Studies for the transformation of carbocycles into carbohydrates: Approach toward the synthesis of higher sugar derivatives

Article abstract of DOI:10.1016/j.carres.2003.10.026

A highly stereocontrolled synthesis of a β-D-ribo-hept-6- ulopyranosuronamide derivative, a useful intermediate for the synthesis of other higher sugars, has been developed using naturally occurring (-)-quinic acid as a chiral starting material. The trans

Full text of DOI:10.1016/j.carres.2003.10.026

Carbohydrate
RESEARCH
Carbohydrate Research 339 (2004) 665–671
Studies for the transformation of carbocycles into carbohydrates:
approach toward the synthesis of higher sugar derivatives
*
ꢀ
Lucia Helena Brito Baptistella and Giselle Cerchiaro
ꢀ
Instituto de Quımica, UNICAMP, CP 6154, 13084-971 Campinas, SP, Brazil
Received 2 August 2003; accepted 23 October 2003
Abstract—Ahighly stereocontrolled synthesis of a b-
D
-ribo-hept-6-ulopyranosuronamide derivative, a useful intermediate for the
synthesis of other higher sugars, has been developed using naturally occurring ())-quinic acid as a chiral starting material. The
transformation of carbocycle to carbohydrate, a key step in this sequence, occurred in a one-pot reaction: an ozonolysis carried out
under mild conditions.
ꢀ 2003 Elsevier Ltd. All rights reserved.
Keywords: Higher sugars; Quinic acid; Heptulopyranosuronamide
1. Introduction
())-Quinic acid [(1sn,3R,4sn,5R)-tetrahydroxycycloh-
exanecarboxylic acid6] (1), a widespread natural prod-
uct, isolated in high enantiomeric purity either from
its main plant source, Chinchona bark,7 or from
recombinant microbial biocatalyses,8 is commercially
available and a very attractive starting material for
stereocontrolled multistep synthesis of naturally occur-
ring substances and related compounds.9 In the past, it
has seen only limited use as a chiral synthetic precursor,
but over the years its applications in this field have been
growing rapidly, and a broad spectrum of compounds
have been synthesized. Considering the basic cyclohex-
ane skeleton of quinic acid, rich in functional groups as
well as in asymmetric and pseudoasymmetric carbons, it
is natural that its major use has been for the prepara-
tion of compounds featuring cyclohexane-substituted
frameworks, and these syntheses are well documented in
the literature.9–11 The structural features of quinic acid
also ensure a measure of regio- and stereo-control in
chemical manipulations that are not easily matched by
other organic compounds, and its application in organic
synthesis has been extended to the preparation of
The term higher sugars is customarily employed with
monosaccharides containing seven or more consecutive
carbon atoms in the chain. They have been identified as
subunits in various natural products and it is now well
recognized that they play prominent roles in numerous
biological processes.1 For example, some seven- and
eight-carbon atom sugars are important components in
bacterial lipopolysaccharides,2 the nine-carbon sialic
acids, the core class of higher sugars, occur as terminal
residues of glycoconjugates involved in recognition
phenomena,3 and some C10 to C12 sugars,4 the rarest
higher aldoses, have been identified as components of
antibiotics (see Fig. 1). Such higher sugars have
attracted considerable attention, and the expanding
knowledge of their biological properties, allied with
their limited availability from natural sources, make the
elaboration of practical routes to derivatives or ana-
logues an attractive challenge.5 Herein we report our
studies on the synthesis of a higher sugar from quinic
acid.
For the synthesis of polycyclic compounds from quinic acid see
Ref. 11.
