Asymmetric synthesis of tert-butyl ((1R,4aR,8R,8aR)-1-hydroxyoctahydro-1H-isochromen-8-yl)carbamate

Article abstract of DOI:10.1016/j.tetasy.2017.10.005

The asymmetric synthesis of methyl (E)-4-((1R,2S,3R)-3-amino-2-((E)-2-methoxycarbonyl-eten-1-yl)cyclohexyl)but-2-enoate 14 has been achieved from dimethyl (2E,7E)-nona-2,7-dienedioate 2. A key step is the asymmetric synthesis of 1-hydroxyoctahydro-1H-isochromene derivative 5 whose X-ray analysis corroborated the stereochemistry of the new stereocenters. The asymmetric synthesis of the isochromenyl acetate derivative 11 shows the potential of this methodology for fused cyclohexanic system heterocyclic synthesis.

Full text of DOI:10.1016/j.tetasy.2017.10.005

Tetrahedron: Asymmetry 28 (2017) 1394–1400
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of tert-butyl ((1R,4aR,8R,8aR)-1-
hydroxyoctahydro-1H-isochromen-8-yl)carbamate
Alfonso G. Rubia a, Mateo M. Salgado a, Carlos T. Nieto a, Alejandro Manchado a, David Díez a,
Francisca Sanz b, Narciso M. Garrido a,
⇑
a Dpto. de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Salamanca, Plaza de los Caídos 1-5, 37008 Salamanca, Spain
b X-ray-Diffraction Service from Nucleus, Plaza de los Caídos 1-5, 37008 Salamanca, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric synthesis of methyl (E)-4-((1R,2S,3R)-3-amino-2-((E)-2-methoxycarbonyl-eten-1-yl)cy-
clohexyl)but-2-enoate 14 has been achieved from dimethyl (2E,7E)-nona-2,7-dienedioate 2. A key step is
the asymmetric synthesis of 1-hydroxyoctahydro-1H-isochromene derivative 5 whose X-ray analysis
corroborated the stereochemistry of the new stereocenters. The asymmetric synthesis of the isochrome-
nyl acetate derivative 11 shows the potential of this methodology for fused cyclohexanic system hetero-
cyclic synthesis.
Received 7 August 2017
Revised 30 August 2017
Accepted 6 October 2017
Dedicated to the memory of Dr. Howard
Flack
Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction
removed as detailed above, it gives greater versatility to the
above procedure.
The strategies for building stereoselectively substituted cyclo-
hexanic ring are very powerful synthetic tools as they are incorpo-
rated in naturally occurring products. Representative examples
are: morphine1 with a cyclohexanic ring trans,trans-trisubstituted,
luciduline2 cis,cis-trisubstituted and with a cis-decahydroquinoline
skeleton pumiliotoxin C.3 Because of its structure, featuring several
stereogenic centers (Fig. 1), an impressive effort has been devoted
to its asymmetric synthesis and nowadays we have developed a
methodology towards the synthesis of morphine analogues in view
to search for structure activity relationship (SAR).4
Herein, we have focused on the potential of domino reactions
initiated by the Michael addition of chiral lithium amide (R)- or
(S)-N-benzyl-N-a-methylbenzylamide (R)- or (S)-1 to (2E,7E)-
nonadiendioate 2 to provide stereoselectively the corresponding
cyclohexane derivative 3, that is a powerfull tool in the synthesis
of heterocyclic derivatives by transformation of the side chains
and it is used in the synthesis of a diester incorporating a cyclohex-
anic ring in its structure.
2. Results and discussion
Davies et al. have illustrated the scope, limitations and syn-
thetic applications of the conjugate addition of enantiomerically
pure lithium amides as homochiral ammonia equivalents.5 We
With the amino-cyclohexane derivative 3 in hand6 (Scheme 1)
and given the large steric volume represented by the benzyl groups
in the N atom and taking into account the nucleophilicity of the
amine, we decided to synthesize carbamate 4 by hydrogenolysis
of 3 in the presence of Boc anhydride.8 This provided 4 in 90% yield
in a single step, the reduction of which with DIBALH was per-
formed as shown in Scheme 2 and with the results shown in
Table 1.
When using a DIBALH ratio of 1.2 (entry 1), reduction products,
lactols 5 and 6 and a large amount of starting material (50%) were
separated from the reaction mixture. Using a ratio of 4 mmol per
mmol (entry 3) the lactols were obtained in 58% in a 3:1 ratio,
but 38% of the diol 7 is obtained, which nevertheless is readily
available by reduction with LAH (77%). Using an amount of 3.2
mmol per mmol in addition to the diol (25%), 57% of lactols
are obtained in a 1:1 ratio. This implies a non-chemoselective
have demonstrated the use of chiral lithium (a-methylbenzyl)ben-
zylamide (R)- or (S)-1 to initiate the asymmetric conjugate addi-
tion cyclisation of nona-2,7-diendioate (Scheme 1) to generate
chiral cyclohexane derivatives 3,6 and applied it to the synthesis
of (1R,5R,9R)-2-azabicyclo[3.3.1]nonane-9-carboxylic acid (mor-
phanic acid), with a morphan scaffold, which was used in the syn-
thesis of a new class of opioid receptor ligands.4
Elimination of the chiral auxiliary gave (R)-methyl cyclohex-1-
enecarboxylate, which has been used in the synthesis of pumil-
iotoxin C.6a,7 Since cyclohexane can incorporate the amine of the
chiral auxiliary, which is used in this methodology or can be
⇑
Corresponding author. Tel.: +34 666589065; fax: +34 923 294574.
E-mail address: nmg@usal.es (N.M. Garrido).
https://doi.org/10.1016/j.tetasy.2017.10.005
0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.

