 ketone.8
selectivity is not a prerequisite of a successful reaction. The other
regioisomer 7 contains two new stereogenic centres created during
the aldol reaction. Dehydration or epimerisation
a to the carbonyl
groups in the starting material or any of the products could in-
crease the number of compounds formed, decreasing the product
yield and making isolation more problematic.
‘Directed’ aldol-like reactions, such as the Horner–Wadsworth–
Emmons reaction,14 the aldol reaction of an -dichloroketone,15
a,a
dithioacetal derivatives,15
a
-silylketones,16 enol ethers,17 etc.18
have been reported before for the synthesis of carbocycles from
carbohydrates, but the aldol reaction itself (the ‘undirected’ aldol)
is an attractive and under-explored alternative. In this Note, I
describe a short synthetic route to the required building block 1,
* Tel.: +46 8 16 2481; fax: +46 8 15 4908.
E-mail address: ian.cumpstey@sjc.oxon.org
using an L-proline mediated aldol reaction as the key step.
0008-6215/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2010.03.030

I. Cumpstey / Carbohydrate Research 345 (2010) 1056–1060
1057
from the diketone by flash column chromatography. The aldol
reaction was best carried out with -proline (1 equiv) in DMSO,
C-5=C-5a unsaturation:
reduce for the carbasugar
or keep for valienamines
L
Allylic alcohol:
differential protection
at C-1 for conversion
to electrophiles
heating to 50 °C. This gave a reproducible mixture of products con-
sisting of the two C-5 diastereomers of the desired regioisomer (6a
and 6b) and a single diastereomer of the undesired regioisomer
(7a) in a 10:2:3 ratio. This mixture was inseparable by chromatog-
raphy in pentane–EtOAc and was used in the next step.
OH
BnO
BnO
OBn
Benzyl ethers: removable
by Birch reduction, catalytic
hydrogenation or acetolysis
OBn
Dehydration with POCl3 in pyridine gave the
a,b-unsaturated
Stereochemistry at C-1—C-4:
ketone 88 derived from the required regioisomers (6a and 6b),
while the undesired regioisomer (7a) was recovered unreacted
after the reaction. This made the reaction difficult to follow by
TLC, but it was usually finished after 15–17 h. Finally, reduction
under Luche conditions, with the addition of THF as co-solvent to
aid solubility, proceeded with good diastereoselectivity to give
the target compound (1, 90%) along with its C-1 epimer (2, 5%),
which were separable by column chromatography (CH2Cl2–Et2O).
The 1H and 13C NMR data and optical rotations for 1 and 2 were
in agreement with the data already reported for these two com-
matches β-D-galactose
Figure 1. The target compound 1.
O
1a
1
OH
5a
6
6
X
1
O
BnO
5
BnO
5
2
∗
∗
2
4
∗
3
4
3
BnO
OBn
BnO
OBn
OBn
OBn
6
3
pounds.8,9 The assignment of stereochemistry based on J1,2
OBn
coupling constants relies on both compounds occupying 2H3 half-
chair conformations, which is expected for 1 (three eq and one ax
substituent in 2H3), but not necessarily for 2 (two eq and two ax
X
OH
6
O
O
∗
BnO
BnO
1
CH3
5
1a
∗
2
∗
∗
3
4
OBn
BnO
OBn
3
substituents in both 2H3 and 3H2).23 Indeed, the values of J2,3
OBn
OBn
7
3
(9.2 and 8.9 Hz, i.e., ax–ax) and also the less diagnostic J3,4
(3.5 Hz) are consistent with a 2H3 and not a 3H2 conformation for
both compounds. Allylic A1,2 strain between C-6 and O-4 destabi-
lises the 3H2 conformation more than the 2H3 in 2, in contrast to
the related lyxo derivatives23 where the opposite is true.24
þ
Scheme 1. The regioselectivity problem in the aldol reaction. X = O or NR2
Stereogenic centres that are potentially prone to racemisation (i.e., to carbonyl
groups) in the starting material and products are indicated with asterisks.
.
a
Some aspects of the aldol reaction are worthy of further com-
ment. I also tested some other reaction conditions, including strong
base (Li-HMDS in THF, ꢀ78 °C), weak base (Et3N in CH2Cl2) and
secondary amine/enamine (e.g., pyrrolidine in CH2Cl2, with or
without AcOH). These alternative reaction conditions all gave dia-
stereomers of the undesired regioisomer 7 as the major products,
and only minor or trace amounts of the required regioisomer 6.
