Michael, Michael-aldol and Michael-Michael reactions of enolate equivalents of butane-2,3-diacetal protected glycolic acid derivatives

Article abstract of DOI:10.1039/b512410g

Consecutive coupling reactions of butane-2,3-diacetal protected glycolic acid derivatives with Michael acceptors and aldehydes are reported. An enantiopure sample of this building block was used to kinetically resolve a chiral Michael acceptor present as a racemic mixture of enantiomers. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b512410g

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A R T I C L E
Michael, Michael–aldol and Michael–Michael reactions of enolate
equivalents of butane-2,3-diacetal protected glycolic acid derivatives
Steven V. Ley,* Darren J. Dixon, Richard T. Guy, Fe´lix Rodr´ıguez and Tom D. Sheppard
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK
CB2 1EW. E-mail: svl1000@cam.ac.uk; Fax: +44 (0)1223 336442; Tel: +44 (0)1223 336398
Received 6th September 2005, Accepted 30th September 2005
First published as an Advance Article on the web 19th October 2005
Consecutive coupling reactions of butane-2,3-diacetal protected glycolic acid derivatives with Michael acceptors and
aldehydes are reported. An enantiopure sample of this building block was used to kinetically resolve a chiral Michael
acceptor present as a racemic mixture of enantiomers.
purified by silica gel chromatography to give the corresponding
Introduction
Michael adducts 3–10 (Table 1). The reactions proceeded with
Multi-component and sequential reaction cascades are proving
generally good to excellent yields and selectivities. No axially-
useful in complex molecule synthesis, especially for the rapid
alkylated products were observed, and the structures of products
production of compound libraries. The one-pot nature of these
5, 6, 8, and 10 were additionally confirmed by single crystal
X-ray diffraction. The product stereochemistry is consistent
processes inevitably leads to a reduction in costs, time and waste
products.1 Amongst the more powerful of these processes are
with the Michael acceptor approaching the lithium enolate
domino or consecutive sequences such as the Ugi reaction2 and
from the face opposite to the axial 1,3-related methoxy groups
related examples, MIMIC chemistry as introduced by Posner
(see A in Fig. 2).8 Also, the assigned configuration of the
et al.,3 and the whole range of tandem reaction sequences.4 These
products is compatible with a combination of the two trigonal
chemistries rapidly produce functionally-dense architectures
centres involved in the reaction according to the model shown
useful in many different areas of science. Nevertheless, while
in B (Fig. 2).9 The Michael acceptor is always approached
these methods create desirable features around a central core,
by the same face of the enolate, irrespective of its geometry
more often than not they lack stereocontrol and lead to
(Z or E).
mixtures of diastereoisomers. The discovery of new sequences
that give greatly improved enantio- and diastereo-selectivity in
the coupling process is therefore important.
Accordingly, we have studied the use of the butane-2,3-
diacetal (BDA) desymmetrized glycolic acid derivatives 1 and
25 (Fig. 1) for these types of reactions: the excellent levels
of stereocontrol imparted by these building blocks in lithium
enolate alkylation, aldol and Michael reactions, and the abun-
dance of biologically active and pharamaceutically-significant
a-hydroxy acids6 make them ideal candidates for such a study.
It was anticipated that 1 and 2 would act as a source of
Fig. 2 Approaching models of the two trigonal centres in the reaction
chirality to influence further stereochemistry in subsequent
of lithium enolates derived from BDA desymmetrized glycolic acid 1
C–C bond forming events. Here we report in full on the
and Michael acceptors.
highly diastereoselective Michael addition7 reactions of 1 and
2 with a range of acceptors and on new stereoselective, one-
pot consecutive reactions that lead to a-hydroxy acid derivatives
with up to five new stereogenic centres in high yield and high
diastereoisomeric excess.
This reaction was extended to the alkylated glycolates 11 and
135 which underwent highly diastereoselective reactions with
trans-2-nitrostyrene to give the glycolate derivatives 12 and 14,
each bearing a fully-substituted carbon atom (Scheme 1).
Fig. 1
Michael additions
Prior to the study of multi-component coupling reactions we
embarked on a preliminary study to evaluate the diastereose-
lectivity in Michael addition reactions of the lithium enolates
generated from 1 and 2. In the initial experiments, 1 or 2
was treated with lithium hexamethyldisilazide (LHMDS) in
THF at −78 ◦C and allowed to react with a small series of
Michael acceptors, added via syringe. The crude product was
Scheme
1 a) KHMDS, trans-2-nitrostyrene, 57%; b) KHMDS,
trans-2-nitrostyrene, 25%.
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 0 9 5 – 4 1 0 7
4 0 9 5
©

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Table 1 Asymmetric Michael addition reactions of 1 or 2
Table 2 a-Hydroxy methyl ester derivatives obtained from the Michael
adducts
Entry Michael acceptor Dra
Yield Product
61%
Entry
1
Adduct
Yield
94%
Product
1
2
3
14 : 1
3
4
5
3a
15
16
10 : 1
13 : 1
35%b
30%
2
7
74%
3
4
8
95%
91%
17
18
4
5
22 : 1
65 : 1
63%
90%
6
7
10
a The enantiomeric starting material was used.
6
7
8
34 : 1
96%
8
1.4 : 1c 55%
9
16 : 1
98%
10
a Determined by 1H NMR of the crude reaction product. The di-
astereoselectivities indicated reflect ratio at the newly formed side-chain
stereogenic centres. b 33% of starting BDA-protected glycolic acid was
recovered. c Mixture at the a-position to the nitro group. The dr of each
diastereomer was found to be >20 : 1.
Scheme 2 a) Raney-Ni; b) SiO2, 73% over two steps; c) (Boc)2O, Et3N,
DMAP; d) NaOMe, MeOH; e) Ph3PHBr, MeOH, 69% over three steps.
22, 23 (Scheme 3) were obtained as a mixture of only two
diastereoisomers in a process leading to two new C–C bonds
and three new stereogenic centres (Table 3). When trimethyl
borate was added at the intermediate Michael reaction stage,
improved selectivity was noted in the final product.
To prove that the BDA group could be readily removed,
Michael adducts 3, 7, 8 and 10 were treated with HCl in methanol
to give the corresponding methyl esters 15–18 (Table 2). As
expected, when 7 was reacted under these conditions (entry 2),
we obtained the ring-opened product 16 in 74% yield.
To further illustrate the utility of the Michael adducts, we
transformed the nitrostyrene adduct 8 firstly to functionalised
c-lactam 19 (Scheme 2) by reduction of the nitro group, partial
deprotection and cyclization, and subsequently to a-hydroxy-
c-amino ester 20 by reaction with methoxide in methanol and
finally a catalytic quantity of triphenylphosphine hydrobromide.
This sequence illustrates the potential for diverse changes in the
products which could be of use in compound library generation
at a later stage, or as building-blocks for natural product
synthesis programmes.
Scheme 3 a) LHMDS (1.05 eq.), THF, −78 ◦C, 10 min; b) 5,6-dihy-
dro-2H-pyran-2-one or coumarin; c) additive; d) RCHO.
Michael–aldol reactions
The structures of the products were determined by detailed
1H and 13C NMR analysis and, in the case of 21 and 22, single
crystal X-ray diffraction methods. These studies indicate that
the diastereomers are epimeric at the carbon atom that bears
the free hydroxyl group in the final aldol coupling product.
The stereochemical outcome of the reactions suggest the first
Michael acceptor approaches the lithium enolate derived from
Sequential Michael–aldol reactions of 1 and 2 were next ex-
plored. Once again, 2 was deprotonated with LHMDS (1 equiv.)
in THF at −78 ◦C and treated with a Michael acceptor (5,6-
dihydro-2H-pyran-2-one or coumarin). After 30 min a second
electrophile, either benzaldehyde or anisaldehyde, was added
and the corresponding three-component coupled products 21,
4 0 9 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 0 9 5 – 4 1 0 7

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Table 3 Michael–aldol reactions
the glycolate 1 as discussed previously. This enolate then
undergoes a syn-aldol addition to the aldehyde presumably
through a closed twist-boat transition state (Fig 3).10,11
Michael
Entry acceptor
R
Additive Dra
Yieldb
1
Ph
—
2.8 : 1 74%
21
21
22
22
23
2
3
4
5
Ph
B(OMe)3 4.0 : 1 72%
Fig. 3 Proposed transition state for Michael–aldol reactions.
4-MeO-C6H4
—
2.5 : 1 66%
Michael–Michael reactions
A consecutive Michael–Michael reaction was next investigated.
Reaction of the enolate of 1 with either 5,6-dihydro-2H-pyran-
2-one or coumarin, followed by either trans-b-nitrostyrene, 1-
nitro-1-cyclohexene or trans-chalcone led to the corresponding
addition products 24–27 (Scheme 4, Table 4) in a sequence
that established two new C–C bonds and up to five stereogenic
centres in a single step. X-Ray crystallography performed on
crystals of 24, 26 and 27 confirmed the stereochemical outcome.
4-MeO-C6H4 B(OMe)3 5.2 : 1 63%
4-MeO-C6H4
—
3.2 : 1 73%
6
4-MeO-C6H4 B(OMe)3 3.3 : 1 64%
23
a Determined by 1H NMR of the crude reaction product. b Yield based
on starting BDA desymmetrised glycolic acid derivative.
Scheme 4 a) LHMDS (1.05 eq.), THF, −78 ◦C, 10 min; b) 5,6-
dihydro-2H-pyran-2-one or coumarin; c) trans-b-nitrostyrene, 1-ni-
tro-1-cyclohexene or trans-chalcone.
Table 4 Michael–Michael reactions
Entry
1
1st component
2nd component
Dra
3 : 1
Yieldb
80%
Product
24
25
2
3
>20 : 1
81%
90%
>20 : 1
26
27
4
>20 : 1
95%
a Determined by 1H NMR of the crude reaction product. b Yield based on starting BDA desymmetrised glycolic acid derivative.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 0 9 5 – 4 1 0 7
4 0 9 7

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Mechanistically, the second Michael addition seems to occur
through a closed (chelated) transition state previously proposed
for related reactions.9
A tandem Michael–Michael-deprotection sequence was also
studied. The enolate of 1 was reacted with coumarin followed
by trans-chalcone, and finally with trimethylsilyl chloride and
methanol to give 28 in 76% overall yield and a diastereomeric
ratio of 20 : 1 (Scheme 5). We have also shown that 25 can
be reduced with Raney-nickel to the primary amine which
spontaneously ring opens the coumarin lactone to give a c-
lactam. This gives 29 after the usual methanolysis (Scheme 6).
These examples illustrate the potential of this methodology
to efficiently obtain highly-functionalized compounds as single
enantiomers from simple starting materials.
Scheme 7 a) 33, TBAT, THF, rt; b) 34 (3 equiv.), TBAT, THF, −78 ◦C,
c) TBAF–AcOH, THF, rt, 85% over three steps, dr 14.1 : 1.5 : 1.0
(1H NMR).
Scheme 5 a) LHMDS (1.05 eq.), THF, −78 ◦C, 10 min; b) coumarin
c) chalcone; d) MeOH, TMSCl; 76% over four steps; dr 20 : 1.
Fig. 4 Proposed transition state for Michael reaction of silyl ketene
acetal 30 with (R)-cryptone 34.
Scheme 6 a) Raney-Ni; b) MeOH, TMSCl; 86% over two steps.
cryptone, ketone 32 was obtained in a dr of 8.1 : 1.2 : 1.0 : 0.4
(1H NMR; normalized to the minor diastereomer in Scheme 7
above). The enantiomeric excess of recovered cryptone was 92%
(chiral HPLC), and the combined yield of ketone diastereomers
67%. Ketene acetal 30 also underwent a successful Michael
addition with cyclohexenone under TBAT catalysis to yield
ketone 5 as the major diastereomeric product in 89% yield
(Scheme 8). Only a 30% yield of 5 was obtained using the lithium
enolate conditions described above (Table 1).
Kinetic resolution
The lithium enolates of 1 and 2 have been shown to react
well with a range of Michael acceptors, but the scope of this
reaction is limited by their propensity to undergo competitive
aldol and deprotonation processes. For a synthetic project,
we were interested in the Michael addition of 2 with chiral
cyclohexenones such as cryptone 34.12 It was hoped that
enantiopure 2 would react more quickly with one enantiomer
of racemic cryptone than the other and thereby result in a
single product bearing three stereocentres in a useful level
of selectivity, without recourse to an asymmetric synthesis of
the Michael acceptor—a non-trivial undertaking.13 A softer,
less basic enolate equivalent was thought necessary to favour
Michael addition over aldol reaction or deprotonation and
the trimethylsilyl ketene acetal 30 was investigated.14 It was
found that a one pot,15 TBAT16 (tetra-N-butylammonium
triphenyldifluorosilicate)-catalyzed ketene acetal formation and
Michael addition to cryptone gave the ketone 32 in excellent
yield and diastereoselectivity (Scheme 7); the stereochemistry of
32 was confirmed by X-ray crystallography.
Kinetic resolution—aldol
A Michael–aldol sequence based on this kinetic resolution was
next investigated. Trimethylsilyl enol ether intermediate 31 was
elaborated to alcohols 36 and 37 in 35% yield from 30 and a
dr of 1.1 : 1 using BF3.THF and propionaldehyde.19 As this
aldol reaction was essentially unselective, 31 was brominated
using NBS and the resulting a-bromoketone 38 reacted with
propionaldehyde, triphenyltin hydride and triethylborane20 to
give alcohol 36, this time as the only discernable diastereomer.
The stereochemistry of 36 was determined by X-ray analysis,
and can be accounted for by the six-membered transition state
shown (Scheme 9).
The reaction is proposed to proceed through a closed transi-
tion state in which the R enantiomer of cryptone is attacked by
the ketene acetal from the opposite side of the cryptone ring to
the isopropyl group (Fig. 4).17
Conclusion
Trimethylsilyl ketene acetal 30 could also be prepared using
LDA and TMSCl, and purified by distillation.18 When one
equivalent was used to kinetically resolve one equivalent of
It has been shown that 1, 2 and their alkylated derivatives
undergo highly diastereoselective Michael addition reactions
with a range of acceptors. The tandem reaction sequences effect
4 0 9 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 0 9 5 – 4 1 0 7

