Stereoselective synthesis of the α-glucosidase inhibitor nectrisine

Article abstract of DOI:10.1016/j.tetlet.2003.08.030

The α-glucosidase inhibitor nectrisine was synthesised in 12 steps (31% overall yield) starting from D-serine. The three contiguous stereocentres of this iminosugar were introduced via a highly diastereoselective boron mediated glycolate aldol reaction.

Full text of DOI:10.1016/j.tetlet.2003.08.030

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7649–7653
Stereoselective synthesis of the a-glucosidase inhibitor nectrisine
Alison N. Hulme* and Charles H. Montgomery
School of Chemistry, The University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, UK
Received 19 June 2003; revised 30 July 2003; accepted 8 August 2003
Abstract—The a-glucosidase inhibitor nectrisine was synthesised in 12 steps (31% overall yield) starting from
D-serine. The three
contiguous stereocentres of this iminosugar were introduced via a highly diastereoselective boron mediated glycolate aldol
reaction.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
demonstrate the utility of aldehyde 3 by disclosing our
synthesis of the related iminosugar nectrisine 2.
Oligosaccharides have been shown to play important
roles in a large number of biological recognition events
that range from cell–cell communication, fertilization,
and cell differentiation, to pathological processes
including cancer metastasis, and inflammation.1 Imino-
analogues of sugars (also known as azasugars) are
known to behave as glycosidase2 or glycosyltransferase3
inhibitors by acting as transition state mimics, where
the flattened pyrrolidine ring and protonated nitrogen
mimic the distorted structure of the glycosyl cation
intermediate.4 Hence, this class of sugar mimetics offers
therapeutic potential in areas such as inflammatory
diseases, lysosomal storage disorders, and cancer.5 Two
such iminosugars are the pyrrolidine 1,4-dideoxyimino-
2. Results and discussion
A number of serine derived aldehydes can be found in
the literature.11 Unfortunately, many of these demon-
strate a propensity to undergo racemisation and/or
exhibit poor diastereoselectivity under nucleophilic
addition.12 However, the addition of nucleophiles to
N,N-dibenzyl protected amino aldehydes has been
shown to take place with high diastereoselectivity under
both chelation and non-chelation controlled conditions
making aldehyde 3 an attractive building block.13 The
key step in our synthetic strategy was the construction
of the diol motif in 4 which we envisaged could be
achieved via either dihydroxylation of a g-amino-a,b-
unsaturated ester, or a boron-mediated asymmetric
aldol condensation. Protecting group ‘tuning’ of the
dihydroxylation reaction of g-amino-a,b-unsaturated
ester derivatives has been reported for a range of less
complex amino acid derivatives,14 and the dihydroxyla-
tion reaction of a number of carbamate and oxazoline
protected serine derivatives has also been reported.15
D
-arabinitol (DAB-1) 16 and the polyhydroxylated
dihydropyrrole nectrisine (FR 900483) 27 (Fig. 1).
These compounds are extremely potent a-glucosidase
inhibitors [IC50 1.8×10−7 and 4.8×10−8 M, respectively
(yeast a-glucosidase)],8 and the synthesis of nectrisine 2
and related unsaturated analogues has attracted the
attention of a number of groups.9 We recently reported
an extremely efficient synthesis of DAB-1 (1) from
serine-derived aldehyde 3.10 In this paper, we further
Figure 1. Retrosynthetic analysis of the polyhydroxylated plant alkaloids DAB-1 (1) and nectrisine 2.
Keywords: iminosugars; glycolate aldol; glycosidase inhibitors.
* Corresponding author. Tel.: +44-(0)131-650-4711; fax: +44-(0)131-650-4743; e-mail: alison.hulme@ed.ac.uk
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.030

7650
A. N. Hulme, C. H. Montgomery / Tetrahedron Letters 44 (2003) 7649–7653
The dihydroxylation reaction of g-amino-a,b-unsatu-
rated ester derivatives has recently been used in the
synthesis of several natural product targets including
deoxyaminohexoses,16a polyhydroxylated indolizidine
plant alkaloids,16b,c and a,b-dihydroxy-g-aminoacids16d
including hydroxystatine isosteres,16e and the AI-77’s.16f
On the other hand, the glycolate aldol reaction has
recently been shown to represent a viable alternative to
the dihydroxylation reaction, offering both syn and anti
diastereocontrol.17
by use of AD-mix-b, but again the reaction rate was
very slow (7 days) and the diastereoselectivity modest
(32:68, 6:7). Separation of the desired syn diastereomer
7, conversion to the corresponding Weinreb amide and
removal of the N-benzyl protecting groups using Pearl-
man’s catalyst resulted in conversion in situ to the
previously reported lactam 8.10 In an attempt to
improve the alkene reactivity towards dihydroxylation,
ester 5 was reduced to alcohol 9. This allylic alcohol
was found to undergo dihydroxylation more readily
than its ester counterpart (75% yield, 60 h), but simi-
larly disappointing levels of diastereoselectivity (ꢀ3:1)
were observed, deterring further investigation of this
route.