A. G. Rubia et al. / Tetrahedron: Asymmetry 28 (2017) 1394–1400
1395
RO
NHBoc
COOMe
COOMe
Me
N
H
Me
O
NMe
N
4
H
H
H
O
ii
i
HO
luciduline
pumiliotoxin C
R = H, morphine
R = Me, codeine
BocHN
BocHN
OH
NHBoc
H
H
H
Figure 1. Representative aminocyclohexanic structures.
CH2OH
CH2OH
O
O
+
+
OH
H
6
reduction of each of the esters to the corresponding alcohol. When
the remaining ester was reduced to the aldehyde, it was stabilized
as a lactol, either 1-hydroxyperhydroisochromene 5 or 3-hydrox-
yperhydroisochromene 6, which have two fused six membered
rings and possess the functionality required for homologation.
7
5
Scheme 2. Reagents and conditions: (i) DIBALH, results in Table 1; (ii) LAH, 77%.
Compound 5, with an a-hydroxyl group at C-1, was obtained by
chromatography; its 1H NMR showed relevant signals at d (ppm):
3.43 (1H, cd, J = 8.3 and 2.5 Hz (1H, broad s, OH), 4.64 (1H, dd, J
= 11.2 and 3.9 Hz, H-3eq), 4.39 (1H, td, J = 11.2 and 2.5 Hz, H-3a),
5.12 (1H, brs, H-1). The coupling constants allow the assignment
of the axial and equatorial arrangement of some of the hydrogens.
The 1H/1H (COSY) and heteronuclear 1H/13C HMQC and HMBC two-
dimensional correlation experiments, allows the determination of
the structure as well as the assignment of all of the spectroscopic
data. The connectivity of C-1 with H-8a fixes the hydroxyl position.
The relative stereochemistry was established by ROESY and NOE
differential experiments whose results are shown in Figure 2.
H-1 saturation shows an NOE with the hydrogen attached to the
nitrogen, which fixes the stereochemistry of hydrogen on C-1 as b
Table 1
Reduction results within different ratio of DIBALH.
Entry 4/
DIBALH
mmol ratio
T/°C Time
5/
%
6/
%
7/
%
4/ gglobal/
(min)
%
%
1
2
3
0.128
0.269
0.515
1.2
4.0
3.2
ꢀ78
ꢀ78
ꢀ78
20 15 18
30 15 43 38
35 27 30 25
4
50 87
–
–
96
82
10%
H
2%
H
H
N
5%
H
Boc
H
(equatorial) and that on hydroxyl as
a
(axial). Finally, the absolute
O
H
H
stereochemistry of 5 was confirmed by X-ray diffraction (Fig. 3),
with an (R)-configuration for the four stereogenic centers of the
molecule. It therefore corroborates the absolute stereochemistry
assigned to diester 3, the direct cyclization product of dimethyl
nona-2,7-dienedioate, which was assigned based on the known
sense of the stereoselective addition of the chiral lithium amide
and exhaustive 1H NMR analysis.
2%
H
H
O
5%
H
H
H
5%
Figure 2. 1H NMR stereo chemical analysis of 5.
very close to the value for the Ccyclohexane-Nsp2 distance of 1.455
(3) Å reported for methyl N-cyclohexylcarbamate.9 On the other
hand, the C9–N1 and C9–O3 bond lengths are approximately the
same as those found in most amides and in carboxylic acids.10 Such
distances, along with the angles about C9 suggest a structure for
the carbamate group with a delocalized double bond involving
O3–C9–N1, with the O4 atom experiencing a slight reduction in
electron density, thus weakening the C9–O4 bond. The cyclohex-
ane ring [C40–C5–C6–C7–C8–C80] and tbutyl group [C10–C11–
C12–C13] are inclined to the mean plane of the carbamate [N1–
C9–O3–O4] unit by 82.4(2) and 88.4(1)°, respectively. In the
extended structure of 5, the hydrogen bonds are one of the primary
Colourless prism-like crystals of 5 were obtained by slow evap-
oration of EtAcO/hexane solution at room temperature. The solid-
state structure (Fig. 3) was determined by single crystal X-ray
diffraction techniques. Molecules of 5 were crystallized in the
orthorhombic P212121 space group. The crystal contains one mole-
cule in the asymmetric unit. The molecule of 5 is a carbamate com-
pound with a tert-butyl group and a 1-hydroxyoctahydro-1H-
isochromen-8-yl group as substituents. The planar conformation
of the carbamate group is established from the torsion angle N1–
C9–O3–O4 = 179.4(3)°. The hydroxyl group at the C1 atom is
twisted with the isochroman derivative being the O2–C1–C80–C40
torsion angle of 67.3(4)°. The N1–C8 bond length of 1.457(4) Å is
Ph
Ph
NHBoc
Ph
N
Ph
N
COOMe
Li
COOMe
NH
i
COOMe
COOMe
(R)-1
COOMe
H
COOMe
COOH
86%
4
2
3
morphanic acid
H
H
Ph
N
COOMe
Ph
N
COOMe
COOMe
Li
N
H
pumiliotoxin C
i: H2/Pd(OH)2-C/AcOEt/Boc2O
Scheme 1. Domino reaction to obtain cyclohexane rings and their application to the synthesis of morphanic acid and pumiliotoxine C.

1396
A. G. Rubia et al. / Tetrahedron: Asymmetry 28 (2017) 1394–1400
The oxidation of diol 7 with TPAP gave isomeric lactones 8 and 9
in 85% yield and a 4:1 ratio. This shows that the less hindered alco-
hol is oxidized more easily (the mixture could not be resolved
chromatographically), the same happens with other oxidants such
as Collins reagent (CrO3/Pyr).12 When the epimer mixture 6 was
oxidized with TPAP, isochromen-3-one 8 (Scheme 3) was obtained
as the only reaction product.