* Corresponding author. E-mail: lhbb@iqm.unicamp.br
0008-6215/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2003.10.026

666
L. H. B. Baptistella, G. Cerchiaro / Carbohydrate Research 339 (2004) 665–671
OH
HO
HO
HO
OH
OH
OH
OH
HO
NHAc
O
OH
OH
COOH
OH
O
O
R'O
OH
NR2
O
OH
OH
OH
COOH
OH
HO
OH
OH
OH
NH2
3-deoxy -D-manno-2-octulosonic acid
OH
Kdo
OH
Hikozamine
N-acetylneuraminic acid
L-glycero -D-mannoheptose
Figure 1. Representative examples of higher sugars.
open-chain compounds,9;12 substituted cyclopentane
skeletons,9;13 and nitrogenous heterocyclic targets.9;14
Surprisingly, only two publications describe the use of
quinic acid as starting material for the preparation of
oxygenated heterocycles, a d-lactone15 and a tetrahyd-
ropyran16 and, to the best of our knowledge, the syn-
thesis of carbohydrates from this versatile substrate has
not yet been reported.
sequence being an ozonolysis carried out under mild
conditions.
2. Results and discussion
Starting with quinic acid, Scheme 1 illustrates the syn-
thetic pathway toward the b-D-ribo-hept-6-ulopyr-
In this paper, we disclose a concise, stereocontrolled
route for the conversion of the quinic acid (1) into a
heptulopyranosuronamide derivative, a seven-carbon
sugar that may be considered as a useful intermediate
for the synthesis of other higher carbohydrates. The
pattern of substitutions created in the six-membered ring
of quinic acid permitted the carbocycle to carbohydrate
transformation in a one-pot reaction, a key step in this
anosuronamide derivative 7. The reproducible
acid-catalyzed reaction of ())-1 with acetone, according
to Stoodley and co-workers13, led to the isopropylidene
quinide acetal 2 in excellent yield.
To have a compound with the C-3 secondary alcohol
free, which satisfies the requirements of functional group
compatibilities for the next steps, a ring-opening ami-
nolysis of the lactone was performed. It is known that,
O
C
O
O
HOOC OH
1
OH
OH
C
C
OH
RHN
HO
RHN
O
c
a
b
O
d
3
5
3
O
HO
OH
O
4
OH
1
O
O
O
O
4
2
3b
CONHR
CONHR
1
CONHR
5
HO
O
2
CONHR
O
6
2
3
O
e
f
3
1
HO
OHC
O
O
O
HO
O
3
O
O
O
O
O
7b
6
7a
5
R= C6H11
Scheme 1. Reagents and conditions: (a) acetone, H2SO4, Na2SO4, reflux, 1 h, quant.; (b) C6H11NH2, microwave irradiation (see Table 1); (c) PCC,
ꢁ
CH2Cl2, MS 4 A, rt, 3 h, 81%; (d) POCl3, py, rt, 25 h, 85%; (e) NaBH4, MeOH, 0 ꢁC, 25 min, 77%; (f) O3, CH2Cl2, )78 ꢁC, 5 min, then (CH3)2S,
)78 ꢁC to rt, 81%.

L. H. B. Baptistella, G. Cerchiaro / Carbohydrate Research 339 (2004) 665–671
667
Table 1. Comparative results in representative aminolysis reactions of 2 using classical and microwave-induced procedures
Entry
121a
Conditons
Reaction time
48 h
Product (yields)a
Benzylamine (1 equiv), AlMe3–toluene 2 M
(1 equiv), CH2Cl2, rt fi 40 ꢁC
Starting material 2 recovered
O
C
OH
1
2
3
Benzylamine (2 equiv), chlorobenzene, reflux
Benzylamine (1.5 equiv), MWb (500–600 W)
24 h
(20%)
(90%)
HN
HO
6 minc
3
O
O
3a
O
C
4
5
6
Cyclohexylamine (2 equiv), MWb (500–600W)
Cyclohexylamine (2 equiv), MWd (550 W/50 W)
Cyclohexylamine (1 equiv), MWd (550 W/50 W)
15 minc
10 mine
20 mine
(84%)
(82%)
(97%)
OH
1
HN
HO
3
O
3b
O
aThe yields are based on isolated products.
bReactions carried out in a domestic microwave equipment, in a screw-capped Teflon vessel.
cPeriods of heating intercalated with periods of standing without irradiation in the oven.
dReactions carried out in a microwave equipment intended for organic synthesis, operating with power control.
ePeriods of heating at 550 W intercalated with periods at 50 W.
in general, the conversion of lactones to amides requires
rather harsh conditions, such as high temperatures and/
or long reaction times,17 high pressures,18 or strong
alkali-metal catalysts.19 The use of milder catalysts20
or other amidating agents, including transition-metal
derivatives,21 has also been reported, but we decided to
explore a direct method for the conversion of the inac-
tivated lactone 2 into a highly stable hydroxy amide
derivative by employing a microwave-assisted reaction.
