Remote stereocontrol in reactions between 4- and 5-alkoxyalk-2- enylstannanes and 1-alkoxycarbonylimines and analogues: Stereoselective approaches to novel α-amino acids

Article abstract of DOI:10.1039/c2ob25097g

Reactions of the allyltin trichloride 45 generated from (4S)-4-benzyloxypent-2-enyl(tributyl)stannane 1 with imines prepared from glyoxylates proceed with useful levels of 1,5-stereocontrol in favour of (4E)-2,6-anti-2-(alkylamino)-6-benzyloxyhept-4-enoat

Full text of DOI:10.1039/c2ob25097g

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PAPER
Remote stereocontrol in reactions between 4- and 5-alkoxyalk-2-
enylstannanes and 1-alkoxycarbonylimines and analogues: stereoselective
approaches to novel α-amino acids†‡
David J. Hallett, Nongluk Tanikkul and Eric J. Thomas*
Received 13th January 2012, Accepted 15th March 2012
DOI: 10.1039/c2ob25097g
Reactions of the allyltin trichloride 45 generated from (4S)-4-benzyloxypent-2-enyl(tributyl)stannane 1
with imines prepared from glyoxylates proceed with useful levels of 1,5-stereocontrol in favour of (4E)-
2,6-anti-2-(alkylamino)-6-benzyloxyhept-4-enoates 49. This stereoselectivity, controlled by the chirality
of the stannane, dominates over any intrinsic stereochemical bias of the imine although a small amount of
matching and mis-matching was observed. The allyltin trichloride 77 prepared from (4S)-4-(tert-
butyldimethylsilyloxy)pent-2-enyl(tributyl)stannane 52 reacts with 1-alkoxycarbonylimines with the
opposite 1,5-stereoselectivity to give the (4E)-2,6-syn-diastereoisomers 79. Matching and mismatching
was more pronounced for tin(IV) chloride mediated reactions of (4R)-5-benzyloxy-4-methylpent-2-enyl
(tributyl)stannane 80 with chiral 1-alkoxycarbonylimines but useful stereoselectivity in favour of (4E)-
2,6-syn-2-alkyl- and arylthio-amino-7-benzyloxy-6-methylhept-4-enoates 177 was observed for reactions
with achiral imines and similar, but reduced, stereoselectivity was observed for the 5-tert-
butyldimethylsilyloxypentenylstannane 82. However, excellent 1,5-stereocontrol in favour of the (4E)-2,6-
anti-isomers 179 was found using the 4,5-bis-alkoxypent-2-enylstannane 106. Modest (4E)-2,7-anti-
stereoselectivity was observed in the analogous tin(IV) bromide mediated reactions of (S)-5-methoxy- and
(S)-5-hydroxyhex-2-enyl(tributyl)stannanes (S)-123 and (S)-122 with achiral 1-alkoxycarbonylimines but
in this series the intrinsic stereochemical bias of the imine controls the facial selectivity of reactions of
chiral 1-alkoxycarbonylimines. Useful (4E)-2,6-anti-stereoselectivity was also observed in the tin(IV)
chloride promoted reaction of the 4-benzyloxypent-2-enylstannane 1 with an oxime O-benzyl ether.
1,6- and 1,7-stereocontrol.8,9 For example the 4-benzyloxypent-
2-enylstannane 1 on transmetalation with tin(IV) chloride gener-
Introduction
Reactions between imines and organometallic reagents are
widely employed for the stereoselective synthesis of amines1 and
useful diastereoselectivities have been found for reactions of
imines that have chiral N-substituents.2 Many procedures are
also available for the enantioselective synthesis of amines from
achiral imines using either chiral reagents or catalysts.3 Reactions
of allylic organometallic reagents,4 including allylstannanes5,6
and allylboranes,7 have been widely studied in this context.
Tin(IV) halide mediated reactions of 4-, 5- and 6-alkoxyalk-2-
enylstannanes with aldehydes proceed with useful levels of 1,5-,
ates an allyltin trichloride that reacts with aldehydes with excel-
lent stereoselectivity in favour of (Z)-1,5-syn-5-benzyloxypent-3-
enols 2.10 We here report on the tin(IV) halide mediated reactions
of 4- and 5-alkoxy- and 5-hydroxy-alk-2-enylstannanes with
imines, in particular with 1-alkoxycarbonyl imines, that proceed
with useful levels of 1,5- and 1,6-stereocontrol.11
The School of Chemistry, The University of Manchester, Manchester,
M13 9PL, UK. E-mail: e.j.thomas@manchester.ac.uk; Fax: +44 (0) 161
275 4939; Tel: +44 (0) 161 275 4613
†This article is part of the Organic & Biomolecular Chemistry 10th
Anniversary issue.
‡Electronic supplementary information (ESI) available: includes full
experimental details and compound characterisation for compounds not
included in the text. CCDC 862199, 862200. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/
c2ob25097g
Results and discussion
Preliminary studies of reactions of alk-2-enyltin trichlorides and
imines
The remote stereocontrol observed during reactions between
alkoxyalk-2-enylstannanes and aldehydes involved participation
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of allyltin trihalides at −78 °C formed by transmetalation of alk-
2-enyl(tributyl)stannanes using tin(IV) chloride and bromide.8,9
The reactivity of a series of imines towards such intermediates at
−78 °C was therefore evaluated using prop-2-enyltin trichloride
generated from prop-2-enyl(tributyl)stannane 3.6
No imine addition products were found for the imines 4 and
5, prepared from ( )-α-methylbenzylamine and either benzal-
dehyde or 2-methylpropanal, and prop-2-enyltin trichloride,
although the expected adducts 6 and 7 were obtained using
either titanium(IV) chloride or boron trifluoride diethyl etherate
to promote the reaction with stannane 3.5a The homoallylic car-
bamate 9 was obtained from the reaction between N-ethoxycar-
bonylimine 8 and prop-2-enyltin trichloride but this imine did
not react with the allyltin trichloride generated from the
4-benzyloxypent-2-enyl(tributyl)stannane 1. Instead the only
product isolated was the (3Z)-1,5-syn-5-benzyloxy-1-phenylhex-
3-enol 10. This must have been derived from benzaldehyde gen-
erated by hydrolysis of the imine during the work-up of the reac-
tion, see Scheme 1.10
Scheme 2 Stereoselectivity in the reaction between the chiral imine 11
and prop-2-enyltin trichloride. Reagents and conditions: (i) 3, SnCl4,
−78 °C, 15 min, (R)-11, −78 °C, 4 h, then satd. aq. NH4Cl (90%;
12 : 13 = 93 : 7); (ii) KOtBu, THF, −78 °C, 10 min (88%; 12 : 13 =
15 : 85).
Scheme 3 Synthesis of the carbamate 14. Reagents and conditions: (i)
3, SnCl4, −78 °C, 15 min, (S)-11, −78 °C, 4 h, then satd. aq. NH4Cl
(88%; 93 : 7); (ii) Cl3CC(CH3)2OC(O)Cl, 1,4-dioxane, K2CO3, heat
under reflux, 16 h (90%).
Scheme 1 Preliminary studies. Reagents and conditions: (i) 3, SnCl4,
−78 °C, 15 min, 8, −78 °C, 4 h, then satd. aq. NH4Cl (92%); (ii) 1,
SnCl4, −78 °C, 15 min, 8, −78 °C, 4–12 h, then satd. aq. NH4Cl
(81–79%).
Fig. 1 Structure of the carbamate 14 as established by X-ray
diffraction.
The successful reaction of the N-ethoxycarbonylimine 8 with
prop-2-enyltin trichloride indicated that an electron withdrawing
group on the imine could promote the reaction and so reactions
of the imine (R)-117 derived from butyl glyoxalate and (R)-α-
phenylethylamine were investigated. This imine reacted with
prop-2-enyltin trichloride efficiently and with a useful level of
diastereoselectivity to give the 2-(alkylamino)pent-4-enoates 12
and 13, ratio 93 : 7, see Scheme 2. The configurations of these
products were assigned by comparison with authentic samples
prepared by treatment of the imine 11 with 9-borabicyclo[3.3.1]
nonane,7 and were confirmed by the X-ray crystal structure‡ of
the 2,2,2-trichloro-1,1-dimethylethoxycarbonyl derivative 14 of
the major product from the prop-2-enyltin trichloride reaction
with the enantiomeric imine (S)-11, see Scheme 3 and Fig. 1. Of
interest was the observation that the (2S)-2-(alkylamino)penteno-
ate 12 was the major product from the reaction of the imine (R)-
11 with prop-2-enyltin trichloride, whereas the (2R)-epimer 13
was the dominant product from the reaction with 9-BBN.7 Inter-
estingly, the (2S)-2-(alkylamino)pentenoate 12 epimerized to
give mainly the (2R)-epimer 13 on treatment with potassium
tert-butoxide in tetrahydrofuran at −78 °C followed by an
aqueous work-up.
(E)-1,5-anti-Stereocontrol in reactions of 4-benzyloxypent-2-enyl-
(tributyl)stannane 1 and 1-alkoxycarbonylimines
Having established that the (R)-imine (R)-11 reacted efficiently
with prop-2-enyltin trichloride, the reactions of this and analo-
gous imines with the allyltin trichloride generated from the (4S)-
4-benzyloxypent-2-enylstannane 1 were investigated. Optimum
results were found when the reaction of the allyltin trichloride
generated from the pent-2-enylstannane 1 and the (S)-imine
(S)-11 were carried out at −45 °C for 12 h. Under these con-
ditions, the (4E)-2,6-anti-2-(alkylamino)-6-benzyloxyhept-4-
enoate 15 was the major product with only traces of its 2-epimer
16 being detected, 15 : 16 = 96 : 4. The reaction of the (R)-imine
(R)-11 with the allyltin trichloride generated from stannane 1
was only slightly less stereoselective, the (4E)-2,6-anti-2-(alkyl-
amino)-6-benzyloxyhept-4-enoate 17 being the major product
together with ca. 10% of its epimer 18, see Scheme 4.
Structures were initially assigned to the amino acid derivatives
15/16 and 17/18 using spectroscopic data. The coupling con-
stants, J4,5, between the vinylic protons for the alkenes 15/16
and 17/18 were ca. 16 Hz showing the presence of (E)-double-
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Scheme 4 Tin(IV) chloride mediated reactions of the alkenylstannane 1
with chiral imines. Reagents and conditions: (i) 1, SnCl4, 78 °C, 15 min,
either (S)-11 or (R)-11, −45 °C, 12 h, then satd. aq. NH4Cl (15/16, 73%;
15 : 16 = 96 : 4; 17/18, 72%; 17 : 18 = 92 : 8).
bonds. Of note, H(2) for the 1,3-like-epimers 13, 16, 17 was
invariably more shielded than H(2) for the 1,3-unlike-epimers
12, 15 and 18 (13, δ3.1, 12, δ3.35; 16, δ3.13, 15, δ3.43; 17,
δ3.14, 18, δ3.43), and this was found to be a reliable guide to
the configuration at C(2) for all the 2-(α-methylbenzylamino)
esters prepared during this work. However, to confirm the stereo-
chemical assignments at C(2), correlation was made using the
lactones 22 and 26 prepared from the 2-(alkylamino)pentenoates
12 and 13, see Scheme 5. Thus, following cbz-protection of the
amino esters 12 and 13, ozonolysis of the resulting carbamates
19 and 23 with a reductive work-up gave the alcohols 20 and 24.
Cyclisation in acidic methanol then gave the lactones 21 and 25
and these were N-deprotected to the amines 22 and 26 using
transfer hydrogenolysis, see Scheme 5. These amines were easily
Scheme 5 Stereochemical correlations. Reagents and conditions: (i)
BnOCOCl, K2CO3, CHCl3, heat, 16 h (83–94%); (ii) (a) O3, MeOH,
−78 °C, 1.5 h, then Me2S, r.t., 1 h (b) NaBH4, MeOH, 0 °C – r.t.,
30 min; (iii) MeOH, aq. HCl, 16 h (72–86% two steps); (iv) MeOH,
NH4O2CH, 10% Pd/C, r.t., 30 min (71–85%).
1
distinguished by H NMR and the structure of the 1,3-like-cbz-
aminolactone 25 was confirmed by a single crystal X-ray struc-
ture determination, see Fig. 2.‡ Following this sequence, the
major product from the reaction of the imine (S)-11 with the
stannane 1 gave the enantiomeric 1,3-unlike aminolactone
ent-22 and the aminolactone 26 was obtained from the major
product from the reaction between the imine (R)-11 and the stan-
nane 1, so confirming the assigned configurations.
Fig. 2 Structure of the 2-(alkylamino)lactone 25 as established by
X-ray diffraction.
The reactions of the allyltin trichloride generated from the (S)-
4-benzyloxypent-2-enylstannane 1 with the imines (S)-11 and
(R)-11 both proceed with useful 1,5-stereoselectivity in favour of
the (4E)-2,6-anti-hept-4-enoates 15 and 17. These imines, as
judged from the reaction with the achiral prop-2-enyltin trichlo-
ride, would prefer to give 2-(α-methylbenzylamino)alk-4-
enoates with the 1,3-unlike configuration between C(2) and the
(α-methylbenzylamino) substituent, e.g. 12. This was consistent
with the small degree of matching and mismatching observed for
the reactions of the enantiomeric imines (S)- and (R)-11 with the
(S)-4-benzyloxpent-2-enylstannane 1, 96 : 4 vs. 92 : 8, but
overall the stereoselectivities of these reactions were primarily
controlled by the allyltin trichloride.
It now remained to investigate the stereoselectivities of tin(IV)
chloride mediated reactions of the 4-benzyloxypent-2-enylstan-
nane 1 with achiral 1-alkoxycarbonylimines. The reactions of the
o-nitrophenylsulfanylimine 2912 and the two imines 32 and 35
with the allyltin trichloride generated from the (S)-4-benzyloxy-
pent-2-enylstannane 1 were found to be usefully stereoselective
(ca. 90 : 10) with the (E)-2,6-anti-2-amino-6-benzyloxyhept-4-
enoates 30, 33 and 36 being the major products, see Scheme 6.
Scheme 6 Tin(IV) chloride mediated reactions of the alkenylstannane 1
with achiral imines. Reagents and conditions: (i) 1, 78 °C, SnCl4,
15 min, either 29, 32, or 35, −45 °C, 12 h, then satd. aq. NH4Cl (30/31,
87%, 30 : 31 = 90 : 10; 33/34, 86%; 33 : 34 = 90 : 10; 36/37, 78%;
36 : 37 = 91 : 9).
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Fig. 3 Cyclic and open-chain transition structures for the reaction of
the allyltin trichloride 45 with achiral imines.
Scheme 7 Assignment of configuration to the products from the reac-
tions of stannane 1 with achiral imines. Reagents and conditions: (i) (a)
HCl, MeOH, r.t., 2 h, (b) K2CO3, MeO2CCl, CHCl3, r.t., 16 h (87%);
(ii) (a) O3, MeOH, −78 °C, 90 min, Me2S, r.t., 1 h (b) NaBH4, 0 °C –
r.t., 30 min (c) AcOH, CHCl3, reflux, 16 h (73%); (iii) (a) HCl, MeOH,
r.t., 2 h, (b) Ac2O, Et3N, DMAP, CH2Cl2, r.t., 16 h (82%); (iv) HCO2H,
MeOH, 10% Pd/C, r.t., 16 h (41, 79%; 42, 5%); (v) Ac2O, Et3N,
DMAP, CH2Cl2, r.t.,16 h (95%); (vi) K2CO3, MeOH, H2O, heat under
reflux, 16 h, then CH2N2, Et2O, r.t., 30 min (91%); vii, (a) HCO2H,
MeOH, 10% Pd/C, r.t., 16 h (b) Ac2O, Et3N, DMAP, CH2Cl2, r.t., 16 h
(80%).
Structures were assigned to the products in Scheme 6 on the
basis of spectroscopic data and by correlation with known com-
pounds, see Scheme 7. 1H NMR coupling constants between the
vinylic protons confirmed their (E)-configurations. Only one
isomer was detected from the reaction of the sulfanylimine 2913
and stannane 1 and this was correlated with the methoxycarbo-
nyl derivative (R)-3914 of (R)-homoserine lactone by conversion
into the carbamate 38, ozonolysis with a reductive work up, and
lactonisation of the resulting hydroxyester. This established the
(2R)-configuration of the major product 30 and, as the carbamate
39 had an e.e. of ca. 80%, the stereoselectivity of the reaction
between stannane 1 and the sulfanylimine 29 was estimated to
be ca. 90 : 10. The product mixture from the sulfanylimine 29
was also converted into the 6-acetoxy-2-acetamidoheptanoate 43
by replacement of the group on nitrogen to give the acetamide
40, hydrogenation with hydrogenolysis to give the alcohol 41
together with a small amount of the O-hydrogenolysis product
42, and O-acetylation. Comparison of the 2,6-anti-ester-amide
43 with its syn-diastereoisomer 73 prepared later, showed that
about 10% of the syn-diastereoisomer was present so confirming
the ratio of the 2,6-anti- to 2,6-syn-products 30 : 31 to be ca.
90 : 10.
The benzhydryl products 33 and 34 could not be separated
but were distinguishable by 1H NMR. Following ester exchange,
the methyl ester 44 was taken through to the acetamidoheptano-
ate 43 by hydrogenation and hydrogenolysis followed by O- and
N-acetylation. This confirmed that the major product from
the reaction of the alkenylstannane 1 with the N-benzhydryl-
imine 32 had been the 2,6-anti-product 33 as shown. The
2,6-anti-configuration was assigned to the major product 36
from the reaction of the stannane 1 with the dimethylbenzyl-
imine 35 by analogy, the ratio 36 : 37 being determined by
1H NMR.
Fig. 4 Cyclic transition structures for reactions of allyltin trichlorides
with chiral imines (R)-11 and (S)-11.
The tin(IV) chloride promoted reactions of the 4-benzyloxy-
pentenylstannane 1 with achiral imines proceed to give (E)-2,6-
anti-2-amino-6-benzyloxyhept-4-enoates as observed for the
chiral imines (R)- and (S)-11. This stereoselectivity differs from
that observed for the analogous reactions with aldehydes where
(3Z)-alk-3-enols 2 were obtained as the dominant products.
The mechanisms of these reactions have not been studied in
detail but, following trapping experiments,15 it is believed that
transmetalation of stannane 1 by tin(IV) chloride at −78 °C, gen-
erates the reactive allyltin trichloride 45 stereoselectively by
intramolecular delivery of the trichlorotin group by the oxygen
of the benzyloxy substituent.8,9 The formation of the (4E)-2,6-
anti-products 49 from the reactions with the 2-alkoxycarbonyl-
imines 46 and the allyltin trichloride 45 would then be consistent
with participation of either the cyclic 6-membered, chair-like
transition structure 47 or the open-chain process 48. In both
cases the intermediate (3S,4S)-allyltin trichloride 45 is reacting
with the si face of the imine to give the product with the
(R)-configuration at C(2) as the major product with concomitant
formation of the (E)-double-bond, see Fig. 3.16
The cyclic transition structure 50 is consistent with the pre-
ferred formation of the amine 12 from the reaction of the chiral
imine (R)-11 with prop-2-enyltin trichloride. The analogous
cyclic transition structure 51 is consistent with the matching seen
in the reaction between the chiral imine (S)-11 and the allyltin
trichloride 45,18 see Fig. 4.
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1,5-syn-Stereocontrol using 4-(tert-butyldimethysilyloxy)pent-2-
enyl(tributyl)stannane (52)
The 4-(tert-butyldimethylsilyloxy)pent-2-enylstannane 52 shows
reversed, albeit somewhat reduced, stereoselectivity in tin(IV)
chloride mediated reactions with aldehydes compared with the
4-(benzyloxy)pent-2-enylstannane 1.19 Therefore, it was of inter-
est to investigate analogous reactions of stannane 52 with 1-
alkoxycarbonylimines. The tin(IV) chloride mediated reactions of
the stannane 52 with the chiral imines (S)-11 and (R)-11, pro-
ceeded with modest stereoselectivities, but unlike the reactions
with the 4-benzyloxystannane 1, the (E)-2,6-syn-diastereo-
isomers 53 and 55 were the major products, see Scheme 8. The
stereoselectivity of the reaction with the (R)-imine (R)-11 was
slightly better than that observed for the (S)-imine (S)-11, con-
sistent with the preference of the chiral imines to form 1,3-
unlike-epimers, vide supra.
Scheme 9 Reactions of the 4-(tert-butyldimethylsilyloxy)pent-2-enyl-
stannane 52 with achiral imines. Reagents and conditions: (i) 52, SnCl4,
78 °C, 15 min, add imine, −45 °C, 12 h, then satd. aq. NH4Cl (58/60,
85%; 58 : 60 = 75 : 25; 62/63, 91%; 62 : 63 = 75 : 25; 64/65, 74%;
64 : 65 = 75 : 25); (ii) TBAF, THF, 0 °C 12 h (79%).
The tin(IV) chloride mediated reactions of the 4-(tert-butyl-
dimethylsilyloxy)pent-2-enylstannane 52 with the achiral imines
29, 32 and 35 were also examined, see Scheme 9. In all cases,
an approximately 3 : 1 mixture of products was obtained in
favour of the (E)-1,5-syn-diastereoisomers 58, 62 and 64.
Structures were initially assigned to the products 58, 60,
62–65 by analogy with the corresponding reactions of stannane
52 with the chiral imines (S)-11 and (R)-11. The epimeric pro-
ducts 58/60, 62/63 and 64/65 could not be separated. In the
N-diphenylmethyl series, the two products 62 and 63 were dis-
tinguishable by 1H NMR and were shown to be epimers by con-
version into a 3 : 1 mixture of ent-63 and ent-62 by desilylation
followed by a Mitsunobu inversion using levulinic acid. Reduc-
tive cleavage of the resulting levulinate 67 using sodium borohy-
dride and silylation of the free hydroxyl group then gave ent-63
(containing ca. 25% of its 2-epimer ent-62) whose 1H NMR
spectrum corresponded to that of the minor product from the
allylstannane reaction, see Scheme 10. To confirm the configur-
ation at C(2) of the major product 62, the 3 : 1 mixture of
epimers 62 and 63 was saponified and re-esterified using diazo-
methane to give the methyl ester 69. Following desilylation and
conversion of the alcohol 70 into the acetate 71, hydrogenation/
hydrogenolysis and N-acetylation gave the 2,6-syn-2-acetamido-
6-acetoxyheptanoate 73 (still containing ca. 25% of its 2-
epimer), see Scheme 10. Comparison with the 2,6-anti-epimer
43 (see Scheme 7) confirmed that the major product from the
reaction of stannane 52 with imine 32 was indeed the 2,6-syn-
diastereoisomer 62. Structures were assigned to the products 58
and 60 from the reaction with the N-phenylsulfanylimine 29 by
analogy. Their ratio and double-bond geometry were established
Scheme 8 Reactions of the 4-silyloxypent-2-enylstannane 52 with
chiral imines. Reagents and conditions: (i) 52, 78 °C, SnCl4, 15 min,
either (S)-11 or (R)-11, −45 °C, 12 h, then satd. aq. NH4Cl (53/54, 76%;
53 : 54 = 66 : 34; 55/56, 93%; 55 : 56 = 73 : 27); (ii) KOtBu, THF,
−78 °C, 10 min (86%; 55 : 56 = 15 : 85); (iii) BnOCOCl, K2CO3,
CHCl3, heat, 16 h (79%); (iv) (a) O3, MeOH, −78 °C, 1.5 h, then Me2S,
r.t., 1 h (b) NaBH4, MeOH, 0 °C – r.t., 30 min (c) MeOH, aq. HCl, 16 h
(21, 48% 3 steps); (v) MeOH, ammonium formate, 10% Pd/C, r.t.,
30 min (66%).
Structures were assigned to the products 53–56 on the basis of
spectroscopic data. In all cases the coupling between the vinylic
protons, J4,5, was ca. 15 Hz, consistent with the (E)-configur-
ation assigned to the double-bonds. The configuration at C(2)
was assigned on the basis of the increased shielding of H(2) for
the 1,3-like-epimers 53 and 56 (53, δ3.00, 54, δ3.29; 55, δ3.29,
56, δ3.01) and was confirmed for the major isomer 55 from the
reaction with the (R)-imine (R)-11 by correlation with the
lactone 22, see Scheme 8. Treatment of the 1,3-unlike epimer 55
with potassium tert-butoxide also initiated epimerisation to give
more of the 1,3-like epimer 56.
1
by H NMR and confirmed by desilylation and separation of the
alcohols 59 and 61. The products 64 and 65 from the reaction of
stannane 50 with the imine 35 were distinguishable by 13C NMR
and the major acetate 75, prepared by desilylation and O-acety-
lation, was shown to be an (E)-alkene by 1H NMR.
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trichloride with imines, e.g. via the cyclic transition structure 78,
would lead to the observed overall 2,6-syn-stereoselectivity.
(E)-1,5-syn-Stereocontrol using 5-benzyloxy- and 5-(tert-
butyldimethylsilyloxy)-4-methylpent-2-enyl(tributyl)stannanes
80 and 82 with imines
Transmetalation of the (R)-5-benzyloxy-4-methylpent-2-enyl
(tributyl)stannane 80 with tin(IV) chloride generates an allyltin
trichloride that reacts with aldehydes with useful diastereoselec-
tivity in favour of the (Z)-1,5-anti-diastereoisomers 81.8 In this
series, the corresponding 5-(tert-butyldimethylsilyloxy)pentenyl-
stannane 82 also gives rise to the (Z)-1,5-anti-diastereoisomers
83 but with somewhat reduced stereoselectivity.19 The stereo-
selectivities of reactions of these pent-2-enylstannanes with
imines were investigated.
Scheme 10 Confirmation of the structures of the products from the
reactions of stannane 52 with achiral imines. Reagents and conditions:
(i) TBAF, THF, r.t., 6 h (96%); (ii) Ph3P, levulinic acid, THF, DEAD, r.t.,
16 h (83%); (iii) NaBH4, MeOH, 0 °C–r.t., 30 min (90%); (iv) TBSCl,
imid., CH2Cl2, r.t., 16 h (ca. 100%); (v) K2CO3, MeOH, H2O, heat
under reflux, 16 h, then CH2N2, ether, r.t., 30 min (98%); (vi) TBAF,
THF, r.t., 16 h (97%); (vii) Ac2O, Et3N, DMAP, CH2Cl2, 16 h (99%);
(viii) TsNHNH2, DME, NaOAc, heat under reflux, 16 h (99%); (ix)
HCO2H, MeOH, 10% Pd/C, r.t., 16 h, then Ac2O, Et3N, DMAP,
CH2Cl2, r.t., 16 h (85%); (x) TBAF, THF, r.t., 4 h (86%); (xi) Ac2O,
Et3N, DMAP, CH2Cl2, r.t., 16 h (94%).
Following the usual procedure, the 5-benzyloxy-4-methyl-
pent-2-enylstannane 80 was transmetalated using tin(IV) chloride
and the allylin trichloride so formed allowed to react with the
chiral imines (R)-11 and (S)-11 and with the achiral imines 29
Fig. 5 2,6-syn-Stereoselectivity in reactions of the 4-(tert-butyl-
dimethylsilyloxy)pent-2-enylstannane 52 and imines.
The preferred formation of the 2,6-syn-products from the
tin(IV) chloride promoted reactions of the 4-(tert-butyldimethyl-
silyloxy)pent-2-enylstannane 52 and imines is consistent with
participation of the non-coordinated allyltin trichloride 77
formed by transmetalation of the tributylstannane 52 on the less
hindered face of the double-bond away from the allylic O-TBS
substituent in conformation 76 in which the allylic methyl group is
in the less hindered exo-position, see Fig. 5. Reaction of this allyltin
Scheme 11 Reactions of the 5-benzyloxy-4-methylpent-2-enylstan-
nane 80 with imines. Reagents and conditions: (i) 80, 78 °C, SnCl4,
15 min, add imine, −45 °C, 12 h, then satd. aq. NH4Cl (84/85,76%;
84 : 85 = 95 : 5; 86/88, 96%; 86 : 88 = 60 : 40; 90/91, 74%; 90 : 91 =
95 : 5; 92/93, 78%; 92 : 93 = 95 : 5); (ii) BnOC(O)Cl, K2CO3, CHCl3,
heat under reflux 16 h (84%).