The synthesis of aldehyde 3 was achieved in five steps
from
D
-serine with 88% overall yield and >98% ee,
using our previously reported procedure.10,18 This alde-
hyde was found to be stable to racemisation on storage
at 4°C for up to 48 h. Aldehyde 3 was converted to the
a,b-unsaturated ester 5 in excellent yield (95%) under
Horner–Wadsworth–Emmons conditions using the mild
base Ba(OH)2 (Scheme 1).19 Osmium tetroxide
catalysed dihydroxylation resulted in a moderate yield
(59%) of diols 6 and 7 in a 65:35 diastereomeric ratio,
favouring the undesired all-syn diol 6.20,21 The use of
AD-mix-a resulted in a very sluggish reaction and only
a modest improvement in yield (65% based on unrecov-
ered starting material) and no apparent increase in
diastereoselectivity. However, the diastereoselectivity
could be overturned in favour of the desired syn diol 7
We have previously shown that reaction of aldehyde 3
with Evan’s chiral glycolate equivalent 1022 affords the
desired syn aldol adduct (Felkin–Anh product) 11 in
excellent yield as a single diastereomer (Scheme 2).10
Aldol adduct 11 may be converted to pyrrolidinone 8
via Weinreb amide 12 in 71% over the two steps.10 This
combination of Evans oxazolidinone and a-chiral alde-
hyde was shown to represent a ‘matched’ stereo-induc-
tive pairing,23 by the stereochemical outcome of the
reaction of methyl benzyloxyacetic acid 1324 with alde-
hyde 3 which also provided a single diastereomeric
aldol adduct 1425 in good yield (75%). The identity of
Scheme 1. Reagents and conditions: (a) (MeO)2POCH2CO2Me, Ba(OH)2 (activated), THF:H2O (40:1), rt, 1 h; 3, THF, rt, 18 h
(95%); (b) OsO4 (18 mol%), NMO, acetone:H2O (8:1), rt, 5 h (59%, 65:35 ratio 6:7); (c) AD-mix-a, MeSO2NH2, acetone:H2O
(3:1), rt, 7 d (65%, 66:34 ratio 6:7); (d) AD-mix-b, MeSO2NH2, acetone:H2O (3:1), rt, 7 d (68%, 32:68 ratio 6:7); (e) LiAlH4, Et2O,
−78°C, 45 min (85%).
Scheme 2. Reagents and conditions: (a) i. Et3N, n-Bu2BOTf, CH2Cl2, −78°C to 0°C, 3 h; ii. 3, −78°C to 0°C, 2.5 h (82% for 11,
i
87% for 17); (b) (MeO)NHMe·HCl, Me3Al, THF, −30°C; 11 or 17, 0°C, 2.5 h (100% for 12, 90% for 18); (c) i. Pr2NEt,
n-Bu2BOTf, Et2O, −78°C, 1.5 h; ii. 3, −78°C to 0°C, 2 h (75%); (d) (MeO)NHMe·HCl, Me3Al, THF, −30°C; 14, −30°C to rt, 18
h (91%); (e) Pd(OH)2, H2, MeOH, rt, 72 h (71% for 8, 65% for 15).

A. N. Hulme, C. H. Montgomery / Tetrahedron Letters 44 (2003) 7649–7653
7651
14 was confirmed by its one-step conversion to the
previously reported Weinreb amide 12. The same reac-
tion sequence has also allowed the synthesis of the
methyl pyrrolidinone analogue (R=Me, 15)26 via reac-
tion of acylated Evans auxiliary 16 to give a single
diastereomer of aldol adduct 17, conversion of this
adduct to Weinreb amide 18 and subsequent deprotec-
tion and cyclisation (51% for three steps from 16 to 15).
and AlMe3. All-syn amide 21 was converted to the
diastereomeric pyrrolidinone 22 in good yield (69%).