In synthetic organic chemistry, the advantages of this
methodology, when compared with conventional heat-
ing methods, are described by several reviews.22 In the
present particular case, treatment of 2 with freshly dis-
tilled primary amines, such as benzylamine and cyclo-
hexylamine, gave, after few minutes under microwave
irradiation either in a household oven or in equipment
intended for organic synthesis (power control), excellent
yields of the corresponding hydroxy amides 3. These
results, including comparison with classical heating
methods, are given in Table 1. Thus, faster, cleaner,
solvent-free, and higher yield microwave-assisted ami-
nolysis reactions, without any catalysis, could be
achieved with 2.23
the isolated ketone 4 was treated with freshly distilled
phosphorus oxychloride–pyridine, furnishing enone 5 in
69% overall yield (Scheme 1). Tests for a concomi-
tant oxidation–b-elimination of the chemical groups
involved with PCC in pyridine, as proposed by Shing
and Tang24 with analogous compounds, were also per-
formed, but in this case 5 was obtained from 3b in only
53% yield.
Mild reduction of the carbonyl group in 5 was
accomplished with NaBH4, giving the allylic alcohol 6 in
77% yield. As expected, this condition guaranteed
a chemo- and stereo-selective reduction, the hydride
attack proceeding almost exclusively from the less
hindered a-face of the keto group. A2D NOESY
experiment shows interactions, which demonstrate the
C-3-(S) configuration on 6, as for example NOE corre-
lations between H-3 and H-5 and between H-3 and
H-6(a). Small signals, always presented on the 1H NMR
spectra of crude 6, were attributed to the C-3 epimer of 6
(less than 8% yield).
Finally, with the desired functionality on the C-1–C-3
fragment of the carbocyclic system, an ozonolysis reac-
tion was applied with 6. After 5 min of treatment with
ozone at )78 ꢁC, reductive decomposition of the crude
ozonide, also at low temperature, led to a product
identified as the hemiacetal 7b. This result suggests that
the transformation of carbocycle to sugar actually
occurred as expected, namely in sequence with
From 3b, a classical synthetic sequence was used to
promote a regioselective C-1–C-2 elimination of the
tertiary hydroxyl moiety. First, the secondary alcohol
group of 3b was oxidized with pyridinium chlorochro-
mate (PCC) in the presence of molecular sieves, and then

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L. H. B. Baptistella, G. Cerchiaro / Carbohydrate Research 339 (2004) 665–671
COR
COR
HO
COR
COR
O
O
1
6
2
5
O
2
3
3
HO
1
HO
O
OHC
O
O
O
O
3
O
O
O
O
9b
5
8
9a
R =éster or amide
Scheme 2. Partial route for the preparation of a-
D
-arabino-hept-6-ulopyranosuronic derivative from quinic acid.
ozonolysis product formation. Compound 7a may be
suggested as an intermediate, but it was never isolated.
The hydroxyl group at C-1 on 7b was proposed to be
exo by examination of the 1H NMR spectral data, which
automatic magnetic stirrer, controlled via a Pentium-
based terminal. Optical rotations were measured on a
Carl Zeiss Polamat polarimeter using a Hg lamp and are
corrected. IR spectra were measured for KBr pellets or
films on KBr disks using a Bomem MB-series FT-IR
spectrometer. NMR spectra were recorded on Bruker
AC.P-300, Varian Gemini 300 or Varian Inova 500
spectrometers, using CDCl3 as solvent. Mass spectra
and high resolution MS were recorded on VG Autospec
equipment, with electron impact of 70 eV or chemical
ionization with isobutane.
3
shows J1;2 ꢀ 0 Hz (/ ꢀ 90ꢁ).