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Experimental
All reactions were performed under an atmosphere of argon
and carried out using oven dried glassware, cooled under a
continuous stream of argon prior to use, unless otherwise
stated. Diethyl ether (Et2O) and tetrahydrofuran (THF) were
distilled from either sodium benzophenone ketyl or lithium alu-
minium hydride–calcium hydride; dichloromethane (CH2Cl2),
acetonitrile (MeCN), toluene (PhMe) and benzene (PhH) from
calcium hydride; methanol (MeOH) from magnesium methoxide
and triethylamine (Et3N) from potassium hydroxide. All other
reagents and solvents were purified by standard procedures or
were used as supplied from commercial sources. The BDA-
glycolates 1 and 2 were recrystallised to >99% ee (as measured
by chiral GC) before use. Column chromatography was carried
out using Merck Kieselgel (230–400 mesh) or pre-packed silica
columns (Biotage). Melting points were performed on a Reichert
hot stage apparatus and are uncorrected. Boiling points were
measured during distillation. Optical rotations were measured
using a Perkin Elmer Model 343 polarimeter and [a]2D5 values
are given in 10−1 deg cm2 g−1, concentration (c) in g per 100 ml.
Infrared spectra were recorded on a Perkin Elmer “Spectrum
One” spectrometer equipped with an attenuated total reflectance
(ATR) sampling accessory. Spectra were recorded either neat or
using thin films deposited from chloroform, dichloromethane or
methanol solutions. Microanalyses were determined using a CE-
440 Elemental Analyser. HPLC was performed on an Agilent
1100 series HPLC using HPLC-grade solvents and UV detection
at the specified wavelength. Mass spectra were obtained on
Kratos Concept 1H, Micromass Q-TOF or Bruker BIOAPEX
4.7E T FTICR spectrometers, using electron impact (EI) or
electrospray (ESI) techniques. NMR spectra were recorded on
Bruker DRX-600, DRX-500 or DPX-400 spectrometers, in
CDCl3 at 300 K, unless otherwise stated.
Scheme 8 a) TMSCl, LDA, THF, −78 ◦C, 100%; b) cyclohexenone,
TBAT, THF, −78 ◦C to rt; c. TBAF–AcOH, 0 ◦C to rt, THF, 89% over
2 steps, dr 29.1 : 1.1 : 1 (1H NMR).
(3R,5S,6S,1ꢀS)-5,6-Dimethoxy-5,6-dimethyl-3-
(3-oxocyclopentyl)-[1,4]dioxan-2-one (3)
Lithium bis(trimethylsilyl)amide (0.20 ml, 1 M solution in THF,
0.20 mmol) was added drop-wise to a solution of glycolate 1
(38 mg, 0.20 mmol) in THF (1.5 ml) at −78 ◦C. The pale
yellow solution was stirred for 15 min, warmed to −50 ◦C,
and stirred for a further 15 min. Cyclopentenone (0.◦20 ll,
0.24 mmol) was added, and the solution stirred at −50 C for
3 h. The reaction was quenched by addition of acetic acid (24 ll,
0.4 mmol), diluted with ether (4 ml) and allowed to warm to
rt. After 30 min, the resulting suspension was filtered through
a short plug (1–2 cm) of silica gel, eluting with ether, and the
mixture concentrated in vacuo to give the crude product. This
was purified by column chromatography to give the ketone as
a white solid (33 mg, 61%): dH (400 MHz, CDCl3) 1.37 (3H, s,
Me), 1.50 (3H, s, Me), 2.00–2.06 (2H, m, CHHCH2C(O)), 2.10–
2.20 (1H, m, CH2CHHC(O)), 2.26–2.46 (3H, m, CHCHHC(O),
CH2CHHC(O)), 2.89–2.97 (1H, m, CHCH2C(O)), 3.29 (3H, s,
OMe), 3.43 (3H, s, OMe), 4.22 (1H, d, J 3.9, OCHC(O)), dC
(100 MHz, CDCl3) 16.9, 17.7, 24.0, 38.0, 38.5, 40.8, 49.2, 49.9,
72.1, 98.2, 105.2, 169.2, 218.6; mmax (film/cm−1) 2953, 1734, 1380,
1257, 1218, 1145, 1117, 1090, 1046, 1025; found (EI): calcd◦for
C13H20O6Na [M + Na]+ 295.1158, found: 295.1148; mp 129 C;
[a]2D5 +133.4 (c 1.03, CHCl3).
Scheme 9 a) C2H5CHO, BF3·Et2O, CH2Cl2, −78 ◦C, 35% (from 30, dr
1.1 : 1; b) NBS, THF, 0 ◦C, 41% (from 30); c) Ph3SnH, Et3B, C2H5CHO,
toluene, rt, 63%.
the one-pot assembly of up to five stereocentres to give multi-
functional products rapidly and efficiently with a high level of
stereocontrol. The simplicity of the overall processes and the
high yields of relatively clean products make them ideal for the
design of compound arrays.
The selective kinetic resolution of cryptone 34 marks a new
paradigm in the chemistry of glycolates 1 and 2. To the best of
our knowledge it is the first report of either a TBAT-catalyzed
Michael addition of a silyl ketene acetal, or the use of ethyl
(trimethylsilyl)acetate as the source of silicon in this type of
reaction. Its extension to a variety of other chiral and achiral
Michael acceptors and application in total synthesis is ongoing
and additional results will be disclosed in due course.
(3S,5R,6R,1ꢀS)-5,6-Dimethoxy-5,6-dimethyl-3-
(5-oxotetrahydrofuran-3-yl)-[1,4]dioxan-2-one (4)
Lithium bis(trimethylsilyl)amide (0.40 ml, 1 M solution in THF,
0.40 mmol) was added drop-wise to a solution of glycolate 2
(76 mg, 0.40 mmol) in THF (1.2 ml) at −78 ◦C. The pale yellow
solution was stirred for 15 min. A solution of 2(5H)-furanone
(37 mg, 0.44 mmol in 1.2 ml THF) was drop-wise over 30 min.
The solution was stirred for 30 min at −78 ◦C, quenched by
addition of silica gel (100 mg), and diluted with ether (8 ml), and
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 0 9 5 – 4 1 0 7
4 0 9 9

