Concise and highly selective asymmetric synthesis of acosamine from sorbic acid

Article abstract of DOI:10.1016/j.tetlet.2010.12.035

Diastereoselective conjugate addition of lithium (R)-N-benzyl-N-(α- methylbenzyl)amide to tert-butyl sorbate and subsequent chemo- and diastereoselective ammonium-directed olefinic oxidation of the resultant conjugate addition product {tert-butyl (3S,αR)-3-[N-benzyl-N-(α- methylbenzyl)amino]hex-4-ene} have been used as the key steps in a concise and highly selective asymmetric synthesis of the 2,3,6-trideoxy-3-aminohexose l-acosamine. This sequence of two chemical operations allows rapid assembly of the molecular architecture and facilitates the de novo asymmetric synthesis of methyl N,O-diacetyl-α-l-acosaminide in only 7 steps from commercially available sorbic acid in 15% overall yield.

Full text of DOI:10.1016/j.tetlet.2010.12.035

Tetrahedron Letters 52 (2011) 2216–2220
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Concise and highly selective asymmetric synthesis of acosamine
from sorbic acid
Sharan K. Bagal b, Stephen G. Davies a, , Ai M. Fletcher a, James A. Lee a, Paul M. Roberts a, Philip M. Scott a,
⇑
James E. Thomson a
a Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
b Pfizer Global R&D, Sandwich, Kent CT13 9NJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 22 December 2010
Diastereoselective conjugate addition of lithium (R)-N-benzyl-N-(a-methylbenzyl)amide to tert-butyl
sorbate and subsequent chemo- and diastereoselective ammonium-directed olefinic oxidation of the
resultant conjugate addition product {tert-butyl (3S, R)-3-[N-benzyl-N-( -methylbenzyl)amino]hex-4-
ene} have been used as the key steps in a concise and highly selective asymmetric synthesis of the
2,3,6-trideoxy-3-aminohexose -acosamine. This sequence of two chemical operations allows rapid
assembly of the molecular architecture and facilitates the de novo asymmetric synthesis of methyl
a
a
Dedicated to Professor Harry H. Wasserman
on the occasion of his 90th birthday
L
Keywords:
2,3,6-Trideoxy-3-aminohexose
Conjugate addition
N,O-diacetyl-
a
-
L
-acosaminide in only 7 steps from commercially available sorbic acid in 15% overall yield.
Ó 2010 Elsevier Ltd. All rights reserved.
Ammonium-directed olefinic oxidation
Acosamine
1. Introduction
ing the conjugate addition of lithium (R)-N-benzyl-N-(a-methyl-
benzyl)amide17 to tert-butyl sorbate and the chemo- and
Compounds incorporating the amino sugar scaffold are preva-
lent in nature and play important biological roles: for example,
they are present in skeletal tissues1 and biopolymers such as body
movement lubricants,2 and are also involved in chemical signal-
ling.3 The 2,3,6-trideoxy-3-aminohexose family of amino sugars
comprises daunosamine 1,4 3-epi-daunosamine 2,5 ristosamine 36
and acosamine 4.7 One of the most important roles of these com-
pounds is their occurrence as the glycosidic fragment of a variety
of naturally occurring and synthetic antibiotics.8 For instance, nat-
urally occurring daunorubicin 59 and doxorubicin 610 contain an
diastereoselective ammonium-directed olefinic oxidation18 of the
resultant conjugate addition product {tert-butyl (3S,aR)-3-[N-ben-
zyl-N-(a-methylbenzyl)amino]hex-4-ene} as the key steps to
introduce the stereochemistry.19
2. Results and discussion
Sorbic acid 8 was converted to the corresponding methyl and
tert-butyl esters 9 and 10 under standard conditions (MeOH/H+
and isobutylene/H+, respectively).20 Conjugate addition of lithium
-daunosamine residue and are approved as anti-cancer agents11
(R)-N-benzyl-N-(a
-methylbenzyl)amide 11 (99% ee)21 to both 9
L
(R = Me) and 10 (R = tBu) proceeded to give the corresponding
known b-amino esters 1219 and 1322 as single diastereoisomers
(>99:1 dr), which were isolated in 77 and 92% yield, respectively23
(Scheme 1).
whilst the synthetic analogue epirubicin 7 (containing an L-acos-
amine residue) is marketed by Pfizer as PharmorubicinÒ as a treat-
ment for breast cancer12 (Fig. 1).