Once the lactols were synthesized, we decided to test the Wittig
reaction to obtain an unsaturated ester group that could be used as a
new Michael acceptor. When lactol 6 was treated with methoxycar-
bonylmethylenetriphenylphosphorane in refluxing toluene
(Scheme 4), the expected alcohol 10 was obtained in low yield (25%).
When the Horner–Wadsworth–Emmons reaction was carried
out using dimethyl methoxycarbonylmethylphosphonate in the
presence of NaH and K2CO3, in addition to alcohol 10 (20%), tetrahy-
dropyran derivative 11 was obtained in 45%. As shown in Figure 5,
the cyclic product was formed by Michael addition of the alcoholate
formed by deprotonation of the hydroxyl group with NaH.
The stereochemistry of the new stereogenic center of the perhy-
droisochromene derivative 11 was determined by the ROESY
NHBoc
NHBoc
H
Figure 3. Molecular structure of C14H25NO4 5. Displacement ellipsoids are drawn at
the 50% probability level. Hydrogen atoms are shown as spheres of arbitrary radius.
H
i
O
O
90%
OH
O
factors in the building of the crystal network (Table 2). In the crys-
tal, O2–H2ꢁꢁꢁO1 (dotted light-blue lines) hydrogen bonds between
the hydroxyl group and the oxygen atom of the isochromene deriva-
tive link adjacent molecules, which are oriented in opposite direc-
tions (Fig. 4a). The NH groups act as hydrogen-bond donors and the
C@O groups as acceptors to form intermolecular N1–HN1ꢁ ꢁ ꢁO3
(dotted purple lines) hydrogen bonding, thus generating extended
ribbons along the a axis (Fig. 4b). The two six-membered rings in
the isochromene derivative adopt a chair conformation. The amide
H atom is antiperiplanar to the carbonyl group, as has been
observed for monosubstituted amides.11
H
H
6
8
NHBoc
NHBoc O
H
CH2OH
i
O
CH2OH
85%
8:9 (4:1)
7
H
9
Scheme 3. Reagents and conditions: (i) TPAP/NMO.
Table 2
Hydrogen-bond geometry (Å, °).
D–Hꢁ ꢁ ꢁA
D–H
Hꢁ ꢁ ꢁA
Dꢁ ꢁ ꢁA
D–Hꢁ ꢁ ꢁA
O2–H2ꢁ ꢁ ꢁO1
0.82
0.86
1.980
2.202
2.747(4)
3.019(4)
155.4
158.6
N1–HN1ꢁ ꢁ ꢁO3
Figure 4. (a) A view of the O2–H2ꢁ ꢁ ꢁO1 (dotted light-blue lines), (b) N1–HN1ꢁ ꢁ ꢁO3 (dotted purple lines) hydrogen bonds in the structure of C14H25NO4 5.

A. G. Rubia et al. / Tetrahedron: Asymmetry 28 (2017) 1394–1400
1397
NHBoc
H
NHBoc
H
NHBoc
CH2OH
O
O
i or
ii
+
COOMe
COOMe
OH
H
H
6
10
11
i: Wittig:
ii: Horner-Wadsworth-Emmons
Wittig: 25% 10
H-W-E: 20% 10 and 45% 11
Scheme 4. Reagents and conditions: (i) MeOCOCHPPh3/NaH; (ii) (EtO)2POCH2COOMe/NaH/K2CO3.
H
Na+
O−
H
Boc
NHBoc
Na+
N
NHBoc
H
O
H
O−
H
H
COOMe
XI
H
H1
H
H
COOMe
COOMe
H1A'
H
11
Figure 5. ROESY experiment for compound 11 and proposed mechanism for its formation.
experiment, with the most important correlations shown in Fig-
ure 5; the coupling between H-1ax and H-10 established the config-
uration of C-3 to be (S).
An efficient method for synthesizing derivatives with an iso-
chromene skeleton in a single reaction step from lactol 6 type com-
tion product 3, and that of the related compounds. The asymmetric
synthesis of cyclohexane dienes 13 and 14 has also been carried
out. The synthesis involved the homologation of the initial diene
3 with an extra cyclohexanic ring and an additional amine func-
tion; we anticipate that this could be used to obtain important
polycyclic systems. The synthesis of the cyclohexane alcohol 11,
pounds (Fig. 5) is described. The
a,b-unsaturated alcohol 10 is an
interesting intermediate for the preparation of condensed cyclo-
hexane rings with different substitution patterns, as it already
has a Michael acceptor by oxidation of the alcohol and a further
Wittig or Horner–Wadsworth–Emmons reaction to guarantee the
required bisunsaturated system.
which has an a,b-unsaturated ester, could allow homologation in
a sequential manner.
4. Experimental
4.1. General
We decided to synthesise the bisunsaturated compound from diol
7, by Swern oxidation reaction (Scheme 5) to obtain dialdehyde 12,
but it proved very labile and decomposed on attempted purification.
Thus, the crude from the Swern reaction13 was subjected
directly to the Horner–Wadsworth–Emmons reaction and after
chromatography, diene 13 (45%) was obtained. The 1H NMR spec-
trum clearly showed the existence of two conjugated ester groups,
d: 5.78 (1H, d, J = 15.6 Hz, H-20), 6.70 (1H, dd, J = 15.6 and 10.3 Hz,
H-10) for one of them and 5.81 (1H, d, J = 15.2 Hz, H-2), 6.80 (1H,
ddd, J = 15.2, 8.0 and 6.0 Hz, H-3) for the other. In the 13C NMR
spectrum, the carbonyls of the esters at 166.4 and 166.9 ppm
and that of four olefinic methines are observed at 123.1, 123.9,
146.9 and 149.6 ppm. When the amine was deprotected with
TFA, the expected product 14 was obtained (85%). Compounds 13
and 14 are an upper homologue diene of the nona-2,7-diendioate
6 starting product, with an additional cyclohexane ring and three
stereogenic centers.