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allowed to warm to rt. After 30 min, the resulting suspension
was filtered through a short plug (1–2 cm) of silica gel, eluting
with ether, and the mixture concentrated in vacuo to give the
crude product. This was purified by column chromatography to
give the ketone as a white solid (38 mg, 35%): dH (400 MHz,
CDCl3) 1.39 (3H, s, Me), 1.50 (3H, s, Me), 2.62 (1H, dd, J 17.8,
8.4, CHHC(O)), 2.67 (1H, dd, J 17.8, 8.8, CHHC(O)), 3.18–
3.26 (1H, m, CHCH2C(O)), 3.31 (3H, s, OMe), 3.43 (3H, s,
OMe), 4.19 (1H, d, J 4.8, OCHC(O)O), 4.35 (1H, dd, J 10.9,
7.1, CHHO), 4.37 (1H, dd, J 10.9, 7.1, CHHO); dC (100 MHz,
CDCl3) 16.8, 17.6, 30.5, 37.4, 49.2, 50.1, 68.7, 70.0, 98.4, 105.6,
168.1, 176.1; mmax (film/cm−1) 2952, 2844, 1776, 1742, 1459, 1382,
1267, 1217, 1177, 1149, 1118, 1033, 1007; found (EI): calcd for
C12H18O7Na [M + Na]+ 297.0950, found: 297.0952; mp 120–
123 ◦C; [a]2D5 −150.2 (c 0.48, CHCl3).
ether, and the mixture concentrated in vacuo to give the crude
product. Unreacted 5,6-dihydro-2H-pyran-2-one was removed
by heating the crude product to 100 ◦C under a vacuum of
approximately 1 mmHg, and the residue purified by column
chromatography to give the lactone as a white solid (36 mg,
63%): dH (400 MHz, CDCl3) 1.27 (3H, s, Me), 1.30 (3H, s, Me),
2.60 (3H, s, OMe), 2.84 (1H, dd, J 16.2, 1.7), 2.92 (1H, dd, J
16.2, 7.2), 3.31 (3H, s, OMe), 3.76–3.79 (1H, m, CHCH2C(O)),
4.37 (1H, d, J 3.2, OCHC(O)), 7.03–7.08 (2H, m, Ar), 7.18
(1H, dd, J 7.6, 1.7, Ar), 7.25–7.29 (1H, m, Ar); dC (100 MHz,
CDCl3) 16.2, 17.5, 32.9, 37.7, 49.4, 49.4, 74.9, 98.5, 105.4, 116.8,
120.4, 124.0, 129.1, 129.6, 153.3, 167.5, 167.7; mmax (film/cm−1)
1743, 1384, 1260, 1150, 1035; found (ESI) [MNa]+ 311.1107,
◦
C13H20O7Na requires 311.1103; mp 129–131 C; [a]2D5 −161.6
(c 0.80, CHCl3).
(1ꢀR,3S,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-3-
(3-oxocyclohexyl)-[1,4]dioxan-2-one (5)
(4S,3ꢀS,5ꢀR,6ꢀR)-4-(5,6-Dimethoxy-5,6-dimethyl-3-oxo-
[1,4]dioxan-2-yl)-chroman-2-one (7)
Procedure 1. Lithium bis(trimethylsilyl)amide (0.36 ml, 1 M
solution in THF, 0.36 mmol) was added drop-wise to a
solution of glycolate 2 (62 mg, 0.33 mmol) in THF (2.5 ml)
at −78 ◦C. After 10 min, a solution of cyclohexenone (32 ll,
0.33 mmol in 0.6 ml THF) was added via cannula. The reaction
was allowed to warm to rt overnight, quenched with acetic acid
(39 ll, 0.65 mmol), diluted with ether (10 ml), filtered through
a pad of silica, eluting with ether (50 ml) and concentrated
in vacuo. The residue was purified by column chromatography
(silica, 3 : 1 petrol : ether with 1% triethylamine, eluting to 2 :
1 petrol : ether with 1% triethylamine) to give the ketone as a
white solid (28 mg, 30%).
Lithium bis(trimethylsilyl)amide (0.20 ml, 1 M solution in THF,
0.20 mmol) was added drop-wise to a solution of glycolate 1
(38 mg, 0.20 mmol) in THF (1.5 ml) at −78 ◦C. The pale yellow
solution was stirred for 15 min. Coumarin (32 mg, 0.20 mmol,
solution in 0.5 ml THF) was added, and the solution stirred for
◦
at −78 C for 30 min. The reaction was quenched by addition
of acetic acid (24 ll, 0.4 mmol), diluted with ether (4 ml) and
allowed to warm to rt. After 30 min, the resulting suspension was
filtered through a short plug (1–2 cm) of silica gel, eluting with
ether, and the mixture concentrated in vacuo to give the crude
product. This was purified by column chromatography to give
the lactone as a white solid (60 mg, 90%): dH (400 MHz, CDCl3)
1.27 (3H, s, Me), 1.30 (3H, s, Me), 2.60 (3H, s, OMe), 2.84 (1H,
dd, J 16.2, 1.7), 2.92 (1H, dd, J 16.2, 7.2), 3.31 (3H, s, OMe),
3.76–3.79 (1H, m, CHCH2C(O)), 4.37 (1H, d, J 3.2, OCHC(O)),
7.03–7.08 (2H, m, Ar), 7.18 (1H, dd, J 7.6, 1.7, Ar), 7.25–7.29
(1H, m, Ar); dC (100 MHz, CDCl3) 16.2, 17.5, 32.9, 37.7, 49.4,
49.4, 74.9, 98.5, 105.4, 116.8, 120.4, 124.0, 129.1, 129.6, 153.3,
167.5, 167.7; mmax (film/cm−1) 2942, 1771, 1741, 1613, 1589, 1491,
1456, 1425, 1379, 1361, 1346, 1289, 1263, 1242, 1217, 1167, 1147,
1130, 1109, 1076, 1035, 1002; found (ESI): calcd for C17H20O7Na
[M + Na]+ 359.1107, found: 359.1109; mp 176 ◦C; [a]2D5 −211.6
(c 0.85, CHCl3).
Procedure 2. Ketene acetal 30 (1.0 ml, 3.62 mmol) was added
drop-wise to a solution of cyclohexenone (0.29 ml, 3.02 mmol)
and TBAT (18 mg, 33 lmol) in THF (4 ml) at −78 ◦C. The
reaction was allowed to warm to rt overnight and re-cooled to
0 ◦C. A solution of TBAF (1 ml, 1 M solution in THF, 1.0 mmol)
and acetic acid (1 ml, 17.5 mmol) were added and the mixture
allowed to warm to rt and stirred for 4 h. The reaction was
quenched with sodium bicarbonate solution (10 ml), extracted
with ether (3 × 20 ml), washed with brine (20 ml), dried
(magnesium sulfate) and concentrated in vacuo. The residue
was purified by column chromatography (Biotage, silica, 1 : 1
petrol : ether) to give the ketone as a white solid (769 mg,
89%): dH (400 MHz; CDCl3) 1.37 (3H, s, Me), 1.47 (3H, s,
Me), 1.59–1.63 (1H, m, CHHCH2C(O)), 1.66–1.70 (1H, m,
CHHCH2CH2C(O)), 1.79–1.86 (1H, m, CHHCH2CH2C(O)),
2.05–2.11 (1H, m, CHHCH2C(O)), 2.20–2.28 (1H, td, J 13.1,
6.3, CH2CHHC(O)), 2.33–2.46 (4H, m, CHCH2C(O), 2 ×
CHCHHC(O), CH2CHHC(O)), 3.27 (3H, s, OMe), 3.40 (3H, s,
OMe), 4.00 (1H, d, J 2.2, OCHC(O)); dC (100 MHz; CDCl3)
16.9, 17.8, 24.7, 25.4, 40.9, 41.1, 43.8, 49.1, 49.9, 73.1, 98.2, 105.1,
168.8, 210.7; mmax (film)/cm−1 2951, 1749, 1712, 1450, 1381,
1256, 1224, 1148, 1124, 1036; found (ESI)◦[MNa]+ 309.1380,
C14H22O6Na requires 309.1314; mp 79–81 C; [a]2D5 −167.2 (c
0.5, CHCl3); found C 58.70%, H 7.68%, C14H22O6 requires C
58.72%, H 7.74%.
(3R,5S,6S,1ꢀS)-5,6-Dimethoxy-5,6-dimethyl-3-(2-nitro-
1-phenyl-ethyl)-[1,4]dioxan-2-one (8)
Lithium bis(trimethylsilyl)amide (0.20 ml, 1 M solution in THF,
0.20 mmol) was added drop-wise to a solution of glycolate 1
(38 mg, 0.20 mmol) in THF (1.5 ml) at −78 ◦C. The pale yellow
solution was stirred for 15 min. trans-2-Nitrostyrene (30 mg,
0.20 mmol, solution in 0.5 ml THF) was added, and the solution
stirred for at −78 ◦C for 15 min. The reaction was quenched by
addition of acetic acid (24 ll, 0.4 mmol), diluted with ether (4 ml)
and allowed to warm to rt. After 30 min, the resulting suspension
was filtered through a short plug (1–2 cm) of silica gel, eluting
with ether, and the mixture concentrated in vacuo to give the
crude product. This was purified by column chromatography to
give the nitroalkane as a white solid (65 mg, 96%): dH (400 MHz,
CDCl3) 1.34 (3H, s, Me), 1.42 (3H, s, Me), 2.73 (3H, s, OMe),
3.32 (3H, s, OMe), 4.23 (1H, ddd, J 9.6, 6.3, 3.5, CHPh), 4.51
(1H, d, J 3.5, OCHC(O)), 4.70 (1H, dd, J 12.8, 6.3, CHHNO2),
5.03 (1H, dd, J 12.8, 9.6, CHHNO2), 7.27–7.36 (5H, m, Ph); dC
(100 MHz, CDCl3) 16.8, 17.7, 45.0, 49.0, 49.2, 70.5, 75.8, 98.6,
105.2, 128.1, 128.2, 129.9, 134.3, 167.2; mmax (film/cm−1) 2968,
2366, 2068, 1721, 1551, 1497, 1457, 1427, 1379, 1353, 1328, 1292,
1255, 1217, 1155, 1116, 1080, 1048, 1034, 1012; found (EI): calcd
for C16H21O7NNa [M + Na]+ 362.1216, found: 362.1211; mp
108 ◦C; [a]2D5 +145.0 (c 1.00, CHCl3).
(3S,5R,6R,1ꢀR)-5,6-Dimethoxy-5,6-dimethyl-3-
(2-oxotetrahydropyran-4-yl)-[1,4]dioxan-2-one (6)
Lithium bis(trimethylsilyl)amide (0.20 ml, 1 M solution in THF,
0.20 mmol) was added drop-wise to a solution of glycolate 1
(38 mg, 0.20 mmol) in THF (1 ml) at −78 ◦C. The pale yellow
solution was stirred for 15 min. 5,6-Dihydro-2H-pyran-2-one
(17 ll, 0.20 mmol) was added, and the solution stirred for at
−78 ◦C for 30 min. The reaction was quenched by addition
of acetic acid (24 ll, 0.4 mmol), diluted with ether (4 ml) and
allowed to warm to rt. After 30 min, the resulting suspension was
filtered through a short plug (1–2 cm) of silica gel, eluting with
4 1 0 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 0 9 5 – 4 1 0 7

View Article Online
(3R,5S,6S,1ꢀS,2ꢀR)-5,6-Dimethoxy-5,6-dimethyl-3-(2-nitro-1-
phenylpropyl)-[1,4]dioxan-2-one (major diastereomer) (9) and
(3R,5S,6S,1ꢀS,2ꢀS)-5,6-dimethoxy-5,6-dimethyl-3-(2-nitro-1-
phenylpropyl)-[1,4]dioxan-2-one (minor diastereomer)
(3S,5R,6R)-5,6-Dimethoxy-3,5,6-trimethyl-3-((R)-2-nitro-1-
phenylethyl)-[1,4]dioxan-2-one (12)
Potassium bis(trimethylsilyl)amide (0.5 M in toluene, 0.84 ml,
0.42 mmol) was added drop-wise to a stirred solution of (R,R)-
137 (77 mg, 0.38 mmol) in THF (0.75 ml) at −78 ◦C. After
stirring for 15 min, trans-2-nitrostyrene (57 mg, 0.38 mmol)
in THF (0.63 mmol) was added drop-wise via cannula. The
solution was stirred for a further 4 h at −78 ◦C then acetic
acid (50 ll, 0.84 mmol) was added and the solution warmed to
rt. The reaction mixture was filtered through a small plug of
silica gel, eluting with ether (20 ml) and the filtrate concentrated
in vacuo. The residue was purified by column chromatography
(ether–petrol 1 : 9 then 3 : 17) to give the nitroalkane as a white
prisms (64 mg, 57%): dH (400 MHz, CDCl3) 1.34 (3H, s, Me),
1.43 (3H, s, Me), 1.49 (3H, s, Me), 3.07 (3H, s, OMe), 3.24 (3H, s,
OMe), 4.16 (1H, dd, J 10.6, 4.8, PhCH), 4.85 (1H, dd, J 13.5,
10.6, O2NCHH), 4.97 (1H, dd, J 13.5, 4.8, O2NCHH), 7.24–
7.28 (5H, m, Ph); dC (100 MHz, CDCl3) (100 MHz, CDCl3)
17.5, 18.0, 24.7, 49.4, 49.5, 50.7, 75.5, 77.1, 99.0, 106.1, 127.86,
127.87, 130.4, 134.7, 170.8; mmax (film/cm−1) 2950, 1737, 1554,
1378; Found (ES): [MNa]+ 376.1385, C17H23NO7Na requires
Lithium bis(trimethylsilyl)amide (0.20 ml, 1 M solution in THF,
0.20 mmol) was added drop-wise to a solution of glycolate
1 (38 mg, 0.20 mmol) in THF (1 ml) at −78 ◦C. The pale
yellow solution was stirred for 15 min. 2-Nitro-1-phenylpropene
(36 mg, 0.22 mmol, solution in 0.5 ml THF) was added, and
the solution stirred for at −78 ◦C for 30 min. The reaction
was quenched by addition of acetic acid (30 ll, 0.5 mmol,
solution in 0.5 ml ether), diluted with ether (4 ml) and allowed
to warm to rt. After 30 min, the resulting suspension was
filtered through a short plug (1–2 cm) of silica gel, eluting with
ether, and the mixture concentrated in vacuo to give the crude
product. This was purified by column chromatography to give
the nitroalkanes as white solids (39 mg, 55% and 21 mg, 30%):
(major diastereomer) dH (400 MHz, CDCl3) 1.31 (3H, s, Me),
1.41 (3H, s, Me), 1.75 (3H, d, J 6.6, CHMe), 2.62 (3H, s, OMe),
3.34 (3H, s, OMe), 3.81 (1H, dd, J 11.2, 3.2, CHPh), 4.55 (1H,
d, J 3.2, CHCO), 5.29 (1H, dq, J 11.2, 6.6, CHMe), 7.21–7.23
(3H, m, Ph), 7.33–7.35 (2H, m, Ph); dC (100 MHz, CDCl3) 16.8,
17.7, 18.3, 48.9, 49.3, 50.6, 70.6, 84.8, 98.7, 105.0, 127.8, 127.9,
130.5, 133.9, 167.2; mmax (film/cm−1) 2942, 1737, 1552, 1495,
1456, 1382, 1353, 1328, 1296, 1256, 1199, 1178, 1152, 1119,
1081, 1049, 1035; found (EI): calcd for C17H23O7NNa [M +
Na]+ 376.1372, found: 376.1356; mp 153 ◦C; [a]2D5 +60.0 (c 0.15,
CHCl3); (minor diastereomer) dH (400 MHz, CDCl3) 1.31 (3H, s,
Me), 1.35 (3H, d, J 6.8, CHMe), 1.43 (3H, s, Me), 2.68 (3H, s,
OMe), 3.27 (3H, s, OMe), 3.83 (1H, dd J 11.4, 3.2, CHPh),
4.33 (1H, d, 3.2, CHCO), 5.32 (1H, dq J 11.4, 6.8, CHMe),
7.27–7.29 (3H, m, Ph), 7.34–7.36 (2H, m, Ph); dC (100 MHz,
CDCl3) 16.8, 17.7, 18.8, 48.9, 49.2, 50.9, 70.2, 83.4, 98.5, 105.1,
128.0, 128.2, 130.8, 133.8, 167.2; mmax (film/cm−1) 2947, 1740,
1547, 1499, 1457, 1391, 1380, 1356, 1329, 1296, 1263, 1215, 1179,
1147, 1119, 1078, 1029, found (EI): calcd for C17H23O7NNa [M +
◦
376.1372; mp 116–118 C; [a]2D5 −99.1 (c 0.32, CHCl3); anal.
calc. for C17H23NO7 C, 57.78; H, 6.56; N, 3.96; Found: C, 58.08;
H, 6.62; N, 3.84%.
(3S,5R,6R)-3-Benzyl-5,6-dimethoxy-5,6-dimethyl-3-((R)-2-
nitro-1-phenylethyl)-[1,4]dioxan-2-one (14)
Potassium bis(trimethylsilyl)amide (0.5 M in toluene, 0.42 ml,
0.21 mmol) was added drop-wise to a stirred solution of (R,R)-
139 (53 mg, 0.19 mmol) in THF (0.4 ml) at −78 ◦C. After stirring
for 15 min, trans-2-nitrostyrene (29 mg, 0.19 mmol) was added
in THF (0.6 ml) drop-wise via cannula. The solution was stirred
for a further 60 min at −78 ◦C then acetic acid (26 ll, 0.42 mmol)
was added and the solution warmed to rt. The reaction mixture
was filtered through a small plug of silica gel, eluting with ether
(20 ml) and the filtrate concentrated in vacuo. The residue was
purified by column chromatography (ether–petrol 1 : 9 then 3 :
17) to give the nitroalkane as a white prisms (20 mg, 25%):
dH (400 MHz, CDCl3) 1.44 (3H, s, Me), 1.48 (3H, s, Me),
3.01 (3H, s, OMe), 3.12 (1H, d, J 14.8, CHHPh), 3.22 (3H, s,
OMe), 3.28 (1H, d, J 14.8, CHHPh), 4.26 (1H, dd, J 11.7,
3.8, CHPh), 4.89 (1H, dd, J 13.3, 11.7. CHHNO2), 5.16 (1H,
dd, J 13.3, 3.8, CHHNO2), 7.10–7.15 (2H, m, Ph), 7.15–7.22
(3H, m, Ph), 7.22–7.29 (5H, m, Ph); dC (100 MHz, CDCl3) 17.6,
18.3, 42.0, 48.6, 49.4, 49.8, 75.9, 81.0, 99.4, 106.4, 127.1, 127.7,
127.8, 128.4, 130.6, 130.8, 134.1, 135.4, 168.9; mmax (film/cm−1)
2949, 1743, 1555, 1379; found (ES): [MNa]+ 452.1694,
◦
Na]+ 376.1372, found: 376.1364; mp 117–119 C; [a]2D5 +139.3
(c 0.41, CHCl3).
(3S,5R,6R,1ꢀR,2ꢀS)-5,6-Dimethoxy-5,6-dimethyl-3-
(2-nitrocyclohexyl)-[1,4]dioxan-2-one (10)
Lithium bis(trimethylsilyl)amide (0.20 ml, 1 M solution in THF,
0.20 mmol) was added drop-wise to a solution of glycolate
1 (38 mg, 0.20 mmol) in THF (1 ml) at −78 ◦C. The pale
yellow solution was stirred for 15 min. 1-Nitro-1-cyclohexene
(25 ll, 0.22 mmol, solution in 0.5 ml THF) was added, and
the solution stirred at −78 ◦C for 30 min. The reaction was
quenched by addition of acetic acid (30 ll, 0.5 mmol), diluted
by drop-wise addition of ether (3 ml), stirred for 10 min at
−78 ◦C and allowed to warm to rt. After 30 min, the resulting
suspension was filtered through a short plug (1–2 cm) of
silica gel, eluting with ether, and the mixture concentrated in
vacuo to give the crude product. This was purified by column
chromatography to give the nitroalkane as a white solid (62 mg,
98%): dH (400 MHz, CDCl3) 1.32 (3H, s, Me), 1.33–1.39
(1H, m, CHHCH2CHNO2), 1.44 (3H, s, Me), 1.50–1.61 (2H,
m, CHHCH2CH2CHNO2, CHHCHCHNO2), 1.74–1.82 (1H,
m, CHHCHNO2), 1.84–1.93 (2H, m, CHHCH2CH2CHNO2,
CHHCH2CHNO2), 2.00–2.13 (1H, m, CHHCHCHNO2), 2.31–
2.35, 1H, m, CHHCHNO2), 2.52–2.58 (1H, m, CHCHNO2),
3.27 (3H, s, OMe), 3.37 (3H, s, OMe), 4.33 (1H, d, J 3.6,
OCHC(O), 4.83 (1H, q, J 4.3, CHNO2); dC (100 MHz, CDCl3)
16.6, 17.6, 20.5, 22.4, 24.0, 29.5, 41.8, 49.3, 49.8, 71.9, 84.2,
98.0, 105.3, 168.7; mmax (film/cm−1) 2948, 1744, 1550, 1449,
1379, 1268, 1148, 1035; found (ESI): calcd for C14H23O7NNa
[M + Na]+ 340.1372, found: 340.1373; mp 131 ◦C; [a]2D5 −204.2
(c 0.24, CHCl3).
◦
C23H27NO7Na requires 452.1685; mp 162–163 C; [a]2D5 −90.8
(c 0.25, CHCl3).
General procedure for the preparation of 15–18
A solution of HCl in MeOH was prepared by adding trimethylsi-
lyl chloride (0.35 ml) to MeOH (5 ml) at 0 ◦C. This solution was
added to 1 mmol of adduct and the mixture allowed to stir at rt
for 1 h. The solution was concentrated in vacuo and the residue
purified by column chromatography.
Methyl (S,S)-hydroxy-(3-oxocyclopentyl)acetate (15). Clear
gum: dH (400 MHz, CDCl3) 1.77–1.95 (2H, m, CHHCH2C(O)),
2.12–2.19 (2H, m, CHCHHC(O), CHHC(O)), 2.29–2.41
(2H, m, CHCHHC(O), CHHC(O)), 2.59–2.66 (1H, m,
CHCH2C(O)), 2.85 (1H, d, J 5.0, OH), 3.83 (3H, s, OMe),
4.24 (1H, t, J 5.0, CHOH); dC (100 MHz, CDCl3) 23.2, 38.1,
40.0, 41.0, 52.8, 71.6, 174.5, 217.8; mmax (film/cm−1) 3442, 2958,
1728, 1439, 1403, 1211, 1158, 1105, 1076, 1015; found (ESI):
[MNa]+ 195.0641, C8H12O4Na requires 195.0633; [a]2D5 +59.0
(c 1.00, CHCl3).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 0 9 5 – 4 1 0 7
4 1 0 1