Owing to their biological significance, the members of this fam-
ily of amino sugars are popular synthetic targets and a variety of
approaches reliant on manipulation of carbohydrate13 and non-
carbohydrate14 chiral pool starting materials, as well as asymmet-
ric syntheses,15 have been reported.16 In this Letter we report an
efficient and highly selective asymmetric synthesis of methyl
We have previously reported a method to effect the chemo- and
diastereoselective olefinic oxidation of a range of conformationally
constrained cycloalkenyl amines reliant on protection of the nitro-
gen atom against oxidation by in situ conversion to the corre-
sponding ammonium ion24 and have recently applied this
methodology to the asymmetric synthesis of the imino sugars
(+)-1-deoxynojirimycin and (+)-1-deoxyaltronojirimycin.25 We
envisaged that application of this protocol to the conformationally
labile acyclic alkenyl amines 12 and 13 would enable diastereose-
lective oxidation of the olefin. Attempted oxidation of 12 with
N,O-diacetyl-a-L-acosaminide in 7 steps from sorbic acid, employ-
⇑
Corresponding author.
E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.035

S. K. Bagal et al. / Tetrahedron Letters 52 (2011) 2216–2220
2217
Me
HO
O
OH
Me
HO
O
OH
F3C
O
Ph
H
O
H
(i)
O
Ph
N
R2N
NH2
NH2
H
Me
H
L
-daunosamine 1
L-3-epi-daunosamine 2
CO2Me
Me
H
Me
O
OH
Me
O
OH
12, >99:1 dr
CO2Me
14
HO
HO
L
NH2
NH2
-acosamine 4
L-ristosamine 3
Ph
O
OH
O
(ii)
O
OH
R
CO2Me
Ph
N
Me
O
CO2Me
Me
16, 23% (from 12)
15, 10%, 95:5 dr
H
>99:1 dr, 95:5 er
Me
O
O
OH
O
OMe
Scheme 2. Reagents and conditions: (i) F3CCO2H, F3CCO3H, CH2Cl2, rt, 16 h; (ii) m-
CPBA, CHCl3, 0 °C, 30 min.
HO
NH2
daunorubicin 5, R = H
12 is, therefore, consistent with an ammonium-directed epoxida-
tion step proceeding via transition state model 14 in which
1,3-allylic strain is minimised (Scheme 2). The very high diastere-
oselectivity of this reaction is remarkable, and is consistent with
our previous observations concerning the diastereoselective
doxorubicin 6, R = OH
O
O
OH
OH
O
O
OH
H
HO
synthesis of carbonates from tertiary allylic amines with
a
Me
HO
O
OMe
stereocentre to the amino functionality: significant levels of
a
diastereoselectivity are imparted in ammonium-directed reactions
of these substrates even in the absence of significant levels of
1,3-allylic strain.29
NH2
epirubicin (Pharmorubicin®) 7
Treatment of epoxide 15 with aqueous HBF4 in CH2Cl2 gave
complete conversion to a mixture of products containing six-mem-
bered ring lactone 17 (major product) and five-membered ring lac-
tone 18 (minor product) as the principal components, along with
several unidentifiable impurities (Scheme 3). Unfortunately, nei-
ther chromatography nor recrystallisation enabled separation of
these impurities on a preparative scale, although recrystallisation
of an aliquot gave fine crystals of six-membered ring lactone 17.
Single crystal X-ray diffraction allowed unambiguous assignment
of the relative configuration within 17, with the absolute
Figure 1. Structures of L-daunosamine 1, L-3-epi-daunosamine 2, L-ristosamine 3,
-acosamine 4, daunorubicin 5, doxorubicin 6 and epirubicin 7.