All chemical reagents were purchased from Sigma–Aldrich or
Acros. High-purity reaction solvents were purified accordingly to
literature. All reactions were carried out in borosilicate PyrexÒ type
glassware and under inert conditions, using Ar as inert gas. Reac-
tion monitoring was followed by TLC, type Merck 60 F254, which
visualization was achieved with UV light and ninhydrin as appro-
priate stain. Flash chromatography was carried out on Kieselgel
40 (Merck, 0.040–0.063) silica. Yields and characterization data
belong to chromatography purified compounds. Deuterated sol-
vents were purchased from Carlo Erba. Optical rotations were mea-
sured on a Perkin Elmer 241 polarimeter in 1 dm cells ([
Infrared spectra were recorded on a Shimadzu IRAffinity-1 (IR).
NMR experiments were recorded on
Varian 200 VX (1H
a]
20).
D
a
MR/200 MHz, 13C NMR/50 MHz) and on a Bruker DRX 400 (1H
NMR/400 MHz). 2D HMBC and HMQC or representative com-
pounds were also recorded to assign protons and carbons on new
structures. Chemical shifts are reported in ppm (parts per million)
relative to referenced values. High-resolution mass spectrometry
(HRMS) analyses were performed on an Applied Biosystems QSTAR
XL (ESI, electrospray ionization) and in a VG-TS 250 (EI, electronic
impact), at 70 eV (m/z).
3. Conclusions
X-ray diffraction data of 8-boc-amino-perhydroisochromen-1-
ol 5 have been obtained, which allowed the determination of its
relative stereochemistry and corroborate that of the direct cycliza-
NH2
NHBoc
NHBoc
CH2OH
NHBoc
CHO
COOMe
COOMe
COOMe
COOMe
ii
ii
i
CH2OH
CHO
14
13
7
12
Scheme 5. Reagents and conditions: (i) (a) (COCl)2; (b) DMSO; (c) NEt3; (ii) NaH/(EtO)2POCH2COOMe; (iii) TFA.

1398
A. G. Rubia et al. / Tetrahedron: Asymmetry 28 (2017) 1394–1400
4.2. Methyl (1R,2R,6R)-2-N-benzyl-N-
a
-methylbenzylamino-6-
tion containing 17.4 g of NaHCO3 and 6 spatulas of anhydrous Na2-
(methoxycarbonylmethyl)-cyclohexanecarboxylate 3
SO4 and then stirred at room temperature, filtered over Celite and
the solvent evaporated to give 161 mg of reaction crude, which
was chromatographed on flash silica and eluted with hexane/
EtAcO 1:1, 25 mg (27%) of 5 being isolated and 27 mg (30%) of 6
and 24 mg (25%) of 7 as a clear oil.
At first, n-BuLi 12.4 ml (19.9 mmol) of 1.6 M was added drop-
wise to a stirred solution of 5.1 g (22.0 mmol) of N-benzyl-N-a-
methylbenzylamine (R)-1 in 15 ml of THF at ꢀ78 °C under an N2
atmosphere and the resulting solution stirred for 30 min. Subse-
Compound 5 was crystallized from Hexane/EtAcO 9:1, m.p. =
quently a solution of the
a
,b-unsaturated diester 2 (2.3 g, 11.0
174 °C; [
a
]
26 = ꢀ38.0 (c 0.5, CHCl3); IR (neat):
mmax = 3352, 2917,
D
mmol), dissolved in 8 ml of THF was added dropwise to the lithium
amide solution via cannula and stirred at ꢀ78 °C for 4 h before the
addition of saturated aqueous NH4Cl (18 mL) and warming to room
temperature. The crude reaction mixture was partitioned between
DCM and brine and the organic layers concentrated in vacuo. The
residue was partitioned between DCM and 10% citric acid solution,
organic layer washed in succession with aqueous NaHCO3 solution
and brine, dried and concentrated in vacuo. Purification via column
chromatography on silica (1:4, EtAcO: Hexane) gave 3 (4.5 g, 86%)
1680, 1527, 1057; 1H NMR (400 MHz, CDCl3): d = 0.81–1.02(1H,
cd, J = 9.5, 3.7 Hz, H-5A), 1.05–1.52(1H, t, J = 11.4 Hz, H-8a), 1.15–
1.35(1H, m, H-7A), 1.30–1.38(1H, m, H-4A), 1.35–1.50(1H, m, H-
6A), 1.42(9H, s, C(CH3)3), 1.45–1.55(1H, broad d, J = 13.0), 1.55–
1.70(1H, m, H-5), 1.70–1.80(1H, m, H-6A), 1.75–1.85(1H, m, H-
4a), 1.90–2.00(1H, broad d, J = 13.0 Hz, H-7A), 3.43(1H, cd, J = 8.3,
2.5 Hz, H-8), 3.64(1H, dd, J = 11.2, 3.9 Hz, H-3ec), 4.39(1H, broad
d, J = 8.2 Hz, NH), 4.45(1H, broad s, OH), 4.64(1H, td, J = 11.2, 2.5
Hz, H-3ax), 5.12(1H, broad s, H-1) ppm; 13C NMR (200 MHz,
CDCl3): d = 24.4(CH2, C-6), 28.3(3CH3, C(CH3)3), 31.9(CH, C-4a),
32.4(CH2, C-4), 32.5(CH2, C-5), 33.5(CH2, C-6), 49.9(CH, C-8), 52.6
(CH, C-8a), 59.9(CH2, C-3), 80.1(C, C(CH3)3), 90.7(CH, C-1), 156.8
as a clear oil; [a] mmax = 3459,
26 = +3.9 (c 1.9, CHCl3); IR (neat):
D
2947, 1738, 1435, 1028; 1H NMR (400 MHz, CDCl3): d = 0.85(1H,
m, H-4A), 1.20–1.30(1H, m, H-3A), 1.30(1H, m, H-5A), 1.36(3H, d,
J = 6.8 Hz, C(a)Me), 1.65(1H, m, H-3B), 1.73(1H, m, H-4B), 1.95
(C, COO), HRMS (ESI): m/z (M+Na) calcd for C14H25NO4,
(1H, m, H-5B), 1.95(1H, m, H-6), 2.01(1H, dd, J = 11.8, 10.3 Hz, H-
8A), 2.15(1H, dd, J = 11.8, 2.8 Hz, H-8B), 2.29(1H, dd, J = 11.4,
11.0 Hz, H-1), 3.12(1H, ddd, J = 11.0, 11.0, 3.6 Hz, H-2), 3.41(3H,
s, OCH3), 3.63(3H, s, OCH3), 3.64(1H, AB, J = 13.6 Hz, NCHAHPh),
294.1676; found 294.1672.