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Dimethyl (2S,3S)-2-hydroxy-3-(2-hydroxyphenyl)pentanedioate
(16). Clear gum: dH (400 MHz, CDCl3) 2.87 (1H, dd, J 16.8,
7.0, CHHCO2Me), 3.15 (1H, dd, J 16.8, 8.3, CHHCO2Me),
3.65 (3H, s, OMe), 3.69 (3H, s, OMe), 3.83 (1H, ddd, J 8.3, 7.0,
3.3, CHAr), 4.68 (1H, d, J 3.3, CHOH), 6.80 (1H, dt, J 7.5,
1.1, Ar), 6.86 (1H, dd, J 8.1, 1.1), 7.05 (1H, dd, J 7.5, 1.6, Ar),
7.13 (1H, dt, J 7.8, 1.6), 7.60 (1H, br s, OH); dC (100 MHz,
CDCl3) 34.6, 42.7, 51.9, 52.8, 73.5, 118.1, 120.5, 124.3, 129.3,
131.3, 154.9, 172.7, 173.3; mmax (film/cm−1) 3417, 2956, 1738,
1456, 1224, 1107; found (ESI): [MNa]+ 291.0847, C13H16O6Na
requires 291.0845; [a]2D5 +37.8 (c 0.55, CHCl3).
Methyl (2R,3S)-2-hydroxy-4-nitro-3-phenylbutyrate (17).
White solid: dH (400 MHz, CDCl3) 2.96 (1H, d, J 5.6, OH),
3.68 (3H, s, OMe), 3.97–4.02 (1H, m, CHPh), 4.55–4.58 (1H,
m, CHOH), 4.77 (1H, dd, J 13.4, 7.2, CHHNO2), 5.00 (1H, dd,
J 13.4, 8.1, CHHNO2), 7.22–7.31 (5H, m, Ph); dC (100 MHz,
CDCl3) 46.5, 52.8, 70.8, 76.2, 128.5, 128.5, 128.8, 134.1, 172.7;
mmax (film/cm−1) 3234, 2973, 1733, 1677, 1606, 1541, 1491, 1456,
1380, 1345, 1264, 1239, 1215, 1177, 1148, 1119, 1100, 1047,
1033; found (ES): [◦MNa]+ 262.0686, C11H13NO5Na requires
262.0691; mp 74–76 C; [a]2D5 −17.2 (c 0.72, CHCl3).
solution in MeOH, 0.03 mmol) was added and the solution
stirred for 30 min. The reaction was diluted with ether (2 ml) and
ammonium chloride solution (2 ml), extracted with ether (5 ml),
washed with brine (5 ml), dried (MgSO4) and concentrated in
vacuo. The residue was purified by column chromatography
(silica, petrol : EtOAc 1 : 1) to give O-C(Me)(OMe)C(O)Me
20 (40 mg, 76%). Triphenylphosphine hydrobromide (0.3 ml,
0.01 M solution in MeOH, 3 lmol) was added to a solution
of O-C(Me)(OMe)C(O)Me 20 (14 mg, 0.034 mmol) in MeOH
(2 ml) at rt. The solution was stirred overnight and concentrated
in vacuo, and the residue purified by column chromatography
(silica, petrol : ether 1 : 1 to 1 : 2) to give 20 as a clear gum
(10 mg, 95%; 69% over three steps): dH (400 MHz; CDCl3) 1.44
(9H, s, C(Me)3), 3.27–3.35 (2H, m, OH, CHPh), 3.41–3.46 (1H,
m, CHH), 3.62 (3H, s, OMe), 3.72–3.80 (1H, m, CHH), 4.55
(1H, dd, J 5.6, 3.1, CHOH), 4.74 (1H, br s, NH), 7.23–7.30 (5H,
m, Ph), dC (100 MHz; CDCl3) 28.4, 42.3, 48.9, 52.3, 71.3, 79.8,
127.6, 128.4, 128.8, 137.1, 156.5, 173.8; mmax (film)/cm−1 3360,
2977, 1738, 1712, 1518, 1454, 1393, 1367, 1251, 1169, 1118, 1014;
found (ESI) [MNa]+ 332.1462, C16H23NO5Na requires 332.1474;
[a]2D5 −18.2 (c 0.70, CHCl3).
Methyl (S,1ꢀR,2ꢀS)-hydroxy-(2-nitrocyclohexyl)-acetate (18).
White solid: dH (400 MHz, CDCl3) 1.28–1.41 (1H, m,
CHHCH2CH2CHNO2), 1.54–1.61 (1H, m, CHHCH2CHNO2),
1.64–1.85 (3H, m, CHHCHCHNO2, CHHCH2CHNO2,
CHHCHNO2), 1.88–1.93 (1H, m, CHHCH2CH2CHNO2),
1.96–2.06 (1H, m, CHHCHCHNO2), 2.15–2.21 (1H, m,
CHCHNO2), 2.32–2.42 (1H, m, CHHCHNO2), 2.75 (1H, d,
J 5.8, OH), 3.80 (3H, s, OMe), 4.35 (1H, t, J 5.7, CHOH),
4.74–4.79 (1H, m, CHNO2); dC (100 MHz, CDCl3) 20.7, 22.5,
24.3, 29.9, 43.6, 52.8, 71.8, 83.2, 174.0; mmax (film/cm−1) 3476,
2928, 1738, 1547, 1449, 1376, 1222, 1121; found (ESI):◦[MNa]+
240.0843, C9H15NO5Na requires 240.0848; mp 56–57 C; [a]D25
+30.0 (c 0.14, CHCl3).
(3S,5R,6R)-3-[(3R,4R)-3-((R)-Hydroxyphenylmethyl)-2-
oxotetrahydropyran-4-yl]-5,6-dimethoxy-5,6-dimethyl-
[1,4]dioxan-2-one (major diastereomer) (21) and (3S,5R,6R)-
3-[(3R,4R)-3-((S)-hydroxyphenylmethyl)-2-oxotetrahydropyran-
4-yl]-5,6-dimethoxy-5,6-dimethyl-[1,4]dioxan-2-one (minor
diastereomer)
Lithium bis(trimethylsilyl)amide (0.20 ml, 1 M solution in THF,
0.20 mmol) was added drop-wise to a solution of glycolate 2
(38 mg, 0.20 mmol) in THF (1.5 ml) at −78 ◦C. The pale yellow
solution was stirred for 15 min. 5,6-Dihydro-2H-pyran-2-one
(20 mg, 0.20 mmol) was added, and the solution stirred for 1 h
at −78 ◦C. Benzaldehyde (25 mg, 0.24 mmol) was added, and the
solution stirred for 30 min at −78 ◦C. The reaction was quenched
by addition of acetic acid (24 ll, 0.4 mmol), diluted with ether
(4 ml) and allowed to warm to rt. After 30 min, the resulting
suspension was filtered through a short plug (1–2 cm) of silica
gel, eluting with ether, and the mixture concentrated in vacuo to
give the crude product. Unreacted 5,6-dihydro-2H-pyran-2-one
and benzaldehyde was removed by heating the crude product
to 100 ◦C under a vacuum of approximately 1 mmHg, and the
residue purified by column chromatography (silica, ether) to give
the alcohol as a white solid (58 mg, 74%): (major diastereomer)
dH (400 MHz, CDCl3) 1.28 (3H, s, Me), 1.38 (3H, s, Me), 1.58–
1.65 (1H, m, CHHCHHO), 1.95–2.04 (1H, m, CHHCHHO),
2.91 (3H, s, OMe), 2.97 (1H, d, J 4.4, OH), 3.00–3.06 (1H,
m, CHCHC(O)O), 3.09 (1H, d, J 2.7, OCHC(O)O), 3.13–3.18
(1H, m, CHCHC(O)OCHH), 3.34 (3H, s, OMe), 4.20 (1H, dt,
J 10.5, 2.4, CHHOC(O)), 4.36–4.41 (1H, m, CHHOC(O)), 5.52
(1H, s, CHOH), 7.29 (1H, d, J 7.3, Ph), 7.36 (2H, t, J 7.3,
Ph), 7.47 (2H, d, J 7.5, Ph); dC (100 MHz, CDCl3) 16.8, 17.5,
24.1, 33.5, 48.3, 49.0, 49.8, 67.6, 71.3, 73.7, 98.1, 105.1, 125.8,
128.0, 128.8, 141.0, 168.3, 173.4; mmax (film/cm−1) 3423, 2951,
1726, 1453, 1384, 1276, 1215, 1151, 1133, 1086, 1053, 1035;
found (ESI): calcd for C20H26O8Na [M + Na]+ 417.1525, found:
(3R,4S)-3-((S)-1-Methoxy-1-methyl-2-oxopropoxy)-4-
phenylpyrrolidin-2-one (19)
Raney-nickel (0.30 g, 50% suspension in water) was rinsed with
MeOH (5 ml × 5) and EtOAc (5 ml × 2) and suspended in
EtOAc (5 ml). Glycolate 8 (50 mg, 0.18 mmol) was added to
this suspension and the reaction stirred under a balloon of
hydrogen for 16 h.21 The Raney-nickel was removed by filtration,
the solution concentrated in vacuo, and re-dissolved in CH2Cl2
(5 ml). Silica gel (200 mg) was added and the suspension stirred
at rt overnight. The suspension was filtered and concentrated
in vacuo, and the residue purified by column chromatography
(silica, EtOAc) to give the lactam as a clear oil (32 mg, 78%):
dH (400 MHz; CDCl3) 1.02 (3H, s, MeC), 2.22 (3H, s, MeC(O)),
3.22 (3H, s, OMe), 3.38 (1H, dd, J 9.6, 8.4, CHPh), 3.52 (1H,
q, J 8.3, CHHNH), 3.72 (1H, ddd, J 9.7, 8.3, 1.4, CHHNH),
4.52 (1H, d, J 8.4, CHO), 6.29 (1H, br s, NH), 7.27–7.30 (3H,
m, Ph), 7.35–7.38 (2H, m, Ph); dC (125 MHz; CDCl3) 21.5, 26.1,
29.7, 46.0, 49.6, 51.0, 75.3, 102.8, 127.8, 129.0, 139.3, 173.9,
205.9; mmax (film/cm−1) 3282, 2920, 1717, 1491, 1456, 1356, 1254,
1167, 1116, 1047; found (ESI) [MNa]+ 300.1205, C15H19NO4Na
requires 300.1212; [a]D25 (ent-19) −24.4 (c 0.14, CHCl3).
◦
417.1531; mp 189–191 C; [a]2D5 −89.3 (c 0.8, CHCl3); (minor
diastereomer) dH (400 MHz, CDCl3) 1.36 (3H, s, Me), 1.44 (3H, s,
Me), 1.68 (1H, dqn, J 7.3, 3.3, CHHCHHO), 1.94 (1H, dqn, J
7.3, 3.2, CHHCHHO), 2.74 (1H, dq, J 7.1, 2.8, CHCHC(O)O),
3.21 (3H, s, OMe), 3.22–3.25 (1H, m, CHCHC(O)OCHH), 3.36
(3H, s, OMe), 3.75 (1H, d, J 3.7, OH), 3.77 (1H, d, J 2.8,
OCHC(O)O), 3.89 (1H, ddd, J 10.9, 7.8, 3.3, CHHOC(O)),
4.35 (1H, ddd, J 10.9, 7.4, 3.2, CHHOC(O)), 5.18 (1H, dd, J
6.2, 3.7, CHOH), 7.29–7.39 (3H, m, Ph), 7.43–7.46 (2H, m, Ph);
dC (100 MHz, CDCl3) 16.9, 17.6, 24.5, 34.9, 47.5, 49.3, 49.9,
67.3, 71.7, 74.5, 98.3, 105.3, 126.6, 128.4, 128.7, 140.5, 168.5,
173.3; mmax (film/cm−1) 3526, 2950, 2837, 1734, 1459, 1405, 1382,
1328, 1268, 1223, 1172, 1152, 1125, 1100, 1085, 1067, 1050, 1038,
Methyl (2R,3S)-4-tert-butoxycarbonylamino-2-hydroxy-3-
phenylbutyrate (20)
Triethylamine (11 ll, 0.08 mmol), tert-butoxycarbonylanhydride
(35 mg, 0.16 mmol) and 4-dimethylaminopyridine (cat) were
added to a solution of lactam 19 (22 mg, 0.08 mmol) in CH2Cl2
(1 ml) at rt. The solution was stirred overnight, concentrated
in vacuo and the residue directly purified by column chro-
matography to give N-Boc 19 (29 mg, 95%). Sodium methoxide
(0.39 ml, 0.33 M solution in MeOH, 0.13 mmol) was added
to a solution of N-Boc 19 (49 mg, 0.13 mmol) in MeOH at
0 ◦C. After 1 h, additional sodium methoxide (0.08 ml, 0.33 M
4 1 0 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 0 9 5 – 4 1 0 7