This material was found to be identical to that gener-
ated by the two-step conversion of all-syn diol 6 to 22.28
A number of different routes to the synthesis of nec-
trisine 2 from either the Weinreb amide 12, or pyrrolidi-
none 8, were pursued, but we found that partial
reduction of the pyrrolidinone followed by dehydration
proved the most fruitful (Scheme 4). Direct reduction of
8 with DIBAL-H or Super Hydride® gave no reaction.
We therefore surmised that introduction of an electron
withdrawing protecting group on the nitrogen atom, as
has been used in the reduction of other lactams,9c,29
might improve the yield of the desired pyrrolidinol.
Initial attempts to effect a global Boc protection
resulted only in the isolation of a compound which was
tentatively assigned as dihydropyrrol-2-one 23. Thus
prior protection of the diol was required, followed by
N-Boc activation to give 24.30 As predicted, the
increased carbonyl electrophilicity resulting from N-
Boc protection facilitated the smooth reduction of the
lactam with Super Hydride® even at −78°C to give 25.
This strategy was similarly successful for the synthesis
Aldol addition of the enolate of the enantiomeric glyco-
late equivalent (ent-10) to aldehyde 3 resulted in the
formation of a separable 9:1 diastereomeric mixture of
syn aldol adducts 19 and 20 (Scheme 3).27 Thus whilst
the Felkin–Anh selectivity of aldehyde 3 is sufficiently
high to provide a single diastereomeric adduct in the
‘matched’ case, or in the absence of a chiral auxiliary,
the directing power of aldehyde 3 can easily be over-
come under ‘mis-matched’ conditions. This would allow
the generation of a range of aldol stereoisomers with
high diastereoselectivities, simply by judicious choice of
chiral auxiliary and chirality of aldehyde 3 (derivable
from
L
- or
D
-serine). Aldol adducts 19 and 20 were
converted to Weinreb amides 21 and 12, respectively,
on treatment with N,O-dimethylhydroxylamine·HCl
Scheme 3. Reagents and conditions: (a) i. Et3N, n-Bu2BOTf, CH2Cl2, −78°C to 0°C, 3 h; ii. 3, −78°C to 0°C, 2.5 h (79%, 9:1 ratio
19:20); (b) (MeO)NHMe·HCl, Me3Al, THF, −30°C; 19 or 20, −30°C to 0°C, 24 h (94% for 21, 93% for 12); (c) Pd(OH)2, H2,
MeOH, rt, 72 h (69%); (d) (MeO)NHMe·HCl, Me3Al, THF, −30°C; 6, −30°C to rt, 24 h (93%); (e) Pd(OH)2, H2, MeOH, rt, 24
h (85%).
Scheme 4. Reagents and conditions: (a) Boc2O, Et3N, DMAP (cat.), CH2Cl2, rt, 30 min (86%); (b) TBSOTf, 2,6-lutidine, CH2Cl2,
rt, 3 h (85% for R=OTBS, 94% for R=Me); (c) Boc2O, Et3N, DMAP (cat.), CH2Cl2, rt, 1.5 h (96% for 24, 97% for 27); (d)
LiEt3BH, THF, −78°C, 15 min (96% for 25, 93% for 26); (e) i. 6N HCl (aq.), THF, 50°C, 2 h; ii. Dowex 1X2 (HO−), H2O (80%).

7652
A. N. Hulme, C. H. Montgomery / Tetrahedron Letters 44 (2003) 7649–7653
of the methyl analogue 26 via Boc-activated pyrrolidi-
none 27 (85% yield over three steps from 15). Heating
amino alcohol 25 with 6N HCl at 50°C for 2 h led to
the clean removal of all of the protecting groups and
the formation of an intermediate aminosugar 28.9c Neu-
tralisation and purification by ion-exchange chromato-
graphy [Dowex 1X2 (HO−)] provided nectrisine 2 in
excellent yield.31
tin, R.; Wu, J. Y.; Laslo, K.; Siuzdak, G.; Wong, C. H.
J. Am. Chem. Soc. 1997, 119, 8146–8151; (e) Kayakiri,
H.; Nakamura, K.; Takase, S.; Setoi, H.; Uchida, I.;
Terano, H.; Hashimoto, M.; Tada, T.; Koda, S. Chem.