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Scheme 13 Reactions of the 5-(tert-butyldimethylsilyloxy)-4-methyl-
pent-2-enylstannane 82 with imines. Reagents and conditions: (i) 82,
SnCl4, 78 °C, 15 min, add imine, −45 °C, 12 h, then satd. aq. NH4Cl
(97/98, 74%; 97 : 98 = 95 : 5; 99/100, 80%; 99 : 100 = 75 : 25; 101/102,
77%; 101 : 102 = 80 : 20).
Scheme 12 Confirmation of the structures of the products from reac-
tions of imines with the pent-2-enylstannane 80. Reagents and con-
ditions: (i) BnOC(O)Cl, K2CO3, CHCl3, heat under reflux, 16 h (87%);
(ii) (a) O3, MeOH, −78 °C, 90 min, Me2S, r.t., 1 h (b) NaBH4, 0 °C to
r.t., 30 min (80%) (c) aq. HCl, MeOH, r.t., 16 H (80%); (iii) ammonium
formate, 10% Pd/C, MeOH, r.t., 3 min (82%); (iv) HCl, MeOH, r.t., 2 h,
MeOC(O)Cl, K2CO3, CHCl3, r.t., 16 h (77%); (v) (a) O3, MeOH,
−78 °C, 90 min., Me2S, r.t., 1 h, (b) NaBH4, r.t., 30 min (c) glacial
HOAc, CHCl3, heat under reflux 16 h (62%); (vi) DIBAL-H, CH2Cl2,
−78 °C, to r.t., 1 h (92%).
the (E)-2,6-syn-hept-4-enoate 97 but only modest stereoselectiv-
ities, albeit still in favour of the (E)-1,5-syn-diastereoisomers
99 and 101 were observed for the mismatched reaction with the
(S)-imine (S)-11 and for the reaction with the achiral imine 29.
The C(2) configurations of the products 97–100 prepared from
the chiral imines (R)-11 and (S)-11 were assigned using the rela-
tive chemical shifts of H(2), and the structures of the products
101 and 102 from the achiral imine 29 were assigned by
analogy.
These reactions of the 5-benzyloxy- and 5-(tert-butyl-
dimethylsilyloxy)-4-methylpent-2-enylstannanes 80 and 82 with
imines are consistent with transmetalation generating the allyltin
trichlorides 103 (R = Bn, TBS).8,19 These intermediates can then
react with the imines via the cyclic transition structure 104 to
give the (E)-2,6-syn-products 105, see Fig. 6. An open chain
transition structure analogous to 48 would give the same overall
result. Unlike, the 4-alkoxypent-2-enylstannanes 1 and 52, it
would appear that the 5-benzyloxy- and 5-(tert-butyldimethyl-
silyloxy)pentenylstannanes 80 and 82 are transmetalated with
the same diastereofacial selectivity to give the (3R,4S)-allyltin
trichlorides 103, albeit more stereoselectively from the 5-benzyl-
oxystannane 80. This is consistent with the preferred formation
of the (Z)-1,5-anti-products 81 and 83 in their tin(IV) chloride
promoted reactions with aldehydes.
and 32, see Scheme 11. Useful stereoselectivities were observed
for the matched reaction with the (R)-imine (R)-11 and with
the achiral imines 29 and 32 in favour of the (E)-2,6-syn-hept-4-
enoates 84, 90 and 92, but only modest stereoselectivity, albeit
still in favour of the (E)-1,5-syn-diastereoisomer 86, was
observed for the mismatched reaction with the (S)-imine (S)-11.
The C(2)-configurations of the products 84–86 and 88 from
the chiral imines (R)-11 and (S)-11 were initially assigned using
the relative chemical shifts of H(2). The C(2) configuration of
the major product 84 from the (R)-imine (R)-11 was confirmed
by cbz-protection of the 2-amino group and ozonolysis of the
carbamate 94 with a reductive work up followed by lactonisation
to the 2-amidolactone 21. This was converted into the 2-(alkyl-
amino)lactone 22 prepared earlier, see Scheme 12. Structures
were assigned to the products 86 and 88 from the (S)-imine
(S)-11 by their H(2) chemical shifts, these products being more
easily separated as their N-cbz-derivatives 87 and 89. The major
product 90 from reaction of stannane 80 with the N-sulfanyl-
imine 29 was converted into the carbamate 95. Ozonolysis with
a reductive work up and lactonisation then gave the lactone
(S)-3914 so confirming its configuration at C(2). The structure of
the major product isolated from the achiral imine 32 was
assigned by analogy, its double-bond configuration being estab-
lished by the vinylic coupling constant of 15.5 Hz observed for
the DIBAL-H reduction product 96, see Scheme 12.
(E)-1,5-anti-Stereocontrol using (S)-4-(2-
trimethylsilylethoxymethoxy)-5-(tert-butyldimethylsilyloxy)pent-
2-enyl(tributyl)stannane 106
It was of interest to investigate the reactions of dialkoxyalk-2-
enylstannanes with imines to see if these could proceed with
useful levels of remote stereocontrol. Tin(IV) chloride mediated
reactions of the 4-(trimethylsilylethoxymethoxy)-5-(tert-butyldi-
methylsilyloxy)pent-2-enylstannane 106 with aldehydes have
been found to proceed with useful levels of stereoselectivity in
favour of the (Z)-1,5-syn-distereoisomers 107 and these products
have been used in stereoselective syntheses of 2,6-disubstituted
Following the usual procedure, the 5-(tert-butyldimethylsilyl-
oxy)-4-methylpent-2-enylstannane 82 was transmetalated using
tin(IV) chloride and the allyltin trichloride so formed allowed to
react with the chiral imines (R)-11 and (S)-11 and the achiral
imine 29, see Scheme 13. Useful stereoselectivity was observed
for the matched reaction with the (R)-imine (R)-11 in favour of
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Scheme 15 Synthesis of a pipecolic acid derivative. Reagents and con-
ditions: (i) TsNHNH2, DME, NaOAc, heat under reflux 18 h (90%); (ii)
HCl, MeOH, r.t., 2 h (ca. 100%); (iii) (a) HCO2H, MeOH, 10% Pd/C,
r.t., 16 h (b) Boc-ON, Et3N, CH2Cl2, heat under reflux, 3 h (70%); (iv)
2-mesitylenesulfonyl chloride, py., 0 °C, 16 h (83%); (v) KOtBu, THF,
−78 °C, 5 min (83%); (vi) TFA, CHCl3, r.t., 2 h (68%).
Fig. 6 Cyclic transition structures for the reactions of allyltin trichlo-
rides generated from the allylstannanes 80 and 82 with imines.
Structures were assigned to the products 108–110 from the
chiral imines by analogy with earlier work and were consistent
with the H(2) chemical shifts for the like- and unlike-1,3-epimers
109 and 110. The C(2) configuration of the product 111 from the
achiral imine 29 was established by ozonolysis of the acetamide
112 prepared from the sulfanamide 111 and conversion of the
ozonolysis product into the known (S)-N-acetyl homoserine
lactone (S)-113,21 see Scheme 14. The structure of the product
115 from the achiral imine 114 was assigned by analogy.
The preference for formation of the (E)-2,6-anti-products 108,
109, 111 and 115 in these reactions follows the stereoselectivity
observed for the reactions between the 4-benzyloxystannane 1
and 1-alkoxycarbonyl imines. Analogous intermediates may be
involved, see Fig. 3 and 4.
To show the potential of these products for synthesis, the
product 115 from the benzhydryl imine 114 was converted into
the methyl 6-(hydroxymethyl)pipecolinate 121, see Scheme 15.
Thus, diimide reduction gave the heptanoate 116 that was depro-
tected and taken through to the Boc-protected aminodiol 118.
Selective sulfonylation of the primary alcohol gave the mesity-
lenesulfonate 119 and treatment with base converted this into the
epoxide 120. This was converted into the pipecolic acid deriva-
tive 121 using trifluoroacetic acid that promoted cleavage of the
tert-butoxycarbonyl group and cyclisation. The structure of the
Scheme 14 Reactions of the stannane 106 with imines. Reagents and
conditions: (i) 106, 78 °C, SnCl4, 15 min, add imine, −45 °C, 12 h, then
satd. aq. NH4Cl (108, 72%; 109/110, 68%; 109 : 110 = 96 : 4; 111, 81%;
115, 72%); (ii) Ac2O, Et3N, DMAP, CHCl3, heat under reflux, 16 h
(74%); (iii) (a) O3, MeOH, −78 °C, 90 min., Me2S, r.t., 1 h (b) NaBH4,
0 °C – r.t., 30 min (c) glacial HOAc, CHCl3, heat under reflux 16 h
(60%).
tetrahydropyrans.20 Reactions of the stannane 106 with 1-alkoxy-
carbonyl imines were therefore investigated.
1
final product was assigned on the basis of the H NMR data.
These were more consistent with the pipecolic acid structure
shown than the alternative seven-membered ring containing
isomer. In particular the diastereotopic exocyclic methylene
hydrogens were observed as sharp double-doublets at δ3.44 and
δ3.61, and H(2) was a doublet of doublets at δ3.34 with axial-
axial and axial-equatorial coupling constants of 10.8 and 2.6 Hz.
It was found that the tin(IV) chloride mediated reactions of the
stannane 106 with both chiral and achiral aldehydes proceeded
with excellent stereocontrol in favour of (E)-2,6-anti-2-(alkyl-
amino)hept-4-enoates 108, 109, 111 and 115, see Scheme 14.
For the matched reaction with the (R)-imine (R)-11 and for the
reactions with the achiral imines 29 and 114 the overall stereose-
lectivity was greater than 98 : 2 in favour of the (4E)-2,6-anti-
diastereoisomers and other products were not detected. For the
reaction with the mismatched imine (S)-11, a minor product
assumed to be the (4E)-1,5-syn-epimer 110 was detected, but
even in this case the stereoselectivity was ca. 96 : 4.
(E)-1,6-Stereocontrol in reactions between 5-hydroxy- and 5-
methoxyhex-2-enylstannanes (S)-122 and (S)-123 with imines
Transmetalation of the 5-hydroxy- and 5-methoxyhex-2-enyl(tri-
butyl)stannanes (R)-122 and (R)-123 using tin(IV) bromide gen-
erates allyltin tribromides that react with aldehydes with useful
levels of 1,6-stereocontrol to give the (Z)-1,6-syn-alk-3-enols
124 and 125.8 Better results were obtained using tin(IV) bromide
rather than tin(IV) chloride in these reactions. It was therefore
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decided to investigate the stereoselectivity of reactions of the
hex-2-enylstannanes 122 and 123 with imines.
For the tin(IV) bromide promoted reactions between the chiral
imines (S)-11 and (R)-11 and the (S)-5-methoxyhex-2-enylstan-
nane (S)-123, the major products 127 and 128 had the unlike
configuration at C(2) relative to the stereogenic centre derived
from the imine as shown by the H(2) chemical shifts of the like-
and unlike-1,3-stereoisomers. It would appear that the stereo-
selectivities of these reactions are controlled primarily by the
imine and not by the intermediate allyltin tribromide, see
Scheme 16. Similar results were obtained using tin(IV) chloride
although the yields were slightly lower.
Scheme 17 Tin(IV) bromide promoted reaction of stannane (S)-123
and imine 29. Reagents and conditions: (i) (S)-123, 78 °C, SnBr4,
15 min, add imine, −50 °C, 9 h, then satd. aq. NH4Cl (130/134, 58%;
130 : 134 = 70 : 30); (ii) HCl, MeOH, MeOH, r.t., 2 h (131/135, 92%);
(iii) (S)- or (R)-Mosher’s acid chloride, Et3N, DMAP, CH2Cl2, r.t., 15 h
(132/136, 74%, 132 : 136 = 70 : 30; 133/137, 77%, 133 : 137 = 70 : 30);
(iv) MeOC(O)Cl, K2CO3, CHCl3, r.t., 16 h [138 plus ca. 25% C(2)-
epimer, 83%]; (v) (a) O3, MeOH, 90 min., Me2S, r.t., 90 min (b)
NaBH4, MeOH, 0 °C–r.t., 1 h (c) glacial HOAc, CHCl3, heat under
reflux, 16 h (58%; ca. 60% e.e.).
Scheme 16 Reactions between the 5-methoxyhex-2-enylstannane (S)-
123 and chiral imines. Reagents and conditions: (i) (S)-123, 78 °C,
SnBr4, 15 min, add imine, −50 °C, 8 h, then satd. aq. NH4Cl (126/127,
68%; 126 : 127 = 16 : 84; 128/129, 72%; 128 : 129 = 92 : 8); (ii) (S)-
123, 78 °C, SnCl4, 15 min, add imine, −50 °C, 8 h, then satd. aq.
NH4Cl (126/127, 46%; 126 : 127 = 13 : 87; 128/129, 58%; 128 : 129 =
75 : 25).
The tin(IV) bromide promoted reaction between the 5-methoxy-
hex-2-enylstannane (S)-123 and the achiral imine 29 gave a
mixture of epimeric 2-amino-oct-4-enoates 130 and 134 see
Scheme 17. These sulfanylamines could not be separated. On
treatment with aqueous hydrogen chloride in methanol, they
were cleaved to give a mixture of the corresponding amines 131
and 135. This mixture was esterified with (S)- and (R)-Mosher’s
acid chlorides to give the separable Mosher’s derivatives 132/
136 and 133/137. From the ratio of these derivatives it was esti-
mated that the initial product mixture from the allylstannane con-
tained the epimeric products in a 70 : 30 ratio. To establish the C
(2) configuration of the major product, the mixture of amines
131 and 135 was converted into the carbamate 138 and ozonoly-
sis with a reductive work-up and lactonisation of the hydroxyl
ester so obtained gave the lactone (S)-39 identified by compari-
son with an authentic sample.14 The major product from the
allyltin reaction was therefore identified as the (2S)-epimer 130
with a reaction selectivity of ca. 70 : 30. The shielding effects of
the phenyl group in the Mosher’s derivatives were consistent
with this assignment.22
Scheme 18 Tin(IV) bromide promoted reactions of the stannane (S)-
123 and imines 32 and 147. Reagents and conditions: (i) (S)-123, 78 °C,
SnBr4, 15 min, add imine, −45 °C or −50 °C, 22–24 h, then satd. aq.
NH4Cl (139/140, 62%; 139 : 140 = 70 : 30; 148/149, 57%; 148 : 149 =
70 : 30); (ii) 10% Pd–C, ammonium formate, MeOH, r.t., 1 h (141/144,
92% from 139/140; 96% from 148/149); (iii) (S)- or (R)-Mosher’s acid
chloride, Et3N, DMAP, CH2Cl2, r.t., 15 h (142/145, 76%, 142 : 145 =
70 : 30 from 139/140; 143/146, 75%, 143 : 146 = 70 : 30 from 139/140;
142/145, 77%, 142 : 145 = 70 : 30 from 148/149; 143/146, 71%,
143 : 146 = 70 : 30 from 148/149).
and N-benzyl imines 32 and 147 were also investigated. Transfer
hydrogenation of the mixtures of products that were obtained in
each case effected debenzylation and double-bond hydrogen-
ation. Mosher & Dale’s derivatisation of the hydrogenolysis pro-
ducts allowed an estimate of the stereoselectivities of the original
reactions and a comparison of the 1H NMR spectra of the
Mosher’s derivatives was used to assign configurations to the
products at C(2).22 The N-benzyhydryl and N-benzylimines were
thus shown to react with the allyltin tribromide generated from
The tin(IV) bromide promoted reactions between the (S)-5-
methoxyhexenylstannane (S)-123 and the achiral N-benzyhydryl
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the (S)-5-methoxy-hex-2-enylstannane (S)-120 with ca. 70 : 30
stereoselectivities in favour of the (2S)-epimers 139 and 148, see
Scheme 18.
Tin(IV) bromide promoted reactions of the (S)-5-hydroxyhex-
2-enylstannane (S)-122 with the chiral imines (S)-11 and (R)-11
and with the achiral sulfenimine 29 gave similar results to those
obtained for the 5-methoxyhexenylstannane (S)-123. The reac-
tions of the chiral imines were dominated by their preference for
formation of the 1,3-unlike epimers 151 and 152 and the achiral
imine 29 reacted with a preference for formation of the (E)-2,7-
anti-diastereoisomer 154. Structures were assigned to the pro-
ducts from the chiral imines (S)-11 and (R)-11 using the relative
chemical shifts of H(2). The epimeric products from the achiral
imine 29 could not be distinguished by NMR. The ratio of
86 : 14 was estimated from the ratios of the diastereoisomeric
Mosher’s derivatives 156/160 and 157/161 that were also used
to assign the C(2) configuration of the major product 154,22 see
Scheme 19.
Fig. 7 Cyclic transition structure for the reaction of allyltin tribromides
generated from the allylstannanes (S)-122 and (S)-123 with imines.
Scheme 20 Reactions between allyltin trichlorides and oximes or
hydrazones. Reagents and conditions: (i) 3, SnCl4, −78 °C, 15 min, 165
or 166, −78 °C, 4 h, then satd. aq. NH4Cl (168, 82%, 169, 80%); (ii) 3,
SnCl4, −78 °C, 15 min, 167, −45 °C, 50 h, then satd. aq. NH4Cl (170,
61%); (iii) 1, SnCl4, 78 °C, 15 min, either 165 or 166, −78 °C or
−45 °C, 50 h, then satd. aq. NH4Cl (171/173, 67%; 171 : 173 = 85 : 15;
172/174, 64%; 172 : 174 = 87 : 13); (iv) TsNHNH2, NaOAc, DME, heat
under reflux, 2 h (96%; 175 : 176 = 85 : 15); (v) (a) HCO2H, MeOH,
10% Pd/C, r.t., 16 h (b) Ac2O, Et3N, DMAP, CH2Cl2, r.t., 16 h (88%;
43 : 73 = 90 : 10).
Scheme 19 Reactions of the 5-hydroxyhexenylstannane (S)-122 with
imines. Reagents and conditions: (i) (S)-122, 78 °C, SnBr4, 15 min, add
imine, −45 °C, 24 h, then satd. aq. NH4Cl (150/151, 69%; 150 : 151 =
13 : 87; 152/153, 55%; 152 : 153 = 74 : 26; 154/158, 60%; 154 : 158 =
86 : 14); (ii) HCl, MeOH, MeOH, r.t., 2 h (155/159, 97%); (iii) (S)- or
(R)-Mosher’s acid chloride, Et3N, DMAP, CH2Cl2, r.t., 15 h (156/160,
69%, 156 : 160 = 86 : 14; 157/161, 64%, 157 : 161 = 86 : 14).
1,5-Stereocontrol in reactions between the 4-benzyloxypent-2-
enylstannane 1 and oximes
Preliminary studies were carried out on reactions between allyltin
trichlorides with oximes and a hydrazone, see Scheme 20. The
reactions of prop-2-enyltin trichloride with the oximes 165 and
166 were complete after 4 h at −78 °C; the hydrazone 167 was
less reactive requiring 50 h at −45 °C for completion. The reac-
tions of the oximes 165 and 166 with the 4-benzyloxypent-2-
enylstannane 1 also required 50 h at −45 °C and at −78 °C,
respectively, for completion. Nevertheless, these were stereo-
selective, giving mixtures of the (E)-2,6-anti- and (E)-2,6-syn-
products in which the (E)-2,6-anti-epimers 171 and 172 were
preferred, 2,6-anti : 2,6-syn = ca. 85 : 15. The structure of the
major epimer from the reaction with the O-benzyloxime 165 was
shown to correspond to the 2,6-anti-isomer 171 by reduction of
the mixture of products 171 and 173 to give the heptanoates 175
and 176 followed by hydrogenolysis and acetylation. The major
There would appear to be a modest preference for formation
of the (E)-2,7-anti-diastereoisomers 130, 139, 148 and 154 in
the tin(IV) bromide promoted reactions between the 5-methoxy-
and 5-hydroxy-hex-2-enylstannanes (S)-123 and (S)-122 with
the achiral imines 29, 32 and 147 although the stereoselectivities
of the analogous reactions with the chiral imines (S)-11 and
(R)-11 were dominated by the preference of the imine. The for-
mation of the (E)-2,7-anti-isomers from the achiral imines is
consistent with participation of the allyltin tribromide 162 that
reacts with the imines via the chair-like transition structure 163
(or via an alternative open-chain process), see Fig. 7. Partici-
pation of the allyltin tribromide 162 has been invoked to explain
the stereoselectivities of reactions of stannanes 122 and 123 with
aldehydes.8
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2-acetamido-6-acetoxyheptanoate so obtained was found to cor-
respond to the 2,6-anti-epimer 43 that had been prepared earlier.
The products 172 and 174 from the reaction of the allyltin tri-
chloride derived from the allylstannane 1 and the oxime 166
were unstable to storage. In this case, the major product was
assigned the 2,6-anti-configuration by analogy with the selective
formation of the 2,6-anti-epimer 171, see Scheme 20.
methoxyhex-2-enylstannanes (S)-122 and (S)-123 with achiral
imines showed some 1,6-stereocontrol in favour of (4E)-2,7-anti-
epimers, but the stereoselectivities of reactions with chiral
imines were dominated by the stereochemical preferences of the
imines. These results are summarised in Fig. 8.
The stereoselectivities of these reactions are consistent with
stereoselective transmetalation of the alk-2-enylstannanes to gen-
erate the allyltin trihalides that had been postulated previously to
explain remote stereocontrol in analogous reactions with alde-
hydes.8,9 However, aldehydes give rise to the formation of (Z)-
alkenes whereas (E)-alkenes were obtained for reactions with
imines. This reversal in stereoselectivity is consistent with either
six-membered cyclic or open-chain transition structures for the
reactions of the intermediate allyltin trihalides with imines, cf.
Fig. 3. However, since imines with electron withdrawing substi-
tuents were found to be the more reactive towards allyltin triha-
lides, that themselves are electron deficient reagents, it may be
that the cyclic transition structures in which the imine is acti-
vated by co-ordination to the tin are involved, see Fig. 3–7. If
this is the case, the preference for (E)-alkene formation may be
due to the unfavourable 1,3-diaxial interactions between the
group next to tin and the substituent on the nitrogen of the imine
that would be present in the analogous transition structures for
(Z)-alkene formation.8,9,15,16
Summary and conclusions
It has been shown that tin(IV) chloride promoted reactions of the
4-alkoxypent-2-enylstannane
1 with 1-alkoxycarbonylimines
proceed with useful stereocontrol, typically greater than 90 : 10,
in favour of (4E)-2,6-anti-2-alkylamino-6-alkoxyheptenoates 49.
This stereoselectivity overwhelmed the intrinsic diastereofacial
preferences of N-α-methylbenzylimines. Analogous reactions of
the 5-benzyloxy-4-methylpent-2-enylstannane 80 showed more
enhanced matching and mismatching with the chiral imines but
nevertheless showed useful 1,5-stereocontrol in reactions with
achiral 1-alkoxycarbonylimines. The 4-alkoxy-5-silyloxypent-2-
enylstannane 106 was also found to react with 1-alkoxycarbonyl-
imines with excellent stereocontrol in favour of the (4E)-2,6-
anti-2-alkylamino-6-alkoxyheptenoates 179. The use of (tert-
butyldimethylsilyloxy) substituted pent-2-enylstannanes in these
reactions demonstrated complementary effects in that in the 4-
alkoxy series the 1,5-stereoselectivity was reversed to give the
2,6-syn-diastereoisomers 79 albeit with lower overall stereoselec-
tivity, whereas it was just slightly reduced in the 5-alkoxy series.
Tin(IV) bromide promoted reactions of the 5-hydroxy- and 5-
The reactions of allyltin trihalides with imines tend to be
slower than the analogous reactions with aldehydes. As epimeric
allyltin trihalides can epimerise at the stereogenic centre next to
the tin,15 this may account for the reduced stereoselectivities
observed for the reactions of the 5-alkoxystannanes with mis-
Fig. 8 Summary of remote stereoselectivities of reactions between imines and alkoxy- and hydroxy-stannanes.
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matched chiral imines. Nevertheless for alk-2-enylstannanes
with alkoxy substituents leading to 1,5-stereocontrol, stereoselec-
tivities in excess of 90 : 10 were observed with achiral imines
and this chemistry should be synthetically useful for the syn-
thesis of novel α-amino acids.
was then added and the mixture stirred vigorously whilst being
allowed to warm to ambient temperature. Water was added and
the mixture extracted DCM. The aqueous phase was basified to
pH 10 by the addition of aqueous sodium hydroxide (1 M) and
washed with DCM. The organic extracts were dried (MgSO4)
and concentrated under reduced pressure. Chromatography of the
residue gave the product.
In some cases, water (0.5 mL) was added to the reaction
mixture and, after stirring to ambient temperature, silica was
added (ca. 5 g). The solvent was then carefully removed under
reduced pressure to afford a powder that was applied to a
column of silica gel.
Experimental
General experimental procedures
NMR spectra were obtained using Varian Unity 500, Bruker AC
300, or Varian XL 300 spectrometers. Chemical shifts are quoted
in parts per million downfield from tetramethylsilane. Low resol-
ution MS were obtained on a Fisons VG Trio 2000 spectrometer,
using electron impact (EI) and chemical ionisation (CI) modes.
Fast atom bombardment (FAB) and high resolution mass
measurements were acquired on a Kratos Concept spectrometer.
IR spectra were measured on an ATI Mattson Genesis Series
FTIR spectrometer as evaporated thin films on sodium chloride
plates. Optical rotations were measured at 589 nm at ambient
temperature using an Optical Activity AA-100 polarimeter.
All non-aqueous reactions were performed in oven (140 °C)
or flame-dried glassware under an inert atmosphere of dry nitro-
gen or argon. Solvents were dried immediately prior to use by
distillation under an atmosphere of dry nitrogen from sodium
benzophenone ketyl (diethyl ether, tetrahydrofuran, hexane),
calcium hydride (DCM, dimethyl sulfoxide) or anhydrous pot-
assium hydroxide (triethylamine, diisopropylamine, pyridine).
Analytical grade toluene and benzene were dried over sodium
wire for 24 h prior to use. Methanol was dried over magnesium
turnings and then distilled. Petrol refers to that fraction of light
petroleum ether which boils between 40 and 60 °C and was
redistilled prior to use. Butyllithium was supplied as a solution
in hexanes and was titrated against anhydrous butanol in tetra-
hydrofuran using 2,2′-dipyridyl as indicator. Ether refers to
diethyl ether whilst brine refers to saturated aqueous sodium
chloride. Preparative column chromatography was carried out
using Merck silica 9385 (230–400 ASTM mesh) or Merck silica
gel 60H (40–63μ, 230–300 mesh). Analytical high performance
liquid chromatography (HPLC) was carried out using a pump
controlled Gilson assembly with a Dynamax 60Å silica column
with (dimensions of 21.4 × 250 mm) and a guard column, moni-
toring at 254 nm using a Gilson 115 UV detector.
General procedure for the deprotection of
nitrophenylsulfanylamines
The nitrophenylsulfanylamine was dissolved in the minimum
volume of methanol and saturated methanolic hydrogen chloride
(typically 10 mL for 1 mmol of substrate) added. The resulting
yellow suspension was stirred at ambient temperature for 2 h
before concentration under reduced pressure. The residue was
suspended in chloroform and extracted twice with aqueous
hydrogen chloride (1 M). The aqueous washings were basified
by the addition of solid sodium hydrogen carbonate and the
mixture extracted into ether. The organic phase was dried
(MgSO4) and concentrated under reduced pressure.