Crystal structure determination. A suitable single crystal of 5
compound was mounted on glass fibre for data collection on a four
circle Seifert XRD 3003 SC diffractometer. Data were collected at
3.83(1H, AB, J = 13.6 Hz, NCHHBPh), 3.96(1H, c, J = 6.8 Hz, C(
7.15–7.35(10H, m, Ar-H) ppm; 13C NMR (200 MHz, CDCl3): d =
16.1(CH3, C( )Me), 24.5(CH2, C-3), 28.5(CH2, C-5), 30.2(CH2, C-4),
37.3(CH, C-6), 39.4(CH2, C-8), 49.9(CH2, NCH2Ph), 51.2(CH3,
OCH3), 51.4(CH3, OCH3), 54.5(CH, C-1), 56.8(CH, C( )), 58.6(CH,
C-2), 126.4–129.1(10H, C-Ar), 140.6(C, Cipso), 144.1(C, Cipso), 172.4
(C, COOMe), 174.1(C, COOMe) ppm; HRMS (ESI): m/z (M+H) calcd
for C26H34NO4, 424.2488; found, 424.2486.
a
)H),
298(2) K using Cu
monochromator and the
K
x
radiation (k = 1.54178 Å), graphite
-2h scan technique. The unit cell param-
a
a
eters were determined by least squares refinement on the 2h val-
ues of 25 strong well centered reflections in the range 16 < 2h <
40°. The structure was solved by direct methods combined with
difference Fourier synthesis and refined by full-matrix least-
squares procedures, with anisotropic thermal parameters in the
last cycles of refinement for all non-hydrogen atoms. The refine-
ment was based on F2 for all reflections, and weighted R factors
(wR) and all goodness-of-fit (GoF) values are based on F2, while
a
4.3. Methyl (1R,2R,6R)-2-((tert-butoxycarbonyl)amino)-6-(2-
methoxycarbonylmethyl)cyclohexanecarboxylate 4
conventional R factors (R) are based on F. The Fo2 > 2 (Fo2) crite-
r
rion was used only for calculating the R factors and it is not rele-
vant to the choice of reflections for the refinement. The R factors
based on F2 are about twice as large as those based on F. Scattering
factors were taken from the International Tables for Crystallogra-
phy.14 The hydrogen atoms were positioned geometrically. All cal-
culations were performed using CRYSOM15 software for data
collection, XRAY8016 for data reduction, SHELXTL17 to resolve
and refine the structure and MERCURY to prepare molecular and
crystal structures drawings.18 Crystallographic data for the struc-
ture has been deposited at the Cambridge Crystallographic Data
To a solution of 1.8 g (4.69 mmol) of 3 in 8 ml of AcOEt were
added 710 mg of 20% Pd(OH)2 on carbon and 1.1 g (5.16 mmol)
of Boc2O. This mixture was stirred under a hydrogen atmosphere
(4 atm) for 72 h. The solution was filtered over Celite while wash-
ing with CH2Cl2. The solvent was evaporated to give 1.57 g of reac-
tion crude. The excess Boc2O was removed by distilling under
reduced pressure of 10-1 mmHg and in the temperature range of
26
60 to 70 °C. 1.4 g (90%) of 4 were obtained as a clear oil; [
+10.6 (c 1.0, CHCl3); IR (neat):
a]
=
D
m
max = 3367, 2956, 1734, 1517,
1170; 1H NMR (400 MHz, CDCl3): d = 0.95(1H, m, H-4A), 1.10(1H,
m, H-3A), 1.42(9H, s, C(CH3)3), 1.30–1.50(1H, m, H-5A), 1.75–1.95
(2H, m, H-3B, H-4B), 2.05–2.20(4H, m, H-6, H-5, H-8), 2.30(1H,
m, H-1), 3.60–3–70(1H, m, H-2), 3.62(3H, s, OCH3), 3.71(3H,s,
OCH3), 4.52(1H, d, J = 5.6 Hz, NH); ppm; 13C NMR (100 MHz,
CDCl3): d = 24.1(CH2, C-4), 28.5(3CH3, C(CH3)3, 30.6(CH2, C-5),
33.0(CH2, C-3), 36.3(CH, C-6), 39.3(CH2, C-8), 51.1(CH3, OCH3),
51.8(CH3, OCH3), 56.1(2CH, C-1, C-2), 79.0(C, C(CH3)3), 155.0(C,
NCOOtBu), 172.4(C, COOCH3), 173.7(C, COOCH3) ppm; HRMS
(ESI): m/z (M+Na) calcd for C16H27NO6, 325.1736; found 352.1672.
Centre, CCDC 1565401.