L
(i) or (ii)
CO2H
CO2R
Me
Me
8
9, R = Me, 94%
10, R = tBu, 80%
(iii)
(4S,5R,6S,
uration of the (R)-
a
R)-configuration being assigned from the known config-
-methylbenzyl stereocentre (Fig. 2).30 Five-
Ph
Ph
a
membered ring lactone 18 was assigned as the minor product on
Ph
N
Li
Ph
N
the basis of 1H NMR chemical shift and 1H–1H NMR COSY analyses,
CO2R
whilst the absolute (4S,5R,10S,
aR)-configuration was assigned by
(R)-11
Me
12, R = Me, 77%, >99:1 dr
analogy to that unambiguously established for 17, and by single
crystal X-ray analysis of a derivative (vide infra). The observation
of six-membered ring lactone 17 as the major product from this
reaction is consistent with a mechanism involving regioselective
ring opening of the epoxide at C(5) in an SN2-type fashion by
H2O31 followed by lactonisation under the acidic reaction condi-
tions. The direct formation of lactones 17 and 18 from b-amino es-
ters 12 and 13 was, therefore, investigated: in each case, treatment
with m-CPBA (4 equiv) in the presence of aqueous HBF425 gave six-
membered ring lactone 17 as the major product along with five-
membered ring lactone 18 as the minor product. Substantial peak
overlap in the 1H NMR spectra (as well as the presence of uniden-
tifiable impurities) precluded an accurate determination of the ra-
tio of six-membered ring lactone 17 to five-membered ring lactone
18 within these product mixtures, although in each case it was
estimated as ꢁ3:1 (Scheme 3).
13, R = t Bu, 92%, >99:1 dr
Scheme 1. Reagents and conditions: (i) SOCl2, MeOH, ꢂ10 °C to rt, 2 h; (ii)
isobutylene, H2SO4 (concd aq), CH2Cl2, 0 °C to rt, 48 h; (iii) lithium (R)-N-benzyl-N-
a-methylbenzyl)amide 11, THF, ꢂ78 °C, 2 h.
(
m-CPBA in the presence of Cl3CCO2H under our literature condi-
tions24a returned only starting material, although use of the more
reactive peracid F3CCO3H26 in the presence of F3CCO2H resulted
in complete conversion to epoxide 15 in 95:5 dr, and with quanti-
tative mass return. Unfortunately, epoxide 15 proved somewhat
unstable towards chromatographic purification and was isolated
in only 10% yield and 95:5 dr (a number of unidentifiable products
of decomposition were also isolated). The absolute configurations
of the C(4)- and C(5)-stereocentres within 15 were determined
by correlation to the known epoxide (R,R)-16:27 treatment of 15
with m-CPBA in CHCl3 promoted N-oxide formation and subse-
quent regioselective Cope elimination to give 16, which was iso-
Hydrogenolysis of a mixture of six-membered ring lactone 17
and five-membered ring lactone 18 in the presence of Boc2O in
EtOAc gave a 70:30 mixture of the six- and five-membered ring
N-Boc protected lactones 19 and 20, which were separated via
flash column chromatography to give 19 and 20 in 25 and 8% over-
lated in 23% yield (2 steps from 12), >99:1 dr and 95:5 er28 {½a D25
ꢀ
+9.0 (c 0.4 in CHCl3); lit.27 for >99:1 er ½a D26
ꢀ
+10.2 (c 0.4 in CHCl3)}.
The stereochemical outcome of the epoxidation of b-amino ester
all yield (respectively) in 2 steps from N-benzyl-N-a-methylbenzyl

2218
S. K. Bagal et al. / Tetrahedron Letters 52 (2011) 2216–2220
O
Me
HO
O
O
O
Ph
Ph
HO
(ii)
(i)
+
Ph
N
Ph
N
O
Me
N
Ph
N
Ph
CO2Me
CO2R
Me
Me
Ph
Major product 17
Ph
Minor product 18
12, R = Me, >99:1 dr
13, R = t Bu, >99:1 dr
15, 95:5 dr
Scheme 3. Reagents and conditions: (i) HBF4 (40% w/w in H2O), CH2Cl2, rt, 48 h; (ii) HBF4 (40% w/w in H2O), m-CPBA (4 equiv), CH2Cl2, rt, 48 h.