General procedure for the preparation of methyl carbamates
Anhydrous potassium carbonate (2 molar equivalents) and
methyl chloroformate (2 molar equivalents) were added to the
amine and the suspension stirred at ambient temperature for
16 h. Water was added and, after 10 min, the mixture was
extracted with chloroform. The organic layer was dried
(MgSO4), absorbed on to silica and the resulting powder applied
to a column of silica gel.
General procedure for the cbz-protection of α-amino esters
Anhydrous potassium carbonate (2 molar equivalents) and
benzyl chloroformate (1.3 molar equivalents) were added to the
α-amino ester in chloroform (typically 10 mL for a 1 mmol and
the mixture was heated under reflux for 16 h. After cooling to
ambient temperature, chloroform was added and the mixture
washed with water and brine. The organic extracts were dried
(MgSO4), absorbed on to silica and the resulting powder was
applied to a column of silica gel.
The imines were prepared following literature procedures;7 for
the (S)-imine (S)-11, [α]D −48 (c 1.1 in CHCl3), −24.04 (neat)
[lit.7 −18.2 (neat)]; for the (R)-imine (R)-11, [α]D +46.3 (c 1.7 in
CHCl3), +25.9 (neat).
General procedure for the reaction of an alkoxyalk-2-
enylstannane with an imine
General procedure for the ozonolysis of unsaturated α-amido
esters followed by reduction using NaBH4 and lactonisation
The tin(IV) halide in DCM was cooled to −78 °C and the allyl-
stannane (1.05 molar equivalents based on the amount of Lewis
acid) in cooled (−78 °C) DCM was added. After fifteen minutes,
the imine (1.05 molar equivalents based on the amount of Lewis
acid) in DCM was added dropwise by syringe over five minutes
whilst maintaining the reaction at −78 °C. The resulting solution
or suspension was stirred at either −78 °C, −50 °C or −45 °C
for the appropriate time. Saturated aqueous ammonium chloride
The α-amido ester in methanol (typically 20 mL for 1 mmol of
substrate) was cooled to −78 °C and ozone bubbled through the
solution for 90 min at −78 °C (a permanent blue colour appeared
after ca. twenty minutes depending on the scale). The mixture
was purged with nitrogen, methyl sulfide (3 molar equivalents
based on the cbz-derivative) was added as a single portion and
the reaction mixture stirred whilst being allowed to warm to
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General procedures for the acylation of α-amino esters
ambient temperature over 1 h. After concentration under reduced
pressure, the residue was dissolved in methanol and the solution
was cooled to 0 °C.
The α-amino ester was dissolved in DCM (typically 10 mL for a
1 mmol reaction) and triethylamine (3 molar equivalents), acetic
anhydride (1.5 molar equivalents) and DMAP (catalytic) were
added. The mixture was stirred at ambient temperature for 16 h
before water was added to the reaction mixture and the stirring
continued for 10 min. DCM was added and the organic extract
washed with a saturated aqueous sodium hydrogen carbonate
and dried (MgSO4). This solution was absorbed on to silica and
the resulting powder applied to a column of silica gel.
Alternatively, the α-amino ester was dissolved in DCM (typi-
cally 10 mL for a 1 mmol reaction) and triethylamine (6 molar
equivalents), acetic anhydride (3 molar equivalents) and DMAP
(catalytic) were added. This mixture was stirred at ambient temp-
erature for 16 h then worked up as above.
Sodium borohydride (4 molar equivalents based on the sub-
strate) was added and the reaction mixture stirred at ambient
temperature for 30 min. Saturated aqueous ammonium chloride
was added and the mixture concentrated under reduced pressure.
The residue was suspended in DCM, and the mixture washed
with water, aqueous hydrogen chloride (0.1 M) and water and
then dried (MgSO4). Concentration under reduced pressure gave
the alcohol.
The alcohol was dissolved in the minimum volume of metha-
nol, hydrochloric acid (37% w/v) was added (typically 5 mL for
a 1 mmol reaction) and the reaction mixture stirred at ambient
temperature for 16 h. The resulting suspension was poured into
water and solid sodium hydrogen carbonate added until neutral.
The methanol was removed under reduced pressure and the
aqueous residue extracted twice with ethyl acetate. The organic
extracts were washed with brine, dried (MgSO4) and absorbed
on to silica. The resulting powder was applied directly to a
column of silica gel and elution with hexane–ethyl acetate (4 : 1)
afforded the lactones.
General procedure for the diimide reduction of alkenes
The alkene and toluene 4-sulfonylhydrazine (10 molar equiva-
lents based on the alkene) in DME (typically 15 mL for a
1 mmol reaction) were heated under reflux. Anhydrous sodium
acetate (10 molar equivalents based on the alkene) dissolved in
the minimum volume of water was added over a period of two
hours whilst maintaining the reaction under reflux. The heating
was continued for a further 16 h and the reaction was then
cooled to ambient temperature and concentrated under reduced
pressure. The residue was suspended in ether and the mixture
washed with saturated aqueous sodium hydrogen carbonate and
water then dried (MgSO4). The solution was absorbed on to
silica and the resulting powder applied to a column of silica gel.
Alternatively, the alcohol was dissolved in chloroform (ca.
10 mL for a 1 mmol reaction), glacial acetic acid (catalytic) was
added and the solution heated under reflux for 16 h. After
cooling to ambient temperature, the mixture was washed with a
saturated aqueous sodium hydrogen carbonate, dried (MgSO4)
and absorbed on to silica. The ensuing powder was applied to a
column of silica gel.
General procedure for the removal of the cbz-group from
homoserine lactone derivatives
Ethyl N-(1-phenylbut-3-en-1-yl)carbamate 9
The general procedure using tin(IV) chloride (261 mg,
1.00 mmol) in DCM (5 mL), prop-2-enyl(tributyl)stannane 3
(348 mg, 1.05 mmol) in DCM (5 mL) and imine 8 (186 mg,
1.05 mmol) after 4 h at −78 °C with chromatography using
hexane–ether–triethylamine (80 : 19.5 : 0.5) as eluent gave the
title compound 9 (201 mg, 92%) as a colourless liquid (Found:
Ammonium formate (5 molar equivalents based on the lactone)
and 10% Pd/C (10% w/w based on the lactone) were added to
the cbz-protected lactone in methanol (typically 0.05 molar con-
centration) and the mixture stirred at ambient temperature for
30 min. The mixture was filtered (Whatman glass microfibre
filter paper GF/A) and the solution absorbed on to silica. The
resulting powder was applied to a small column of silica gel.
Elution with chloroform–methanol–triethylamine (99 : 0.5 : 0.5)
gave the amino lactone.
M+ + NH4, 237.1596. C13H21N2O2 requires M, 237.1603); νmax
/
cm−1 701, 761, 918, 994, 1048, 1077, 1098, 1173, 1253, 1334,
1373, 1440, 1534, 1642, 1693, 2981 and 3324; δH (300 MHz,
CDCl3) 1.26 (3 H, t, J 7.1, CH3), 2.56–2.60 (2 H, m, 2-CH2),
4.13 (2 H, q, J 7.1, CH3CH2), 4.80 (1 H, m, 1-H), 5.09 (1 H, br
s, NH), 5.12–5.19 (2 H, m, 4-H2), 5.73 (1 H, m, 3-H) and
7.26–7.40 (5 H, m, ArH); δC (75 MHz, CDCl3) 14.58, 41.14,
54.38, 60.91, 118.40, 126.24, 127.29, 128.57, 133.84, 142.18
and 155.94; m/z (CI) 237 (M+ + 18, 100%) and 220 (M+ + 1,
12).
General procedure for the removal of benzyl and benzhydryl
groups from α-amino esters
A solution of formic acid (98%) in methanol (10% v/v) was
freshly prepared and the protected amino ester was dissolved in
this solution typically at ∼0.075 molar concentration. 10% Pd/C
(15% w/w based on the ester) was added and the reaction
mixture stirred at ambient temperature for 16 h. The mixture was
filtered (Whatman glass microfibre filter paper GF/A) and the
solution concentrated under reduced pressure to give an oil. Any
remaining formic acid was removed by adding heptane to the
residue and concentrating under a high vacuum (three times).
Butyl (2S)- and (2R)-2-[(R)-(1-phenylethyl)amino]pent-4-enoate
12 and 13
The general procedure using tin(IV) chloride (12.48 g,
47.9 mmol) in DCM (40 mL), prop-2-enyl)tributyl)stannane 3
(16.66 g, 50.3 mmol) in DCM (40 mL) and the (R)-imine (R)-11
(11.74 g, 50.3 mmol) after 4 h at −78 °C with chromatography
6142 | Org. Biomol. Chem., 2012, 10, 6130–6158
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using petrol–ether–triethylamine (90 : 9.5 : 0.5) as eluent gave
the title compounds 12 and 13 (11.87 g, 90%) as a colourless
liquid, ratio 12 : 13 = 93 : 7 (1H NMR). Samples of each isomer
were obtained by preparative scale HPLC (Rainin Dynamax
silica column, UV at 254 nm, eluent hexane–ethyl acetate 6 : 1,
flow rate 15 mL min−1): the less polar minor (2R)-pent-4-enoate
137 (Found: M+ + H, 276.1959. C17H26NO2 requires M,
276.1964); [α]D +33 (c 1.0 in CHCl3); νmax/cm−1 771, 921,
1151, 1186, 1218, 1454, 1646, 1732, 2963 and 3331; δH
(500 MHz, CDCl3) 0.91 (3 H, t, J 7.3, CH3CH2), 1.30–1.38 (2
H, m, CH3CH2), 1.31 (3 H, d, J 6.4, CHCH3), 1.58 (2 H, qn, J
6.6, CH2CH2O), 1.90 (1 H, br s, NH), 2.29–2.32 (2 H, m, 3-H2),
3.07 (1 H, t, J 6.4, 2-H), 3.69 (1H, q, J 6.4, CHCH3), 4.10 (2 H,
t, J 6.6, CH2O), 5.01–5.06 (2 H, m, 5-H2), 5.68 (1 H, m, 4-H)
and 7.27–7.31 (5 H, m, ArH); δC (75 MHz, CDCl3) 13.69,
19.15, 25.34, 30.75, 38.27, 56.60, 58.61, 64.40, 117.74, 126.92,
127.06, 128.40, 133.84, 145.01 and 175.31; m/z (CI) 276 (M+ +
1, 100%); the more polar major (2S)-pent-4-enoate 12 (Found:
C, 74.1; H, 9.5; N, 5.0. C17H25NO2 requires C, 74.1; H, 9.2; N,
5.1); [α]D +23.2 (c 0.6 in CHCl3); νmax/cm−1 762, 917, 967,
996, 1026, 1064, 1183, 1273, 1342, 1372, 1453, 1493, 1603,
1641, 1734, 2961 and 3330; δH (500 MHz, CDCl3) 0.89 (3 H, t,
J 7.5, CH3CH2), 1.28–1.35 (2 H, m, CH3CH2), 1.32 (3 H, d, J
6.6, CHCH3), 1.53 (2 H, qn, J 7.1, CH2CH2O), 1.86 (1 H, br s,
NH), 2.37–2.40 (2 H, m, 3-H2), 3.35 (1 H, t, J 6.3, 2-H), 3.76
(1H, q, J 6.6, CHCH3), 3.93–4.02 (2 H, m, CH2O), 5.02–5.10 (2
H, m, 5-H2), 5.74 (1 H, m, 4-H) and 7.27–7.32 (5 H, m, ArH);
δC (75 MHz, CDCl3) 13.78, 19.21, 23.22, 30.69, 37.52, 56.09,
58.70, 64.45, 117.80, 126.66, 127.00, 128.28, 133.55, 145.02
and 174.33; m/z (CI) 276 (M+ + 1, 100%).
the α-amino ester ent-12 (1.0 g, 3.64 mmol) in 1,4-dioxane
(20 mL) and the mixture was heated under reflux for 16 h. After
cooling to ambient temperature and concentration under reduced
pressure, the residue was suspended in ether (60 mL). The sol-
ution was washed with water and brine, dried (MgSO4) and
absorbed on to silica. The resulting powder was applied to a
column of silica gel to give the title compound 14 (1.57 g, 90%)
as a colourless oil that crystallised on standing as colourless
prisms, m.p. 71–72 °C; [α]D −24.7 (c 1.2 in CH2Cl2); νmax/cm−1
701, 798, 848, 892, 916, 994, 1027, 1074, 1166, 1319, 1369,
1385, 1420, 1454, 1497, 1642, 1706, 1740 and 2960; δH
(300 MHz, CDCl3) 0.97 (3 H, t, J 7.3, CH3CH2), 1.44 (2 H,
hex, J 7.5, CH3CH2), 1.56–1.69 (2 H, m, CH2CH2O), 1.62 (3 H,
d, J 7.2, CHCH3), 1.99 and 2.04 (each 3 H, s, CH3), 2.31 (0.4
H, m, 3-H, minor rotamer), 2.73 (1 H, m, 3-H), 2.86 (0.6 H, m,
3-H, major rotamer), 3.49 (0.6 H, dd, J 8.1 and 5.1, 2-H, major
rotamer), 4.01–4.24 (2.4 H, m, CH2O and 2-H, minor rotamer),
4.56 (1 H, m, 5-H), 4.68 (1 H, m, 5-H), 5.08 (0.4 H, m, 4-H,
minor rotamer), 5.26 (0.6 H, m, 4-H, major rotamer), 5.66 (1H,
m, PhCH) and 7.34–7.39 (5 H, m, ArH); δC (75 MHz, CDCl3,
major rotamer) 13.72, 16.57, 19.27, 21.56, 21.66, 30.66, 35.18,
55.04, 56.70, 65.02, 88.95, 116.58, 128.07, 128.46, 135.32,
139.72, 148.54, 152.44 and 171.34; m/z (CI) 480 (M+ + 1,
10%), 478 (M+ + 1, 10) and 276 (100).
The enantiomeric carbamate ent-14 was similarly prepared
(Found: C, 55.1; H, 6.4; N, 2.9. C22H30Cl3NO4 requires C, 55.2;
H, 6.3; N, 2.9); [α]D +23 (c 1.04 in CH2Cl2). Spectroscopic data
were identical to those of the enantiomer 14.
Potassium tert-butoxide in THF (1 M; 11 mL) was added to
the (S)-ester 12 (2.76 g, 10 mmol) in cooled (−78 °C) THF
(30 mL) over a period of five minutes with and the mixture
stirred at −78 °C for ten minutes. Water (10 mL) was added and
mixture stirred vigorously whilst warming to ambient tempera-
ture. After concentration under reduced pressure, the residue dis-
solved in ether and the solution washed with water, brine, dried
(MgSO4) and absorbed on to silica. The resulting powder was
applied to a column of silica gel and elution with hexane–ether–
triethylamine (90 : 9.5 : 0.5) gave the esters 12 and 13 (2.43 g,
88%) in the ratio 17 : 83 (1H NMR). Preparative scale HPLC
gave the (2R)-isomer 13 (1.67 g) together with the (2S)-isomer
12 (346 mg) as colourless oils.
Following the general procedure, tin(IV) chloride (1.13 g,
4.34 mmol) in DCM (7 mL), prop-2-enyl(tributyl)stannane 3
(1.51 g, 4.56 mmol) in DCM (7 mL) and the (S)-imine (S)-11
(1.07 g, 4.57 mmol) after chromatography using petrol–ether–
triethylamine (90 : 9.5 : 0.5) as eluent, gave butyl (2R)- and (2S)-
2-[(S)-(1-phenylethyl)amino]-pent-4-enoate ent-12 and ent-13
(1.05 g, 88%) as a colourless liquid, ent-12 : ent-13 = 93 : 7
(1H NMR). Further chromatography gave the (2R)-isomer ent-
12, [α]D −23 (c 1.0 in CHCl3). Spectroscopic data were identical
to those of the enantiomer 12.
Butyl (2R,6S,E)- and (2S,6S,E)-6-benzyloxy-2-[(S)-
(1-phenylethyl)amino]hept-4-enoate 15 and 16
The general procedure using tin(IV) chloride (651 mg,
2.50 mmol) in DCM (8 mL), the 4-benzyloxypent-2-enylstan-
nane 1 (1.22 g, 2.62 mmol) in DCM (8 mL) and the imine (S)-
11 (612 mg, 2.62 mmol) in DCM (8 mL) after 12 h at −45 °C
and
chromatography
using
petrol–ether–triethylamine
(90 : 9.5 : 0.5) as eluent gave the title compounds 15 and 16
(747 mg, 73%) as a colourless oil, ratio 15 : 16 = 96 : 4
(1H NMR). Further chromatography using petrol–ether (9 : 1) as
the eluent gave a sample of the major (2R)-epimer 15 as a col-
ourless oil (Found: M+ + H, 410.2690. C26H36NO3 requires M,
410.2695); [α]D −26 (c 1.6 in CHCl3); νmax/cm−1 700, 736, 972,
1028, 1071, 1153, 1182, 1275, 1372, 1453, 1494, 1732, 2870,
2963 and 3360; δH (300 MHz, CDCl3) 0.95 (3 H, t, J 7.3,
CH3CH2), 1.30 (3 H, d, J 6.5, 7-H3), 1.34–1.44 (2 H, m,
CH3CH2), 1.39 (3 H, d, J 6.5, CHCH3), 1.60 (2 H, qn, J 7.4,
CH2CH2O), 1.94 (1 H, br s, NH), 2.35–2.51 (2 H, m, 3-H2),
3.43 (1 H, t, J 6.1, 2-H), 3.84 (1 H, q, J 6.5, PhCH), 3.92 (1 H,
qn, J 6.8, 6-H), 4.04 (2 H, t, J 6.7, CH2CH2O), 4.38 and 4.57
(each 1 H, d, J 11.9, PhHCHO), 5.53 (1 H, dd, J 15.5 and 7.5,
5-H), 5.63 (1 H, dt, J 15.5 and 6.7, 4-H) and 7.24–7.38 (10 H,
m, ArH); δC (75 MHz, CDCl3) 13.70, 19.15, 21.71, 23.21,
30.66, 35.93, 56.10, 58.85, 64.55, 69.73, 75.47, 126.75, 127.17,
127.39, 127.69, 128.34, 128.46, 135.53, 138.85, 145.23 and
174.46; m/z (CI) 410 (M+ + 1, 100%). Minor peaks in the
mixture of epimers were attributed to the (2S)-epimer 16; δH
(300 MHz, CDCl3) 3.13 (t, J 6.1, 2-H).
Butyl (2R)-2-{(2,2,2-trichloro-1,1-dimethylethoxy)carbonyl-
[(S)-(1-phenylethyl)]amino}pent-4-enoate 14
Anhydrous potassium carbonate (1.0 g), (2,2,2-trichloro-1,1-
dimethyl)ethyl chloroformate (1.0 g, 4.17 mmol) was added to
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Butyl (2R,6S,E)- and (2S,6S,E)-6-benzyloxy-2-[(R)-(1-phenyl-
ethyl)amino]hept-4-enoate 17 and 18
methanol to afford the title compound 21 (1.57 g, 79%) as a
white powder. A single recrystallisation from DCM–hexane gave
the lactone 21 as colourless needles, m.p. 151–153 °C (Found:
C, 70.6; H, 6.3; N, 4.3. C20H21NO4 requires C, 70.8; H, 6.25; N,
4.15); [α]D +21 (c 1.1 in CHCl3); νmax/cm−1 699, 1027, 1139,
1180, 1210, 1277, 1310, 1426, 1450, 1696, 1779 and 2976; δH
(300 MHz, CDCl3, mixture of rotamers) 1.64–1.80 (1 H, m),
1.68 (3 H, d, J 7, CHCH3), 2.21 (0.45 H, m, minor rotamer),
2.46 (0.55 H, m, major rotamer), 3.66 (1 H, m, 3-H), 3.90–4.12
(1.45 H, m, 5-H), 4.44 (0.55 H, m, 5-H, major rotamer), 5.11
(0.45 H, d, J 12, PhHCH, minor rotamer), 5.23–5.36 (1.55 H, m,
PhHCH), 5.57 (0.55 H, m, CHCH3 major rotamer), 5.73 (0.45
H, m, CHCH3, minor rotamer) and 7.30–7.45 (10 H, m, ArH);
δC (75 MHz, CDCl3, both rotamers) 16.46, 17.15, 26.41, 27.37,
51.48, 52.51, 54.22, 54.33, 65.10, 65.56, 67.78, 68.28, 127.45,
127.67, 127.90, 127.95, 128.25, 128.37, 128.44, 128.61, 128.74,
135.55, 136.21, 140.11, 154.79, 154.99, 174.75 and 174.96; m/z
357 (M+ + 18, 100%) and 340 (M+ + 1, 15).
The general procedure using tin(IV) chloride (782 mg,
3.00 mmol) in DCM (9 mL), the 4-benzyloxypent-2-enylstan-
nane 1 (1.47 g, 3.16 mmol) in DCM (9 mL) and the imine (R)-
11 (735 mg, 3.15 mmol) in DCM (9 mL) after 12 h at −45 °C
and
chromatography
using
petrol–ether–triethylamine
(90 : 9.5 : 0.5) as eluent gave the title compounds 17 and 18
(884 mg, 72%) as a colourless oil, ratio 17 : 18 = 92 : 8
(1H NMR). Further chromatography using petrol–ether (9 : 1) as
the eluent gave a sample of the major (2R)-epimer 17 as a col-
ourless oil (Found: M+ + H, 410.2692. C26H36NO3 requires
M, 410.2695); [α]D +33 (c 1.4 in CHCl3); νmax/cm−1 699, 736,
972, 1029, 1071, 1153, 1180, 1372, 1454, 1495, 1733, 2870,
2963 and 3334; δH (300 MHz, CDCl3) 0.98 (3 H, t, J 7.3,
CH3CH2), 1.30 (3 H, d, J 6.4, 7-H3), 1.34–1.45 (2 H, m,
CH3CH2), 1.37 (3 H, d, J 6.5, CHCH3), 1.64 (2 H, qn, J 7.3,
CH2CH2O), 1.85 (1 H, br s, NH), 2.35–2.40 (2 H, m, 3-H2),
3.14 (1 H, t, J 6.7, 2-H), 3.76 (1 H, q, J 6.5, PhCH), 3.91 (1 H,
qn, J 6.8, 6-H), 4.10–4.24 (2 H, m, CH2CH2O), 4.37 and 4.54
(each 1 H, d, J 11.9, PhHCHO), 5.49 (1 H, dd, J 15.5 and 7.4,
5-H), 5.60 (1 H, dt, J 15.5 and 6.7, 4-H) and 7.30–7.36 (10 H,
m, ArH); δC (75 MHz, CDCl3) 13.69, 19.16, 21.65, 25.34,
30.77, 36.75, 56.68, 58.93, 64.48, 69.78, 75.55, 126.93, 127.38,
127.69, 127.85, 128.34, 128.40, 135.27, 138.90, 145.01 and
175.2; m/z (CI) 410 (M+ + 1, 100%). Minor peaks in the mixture
of epimers were attributed to the (2S)-epimer 18; δH (300 MHz,
CDCl3) 2.43–2.50 (m, 3-H2), 3.43 (t, J 6.7, 2-H), 4.04 (t, J 6.7,
CH2CH2O).
(3S)-3-[(R)-1-(phenyl)ethyl]aminobutyrolactone 22
The general procedure using lactone 21 (150 mg, 0.442 μmol),
ammonium formate (139 mg, 2.20 mmol) and 10% Pd/C
(15 mg) gave the title compound 22 (64 mg, 71%) as a colour-
less oil (Found: M+ + 1, 206.1179. C12H16NO2 requires M,
206.1181); [α]D +29.6 (c 1.5 in CHCl3); νmax/cm−1 1022, 1165,
1311, 1378, 1452, 1494, 1604, 1772, 2915 and 3326; δH
(300 MHz, CDCl3) 1.45 (3 H, d, J 6.7, CHCH3), 2.06–2.20 (2
H, m, 4-H and NH), 2.45 (1 H, m, 4-H), 3.35 (1 H, dd, J 10.9
and 8.1, 3-H), 3.84 (1 H, q, J 6.7, CHCH3), 4.10 (1 H, ddd, J
11.0, 9.3 and 6.0, 5-H), 4.36–4.43 (1 H, m, 5-H) and 7.28–7.42
(5 H, m, ArH); δC (75 MHz, CDCl3) 24.43, 30.85, 53.91, 56.49,
65.67, 126.41, 127.46, 128.84, 143.90 and 177.62; m/z (CI) 206
(M+ + 1, 100%).
Butyl (2S)-2-{benzyloxycarbonyl-[(R)-(1-phenyl)ethyl]amino}-
pent-4-enoate 19
The general procedure using amino ester 12 (1.80 g,
6.54 mmol), anhydrous potassium carbonate (1.81 g,
13.10 mmol) and benzyl chloroformate (1.20 mL, 8.51 mmol)
after chromatography using hexane–ether (98 : 2 to 9 : 1) gave
the title compound 19 (2.44 g, 91%) as a colourless oil (Found:
C, 73.2; H, 7.7; N, 3.7. C25H31NO4 requires C, 73.3; H, 7.6; N,
3.4); [α]D +32.5 (c 0.6 in CHCl3); νmax/cm−1 700, 741, 769,
916, 996, 1028, 1043, 1075, 1135, 1209, 1261, 1310, 1380,
1428, 1497, 1701, 1741 and 2960; δH (400 MHz, toluene-d8,
90 °C) 0.79 (3 H, t, J 7.3, CH3CH2), 1.21 (2 H, hex, J 7.4,
CH3CH2), 1.39 (2 H, qn, J 7.1, CH2CH2O), 1.51 (3 H, d, J 6.6,
CHCH3, major rotamer), 1.61 (3 H, d, J 7.0, CHCH3, minor
rotamer), 2.16 (1 H, m, 3-H), 2.88 (1 H, m, 3-H), 3.63 (1 H, dd,
J 7.8 and 5.6, 2-H), 3.86–4.02 (2 H, m, CH2CH2O), 4.57–4.71
(2 H, m, 5-H2), 5.07 and 5.13 (each 1 H, d, J 12.4, PhHCHO),
5.43 (1 H, m, 4-H), 5.56 (1 H, q, J 6.6, PhCH) and 7.00–7.26
(10 H, m, ArH); m/z (CI) 410 (M+ + 1, 30%) and 276 (100).
Butyl (2R)-2-{benzyloxycarbonyl-[(R)-(1-phenyl)ethyl]amino}-
pent-4-enoate 23
The general procedure using amine 13 (1.0 g, 3.63 mmol), anhy-
drous potassium carbonate (1.0 g, 7.24 mmol) and benzyl
chloroformate (666 μL, 4.72 mmol) after chromatography using
hexane–ether (98 : 2 to 9 : 1) as eluent gave the title compound
23 (1.40 g, 94%) as a colourless oil (Found: M+ + Na, 432.2152.
C25H31NO4Na requires M, 432.2151; [α]D +38.2 (c 1.1 in
CHCl3); νmax/cm−1 699, 745, 910, 1028, 1140, 1208, 1309,
1428, 1453, 1703, 1733 and 2957; δH (300 MHz, CDCl3, a
mixture of rotamers) 0.88 (3 H, t, J 7.1, CH3CH2), 1.11–1.26 (2
H, m, CH3CH2), 1.27–1.40 (2 H, m, CH2CH2O), 1.60 (3 H, d, J
7.1, CHCH3), 2.50–2.80 (1 H, m, 3-H), 2.90–3.10 (1 H, m, 3-
H), 3.52–3.95 (3 H, m, 2-H and CH2CH2O), 5.10–5.35 (4 H, m,
5-H2 and PhCH2), 5.50–5.80 (1 H, m, 4-H), 5.90 (1 H, q, J 7.1,
CHCH3) and 7.25–7.49 (10 H, m, ArH); m/z (FAB) 432 (M+ +
23, 2%), 410 (M+ + 1, 40) and 276 (100).