The tetrabenzyl
D-galactose starting material 3 is available
either from galactose via the thioglycoside,19 from the commer-
cially available methyl galactosides by benzylation–hydrolysis,20
or from lactose also by benzylation–hydrolysis and purifica-
tion.21,22 Addition of the methyl Grignard reagent proceeded in
high yield to give the deoxyheptitols 4 as a diastereomeric mixture
(ca. 2:1) that was not separated (Scheme 2). Oxidation under
Swern conditions gave the diketone 5. Small amounts of more
polar aldol by-products were formed, which could be separated
Running the reaction with less than 1 equiv
L-proline gave low con-
versions of starting material (using 0.3 equiv
L-proline, a yield of
HO
O
O
OH
OH
O
BnO
BnO
BnO
BnO
BnO
BnO
(i)
(ii)
OBn
OBn
OBn
OBn
OBn
OBn
3
5
4
(iii)
OBn
OH
OH
CH3
BnO
BnO
O
OBn
BnO
OBn
OBn
OBn
7a
O
1
BnO
BnO
(v)
(iv)
+
OBn
+
OBn
OH
OH
O
8
BnO
BnO
BnO
BnO
OBn
OBn
OBn
OBn
6a,b
2
Scheme 2. Reagents and conditions: (i) MeMgBr (2.8 equiv), THF, 0 °C?50 °C; (ii) (COCl)2 (6 equiv), DMSO (9 equiv), CH2Cl2, ꢀ78 °C, Et3N (18 equiv), 84% from 3; (iii)
L-
proline (1 equiv), DMSO, 50 °C, 57% (6a:6b:7a, 10:2:3); (iv) POCl3 (5 equiv), pyridine; 8, 70%; 7a, 13%; (v) NaBH4 (1.5 equiv), CeCl3ꢁ7H2O (1.2 equiv), MeOH, THF; 1, 90%; 2, 5%.

1058
I. Cumpstey / Carbohydrate Research 345 (2010) 1056–1060
24% of the same mixture of aldol products was obtained after 14 h
at 50 °C, along with recovered starting material 55%), which indi-
cates that L-proline does not appear to turn over catalytically effi-
ciently, if at all, in this reaction. The reaction was rather slow at rt.
It was possible to separate the two diastereomers of the required
aldol product (6a and 6b) by flash chromatography (CH2Cl2–
Et2O); but the major diastereomer 6a could not be completely sep-
arated from its regioisomer 7a. Each of the two diastereomers 6a
and 6b was separately converted with phosphoryl chloride and
pyridine into the same dehydrated product 8, proving that they
mixture was poured into NH4Cl (satd aq, 150 mL), and the mixture
extracted with EtOAc (2 ꢂ 150 mL). The combined organic extracts
were dried (Na2SO4), filtered and concentrated in vacuo. The resi-
due was dissolved in pentane–EtOAc (1:1) and filtered through a
plug of silica. The solution was concentrated in vacuo to give a res-
idue (12.2 g) that was used in the next step without further
purification (diastereomeric ratio ca. 2:1, estimated from 1H NMR
spectrum).
Alternatively, the mixture of diols 4 (93–97%) could be obtained
pure by flash column chromatography (pentane–EtOAc, 2:1); 1H
NMR selected data: (400 MHz, CDCl3) dH 1.18 (3H, d, J1,1a 6.4 Hz,
CH3-1a), 1.21 (3H, d, J1,1a 6.4 Hz, CH3-1a); 13C NMR (100 MHz,
CDCl3) dC 19.5, 20.6 (2 ꢂ q, 2 ꢂ C-1a), 67.0, 67.6, 69.9, 70.4, 77.7,
77.8, 79.9, 80.9, 82.2, 82.8 (10 ꢂ d, 2 ꢂ C-1, 2 ꢂ C-2, 2 ꢂ C-3,
2 ꢂ C-4, 2 ꢂ C-5), 70.9, 71.1 (2 ꢂ t, 2 ꢂ C-6), 73.4, 73.5, 73.9, 74.5,
74.9, 75.1 (6 ꢂ t, 8 ꢂ PhCH2), 127.8, 127.9, 127.9, 127.9, 127.9,
128.0, 128.1, 128.2, 128.2, 128.3, 128.5, 128.6, 128.6 (13 ꢂ d, Ar-
CH), 138.0, 138.0, 138.2, 138.3 (4 ꢂ s, Ar-C); m/z (ES+) 579
(M+Na+, 100%); HRESMS calcd for C35H40O6Na (MNa+) 579.2717;
found 579.2700.