O
Me
HO
O
O
O
HO
+
Me
N
Ph
N
Ph
Ph
Ph
18
17
(i)
O
Me
HO
O
O
O
HO
Me
+
NHBoc
NHBoc
19, 25% from 12
20, 8% from 12
>99:1 dr
>99:1 dr
Scheme 4. Reagents and conditions: (i) H2 (5 atm), Pd(OH)2/C (50% w/w substrate),
EtOAc, rt, 48 h.
Figure 2. Chem 3D representation of the single crystal X-ray structure of 17 (some
H atoms omitted for clarity).
tion within the N-benzyl-N-
membered ring lactone 17. The observation that a mixture of N-
benzyl-N- -methylbenzyl protected lactones 17 and 18 is con-
a-methylbenzyl protected six-
a
verted into a mixture of N-Boc protected lactones 19 and 20 sup-
ports the structural and stereochemical assignments made for N-
benzyl-N-a-methylbenzyl protected five-membered ring lactone
18 (Scheme 4).
Treatment of six-membered ring lactone 19 with DIBAL-H re-
sulted in a mixture of the six- and five-membered ring lactols 21
and 22 (as mixtures of anomers), which were immediately treated
with HCl in MeOH followed by peracetylation and recrystallisation
Figure 3. Chem 3D representation of the single crystal X-ray structure of 19 (some
H atoms omitted for clarity).
to give methyl N,O-diacetyl-a-L-acosaminide 24 (>95:5 a/b ano-
meric mixture) in 10% isolated yield (3 steps). An analogous se-
quence of reactions was applied to five-membered ring lactone
20 to deliver methyl N,O-diacetyl-
anomeric mixture) in 20% isolated yield (3 steps). Alternatively,
hydrogenolysis of a mixture of N-benzyl-N- -methylbenzyl pro-
a-L-acosaminide 24 (>95:5 a/b
a
tected six- and five-membered ring lactones 17 and 18 followed
by purification of the crude reaction mixture by filtration through
a short plug of silica gel gave a 70:30 mixture of N-Boc protected
6- and 5-membered ring lactones 19 and 20 (in 55% yield from
b-amino ester 13), which was reduced upon treatment with
DIBAL-H, followed by sequential treatment with HCl in MeOH,
peracetylation and recrystallisation to give methyl N,O-diacetyl-
a-L-acosaminide 24 (>95:5 a/b anomeric mixture) in 38% yield (3
steps). This corresponds to an overall yield of 15% in 7 steps from
sorbic acid 8 (Scheme 5). The relative configuration within 24
was unambiguously established by single crystal X-ray diffraction
(Fig. 5)34,35 whilst the absolute configuration was inferred from the
Figure 4. Chem 3D representation of the single crystal X-ray structure of 20 (some
H atoms omitted for clarity).