View Article Online
1009; found (ESI): calcd for C20H26O8Na [M + Na]+ 417.1525,
found: 417.1505; mp 172–173 ◦C; [a]D25 −125.2 (c 0.5, CHCl3).
When B(OMe)3 was used as an additive, 1.3 equiv. was added
via syringe immediately before the aldehyde.
to rt. After 30 min, the resulting suspension was filtered through
a short plug (1–2 cm) of silica gel, eluting with ether, and the
mixture concentrated in vacuo to give the crude product which
was purified by column chromatography (silica, petrol : EtOAc
1 : 1) to give the alcohol as a white solid (69 mg, 73%): (major
diastereomer) dH (400 MHz, CDCl3) 1.25 (6H, s, 2 × Me), 2.45
(1H, br s, OH), 2.55 (3H, s, OMe), 3.08 (1H, dd, J 9.6, 1.0,
CHCHC(O)O), 3.21 (1H, d, J 3.1, CHCHC(O)O), 3.26 (3H, s,
OMe), 3.80 (3H, s, OMe), 4.15 (1H, d, J 3.1, OCHC(O)O),
4.50 (1H, d, J 9.6, CHOH), 6.84 (2H, d, J 8.7, Ar), 6.99–7.07
(3H, m, Ar), 7.10 (2H, d, J 8.7, Ar), 7.26–7.29 (1H, m, Ar); dC
(100 MHz, CDCl3) 16.1, 17.5, 40.5, 49.3, 49.4, 51.8, 55.3, 72.6,
74.8, 98.5, 105.4, 114.4, 116.5, 118.8, 124.1, 127.6, 129.2, 130.0,
132.0, 152.8, 160.0, 167.4, 167.8; mmax (film/cm−1) 3461, 2946,
2840, 1740, 1612, 1588, 1514, 1490, 1457, 1379, 1360, 1300, 1248,
1221, 1151, 1110, 1078, 1032; found (ESI): calcd for C25H28O9Na
[M + Na]+ 495.1631, found: 495.1609; mp 78–81 ◦C; [a]2D5 −131.9
(c 0.36, CHCl3).
(3S,5R,6R)-3-(3R,4R)-3-[(R)-Hydroxy-(4-methoxyphenyl)-
methyl]-2-oxotetrahydropyran-4-yl}-5,6-dimethoxy-5,6-
dimethyl-[1,4]dioxan-2-one (major diastereomer) (22) and
(3S,5R,6R)-3-(3R,4R)-3-[(S)-hydroxy-(4-methoxyphenyl)-
methyl]-2-oxotetrahydropyran-4-yl}-5,6-dimethoxy-5,6-
dimethyl-[1,4]dioxan-2-one (minor diastereomer)
Lithium bis(trimethylsilyl)amide (0.20 ml, 1 M solution in THF,
0.20 mmol) was added drop-wise to a solution of glycolate 2
(38 mg, 0.20 mmol) in THF (0.6 ml) at −78 ◦C. The pale yellow
solution was stirred for 20 min. 5,6-Dihydro-2H-pyran-2-one
(20 ll, 0.20 mmol, solution in 0.5 ml THF) was added, and
the solution stirred for 30 min at −78 ◦C. p-Anisaldehyde (26 ll,
0.22 mmol, solution in 0.5 ml THF) was added, and the solution
stirred for 30 min at −78 ◦C. The reaction was quenched by
addition of acetic acid (24 ll, 0.4 mmol), diluted with ether
(4 ml) and allowed to warm to rt. After 30 min, the resulting
suspension was filtered through a short plug (1–2 cm) of silica
gel, eluting with ether, and the mixture concentrated in vacuo
to give the crude product which was twice purified by column
chromatography (silica, petrol : EtOAc 2 : 1 eluting to 1 : 1; then
silica, ether : CH2Cl2 1 : 2) to give the alcohol as a white solid
(56 mg, 66%): (major diastereomer) dH (500 MHz, CDCl3) 1.29
(3H, s, Me), 1.39 (3H, s, Me), 1.56–1.66 (1H, m, CHHCH2O),
1.94–2.05 (1H, m, CHHCH2O), 2.93 (1H, d, J 5.1, OH), 2.94–
3.01 (1H, m, CHCHC(O)O), 2.97 (3H, s, OMe), 3.12 (1H, dd,
J 8.1, 3.3, CHCHC(O)O), 3.21 (1H, d, J 2.6, OCHC(O)O),
3.34 (3H, s, OMe), 3.78 (3H, s, OMe), 4.17 (1H, td, J 10.6, 2.6,
CH2CHHO), 4.36 (1H, ddd, J 10.6, 4.8, 3.7, CH2CHHO), 5.42
(1H, br t, J 3.7, CHOH), 6.87 (2H, d, J 8.8, Ar), 7.36 (2H, d,
J 8.8, Ar); dC (125 MHz, CDCl3) 16.8, 17.6, 24.0, 33.8, 48.3,
49.0, 49.8, 55.3, 67.6, 71.3, 73.5, 98.1, 105.1, 114.1, 127.0, 133.0,
159.3, 168.4, 173.5; mmax (film/cm−1) 3458, 2958, 1725, 1612,
1513, 1458, 1384, 1251, 1215, 1151, 1076, 1035; found (ESI):
calcd for C21H28O9Na [M + Na]+ 447.1631, found: 447.1613; mp
65–67 ◦C; [a]D25 −106.4 (c 0.1, CHCl3); (minor diastereomer) dH
(400 MHz, CDCl3) 1.36 (3H, s, Me), 1.45 (3H, s, Me), 1.63–1.71
(1H, m, CHHCH2O), 1.91–1.99 (1H, m, CHHCH2O), 2.94–
3.01 (1H, dq, J 7.3, 2.7, CHCHC(O)O), 3.19–3.22 (1H, m,
CHCHC(O)O), 3.22 (3H, s, OMe), 3.36 (3H, s, OMe), 3.80
(3H, s, OMe), 3.80–3.81 (1H, m, OCHC(O)O), 3.87–92 (1H, m,
CH2CHHO), 4.36 (1H, ddd, J 10.6, 7.2, 3.1, CH2CHHO), 5.15
(1H, d, J 6.4, CHOH), 6.90 (2H, d, J 8.6, Ar), 7.36 (2H, d, J
8.6, Ar); dC (100 MHz, CDCl3) 16.9, 17.6, 24.5, 35.0, 47.6, 49.3,
49.9, 55.3, 67.3, 71.9, 74.3, 98.3, 105.3, 114.1, 127.9, 132.4, 159.6,
168.6, 173.4; mmax (film/cm−1) 2958, 1726, 1513, 1383, 1253, 1150,
1036, found (ESI): calcd for C21H28O9Na [M + Na]+ 447.1631,
found: 447.1614; mp 45–48 ◦C; [a]D25 −146.7 (c 0.03, CHCl3).
When B(OMe)3 was used as an additive, 1.3 equiv. was added
via syringe immediately before the aldehyde.
When B(OMe)3 was used as an additive, 1.3 equiv. was added
via syringe immediately before the aldehyde.
(3R,5S,6S)-5,6-Dimethoxy-5,6-dimethyl-3-[(3R,4S)-3-((R)-2-
nitro-1-phenylethyl)-2-oxotetrahydropyran-4-yl]-[1,4]dioxan-2-
one (major diastereomer) (24) and (3R,5S,6S)-5,6-dimethoxy-
5,6-dimethyl-3-[(3ꢀR,4ꢀS)-3-((S)-2-nitro-1-phenylethyl)-2-
oxotetrahydropyran-4-yl]-[1,4]dioxan-2-one (minor
diastereomer)
Lithium bis(trimethylsilyl)amide (0.20 ml, 1 M solution in THF,
0.20 mmol) was added drop-wise to a solution of glycolate 2
(38 mg, 0.20 mmol) in THF (0.8 ml) at −78 ◦C. The pale yellow
solution was stirred for 20 min. 5,6-Dihydro-2H-pyran-2-one
(22 mg, 0.22 mmol, solution in 0.5 ml THF) was added, and the
solution stirred for 1 h at −78 ◦C. trans-2-Nitrostyrene (33 mg,
0.22 mmol, solution in 0.5 ml THF) was added, and the solution
stirred for 1.5 h at −78 ◦C. The reaction was quenched by
addition of acetic acid (24 ll, 0.4 mmol), diluted with ether (4 ml)
and allowed to warm to rt. After 30 min, the resulting suspension
was filtered through a short plug (1–2 cm) of silica gel, eluting
with ether, and the mixture concentrated in vacuo to give the
crude product which was purified by column chromatography
(silica, petrol : ether 1 : 2) to give the nitroalkanes as white
solids (56 mg, 64% and 14 mg, 16%): (major diastereomer) dH
(400 MHz, CDCl3) 1.34 (3H, s, Me), 1.44 (3H, s, Me), 1.72–1.80
(1H, m, CHHCH2O), 1.97–2.09 (1H, m, CHHCH2O), 2.64–2.70
(1H, m, CHCH2CH2), 3.11 (1H, dd, J 6.5, 5.6, CHC(O)O), 3.18
(3H, s, OMe), 3.35 (3H, s, OMe), 3.84–3.89 (2H, m, OCHC(O),
PhCH), 4.12 (1H, ddd, J 11.3, 8.5, 3.7, CH2CHHO), 4.42 (1H,
ddd, J 11.3, 6.5, 4.1, CH2CHHO), 4.89 (1H, dd, J 13.7, 8.5,
CHHNO2), 4.93 (1H, dd, J 13.7, 6.7, CHHNO2), 7.29–7.39
(5H, m, Ph); dC (100 MHz, CDCl3) 16.8, 17.6, 22.7, 37.7, 45.4,
45.4, 49.2, 49.9, 67.1, 71.6, 77.5, 98.5, 105.5, 128.1, 128.6, 129.4,
137.1, 168.0, 171.4; mmax (film/cm−1) 2950, 1730, 1553, 1456,
1380, 1326, 1266, 1212, 1151, 1115, 1080, 1050, 1035; found
(ESI): calcd for C21H27O9NNa [M + Na]+ 460.1584, found:
◦
460.1584; mp 157 C; [a]D25 +133.1 (c 0.48, CHCl3); (minor
diastereomer) dH (500 MHz, CDCl3) 1.41 (3H, s, Me), 1.42–
1.46 (1H, m, CHHCH2O), 1.51 (3H, s, Me), 1.99–2.07 (1H, m,
CHHCH2O), 2.60–2.64 (1H, m, CHCH2CH2), 3.21 (1H, dd, J
9.3, 3.1, CHC(O)O), 3.30–3.34 (1H, m, CH2CHHO), 3.38 (3H, s,
OMe), 3.41 (3H, s, OMe), 3.77–3.81 (1H, ddd, J 9.0, 5.6, 3.2,
PhCH), 4.13 (1H, dt, J 11.0, 3.5, CH2CHHO), 4.40 (1H, d, J 2.5,
OCHC(O)O), 4.81 (1H, dd, J 14.3, 5.6, CHHNO2), 5.54 (1H,
dd, J 14.3, 9.0, CHHNO2), 7.28–7.29 (2H, m, Ph), 7.35–7.40
(3H, m, Ph); dC (125 MHz, CDCl3) 16.7, 17.5, 23.0, 38.3, 43.5,
44.2, 49.3, 49.8, 67.4, 69.5, 77.4, 98.3, 105.3, 128.6, 128.8, 129.2,
135.1, 168.6, 170.9; mmax (film/cm−1) 2954, 1728, 1553, 1381,
1276, 1151, 1082, 1036; found (ESI): calcd for◦C21H27O9NNa
[M + Na]+ 460.1584, found: 460.1566; mp 206 C; [a]2D5 +34.0
(c 0.3, CHCl3).
(3R,4S)-4-((2S,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-
3-oxo-[1,4]dioxan-2-yl)-3-[(R)-hydroxy-(4-
methoxyphenyl)methyl]chroman-2-one (23)
Lithium bis(trimethylsilyl)amide (0.20 ml, 1 M solution in THF,
0.20 mmol) was added drop-wise to a solution of glycolate 2
(38 mg, 0.20 mmol) in THF (0.8 ml) at −78 ◦C. The pale yellow
solution was stirred for 20 min. Coumarin (30 mg, 0.20 mmol,
solution in 0.5 ml THF) was added, and the solution stirred for
◦
30 min at −78 C. p-Anisaldehyde (26 ll, 0.22 mmol, solution
in 0.5 ml THF) was added, and the solution stirred for 30 min at
◦
−78 C. The reaction was quenched by addition of acetic acid
(24 ll, 0.4 mmol), diluted with ether (4 ml) and allowed to warm
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 0 9 5 – 4 1 0 7
4 1 0 3