Oxalyl chloride (11.2 mL, 130 mmol) was dissolved in CH2Cl2
(50 mL) and cooled to ꢀ78 °C under N2. DMSO (13.8 mL,
194 mmol) was dissolved in CH2Cl2 (50 mL) and added by cannula
under N2. Gas was evolved. The mixture was stirred at ꢀ78 °C for
20 min, after which time, a solution of the crude diols 4 (12.2 g)
in CH2Cl2 (40 + 10 mL) was added by cannula under N2. After
35 min, a precipitate had formed. The reaction mixture was
warmed to ꢀ40 °C and stirred at this temperature for 30 min.
The mixture was then re-cooled to ꢀ78 °C, and Et3N (54 mL,
390 mmol) was added. After 15 min, the mixture was removed
from the cooling bath and allowed to warm to rt. A large amount
of precipitate had formed. After a further 2 h, TLC (pentane–EtOAc,
2:1) showed the complete consumption of starting material (Rf
0.2), and the formation of a major product (Rf 0.5). Toluene
(400 mL) was added, and the precipitate was removed by filtration.
The residue was washed with toluene (100 mL), and the filtrate
was concentrated in vacuo to give the crude product. Purification
by flash column chromatography (pentane–EtOAc, 5:1?4:1?2:1)
gave the diketone 5 (9.98 g, 84% from 3) as a colourless oil; 1H
were indeed C-5 epimers and not the result of epimerisation
a to
a carbonyl group. The relative stereochemistry of the major regio-
isomeric impurity 7a was not assigned.
Achieving the required regioselectivity appears to be more dif-
ficult in the intramolecular aldol reaction of the benzyl ether pro-
tected diketone 5 than for Shing’s cyclic acetal protected systems.
Nevertheless, the reaction sequence described in this Note with an
L-proline mediated aldol reaction as key step delivered the key
compound 1 on scales of up to several grams. The synthesis de-
scribed herein is also, at five steps, and with a 30% overall yield
from tetrabenzyl galactose 3, shorter than previously reported syn-
theses of this compound. The results of research into pseudodisac-
charide formation from the compound described will be reported
in due course.
1. Experimental
1.1. General methods
Proton nuclear magnetic resonance (1H) spectra were recorded
on Bruker Avance II 400 (400 MHz) or 500 (500 MHz) spectrome-
ters; multiplicities are quoted with standard abbreviations or as
apparent triplet (at), apparent triplet of doublets (atd), doublet of
apparent triplets (dat), or apparent quartet (aq). Carbon nuclear
magnetic resonance (13C) spectra were recorded on Bruker Avance
II 400 (100 MHz) or 500 (125 MHz) or Varian Mercury 400
(100 MHz) spectrometers, and multiplicities assigned by DEPT.
Spectra were assigned using COSY, HSQC and DEPT experiments.
All chemical shifts are quoted on the d scale in ppm. Residual sol-
vent signals were used as an internal reference. Low- and high-res-
olution electrospray (HRESMS) mass spectra were recorded using a
Bruker Microtof instrument. Optical rotations were measured on a
Perkin–Elmer 241 polarimeter with a path length of 1 dm; concen-
trations are given in g/100 mL. Thin layer chromatography (TLC)
was carried out on Merck Kieselgel sheets, pre-coated with
60F254 silica. Plates were visualised with UV light and developed
using 10% sulfuric acid, or an ammonium molybdate (10% w/v)
and cerium(IV) sulfate (2% w/v) solution in 10% sulfuric acid. Flash
*
NMR (400 MHz, CDCl3) dH 2.14 (3H, s, CH3-1a), 4.04 (1H , d, J
4.4 Hz), 4.11–4.19 (3H*, m, H-6), 4.27 (1H, d, J6,6 18.1 Hz, H-60),
0
4.36–4.58 (8H, m, 4 ꢂ PhCH2), 7.19–7.34 (20H, m, Ar-H); 13C
NMR (100 MHz, CDCl3) dC 27.7 (q, C-1a), 72.8, 73.3, 73.8, 74.6,
77.4 (5 ꢂ t, C-6, 4 ꢂ PhCH2), 80.9, 81.1, 84.8 (3 ꢂ d, C-2, C-3, C-4),
128.0, 128.1, 128.1, 128.3, 128.3, 128.4, 128.5, 128.5, 128.6, 128.7
(10 ꢂ d, Ar-CH), 136.8, 137.1, 137.3, 137.5 (4 ꢂ s, 4 ꢂ Ar-C),
207.1, 209.2 (2 ꢂ s, C-1, C-5); m/z (ES+) 575 (M+Na+, 100%);
HRESMS calcd for C35H36O6Na (MNa+) 575.2404; found 575.2383.