Pharm. Bull. 1991, 39, 2807–2812; (f) Chen, S.-H.; Dan-
ishefsky, S. J. Tetrahedron Lett. 1990, 31, 2229–2232.
10. Hulme, A. N.; Montgomery, C. H.; Henderson, D. K. J.
Chem. Soc., Perkin Trans. 1 2000, 1837–1841.
11. (a) Fehrentz, J. A.; Castro, B. Synthesis 1983, 676–678;
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3824–3831; (e) Reetz, M. T. Angew. Chem., Int. Ed. Engl.
1991, 30, 12.
In conclusion, we have synthesized nectrisine 2 in 12
steps from
D-serine with an overall yield of 32%. The
key carbonꢀcarbon bond forming reaction, a glycolate
aldol condensation, was shown to take place with excel-
lent diastereoselectivity. Furthermore, the aldol based
approach offers a flexible strategy for the synthesis of a
range of stereoisomers and other analogues of this
iminosugar.
12. Jurzac, J.; Golebiowski, A. Chem. Rev. 1989, 89, 149–
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13. (a) Reetz, M. T. Chem. Rev. 1999, 99, 1121–1162; (b)
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Acknowledgements
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The authors gratefully acknowledge the EPSRC (GR/
96309957 to CHM) for funding this work.
15. (a) Ikota, N.; Hirano, J.; Gamage, R.; Nakagawa, H.;
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20. Compound 6 was unambiguously determined as the all-
syn product by single crystal X-ray diffraction.
21. All new compounds gave spectroscopic data in agreement
with their assigned structures: 6; mp 112–113°C; [h]D
−32.9 (c 1.4, CHCl3); wmax (neat)/cm−1 3530, 1747; lH
(250 MHz, CDCl3) 7.73–7.17 (20H, m), 4.30 (1H, br s),
3.97–3.87 (4H, m), 3.94 (2H, d, J=13.0), 3.78 (3H, s),
3.53 (2H, d, J=13.0), 3.13 (1H, dddꢀdt, J=8.2, 4.0),
2.85 (1H, br s), 1.11 (9H, s); lC (50.3 MHz, CDCl3)
173.3, 138.5 (2C), 135.6 (2C), 135.6 (2C), 132.5 (2C),
130.0, 129.9, 129.0 (4C), 128.4 (4C), 127.8 (4C), 127.3
(2C), 70.5, 68.2, 59.5, 59.0, 54.4 (2C), 52.2, 26.7 (3C),
18.9. 7; [h]D −30.6 (c 1.15, CHCl3); wmax (neat)/cm−1 3482,
1738; lH (250 MHz, CDCl3) 7.74–7.20 (20H, m), 4.66
(1H, br s), 4.12–4.07 (4H, m), 4.06 (2H, d, J=13.4), 3.77
(3H, s), 3.53 (2H, d, J=13.4), 3.04 (1H, dt, J=9.4, 5.7),
2.75 (1H, br s), 1.08 (9H, s); lC (50 MHz, CDCl3) 174.3,

A. N. Hulme, C. H. Montgomery / Tetrahedron Letters 44 (2003) 7649–7653
7653
139.3 (2C), 135.6 (2C), 135.5 (2C), 132.6, 132.5, 129.9
(2C), 128.9 (4C), 128.2 (4C), 127.8 (4C), 127.0 (2C), 72.4,
70.5, 61.5, 58.7, 54.9 (2C), 52.3, 26.7 (3C), 18.9.
10.7), 3.98 (2H, d, J=13.7), 3.67 (2H, d, J=13.7), 3.41
(1H, dt, J=7.7, 5.3), 3.30 (1H, dd, J=13.6, 3.2), 2.74
(1H, dd, J=13.6, 9.2), 1.10 (9H, s); lC (50.3 MHz,
CDCl3) 171.7, 153.1, 140.0 (2C), 137.4, 135.7 (2C), 135.6
(2C), 135.0, 133.1, 133.0, 129.7 (2C), 129.3 (2C), 129.1
(4C), 128.8 (2C), 128.1 (2C), 128.0 (4C), 127.9 (2C), 127.7
(4C), 127.5, 127.2, 126.7 (2C), 78.3, 72.2, 72.0, 66.7, 61.5,
59.7, 54.7 (3C), 37.7, 26.7 (3C), 18.9.