sign of the specific rotation {½a D25
ꢀ
ꢂ116 (c 0.5 in MeOH); ½a D25
ꢂ177
ꢀ
(c 1.0 in MeOH); lit.7a for sample of methyl N,O-diacetyl-
L-acosami-
protected b-amino ester 12. The relative configurations within six-
membered ring lactone 19 and five-membered ring lactone 20
were unambiguously assigned by single crystal X-ray diffraction
(Figs. 3 and 4),32,33 with the absolute configuration assigned in
each case from the known absolute configuration at C(4) [formed
nide isolated from natural source36
½
a 2D0
ꢀ
ꢂ84 (c 0.5 in MeOH); lit.7c
for sample of methyl N,O-diacetyl-a-D-acosaminide isolated from
natural source ½a D20
ꢀ
+204 (c 0.3 in MeOH); lit.7c for sample of
methyl N,O-diacetyl-b-D-acosaminide isolated from natural source
a 2D0
ꢀ
+39 (c 0.3 in MeOH); lit.15b for 80:20
a
/b anomeric mixture of
upon conjugate addition of lithium (R)-N-benzyl-N-(a-methylben-
½
-acosaminide ½a D23
ꢀ
+87.5 (c 0.5 in MeOH)}.37
zyl)amide 11] and by reference to the known absolute configura-
methyl N,O-diacetyl-
D

S. K. Bagal et al. / Tetrahedron Letters 52 (2011) 2216–2220
2219
OH
O
Me
O
O
Me
HO
O
OH
O
O
(i)
(i)
HO
HO
Me
+
HO
Me
NHBoc
19, >99:1 dr
NHBoc
NHBoc
NHBoc
21
22
20, >99:1 dr
(ii)
O
Me
HO
O
OMe
Me
HO
O
O
Me
O
OMe
O
(i), (ii)
(iii)
HO
Me
+
AcO
NH2•HCl
NHBoc
19
19:20, 70:30 mixture, 55% yield from 13
NHAc
NHBoc
20
23
methyl N,O-diacetyl-α-
L
-acosaminide 24
>95:5 α:β anomeric mixture
10% from 19, 20% from 20
38% from a 70:30 mixture of 19:20
Scheme 5. Reagents and conditions: (i) DIBAL-H, CH2Cl2, ꢂ78 °C, 30 min; (ii) MeOH, HCl (concn aq), rt, 16 h; (iii) Ac2O, pyridine, DMAP, rt, 30 min.
7. (a) Lomakina, N. N.; Spiridonova, I. A.; Sheinker, Y. N.; Vlasova, T. F. Khim. Prir.
Soedin. 1973, 9, 101; (b) Spiridonova, I. A.; Yurina, M. S.; Lomakina, N. N.;
Sztaricskai, F.; Bognar, F. Antibiotiki 1976, 21, 304; (c) Harada, K.; Ito, S.; Suzuki,
M. Carbohydr. Res. 1979, 75, C17.
8. Weymouth-Wilson, A. C. Nat. Prod. Rep. 1997, 14, 99.
9. Di Marco, A.; Gaetani, M.; Dirogotti, L.; Soldati, M.; Bellini, O. Nature 1964, 201,
706.
10. Arcamone, F.; Cassinelli, G.; Fantani, G.; Grein, A.; Orezzi, P.; Pol, C.; Spalla, C.
Biotechnol. Bioeng. 1969, 11, 1101.
11. Weiss, R. B. Semin. Oncol. 1992, 19, 670.
12. Zaya, M. J.; Hines, R. N.; Stevens, J. C. Drug Metab. Dispos. 2006, 34, 2097.
13. See, for example: Roger, P.; Monneret, C.; Fournier, J.-P.; Choay, P.; Gagnet, R.;
Gosse, C.; Letourneux, Y.; Atassi, G.; Gouyette, A. J. Med. Chem. 1989, 32, 16;
Kovacs, I.; Herczegh, P.; Sztaricskai, J. Tetrahedron 1991, 37, 7837; Renneberg,
B.; Ling, Y.-M.; Laatsch, H.; Fiebig, H.-H. Carbohydr. Res. 2000, 329, 861; Shi, W.;
Coleman, R. S.; Lowary, T. L. Org. Biomol. Chem. 2009, 7, 3709.
14. See, for example: Hirama, M.; Shigemoto, T.; Itô, S. J. Org. Chem. 1987, 52, 3342;
Konradi, A. W.; Pedersen, S. F. J. Org. Chem. 1990, 55, 4506; Hatanaka, M.; Ueda,
I. Chem. Lett. 1991, 61.
Figure 5. Chem 3D representation of the single crystal X-ray structure of 24 (some
H atoms omitted for clarity).
3. Conclusion
15. See, for example: (a) Wovkulich, P. M.; Uskovic´, M. R. Tetrahedron 1985, 41,
3455; (b) Ginesta, X.; Pastó, M.; Pericàs, M. A.; Riera, A. Org. Lett. 2003, 5, 3001;
(c) Sugiura, M.; Hirano, K.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 7182; (d)
Matsushima, Y.; Kino, J. Tetrahedron Lett. 2005, 46, 8609.