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(3R,4R)-4-((2R,5S,6S)-5,6-Dimethoxy-5,6-dimethyl-3-oxo-
[1,4]dioxan-2-yl)-3-((R)-2-nitro-1-phenylethyl)chroman-2-
one (25)
(3R,4R)-4-((2R,5S,6S)-5,6-Dimethoxy-5,6-dimethyl-3-oxo-
[1,4]dioxan-2-yl)-3-((R)-3-oxo-1,3-diphenylpropyl)chroman-2-
one (27)
Lithium bis(trimethylsilyl)amide (0.60 ml, 1 M solution in THF,
0.60 mmol) was added drop-wise to a solution of glycolate 2
(114 mg, 0.60 mmol) in THF (2.5 ml) at −78 ◦C. The pale yellow
solution was stirred for 15 min. Coumarin (88 mg, 0.60 mmol,
solution in 1 ml THF) was added, and the solution stirred for
1 h at −78 ◦C. trans-2-Nitrostyrene (89 mg, 0.60 mmol, solution
in 1 ml THF) was added, and the solution stirred for 2 h at
Lithium bis(trimethylsilyl)amide (0.20 ml, 1 M solution in THF,
0.20 mmol) was added drop-wise to a solution of glycolate 2
(38 mg, 0.20 mmol) in THF (0.8 ml) at −78 ◦C. The pale
yellow solution was stirred for 20 min. Coumarin (33 mg,
0.22 mmol, solution in 0.5 ml THF), and the solution stirred
for 20 min at −78 ◦C. Chalcone (45 mg, 0.22 mmol, solution
in 0.5 ml THF) was added, and the solution stirred for 30 min
at −78 ◦C. The reaction was quenched by addition of acetic
acid (30 ll, 0.5 mmol), stirred for 10 min at −78 ◦C, diluted
with ether (4 ml) and allowed to warm to rt. After 30 min, the
resulting suspension was filtered through a short plug (1–2 cm)
of silica gel, eluting with ether, and the mixture concentrated in
vacuo to give the crude product which was purified by column
chromatography (silica, petrol : ether : CH2Cl2 5 : 1 : 10) to give
the ketone as a white solid (103 mg, 95%): dH (400 MHz, CDCl3)
1.26 (6H, s, 2 × Me), 2.56 (3H, s, OMe), 3.07 (1H, d, J 11.5,
CHCHC(O)O), 3.19 (1H, d, J 3.3, CHCHC(O)O), 3.28 (3H, s,
OMe), 3.34–3.40 (1H, m, PhCH), 3.50 (1H, dd, J 17.6, 8.3,
PhC(O)CHH), 3.59 (1H, dd, J 17.6, 4.9, PhC(O)CHH), 4.13
(1H, d, J 3.3, OCHC(O)), 6.98 (1H, dd, J 7.5, 1.0, Ph), 7.05–
7.13 (4H, m, Ph), 7.21–7.39 (6H, m, Ph), 7.49 (1H, t, J 7.4, Ph),
7.82 (2H, d, J 7.3, Ph); dC (100 MHz, CDCl3) 16.2, 17.5, 39.7,
41.4, 43.0, 49.3, 49.3, 49.4, 74.8, 98.5, 105.2, 116.5, 118.7, 124.3,
127.7, 127.8, 127.9, 128.5, 129.1, 129.3, 130.5, 133.0, 136.8,
140.5, 152.8, 167.2, 169.3, 197.1; mmax (film/cm−1) 2948, 1764,
1729, 1689, 1591, 1495, 1448, 1429, 1377, 1294, 1267, 1224,
1165, 1148, 1110, 1074, 1046, 1032, 1013, 1001; found (ESI):
calcd for C32H32O8Na [M + Na]+ 567.1995, found: 567.1969;
mp 75–77 ◦C; [a]2D5 +146.2 (c 0.69, CHCl3).
◦
−78 C. The reaction was quenched by addition of acetic acid
(72 ll, 1.2 mmol), diluted with ether (12 ml) and allowed to
warm to rt. After 30 min, the resulting suspension was filtered
through a short plug (1–2 cm) of silica gel, eluting with ether,
and the mixture concentrated in vacuo to give the crude product
which was purified by column chromatography (silica, petrol :
ether : CH2Cl2 2 : 1 : 2) to give the nitroalkane as a white solid
(236 mg, 81%): dH (400 MHz, CDCl3) 1.26 (6H, s, 2 × Me),
2.55 (3H, s, OMe), 3.04 (1H, d, J 11.9, CHCHC(O)O), 3.15
(1H, d, J 3.2, CHCHC(O)O), 3.28 (3H, s, OMe), 3.31–3.39 (1H,
m, CHPh), 4.14 (1H, d, J 3.4, OCHC(O)O), 4.79–4.81 (2H,
m, 2 × CHHNO2), 6.95 (1H, dd, J 7.6, 1.3, Ar), 6.99–7.02
(2H, m, Ar), 7.10–7.15 (2H, m, Ar), 7.13–7.39 (4H, m, Ar); dC
(100 MHz, CDCl3) 16.1, 17.4, 41.1, 42.7, 46.8, 49.3, 49.5, 74.7,
77.2, 78.3, 98.6, 105.3, 116.6, 117.8, 124.8, 127.6, 129.1, 129.6,
130.5, 135.2, 152.4, 166.9, 167.9; mmax (film/cm−1) 2950, 1745,
1589, 1557, 1490, 1458, 1379, 1295, 1222, 1167, 1122, 1111, 1085,
1036; found (ESI): calcd for C25H27NO9Na [M + Na]+ 508.1884,
found: 508.1590; mp 82 ◦C; [a]D25 +85.3 (c 0.8, CHCl3).
(3S,4S)-4-((2S,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-3-oxo-
[1,4]dioxan-2-yl)-3-((1R,2R)-2-nitrocyclohexyl)-chroman-2-
one (26)
Methyl (R)-hydroxy[(3R,4R)-2-oxo-3-((R)-3-oxo-1,3-
diphenylpropyl)-chroman-4-yl]acetate (28)
Lithium bis(trimethylsilyl)amide (0.20 ml, 1 M solution in THF,
0.20 mmol) was added drop-wise to a solution of glycolate 2
(38 mg, 0.20 mmol) in THF (0.8 ml) at −78 ◦C. The pale yellow
solution was stirred for 20 min. Coumarin (33 mg, 0.22 mmol,
solution in 0.5 ml THF), and the solution stirred for 20 min at
−78 ◦C. Chalcone (45 mg, 0.22 mmol, solution in 0.5 ml THF)
was added, and the solution stirred for 30 min at −78 ◦C. A
solution of trimethylsilyl chloride (0.35 ml) in MeOH (5 ml)
was added at −78 ◦C and the reaction allowed to warm to
rt overnight. The resulting suspension was filtered through a
short plug (1–2 cm) of silica gel, eluting with ether, and the
mixture concentrated in vacuo to give the crude product which
was purified by column chromatography (silica, petrol : EtOAc
1 : 1) to give the alcohol as a white solid (65 mg, 74%): dH
(400 MHz, CDCl3) 2.84 (1H, d, J 5.8, OH), 2.95 (1H, d, J 2.5,
CHCHOH), 3.21 (1H, d, J 11.6, CHC(O)O), 3.31–3.40 (1H,
m, CHPh), 3.56 (2H, d, J 6.6, CHHC(O)), 3.69 (3H, s, OMe),
4.22 (1H, dd, J 5.6, 3.1), 6.78 (1H, d, J 6.7, Ar), 7.06–7.15
(4H, m, Ar), 7.22–7.40 (6H, m, Ar), 7.50 (1H, t, J 7.4), 7.81
(2H, d, J 7.3, Ar); dC (100 MHz, CDCl3) 39.8, 42.9, 43.6, 49.1,
52.6, 74.7, 117.1, 117.7, 124.6, 127.5, 127.9, 127.9, 128.0, 128.4,
128.9, 129.0, 129.8, 133.0, 136.7, 140.7, 152.2, 172.2, 197.2; mmax
(film/cm−1) 3508, 2953, 1754, 1732, 1678, 1590, 1492, 1461,
1438, 1414, 1362, 1222, 1175, 1109, 1024; found (ESI): calcd◦for
C27H24O6Na [M + Na]+ 467.1471, found: 467.1469; mp 83 C;
[a]2D5 +30.5 (c 1.4, CHCl3).
Lithium bis(trimethylsilyl)amide (0.20 ml, 1 M solution in THF,
0.20 mmol) was added drop-wise to a solution of glycolate 2
(38 mg, 0.20 mmol) in THF (0.8 ml) at −78 ◦C. The pale yellow
solution was stirred for 20 min. Coumarin (33 mg, 0.22 mmol,
solution in 0.5 ml THF), and the solution stirred for 20 min
at −78 ◦C. 1-Nitro-1-cyclohexene (25 ll, 0.22 mmol, solution
in 0.5 ml THF) was added, and the solution stirred for 3 h
at −78 ◦C. The reaction was quenched by addition of acetic
acid (30 ll, 0.5 mmol), stirred for 10 min at −78 ◦C, diluted
with ether (4 ml) and allowed to warm to rt. After 30 min, the
resulting suspension was filtered through a short plug (1–2 cm)
of silica gel, eluting with ether, and the mixture concentrated in
vacuo to give the crude product which was purified by column
chromatography (silica, petrol : CH2Cl2 1 : 2 to CH2Cl2 to
petrol : CH2Cl2 : ether 2 : 1) to give the nitroalkane as a white
solid (83 mg, 90%): dH (400 MHz, CDCl3) 1.24 (3H, s, Me),
1.28 (3H, s, Me), 1.35 (1H, tt, J 13.3, 3.2, CHHCH2CHNO2),
1.49–1.61 (3H, m, CHHCH2CHNO2, CHNO2CHCH, CHH-
CHNO2), 1.62–1.68 (1H, m, CHHCHCHNO2), 1.74–
1.79 (1H, m, CHHCH2CHCHNO2), 1.81–1.88 (1H,
m, CHHCH2CHCHNO2), 2.06 (1H, dq,
J 12.8, 4.2,
CHHCHCHNO2), 2.40–2.45 (1H, m, CHHCHNO2), 2.58
(3H, s, OMe), 3.09 (1H, dd, J 11.1, 1.1, CHCHC(O)O), 3.29
(3H, s, OMe), 3.79 (1H, d, J 2.5, CHCHC(O)O), 4.35 (1H, d,
J 3.0, OCHC(O)O), 4.67–4.69 (1H, m, CHNO2), 7.02 (1H, dd,
J 8.2, 1.0, Ar), 7.09 (td, J 7.5, 1.2, Ar), 7.18 (dd, J 7.6, 1.7),
7.28–7.32 (1H, m, Ph); dC (100 MHz, CDCl3) 16.1, 17.5, 19.9,
23.7, 24.9, 31.6, 38.1, 40.2, 45.5, 49.4, 49.6, 75.2, 82.9, 98.6,
105.5, 116.4, 118.2, 124.4, 129.3, 130.3, 152.7, 167.6, 167.7; mmax
(film/cm−1) 2942, 2866, 1766, 1745, 1548, 1490, 1459, 1380,
1303, 1223, 1194, 1156, 1122, 1111, 1095, 1079, 1036; found
(ESI): calcd for C23H29NO9Na [M + Na]+ 486.1740, found:
486.1728; mp 168–171 ◦C; [a]D25 −175.1 (c 0.4, CHCl3).
Methyl (2R,3R)-2-hydroxy-3-(2-hydroxyphenyl)-3-((3R,4R)-4-
phenylpyrrolidin-3-yl)propionate (29)
Raney-nickel (0.60 g, 50% suspension in water) was rinsed
with MeOH (5 ml
and suspended in a 1 : 1 mixture of EtOAc : MeOH
×
5) and EtOAc (5 ml
×
2)
(6 ml). Glycolate 25 (100 mg, 0.20 mmol) was added to this
4 1 0 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 0 9 5 – 4 1 0 7