(3S)-3-{N-Benzyloxycarbonyl-[(R)-1-(phenyl)ethyl]amino}-
butyrolactone 21
(3R)-3-{N-Benzyloxycarbonyl-[(R)-1-(phenyl)ethyl]amino}-
butyrolactone 25
The general procedure using the cbz-protected aminoester 19
(2.40 g, 5.86 mmol), ozone, methyl sulfide (1.29 mL,
17.57 mmol) and sodium borohydride (887 mg, 23.45 mmol)
gave the alcohol 20 that was cyclised using hydrogen chloride in
The general procedure using the cbz-protected aminoester 23
(1.40 g, 3.42 mmol), ozone, methyl sulfide (753 μL,
6144 | Org. Biomol. Chem., 2012, 10, 6130–6158
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10.25 mmol) and sodium borohydride (517 mg, 13.67 mmol)
gave the alcohol 23 that was cyclised using hydrogen chloride in
methanol to afford the title compound 25 (838 mg, 72%) as a
white powder. A single recrystallisation from DCM–hexane gave
the lactone 25 as colourless needles, m.p. 126–128 °C (Found:
C, 70.5; H, 6.1; N, 4.3. C20H21NO4 requires C, 70.8; H, 6.2; N,
4.1); [α]D +43 (c 0.5 in CHCl3); νmax/cm−1 699, 751, 1023,
1143, 1178, 1214, 1271, 1308, 1426, 1496, 1697, 1780 and
2977; δH (300 MHz, CDCl3, mixture of rotamers) 1.54 (3 H, d,
J 6.9, CHCH3), 2.27–2.42 and 2.55–2.67 (each 1 H, m), 3.65
(1 H, t, J 9.5, 3-H), 3.95–4.15 (1.5 H, m, 5-H), and 4.45 (0.5 H,
m, 5-H), 5.02–5.35 (2 H, m, PhCH2), 5.50 and 5.69 (each 0.5 H,
m, CHCH3), 7.24–7.39 (8 H, m, ArH) and 7.46–7.52 (2 H, m,
ArH); δC (75 MHz, CDCl3, both rotamers) 17.86, 18.60, 27.54,
28.50, 51.16, 51.86, 54.22, 64.68, 65.04, 67.77, 68.19, 127.32,
127.70, 127.90, 128.21, 128.52, 135.56, 136.03, 139.54, 154.80
and 173.51; m/z (CI) 357 (M+ + 18, 100%) and 340 (M+ + 1,
12).
the alcohol ent-20 that was cyclised using hydrogen chloride in
methanol to afford the amidolactone ent-21 (342 mg, 86%) as a
white powder. A single recrystallisation from DCM–hexane gave
the lactone ent-21 as colourless needles, m.p. 152–153 °C; [α]D
−21.4 (c 1.6 in CHCl3) (Found: C, 70.6; H, 6.25; N, 4.3%.
C20H21NO4 requires C, 70.8, H, 6.25; N, 4.5%).
The general procedure using lactone ent-21 (150 mg,
0.442 μmol), ammonium formate (139 mg, 2.20 mmol) and
10% Pd/C (15 mg) gave the aminolactone ent-22 (71 mg, 78%)
as a colourless oil, [α]D −27.9 (c 1.5 in CHCl3).
Butyl (2R,6S,E)-6-benzyloxy-2-{[benzyloxycarbonyl-[(R)-(1-
phenylethyl)amino]}hept-4-enoate 28
The general procedure using amino-ester 17 (600 mg,
1.46 mmol), anhydrous potassium carbonate (405 mg,
2.93 mmol) and benzyl chloroformate (269 μL, 1.91 mmol) after
chromatography using hexane–ether (9 : 1) gave the title com-
pound 28 (662 mg, 83%) as a colourless oil (Found: M+ + Na,
566.2896. C34H41NO5Na requires M, 566.2882; [α]D +34 (c 0.9
in CHCl3); νmax/cm−1 699, 742, 916, 1073, 1209, 1309, 1428,
1453, 1703, 1738 and 2963; δH (300 MHz, DMSO-d6, 60 °C)
0.88 (3 H, t, J 7.1, CH3CH2), 1.16–1.24 (2 H, m, CH3CH2),
1.26 (3 H, d, J 6.4, 7-H3), 1.37 (2 H, qn, J 6.7, CH2CH2O), 1.63
(3 H, d, J 7.1, CHCH3), 2.69 (1 H, m, 3-H), 2.90 (1 H, m, 3-H),
3.82 (1 H, t, J 6.3, 2-H), 3.98 (2 H, q, J 6.6, CH2CH2O), 4.03
(1 H, m, 6-H), 4.42 and 4.54 (each 1 H, d, J 12.3, PhHCH), 5.11
and 5.21 (1 H, d, J 12.5, PhHCH), 5.35 (1 H, q, J 7.1, CHCH3),
5.51 (1 H, dd, J 15.4 and 6.9, 5-H), 5.77 (1 H, dt, J 15.4 and
7.6, 4-H) and 7.32–7.48 (15 H, m, ArH); m/z (FAB) 566 (M+ +
23, 3%), 544 (M+ + 1, 100) and 436 (100).
The general procedure using cbz-protected amino-ester 28
(600 mg, 1.10 mmol), ozone, methyl sulfide (243 μL,
3.31 mmol) and sodium borohydride (167 mg, 4.41 mmol) gave
the alcohol 24 that was cyclised using hydrogen chloride in
methanol to afford the lactone 25 as a white powder (288 mg,
77%). A single recrystallisation from DCM–hexane gave the
lactone 25 as colourless needles, [α]D +42.6 (c 1.0 in CHCl3).
The general procedure using amidolactone 25 (150 mg,
0.442 μmol), ammonium formate (139 mg, 2.20 mmol) and
10% Pd/C (15 mg) gave the aminolactone 26 as a colourless oil
(66 mg, 73%), [α]D +103.6 (c 1.2 in CHCl3).
(3R)-3-[(R)-1-(phenyl)ethyl]aminobutyrolactone 26
The general procedure using lactone 25 (150 mg, 0.442 μmol),
ammonium formate (139 mg, 2.20 mmol) and 10% Pd/C
(15 mg) gave the title compound 26 (77 mg, 85%) as a colour-
less oil (Found: M+ + H, 206.1178. C12H16NO2 requires
M, 206.1181); [α]D +105 (c 1.7 in CHCl3); νmax/cm−1 704, 766,
953, 1021, 1161, 1216, 1267, 1311, 1377, 1452, 1492, 1771,
2968 and 3323; δH (300 MHz, CDCl3) 1.36 (3 H, d, J 6.6,
CHCH3), 1.79 (1 H, m, 4-H), 1.90 (1 H, m, 4-H), 2.13 (1 H, br
s, NH), 3.34 (1 H, dd, J 11.0 and 8.1, 3-H), 3.95 (1 H, ddd, J
11.0, 9.3 and 6.1, 5-H), 4.08 (1 H, q, J 6.6, CHCH3), 4.16–4.22
(1 H, m, 5-H) and 7.19–7.35 (5 H, m, ArH); δC (75 MHz,
CDCl3) 25.38, 32.54, 56.28, 58.87, 66.34, 127.78, 128.06,
129.18, 145.57 and 178.68; m/z (CI) 206 (M+ + 1, 100%).
Butyl (2R,6S,E)-6-benzyloxy-2-{[benzyloxycarbonyl-[(S)-(1-
phenylethyl)amino]}hept-4-enoate 27
The general procedure using the amino-ester 15 (575 mg,
1.40 mmol), anhydrous potassium carbonate (388 mg,
2.81 mmol) and benzyl chloroformate (257 μL, 1.82 mmol) after
chromatography using hexane–ether (9 : 1) as eluent gave the
title compound 27 (649 mg, 85%) as a colourless oil (Found: M+
+ Na, 566.2898. C34H41NO5Na requires M, 566.2883; [α]D −22
(c 2.0 in CHCl3); νmax/cm−1 699, 738, 975, 1073, 1210, 1308,
1430, 1453, 1496, 1703, 1738 and 2962; δH (300 MHz, DMSO-
d6, 80 °C) 0.96 (3 H, t, J 7.3, CH3CH2), 1.16 (3 H, d, J 6.3, 7-
H3), 1.35–1.43 (2 H, m, CH3CH2), 1.54–1.63 (2 H, m,
CH2CH2O), 1.65 (3 H, d, J 7.1, CHCH3), 2.09 (1 H, m, 3-H),
2.72 (1 H, m, 3-H), 3.72 (1 H, qn, J 6.6, 6-H), 3.92 (1 H, dd, J
7.4 and 5.6, 2-H), 4.00–4.13 (2 H, m, CH2CH2O), 4.31 and 4.42
(each 1 H, d, J 12.2, PhHCH), 5.03 (1 H, dd, J 15.6 and 7.3, 5-
H), 5.16 and 5.22 (each 1 H, d, J 11.6, PhHCH), 5.48 (1 H, q, J
7.1, CHCH3), 5.67 (1 H, dt, J 15.6 and 7.0, 4-H) and 7.32–7.50
(15 H, m, ArH); m/z (FAB) 566 (M+ + 23, 3%) and 436 (100).
The general procedure using cbz-protected amino-ester 27
(640 mg, 1.18 mmol), ozone, methyl sulfide (259 μL,
3.53 mmol) and sodium borohydride (178 mg, 4.71 mmol) gave
Butyl (E)-2-(diphenylmethylimino)ethanoate 32
Butyl glyoxylate monohydrate (6.06 g, 40.9 mmol) and diphe-
nylmethylamine (7.05 mL, 40.9 mmol) in benzene (100 mL)
were heated under reflux with azeotropic removal of water for
2 h. Cooling to ambient temperature and concentration under
reduced pressure gave an oil that solidified on standing. This
solid was stirred with ice-cold hexane for 1 h and dried under a
high vacuum (0.1 mm Hg) to afford the title compound 32
(10.87 g 90%) as a white powder, m.p. 46–47 °C (Found: C,
77.3; H, 7.4; N, 4.75. C19H21NO2 requires C, 77.3; H, 7.2; N,
4.74); νmax/cm−1 700, 745, 860, 1028, 1062, 1199, 1293, 1366,
1392, 1453, 1494, 1601, 1648, 1721, 1749 and 2960; δH
(300 MHz, CDCl3) 0.99 (3 H, t, J 7.4, CH3CH2), 1.46 (2 H,
hex, J 7.6, CH3CH2), 1.75 (2 H, qn, J 6.9, CH2CH2O), 4.33
This journal is © The Royal Society of Chemistry 2012
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(2 H, t, J 6.8, CH2O), 5.73 (1 H, s, CH), 7.27–7.40 (10 H, m,
ArH) and 7.82 (1 H, s, HCvN); δC (75 MHz, CDCl3) 13.71,
19.08, 30.54, 65.69, 77.54, 127.54, 127.83, 128.65, 141.71,
153.71 and 163.23; m/z (CI) 296 (M+ + 1, 80%) and 167 (100).
2.70 mmol) in DCM (6 mL) after 12 h at −45 °C and chromato-
graphy using petrol–ether–triethylamine (93 : 6.5 : 0.5) as eluent
gave the title compounds 33 and 34 (1.04 g, 86%) as a colourless
oil, ratio 33 : 34 = 90 : 10 (1H NMR) (Found: M+ + H, 472.2848.
C31H38NO3 requires M, 472.2852); [α]D −19 (c 0.7 in CHCl3);
νmax/cm−1 699, 743, 971, 1028, 1070, 1092, 1117, 1151, 1184,
1453, 1493, 1730, 2870, 2931, 2961, 3028, 3061 and 3339; δH
(500 MHz, CDCl3) major isomer 0.92 (3 H, t, J 7.3, CH3CH2),
1.26 (3 H, d, J 6.5, 7-H3), 1.35 (2 H, hex, J 7.3, CH3CH2), 1.60
(2 H, qn, J 7.3, CH2CH2O), 2.17 (1 H, br s, NH), 2.33–2.49 (2
H, m, 3-H2), 3.30 (1 H, t, J 6, 2-H), 3.88 (1 H, q, J 6.8, 6-H),
4.07–4.13 (2 H, m, CH2CH2O), 4.31 and 4.48 (each 1 H, d,
J 11.8, PhHCH), 4.82 (1 H, s, Ph2CH), 5.49 (1 H, dd, J 16.0 and
8.0, 5-H), 5.63 (1 H, dt, J 16.0 and 7.6, 4-H), 7.15–7.22 (2 H,
m, ArH), 7.22–7.33 (9 H, m, ArH), 7.34–7.37 (2 H, m, ArH)
and 7.40–7.43 (2 H, m, ArH); minor isomer 0.915 (3 H, t, J 7.2,
CH3CH2), 1.25 (3 H, d, J 6.5, 7-H3), 4.26 and 4.43 (each 1 H, d,
J 11.6, PhHCH), 4.81 (1 H, s, Ph2CH), 5.44 (1 H, dd, J 16.0 and
8.0, 5-H) and 5.59 (1 H, dt, J 16.0 and 7.3, 4-H); δC (75 MHz,
CDCl3) major isomer 14.40, 19.88, 22.41, 31.47, 37.27, 59.72,
65.28, 66.11, 70.53, 76.28, 127.92, 128.00, 128.06, 128.31,
128.38, 128.53, 129.03, 129.21, 129.25, 136.27, 139.56, 143.50,
144.93 and 175.48; m/z (CI) 472 (M+ + 1, 100%).
Butyl (E)-2-[(1-methyl-1-phenyl)ethylimino]ethanoate 35
Butyl glyoxylate monohydrate (2.0 g, 13.5 mmol) and 1-methyl-
1-phenylethylamine (1.82g, 13.5 mmol) were dissolved in
benzene (40 mL) and heated under reflux for 2 h with azeotropic
removal of water. After cooling to ambient temperature and con-
centration under reduced pressure, the residue was dried under a
high vacuum (0.5 mm Hg) for 16 h to afford the title compound
35 (3.30g, 99%) as a pale yellow solid (Found: M+ + H,
248.1646. C15H22NO2 requires M, 248.1657); νmax/cm−1 700,
766, 1027, 1065, 1102, 1197, 1253, 1293, 1345, 1386, 1463,
1494, 1648, 1721, 1749, 2873, 2934 and 2963; δH (300 MHz,
CDCl3) 0.98 (3 H, t, J 7.3, CH3CH2), 1.43 (2 H, hex, J 7.6,
CH3CH2), 1.69 (6 H, s, 2 × CH3), 1.74 (2 H, qn, J 7.8,
CH2CH2O), 4.31 (2 H, m, CH2O), 7.27–7.45 (5 H, m,ArH),
7.54 (1 H, s, HCvN); δC (75 MHz, CDCl3) 13.71, 19.05, 29.23,
30.55, 64.52, 65.62, 126.20, 126.99, 128.42, 145.46, 150.88 and
163.809; m/z (CI) 248 (M+ + 1, 100%) and 119 (50).
Butyl (2R,6S,E)- and (2S,6S,E)-6-benzyloxy-2-(1-methyl-1-
Methyl (2R,6S,E)-6-benzyloxy-2-[(2-nitrophenyl)sulfanylamino]-
phenylethyl)aminohept-4-enoates 36 and 37
hept-4-enoate 30
Following the general procedure, tin(IV) chloride (672 mg,
2.58 mmol) in DCM (7 mL), 4-benzyloxypent-2-enylstannane 1
(1.26 g, 2.71 mmol) in DCM (7 mL) and imine 35 (670 mg,
2.71 mmol) in DCM (7 mL) after 12 h at −45 °C and chromato-
graphy using petrol–ether–triethylamine (85 : 14.5 : 0.5) as
eluent gave the title compounds 36 and 37 (852 mg, 78%) as a
colourless oil, ratio 36 : 37 = 91 : 9 (1H NMR) (Found: M+ + H,
424.2872. C27H38NO3 requires M, 424.2852); νmax/cm−1 699,
735, 765, 971, 1072, 1174, 1445, 1453, 1731, 2969 and 3334;
δH (300 MHz, CDCl3) major isomer 0.94 (3 H, t, J 7.3,
CH3CH2), 1.30 (3 H, d, J 6.6, 7-H3), 1.35 (2 H, hex, J 7.7,
CH3CH2), 1.45 and 1.47 (each 3 H, s, CH3), 1.57 (2 H, qn, J
7.5, CH2CH2O), 2.29–2.34 (2 H, m, 3-H2), 3.12 (1 H, t, J 6.5,
2-H), 3.90 (1 H, qn, J 6.8, 6-H), 4.00 (2 H, t, J 6.7, CH2CH2O),
4.37 and 4.55 (each 1 H, d, J 11.9, PhHCH), 5.49 (1 H, dd,
J 15.3 and 7.1, 5-H), 5.61 (1 H, dt, J 15.3 and 6.3, 4-H),
7.24–7.40 (8 H, m, ArH) and 7.51–7.53 (2 H, m, ArH); minor
isomer 1.28 (3 H, d, J 6.7, 7-H3), 3.11 (1 H, t, J 6.5, 2-H),
3.95–4.05 (2 H, m, CH2CH2O), 4.39 and 4.58 (each 1 H, d,
J 11.9, PhHCH) and 5.45 (1 H, dd, J 15.3 and 7.0, 5-H); δC
(75 MHz, CDCl3) major isomer 13.74, 19.17, 21.71, 28.15,
30.61, 31.33, 38.48, 56.28, 64.61, 69.78, 75.64, 126.25, 126.51,
127.40, 127.70, 128.06, 128.30, 128.36, 135.18, 138.93, 147.48
and 176.36; minor isomer 38.52, 56.34, 135.06 and 176.44; m/z
(CI) 424 (M+ + 1, 100%).
Following the general procedure, tin(IV) chloride (683 mg,
2.62 mmol) in DCM (5 mL), the 4-benzyloxypent-2-enylstan-
nane 1 (1.28 g, 2.75 mmol) in DCM (5 mL) and the imine 29
(661 mg, 2.75 mmol) in DCM (5 mL) after 12 h at −45 °C
and
chromatography
using
hexane–ether–triethylamine
(60 : 39.5 : 0.5) as eluent gave the title compound 30 (950 mg,
87%) as a yellow oil. Preparative scale HPLC using a silica
resolve cartridge, UV at 255 nm, eluent hexane–ethyl acetate
(8 : 1), flow rate 2 mL min−1 gave the (2R)-epimer 30 (Found:
M+ + Na, 439.1314. C21H24N2O5SNa requires M, 439.1304);
[α]D −29.5 (c 0.4 in CHCl3); νmax/cm−1 699, 726, 790, 1101,
1208, 1220, 1308, 1340, 1449, 1515, 1736, 3030 and 3347; δH
(500 MHz, methanol-d4) 1.45 (3 H, d, J 6.4, 7-H3), 2.72 (1 H,
m, 3-H), 2.82 (1 H, m, 3-H), 3.78 (1 H, dd, J 7.3 and 5.8, 2-H),
3.92 (3 H, s, CH3O), 4.16 (1 H, qn, J 6.6, 6-H), 4.58 and 4.73
(each 1 H, d, J 11.8, PhHCH), 5.74 (1 H, dd, J 15.4 and 7.7, 5-
H), 5.93 (1 H, dt, J 15.4 and 7.3, 4-H), 7.43–7.50 (6 H, m,
ArH), 7.83 (1 H, ddd, J 7.9, 7.9 and 1.5, ArH), 8.32 (1 H, dd,
J 8.3 and 1.3) and 8.43 (1 H, dd, J 8.2 and 1.4, ArH); δH
(500 MHz, CDCl3) 3.30 (1 H, d, J 8.7, NH); δC (63 MHz,
CDCl3) 21.55, 36.35, 52.38, 63.54, 69.96, 75.49, 124.47,
124.76, 125.73, 126.06, 127.41, 127.54, 128.32, 133.74, 136.87,
138.65, 142.58, 144.82 and 173.36; m/z (FAB) 439 (M+ + 23,
100%).
Butyl (2R,6S,E)- and (2S,6S,E)-6-benzyloxy-2-(diphenylmethyl)-
aminohept-4-enoates 33 and 34
Methyl (2R,6S,E)-6-benzyloxy-2-(methoxycarbonylamino)hept-
4-enoate 38
Following the general procedure, tin(IV) chloride (671 mg,
2.58 mmol) in DCM (6 mL), 4-benzyloxypent-2-enylstannane 1
(1.26 g, 2.71 mmol) in DCM (6 mL) and the imine 32 (799 mg,
Following the general procedures, following deprotection of the
sulfanylamines 30 (and 31) (180 mg, 0.432 μmol, 9 : 1) using
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Methyl (2R,6S)-2-acetamido-6-hydroxyheptanoate 41
hydrogen chloride in methanol, treatment of the free amines with
anhydrous potassium carbonate (138 mg, 0.864 μmol) and
methyl chloroformate (67 μl, 0.867 μmol), after chromatography
using hexane–ether (65 : 35) as eluent gave the title compound
38 (121 mg, 87%); the minor (2S)-epimer was not detected
(Found: M+ + NH4, 339.1913. C17H27N2O5 requires M,
339.1920); [α]D −79 (c 0.43 in CHCl3); νmax/cm−1 699, 738,
1065, 1211, 1355, 1441, 1453, 1522, 1726, 2954 and 3338; δH
(300 MHz, CDCl3, 50 °C) 1.23 (3 H, d, J 6.4, 7-H3), 2.40–2.64
(2 H, m, 3-H2), 3.66 and 3.72 (each 3 H, s, CH3O), 3.88 (1 H,
m, 2-H), 4.35 (1 H, d, J 12.0, PhHCH), 4.41 (1 H, m, 6-H), 4.51
(1 H, d, J 12, PhHCH), 5.16 (1 H, br s, NH), 5.46–5.53 (2 H, m,
4-H and 5-H) and 7.22–7.33 (5 H, m, ArH); δC (75 MHz,
CDCl3) 21.61, 35.41, 52.37, 52.45, 53.50, 69.89, 75.20, 125.82,
127.48, 127.69, 128.38, 137.00, 138.69, 156.30 and 172.19; m/z
(CI) 339 (M+ + 1, 100%) and 214 (70).
Following the general procedure for transfer hydrogenation, acet-
amide 40 (90 mg, 0.295 μmol) gave a yellow oil that was dis-
solved in chloroform, absorbed on to silica and the resulting
powder applied to a column of silica gel. Elution with chloro-
form–methanol (99 : 1) gave methyl (R)-2-acetamidoheptanoate
42 (3 mg, 5%), as a colourless oil (Found: M+ + H, 202.1442.
C10H20NO3 requires M, 202.1443); [α]D −29.6 (c 0.6 in CHCl3);
νmax/cm−1 1153, 1180, 1211, 1374, 1437, 1546, 1656, 1747,
2861, 2955 and 3289; δH (300 MHz, CDCl3) 0.90 (3 H, t, J 6.7,
7-H3), 1.21–1.40 (6 H, m, 4-H2, 5-H2 and 6-H2), 1.68 and 1.80
(each 1 H, m, 3-H), 2.05 (3 H, s, CH3CO), 3.77 (3 H, s, CH3O),
4.63 (1 H, m, 2-H) and 6.10 (1 H, d, J 7.0, NH); δC (75 MHz,
CDCl3) 13.94, 22.41, 23.18, 24.85, 31.35, 32.48, 52.17, 52.31,
169.77 and 173.33; m/z (CI) 219 (M+ + 18, 20%) and 202 (M+
+ 1, 100). Further elution with chloroform–methanol (96 : 4)
gave the title compound 41 (51 mg, 79%) as a colourless oil con-
taining ca. of its epimer at C(2) (Found: M+ + H, 218.1392.
C10H20NO4 requires M, 218.1392); νmax/cm−1 1038, 1147,
1213, 1375, 1438, 1549, 1659, 1745, 2958, 3073 and 3290; δH
(300 MHz, CDCl3) 1.20 (3 H, d, J 6.2, 7-H3), 1.30–1.91 (6 H,
m, 3-H2, 4-H2 and 5-H2), 2.01 (1 H, br s, OH), 2.03 (3 H, s,
CH3CO), 3.77 (3 H, s, CH3O), 3.76 (1 H, m, 6-H), 4.63 (1 H,
m, 2-H) and 6.30 (1 H, d, J 7.9, NH); δC (75 MHz, CDCl3)
21.48, 23.16, 23.69, 32.40, 38.44, 52.04, 52.41, 67.52, 170.07
and 173.21; minor (2S)-epimer 23.56, 32.48 and 67.60; m/z (CI)
218 (M+ + 1, 100%).
(R)-3-(Methoxycarbonylamino)butyrolactone 39
Following the general procedures, the hept-2-enoate 38 (125 mg,
0.389 μmol), ozone, methyl sulfide (86 μL, 1.17 mmol) and
sodium borohydride (59 mg, 1.56 mmol) gave the corresponding
alcohol that was cyclised using glacial acetic acid in chloroform
with chromatography using ethyl acetate–hexane–triethylamine
(60 : 39.5 : 0.5) as eluent to give the title compound 39 (45 mg,
73%) as a white powder, m.p. 95–96 °C (lit.14 95–97 °C)
(Found: C, 45.6; H, 5.9; N, 8.7. C6H9NO4 requires C, 45.3; H,
5.7; N, 8.8); [α]D +29.7 (c 0.7 in MeOH) [lit.14 for the (S)-enan-
tiomer −39.5 (c 1 in MeOH)]; νmax/cm−1 1019, 1063, 1177,
1197, 1257, 1293, 1381, 1532, 1713, 1777, 2958 and 3336; δH
(300 MHz, CDCl3) 2.27 and 2.78 (each 1 H, m, 4-H), 3.74 (3 H,
s, CH3O), 4.29 (1 H, m, 3-H), 4.40–4.51 (2 H, m, 5-H2) and
5.50 (1 H, br s, NH); δC (75 MHz, CDCl3) 30.22, 50.49, 52.66,
65.80, 156.80 and 175.19; m/z (CI) 181 (M+ + 18, 90%) and
164 (M+ + 1, 100).
Methyl (2R,6S)-2-acetamido-6-acetoxyheptanoate 43
Following the general procedure for acetylation, the alcohol 41
(22 mg, 0.101 μmol, 9 : 1), triethylamine (42 μL, 0.301 μmol),
acetic anhydride (16 mg, 0.157 μmol) and DMAP (0.5 mg,
4 μmol) after chromatography using chloroform–methanol
(99 : 1) as eluent gave the title compound 43 (25 mg, 95%) as a
colourless oil containing ca. 10% of its (2S)-epimer (Found: M+
+ H, 260.1503. C12H22NO5 requires M, 260.1498); νmax/cm−1
803, 1023, 1092, 1150, 1251, 1373, 1439, 1540, 1657, 1734,
2866, 2953 and 3283; δH (500 MHz, CDCl3) 1.22 (3 H, d, J 6.3,
7-H3), 1.20–1.84 (6 H, m, 3-H2, 4-H2 and 5-H2), 1.99 (6 H, s, 2
× CH3CO), 3.71 (3 H, s, CH3O), 4.55 (1 H, dt, J 5.4 and 7.7, 2-
H), 4.85 (1 H, m, 6-H) and 6.03 (1 H, d, J 7.7, NH); δC
(75 MHz, CDCl3) 20.03, 21.15, 21.36, 23.15, 32.08, 35.34,
52.02, 52.39, 70.28, 169.87, 170.86 and 173.04; minor (2S)-
epimer 19.93, 32.29 and 70.57; m/z (CI) 277 (M+ + 18, 70%)
and 260 (M+ + 1, 100).