*
It was not possible to unambiguously assign the resonances
column chromatography was carried out on silica gel (35–70 lm,
for H-2, H-3 and H-4.
Grace). CH2Cl2 was distilled from calcium hydride. THF and pyri-
dine were dried over 4 Å molecular sieves. DMSO was from Schar-
lau, MeOH was from VWR and were used as supplied. Other
reagents were used as supplied. Reactions performed under an
atmosphere of nitrogen were maintained by an inflated balloon.
Further elution gave a mixture of aldol by-products (0.47 g, 4%)
as a colourless oil.
1.3. (4S,5S,6R)-4,5,6-Tris(benzyloxy)-3-((benzyloxy)methyl)
cyclohex-2-enone (8)
1.2. 3,4,5,7-Tetra-O-benzyl-1-deoxy-L-arabino-hepto-2,6-
Diketone
5 (7.50 g, 13.6 mmol) was dissolved in DMSO
diulose (5)
(120 mL). -Proline (1.56 g, 13.6 mmol) was added, which did not
L
all dissolve, and the mixture was stirred at 50 °C in air. After 8 h,
TLC (pentane–EtOAc, 3:1) showed little starting material remain-
ing (Rf 0.3) and the formation of a major product (Rf 0.2). At this
point, the reaction mixture was rather dark in colour, and most
of the proline had dissolved. A small amount of white solid re-
mained out of solution. The mixture was added to water
(500 mL) and brine (250 mL), and extracted with EtOAc (250 +
200 + 200 mL). The combined organic extracts were dried
The lactol 3 (11.6 g, 21.6 mmol) was dissolved in THF (150 mL)
and cooled to 0 °C under N2. Methylmagnesium bromide (43 mL of
a 1.4 M solution in THF/toluene; 60.3 mmol) was added by cannula
under N2. After 10 min, the reaction mixture was removed from
the cooling bath and heated to 50 °C. After a further 3 h 40 min,
TLC (toluene–EtOAc, 3:1) showed complete conversion of starting
material (Rf 0.3) into two products (Rf 0.25 and 0.2). The reaction

I. Cumpstey / Carbohydrate Research 345 (2010) 1056–1060
1059
(Na2SO4), filtered and concentrated in vacuo. The residue was puri-
fied by flash column chromatography (pentane–EtOAc, 7:2?5:2)
to give first a fraction containing the starting diketone, but which
was very impure and unusable (543 mg); then the aldol products
NMR (125 MHz, CDCl3) dC 23.2 (q, C-1a), 72.7, 72.9, 73.1 (3 ꢂ t,
3 ꢂ PhCH2), 75.7 (s, C-1), 76.1 (t, PhCH2), 80.1 (d, C-3), 80.5 (d, C-
4), 81.1 (d, C-2), 82.6 (d, C-6), 127.9, 128.0, 128.2, 128.3, 128.4,
128.4, 128.5, 128.5, 128.6, 128.7 (11 ꢂ d, Ar-CH), 136.9, 137.2,
138.0, 138.2 (4 ꢂ s, 4 ꢂ Ar-C), 205.2 (s, C-5).
as
a mixture of diastereomers and regioisomers 6a, 6b, 7a
(4.31 g, 57%). This was the total yield after repurification of mixed
fractions by a second flash chromatography column in the same
elution solvent. Ratio 6a:6b:7a, 10:2:3 (determined from the 1H
NMR spectrum). m/z (ES+) 575 (M+Na+, 100%); HRESMS (ES+) calcd
for C35H36O6Na (MNa+) 575.2404; found 575.2392.
1.4. 2,3,4,6-Tetra-O-benzyl-5a-carba-a-L-arabino-hex-5(5a)-
enopyranose (1) and 2,3,4,6-tetra-O-benzyl-5a-carba-b-
L-
arabino-hex-5(5a)-enopyranose (2)
This mixture was used in the subsequent step, but by flash col-
umn chromatography (CH2Cl2–Et2O, 25:1), it was possible to sepa-
rate 6b from the other two isomers, and also obtain 6a
contaminated only by small amounts of 7a.