View Article Online
suspension and the reaction stirred under a balloon of hydrogen
overnight. The Raney-nickel was removed by filtration, the
solution concentrated in vacuo, and the residue purified by
column chromatography (silica, EtOAc : MeOH 10 : 1) to
give a white solid (84 mg, 93%). A sample of this (38 mg)
was dissolved in 1 ml of a pre-mixed solution of trimethylsilyl
chloride (0.35 ml) in MeOH (5 ml). The solution was stirred at rt
for 1 h, concentrated in vacuo and the residue purified by column
chromatography (EtOAc : MeOH 10 : 1) to give the alcohol as a
clear gum (27 mg, 92%; 86% over 2 steps): dH (400 MHz, CDCl3)
3.18 (1H, dd, J 10.1, 4.4, CHC(O)N), 3.23–3.32 (1H, m, CHPh),
3.41 (1H, t, J 8.9, CHHNH), 3.51 (1H, t, J 8.9, CHHNH),
3.60 (3H, s, OMe), 3.72 (1H, t, J 4.4, CHCHOH), 4.88 (1H,
d, J 2.7, CHOH), 6.20 (1H, br s, OH/NH), 6.38 (1H, br s,
NH/OH), 6.89 (1H, t, J 7.6, Ar), 6.93 (1H, d, J 8.0, Ar), 7.16–
7.38 (7H, m, Ar); dC (100 MHz, CDCl3) 44.9, 48.7, 52.6, 54.2,
74.7, 77.2, 118.3, 121.1, 122.8, 127.7, 128.9, 129.0, 129.1, 131.8,
139.9, 154.9, 173.4, 179.0; mmax (film/cm−1) 3275, 1743, 1670,
1456, 1231, 1127; found (ESI): calcd for C20H21NO5Na [M +
Na]+ 378.1317, found: 378.1302; [a]D25 −35.0 (c 0.46, CHCl3).
the collecting of fractions commenced. After a further 3.5 litres
of this eluant, the polarity was increased (8 : 1 petrol : ether).
All mixed fractions were discarded. After evaporation and
distillation of the appropriate unmixed fractions, cryptone was
obtained as a colourless oil (5 g, ∼50% product recovery): bp
97 ◦C/11 mmHg (lit. 103–104 ◦C/15 mmHg); dH (400 MHz;
CDCl3) 0.96 (3H, d, J 6.3, CHMe), 0.97 (3H, d, J 6.3,
CHMe), 1.72–1.88 (2H, m, CHHCHCHMe2, CHMe2), 1.97–
2.04 (1H, m, CHHCHCHMe2), 2.26–2.38 (2H, m, CHCHMe2,
CHHC(O)), 2.51 (1H, dt, J 16.6, 4.2, CHHC(O)), 6.00 (1H,
dd, J 10.3, 2.5, C(O)CHCH), 6.89 (1H, d, J 10.3, C(O)CH); dC
(100 MHz; CDCl3) 19.5, 19.6, 25.3, 31.5, 37.4, 42.5, 129.7, 154.2,
200.0; found (ESI) [MH]+ 139.1116, C9H15O requires 139.1117.
HPLC conditions: Chirapak AD column, 95.5 : 0.5 hexane :
isopropanol, 1 ml min−1; 215 nm.
(1ꢀR,2ꢀR,3S,5R,6R)-3-(2-Isopropyl-5-oxocyclohexyl)-5,6-
dimethoxy-5,6-dimethyl-[1,4]dioxan-2-one (32)22
Procedure 1. Ethyl (trimethylsilyl)acetate (0.59 ml,
3.23 mmol) was added to a solution of TBAT (9 mg, 17
lmol) and glycolate 2 (308 mg, 1.61 mmol) in THF (0.9 ml)
at rt. After 3 h, 1H NMR analysis of the reaction mixture
showed trimethylsilyl ketene acetal 30 to have been formed
in approximately 50% conversion. The solution was cooled
to −78 ◦C and a second solution of cryptone (0.71 ml,
4.84 mmol) and TBAT (14 mg, 26 lmol) in THF (0.6 ml) was
added via cannula. The reaction was allowed to warm to rt
overnight, concentrated in vacuo and the residue purified by
column chromatography (silica, petrol : ether 20 : 1, with 1%
triethylamine) to give the ketone as a white solid (449 mg,
1.37 mmol, 85%) which was recrystallized (ether–petrol) to aid
characterization.
(5R,6R)-(5,6-Dimethoxy-5,6-dimethyl-[1,4]dioxin-2-
yloxy)trimethylsilane (30)
Procedure 1. n-Butyllithium (15.1 ml, 2.5 M solution in
hexanes, 0.038 mol) was added drop-wise to a solution of
diisopropylamine (5.3 ml, 0.038 mol) in THF (20 ml) at 0 ◦C. The
solution was stirred for 30 min, cooled to −78 ◦C, and then
a solution of glycolate 2 (7.19 g, 0.038 mol) in THF (20 ml)
was added drop-wise, via cannula. The solution was stirred for
◦
3 h at −78 C, then trimethylsilyl chloride (4.8 ml, 0.038 mol)
was added drop-wise and the solution allowed to warm to rt
overnight. The mixture was concentrated in vacuo to give an
orange residue which was distilled directly to afford the ketene
acetal as a colourless oil (7.53 g, 76%), bp 62 ◦C/0.05 mmHg.
Procedure 2. Ketene acetal 30 (0.28 ml, 1.00 mmol) was
added drop-wise to a solution of cryptone (0.15 ml, 1.00 mmol)
and TBAT (6 mg, 11 lmol) in THF (1 ml) at −78 ◦C. The
reaction was allowed to warm to rt overnight. A solution of
TBAF (1 ml, 1 M solution in THF, 1.0 mmol) and acetic acid
(57 ll, 1.0 mmol) were added and the mixture stirred at rt for 4 h.
The reaction was quenched with sodium bicarbonate solution
(5 ml), extracted with ether (3 × 10 ml), washed with brine
(10 ml), dried (magnesium sulfate) and concentrated in vacuo.
The residue was purified by column chromatography (silica,
9 : 1 to 2 : 1 petrol : ether) to give the ketone as a white solid
(208.9 mg, 64%): dH (400 MHz; CDCl3) 0.84 (3H, d, J 6.6,
CHMe), 0.99 (3H, d, J 6.5, CHMe), 1.35 (3H, s, Me), 1.44–1.51
(1H, m, CHHCH2C(O)), 1.47 (3H, s, Me), 1.96–2.04 (3H, m,
CHHCH2C(O), CHCHMe2, CHMe2), 2.21 (1H, dd, J 14.7, 8.6,
CHCHHC(O)), 2.30 (1H, dt, J 16.0, 5.4, CH2CHHC(O)), 2.34–
2.38 (1H, m, CH2CHHC(O)), 2.46–2.48 (1H, m, CHCH2C(O)),
2.63 (1H, dd, J 14.7, 5.3, CHCHHC(O)), 3.27 (3H, s, OMe),
3.40 (3H, s, OMe), 4.18 (1H, d, J 2.6, OCHC(O)); dC (100 MHz;
CDCl3) 16.1, 16.7, 17.7, 21.4, 22.6, 28.4, 39.6, 40.6, 41.4, 42.5,
49.1, 49.7, 72.2, 98.3, 105.3, 168.3, 211.6; mmax (film)/cm−1 2956,
174◦6, 1715, 1460, 1380, 1247, 1204, 1146, 1118, 1092, 1034; mp
95 C; found (ESI) [MNa]+ 351.17780, C17H28O6Na requires
351.1784; [a]2D5 −48.9 (c 0.4, CHCl3).
Procedure 218. Lithium diisopropylamide (8.9 ml, 1.3 M
solution in THF–heptane–ethylbenzene, 0.012 mol) was added
to a solution of glycolate 2 (2.01 g, 0.011 mol) in THF (21 ml) at
−78 ◦C. After 30 min, trimethylsilyl chloride (1.5 ml, 0.011 mol)
was added and the mixture was allowed to warm to rt overnight.
The mixture was concentrated in vacuo to afford a orange
residue which was rapidly filtered through a small pad of Celite
(8 mm deep; 21 mm diameter), eluting with dry hexane (15 ml).
The hexane was removed by evaporation to afford the ketene
acetal as a brown oil (2.91 g, 100%): dH (400 MHz; C6D6) 0.32
(9H, s, SiMe3), 1.48 (3H, s, Me), 1.51 (3H, s, Me), 3.24 (3H, s,
=
OMe), 3.30 (3H, s, OMe), 5.82 (1H, s, C CH); dC (100 MHz;
C6D6) −0.01, 17.1, 17.7, 48.4, 48.9, 96.9, 100.4, 105.3, 144.0; dH
(400 MHz; CDCl3) 0.19 (9H, s, SiMe3), 1.35 (3H, s, Me), 1.48
(3H, s, Me), 3.20 (3H, s, OMe), 3.34 (3H, s, OMe), 5.48 (1H, s,
=
C CH); dC (100 MHz; CDCl3) −0.3, 16.8, 17.3, 48.3, 49.2, 96.3,
100.2, 104.3, 143.5; [a]2D5 −193.5 (c 7.3, PhMe).
Cryptone; 4-isopropylcyclohexen-2-one (34)12
Methyl vinyl ketone (10.9 g, 13.0 ml, 0.16 mol) was added to 1-(3-
methylbut-1-enyl)-piperidine (23.8 g, 0.16 mol) and the solution
stirred at rt. After 24 h, hydrochloric acid (106 ml, 32% solution
in 120 ml water) was added and the mixture stirred at rt for a
(1ꢀS,1ꢀꢀR,2ꢀR,3S,5R,6R,6ꢀR)-3-[2-(1-Hydroxypropyl)-6-
isopropyl-3-oxocyclohexyl]-5,6-dimethoxy-5,6-dimethyl-
[1,4]dioxan-3-one (36)
◦
further 36 h, after which it was refluxed at 105 C for 30 min,
allowed to cool to rt, and extracted into ether (250 ml). The
organic layer was washed with 1.5 M hydrochloric acid (120 ml),
water (250 ml) and brine (250 ml); dried (magnesium sulfate),
and distilled to afford a 2.5 : 1 mixture by 1H NMR of cryptone
and 4-isopropylcyclohexen-3-one as a yellow oil (10.9 g, 50%).
This was purified by column chromatography: a large column
(9.5 cm diameter) was packed with a pad of silica (12.0 cm
deep) and loaded with the cryptone–4-isopropylcyclohexen-
3-one mixture (15 g), prepared above. Four litres of eluant
(10 : 1 petrol : ether) were passed through the column before
Procedure 1. Ketene acetal 30 (0.28 ml, 1.00 mmol) was
added drop-wise to a solution of cryptone (0.36 ml, 2.50 mmol)
and TBAT (6 mg, 11 lmol) in THF (1 ml) at −78 ◦C. The
reaction was allowed to warm to rt overnight and the solution
divided into two equal portions, one of which was used for the
preparation of 36: the solvents were removed in vacuo and the
residue re-dissolved in CH2Cl2 (0.5 ml). The solution was cooled
to −78 ◦C and propionaldehyde (54 ll, 0.75 mmol) followed by
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 0 9 5 – 4 1 0 7
4 1 0 5