26
Compound 6: [a] D = +5.0 (c 1, CHCl3); IR (neat): mmax = 3332,
2936, 1670, 1522, 1175; 1H NMR (400 MHz, CDCl3): d = 0.80–2.01
(6H, m, H-5, H-6, H-7), 2.02(1H, m, H-4a), 1.43(9H, s, C(CH3)3),
2.43(1H, m, H-8a), 3.30(1H, m, H-4A), 3.80(1H, t, J = 11.2 Hz, H-
4B), 3.70(1H, m, H-8), 4.03(1H, dd, J = 11.8 and 3 Hz, H-1A), 4.28
(1H, t, J = 11.8 Hz, H-1B), 4.72(1H, m, H-3), 5.07(1H, d, J = 6.6 Hz,
NH), 5.30(1H, s, OH) ppm; 13C NMR (200 MHz, CDCl3): d = 24.7,
24.8(CH2, C-6), 28.2ꢂ2(CH2, C-5), 28.3, 28.6(3CH3, C(CH3)3), 32.3,
32.3(CH2, C-7), 33.1, 38.8(CH, C-4a), 37.1, 39.8(CH2, C-4), 47.6,
48.1(CH, C-8a), 50.4ꢂ2(CH, C-8), 62.0, 68.6(CH2, C-1), 79.5, 79.6
(C, C(CH3)3), 91.8, 96.6(CH, C-3), 155.7ꢂ2(C, COO); HRMS (ESI):
m/z (M+Na) calcd for C14H25NO4, 294.1676; found, 294.1672.
4.4.
tert-Butyl
((1R,4aR,8R,8aR)-1-hydroxyoctahydro-1H-
isochromen-8-yl)carbamate 5 and tert-butyl ((4aR,8R,8aR)-3-
hydroxyoctahydro-1H-isochromen-8-yl)carbamate 6
4.5. tert-Butyl ((1R,2R,3R)-3-(2-hydroxyethyl)-2-(hydroxymethyl)
To a solution of 184 mg (0.56 mmol) of 4 dissolved in 6 ml of
CH2Cl2, 0.187 ml (1.28 mmol) of 1.5 M DIBALH were slowly added
at ꢀ78 °C and allowed to stir at this temperature for 35 min. Next,
4 ml of water were added and the reaction mixture allowed to
return to room temperature. It was then poured into an ether solu-
cyclohexyl)carbamate 7
To a solution of 57 mg (1.7 mmol) of 4 in 1.5 ml of THF were
added 132 mg (3.5 mmol) of LiAlH4 at 0 °C. The mixture was
allowed to return to room temperature and left stirring for 4 h.

A. G. Rubia et al. / Tetrahedron: Asymmetry 28 (2017) 1394–1400
1399
After this time an ether-water mixture was added and extracted
with ether. The organic phase was dried over anhydrous Na2SO4,
filtered over Celite and evaporated to yield 40 mg (77%) of 7 as a
OH), 3.72(3H, s, COOCH3), 4.42(1H, d, J = 8.6 Hz, NH), 5.84(1H, d, J
= 15.4 Hz, H-300), 6.95(1H, m, H-200); HRMS (ESI): m/z (M+Na) calcd
for C17H29NO5, 350.1934; found, 350.1929.
clear oil; [a] mmax = 3342, 2912,
26 = +45.9 (c 1.6, CHCl3); IR (neat):
D
1670, 1517, 1146; 1H NMR (400 MHz, CDCl3): d = 0.85(1H, m, H-
4A), 0.95(1H, m, H-3A), 1.20–1.40(2H, m, H-5A, H-4B), 1.44(9H, s,
C(CH3)3), 1.60–1.80(4H, m, H-3B, H-5B, H-8A, H-8B), 1.90–2.05
(2H, m, H-1, H-6), 3.50 (1H, m, H-2), 3.60–3.80(4H, m, 2CH2OH),
4.53(1H, d, J = 5.6 Hz, NH) ppm; 13C NMR (200 MHz, CDCl3): d =
25.1(CH2, C-4), 28.5(3CH3, C(CH3)3), 29.9(CH2, C-5), 32.0(CH2, C-
3), 33.5(CH, C-6), 36.3(CH2, C-8), 50.0(CH, C-1), 52.0(CH, C-2),
58.4(CH2, CH2OH), 61.1(CH2, CH2OH), 80.2(C, C(CH3)3), 157.2(C,
4.9. Methyl 2-((3S,4aR,8R,8aR)-8-((tert-butoxycarbonyl)amino)
octahydro-1H-isochromen-3-yl)acetate 11
At first, 5 mg (0.12 mmol) of NaH are dissolved in 0.5 ml of THF
and cooled to 0 °C. Next, 0.02 ml of diethyl methoxycarbonyl-
methylphosphonate wereadded and the mixture was allowed to
stir for 30 min. Then 26 mg (0.10 mmol) of 6 dissolved in 0.5 ml
of THF were added via cannula to room temperature. This mixture
allowed to react for 22 h after which 7 mg (0.05 mmol) of K2CO3
were added and then stirred for 60 h. The organic phase was
extracted with ether, washed with saturated NaCl, dried over
anhydrous Na2SO4, filtered and evaporated to obtain 46 mg of
reaction crude, which was chromatographed on flash silica eluting
with hexane/EtOAc 8:2, isolating 5 mg (20%) of 10 and 15 mg (45%)
of 11, 10 mg of starting product and 16 mg of unreacted phospho-
NCOOtBu); HRMS (ESI): m/z (M+Na) calcd for
C14H27NO4,
296.1838; found, 296.1799.
4.6. tert-Butyl ((4aR,8R,8aR)-3-oxooctahydro-1H-isochromen-8-
yl)carbamate 8
To 7 mg (0.03 mmol) of 6 were added 7.5 mg (0.06 mmol) of
NMO and then both compounds were dissolved in 0.5 ml of CH2Cl2.
Half spatula of sieves was added and stirred at room temperature.