Methyl (2R,6S,E)-2-acetamido-6-benzyloxyhept-4-enoate 40
Following the general procedures, following deprotection of the
sulfanylamines 30 (and 31) (800 mg, 1.92 mmol, 9 : 1) using
hydrogen chloride in methanol and treatment of the free amines
with acetic anhydride (272 μL, 2.88 mmol), triethylamine
(803 μl, 5.76 mmol) and DMAP (5 mg, 41 μmol), after chrom-
atography using hexane–ethyl acetate (1 : 1) as eluent, gave the
title compound 40 (480 mg, 82%) as a colourless oil; the (2S)-
epimer was not detected (Found: M+ + H, 306.1713. C17H24NO4
requires M, 306.1705); [α]D −78.5 (c 0.93 in CHCl3); νmax/cm−1
699, 738, 973, 1072, 1089, 1213, 1372, 1438, 1544, 1657,
1746, 2974 and 3287; δH (300 MHz, CDCl3) 1.28 (3 H, d, J 6.3,
7-H3), 2.03 (3 H, s, CH3CO), 2.52 (1 H, m, 3-H), 2.66 (1 H, m,
3-H), 3.78 (3 H, s, CH3O), 3.92 (1 H, m, 6-H), 4.40 and 4.56
(each 1 H, d, J 11.9, PhHCH), 4.73 (1 H, m, 2-H), 5.53–5.55 (2
H, m, 4-H and 5-H), 6.11 (1 H , d, J 7.4, NH) and 7.28–7.40 (5
H, m, ArH); δC (75 MHz, CDCl3) 21.61, 23.17, 35.20, 51.92,
52.46, 69.84, 75.22, 125.93, 127.49, 127.61, 128.41, 136.84,
138.68, 169.61 and 172.30; m/z (CI) 323 (M+ + 18, 6.5%), 306
(M+ + 1, 4.5) and 198 (100).
Methyl (2R,6S,E)-2-(diphenylmethyl)amino-6-benzyloxyhept-4-
enoate 44
Anhydrous potassium carbonate (293 mg, 2.12 mmol) was
added to a mixture of the butyl esters 33 and 34 (200 mg,
0.424 μmol, 9 : 1) in methanol (5.6 mL) and water (1.4 mL) and
the mixture was heated under reflux for 16 h. After cooling to
ambient temperature and concentration under reduced pressure,
the residue was dissolved in saturated aqueous sodium hydrogen
carbonate. This solution was washed twice with ether, the
aqueous layer was acidified using hydrogen chloride (1 M) and
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6130–6158 | 6147

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the solution extracted with ether. The organic phase was dried
(MgSO4) and concentrated under reduced pressure to ∼10 mL.
An excess of diazomethane in ether was added and the yellow
solution stirred at ambient temperature for 30 min before glacial
acetic acid was added dropwise until a colourless solution was
obtained. Water (20 mL) was added and the organic phase was
washed with saturated aqueous sodium hydrogen carbonate and
dried (MgSO4). Silica was added (ca. 1 g) and the mixture was
concentrated under reduced pressure. The ensuing powder was
applied to a column of silica gel. Chromatography using
hexane–ether (9 : 1) as eluent gave the title compound 44
(166 mg, 91%) as a colourless oil (Found: M+ + H, 430.2374.
C28H32NO3 requires M, 430.2382); νmax/cm−1 701, 743, 974,
1029, 1072, 1200, 1452, 1493, 1735, 2859, 3028 and 3330; δH
(300 MHz, CDCl3) 1.33 (3 H, d, J 6.3, 7-H3), 2.23 (1 H, br s,
NH), 2.45–2.53 (2 H, m, 3-H2), 3.39 (1 H, t, J 6.3, 2-H), 3.75 (3
H, s, CH3O), 3.95 (1 H, m, 6-H), 4.37 and 4.55 (each 1 H, d, J
11.9, PhHCH), 4.88 (1 H, s, Ph2CH), 5.54 (1 H, dd, J 15.4 and
7.5, 5-H), 5.68 (1 H, dt, J 15.4 and 7.9, 4-H) and 7.22–7.49 (15
H, m, ArH); δC (75 MHz, CDCl3) 21.76, 36.59, 51.75, 59.01,
65.40, 69.81, 75.54, 127.26, 127.30, 127.40, 127.57, 127.64,
127.70, 128.36, 128.54, 128.58, 135.65, 138.82, 142.74, 144.14
and 175.24; m/z (CI) 430 (M+ + 1, 100%).
Following the general procedure for transfer hydrogenation,
the 2-(diphenylmethylamino)heptenoate 44 (65 mg, 0.151 μmol)
gave an oil that was acylated using triethylamine (127 μL,
0.911 μmol), acetic anhydride (46 mg, 0.451 μmol) and DMAP
(0.5 mg, 4 μmol) to give, after chromatography using chloro-
form–methanol (99 : 1) as eluent, methyl (R)-2-acetamidohep-
tanoate 42 (2 mg, 7%) as a colourless oil. Further elution using
chloroform–methanol (96 : 4) gave the 2-acetamido-6-acetoxy-
heptanoate 43 (31 mg, 80%) as a colourless oil containing ca.
10% of its (2S)-epimer.
30.67, 36.40, 36.93, 56.14, 59.04, 64.36, 72.95, 75.31, 124.71,
126.82, 127.09, 127.48, 127.56, 128.34, 128.40, 136.58, 138.64,
145.28 and 174.63; m/z (CI) 424 (M+ + 1, 100%); minor epimer
85 δH (500 MHz, CDCl3) 2.24–2.27 (m, 3-H2), 3.01 (t, J 6.4,
2-H) and 3.68 (q, J 6.4, PhCHCH3).
Butyl (2S,6R,E)- and (2R,6R,E)-7-benzyloxy-6-methyl-2-[(S)-
(1-phenylethyl)]aminohept-4-enoate 86 and 88
The general procedure using tin(IV) chloride (679 mg,
2.61 mmol) in DCM (8 mL), 5-benzyloxypentenylstannane 80
(1.31 g, 2.73 mmol) in DCM (8 mL) and the imine (S)-11
(638 mg, 2.73 mmol) in DCM (8 mL) after 12 h at −45 °C and
chromatography using petrol–ether–triethylamine (90 : 9.5 : 0.5)
as eluent gave the title compounds 86 and 88 (762 mg, 69%) as
a colourless oil, 86 : 88 = 60 : 40 (1H NMR). Further chromato-
graphy using petrol–ether (9 : 1) as the eluent gave a sample of
the major (2S)-epimer 86 as a colourless oil (Found: M+ + H,
424.2856. C27H38NO3 requires M, 424.2851); [α]D −40 (c 2 in
CHCl3); νmax/cm−1 700, 737, 971, 1028, 1098, 1182, 1453,
1604, 1732, 2960 and 3329; δH (500 MHz, CDCl3) 0.91 (3 H, t,
J 7.5, CH3CH2), 1.01 (3 H, d, J 6.6, 6-CH3), 1.29 (3 H, d, J 6.6,
PhCHCH3), 1.34 (2 H, hex, J 7.5, CH3CH2), 1.57 (2 H, qn, J
6.8, CH2CH2O), 1.72 (1 H, br s, NH), 2.24–2.27 (2 H, m, 3-H2),
2.43 (1 H, sep, J 6.6, 6-H), 3.02 (1 H, t, J 6.4, 2-H), 3.22 (1 H,
dd, J 8.8 and 7.5, 7-H), 3.32 (1 H, dd, J 9.2 and 6.4, 7-H), 3.68
(1 H, q, J 6.6, PhCHCH3), 4.03–4.12 (2 H, m, CH2CH2O), 4.47
and 4.49 (each 1 H, d, J 13.3, PhHCH), 5.36 (1 H, dt, J 15.6 and
6.8, 4-H), 5.42 (1 H, dd, J 15.6 and 6.4, 5-H) and 7.24–7.33 (10
H, m, ArH); δC (75 MHz, CDCl3) 13.78, 17.16, 19.21, 23.26,
30.78, 36.82, 37.13, 56.56, 58.92, 64.28, 72.88, 75.21, 124.78,
126.67, 126.75, 127.32, 127.40, 128.18, 136.01, 138.42, 144.88
and 175.10; m/z (CI) 424 (M+ + 1, 100%); minor epimer 88 δH
(500 MHz, CDCl3) 0.89 (t, J 7.5, CH3CH2), 1.00 (d, J 6.6, 6-
CH3), 1.31 (d, J 6.6, PhCHCH3), 1.52 (qn, J 7.6, CH2CH2O),
2.33–2.36 (m, 3-H2), 3.24 (t, J 6.4, 2-H), 3.31 (dd, J 9.1 and
7.1, 7-H), 3.75 (q, J 6.6, PhCHCH3) and 3.95 (t, J 6.6,
CH2CH2O); δC (75 MHz, CDCl3) 17.35, 30.68, 36.44, 36.99,
56.12, 59.03, 124.56, 126.84, 126.93, 136.48, 145.01 and
174.39.
Butyl (2S,6R,E)- and (2R,6R,E)-7-benzyloxy-6-methyl-2-[(R)-(1-
phenylethyl)]aminohept-4-enoates 84 and 85
The general procedure using tin(IV) chloride (833 mg,
3.20 mmol) in DCM (9 mL), 5-benzyloxypentenylstannane 80
(1.61 g, 3.36 mmol) in DCM (9 mL) and the imine (R)-11
(783 mg, 3.36 mmol) in DCM (9 mL) after 12 h at −45 °C and
chromatography using petrol–ether–triethylamine (90 : 9.5 : 0.5)
as eluent gave the title compounds 84 and 85 (1.03 g, 76%) as a
colourless oil, 84 : 85 = 95 : 5 (1H NMR). Further chromato-
graphy using petrol–ether (9 : 1) as the eluent gave a sample of
the major (2S)-epimer 84 as a colourless oil (Found: M+ + H,
424.2858. C27H38NO3 requires M, 424.2851); [α]D +28 (c 1.5 in
CHCl3); νmax/cm−1 699, 738, 970, 1028, 1098, 1179, 1453,
1733, 2961 and 3335; δH (500 MHz, CDCl3) 0.89 (3 H, t, J 7.3,
CH3CH2), 1.00 (3 H, d, J 6.6, 6-CH3), 1.27–1.34 (2 H, m,
CH3CH2), 1.31 (3 H, d, J 6.4, PhCHCH3), 1.52 (2 H, qn, J 7.3,
CH2CH2O), 1.76 (1 H, br s, NH), 2.30–2.38 (2 H, m, 3-H2),
2.44 (1 H, m, 6-H), 3.23 (1 H, dd, J 8.8 and 7.1, 7-H), 3.30 (1
H, t, J 6.4, 2-H), 3.32 (1 H, dd, J 9.4 and 6.4, 7-H), 3.76 (1 H,
q, J 6.4, PhCHCH3), 3.91–3.98 (2 H, m, CH2CH2O), 4.46 and
4.48 (each 1 H, d, J 12.2, PhHCH), 5.42 (1 H, dt, J 15.6 and
6.4, 4-H), 5.46 (1 H, dd, J 15.6 and 6.4, 5-H) and 7.24–7.34 (10
H, m, ArH); δC (75 MHz, CDCl3) 13.70, 17.21, 19.15, 23.21,
Butyl (2S,6R,E)- and (2R,6R,E)-7-benzyloxy-6-methyl-2-
{(benzyloxycarbonyl)-[(S)-(1-phenyl)ethyl]amino}hept-4-enoate
87 and 89
The general procedure for protection of amines using the amino-
esters 86 and 88 (326 mg, 0.770 μmol, 86 : 88 = 60 : 40), anhy-
drous potassium carbonate (213 mg, 1.54 mmol) and benzyl
chloroformate (141 μL, 0.926 μmol) after chromatography using
petrol–ether (98 : 2 to 9 : 1) as eluent gave the title compounds
87 and 89 (361 mg, 84%) as a colourless oil. Samples of each
isomer as colourless oils were obtained by preparative HPLC
(Rainin Dynamax silica column, UV at 254 nm, eluent hexane–
ethyl acetate 15 : 1, flow rate 15 mL min−1): (2R)-epimer 89
(less polar, 38% of the mixture) (Found: M+ + Na, 580.3059.
C35H43NO5Na requires M, 580.3039); [α]D −19 (c 1.4 in
CHCl3); νmax/cm−1 698, 737, 1081, 1212, 1290, 1427, 1453,
1703, 1739 and 2961; δH (300 MHz, DMSO-d6, 95 °C) 0.83
6148 | Org. Biomol. Chem., 2012, 10, 6130–6158
This journal is © The Royal Society of Chemistry 2012

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(3 H, d, J 6.9, 6-CH3), 0.87 (3 H, t, J 7.4, CH3CH2), 1.30 (2 H,
hex, J 7.5, CH3CH2), 1.49 (2 H, qn, J 7.3, CH2CH2O), 1.53 (3
H, d, J 7, PhCHCH3), 1.98 and 2.17 (each 1 H, m, 3-H), 2.57 (1
H, m, 6-H), 3.12 (1 H, dd, J 9.2 and 7.0, 7-H), 3.20 (1 H, dd, J
9.2 and 6.1, 7-H), 3.76 (1 H, dd, J 7.1 and 5.9, 2-H), 3.91–4.04
(2 H, m, CH2CH2O), 4.43 (2 H, s, PhCH2), 4.96–4.98 (2 H, m,
4-H and 5-H), 5.06 and 5.11 (each 1 H, d, J 11.8, PhHCH), 5.35
(1 H, q, J 7, PhCHCH3) and 7.23–7.37 (15 H, m, ArH); δH
(300 MHz, toluene-d8, 90 °C) 5.01 (1 H, dd, J 15.2 and 6.8, 5-
H), 5.14 (1 H, dt, J 15.2 and 7.0, 4-H); m/z (CI) 575 (M+ + 18,
100%), 558 (M+ + 1, 50) and 454 (100); (2S)-epimer 87 (more
polar, 62% of the mixture) (Found: M+ + H, 558.3242.
C35H44NO5 requires M, 558.3219); [α]D −34 (c 1.3 in CHCl3);
νmax/cm−1 699, 738, 1027, 1077, 1210, 1296, 1428, 1453, 1496,
1702, 1739 and 2959; δH (300 MHz, DMSO-d6, 95 °C) 0.81 (3
H, t, J 7.2, CH3CH2), 0.96 (3 H, d, J 7.0, 6-CH3), 1.16 (2 H,
hex, J 7.3, CH3CH2), 1.31 (2 H, qn, J 7.0, CH2CH2O), 1.52 (3
H, d, J 7.1, PhCHCH3), 2.40 and 2.55 (each 1 H, m, 3-H), 2.74
(1 H, m, 6-H), 3.26 (1 H, dd, J 9.1 and 7.0, 7-H), 3.34 (1 H, dd,
J 9.1 and 6.3, 7-H), 3.75 (2 H, t, J 6.8, CH2CH2O), 3.91 (1 H,
dd, J 6.6 and 6.6, 2-H), 4.46 (2 H, s, PhCH2), 5.03 and 5.11
(each 1 H, d, J 12.0, PhHCH), 5.23 (1 H, q, J 7.1, PhCHCH3),
5.35–5.51 (2 H, m, 4-H and 5-H) and 7.21–7.38 (15 H, m,
ArH); m/z (CI) 575 (M+ + 18, 30%), 558 (M+ + 1, 35), 454 (70)
and 91 (100).
1.83 mmol) in DCM (5 mL) after 12 h at −45 °C and chromato-
graphy using petrol–ether–triethylamine (93 : 6.5 : 0.5) as eluent
gave the title compound 92 (660 mg, 78%) as a colourless oil,
only the one diastereoisomer being detected by 1H NMR
(Found: M+ + H, 486.3004. C32H40NO3 requires M, 486.3008);
[α]D +1.9 (c 0.6 in CHCl3); νmax/cm−1 700, 744, 971, 1028,
1099, 1183, 1454, 1494, 1600, 1731, 2959 and 3328; δH
(300 MHz, CDCl3) 0.98 (3 H, t, J 7.3, CH3CH2), 1.07 (3 H, d, J
6.8, 6-CH3), 1.40 (2 H, hex, J 7.8, CH3CH2), 1.65 (2 H, qn, J
8.1, CH2CH2O), 2.21 (1 H, br s, NH), 2.40–2.47 (2 H, m, 3-H2),
2.51 (1 H, m, 6-H), 3.26–3.32 (2 H, m, 2-H and 7-H), 3.39 (1 H,
dd, J 9.1 and 6.3, 7-H), 4.15 (2 H, t, J 6.6, CH2CH2O), 4.53 (2
H, s, PhCH2), 4.86 (1 H, s, Ph2CH), 5.51–5.54 (2 H, m, 4-H and
5-H) and 7.21–7.48 (15 H, m, ArH); δC (75 MHz, CDCl3)
13.76, 17.20, 19.22, 30.82, 36.93, 36.98, 59.28, 64.45, 65.42,
72.99, 75.35, 124.96, 125.04, 127.20, 127.40, 127.51, 127.60,
127.69, 128.38, 128.50, 128.54, 136.42, 138.70, 142.96, 144.36
and 175.01; m/z (CI) 486 (M+ + 1, 100%).
Butyl (2S,6R,E)-7-benzyloxy-6-methyl-2-{(benzyloxycarbonyl)-
[(R)-1-phenylethyl]amino}hept-4-enoate 94
The general procedure using the 2-amino-ester 84 (800 mg,
1.89 mmol), anhydrous potassium carbonate (522 mg,
3.78 mmol) and benzyl chloroformate (346 μL, 2.45 mmol) after
chromatography using petrol–ether (9 : 1 to 4 : 1) as eluent gave
the title compound 94 (916 mg, 87%) as a colourless oil (Found:
M+ + Na, 580.3053. C35H43NO5Na requires M, 580.3039); [α]D
+17 (c 1.6 in CHCl3); νmax/cm−1 690, 773, 1077, 1210, 1250,
1292, 1427, 1453, 1702, 1739 and 2969; δH (300 MHz, DMSO-
d6, 95 °C) 0.94 (3 H, d, J 6.7, 6-CH3), 0.97 (3 H, t, J 7.3,
CH3CH2), 1.40 (2 H, hex, J 7.5, CH3CH2), 1.60 (2 H, qn, J 7.8,
CH2CH2O), 1.64 (3 H, d, J 7.1, PhCHCH3), 2.10 and 2.27 (each
1 H, m, 3-H), 2.67 (1 H, m, 6-H), 3.22 (1 H, dd, J 9.3 and 7.0,
7-H), 3.30 (1 H, dd, J 9.3 and 6.1, 7-H), 3.88 (1 H, dd, J 7.3 and
6.1, 2-H), 4.01–4.14 (2 H, m, CH2CH2O), 4.53 (2 H, s, PhCH2),
5.03–5.05 (2 H, m, 4-H and 5-H), 5.19 (2 H, s, PhCH2), 5.45 (1
H, q, J 7.1, PhCHCH3) and 7.33–7.49 (15 H, m, ArH); m/z (CI)
575 (M+ + 18, 100%), 558 (M+ + 1, 70) and 454 (100).
The general procedure using cbz-ester 94 (800 mg,
1.43 mmol), ozone, methyl sulfide (0.316 mL, 4.30 mmol) and
sodium borohydride (217 mg, 5.74 mmol) gave an alcohol that
was cyclised using hydrogen chloride in methanol to afford the
lactone 21 (389 mg, 80%) as a white powder. A single recrystal-
lisation from DCM–hexane gave the lactone 21 as colourless
needles: m.p. 152–153 °C; [α]D +22 (c 0.8 in CHCl3).
Methyl (2S,6R,E)-7-benzyloxy-6-methyl-2-(2-nitrophenyl-
sulfanyl)aminohept-4-enoate 90
The general procedure using tin(IV) chloride (697 mg,
2.68 mmol) in DCM (5 mL), 5-benzyloxypentenylstannane 80
(1.35 g, 2.82 mmol) in DCM (5 mL) and imine 29 (675 mg,
1.83 mmol) in DCM (5 mL) after 12 at −45 °C and chromato-
graphy using hexane–ether–triethylamine (60 : 39.5 : 0.5) as
eluent gave the title compound 90 (850 mg, 74%) as a yellow
oil, only the one diastereoisomer was detected by 1H NMR
(Found: M+
+ H, 431.1650. C22H27N2O5S requires M,
431.1641); [α]D +14 (c 1.05 in CHCl3); νmax/cm−1 699, 736,
788, 851, 973, 1098, 1207, 1305, 1337, 1449, 1511, 1565, 1592,
1740, 2857, 2955 and 3330; δH (300 MHz, CDCl3) 1.09 (3 H, d,
J 6.9, 6-CH3), 2.49–2.70 (3 H, m, 3-H2 and 6-H), 3.29–3.41 (3
H, m, 2-H, 7-H and NH), 3.61 (1 H, m, 7-H), 3.80 (3 H, s,
CH3O), 4.55 (2 H, s, PhCH2), 5.50 (1 H, dt, J 15.0 and 7.0, 4-
H), 5.64 (1 H, dd, J 15.0 and 6.8, 5-H), 7.28 (1 H, ddd, J 7.5,
7.5 and 1.0, ArH), 7.29–7.39 (5 H, m, ArH), 7.62 (1 H, ddd, J
7.5, 7.5 and 1.0, ArH), 8.12 (1 H, dd, J 7.5 and 1.0, ArH) and
8.30 (1 H, dd, J 7.5 and 1.0, ArH); δC (75 MHz, CDCl3) 17.04,
36.84, 37.04, 52.26, 63.70, 73.03, 75.10, 123.60, 123.64,
124.69, 125.73, 127.54, 127.60, 128.35, 133.75, 138.27, 138.48,
142.59, 145.14 and 173.70; m/z (CI) 448 (M+ + 18, 10%), 431
(M+ + 1, 80) and 278 (100).
The general procedure for transfer hydrogenolysis using this
lactone 21 (120 mg, 0.354 μmol), ammonium formate (111 mg,
1.76 mmol) and 10% Pd/C (12 mg) gave the amino-lactone 22
(59 mg, 82%) as a colourless oil, [α]D +32 (c 1.8 in CHCl3).
Methyl (2S,6R,E)-7-benzyloxy-2-(methoxycarbonyl)amino-6-
Butyl (2S,6R,E)-2-(diphenylmethyl)amino-7-benzyloxy-6-
methylhept-4-enoate 95
methylhept-4-enoate 92
The general procedure for removal of o-nitrophenylsulfanylthio
groups and N-methoxycarbonylation using the ester 90 (600 mg,
1.39 mmol), anhydrous potassium carbonate (385 mg,
2.79 mmol) and methyl chloroformate (215 μL, 2.78 mmol)
The general procedure using tin(IV) chloride (455 mg,
1.75 mmol) in DCM (5 mL), 5-benzyloxypentenylstannane 80
(879 mg, 1.83 mmol) in DCM (5 mL) and imine 32 (542 mg,
This journal is © The Royal Society of Chemistry 2012
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after chromatography using hexane–ethyl acetate (4 : 1) as eluent
gave the title compound 95 (360 mg, 77%) as a colourless oil
(Found (M+ + H, 336.1812. C18H26NO5 requires M, 336.1811);
[α]D +19 (c 2.8 in CHCl3); νmax/cm−1 699, 739, 973, 1065,
1210, 1356, 1451, 1519, 1727, 2855, 2955 and 3341; δH
(300 MHz, CDCl3) major rotamer 0.96 (3 H, d, J 6.8, 6-CH3),
2.40–2.50 (3 H, m, 3-H2 and 6-H), 3.21–3.31 (2 H, m, 7-H2),
3.61 and 3.70 (3 H, s, CH3O), 4.36 (1 H, m, 2-H), 4.48 (2 H, s,
PhCH2), 5.25 (1 H, d, J 8.1, NH), 5.30 (1 H, dt, J 15.6 and 7.1,
4-H), 5.46 (1 H, dd, J 15.6 and 7.3, 5-H) and 7.22–7.32 (5 H,
m, ArH); δC (75 MHz, CDCl3) major rotamer 17.02, 35.65,
37.03, 52.26, 53.42, 65.85, 72.97, 75.04, 123.11, 127.51,
127.58, 128.35, 138.41, 138.55, 156.40 and 172.37; m/z (CI)
353 (M+ + 18, 10%) and 336 (M+ + 1, 100).
The general procedure using the carbamate 95 (200 mg,
0.596 μmol), ozone, methyl sulfide (131 μL, 1.78 mmol) and
sodium borohydride (90 mg, 2.38 mmol) gave an alcohol that
was cyclised using glacial acetic acid in chloroform to afford,
after chromatography using ethyl acetate–hexane–triethylamine
(60 : 39.5 : 0.5) as eluent, the 3-(methoxycarbonyl)aminolactone
(S)-39 (59 mg, 62%) as a white powder, [α]D −39 (c 2 in
MeOH).14
chromatography using petrol–ether–triethylamine (90 : 9.5 : 0.5)
as eluent, gave the title compound 108 (772 mg, 72%) as a col-
1
ourless oil, no other diastereoisomer was detected by H NMR
(Found: M+
+ H, 580.3849. C31H58NO5Si2 requires M,
580.3854); [α]D +62 (c 1.18 in CHCl3); νmax/cm−1 667, 700,
777, 838, 938, 970, 1027, 1125, 1251, 1377, 1467, 1735, 2931,
2955 and 3335; δH (300 MHz, CDCl3) 0.07 (9 H, s, 3 × CH3Si),
0.10 (6 H, s, 2 × SiCH3), 0.93 [9 H, s, SiC(CH3)3], 0.98 (2 H,
m, SiCH2), 0.97 (3 H, t, J 7.3, CH3CH2), 1.38 (3 H, d, J 6.4,
PhCHCH3), 1.38 (2 H, hex, J 7.4, CH3CH2), 1.59 (2 H, qn, J
7.3, CH2CH2O), 1.90 (1 H, br s, NH), 2.36–2.51 (2 H, m, 3-H2),
3.38 (1 H, t, J 6.3, 2-H), 3.52–3.82 (5 H, m, 7-H2, PhCHCH3
and SiCH2CH2O), 4.02 (2 H, t, J 6.5, CH2CH2O), 4.13 (1 H, m,
6-H), 4.70 and 4.75 (each 1 H, d, J 6.9, OHCHO), 5.47 (1 H,
dd, J 15.6 and 7.2, 5-H), 5.72 (1 H, dt, J 15.6 and 6.9, 4-H) and
7.26–7.36 (5 H, m, ArH); δC (75 MHz, CDCl3) −5.28, −5.22,
−1.34, 13.70, 18.07, 18.43, 19.14, 23.18, 25.97, 30.64, 36.25,
56.17, 58.88, 64.49, 65.04, 66.48, 77.11, 92.34, 126.76, 127.12,
128.42, 129.72, 130.66, 145.24 and 174.49; m/z (CI) 580
(M+ + 1, 100%).