It is noteworthy that slight modifications of this
sequence (Scheme 2) may permit preparation of the C-3
epimer of the allylic alcohol 6 and, from it, higher sugars
of other series, for example derived from a-D-arabino-
hept-6-ulopyranosuronic compounds as 9, could be
stereoselectively prepared.25
In conclusion, we have demonstrated the possibility of
obtaining optically pure heptoses employing ())-quinic
acid as a chiral template through a synthetic sequence,
which could, in principle, be applied to the preparation
of more complex structures of higher sugars and their
analogues.
3.2. 4,5-O-isopropylidene quinide (2)
Asuspension of ( ))-quinic acid (1) (1.00 g, 5.2 mmol),
anhydrous Na2SO4 (5.00 g, 35 mmol), concentrated
H2SO4 (0.03 mL) and previously purified acetone
(50 mL) was heated under reflux for 1 h. After cooling,
the pH was adjusted to 6–7 with saturated NaHCO3, the
mixture was filtered, and the solvent was evaporated.
The residue was partitioned between water and CH2Cl2,
the organic layer was separated, dried with MgSO4, and
filtered and the solvent was evaporated. Crystallization
of the crude product with 1:1 hexane–EtOAc gave 2 in
3. Experimental
3.1. General methods
())-Quinic acid was purchased from Aldrich (98%). All
solvents were distilled before use and, when necessary,
purified according to known procedures.26 The ozone
generator was constructed at IQ-UNICAMP according
to a literature reference.27 Column chromatography
quantitative yield (1.11 g); mp 140 ꢁC [lit.28 143 ꢁC]; ½aŠ
D
)38ꢁ (c 1.18, CHCl3), [lit.28 ½aŠ )34.46 (CHCl3)]; IR
D
(KBr): mmax 3428, 1774 cmÀ1
;
1H NMR (500 MHz,
CDCl3): d 1.32 and 1.51 (2 · s, 2 · 3H, 2 · CH3), 2.15
(dd, 1H, J6ax;5 3, J6gem 15 Hz, H-6ax), 2.27–2.35 (m, 1H,
H-2eq), 2.38 (ddd, 1H, J4;6eq 2, J6eq;5 7, J6gem 15 Hz,
H-6eq), 2.64 (d, 1H, J2gem 12 Hz, H-2ax), 3.10 (br s, 1H,
OH), 4.30 (ddd, 1H, J4;6eq 2, J3;4 3, J4;5 7 Hz, H-4), 4.49
(dt, 1H, J5;6ax 3, J5;6eq ¼ J4;5 7 Hz, H-5), 4.71 (dd, 1H, J3;4
3, J2eq;3 7 Hz, H-3); 13C NMR (125 MHz, CDCl3): d 24.2
and 26.9 (2 · CH3), 34.2 (C-2), 38.1 (C-6), 71.5 (C-5),
72.1 (C-4), 71.4 (C-1), 75.8 (C-3), 109.8 (Cisoprop:), 179.3
(C@O); HRMS (EI): m=z found 214.0841, m=z calcd for
2 214.0841.
ꢁ
(CC) was performed with silica gel (silica 60 A, 70–230
mesh). Thin-layer chromatography (TLC) was per-
formed on silica gel 60 F254 glass-backed plates
(0.25 mm). Compounds were visualized by dipping the
plates in a cerium sulfate–ammonium molybdate solu-
tion, followed by heating. Preparative TLC was per-
formed using silica gel F254 glass-backed plates (1 mm).