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BF3·Et2O complex (58 ll, 0.5 mmol) added drop-wise. The reac-
tion was stirred for 2 h and quenched by the drop-wise addition
of NaHCO3 (1 ml), extracted with CH2Cl2 (3 × 10 ml), dried
(MgSO4) and concentrated in vacuo. The residue was purified by
column chromatography (silica, 1 : 1 petrol : ether) to give the
alcohol as a white solid (67.7 mg, 35%) which was recrystallized
(CH2Cl2–petrol) for the purposes of characterization.
283221 (10), 283222 (32), 283223 (5), 283224 (38), 283225 (6).
For crystallographic data in CIF or other electronic format see
DOI: 10.1039/b512410g.
Acknowledgements
RTG thanks Dr Richard M. Turner for assistance with the
HPLC. The EPSRC, Novartis, Pfizer Global Research and
Development and the EU (Marie Curie fellowship to FR) are
thanked for financial support, and Drs John Davies and Andrew
Bond for the X-ray structures.
Procedure 2. A solution of a-bromoketone 38 (121.6 mg,
0.299 mmol) and propionaldehyde (22 ll, 0.23 mmol) in toluene
(0.5 ml) was added via cannula to a solution of triphenyltin
hydride (104.8 mg, 0.299 mmol) and triethylborane (0.33 ml,
1 M solution in hexanes, 0.33 mmol) in toluene (0.5 ml) at rt.
The reaction was stirred for 2 h, diluted with ether (100 ml),
washed with a solution of potassium fluoride23,24 (1.6 g in 9.4 ml
water) and filtered through Celite (eluting with ether), dried
(MgSO4) and concentrated in vacuo. The residue was purified
by column chromatography (Biotage, 1 : 1 petrol : ether) to give
the alcohol as a white solid (72.5 mg, 63%): dH (500 MHz; C6D6)
0.88 (3H, d, J 6.7, CHMe), 1.06 (3H, t, J 7.4, CH2Me), 1.09
(3H, d, J 6.7, CHMe), 1.21 (3H, s, Me), 1.29 (3H, s, Me), 1.56–
1.63 (1H, m, CHHCH2C(O)), 1.71–1.86 (3H, m, 2 × CHHMe,
CHMe2), 1.92–1.95 (1H, m, CHCHMe2), 2.00–2.03 (1H, m,
CHHCH2C(O)), 2.11–2.18 (1H, m, CHHC(O)), 2.31–2.38 (1H,
m, CHHC(O)), 2.71–2.73 (1H, m, OH), 2.79 (1H, dd, J 7.4, 3.6,
CHC(O)), 2.93 (3H, s, OMe), 3.08–3.10 (1H, m, CHCHC(O)),
3.15 (3H, s, OMe), 3.82 (1H, br s, CHOH), 4.53 (1H, d, J 2.6,
OCHC(O)); dC (125 MHz; C6D6) 11.0, 16.8, 17.8, 18.5, 21.8,
21.9, 29.0, 29.1, 38.4, 41.3, 42.8, 48.6, 49.4, 53.7, 73.2, 73.4,
98.5, 104.8, 167.9, 214.1; mmax (neat)/cm−1 3485, 2958, 1748, 1703,
1463, 1380, 1251, 1214, 1150, 1122, 1036, mp 111 ◦C; found (ESI)
[MNa]+ 409.2211, C20H34O7Na requires 409.2197; [a]2D5 −76.7 (c
0.1, CHCl3).
References and notes
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(1ꢀS,2ꢀS,3S,5R,6R,6ꢀR)-3-(2-Bromo-6-isopropyl-3-
oxocyclohexyl)-5,6-dimethoxy-5,6-dimethyl-[1,4]dioxan-2-
one (38)
7 D.-P. Jang, J.-W. Chang and B.-J. Uang, Org. Lett., 2001, 3, 983;
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A solution of ketene acetal 30 (2.01 g, 7.68 mmol) in THF
(3 ml) was added drop-wise to a solution of cryptone (2.7 ml,
19.19 mmol) and TBAT (34 mg, 63 lmol) in THF (9 ml) at
−78 ◦C. The reaction was allowed to warm to rt overnight,
and re-cooled to 0 ◦C. NBS (1.09 g, 6.14 mmol) was added
and the reaction allowed to warm to rt and stirred for 4 h. The
reaction was diluted with ether (40 ml), washed with sodium
bicarbonate solution (3 × 20 ml), water (20 ml), and brine
(20 ml); dried (MgSO4), and concentrated in vacuo. By using
1,2,3-trimethoxybenzene (328 mg, 1.92 mmol, 0.25 equiv) as an
internal standard, a yield of 41% for 38 was calculated using
1H NMR. The residue was purified by column chromatography
and recrystallization (ether–petrol); the typical recovery of 38
was 15%: dH (400 MHz; CDCl3) 0.83 (3H, d, J 6.8, CHMe),
0.98 (3H, d, J 6.7, CHMe), 1.39 (3H, s, Me), 1.50 (3H, s, Me),
1.72–1.84 (2H, m, CHMe2, CHHCH2C(O)), 1.97–2.06 (2H, m,
CHCHMe2, CHHCH2C(O)), 2.34–2.43 (1H, m, CHHC(O)),
2.70 (1H, dt, J 16.0, 8.8, CHHC(O)), 2.91 (1H, dt, J 8.0, 1.8,
CHCHBr), 3.33 (3H, s, OMe), 3.43 (3H, s, OMe), 4.66 (1H,
d, J 1.9, OCHC(O)), 4.69 (1H, d, J 8.2, CHBr); dC (100 MHz;
CDCl3) 16.6, 16.8, 17.8, 21.8, 22.0, 28.8, 37.9, 41.4, 49.2, 49.7,
49.8, 56.8, 72.1, 98.5, 105.7, 167.9, 201.9; mmax (neat)/cm−1 2961,
1740, 1717, 1463, 1386, 1269, 1203, 1148, 1115, 1091, 1033; mp
153 ◦C; found (ESI) [MNa]+ 429.0890, C17H27O6BrNa requires
429.0889; found C 49.95%, H 6.59%, C17H27O6Br requires C
50.13%, H 6.68%; [a]2D5 −121.7 (c 0.2, CHCl3).
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X-Ray structures
CCDC reference numbers 171362 (21), 171363 [epi-24 (minor
diastereomer; epimeric at CHPh carbon)], 171364 (24), 171365
(27), 171366 (22), 171367 (26), 171368 [epi-22 (minor diastere-
omer; epimeric at CHOH carbon)], 283219 (36), 283220 (8),
4 1 0 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 0 9 5 – 4 1 0 7

View Article Online
Bull., 1994, 42, 690; K. Aoki and K. Koga, Tetrahedron Lett., 1997,
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1041; K. Nozaki, K. Oshima and K. Utimoto, Bull. Chem. Soc. Jpn.,
1991, 64, 403.
21 The amount of time required by the reaction was found to vary with
the batch of Ra-Ni, and for a particularly active batch, reduction of
the ketone functionality of 19 to give the corresponding secondary
alcohol was observed: dH (400 MHz; CDCl3) 1.14 (3H, s, Me), 1.17
(3H, d, J 6.5, CHMe), 2.65 (3H, s, OMe), 3.38 (1H, q, J 9.5,
NHCHH), 3.45 (1H, q, J 8.6, CHPh), 3.68 (1H, dt, J 9.5, 1.1,
NHCHH), 3.82 (1H, qn, J 6.5, CHMe), 4.81 (1H, d, J 5.4, OH),
4.92 (1H, d, J 8.6, NC(O)CHO), 6.61 (1H, br s, NH), 7.27–7.37 (5H,
m, Ph); dC (100 MHz; CDCl3) 17.7, 20.3, 46.3, 49.3, 50.6, 71.9, 74.9,
103.8, 127.7, 128.1, 128.9, 139.8, 177.2. The reduction proceeded with
high diastereoselectivity, but the stereochemistry at the newly-formed
alcohol stereocentre was not determined.
14 T. V. Rajanbabu, J. Org. Chem., 1984, 49, 2083.
15 E. Nakamura, T. Murofushi, M. Shimizu and I. Kuwajima, J. Am.
Chem. Soc., 1976, 98, 2346.
16 A. S. Pilcher and P. DeShong, J. Org. Chem., 1996, 61, 6901; A. S.
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5166; C. J. Handy, Y. F. Lam and P. DeShong, J. Org. Chem., 2000,
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17 R. Noyori, K. Yokoyama, J. Sakata, I. Kuwajima, E. Nakamura and
M. Shimizu, J. Am. Chem. Soc., 1977, 99, 1265; C. Chuit, R. J. P.
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18 During the course of this work, another group independently
published their own synthesis of racemic 30 and used it in
some palladium-catalyzed arylation methodology: X. Liu and J. F.
Hartwig, J. Am. Chem. Soc., 2004, 126, 5182.
22 Some difficulties were encountered in the reproduction of these
reactions. For best results, it is essential that the TBAT is freshly
recrystallized (from EtOAc) before use.
23 D. Milstein and J. K. Stille, J. Org. Chem., 1979, 44, 1613.
24 J. E. Leibner and J. Jacobus, J. Org. Chem., 1979, 44, 449.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 0 9 5 – 4 1 0 7
4 1 0 7