22. Fuhry, M. A. M.; Holmes, A. B.; Marshall, D. R. J.
Chem. Soc., Perkin Trans. 1 1993, 2743–2746.
23. Masamune, S.; Choy, W.; Peterson, J. S.; Sita, L. R.
Angew. Chem., Int. Ed. Engl. 1985, 24, 1–30.
24. Synthesized via reaction of the sodium salt of benzyl
alcohol with bromoacetic acid, followed by esterification.
25. 14; [h]D −32.2 (c 1.94, CHCl3); wmax (neat)/cm−1 3546,
1751, 1601, 1588, 1494; lH (250 MHz, CDCl3) 7.82–7.15
(25H, m), 4.40 (1H, d, J=10.2), 4.38 (1H, d, J=1.4), 4.18
(1H, dd, J=10.7, 5.6), 4.17–4.10 (1H, m), 4.09 (1H, dd,
J=10.7, 5.6), 3.91 (2H, d, J=13.5), 3.77 (3H, s), 3.62
(2H, d, J=13.5), 3.52 (1H, d, J=10.2), 3.18 (1H, dt,
J=9.1, 5.6), 2.70 (1H, br d, J=9.2), 1.12 (9H, s); lC (62.9
MHz, CDCl3) 172.3, 140.0 (2C), 137.4, 135.6 (2C), 135.5
(2C), 133.1, 132.9, 129.7, 129.6, 129.2 (4C), 128.2 (4C),
127.9 (4C), 127.6 (4C), 127.5, 126.9 (2C), 77.3, 72.8, 72.1,
61.2, 59.1, 54.8 (2C), 51.8, 26.7 (3C), 18.9.
28. 22; [h]D +40.2 (c 1.25, CHCl3); wmax 3305, 1689; lH (250
MHz, CDCl3) 7.67–7.59 (4H, m), 7.41–7.30 (6H, m), 6.52
(1H, br s), 5.00 (1H, br s), 4.42 (1H, br d, J=2.7),
4.12–3.98 (1H, br m), 3.83 (1H, dd, J=10.8, 5.2), 3.76–
3.61 (2H, m), 1.00 (9H, s); lC (62.9 MHz, CDCl3) 175.4,
135.5 (2C), 135.4 (2C), 132.6, 132.4, 129.8, 129.8, 127.8
(4C), 74.9 (2C), 62.6, 55.5, 26.7 (3C), 18.9.
29. For recent examples of the use of this strategy see: (a)
Zhang, J.; Xiong, C.; Wang, W.; Ying, J.; Hruby, V. J.
Org. Lett. 2002, 4, 4029–4032; (b) Mulzer, J.; Schu¨lzchen,
F.; Bats, J.-W. Tetrahedron 2000, 56, 4289–4298; (c) Oba,
M.; Miyakawa, A.; Nishiyama, K. J. Org. Chem. 1999,
46, 9275–9278; (d) Langlois, N. Tetrahedron: Asymmetry
1998, 9, 1333–1336.
26. 15; [h]D −6.4 (c 0.95, CHCl3); wmax (neat)/cm−1 3385,
3272, 1696; lH (250 MHz, CDCl3) 7.66–7.25 (10H, m),
5.86 (1H, br s), 3.80 (1H, dd, J=10.2, 4.5), 3.72 (1H, m),
3.63 (1H, dd, J=10.2, 6.6), 3.52 (1H, dt, J=6.6, 4.5),
2.82 (1H, br s), 2.38 (1H, dqꢀqn, J=7.2), 1.18 (3H, d,
J=7.2), 1.05 (9H, s); lC (62.9 MHz, CDCl3) 176.6, 135.4
(4C), 132.6, 129.9 (2C), 127.8 (4C), 76.9, 65.1, 61.2 (2C),
44.9, 16.7 (3C), 19.0, 13.0.