Finally 2 mg (0.03 mmol) of TPAP were added and the mixture left
to stir for 25 min, after which it was filtered with Celite and normal
silica washing with CH2Cl2. The solvent was evaporated to yield 5
nate. Compound 11: IR (neat):
mmax = 3352, 2922, 1739, 1705,
1527, 1170; 1H NMR (400 MHz, CDCl3): d = 0.80–1.00(2H, m, H-
5A, H-6A), 1.10–1.70(3H, m, H-5B, H-6B, H-7A), 1.16(1H, m, H-
8a), 1.42(9H, s, C(CH3)3), 1.50–1.65(2H, m, H-4), 1.77(1H, m, H-
4a), 1.96(1H, m, H-7B), 2.50(1H, dd, J = 8.2, 6.6 Hz, H-1A0), 2.86
(1H, dd, J = 8.2 and 6.6 Hz, H-1B0), 3.25(1H, m, H-8), 3.39(1H, t, J
= 11.6 Hz, H-1ax), 3.60–3.80(1H, m, H-1ec), 3.69(3H, s, COOCH3),
4.25(1H, d, J = 9.0 Hz, NH), 4.44(1H, m, H-3) ppm; 13C NMR (200
MHz, CDCl3): d = 24.7 (CH2, C-6), 28.6(3CH3, C(CH3)3), 32.5(CH2,
C-5), 32.5(CH2, C-10), 34.1(CH2, C-7), 34.4(CH, C-4a), 35.4(CH2, C-
4), 48.5(CH, C-8a), 50.5(CH, C-8), 52.0(CH3, OCH3), 63.5(CH2, C-1),
70.0(CH, C-3), 79.6(C, C(CH3)3), 155.7(C, COOtBu), 172.2(C,
mg (90%) of 8 as a clear oil; IR (neat): mmax = 3357, 2922, 1739,
1705, 1175; 1H NMR (400 MHz, CDCl3): d = 0.80–1.80(6H, m, H-5,
H-6, H-7), 1.44(9H, s, C(CH3)3), 1.85(1H, m, H-4a), 2.01(1H, m, H-
8a), 2.10(1H, dd, J = 18.4, 12.0 Hz, H-4A), 2.91(1H, dd, J = 18.4,
5.5 Hz, H-4B), 3.35(1H, m, H-8a), 4.11(1H, t, J = 11.6 Hz, H-1ax),
4.35(1H, d, J = 8.7 Hz, NH), 4.50(1H, dd, J = 11.6, 4.3 Hz, H-1ec)
ppm; 13C NMR (200 MHz, CDCl3): d = 24.3(CH2, C-6), 28.5(3CH3, C
(CH3)3), 32.0(CH2, C-5), 33.4(CH2, C-7), 36.0(CH, C-4a), 36.9(CH2,
C-4), 44.7(CH, C-8a), 50.5(CH, C-8), 73.0(CH2, C-1), 80.1(C, C
(CH3)3), 155,6(C, COOtBu), 170.4(C, COO); HRMS (ESI): m/z (M
+Na) calcd for C14H23NO4, 292.1519; found 292.1518.
COOMe); HRMS (ESI): m/z (M+Na) calcd for
C17H29NO5,
350.1938; found, 350.1939.
4.10. Methyl (E)-4-((1R,2S,3R)-3-((tert-butoxycarbonyl)amino)-
2-((E)-2-methoxycarbonyl-eten-1-yl)cyclohexyl)but-2-enoate
4.7. ((4aR,8R,8aR)-1-Oxooctahydro-1H-isochromen-8-yl)carba-
13
mate 9
To 6 mL of CH2Cl2 were added 0.084 mL (0.96 mmol) of (COCl)2
to room temperature. Next, 0.14 ml of DMSO were added. The mix-
ture was cooled to ꢀ60 °C and 120 mg (0.44 mmol) of 7 dissolved
in 2 ml of CH2Cl2 was then added via cannula and the stirring is
maintained at this temperature for 1 h. After this time 0.351 ml
(2.2 mmol) of NEt3 is added and the mixture is stirred for an addi-
tional 15 min, after which the reaction mixture is brought to room
temperature and stirred for 15 min. Add 10 ml of water and extract
with CH2Cl2. The organic phase is dried over anhydrous Na2SO4, fil-
tered and evaporated, yielding 133 mg (90%) of 12.
To 18 mg (0.06 mmol) of 7 were added 30 mg (0.22 mmol) of
NMO and molecular sieves. Both compounds were dissolved in 1
ml of CH2Cl2 and stirred at room temperature. Next, 4 mg (0.14
mmol) of TPAP were added and allowed to stir for 1.5 h, and then
filtered with normal silica and Celite washing with CH2Cl2. The sol-
vent was evaporated to give 15 mg (90%) of a mixture of lactones 8
and 9 in a 4:1 ratio, which were not separable by chromatography.
Compound 9: 13C NMR (200 MHz, CDCl3): d = (Deduced from the
spectrum of the mixture) 24.5(CH2, C-6), 28.6(3CH3, C(CH3)3),
29.5(CH2, C-5), 32.4(CH2, C-7), 33.4(CH2, C-4), 35.7(CH, C-4a),
47.0(CH, C-8a), 51.0(CH, C-8), 73.0 (CH2, C-1), 80.0(C, C(CH3)3),
155,6(C, COOtBu), 173.0(C, COO); HRMS (ESI): m/z (M+Na) calcd
for C14H23NO4, 292.1519; found, 292.1518.