Compounds were visualized under UV light. The
microwave reactions were conducted: (a) in a domestic
oven (Brastemp) operating at 2.45 GHz, 950 W of
delivered power, without temperature control; (b) in a
microwave labstation intended for organic synthesis
(MicroSynth from Milestone) operating at 2.45 GHz,
dual magnetron system with delivered microwave power
of 1000 W, pulsed magnetron power supply, equipped
with a thermocouple temperature control system and an
3.3. N-Benzyl 4,5-O-isopropylidene quinamide (3a)
An 80 mL Pyrex flask containing a mixture of 4,5-O-
isopropylidene quinide (2) (2.00 g, 9.3 mmol) and freshly
distilled benzylamine (1.5 mL, 13.7 mmol) was placed

L. H. B. Baptistella, G. Cerchiaro / Carbohydrate Research 339 (2004) 665–671
669
inside a screw-capped Teflon vessel, and the apparatus
was irradiated in a domestic microwave oven, at 500–
600 W, intercalating periods of heating (2 · 3 min) with
periods of storage in the oven (30 s). After cooling, the
mixture was dissolved in CH2Cl2 and the solution
washed with cold aq 0.5 mol LÀ1 HCl and with saturated
aq NaHCO3. The organic layer was separated, dried
with Na2SO4, filtered and the solvent was evaporated.
Crystallization of the crude product with CH2Cl2–hex-
quinide (2) (0.30 g, 1.4 mmol) and freshly distilled
cyclohexylamine (0.16 mL, 1.4 mmol) was connected to
a temperature sensor, and the apparatus was irradiated
for 20 min in microwave equipment programmed for
power control: 30 s at 550 W, 30 s at 55 W. After cooling,
the mixture was dissolved in CH2Cl2 and the solution
was washed with cold aq 0.5 mol LÀ1 HCl and with
saturated aq NaHCO3. The organic layer was separated,
dried with Na2SO4, and filtered and the solvent was
evaporated. Crystallization of the crude product with
CH2Cl2–hexane gave 3b in 97% yield (0.43 g).
ane gave 3a in 90% yield (2.70 g); mp 99 ꢁC; ½aŠ )9.8ꢁ (c
D
1.02, CHCl3); IR (KBr): mmax 3372, 3025, 1650,
1583 cmÀ1; 1H NMR (500 MHz, CDCl3): d 1.35 and 1.50
(2 · s, 2 · 3H, 2 · CH3), 2.02–2.14 (m, 2H, H-2, H-6),
2.30 (ddd, 1H, J2eq;4 1.5, J2eq;3 3, Jgem 15 Hz, H-2eq), 2.49
(dd, 1H, J5;6eq 5, Jgem 15 Hz, H-6eq), 3.42 (br s, 1H, OH),
3.85 (dt, 1H, J2eq;3 ¼ J3;4 3, J2ax;3 5 Hz, H-3), 4.18 (ddd,
1H, J2eq;4 1.5, J3;4 3, J4;5 7 Hz, H-4), 4.47 (d, Jgem 6 Hz,
CH2benzyl), 4.58 (dt, 1H, J5;6eq ¼ J5;6ax 5, J4;5 7 Hz, H-5),
4.72 (br s, 1H, OH), 7.26–7.40 (m, 6H, NH and
CHarom:); 13C NMR (125 MHz, CDCl3): d 24.3 and 26.9
(2 · CH3), 34.4 (C-6), 37.1 (C-2), 43.3 (CH2benzyl), 65.8
(C-3), 72.1 (C-5), 72.9 (C-1), 75.9 (C-4), 108.7 (Cisoprop:),
127.5, 127.6, 128.8, 137.5 (Carom:), 176.5 (C@O).
3.5. N-Cyclohexyl (1S,4R,5R)-1-hydroxy-4,5-O-isopro-
pylidene-3-oxo-cyclohexane-1- carboxamide (4)
Asuspension of the hydroxyl amide 3b (0.33 g,
1.05 mmol), pyridinium chlorochromate (0.45 g,
ꢁ
2.09 mmol) and 4 Amolecular sieves (0.80 g, ground and
previously activated for 3 h at 300 ꢁC) in anhydrous
CH2Cl2 (60 mL) was stirred at room temperature, under
an inert atmosphere, for 3 h. The solvent was evaporated
and anhydrous ethyl ether (20 mL) was added, stirring
for another 1 h. The mixture was filtered through a small
silica gel column, the column was washed with 10% ethyl
ether–CH2Cl2 and the solvent was evaporated. The
residue was purified by silica gel column chromatogra-
phy (CH2Cl2/MeOH 1%) to give pure 4 in 81% yield
3.4. N-Cyclohexyl 4,5-O-isopropylidene quinamide (3b)
(a) An 80-mL Pyrex flask containing a mixture of 4,5-O-
isopropylidene quinide (2) (0.30 g, 1.4 mmol) and
freshly distilled cyclohexylamine (0.32 mL, 2.8 mmol)
was placed inside a screw-capped Teflon vessel, and the
apparatus was irradiated in a domestic microwave oven,
at 500–600 W, intercalating periods of heating
(3 · 5 min) with periods of storage in the oven (30 s).