30. 24; [h]D −33.1 (c 0.75, CHCl3); wmax (neat)/cm−1 1794,
1761, 1719; lH (250 MHz, CDCl3) 7.66–7.58 (4H, m),
7.45–7.30 (6H, m), 4.31 (1H, t, J=1.5), 4.13–3.96 (2H,
m), 3.88–3.74 (2H, m), 1.38 (9H, s), 1.05 (9H, s), 0.88
(9H, s), 0.86 (9H, s), 0.15 (3H, s), 0.13 (3H, s), 0.12 (3H,
s), 0.10 (3H, s); lC (62.9 MHz, CDCl3) 172.0, 149.7, 135.4
(4C), 133.0, 132.9, 129.7 (2C), 127.7 (4C), 82.9, 78.8, 72.0,
66.7, 62.6, 27.8 (3C), 26.7 (3C), 25.7 (3C), 25.6 (3C), 19.1,
18.0, 17.8, −4.5, −4.6 (2C), −5.2. 27; [h]D −30.0 (c 0.2,
CHCl3); wmax (neat)/cm−1 1791, 1754, 1715; lH (250 MHz,
CDCl3) 7.63–7.56 (4H, m), 7.45–7.33 (6H, m), 4.14 (1H,
dd, J=3.7, 2.4), 3.90–3.85 (2H, m), 3.73 (1H, m), 2.48
(1H, dq, J=7.7, 3.7), 1.43 (9H, s), 1.24 (3H, d, J=7.7),
1.04 (9H, s), 0.85 (9H, s), 0.06 (3H, s), 0.00 (3H, s); lC
(50.3 MHz, CDCl3) 175.5, 149.8, 135.5 (4C), 132.8, 132.5,
129.8 (2C), 127.7 (4C), 82.8, 72.7, 66.8, 62.0, 47.8, 27.8
(3C), 26.8 (3C), 25.5 (3C), 19.1, 17.7, 14.5, −4.5, −4.7.
31. Nectrisine 2; [h]D +21.0 (c 0.4, H2O) [lit.9c [h]D +21.8 (c
0.6, H2O)]; lH (600 MHz, D2O) 7.72 (1H, d, J=2.4), 4.75
(1H, dt, J=5.2, 1.0), 4.11 (1H, t, J=5.3), 3.91 (1H, dd,
J=11.5, 3.9), 3.88 (1H, ddddd, J=5.3, 4.2, 3.9, 2.3, 1.2),
3.79 (1H, dd, J=11.5, 4.2); lC (62.9 MHz, D2O) 170.5,
83.4, 78.2, 76.8, 61.2; m/z (FAB) 131 ([M]+, 38%), 91
(100); HRMS (FAB) (C5H9NO3 requires 131.0582, found
131.0582).
27. 19; [h]D −29.2 (c 0.9, CHCl3); wmax (neat)/cm−1 3331,
1773, 1708; lH (360 MHz, CDCl3) 7.81–7.77 (4H, m),
7.53–7.22 (24H, m), 7.09–7.06 (2H, m), 5.22 (1H, d,
J=2.4), 4.56–4.52 (1H, m), 4.52 (1H, d, J=11.5), 4.50
(1H, ddt, J=9.8, 6.2, 3.1), 4.27 (1H, d, J=11.5), 4.15–
4.11 (1H, m), 4.13 (1H, dd, J=11.3, 4.4) 4.04 (1H, dd,
J=11.3, 8.0), 3.93 (2H, d, J=13.1), 3.86–3.81 (3H, m),
3.56 (1H, td, 8.0, 4.4), 3.30 (1H, dd, J=13.3, 3.1), 2.72
(1H, dd, J=13.3, 9.8), 1.94 (9H, s); lC (90.6 MHz,
CDCl3) 170.7, 153.7, 139.5 (2C), 137.7, 136.2 (4C), 135.8,
133.6, 130.3, 130.2, 129.9 (2C), 129.7 (3C), 129.4 (2C),
129.0, 128.9 (3C), 128.8, 128.7, 128.6 (2C), 128.2 (4C),
128.1 (2C), 127.9, 127.8, 127.6 (2C), 77.8, 72.8, 68.2, 67.2,
62.3, 60.3, 56.2, 54.7 (2C), 38.2, 27.6 (3C), 19.6. 20; [h]D
−33.6 (c 1.00, CHCl3); wmax (neat)/cm−1 3451, 1779, 1705;
lH (360 MHz, CDCl3) 7.77–7.75 (4H, m), 7.51–7.37
(10H, m), 7.35–7.19 (16H, m), 5.46 (1H, d, J=1.7), 4.70
(1H, ddt, J=9.2, 5.2, 3.2), 4.38 (1H, br d, J=7.7), 4.26
(1H, d, J=10.7), 4.22–4.11 (4H, m), 3.99 (1H, d, J=