16. For a review, see: Hauser, F. M.; Ellenberger, S. R. Chem. Rev. 1986, 86, 35.
17. For a review concerning the use of secondary lithium amides (derived from a-
In conclusion, the diastereoselective conjugate addition of lith-
ium (R)-N-benzyl-N-(a-methylbenzyl)amide to tert-butyl sorbate
and subsequent chemo- and diastereoselective ammonium-direc-
ted olefinic oxidation of the resultant conjugate addition product
{tert-butyl (3S,aR)-3-[N-benzyl-N-(a-methylbenzyl)amino]hex-4-
ene} have been used as the key steps in a concise and highly selec-
tive asymmetric synthesis of the 2,3,6-trideoxy-3-aminohexose
methylbenzylamine) as enantiopure ammonia equivalents for conjugate
addition reactions, see: Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron:
Asymmetry 2005, 16, 2833.
18. For a review, see: Kurosawa, W.; Roberts, P. M.; Davies, S. G. Yuki Gosei Kagaku
Kyokaishi J. Synth. Org. Chem. Jpn. 2010, 68, 1295.
L
-acosamine. This sequence of two chemical operations allows ra-
pid assembly of the molecular architecture and facilitates the syn-
thesis of methyl N,O-diacetyl- -acosaminide in only 7 steps from
19. We have previously reported
daunosamine employing syn-dihydroxylation of tert-butyl (3S,
benzyl-N-( -methylbenzyl)amino]hex-4-ene 13 under Sharpless AD
a
route to
L-daunosamine and
D-3-epi-
aR)-3-[N-
a-L
a
commercially available sorbic acid in 15% overall yield. The further
application of this ammonium-directed oxidation protocol towards
the synthesis of other amino sugars is currently underway in our
laboratory.
conditions; see: Davies, S. G.; Smyth, G. D. Tetrahedron: Asymmetry 1996, 7,
1273; Davies, S. G.; Smyth, G. D.; Chippindale, A. M. J. Chem. Soc., Perkin Trans. 1
1999, 3089.
20. Fischer, E.; Speier, A. Ber. Dtsch. Chem. Ges. 1895, 28, 3252; Altschul, R. J. Am.
Chem. Soc. 1946, 68, 2605; Smith, M. B.; March, J. March’s Advanced Organic
Chemistry – Reactions, Mechanisms, and Structure, 5th ed.; John Wiley & Sons:
New York, 2001.
Acknowledgements
21. Enantiopure (R)-
Reductive alkylation of (R)-
benzaldehyde and NaBH4 gave (R)-N-benzyl-N-(
subsequent deprotonation with BuLi in THF generated a pink solution of
lithium (R)-N-benzyl-N-( -methylbenzyl)amide 11.
a
-methylbenzylamine (99% ee) is commercially available.
-methylbenzylamine upon treatment with
-methylbenzyl)amine;
a
The authors would like to thank Pfizer for a CASE studentship
(P.M.S.) and Antoni Riera for providing a 1H NMR spectrum of an
a
80:20
a/b anomeric mixture of methyl N,O-diacetyl-L-a-
a
22. Davies, S. G.; Smyth, G. D. J. Chem. Soc., Perkin Trans. 1 1996, 2467.
23. The higher yield for 13 (resulting from conjugate addition to tert-butyl ester
10) as compared to 12 (resulting from conjugate addition to methyl ester 9)
reflects the decreased propensity of the latter to undergo detritic 1,2-addition;
see: Refs. [17,19,22]. See also: Davies, S. G.; Garrido, N. M.; Kruchinin, D.;
Ichihara, O.; Kotchie, L. J.; Price, P. D.; Price Mortimer, A. J.; Russell, A. J.; Smith,
A. D. Tetrahedron: Asymmetry 1793, 2006, 17.
24. (a) Aciro, C.; Claridge, T. D. W.; Davies, S. G.; Roberts, P. M.; Russell, A. J.;
Thomson, J. E. Org. Biomol. Chem. 2008, 6, 3751; (b) Aciro, C.; Davies, S. G.;
Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2008,
6, 3762; (c) Bond, C. W.; Cresswell, A. J.; Davies, S. G.; Kurosawa, W.; Lee, J. A.;
Fletcher, A. M.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E. J. Org.