The a,b-unsaturated ketone 8 (3.91 g, 7.3 mmol) was dissolved in
a mixture of MeOH (75 mL) and THF (25 mL) and cooled to ꢀ20 °C
under N2. CeCl3ꢁ7H2O (3.26 g, 8.8 mmol) was added, and the solid
dissolved slowly. After 25 min, NaBH4 (416 mg, 11.0 mmol) was
added slowly. After a further 20 min, TLC (pentane–EtOAc, 3:1)
showed complete conversion of starting material (Rf 0.4) into a prod-
uct (Rf 0.2). The mixture was poured into NH4Cl (satd aq, 150 mL)
and brine (100 mL), and extracted with EtOAc (3 ꢂ 150 mL). The
combined organic extracts were dried (Na2SO4), filtered and concen-
trated in vacuo. The residue was purified by flash column chroma-
tography (CH2Cl2–Et2O, 20:1?15:1?10:1) to give first the ‘down’
Data for 6b: 1H NMR (500 MHz, CDCl3) dH 2.62 (1H, dd, J5a,5a
0
14.2 Hz, J 1.1 Hz, H-5a), 2.8 (1H, d, J5a,5a 14.2 Hz, H-5a0), 3.15
0
0
0
(1H, d, J6,6 9.7 Hz, H-6), 3.40 (1H, br s, OH-5), 3.55 (1H, d, J6,6
9.7 Hz, H-60), 3.99 (1H, dd, J 2.6 Hz, J 7.4 Hz, H-3), 4.20–4.23 (2H,
m, H-2, H-4), 4.43, 4.47 (2H, 2 ꢂ d, J 12.2 Hz, PhCH2), 4.49 (1H, d,
J 11.7 Hz, PhCHH0), 4.60–4.62 (2H, m, 2 ꢂ PhCHH0), 4.72–4.77
(2H, m, 2 ꢂ PhCHH0), 4.88 (1H, d, J 11.3 Hz, PhCHH0), 7.24–7.34
(20H, m, Ar-H); 13C NMR (125 MHz, CDCl3) dC 47.5 (t, C-5a), 73.1,
73.6, 73.8, 74.6 (4 ꢂ t, 4 ꢂ PhCH2), 73.2 (t, C-6), 75.5 (s, C-5),
77.7, 82.4 (2 ꢂ d, C-2, C-4), 79.4 (d, C-3), 127.8, 127.9, 128.0,
128.0, 128.1, 128.1, 128.3, 128.5, 128.6, 128.6, 128.6 (12 ꢂ d, Ar-
CH), 137.6, 137.7, 137.7, 138.1 (4 ꢂ s, 4 ꢂ Ar-C), 205.9 (s, C-1).
Data for 6a: 1H NMR data in agreement with the literature val-
ues.17 13C NMR (125 MHz, CDCl3) dC 44.9 (t, C-5a), 73.0 (t, C-6),
73.6, 73.7, 74.3, 75.3 (4 ꢂ t, 4 ꢂ PhCH2), 74.7 (s, C-5), 70.5, 84.5
(2 ꢂ d, C-2, C-4), 81.8 (d, C-3), 127.6, 127.7, 127.9, 128.1, 128.1,
128.2, 128.2, 128.4, 128.4, 128.5, 128.7 (11 ꢂ d, Ar-CH), 137.4,
138.3, 138.5, 138.9 (4 ꢂ s, 4 ꢂ Ar-C), 205.0 (s, C-1).