Butyl (2S,6S,E)- and (2R,6S,E)-7-tert-butyldimethylsilyloxy-6-(2-
(trimethylsilylethoxy)methoxy-2-[(S)-(1-phenylethyl)amino]hept-
4-enoate 109 and 110
(2S,6R,E)-2-(Diphenylmethyl)amino-7-benzyloxy-6-methylhept-
4-en-1-ol 96
The general procedure using tin(IV) chloride (451 mg,
1.73 mmol) in DCM (5 mL), 4,5-bisalkoxypentenylstannane 106
(1.16 g, 1.82 mmol) in DCM (5 mL) and the imine (S)-11
(424 mg, 1.82 mmol) in DCM (5 mL), after 12 h at −45 °C and
chromatography using petrol–ether–triethylamine (90 : 9.5 : 0.5)
as eluent, gave the title compounds 109 and 110 (682 mg, 68%)
as a colourless oil, 109 : 110 = 96 : 4 (1H NMR) (Found: M+ +
H, 580.3843. C31H58NO5Si2 requires M, 580.3854); [α]D +21 (c
0.97 in CHCl3); νmax/cm−1 701, 778, 837, 1027, 1058, 1127,
1180, 1251, 1469, 1734, 2859, 2956 and 3336; δH (300 MHz,
CDCl3) major isomer 0.06 (9 H, s, 3 × CH3Si), 0.10 (6 H, s, 2 ×
CH3Si), 0.93 [9 H, s, SiC(CH3)3], 0.97 (2 H, m, SiCH2), 0.99 (3
H, t, J 7.3, CH3CH2), 1.37 (3 H, d, J 6.4, PhCHCH3), 1.41 (2 H,
hex, J 7.6, CH3CH2), 1.65 (2 H, qn, J 7.0, CH2CH2O), 1.82 (1
H, br s, NH), 2.28–2.47 (2 H, m, 3-H2), 3.10 (1 H, t, J 6.5, 2-H),
3.51–3.81 (5 H, m, 7-H2, PhCHCH3 and SiCH2CH2O),
4.07–4.23 (3 H, m, 6-H and CH2CH2O), 4.70 and 4.73 (each 1
H, d, J 6.9, OHCHO), 5.42 (1 H, dd, J 15.5 and 7.3, 5-H), 5.68
(1 H, dt, J 15.5 and 7.5, 4-H) and 7.27–7.40 (5 H, m, ArH);
minor isomer 3.39 (t, J 6.5, 2-H); δC (75 MHz, CDCl3) major
isomer −5.26, −5.21, −1.34, 13.69, 18.07, 18.44, 19.15, 25.36,
25.98, 30.75, 36.93, 56.60, 58.83, 64.42, 65.03, 66.50, 92.31,
126.91, 127.06, 128.41, 129.92, 130.44, 144.98 and 175.26; m/z
(CI) 580 (M+ + 1, 100%).
Diisobutylaluminium hydride in hexanes (1 M, 3 mL, 3 mmol)
was added to the ester 92 (490 mg, 1.01 mmol) in DCM
(15 mL) at −78 °C and the mixture was stirred to ambient temp-
erature over a period of 1 h. After cooling to −78 °C, saturated
aqueous ammonium chloride (750 μL) was added and the
mixture was stirred vigorously to ambient temperature, then
filtered (Celite) and absorbed onto silica. The resulting white
powder was applied to a column of silica gel and elution with
hexane–ether (3 : 2) gave the title compound 96 (386 mg, 92%)
as a colourless oil (Found: M+ + H, 416.2600. C28H34NO2
requires M, 416.2590); [α]D +35 (c 2.4 in CHCl3); νmax/cm−1
700, 742, 973, 1097, 1361, 1453, 1493, 1599, 2867, 3027, 3332
and 3430; δH (500 MHz, CDCl3) 0.98 (3 H, d, J 7.3, 6-CH3),
1.66 (1 H, br s, OH), 2.00 (1 H, br s, NH), 2.16–2.27 (2 H, m,
3-H2), 2.44 (1 H, sep, J 6.7, 6-H), 2.68 (1 H, m, 2-H), 3.21–3.26
(2 H, m, 1-H2), 3.33 (1 H, dd, J, 10.6 and 5.9, 7-H), 3.57 (1 H,
dd, J 10.6 and 4.3, 7-H), 4.42 (2 H, s, PhCH2), 4.98 (1 H, s,
Ph2CH), 5.34 (1 H, dt, J 15.5 and 7.1, 4-H), 5.44 (1 H, dd, J
15.5 and 7.1, 5-H) and 7.18–7.38 (15 H, m, ArH); δC (75 MHz,
CDCl3) 17.12, 35.09, 37.03, 55.76, 63.55, 64.12, 72.94, 75.17,
125.90, 127.13, 127.19, 127.30, 127.43, 127.51, 127.57, 128.35,
128.55, 128.59, 136.70, 138.57, 143.64 and 144.12; m/z (CI)
416 (M+ + 1, 40%) and 167 (100).
Butyl (2S,6S,E)-7-tert-butyldimethylsilyloxy-6-(2-
trimethylsilylethoxy)methoxy-2-[(R)-(1-phenylethyl)amino]hept-
4-enoate 108
Methyl (2S,6S,E)-7-tert-butyldimethylsilyloxy-6-(2-
trimethylsilylethoxy)methoxy-2-(2-nitrophenylsulfanyl)-
aminohept-4-enoate 111
The general procedure using tin(IV) chloride (481 mg,
1.85 mmol) in DCM (5 mL), the 4,5-bis-alkoxypentenylstannane
106 (1.23 g, 1.93 mmol) in DCM (5 mL) and the imine (R)-11
(452 mg, 1.94 mmol) in DCM (5 mL), after 12 h at −45 °C and
The general procedure using tin(IV) chloride (1.86 g, 7.14 mmol)
in DCM (15 mL), the 4,5-bisalkoxypentenylstannane 106
(4.77 g, 7.50 mmol) in DCM (15 mL) and the imine 29 (1.80 g,
7.49 mmol) in DCM (15 mL), after 12 h at −45 °C and
6150 | Org. Biomol. Chem., 2012, 10, 6130–6158
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chromatography using petrol–ether–triethylamine (60 : 39.5 : 0.5)
as eluent, gave the title compound 111 (3.39 g, 81%) as a yellow
oil, no other diastereoisomer was detected by H NMR (Found:
H, m, 4-H), 4.27–4.36 (1 H, m, 5-H), 4.49 (1 H, t, J 9.0, 3-H),
4.59–4.69 (1 H, m, 5-H) and 6.50 (1 H, br s, NH); δC (75 MHz,
CDCl3) 22.84, 30.27, 49.22, 66.14, 170.79 and 175.76; m/z (CI)
161 (M+ + 18, 95%) and 144 (M+ + 1, 100).
1
M+ + NH4, 604.2900. C26H50N3O7Si2S requires M, 604.2908);
[α]D +25.4 (c 2.05 in CHCl3); νmax/cm−1 736, 780, 837, 973,
1025, 1100, 1250, 1305, 1338, 1513, 1567, 1593, 1742, 2953
and 3331; δH (300 MHz, CDCl3) 0.01 (9 H, s, 3 × CH3Si), 0.09
(6 H, s, 2 × CH3Si), 0.91 [9 H, s, SiC(CH3)3], 0.95 (2 H, t, J
8.9, SiCH2), 2.53–2.77 (2 H, m, 3-H2), 3.45 (1 H, d, J 8.8, NH),
3.56–3.79 (5 H, m, 2-H, 7-H2 and SiCH2CH2O), 3.81 (3 H, s,
CH3O), 4.14 (1 H, dt, J 11.9 and 5.9, 6-H), 4.73 and 4.78 (each
1 H, d, J 6.8, OHCHO), 5.59 (1 H, dd, J 15.5 and 7.0, 5-H),
5.73 (1 H, dt, J 15.5 and 7.1, 4-H), 7.29 (1 H, ddd, J 8.1, 8.1
and 1.1, ArH), 7.68 (1 H, ddd, J 7.9, 7.9 and 1.1, ArH), 8.10 (1
H, dd, J 7.9 and 1.0, ArH) and 8.30 (1 H, dd, J 8.0 and 1.0,
ArH); δC (75 MHz, CDCl3) −5.26, −5.21, −1.41, 18.07, 18.43,
25.82, 25.95, 36.48, 52.39, 63.46, 65.22, 66.27, 92.70, 124.60,
124.77, 125.78, 127.95, 132.67, 133.88, 142.56, 144.98 and
173.48; m/z (CI) 604 (M+ + 18, 4%), 587 (M+ + 1, 2), 439 (50)
and 147 (100).
Methyl (2S,6S,E)-2-(diphenylmethyl)amino-7-tert-
butyldimethylsilyloxy-6-(2-trimethylsilylethoxy)methoxyhept-4-
enoate 115
The general procedure using tin(IV) chloride (313 mg,
1.20 mmol) in DCM (5 mL), the 4,5-bis-alkoxypentenylstannane
106 (802 mg, 1.26 mmol) in DCM (5 mL) and the imine 114
(320 mg, 1.26 mmol) in DCM (5 mL) after chromatography
using petrol–ether–triethylamine (90 : 9.5 : 0.5) as eluent gave
the title compound 115 (519 mg, 72%) as a colourless oil, no
1
other diastereoisomer was detected by H NMR (Found: M+ +
H, 600.3547. C33H54NO5Si2 requires M, 600.3541); [α]D +31
(c 0.45 in CHCl3); νmax/cm−1 702, 778, 836, 1027, 1056, 1106,
1127, 1250, 1453, 1738, 2928, 2952 and 3332; δH (300 MHz,
CDCl3) 0.06 (9 H, s, 3 × CH3Si), 0.10 (6 H, s, 2 × CH3Si),
0.91–0.99 [11 H, m, SiC(CH3)3 and SiCH2], 2.18 (1 H, br s,
NH), 2.40–2.50 (2 H, m, 3-H2), 3.33 (1 H, t, J 6.3, 2-H),
3.52–3.81 (4 H, m, 7-H2 and SiCH2CH2O), 3.74 (3 H, s,
CH3O), 4.14 (1 H, m, 6-H), 4.68 and 4.73 (each 1 H, d, J 6.8,
OHCHO), 4.84 (1 H, s, Ph2CH), 5.45 (1 H, dd, J 15.5 and 7.5,
5-H), 5.76 (1 H, dt, J 15.5 and 7.9, 4-H) and 7.20–7.48 (10 H,
m, ArH); δC (75 MHz, CDCl3) −5.25, −5.20, −1.32, 18.07,
18.46, 25.98, 36.82, 51.67, 59.03, 65.06, 65.38, 66.49, 92.22,
127.23, 127.30, 127.56, 128.53, 128.90, 129.80, 130.63, 142.67,
144.14 and 175.26; m/z (CI) 600 (M+ + 1, 70%) and 90 (100).
Methyl (2S,6S,E)-2-acetamido-7-tert-butyldimethylsilyloxy-6-
(2-(trimethylsilyl)ethoxy)methoxyhept-4-enoate 112
Triethylamine (1.07 mL, 7.68 mmol), acetic anhydride (362 μL,
3.83 mmol) and DMAP (3 mg, 25 μmol) were added to the 2-
(arylsulfanyl)aminoheptenoate 111 (750 mg, 1.28 mmol) in
chloroform (15 mL) and this mixture was heated under reflux for
16 h. After cooling to ambient temperature, water (20 mL) was
added and, after 10 min, by more DCM. The organic layer was
washed with saturated aqueous sodium hydrogen carbonate and
dried (MgSO4). The solution was absorbed on to silica and the
resulting powder applied to a column of silica gel. Elution with
hexane–ethyl acetate (3 : 2) gave the title compound 112
(450 mg, 74%) as a pale yellow oil (Found: M+ + H, 476.2862.
C22H46NO6Si2 requires M, 476.2864); νmax/cm−1 775, 834,
1023, 1102, 1249, 1372, 1437, 1536, 1658, 1746, 2858, 2952
and 3293; δH (300 MHz, CDCl3) 0.05 (9 H, s, 3 × CH3Si), 0.10
(6 H, s, 2 × CH3Si), 0.92 [9 H, s, SiC(CH3)3], 0.96 (2 H, t, J
7.9, SiCH2), 2.05 (3 H, s, CH3CO), 2.50–2.67 (2 H, m, 3-H2),
3.52–3.89 (4 H, m, 7-H2 and SiCH2CH2O), 3.78 (3 H, s,
CH3O), 4.09 (1 H, m, 6-H), 4.67–4.75 (3 H, m, 2-H and
OCH2O), 5.51 (1 H, dd, J 15.5 and 6.9, 5-H), 5.60 (1 H, dt, J
15.5 and 6.7, 4-H) and 6.14 (1 H, d, J 8.7, NH); δC (75 MHz,
CDCl3) −5.27, −1.39, 18.07, 18.42, 23.12, 25.94, 35.14, 51.76,
52.40, 65.09, 66.29, 77.32, 92.43, 127.61, 132.52, 169.67 and
172.22; m/z (CI) 493 (M+ + 18, 5%), 476 (M+ + 1, 4), 418 (10)
and 328 (100).
The general procedure using the 2-acetamidoheptenoate 112
(250 mg, 0.525 μmol), ozone, methyl sulfide (116 μL,
1.58 mmol) and sodium borohydride (80 mg, 2.11 mmol) gave
an alcohol that was cyclised using glacial acetic acid in chloro-
form to give, after chromatography using chloroform–triethyl-
amine (99.5 : 0.5) as eluent, the (S)-acetamidolactone 113
(45 mg, 60%) (Found C, 50.45; H, 6.5; N, 9.5. C6H9NO3
requires C, 50.35; H, 6.5; N, 9.8); [α]D +14.4 (c 1.1 in CH2Cl2),
[α]D −63 (c 1.6 in DMF) [lit.21 −54.7 (in DMF)]; νmax/cm−1
1034, 1179, 1344, 1381, 1428, 1538, 1638, 1783 and 3305; δH
(300 MHz, CDCl3) 2.09 (3 H, s, CH3CO), 2.20 and 2.82 (each 1
Methyl (2S,6S)-2-(diphenylmethyl)amino-7-(tert-butyl-
dimethylsilyloxy)-6-(2-trimethylsilylethoxy)methoxyheptanoate
116
The general procedure using heptenoate 115 (445 mg,
0.742 μmol), toluene 4-sulfonylhydrazine (1.38 g, 7.41 mmol)
and anhydrous sodium acetate (608 mg, 7.41 mmol) after chrom-
atography using hexane–ether–triethylamine (90 : 9.5 : 0.5) as
eluent gave the title compound 116 (402 mg, 90%) as a colour-
less oil (Found: M+ + H, 602.3696. C33H56NO5Si2 requires M,
602.3697); [α]D −21 (c 2.0 in CHCl3); νmax/cm−1 701, 777, 838,
1030, 1104, 1251, 1462, 1737, 2951 and 3336; δH (300 MHz,
CDCl3) 0.05 (9 H, s, 3 × CH3Si), 0.10 (6 H, s, 2 × CH3Si),
0.88–0.99 [11 H, m, SiC(CH3)3 and SiCH2], 1.48–1.73 (6 H, m,
3-H2, 4-H2 and 5-H2), 2.11 (1 H, br s, NH), 3.24 (1 H, t, J 6.3,
2-H), 3.56–3.70 (5 H, m, 6-H, 7-H2 and SiCH2CH2O), 3.74 (3
H, s, CH3O), 4.73 (1 H, d, J 7.1, OHCHO), 4.80 (1 H, s,
Ph2CH), 4.83 (1 H, d, J 7.1, OHCHO) and 7.20–7.50 (10 H, m,
ArH); δC (75 MHz, CDCl3) −5.35, −5.32, −1.37, 18.08, 18.35,
21.73, 25.96, 31.58, 34.12, 51.67, 59.07, 65.12, 65.57, 65.70,
77.90, 94.58, 127.18, 127.32, 127.60, 128.50, 128.52, 142.78,
144.36 and 176.24; m/z (CI) 602 (M+ + 1, 100%).
Methyl (2S,6S)-2-(diphenylmethyl)amino-6,7-dihydroxy-
heptanoate 117
The α-amino ester 116 (301 mg, 0.500 μmol) was dissolved in
saturated hydrogen chloride in methanol (5 mL) and the solution
This journal is © The Royal Society of Chemistry 2012
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stirred at ambient temperature for 2 h. After concentration under
reduced pressure, the residue was dissolved in chloroform,
absorbed on to silica and the resulting powder applied to a
column of silica gel. Elution with hexane–ethyl acetate–metha-
nol (50 : 48 : 2) as eluent gave the title compound 117 (179 mg,
100%) as a colourless oil (Found: M+ + H, 358.2010.
C21H28NO4 requires M, 358.2018); [α]D −23.5 (c 1.7 in CHCl3);
νmax/cm−1 703, 747, 1029, 1058, 1137, 1171, 1202, 1436, 1453,
1492, 1732, 2864, 2946 and 3399; δH (300 MHz, CDCl3)
1.36–1.46, 1.51–1.63 and 1.64–1.75 (each 2 H, m), 2.30 (3 H,
br s, NH and 2 × OH), 3.25 (1 H, t, J 6.5, 2-H), 3.44 (1 H, dd, J
11.1 and 7.4, 7-H), 3.61–3.76 (2 H, m, 6-H and 7-H), 3.76 (3 H,
s, CH3O), 4.81 (1 H, s, Ph2CH) and 7.20–7.50 (10 H, m, ArH);
δC (75 MHz, CDCl3) 21.78, 32.71, 33.60, 51.81, 58.96, 65.63,
66.74, 71.87, 127.30, 127.66, 128.55, 128.57, 142.62, 144.16
and 176.20; m/z (CI) 358 (M+ + 1, 100%).
474.2162); [α]D +6.6 (c +1.9 in CHCl3); νmax/cm−1 816, 972,
1173, 1250, 1355, 1455, 1514, 1712, 1742, 2950 and 3430; δH
(300 MHz, CDCl3) 1.48 [9 H, s, C(CH3)3], 1.48–1.87 (6 H, m,
3-H2, 4-H2 and 5-H2), 2.33 (3 H, s, PhCH3), 2.35 (1 H, br, s
OH), 2.68 (6 H, s, 2 × PhCH3), 3.78 (3 H, s, CH3O), 3.84–3.98
(3 H, m, 6-H and 7-H2), 4.40 (1 H, m, 2-H), 5.10 (1 H, d, J 8.6,
NH) and 7.01 (2 H, s, ArH); δC (75 MHz, CDCl3) 21.04, 22.60,
28.32, 32.09, 32.70, 52.32, 52.95, 69.18, 72.86, 80.08, 130.35,
131.83, 139.96, 143.52, 155.53 and 173.14; m/z (CI) 491 (M+ +
18, 2%), 474 (M+ + 1, 20) and 374 (100).
Methyl (2S,6S)-6,7-epoxy-2-[(1,1-dimethyl)ethoxycarbonyl]-
aminoheptanoate 120
Potassium tert-butoxide (62 mg, 0.552 μmol) was added to the
mesitylate 119 (250 mg, 0.528 μmol) in THF (5 mL) at −78 °C
and the mixture stirred at −78 °C for 5 min. Methanol (500 μL)
and water (500 μL) were added and the mixture was allowed to
warm to ambient temperature. Ether (10 mL) was added and the
solution absorbed on to silica. The resulting powder was applied
to a column of silica gel. Elution using chloroform gave the title
compound 120 (120 mg, 83%) as a colourless oil (Found: M+
273.1581. C13H23NO5 requires M, 273.1576); [α]D +3.79 (c
0.95 in CHCl3); νmax/cm−1 1166, 1212, 1252, 1366, 1454, 1517,
1714, 1745 and 2976; δH (300 MHz, CDCl3) 1.48 [9 H, s, C
(CH3)3], 1.49–1.93 (6 H, m, 3-H2, 4-H2 and 5-H2), 2.50 (1 H,
dd, J 5.1 and 2.9, 7-H), 2.78 (1 H, dd, J 5.1 and 4.7, 7-H), 2.93
(1 H, m, 6-H), 3.76 (3 H, s, CH3O), 4.35 (1 H, m, 2-H) and 5.08
(1 H, d, J 7.6, NH); δC (75 MHz, CDCl3) 21.97, 28.32, 31.88,
32.53, 46.89, 51.84, 52.26, 53.35, 79.95, 155.33 and 173.17;
m/z (CI) 291 (M+ + 18, 10%), 274 (M+ + 1, 30) and 114 (100).
Methyl (2S,6S)-6,7-dihydroxy-2-[(1,1-dimethyl)ethoxycarbonyl]-
aminoheptanoate 118
The general procedure for transfer hydrogenation using the hep-
tanoate 117 (774 mg, 2.17 mmol) gave an oil that was dissolved
in DCM (7.5 mL) and triethylamine (2.5 mL, 17.94 mmol) and
2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (587 mg,
2.38 mmol) were added. The mixture was heated under reflux
for 3 h and cooled to ambient temperature. After concentration
under reduced pressure, the residue was dissolved in chloroform
and the solution washed with saturated aqueous sodium hydro-
gen carbonate, water and brine then dried (MgSO4). The solution
was absorbed onto silica and the ensuing powder applied to a
column of silica gel. Elution with chloroform–methanol (99 : 1
to 99 : 5) as eluent gave the title compound 118 (442 mg, 70%)
as a colourless oil (Found: M+ + H, 292.1769. C13H26NO6
requires M, 292.1760); [α]D +6.14 (c 2.2 in CHCl3); νmax/cm−1
1054, 1167, 1251, 1367, 1440, 1456, 1522, 1696, 1740, 2949
and 3374; δH (300 MHz, CDCl3) 1.46 [9 H, s, C(CH3)3],
1.46–1.85 (6 H, m, 3-H2, 4-H2 and 5-H2), 2.70 (2 H, br s, 2 ×
OH), 3.46 (1 H, dd, J 11.4 and 7.3, 7-H), 3.65 (1 H, dd, J 11.4
and 8.0, 7-H), 3.75 (1 H, m, 6-H), 3.78 (3 H, s, CH3O), 4.33 (1
H, m, 2-H) and 5.21 (1 H, br d, J 8.1, NH); δC (75 MHz,
CDCl3) 21.29, 28.33, 32.31, 32.81, 52.30, 53.11, 66.74, 71.77,
80.11, 155.62 and 173.34; m/z (CI) 292 (M+ + 1, 2%), 236 (40)
and 192 (100).
Methyl (2S,6R)-6-(hydroxymethyl)piperidinyl-2-carboxylate 121
Trifluoroacetic acid (1 mL) was added to the epoxide 120
(100 mg, 0.366 μmol) in chloroform (1 mL) and the solution
was stirred at ambient temperature for 2 h. After concentration
under a high vacuum (0.5 mm Hg), the residue was dissolved in
chloroform and absorbed onto silica. The resulting powder was
applied to a column of silica gel. Elution with chloroform then
chloroform–methanol (95 : 5) gave the title compound 121
(43 mg, 68%) as a colourless oil (Found: M+ + H, 174.1132.
C8H16NO3 requires M, 174.1130); [α]D −14 (c 1.1 in CHCl3);
νmax/cm−1 1046, 1102, 1213, 1295, 1439, 1739, 2934 and 3385;
δH (500 MHz, CDCl3) 1.13 (1 H, m), 1.33–1.42 (2 H, m), 1.52,
1.87 and 1.99 (each 1 H, m), 2.27 (2 H, br s, NH and OH), 2.69
(1 H, m, 6-H), 3.34 (1 H, dd, J 10.8 and 2.6, 2-H), 3.44 (1 H,
dd, J 10.8 and 7.7, 6-CH), 3.61 (1 H, dd, J 10.8 and 3.4, 6-CH)
and 3.70 (3 H, s, CH3O); δC (75 MHz, CDCl3) 24.01, 27.66,
29.26, 51.97, 57.55, 58.78, 66.71 and 173.72; m/z (CI) 174
(M+ + 1, 100%) and 142 (55).
Methyl (2S,6S)-6-hydroxy-2-[(1,1-dimethyl)ethoxycarbonyl]-
amino-7-[(2,4,6-trimethylphenyl)sulfonyloxy]heptanoate 119
2-Mesitylenesulfonyl chloride (206 mg, 0.942 μmol) in pyridine
(5 mL) cooled to 0 °C) was added to the diol 118 (250 mg,
0.858 μmol) in pyridine (1 mL) and the solution stirred at 0 °C
for 16 h. The reaction mixture was concentrated under reduced
pressure and the residue suspended in water and extracted into
chloroform. The organic layer was washed with aqueous hydro-
gen chloride (1 M) and water then dried (MgSO4). After concen-
tration under reduced pressure, the ensuing oil was applied to a
column of silica gel. Elution with chloroform–methanol (99 : 1)
as eluent gave the title compound 119 (337 mg, 83%) as a col-
ourless oil (Found: M+ + H, 474.2161. C22H36NO8S requires M,
Butyl (2S,7S,4E)- and (2R,7S,4E)-7-methoxy-2-[(S)-
(1-phenylethyl)amino]oct-4-enoates 126 and 127
The general procedure using the (S)-5-methoxyhexenylstannane
(S)-123 (63 mg, 0.155 mmol), tin(IV) bromide in DCM (1 M,
155 μL, 0.155 mmol) and the (S)-imine (S)-11 (35 mg,
6152 | Org. Biomol. Chem., 2012, 10, 6130–6158
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0.150 mmol) after 8 h at −50 °C and chromatography using
DCM–ether–triethylamine (90 : 9.5 : 0.5) as eluent gave the title
compounds 126 and 127 (33 mg, 68%) as a colourless oil,
126 : 127 = 16 : 84 (1H NMR). Samples of each were obtained
as colourless oils by preparative HPLC using hexane–ethyl
acetate (2 : 1) as eluent: (2R)-epimer 127 (less polar, 86% of the
mixture), (Found: M+ + H, 348.2537. C21H34O3N requires M,
348.2539); νmax/cm−1 701, 1094, 1136, 1181, 1453, 1733, 2964
and 3395; δH (500 MHz, CDCl3) 0.89 (3 H, t, J 7.5, CH3CH2),
1.09 (3 H, d, J 6.5, 8-H3), 1.31 (2 H, hex, J 7.5, CH3CH2), 1.32
(3 H, d, J 6.5, NCHCH3), 1.52 (2 H, qn, J 7.5, CH2CH2O), 1.87
(1 H, br s, NH), 2.09 and 2.26 (each 1 H, dt, J 14 and 7, 6-H),
2.31 (2 H, t, J 7, 3-H2), 3.26–3.20 (2 H, m, 2-H and 7-H), 3.28
(3 H, s, 7-OCH3), 3.76 (1 H, q, J 6.5, NCHCH3), 3.94 (2 H, t, J
7.5, CH2CH2O), 5.39 (1 H, dt, J 15 and 7.5, 5-H), 5.48 (1 H, dt,
J 15 and 7.5, 4-H) and 7.19–7.29 (5 H, m, ArH); δC (125 MHz,
CDCl3) 13.65, 18.78, 19.07, 23.09, 30.57, 36.22, 39.13, 55.94,
58.87, 64.35, 76.50, 126.75, 126.75, 127.27, 128.33, 129.94,
145.09 and 174.55; m/z (CI) 348 (M+ + 1, 100%): (2S)-epimer
126 (more polar, 14% of the mixture) (Found: M+ + H,
348.2545. C21H34O3N requires M, 348.2539); νmax/cm−1 701,
1094, 1135, 1181, 1372, 1453, 1732, 2962 and 3330; δH
(500 MHz, CDCl3) 0.91 (3 H, t, J 7.5, CH3CH2), 1.09 (3 H, d, J
6.5, 8-H3), 1.31 (3 H, d, J 6.5, NCHCH3), 1.35 (2 H, hex, J 7.5,
CH3CH2), 1.58 (2 H, qn, J 7.5, CH2CH2O), 1.77 (1 H, br s,
NH), 2.09 and 2.22 (each 1 H, dt, J 14 and 7, 6-H), 2.27 (2 H, t,
J 7, 3-H2), 3.03 (1 H, t, J 6.5, 2-H), 3.30 (1 H, m, 7-H), 3.29 (3
H, s, 7-OCH3), 3.69 (1 H, q, J 6.5, NCHCH3), 4.09 (2 H, t, J
7.5, CH2CH2O), 5.34 (1 H, dt, J 15 and 7.5, 5-H), 5.44 (1 H, dt,
J 15 and 7.5, 4-H), 7.21 (1 H, m, ArH) and 7.26–7.29 (4 H, m,
ArH); δC (125 MHz, CDCl3) 13.65, 18.78, 19.09, 25.24, 36.67,
37.05, 39.04, 55.92, 55.95, 58.79, 64.26, 76.50, 126.83, 126.95,
127.55, 128.30, 129.62, 144.95 and 175.28; m/z (CI) 348
(M++1, 100%). Further elution with DCM–ether–triethylamine
(90 : 9.5 : 0.5) gave butyl (2SR,7S,4ZE)-2-hydroxy-7-methoxy-
oct-4-enoate (10 mg, 18%).