Chem. 2009, 74, 6735.
acosaminide.
References and notes
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Mondelli, R. J. Am. Chem. Soc. 1964, 86, 5335.
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family that has not been isolated from natural sources.
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2220
S. K. Bagal et al. / Tetrahedron Letters 52 (2011) 2216–2220
28. The enantiomeric excess of 16 was determined by chiral HPLC analysis, for
which the authors would like to thank Michael C. Willis and Robert H. Snell.
29. Davies, S. G.; Fletcher, A. M.; Kurosawa, W.; Lee, J. A.; Poce, G.; Roberts, P. M.;
Thomson, J. E.; Williamson, D. M. J. Org. Chem. submitted for publication.
30. X-ray crystal structure determination for 17: Data were collected using an Enraf-
X-ray crystal structure data for 20 [C11H19NO5]: M = 245.28, monoclinic, space
group P21, a = 6.1570(7) Å, b = 9.6600(11) Å, c = 11.1643(14) Å, b = 105.274(5)°,
V = 640.56(13) Å3, Z = 2,
l
= 0.100 mmꢂ1, colourless plate, crystal dimensions =
0.04 ꢃ 0.14 ꢃ 0.16 mm3. A total of 1511 unique reflections were measured for
5 < h < 27 and 1511 reflections were used in the refinement. The final
Nonius k-CCD diffractometer with graphite monochromated Mo K
using standard procedures at 150 K. The structure was solved by direct
methods (SIR92); all non-hydrogen atoms were refined with anisotropic
a
radiation
parameters were wR2 = 0.118 and R1 = 0.054 [I > ꢂ3.0r(I)]. Crystallographic
data (excluding structure factors) has been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication number CCDC
794240. Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-
mail: deposit@ccdc.cam.ac.uk].
thermal parameters. Hydrogen atoms were added at idealised positions. The
38
structure was refined using CRYSTALS
.
X-ray crystal structure data for 17 [C21H25NO3]: M = 339.43, monoclinic, space
group P21, a = 10.5740(4) Å, b = 7.1467(3) Å, c = 12.3396(6) Å, b = 99.4375(18)°,
34. The single crystal X-ray structure of methyl N,O-diacetyl-a-L-acosaminide 24
V = 919.87(7) Å3, Z = 2,
l
= 0.081 mmꢂ1, colourless block, crystal dimensions =
has previously been reported; see: Henkel, S.; Menzel, A.; Jäger, V. Z. Kristallogr.
New Cryst. Struct. 1998, 213, 795.
35. X-ray crystal structure determination for 24: Data were collected using an Enraf-
0.12 ꢃ 0.20 ꢃ 0.23 mm3. A total of 2211 unique reflections were measured for
5 < h < 27 and 1868 reflections were used in the refinement. The final
parameters were wR2 = 0.115 and R1 = 0.054 [I > ꢂ3.0
r
(I)]. Crystallographic
Nonius k-CCD diffractometer with graphite monochromated Mo Ka radiation
using standard procedures at 150 K. The structure was solved by direct
methods (SIR92); all non-hydrogen atoms were refined with anisotropic
data (excluding structure factors) has been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication number CCDC
794238. Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-
mail: deposit@ccdc.cam.ac.uk].
thermal parameters. Hydrogen atoms were added at idealised positions. The
38
structure was refined using CRYSTALS
.
X-ray crystal structure data for 24 [C11H19NO5]: M = 245.28, orthorhombic,
space group P212121, a = 5.0041(2) Å, b = 12.5783(5) Å, c = 20.7349(9) Å,
31. For a discussion concerning the regioselectivity of ring opening of epoxides
derived from allylic amines under acidic conditions, see: Refs. [24a,b], and
references cited therein.