To 24 mg (1.04 mmol) of a suspension of NaH (60% in paraffin,
previously washed with THF) in 5 ml of THF were slowly added
0.25 ml (1.38 mmol) of diethyl methoxycarbonylmethylphospho-
nate. It is stirred for 10 min and after which, 122 mg (0.45 mmol)
of 12 dissolved in 1.5 ml of THF is added via cannula. The mixture
was left stirring for 62 h after which 10 ml of water were added
and extracted with ether. The ether phase was washed with H2O
and saturated NaCl, dried over anhydrous Na2SO4, filtered and
evaporated to afford 51 mg (36%) of 13 as a clear oil; IR (neat):
4.8. Methyl (E)-4-((1R,2R,3R)-3-((tert-butoxycarbonyl)amino)-
2-(hydroxymethyl)cyclohexyl)but-2-enoate 10
Approximately 20 mg (0.077 mmol) of 6, 45.6 mg (0.16 mmol)
of methoxycarbonylmethylenephosphorane and 5 ml of toluene
were added and refluxed (110 °C) for 38 h. After this time some
of the solvent was evaporated and the residue was flash chro-
matographed on flash silica, isolating 4 mg of unreacted starting
m
max = 3357, 2941,1729, 1363, 1166; 1H NMR (400 MHz, CDCl3):
d = 0.90(1H, m, H-4A), 1.10(1H, m, H-3A), 1.30–1.50(1H, m, H-
5A), 1.42(9H, s, C(CH3)3), 1.55–1.85(3H, m, H-3B, H-4B, H-5B),
2.05(1H, m, H-400A), 2.15(1H, m, H-6), 2.25(1H, m, H-400B), 2.30
(1H, m, H-1), 3.40 (1H, m, H-2), 4.55(1H, d, J = 5.6 Hz, NH), 3.64
(3H, s, OCH3), 3.72(3H, s, OCH3), 5.78(1H, d, J = 15.6 Hz, H-20),
5.81(1H, d, J = 15.2 Hz, H-300), 6.70(1H, dd, J = 15.6, 10.3 Hz, H-10),
6.80(1H, ddd, J = 15.2, 7.0, 6.0 Hz, H-300) ppm; 13C NMR (200 MHz,
CDCl3): d = 24.5(CH2, C-4), 28.5(3CH3, C(CH3)3, 30.6(CH2, C-5),
material and 6 mg (25%) of 10 as a clear oil; IR (neat): mmax
=
3362, 2917, 1720, 1640, 1512, 1166; 1H NMR (400 MHz, CDCl3):
d = 0.80–2.01(6H, m, H-4, H-5, H-6), 1.46(9H, s, C(CH3)3), 2.05(1H,
m, H-3), 2.16(1H, dd, J = 6.0, 1.5 Hz, H-2), 2.27(1H, t, J = 5.2 Hz, H-
1A00), 2.52(1H, m, H-1B00), 3.47(1H, m, H-1), 3.60–3.80(2H, m, CH2-

1400
A. G. Rubia et al. / Tetrahedron: Asymmetry 28 (2017) 1394–1400
33.3(CH2, C-3), 37.3(CH2, C-100), 40.1(CH, C-6), 51.7(2CH3, s, OCH3),
52.8(CH, C-1), 54.4(CH, C-2) 80.0(C, C(CH3)3), 123.1(CH, C-300),
123.9(CH, C-20), 146.9(CH, C-200), 149.6(CH, C-10), 155.2(C,
NCOOtBu), 166.4(C, COOMe), 166.9(C, COOMe); HRMS (ESI): m/z
(M+Na) calcd for C20H31NO6, 404.2014; found, 404.2043.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetasy.2017.10.005.
References
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To 15 mg (0.039 mmol) of 13 were added 0.5 mL of TFA and 2
mL of CH2Cl2. Stirring was continued for 3.5 h, after which 0.5 ml
of water were added and extracted with CH2Cl2. The organic phase
was washed with 10% NaHCO3 and saturated NaCl and dried over
anhydrous Na2SO4. It was then filtered and evaporated to give
14.5 mg of reaction crude, which was chromatographed on flash
silica eluting with 98:2 CHCl3/MeOH, isolating 13 mg (85%) of 14
as a clear oil;
m
max = 3367, 2917, 1725, 1650, 1433, 1161; 1H
NMR (400 MHz, CDCl3): d = 0.80–1.70(3H, m, H-4A, H-5A, H-6A),
1.70–2.01(4H, m, H-1, H-4B, H-5B, H-6B), 2.30(2H, m, H-400), 2.64
(1H, m, H-2), 3.65–3.80(1H, m, H-3), 3.73(3H, s, OCH3), 3.75(3H,
s, OCH3), 5.75(1H, d, J = 15.6 Hz, H-200), 5.98(1H, d, J = 15.6 Hz, H-
20), 6.67(1H, dd, J = 15.6, 10.2 Hz, H-10), 6.86(1H, ddd, J = 15.6, 8.4,
6.8 Hz, H-300) ppm; 13C NMR (200 MHz, CDCl3): d = 24.1(CH2, C-5),
29.0(CH2, C-4), 30.6(CH2, C-6), 37.3(CH2, C-400), 39.7(CH, C-3),
51.7, 51.9(2CH3, OCH3), 53.3(CH, C-2), 54.5(CH, C-1), 123.1(CH, C-
20), 125.5(CH, C-200), 147.1(CH, C-30), 149.0(CH, C-300), 166.5, 167.0
(2C, COOCH3); HRMS (ESI): m/z (M+H) calcd for C15H24NO4,
282.1700; found, 282.1692.
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Acknowledgments
The authors are grateful for financial support from MINECO,
Spain CTQ2015-68175-R, FEDER Junta de Castilla y León (UIC21)
and Junta de Castilla y León, Spain (SA162A12-1). The authors also
thank Dr. A. M. Lithgow for work on the NMR spectra and Dr. César
Raposo for the Mass spectra and X-ray diffraction service of the
NUCLEUS platform of the University of Salamanca. C.T.N. thanks
Junta de Castilla y León (Spain) for a FPI predoctoral fellowship.