H, t, J 6.5, 3-H2), 3.28 (1 H, m, 7-H), 3.28 (3 H, s, 7-OCH3),
3.31 (1 H, t, J 6.5, 2-H), 3.76 (1 H, q, J 6.5, NCH CH3), 3.95 (2
H, t, J 7.5, CH2CH2O), 5.40 (1 H, dt, J 15.5 and 7.5, 5-H), 5.48
(1 H, dt, J 15.5 and 7.5, 4-H) and 7.19–7.28 (5 H, m, ArH); δC
(125 MHz, CDCl3) 13.65, 18.76, 19.07, 23.08, 30.57, 36.22,
39.11, 55.91, 56.05, 58.89, 64.35, 76.50, 126.77, 127.06,
127.27, 128.33, 129.94, 145.05 and 174.54; m/z (CI) 348 (M+ +
1, 100%); (2R)-epimer 129 (more polar, 8% of the mixture),
[α]D +54 (c 0.36 in DCM) (Found: M+ + H, 348.2535.
C21H34O3N requires M, 348.2539); νmax/cm−1 701, 1183, 1393,
1453 and 1731 and 3331; δH (500 MHz, CDCl3) 0.91 (3 H, t, J
7.5, CH3CH2), 1.08 (3 H, d, J 6.5, 8-H3), 1.30 (3 H, d, J 6.5,
NCHCH3), 1.35 (2 H, hex, J 7.5, CH3CH2), 1.49–1.56 (3 H, m,
CH2CH2O and NH), 2.08 (1 H, dt, J 14 and 7, 6-H), 2.22 (1 H,
dt, J 14 and 7, 6-H), 2.26 (2 H, dd, J 7 and 7, 3-H2), 3.02 (1 H,
t, J 6.5, 2-H), 3.28 (1 H, m, 7-H), 3.29 (3 H, s, 7-OCH3), 3.68 (1
H, q, J 6.5, NCHCH3), 4.08 (2 H, t, J 7.5, CH2CH2O), 5.35 (1
H, dt, J 15.5 and 7.5, 5-H), 5.43 (1 H, dt, J 15.5 and 7.5, 4-H)
and 7.20–7.29 (5 H, m, ArH); m/z (CI) 348 (M+ + 1, 100%).
Butyl (2S,7S,4E)- and (2R,7S,4E)-2-(diphenylmethyl)amino-7-
methoxyoct-4-enoate 139 and 140
The general procedure using the (S)-methoxyhexenylstannane
(S)-123 (192 mg, 0.474 mmol) in DCM (6 mL), the imine 32
(136 mg, 0.460 mmol) in DCM (2 mL) and tin(IV) bromide in
DCM (1 M, 474 μL, 0.474 mmol) after 24 h at −50 °C and
chromatography using hexane–ethyl acetate–triethylamine
(60 : 39 : 1) as eluent gave a mixture of the title compounds 139
and 140 (116 mg, 62%) as a colourless oil, [α]D −21.3 (c 0.84 in
DCM) (Found: M+ + H, 410.2689. C26H36O3N requires M,
410.2695); νmax/cm−1 702, 745, 969, 1027, 1095, 1138, 1183,
1276, 1345, 1453, 1731, 2962 and 3330; δH (300 MHz, CDCl3)
0.98 (3 H, t, J 7.5, CH3CH2), 1.15 (3 H, d, J 6.5, 8-H3), 1.41 (2
H, m, CH3CH2), 1.64 (2 H, m, CH2CH2O), 2.19 (1 H, br s,
NH), 2.24 (2 H, m, 6-H2), 2.44 (2 H, t, J 6.5, 3-H2), 3.27–3.40
(2 H, m, 7-H and 2-H), 3.34 (3 H, s, 7-OCH3), 4.20 (2 H, t, J
7.5, CH2CH2O), 4.86 (1 H, s, NCHPh2), 5.55 (1 H, dt, J 15 and
7.5, 5-H), 5.60 (1 H, dt, J 15 and 7.5, 4-H) and 7.20–7.90 (10
H, m, ArH); δC (75 MHz, CDCl3) 13.64, 18.77, 19.09, 30.67,
36.89, 39.11, 55.91, 59.03, 64.34, 65.26, 76.50, 127.06, 127.27,
127.46, 127.52, 128.37, 128.40, 129.78, 142.78, 144.20 and
174.87; m/z (CI) 410 (M+ + 1, 100%), 348 (5), 182 (5) and
167 (50).
n-Butyl (2S,7S,4E)- and (2R,7S,4E)-7-methoxy-2-[(R)-
(1-phenylethyl)amino]oct-4-enoate 128 and 129
The general procedure using the (S)-5-methoxyhexenylstannane
(S)-123 (59 mg, 0.145 mmol) in DCM (1 mL), the (R)-imine
(R)-11 (33 mg, 0.141 mmol) in DCM (0.5 mL) and tin(IV)
bromide in DCM (1 M, 145 μL, 0.145 mmol) at −50 °C for 8 h
and
chromatography
using
DCM–ether–triethylamine
(90 : 9.5 : 0.5) as the eluent gave the title compounds 128 and
129 (35 mg, 72%) as a colourless oil, 128 : 129 = 92 : 8 (1H
NMR) together with butyl (2SR,7S,4ZE)-2-hydroxy-7-methoxy-
oct-4-enoate (5 mg, 11%) as a colourless oil. Samples of each
title compound were obtained as colourless oils by preparative
HPLC using hexane–ethyl acetate (2 : 1) as the eluent: (2S)-
epimer 128 (less polar, 92% of the mixture), [α]D +12 (c 1.61 in
DCM) (Found: M+ + H, 348.2544. C21H34O3N requires M,
348.2539); νmax/cm−1 701, 969, 1183, 1372, 1454, 1702 and
2964; δH (500 MHz, CDCl3) 0.89 (3 H, t, J 7.5, CH3CH2), 1.08
(3 H, d, J 6.5, 8-H3), 1.31 (2 H, hex, J 7.5, CH3CH2), 1.32 (3 H,
d, J 6.5, NCHCH3), 1.52 (2 H, qn, J 7.5, CH2CH2O), 1.91 (1 H,
br s, NH), 2.10 and 2.22 (each 1 H, dt, J 14 and 7, 6-H), 2.34 (2
Butyl (2S,7S)- and (2R,7S)-2-amino-7-methoxyoctanoate 141 and
144
10% Pd/C (143 mg, 0.1341 mmol) and ammonium formate
(51 mg, 0.805 mmol) were added to the (diphenylmethyl)amino-
octenoates 139 and 140 (110 mg, 0.268 mmol) in dry methanol
(7 mL) at room temperature and the mixture stirred for 1 h then
filtered and the residue washed with methanol. The organic sol-
vents were concentrated under reduced pressure and the residue
was dissolved in DCM and washed with water. The aqueous
phase was extracted with DCM (5 × 10 mL) and the organic
extracts were dried (MgSO4) and concentrated under reduced
pressure to give the title compounds 141 and 144 (61 mg, 92%)
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6130–6158 | 6153

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as a colourless oil, [α]D +1.7 (c 1.5 in DCM) (Found: M+ + H,
246.2071. C13H28O3N requires M, 246.2069); νmax/cm−1 724,
1090, 1179, 1375, 1464, 1618, 1734, 2934 and 3307; δH
(300 MHz, CDCl3) 0.98 (3 H, t, J 7.5, CH3CH2), 1.17 (3 H, d, J
6.5, 8-H3), 1.38–1.47 (8 H, m, 4-H2, 5-H2, CH3CH2 and NH2),
1.53–1.76 (4 H, m, 3-H2 and 6-H2), 1.67 (2 H, hex, J 7.5,
CH2CH2O), 3.29 (1 H, m, 7-H), 3.34 (3 H, s, 7-OCH3), 3.50 (1
H, m, 2-H) and 4.15 (2 H, m, CH2CH2O); δC (75 MHz, CDCl3)
13.60, 18.91, 19.05, 25.14, 25.69, 30.59, 36.08, 55.87, 64.59,
76.51 and 164.90; m/z (CI) 247 (M+ + 2, 14%), 246 (M+ + 1,
100) and 144 (6).
HPLC using hexane–ethyl acetate (90 : 10) as the eluent gave the
less polar, major (2S)-epimer 143 as a colourless oil, [α]D −18.4
(c 1.13 in DCM) (Found: M+ + H, 462.2464. C23H35O5NF3
requires M, 462.2467); νmax/cm−1) 734, 1104, 1167, 1270, 1512,
1697, 1740, 2934 and 3357; δH (300 MHz, CDCl3) 0.97 (3 H, t,
J 7.5, CH3CH2), 1.12 (3 H, d, J 6.5, 8-H3), 1.18–1.35 (6 H, m,
4-H2, 5-H2 and 6-H2), 1.42 (2 H, hex, J 7.5, CH3CH2),
1.62–1.71 (3 H, m, 3-H and CH2CH2O), 1.92 (1 H, m, 3-H),
3.24 (1 H, m, 7-H), 3.30 (3 H, s, 7-OCH3), 3.58 (3 H, d, J 1.5,
CH3O), 4.14 (2 H, m, CH2CH2O), 4.68 (1 H, dt, J 8 and 7.5, 2-
H), 7.11 (1 H, d, J 8, NH), 7.41–7.44 (3 H, m, ArH) and
7.56–7.64 (2 H, m, ArH); δC 13.53, 18.84, 18.95, 24.76, 25.14,
30.43, 32.14, 35.94, 51.87, 55.18, 55.84, 65.39, 76.39, 127.19,
128.35, 129.40, 132.97, 166.03 and 171.85; m/z (CI) 479 (M+ +
18, 10%), 463 (M+ + 2, 20), 462 (M+ + 1, 78), 181(50) and 137
(100); δF-70.3; followed by the more polar, minor (2R)-epimer
146 as a colourless oil, [α]D +1.9 (c 0.34 in DCM) (Found: M+
+ H, 462.2473. C23H35O5NF3 requires M, 462.2467); νmax/cm−1
732, 1102, 1164, 1464,1512, 1695, 1740, 2931 and 3379; δH
(300 MHz, CDCl3) 0.97 (3 H, t, J 7.5, CH3CH2), 1.15 (3 H, d, J
6.5, 8-H3), 1.34–1.47 (6 H, m, 4-H2, 5-H2 and CH3CH2), 1.65
(2 H, m, 6-H2), 1.79 and 1.99 (each 1 H, m, 3-H), 3.30 (1 H, m,
7-H), 3.34 (3 H, s, 7-OCH3), 3.40 (3 H, d, J 1, CH3O), 4.19 (2
H, m, CH2CH2O), 4.66 (1 H, dt, J 8 and 7.5, 2-H), 7.42–7.46 (4
H, m, ArH and NH) and 7.56–7.59 (2 H, m, ArH); m/z (CI) 479
(M+ + 18, 8%), 463 (M+ + 2, 14), 462 (M+ + 1, 56), 181 (52),
121 (52) and 58 (100); δF −70.7.
Butyl (2S,7S,4E)- and (2R,7S,4E)-7-methoxy-2-[(R)-2-methoxy-
2-phenyl-3,3,3-trifluoropropanoyl]amino-octanoates 142 and 145
The procedure outlined above using (S)-Mosher’s acid chloride
(13 μL, 66 μmol), a mixture of the amino-octanoates 141 and
144 (13 mg, 55 μmol), triethylamine (39 μL, 0.273 mmol) and
DMAP (5 mg), after chromatography eluting with petrol–ether
(85 : 15), gave the title compounds 142 and 145 (19 mg, 76%),
as an oil, 142 : 145 = 70 : 30 (1H NMR). Preparative HPLC
using hexane–ethyl acetate (90 : 10) as eluent gave the less polar,
minor (2R)-isomer 145 as a colourless oil, [α]D +5.5 (c 0.51 in
DCM) (Found: M+ + H, 462.2476. C23H35O5NF3 requires M,
462.2467); νmax/cm−1 719, 1104, 1167, 1271, 1513, 1696, 1740,
2934 and 3349; δH (300 MHz, CDCl3) 0.97 (3 H, t, J 7.5,
CH3CH2), 1.13 (3 H, d, J 6.5, 8-H3), 1.16–1.38 (6 H, m, 4-H2,
5-H2 and 6-H2), 1.41 (2 H, hex, J 7.5, CH3CH2), 1.62–1.74 (3
H, m, 3-H and CH2CH2O), 1.91 (1 H, m, 3-H), 3.25 (1 H, m, 7-
H), 3.32 (3 H, s, 7-OCH3), 3.58 (3 H, d, J 1.5, CH3O), 4.18 (2
H, m, CH2CH2O), 4.69 (1 H, dt, J 8.5 and 7.5, 2-H), 7.12 (1 H,
d, J 8.5, NH), 7.41–7.44 (3 H, m, ArH) and 7.58–7.68 (2 H, m,
ArH); m/z (CI) 479 (M+ + 18, 14%), 463 (M+ + 2, 22) and 462
(M+ + 1, 100); δF-70.3; followed by the more polar, major (2S)-
epimer 142 as a colourless oil, [α]D −5.5 (c 1.04 in DCM)
Butyl (2S,7S,4E)- and (2R,7S,4E)-2-benzylamino-7-methoxyoct-
4-enoate 148 and 149
The general procedure using the (S)-methoxyhexenylstannane
(S)-123 (107 mg, 0.265 mmol) in DCM (4 mL), the benzylimine
147 (116 mg, 0.260 mmol) in DCM (1.5 mL) and tin(IV)
bromide in DCM (1 M, 265 μL, 0.265 mmol) after 22 h at
−45 °C and chromatography using petrol–ether–triethylamine
(70 : 29 : 1) as eluent gave the title compounds 148 and 149
(51 mg, 57%) as a colourless oil, [α]D −16.7 (c 1.09 in DCM)
(Found: M+ + H, 334.2385. C20H32O3N requires M, 334.2382);
νmax/cm−1 737, 971, 1095, 1181, 1455, 1731, 2963 and 3330;
δH (300 MHz, CDCl3) 0.98 (3 H, t, J 7.5, CH3CH2), 1.89 (3 H,
d, J 6.5, 8-H3), 1.43 (2 H, m, CH3CH2), 1.67 (2 H, m,
CH2CH2O), 1.89 (1 H, br s, NH), 2.15 and 2.29 (each 1 H, dt, J
14 and 7, 6-H), 2.43 (2 H, t, J 6.5, 3-H2), 3.27–3.40 (2 H, m, 2-
H and 7-H), 3.34 (3 H, s, 7-OCH3), 3.71 and 3.88 (each 1 H, d,
J 13, PhHCH), 4.15 (2 H, t, J 7.5, CH2CH2O), 5.45 (1 H, dt, J
15 and 7.5, 5-H), 5.55 (1 H, dt, J 15 and 7.5, 4-H) and
7.27–7.35 (5 H, m, ArH); δC (75 MHz, CDCl3) 13.63, 18.75,
19.09, 30.66, 36.58, 39.08, 51.90, 55.91, 60.50, 64.38, 76.44,
126.95, 127.31, 128.17, 128.27, 129.88, 139.73 and 174.66; m/z
(CI) 334 (M+ + 1, 100%).
(Found: M+
+ H, 462.2463. C23H35O5NF3 requires M,
462.2467); νmax/cm−1 718, 1104, 1167, 1271, 1513, 1696, 1740
and 3349; δH (300 MHz, CDCl3) 0.97 (3 H, t, J 7.5, CH3CH2),
1.16 (3 H, d, J 6.5, 8-H3), 1.34–1.51 (8 H, m, 4-H2, 5-H2 and
CH3CH2CH2), 1.66 (2 H, m, 6-H2), 1.79 and 1.99 (each 1 H, m,
3-H), 3.31 (1 H, m, 7-H), 3.34 (3 H, s, 7-OCH3), 3.40 (3 H, d, J
1, CH3O), 4.18 (2 H, m, CH2CH2O), 4.67 (1 H, dt, J 8.5 and
7.5, 2-H), 7.43–7.45 (4 H, m, ArH and NH) and 7.58 (2 H, dd, J
7.5 and 3.5, ArH); δC (75 MHz, CDCl3) 13.57, 18.86, 18.96,
24.83, 25.22, 30.44, 32.20, 35.95, 52.14, 54.78, 55.86, 65.32,
76.44, 127.97, 128.52, 129.44, 131.75, 166.00 and 171.94; m/z
(CI) 479 (M+ + 18, 20%), 463 (M+ + 2, 22) and 462 (M+ + 1,
100).
Butyl (2S,7S,4E)- and (2R,7S,4E)-7-methoxy-2-[(S)-2-methoxy-2-
phenyl-3,3,3-trifluoropropanoyl]amino-octanoates 143 and 146
The general procedure using a mixture of the 2-(benzylamino)-
octenoates 148 and 149 (40 mg, 0.128 mmol), 10% Pd/C
(73 mg, 69 μmol) and ammonium formate (44 mg, 0.690 mmol)
after 1 h at room temperature gave a mixture of the 2-amino-
octanoates 141 and 144 (28 mg, 96%) as a colourless oil, [α]D
+3.5 (c 1.3 in DCM).
The procedure outlined above using (R)-Mosher’s acid chloride
(13 μL, 63 μmol), a mixture of the amino-octanoates 141 and
144 (14 mg, 57 μmol), triethylamine (42 μL, 0.287 mmol) and
DMAP (5 mg) after chromatography using petrol–ether (85 : 15)
as eluent gave the title compounds 143 and 146 (20 mg, 75%) as
a pale yellow oil, 143 : 146 = 70 : 30 (1H NMR). Preparative
The general procedure using mixture of the amino-esters 141
and 144 (36 mg, 0.146 mmol), (S)-Mosher’s acid chloride
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(30 μL, 0.160 mmol), triethylamine (106 μL, 0.73 mmol) and
DMAP (6 mg) gave the (R)-Mosher’s amides 142 and 145
(52 mg, 77%), 142 : 145 = 86 : 14, samples of which were iso-
lated by HPLC for characterization and comparison with a
sample prepared earlier. Similarly, the amino-esters 141 and 144
(13 mg, 0.538 mmol), (R)-Mosher’s acid chloride (12 μl,
59 μmol), triethylamine (40 μl, 0.276 mmol) and DMAP (6 mg)
furnished the (S)-Mosher’s amides 143 and 146 (18 mg, 71%),
143 : 146 = 86 : 14, samples of which were isolated by HPLC for
characterization and comparison with other samples.
chromatography using petrol–ether–triethylamine (70 : 29 : 1) as
eluent gave the title compounds 152 and 153 (31 mg, 55%) as a
colourless oil, 152 : 153 = 74 : 26 (1H NMR). Samples were iso-
lated by preparative HPLC eluting with hexane–ethyl acetate
(1 : 1) to give the less polar, minor (2R)-epimer 153 as a colour-
less oil, [α]D +36 (c 0.42 in DCM) (Found: M+ + H, 334.2393.
C20H32O3N requires M, 334.2382); νmax/cm−1 701, 1181, 1273,
1453, 1731, 2963 and 3423; δH (500 MHz, CDCl3) 0.91 (3 H, t,
J 7.5, CH3CH2), 1.17 (3 H, d, J 6.5, 8-H3), 1.30 (3 H, d, J 6.5,
NHCHCH3), 1.34 (2 H, hex, J 7.5, CH3CH2), 1.58 (2 H, qn, J
7.5, CH2CH2O), 1.80 (2 H, br s, OH and NH), 2.03 and 2.18
(each 1 H, dt, J 13 and 6.5, 6-H), 2.24 and 2.31 (each 1 H, dt, J
13 and 6.5, 3-H), 3.06 (1 H, t, J 6.5, 2-H), 3.68 (2 H, q, J 6.5,
HNCHCH3), 3.73 (1 H, m, 7-H), 4.10 (2 H, m, CH2O),
5.36–5.46 (2 H, m, 4-H and 5-H) and 7.19–7.30 (5 H, m, ArH);
m/z (CI) 334 (M+ + 1, 100%); followed by the more polar, major
(2S)-epimer 152 as a colourless oil, [α]D +27.5 (c 2.25 in DCM)
(Found: M+ + H, 334.2384. C20H32O3N requires M, 334.2382);
νmax/cm−1 701,762, 971, 1125, 1183, 1453, 1731, 2963 and
3423; δH (500 MHz, CDCl3) 0.89 (3 H, t, J 7.5, CH3CH2), 1.15
(3 H, d, J 6, 8-H3), 1.31 (2 H, hex, J 7.5, CH3CH2), 1.33 (3 H,
d, J 6.5, NHCHCH3), 1.53 (2 H, qn, J 7.5, CH2CH2O), 2.05 (1
H, dt, J 14 and 7, 6-H), 2.15 (2 H, br s, OH and NH), 2.17 (1 H,
dt, J 13.5 and 6.5, 6-H), 2.36 (2 H, t, J 6.5, 3-H2), 3.32 (1 H, t, J
6.5, 2-H), 3.71–3.77 (2 H, m, 7-H and HNCHCH3), 3.96 (2 H, t,
J 7.5, CH2O), 5.41–5.50 (2 H, m, 4-H and 5-H) and 7.21–7.31
(5 H, m, ArH); m/z (CI) 334 (M+ + 1, 100%).
Butyl (2S,7S,4E)- and (2R,7S,4E)-7-hydroxy-2-[(S)-
(1-phenylethyl)amino]oct-4-enoate 150 and 151
The general procedure using the (S)-hydroxyhexenylstannane
(S)-122 (73 mg, 0.186 mmol) in DCM (2 mL), tin(IV) bromide
in DCM (1 M, 186 μL, 0.186 mmol) and the (S)-imine (S)-11
(42 mg, 0.181 mmol) in DCM (1 mL) after 24 h at −45 °C for
24 h and chromatography using petrol–ether–triethylamine
(70 : 29 : 1) as eluent gave the title compounds 150 and 151
(42 mg, 69%) as a colourless oil, 151 : 150 = 87 : 13 (1H NMR).
Samples were separated by preparative scale HPLC using
hexane–ethyl acetate (1 : 1) as the eluent to give the less polar,
minor (2S)-epimer 150 as a colourless oil, [α]D −48.8 (c 0.83 in
DCM) (Found: M+ + H, 334.2386. C20H32NO3 requires M,
334.2382); νmax/cm−1 702, 763, 970, 1025, 1183, 1274, 1453,
1731, 2963 and 3455; δH (500 MHz, CDCl3) 0.99 (3 H, t, J 7.5,
CH3CH2), 1.15 (3 H, d, J 6.5, 8-H3), 1.31 (3 H, d, J 6.5,
NHCHCH3), 1.36 (2 H, hex, J 7.5, CH3CH2), 1.59 (2 H, qn, J
7.5, CH2CH2O), 1.92 (2 H, br s, OH and NH), 2.05 and 2.17
(each 1 H, dt, J 14 and 7, 6-H), 2.28 (2 H, t, J 6.5, 3-H2), 3.05
(1 H, t, J 6.5, 2-H), 3.69 (1 H, q, J 6.5, NHCHCH3), 3.76 (1 H,
m, 7-H), 4.10 (2 H, m, CH2O), 5.41 (1 H, dt, J 15.5 and 7.5, 5-
H), 5.43 (1 H, dt, J 15 and 7.5, 4-H), 7.22 (1 H, m, ArH) and
7.26–7.30 (4 H, m, ArH); m/z (CI) 334 (M+ + 1, 100%); fol-
lowed by the more polar, major (2R)-epimer 151 as a colourless
oil, [α]D −14.41 (c 2.6 in DCM) (Found: M+ + H, 334.2377.
C20H32O3N requires M, 334.2382); δH (500 MHz, CDCl3) 0.89
(3 H, t, J 7.5, CH3CH2), 1.16 (3 H, d, J 6.5, 8-H3), 1.31 (2 H,
hex, J 7.5, CH3CH2), 1.32 (3 H, d, J 6.5, NHCHCH3), 1.52 (2
H, qn, J 7.5, CH2CH2O), 2.03 (1 H, dt, J 13 and 6.5, 6-H), 2.15
(2 H, br s, OH and NH), 2.18 (1 H, dt, J 13 and 6.5, 6-H), 2.29
and 2.39 (each 1 H, dt, J 13 and 6.5, 3-H), 3.35 (1 H, t, J 6.5, 2-
H), 3.72 (1 H, m, 7-H), 3.74 (1 H, q, J 6.5, NHCHCH3), 3.96 (2
H, t, J 7.5, CH2O), 5.42 (1 H, dt, J 15 and 7.5, 5-H), 5.46 (1 H,
dt, J 15.5 and 7.5, 4-H), 7.21 (1 H, dd, J 8.5 and 4.5, ArH), 7.28
(4 H, d, J 4.5, ArH); δC (125 MHz, CDCl3) 13.65, 19.06, 22.52,
22.75, 30.55, 36.24, 42.48, 56.17, 58.96, 64.53, 66.60, 126.78,
127.15, 128.39, 128.99, 130.10, 144.79 and 174.62; m/z (CI)
334 (M+ + 1, 100%).
Methyl (2S,7S,4E)- and (2R,7S,4E)-7-hydroxy-2-[(2-
nitrophenylsufanyl)amino]oct-4-enoate 154 and 158
The general procedure using the (S)-hydroxyhexenylstannane (S)-
122 (66 mg, 0.169 mmol) in DCM (2 mL), tin(IV) bromide in
DCM (1 M, 169 μL, 0.169 mmol) and the nitrophenylsulfanyl-
imine 29 (39 mg, 0.164 mmol) in DCM (1 mL) after 24 h at
−45 °C and chromatography using DCM–ether–triethylamine
(90 : 9.5 : 0.5) as eluent gave the title compounds 154 and 158
(39 mg, 60%) as a yellow oil, [α]D +3.3 (c 3.92 in DCM)
(Found: M+
+ H, 341.1166. C15H21O5N2S requires M,
341.1171); νmax/cm−1 736, 852, 973, 1098, 1208, 1337, 1447,
1511, 1566, 1592, 1738, 2964 and 3341; δH (500 MHz, CDCl3)
1.17 (3 H, d, J 6.5, 8-H3), 2.13 and 2.21 (each 1 H, dt, J 14 and
7, 6-H), 2.51 and 2.57 (each 1 H, dt, J 13 and 6.5, 3-H), 3.33 (1
H, d, J 8.5, NH), 3.56 (1 H, dt, J 8.5 and 6.5, 2-H), 3.74 (3 H, s,
CH3O), 3.79 (1 H, hex, J 6.5, 7-H), 5.48 (1 H, dt, J 15.5 and
7.5, 5-H), 5.58 (1 H, dt, J 15.5 and 7.5, 4-H), 7.22 and 7.60
(each 1 H, t, J 7.5, ArH), 8.03 (1 H, dd, J 7.5 and 0.5, ArH) and
8.22 (1 H, d, J 7.5, ArH); δC (125 MHz, CDCl3) 22.81, 36.66,
42.31, 52.35, 63.51, 67.00, 124.49, 124.74, 125.71, 127.36,
131.33, 133.80, 142.47, 144.86 and 173.63; m/z (CI) 341
(M+ + 1, 34%), 188 (100), 186 (22) and 126 (50).
Butyl (2S,7S,4E)- and (2R,7S,4E)-7-hydroxy-2-[(R)-
(1-phenylethyl)amino]oct-4-enoate 152 and 153
Methyl (2S,7S,4E)- and (2R,7S,4E)-2-amino-7-hydroxyoct-4-
enoate 155 and 159
The general procedure using the (S)-hydroxyhexenylstannane
(S)-122 (67 mg, 0.171 mmol) in DCM (2 mL), tin(IV) bromide
in DCM (1 M, 171 μL, 0.171 mmol) and the (R)-imine (R)-11
(39 mg, 0.166 mmol) in DCM (1 mL) after 24 h at −45 °C and
Hydrogen chloride in methanol (1 M, 15 mL) was added to the
mixture of nitrophenylsulfanylamines 154 and 158 (104 mg,
0.263 mmol) at room temperature and the suspension was stirred
This journal is © The Royal Society of Chemistry 2012
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for 2 h before concentration under reduced pressure. The solid
residue was suspended in DCM (10 mL) and extracted with
aqueous hydrogen chloride (1 M, 3 × 5 mL). The aqueous phase
was basified by addition of solid sodium hydrogen carbonate
until the solution had a pH ∼10. The solution was then extracted
with ethyl acetate (7 × 8 mL) and the organic extracts dried
(MgSO4), and concentrated under reduced pressure to leave the
title compounds 155 and 159 (48 mg, 97%) as a pale yellow oil,
[α]D +6.9 (c 1.30 in DCM) (Found: M+ + H, 188.1295.