V = 1305.12(9) Å3, Z = 4,
l
= 0.098 mmꢂ1, colourless plate, crystal dimensions =
0.07 ꢃ 0.09 ꢃ 0.25 mm3. A total of 1753 unique reflections were measured for
32. X-ray crystal structure determination for 19: Data were collected using an Enraf-
5 < h < 27 and 1287 reflections were used in the refinement. The final
Nonius k-CCD diffractometer with graphite monochromated Mo K
using standard procedures at 150 K. The structure was solved by direct
methods (SIR92); all non-hydrogen atoms were refined with anisotropic
a
radiation
parameters were wR2 = 0.084 and R1 = 0.053 [I > ꢂ3.0r(I)]. Crystallographic
data (excluding structure factors) has been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication number CCDC
794241. Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-
mail: deposit@ccdc.cam.ac.uk].
thermal parameters. Hydrogen atoms were added at idealised positions. The
38
structure was refined using CRYSTALS
.
X-ray crystal structure data for 19 [C11H19NO5]: M = 245.28, monoclinic, space
group P21, a = 5.5861(3) Å, b = 10.0003(5) Å, c = 11.8509(6) Å, b = 94.139(2)°,
36. No anomeric ratio was reported.
V = 660.30(6) Å3, Z = 2,
l
= 0.097 mmꢂ1, colourless plate, crystal dimensions =
37. Data for methyl N,O-diacetyl-
a
-
L
-acosaminide 24 (>95:5
a
/b anomeric
0.05 ꢃ 0.22 ꢃ 0.25 mm3. A total of 1581 unique reflections were measured for
5 < h < 27 and 1581 reflections were used in the refinement. The final
parameters were wR2 = 0.099 and R1 = 0.067 [I > ꢂ3.0h(I)]. Crystallographic
data (excluding structure factors) has been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication number CCDC
794239. Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-
mail: deposit@ccdc.cam.ac.uk].
mixture): mp 157–159 °C; ½a D25
ꢀ
ꢂ116 (c 0.5 in MeOH); ½a D25
ꢀ
ꢂ177 (c 1.0 in
MeOH); mmax (KBr) 3305 (N–H), 2973, 2916, 2857, 2833 (C–H), 1740 (C@O); dH
(400 MHz, CDCl3) 1.17 (3H, d, J 6.3, C(6)H3), 1.59 (1H, app dt, J 12.5, 3.3,
C(2)HA), 1.90 (3H, s, COMe), 2.07 (3H, s, COMe), 2.21 (1H, dd, J 12.5, 4.4, C(2)HB),
3.33 (3H, s, OMe), 3.89 (1H, dq, J 8.8, 6.3, C(5)H), 4.35–4.50 (2H, m, C(3)H,
C(4)H), 4.70 (1H, d, J 3.3, C(1)H), 5.65 (1H, br d, J 7.3, NH); dC (100 MHz, CDCl3)
17.7, 20.9, 23.3, 36.4, 46.9, 54.6, 65.6, 75.8, 97.5, 169.8, 171.8; m/z (ESI+) 268
+
([M+Na]+, 100%); HRMS (ESI+) C11H19NNaO5 ([M+Na]+) requires 268.1155;
33. X-ray crystal structure determination for 20: Data were collected using an Enraf-
found 268.1162. Data for b-anomer: dH (400 MHz, CDCl3) [selected peaks] 1.20
(3H, d, J 6.1, C(6)H3), 3.45 (3H, s, OMe); dC (100 MHz, CDCl3) [selected peaks]
49.3, 56.6, 70.8.
Nonius k-CCD diffractometer with graphite monochromated Mo K
a radiation
using standard procedures at 150 K. The structure was solved by direct
methods (SIR92); all non-hydrogen atoms were refined with anisotropic
38. Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, C. K.; Watkin, D. J.
CRYSTALS, 2010, Issue 14, Chemical Crystallography Laboratory, University of
Oxford, UK.
thermal parameters. Hydrogen atoms were added at idealised positions. The
38
structure was refined using CRYSTALS
.