alcohol 2 (200 mg, 5%) as a colourless oil; ½a D21
ꢃ
+54.4 (c 1.0, CHCl3)
(lit.8 +75.6); 1H NMR (500 MHz, CDCl3)8 dH 3.88 (1H, d, J6,6
12.5 Hz, H-6), 3.93 (1H, dd, J3,4 3.5 Hz, J2,3 8.9 Hz, H-3), 4.05 (1H,
0
dd, J2,3 8.9 Hz, J1,2 4.4 Hz, H-2), 4.10 (1H, d, J6,6 12.5 Hz, H-60), 4.24
0
(1H, d, J3,4 3.5 Hz, H-4), 4.36 (1H, at, J 4.1 Hz, H-1), 4.39, 4.45 (2H,
2 ꢂ d, J 11.9 Hz, PhCH2), 4.54, 4.84 (2H, 2 ꢂ d, J 11.3 Hz, PhCH2),
4.67 (1H, d, J 11.7 Hz, PhCHH0), 4.73–4.79 (3H, m, PhCH2, PhCHH0),
5.82 (1H, d, J1,5a 4.2 Hz, H-5a), 7.26–7.37 (20H, m, Ar-H); 13C NMR
(125 MHz, CDCl3)8 dC 65.9 (d, C-1), 70.7 (t, C-6), 72.3, 73.6, 73.6,
74.5 (4 ꢂ t, 4 ꢂ PhCH2), 73.8 (d, C-4), 76.8 (2 ꢂ d, C-2, C-3), 126.5
(d, C-5a), 127.7, 127.8, 127.8, 127.8, 127.9, 128.1, 128.1, 128.4,
128.5, 128.5, 128.5, 128.7 (12 ꢂ d, Ar-CH), 137.4, 138.3, 138.4,
138.8, 138.8 (5 ꢂ s, 4 ꢂ Ar-C, C-5).
The mixture of aldol products 6a, 6b, 7a (4.31 g, 7.81 mmol)
was dissolved in pyridine (18 mL) and cooled to 0 °C under N2.
Phosphoryl chloride (3.62 mL, 39 mmol) was added. After 10 min,
the reaction mixture was removed from the cooling bath and stir-
red at rt. After 17 h, TLC (pentane–EtOAc, 3:1) showed some
remaining starting material (Rf 0.2) and the formation of a major
product (Rf 0.4). The mixture was dilued with Et2O (20 mL) and
poured onto crushed ice (ca. 150 mL). HCl (1 M, 100 mL) was
added, and the mixture extracted with Et2O (200 + 100 mL). The
combined organic extracts were washed with brine (100 mL), dried
(Na2SO4), filtered and concentrated in vacuo. The residue was puri-
fied by flash column chromatography (pentane–EtOAc, 9:2?4:1?
Then the ‘up’ alcohol 1 (3.54 g, 90%) as a colourless oil; ½a D21
ꢃ
+12.2 (c 1.0, CHCl3) (lit.9 +15.8); 1H and 13C NMR data in agreement
with the literature values.8,9
Acknowledgement
I thank the Swedish Research Council (Vetenskapsrådet) for its
continued support.
Supplementary data
3:1) to give first the ketone 8 (2.92 g, 70%) as a colourless oil; ½a D21
ꢃ
+66.4 (c 1.0, CHCl3) (lit.8 +66.8); 1H NMR (500 MHz, CDCl3)8 dH 3.92
Supplementary data associated with this article (copies of 1H
and 13C NMR spectra for compounds 1, 2, 4–8) can be found, in
the online version, at doi:10.1016/j.carres.2010.03.030.
0
(1H, dd, J 3.2 Hz, J 8.7 Hz, H-3), 4.06 (1H, dd, J5a,6 1.5 Hz, J6,6
15.8 Hz, H-6), 4.10 (1H, dd, J5a,6 1.4 Hz, J6,6 15.8 Hz, H-60), 4.34
(1H, d, J 3.2 Hz, H-2 or H-4), 4.43 (1H, d, J 8.7 Hz, H-2 or H-4),
4.45, 4.49 (2H, 2 ꢂ d, J 11.9 Hz, PhCH2), 4.57 (1H, d, J 11.4 Hz,
PhCHH0), 4.70–4.72 (2H, m, 2 ꢂ PhCHH0), 4.86–4.91 (2H, m,
2 ꢂ PhCHH0), 4.98 (1H, d, J 11.6 Hz, PhCHH0), 6.12 (1H, at J 1.6 Hz,
H-5a), 7.23–7.41 (20H, m, Ar-H); 13C NMR (125 MHz, CDCl3)8 dC
69.6 (t, C-6), 73.1, 73.8, 74.2, 74.5 (4 ꢂ t, 4 ꢂ PhCH2), 73.7, 80.2
(2 ꢂ d, C-2, C-4), 79.3 (d, C-3), 124.9 (d, C-5a), 127.9, 127.9,
128.1, 128.1, 128.3, 128.4, 128.5, 128.6, 128.6, 128.6 (10 ꢂ d, Ar-
CH), 137.6, 138.0, 138.1, 138.3 (4 ꢂ s, Ar-C), 156.1 (s, C-5), 196.9
(s, C-1).
0
0
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