C9H18O3N requires M, 188.1287); νmax/cm−1 736, 974, 1208,
1438, 1738, 2963 and 3306; δH (300 MHz, CDCl3) 1.22 (3 H, d,
J 6.5, 8-H3), 2.02 (3 H, br s, OH and NH2), 2.18 (2 H, m, 6-H2),
2.45 (2 H, m, 3-H2), 3.69 (1 H, m, 2-H), 3.76 (3 H, s, CH3O),
3.84 (1 H, m, 7-H) and 5.44–5.64 (2 H, m, 4-H and 5-H); δC
(75 MHz, CDCl3) 22.65, 42.23, 51.96, 66.90, 128.36 and
130.53; m/z (CI) 189 (M+ + 2, 12%) and 188 (M+ + 1, 100).
(0.5 mL) after stirring for 15 h and chromatography eluting with
petrol–ether (50 : 50) gave the title compounds 157 and 161
(23 mg, 64%) as a pale yellow oil, 157 : 161 = 86 : 14 (1H and
19F NMR), [α]D −2.83 (c 2.12 in DCM) (Found: M+ + H,
404.1689. C19H25O5NF3 requires M, 404.1685); νmax/cm−1 721,
1106, 1166, 1270, 1440, 1511, 1690, 1744, 2958 and 3415; δH
(300 MHz, CDCl3) 1.05 (2.58 H, d, J 6.5, 8-H3), 1.12 (0.42 H,
d, J 6.5, 8-H3), 1.48 (1 H, br s, OH), 2.04 (2 H, m, 6-H2), 2.44
(2 H, t, J 6.5, 3-H2), 3.29 (0.42 H, s, CH3O), 3.47 (2.58 H, s,
CH3O), 3.56 (1 H, m, 7-H), 3.69 (0.42 H, s, CH3O), 3.70 (2.58
H, s, CH3O), 4.65 (1 H, m, 2-H), 5.14–5.58 (2 H, m, 4-H and 5-
H), 7.08 (0.86 H, d, J 8, NH), 7.32–7.36 (3.14 H, m, ArH and
NH) and 7.46–7.52 (2 H, m, ArH); δC (75 MHz, CDCl3) 22.75,
35.08, 42.10, 51.57, 52.51, 55.22, 66.78, 126.45, 127.25,
128.38, 129.42, 131.66, 166.10 and 171.46; m/z (CI) 421 (M+ +
18, 18%), 405 (M+ + 2, 20) and 404 (M+ + 1, 100); δF −70.4
(major), −70.7 (minor).
Methyl (2S,7S,4E)- and (2R,7S,4E)-7-hydroxy-2-[(R)-2-methoxy-
2-phenyl-3,3,3-trifluoropropanoyl]amino-oct-4-enoate 156 and
160
Methyl glyoxylate O-benzyloxime 165
A suspension of freshly prepared methyl glyoxylate (1.75 g,
19.9 mmol) and O-benzyl hydroxylamine hydrochloride (3.17 g,
19.9 mmol) was heated under reflux in toluene (100 mL) with
azeotropic removal of water for 12 h. After cooling to ambient
temperature and concentration under reduced pressure, the
residue was applied directly to a short column of silica gel.
Elution with hexane–ethyl acetate (95 : 5) gave the title com-
pound 165 (3.5 g, 91%) as a colourless liquid (Found: M+ + H,
194.0813. C10H12NO3 requires M, 194.0817); νmax/cm−1 699,
732, 923, 1005, 1046, 1207, 1274, 1330, 1368, 1441, 1599,
1727, 2952 and 3032; δH (300 MHz, CDCl3) 3.89 (3 H, s, CH3),
5.34 (2 H, s, PhCH2O), 7.40–7.42 (5 H, m, ArH) and 7.60 (1 H,
s, HC = N); δC (75 MHz, CDCl3) 52.56, 78.17, 128.55, 128.60,
128.62, 135.92, 140.92 and 162.41; m/z (CI) 211 (M+ + 18,
100%) and 194 (M+ + 1, 30).
(S)-Mosher’s acid chloride (15 μL, 71.4 μmol) in chloroform
(300 μL) was added dropwise to a vigorously stirred mixture of
the amino alcohols 155 and 159 (11 mg, 56.1 μmol) and solid
sodium hydrogen carbonate (30 mg, 0.361 mmol) in chloroform
(2 mL) containing distilled water (0.5 mL) at room temperature.
The mixture was stirred vigorously at room temperature over-
night then diluted with saturated aqueous sodium hydrogen car-
bonate and extracted with DCM (4 × 5 mL). The organic
extracts were dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue using petrol–ether
(50 : 50) as eluent gave the title compounds 156 and 160 (16 mg,
69%) as a pale yellow oil, 156 : 160 = 86 : 14 (1H and 19F
NMR), [α]D −2.83 (c 2.12 in DCM) (Found: M+ + H, 404.1696.
C19H25O5NF3 requires M, 404.1685); νmax/cm−1 977, 1106,
1167, 1270, 1440, 1515, 1692, 1745, 2960 and 3412; δH
(300 MHz, CDCl3) 1.15 (0.42 H, d, J 6.5, 8-H3), 1.22 (2.58 H,
d, J 6.5, 8-H3), 1.74 (1 H, br s, OH), 2.10 (2 H, m, 6-H2), 2.62
(2 H, m, 3-H2), 3.39 (2.58 H, d, J 1.5, CH3O), 3.55 (0.42 H, d, J
1.5, CH3O), 3.80 (2.58 H, s, CH3O), 3.79 (0.42 H, s, CH3O),
3.84 (1 H, m, 7-H), 4.73 (1 H, m, 2-H), 5.25–5.53 (0.28 H, m,
4-H and 5-H), 5.45 (0.86 H, dt, J 15 and 7.5, 5-H), 5.62 (0.86
H, dt, J 15 and 7.5, 4-H), 7.20 (0.14 H, d, J 8, NH), 7.49 (0.86
H, d, J 8, NH), 7.44–7.50 (3 H, m, ArH) and 7.55–7.58 (2 H, m,
ArH); δC (75 MHz, CDCl3) 22.68, 35.15, 42.27, 51.83, 52.45,
54.82, 66.92, 126.63, 127.97, 128.39, 128.52, 129.49, 131.73,
165.86 and 171.54; m/z (CI) 421 (M+ + 18, 34%), 405 (M+ + 2,
20), 404 (M+ + 1, 100) and 213 (60); δF −70.4 (minor), −70.7
(major).
Methyl glyoxylate oxime 166
A suspension of freshly prepared methyl glyoxylate (4.40 g,
50.0 mmol) and hydroxylamine hydrochloride (3.47 g,
50.0 mmol) was heated under reflux in toluene (100 mL) with
azeotropic removal of water for 12 h. After cooling to ambient
temperature, concentration under reduced pressure gave an oil
that crystallised on standing. This solid was stirred with hexane–
ether (10 : 1) for 1 h, then filtered off and dried under a high
vacuum (0.1 mm Hg) to afford the title compound 166 (4.4 g
85%) as a pale yellow powder, m.p. 53–55 °C (Found: C, 34.8;
H, 6.0; N, 13.1. C10H13NO requires C, 34.6; H, 5.8; N, 13.5);
νmax/cm−1 757, 1031, 1219, 1264, 1318, 1451, 1625, 1727,
2959 and 3330; δH (200 MHz, CDCl3) 3.85 (3 H, s, CH3O) and
7.57 (1 H, s, HC = N); δC (50 MHz, CDCl3) 53.18, 142.08 and
163.37; m/z (CI) 121 (M+ + 18, 100%) and 105 (M+ + 1, 35).
Methyl (2S,7S,4E)- and (2R,7S,4E)-7-hydroxy-2-[(S)-2-methoxy-
2-phenyl-3,3,3-trifluoropropanoyl]amino-oct-4-enoate 157 and
161
Methyl glyoxylate N-tosylhydrazone 167
The above procedure using (R)-Mosher’s acid chloride (20 μL,
0.108 μmol), the amino alcohols 155 and 159 (17 mg,
90.3 μmol) and solid sodium hydrogen carbonate (50 mg,
0.542 mmol) in chloroform (2 mL) containing distilled water
A solution of freshly prepared methyl glyoxylate (3.50 g,
39.7 mmol) and toluene 4-sulfonylhydrazine (7.40 g,
39.7 mmol) was heated under reflux in toluene (100 mL) for
6156 | Org. Biomol. Chem., 2012, 10, 6130–6158
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12 h with azeotropic removal of water. After cooling to ambient
temperature, concentration under reduced pressure gave a white
solid that was stirred with ether for 1 h, then filtered and dried
under high vacuum (0.1 mm Hg) to afford the title compound
167 (10.0 g, 98%) as a white powder m.p. 114–115 °C (Found:
C, 47.1; H, 4.85; N, 10.9; S, 12.2. C10H12N2O4S requires C,
46.9; H, 4.7; N, 10.9; S, 12.5); νmax/cm−1 664, 741, 818, 870,
960, 984, 1059, 1172, 1230, 1364, 1440, 1594, 1711, 2961 and
3175; δH (300 MHz, CDCl3) 2.46 (3 H, s, PhCH3), 3.83 (3 H, s,
CH3O), 6.86 (1 H, s, HCvN), 7.36 (2 H, d, J 8.2, ArH), 7.86 (2
H, d, J 8.3, ArH) and 12.09 (1 H, br s, NH); δC (75 MHz,
CDCl3) 21.66, 52.38, 127.54, 127.90, 129.86, 135.24, 144.74
and 162.06; m/z (CI) 274 (M+ + 18, 100%) and 257 (M+ + 1, 5).
chromatography using hexane–ether (1 : 1) as eluent gave the
title compound 170 (365 mg, 61%) as a colourless oil (Found:
M+ + H, 299.1067. C13H19N2O4S requires M, 299.1066); νmax
/
cm−1 812, 922, 987, 1092, 1162, 1211, 1330, 1438, 1598, 1733,
2953, 3250 and 3306; δH (300 MHz, CDCl3) 2.25–2.45 (2 H, m,
3-H2), 2.42 (3 H, s, PhCH3), 3.60 (1 H, dd, J 6.9 and 5.2, 2-H),
3.71 (3 H, s, CH3O), 3.90 (1 H, dd, J 9.8 and 5.2, CHNH),
5.01–5.07 (2 H, m, 5-H2), 5.60 (1 H, m, 4-H), 6.29 (1 H, d, J
5.2, CHNHNH), 7.29 (2 H, d, J 8.3, ArH) and 7.77 (2 H, d, J
8.1, ArH); δC (75 MHz, CDCl3) 21.68, 34.78, 52.28, 62.93,
118.42, 128.12, 129.41, 132.38, 134.86, 143.88 and 173.57; m/z
(CI) 299 (M+ + 1, 35%) and 143 (100).
Methyl (2R,6S,E)- and (2S,6S,E)-6-benzyloxy-2-
(benzyloxyamino)hept-4-enoates 171 and 173
Methyl (RS)-2-(benzyloxyamino)pent-4-enoate 168
The general procedure using tin(IV) chloride (391 mg,
1.50 mmol) in DCM (5 mL), prop-2-enyl(tributyl)stannane 3
(521 mg, 1.57 mmol) in DCM (5 mL) and the oxime-ether 165
(304 mg, 1.57 mmol) after 4 h at −78 °C and chromatography
using petrol–ethyl acetate–triethylamine (95 : 4.5 : 0.5) as eluent
gave the title compound 168 (288 mg, 82%) as a colourless
liquid (Found: M+ + H, 236.1282. C13H18NO3 requires M,
236.1287); νmax/cm−1 698, 741, 919, 995, 1203, 1363, 1438,
1741, 2951 and 3263; δH (300 MHz, CDCl3) 2.36–2.43 (2 H, m,
3-H2), 3.78 (1 H, m, 2-H), 3.78 (3 H, s, CH3O), 4.75 (2 H, s,
PhCH2O), 5.10–5.17 (2 H, m, 5-H2), 5.76 (1 H, m, 4-H), 5.99 (1
H, d, J 9, NH) and 7.30–7.42 (5 H, m, ArH); δC (75 MHz,
CDCl3) 33.88, 51.99, 63.29, 76.28, 118.16, 127.87, 128.35,
128.50, 133.08, 137.67 and 173.64; m/z (CI) 236 (M+ + 1,
100%).
The general procedure using tin(IV) chloride (296 mg,
1.13 mmol) in DCM (5 mL), the 4-benzyloxypentenylstannane
1 (555 mg, 1.19 mmol) in DCM (5 mL) and the oxime-ether
165 (230 mg, 1.19 mmol) in DCM (5 mL) after 50 h at −45 °C
and chromatography using hexane–ethyl acetate–triethylamine
(95 : 4.5 : 0.5) as eluent gave the title compounds 171 and 173
(281 mg, 67%) as a colourless oil, 171 : 173 = 90 : 10 (1H NMR)
(Found: M+ + H, 370.2025. C22H28NO4 requires M, 370.2018);
νmax/cm−1 698, 738, 973, 1072, 1208, 1366, 1451, 1742, 2862
and 3264; δH (300 MHz, CDCl3) major isomer 1.30 (3 H, d, J
6.3, 7-H3), 2.32–2.42 (2 H, m, 3-H2), 3.74 (1 H, m, 2-H), 3.78
(3 H, s, CH3O), 3.91 (1 H, qn, J 6.4, 6-H), 4.38 and 4.56 (each 1
H, d, J 12, PhHCHO), 4.75 (2 H, s, PhCH2), 5.48–5.63 (2 H, m,
4-H and 5-H), 5.98 (1 H, d, J 9.4, NH) and 7.14–7.41 (10 H, m,
ArH); δH (500 MHz, C6D6) major isomer 5.46 (1 H, dd, J 15.5
and 7.4, 5-H) and 5.51 (1 H, dt, J 15.5 and 6.4, 4-H); δH
(300 MHz, CDCl3) minor isomer 1.25 (d, J 6.3, 7-H3), 3.77 (s,
CH3O), 4.33 and 4.50 (each d, J 11.8, PhHCH) and 4.74 (s,
PhCH2O); δC (75 MHz, CDCl3) major isomer 21.63, 32.43,
52.05, 63.50, 69.80, 75.29, 76.28, 126.94, 127.46, 127.69,
127.90, 128.38, 128.48, 128.85, 135.74, 137.68, 138.80 and
173.59; minor isomer 21.56, 32.37, 68.15, 75.61, 125.99,
126.46, 126.90, 129.20, 130.47, 135.69, 139.20 and 140.66; m/z
(CI) 370 (M+ + H, 50%) and 262 (100).
Methyl (RS)-2-(hydroxyamino)pent-4-enoate 169
The general procedure using tin(IV) chloride (391 mg,
1.50 mmol) in DCM (5 mL), prop-2-enylstannane 3 (521 mg,
1.57 mmol) in DCM (5 mL) and the oxime 166 (163 mg,
1.57 mmol) in DCM (5 mL) after 4 h at −78 °C and chromato-
graphy using hexane–ethyl acetate–triethylamine (60 : 39.5 : 0.5)
as eluent gave the title compound 169 (174 mg, 80%) as a col-
ourless oil which crystallised on standing. Recrystallisation from
ether–hexane gave the hydroxylamine as white needles, m.p.
49–50 °C (Found: C, 50.0; H, 7.5; N, 9.5. C6H11NO3 requires C,
49.65; H, 7.65; N, 9.7); νmax/cm−1 923, 996, 1204, 1225, 1438,
1642, 1742, 2954, 3269 and 3426; δH (300 MHz, CDCl3)
2.31–2.50 (2 H, m, 3-H2), 3.75 (1 H, dd, J 7.8 and 6.8, 2-H),
3.79 (3 H, s, CH3O), 5.10–5.20 (2 H, m, 5-H2), 5.61 (1 H, br s,
OH), 5.76 (1 H, m, 4-H) and 6.75 (1 H, br s, NH); δC (75 MHz,
CDCl3) 33.71, 52.10, 64.43, 118.66, 132.78 and 173.41; m/z
(CI) 163 (M+ + 18, 10%), 146 (M+ + 1, 55), 130 (100) and 128
(40).
Methyl (2R,6S,E)- and (2S,6S,E)-6-benzyloxy-2-(hydroxyamino)-
hept-4-enoates 172 and 174
The general procedure using tin(IV) chloride (417 mg,
1.60 mmol) in DCM (5 mL), 4-benzyloxypentenylstannane 1
(782 mg, 1.68 mmol) in DCM (5 mL) and the oxime 166
(175 mg, 1.68 mmol) in DCM (5 mL) after 50 h at −78 °C and
chromatography using hexane–ethyl acetate–triethylamine
(60 : 39.5 : 0.5) as eluent gave the title compounds 172 and 174
(286 mg, 64%) as a pale yellow oil, 172 : 174 = 87 : 13 (1H
NMR) (Found: M+ + H, 280.1538. C15H22NO4 requires M,
280.1549); νmax/cm−1 699, 737, 1072, 1210, 1440, 1453, 1742,
2865, 2973, 3270 and 3410; δH (300 MHz, CDCl3) major
isomer 1.30 (3 H, d, J 6.3, 7-H3), 2.39–2.54 (2 H, m, 3-H2),
3.77 (1 H, m, 2-H), 3.79 (3 H, s, CH3O), 3.89 (1 H, m, 6-H),
4.40 (1 H, d, J 11.9, PhHCH), 4.45 (1 H, br s, OH), 4.57 (1 H,
d, J 11.9, PhHCH), 5.51–5.69 (2 H, m, 4-H and 5-H), 6.10 (1 H,
Methyl (RS)-2-(toluene-4-sulfonylhydrazino)pent-4-enoate 170
The general procedure using tin(IV) chloride (521 mg, 2.0 mmol)
in DCM (8 mL), prop-2-enyl(tributyl)stannane (695 mg,
2.1 mmol) in DCM (8 mL) and the hydrazone 167 (538 mg,
2.1 mmol) in DCM (8 mL) after 50 h at −78 °C and
This journal is © The Royal Society of Chemistry 2012
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br s, NH) and 7.29–7.38 (5 H, m, ArH); minor isomer 1.29 (d, J
6.3, 7-H3) and 4.37 and 4.53 (each d, J 11.9, PhHCH); m/z (CI)
280 (M+ + 1, 6%), 264 (12) and 172 (100).
Acknowledgements
We thank the ERSPC and GSK for a CASE studentship (to
D. J. H.) and the Thai Government for support (to N.T.). We also
thank Dr. M. Helliwell for the X-ray crystal structure
determinations.
Methyl (2R,6S)- and (2S,6S)-6-benzyloxy-2-(benzyloxyamino)-
heptanoate 175 and 176
The general procedure using the heptenoates 171 and 173
(445 mg, 0.541 μmol, 171 : 173 = 9 : 1), toluene 4-sulfonylhy-
drazine (1.01 g, 5.42 mmol) and anhydrous sodium acetate
(444 mg, 5.41 mmol) after chromatography using hexane–ethyl
acetate (9 : 1) as eluent gave the title compounds 175 and 176
(193 mg, 96%), 175 : 176 = 85 : 15 (1H NMR) as a colourless oil
(Found: M+ + H, 372.2163. C22H30NO4 requires M, 372.2163);
νmax/cm−1 697, 736, 1065, 1205, 1452, 1495, 1740, 2864, 2948
and 3336; δH (300 MHz, CDCl3) major isomer 1.21 (3 H, d, J
6.1, 7-H3), 1.40–1.61 (6 H, m, 3-H2, 4-H2 and 5-H2), 3.46–3.68
(2 H, m, 2-H and 6-H), 3.79 (3 H, s, CH3O), 4.47 and
4.60 (each 1 H, d, J 11.9, PhHCH), 4.72 (2 H, s, PhCH2O), 5.97
(1 H, d, J 10.0, NH) and 7.30–7.40 (10 H, m, ArH); minor
isomer 1.18 (d, J 6.1, 7-H3), 3.78 (s, CH3O), 4.40 and 4.57
(each d, J 11.9, PhHCH) and 4.71 (s, PhCH2O); δC (75 MHz,
CDCl3) major isomer 19.59, 22.11, 29.65, 36.33, 51.94, 63.75,
70.35, 74.46, 76.15, 127.45, 127.64, 127.81, 128.32, 128.35,
128.51, 137.85, 139.03 and 174.68; minor isomer 19.48, 38.32,
68.41, 74.66, 126.02, 126.47, 128.43, 128.81, 129.13, 130.41
and 136.92; m/z (CI) 372 (M+ + 1, 100%), 266 (90) and 264
(60).
Notes and references
1 (a) G. K. Friestad, in Science of Synthesis, ed. D. Enders and E. Schau-
mann, Thieme, Stuttgart, 2009, vol. 40a, p. 305; (b) R. Bloch, Chem.
Rev., 1998, 98, 1407; (c) D. Enders and U. Reinhold, Tetrahedron: Asym-
metry, 1997, 8, 1895.
2 (a) G. Alvaro and D. Savoia, Synlett, 2002, 651; (b) E. Juaristi,
J. L. León-Romo, A. Reyes and J. Escalante, Tetrahedron: Asymmetry,
1999, 10, 2441.
3 G. K. Friestad and A. K. Mathies, Tetrahedron, 2007, 63, 2541.
4 W. Ding and G. K. Friestad, Synthesis, 2005, 2815.
5 (a) G. E. Keck and E. J. Enholm, J. Org. Chem., 1985, 50, 146;
(b) H. Nakamura, H. Iwama and Y. Yamamoto, J. Am. Chem. Soc., 1996,
118, 6641; (c) R. A. Fernandez, A. Stimac and Y. Yamamoto, J. Am.
Chem. Soc., 2003, 125, 14133; (d) D.-S. Deng, P. Liu and J. Cai,
Eur. J. Org. Chem., 2007, 1594; (e) S. Kobayashi and S. Nagayama,
J. Am. Chem. Soc., 1997, 119, 10049.
6 S. Laschat and H. Kunz, J. Org. Chem., 1991, 56, 5883.
7 Y. Yamamoto, S. Nishii, K. Maruyama, T. Komatsu and W. Ito, J. Am.
Chem. Soc., 1986, 108, 7778.
8 J. S. Carey, S. MacCormick, S. J. Stanway, A. Teerawutgulrag and
E. J. Thomas, Org. Biomol. Chem., 2011, 9, 3896.
9 (a) E. J. Thomas, Chem. Rec., 2007, 7, 115; (b) E. J. Thomas, Chem.
Commun., 1997, 411.
10 A. H. MacNeill and E. J. Thomas, Synthesis, 1994, 322.
11 (a) D. J. Hallett and E. J. Thomas, J. Chem. Soc., Chem. Commun., 1995,
657; (b) D. J. Hallett and E. J. Thomas, Tetrahedron: Asymmetry, 1995,
6, 2575.
The general procedure for transfer hydrogenolysis using the
heptanoates 175 and 176 (170 mg, 0.458 μmol, 175 : 176 =
85 : 15) gave an amino-alcohol that was acetylated using triethyl-
amine (383 μL, 2.75 mmol), acetic anhydride (130 μL,
1.37 mmol) and DMAP (3 mg, 25 μmol) to give, after chromato-
graphy using chloroform–methanol (99 : 1) as eluent, the hepta-
noate 43 (105 mg, 88%) as a colourless oil containing ca. 10%
of its epimer 73 (1H NMR).
12 R. G. Lovey and A. B. Cooper, Synlett, 1994, 167.
13 A minor side-product, ca. 5% yield, was isolated from this reaction that
appeared to have incorporated an additional benzyloxy substituent into
the electron deficient nitrophenyl moiety, but the full structure was not
confirmed.
14 H. C. Uzar, Synthesis, 1991, 526.
15 (a) R. Beddoes, L. A. Hobson and E. J. Thomas, Chem. Commun., 1997,
1929; (b) L. A. Hobson, M. Vincent, E. J. Thomas and I. H. Hillier,
Chem. Commun., 1998, 899.
16 Aldehydes react with 1-substituted prop-2-enyl(tributyl)stannanes under
thermal conditions to give (Z)-homoallylic alcohols. This is believed to
be due to unfavourable interactions between the substituent α to tin and
the substituents on the tin when the α-substituent is in the equatorial pos-
ition in a six-membered, chair-like, transition structure (see ref. 17). Reac-
tions of 1-substituted allyltin trihalides, e.g. 45 and 103, with aldehydes
also give (Z)-alk-3-en-1-ols, i.e. 2 and 81, respectively, in their reactions
with aldehydes and analogous transition structures have been invoked for
these processes.8,9 For the reactions of these allyltin trihalides with
imines, it may be that the axial group on the nitrogen in the analogous
chair-like transition structures, see 47 and 51, affects the stereochemical
preference of the group next to tin leading to (E)-alkenes, see Fig. 3
and 4.
Crystal data for carbamate 14
ˉ
C22H30Cl3NO4, MW 478.82, triclinic, space group P1, a =
11.185(5), b = 11.22(1), c = 10.307(5) Å, α = 104.76(5), β =
91.60(4), γ = 100.21(5)°, V = 1227.2(14) Å3, Z = 2, Dc
=
1.296 g cm−3, μ(CuKα) = 3.603 mm−1, F(000) = 504, T =
295 K. Crystal dimensions were 0.55 × 0.33 × 0.28 mm. 3848
reflections measured, 3630 independent reflections (Rint = 0.15),
R1 = 0.073 for the 2627 reflections with I > 2σ(I), wR(F2) =
0.233 (all data); CCDC 862199.‡
17 (a) A. J. Pratt and E. J. Thomas, J. Chem. Soc., Perkin Trans. 1, 1989,
1521; (b) V. J. Jephcote, A. J. Pratt and E. J. Thomas, J. Chem. Soc.,
Perkin Trans. 1, 1989, 1529.
18 Open-chain processes analogousto the transition structure 48 with Cram-
like facial selectivity with respect to the imine are alternatives to the
cyclic transition structures shown in Fig. 4.
Crystal data for the 2-(alkylamino)lactone 25
19 G. W. Bradley, D. J. Hallett and E. J. Thomas, Tetrahedron: Asymmetry,
1995, 6, 2579.
20 (a) R. J. Maguire and E. J. Thomas, J. Chem. Soc., Perkin Trans. 1,
1995, 2477; (b) R. J. Maguire and E. J. Thomas, J. Chem. Soc., Perkin
Trans. 1, 1995, 2487.
21 T. Iwasaki, M. Miyoshi, M. Matsuoka and K. Matsumoto, Chem. Ind.
(London), 1973, 24, 1163.
22 J. A. Dale and H. S. Mosher, J. Am. Chem. Soc., 1973, 95, 512.
C20H21NO4, MW 339.38, orthorhombic, space group P212121, a
= 9.681(3), b = 28.33(1), c = 6.260(2), Å, V = 1716.9(11) Å3, Z
= 4, Dc = 1.313 g cm−3, μ(CuKα) = 0.746 mm−1, F(000) = 720,
T = 295 K. Crystal dimensions were 0.45 × 0.25 × 0.01 mm.
1503 independent reflections, R1 = 0.074 for the 1045 reflections
with I > 2σ(I), Rw(F) = 0.192(all data); CCDC 862200.‡
6158 | Org. Biomol. Chem., 2012, 10, 6130–6158
This journal is © The Royal Society of Chemistry 2012