After cooling, the mixture was dissolved in CH2Cl2 and
the solution was washed with cold aq 0.5 mol LÀ1 HCl
and with saturated aq NaHCO3. The organic layer was
separated, dried (Na2SO4), and filtered and the solvent
was evaporated. Crystallization of the crude product
with CH2Cl2–hexane gave 3b in 84% yield (0.37 g); mp
(0.26 g); ½aŠ )72.1ꢁ (c 0.23, CHCl3); IR (KBr): mmax
D
3370, 3332, 1731, 1650, 1520 cmÀ1; 1H NMR (500 MHz,
CDCl3): d 1.39 and 1.47 (2 · s, 2 · 3H, 2 · CH3), 1.11–
1.91 (m, 10H, cyclohex.), 2.40 (dt, 1H, J2eq;6eq ¼ J5;6 3,
Jgem 16 Hz, H-6eq), 2.63 (dd, 1H, J2eq;6eq 3, Jgem 15 Hz, H-
2eq), 2,77 (dd, 1H, J5;6ax 3, Jgem 16 Hz, H-6), 3.15 (d, 1H,
Jgem 15 Hz, H-2ax), 3.66–3.74 (m, 1H, CHcyclohex:), 4.08
(s, 1H, OH), 4.46 (d, 1H, J4;5 5 Hz, H-4), 4.76– 4.79 (m,
1H, H-5), 6.90 (d, 1H, J 8 Hz, NH); 13C NMR
(125 MHz, CDCl3): d 24.6, 24.7, 25.4, 32.8, 32.9
(Ccyclohex:), 25.8 and 27.2 (2 · CH3), 33.9 (C-6), 47.9
(CHcyclohex:), 49.6 (C-2), 77.3 (C-1), 78.2 (C-5), 78.6 (C-
4), 110.5 (Cisoprop:), 170.7 (C@O), 205.9 (C-3); HRMS
(EI): m=z found 311.1733, m=z calcd for 4 311.1732.
119 ꢁC; ½aŠ )10.0ꢁ (c 0.39, CHCl3); IR (KBr): mmax 3436,
D
3416, 3285, 1663, 1514 cmÀ1
;
1H NMR (300 MHz,
CDCl3): d 1.09 and 1.25 (2 · s, 2 · 3H, 2 · CH3), 0.88–
1.70 (m, 10H, cyclohex.), 1.76 (2 · dt, 2H, J 4, Jgem
15 Hz, H-6 and H-2), 2.03 (ddd, 1H, J2eq;4 1.5, J2eq;3 5,
3.6. N-Cyclohexyl (4R,5R)-4,5-O-isopropylidene-3-oxo-
1-cyclohexene-1-carboxamide (5)
J
gem 15 Hz, H-2eq), 2.19 (dd, 1H, J5;6eq 2.5, Jgem 15 Hz, H-
6eq), 3.07 (s, 1H, OH), 3.44–3.47 (m, 1H, CHcyclohex:),
3.54 (m, 1H, H-5), 3.91 (ddd, 1H, J4;2eq 1.5, J3;4 3, J4;5
7 Hz, H-4), 4.32 (ddd, 1H, J5;6eq 2.5, J5;6ax 3, J4;5 7 Hz, H-
5), 4.73 (d, 1H, J 4 Hz, OH), 6.60 (d, 1H, J 8 Hz, NH);
13C NMR (75 MHz, CDCl3): d 24.6 and 27.3 (2 · CH3),
25.2, 25.8, 33.2, 33.3 (Ccyclohex:), 34.8 (C-6), 37.3 (C-2),
48.7 (CHcyclohex:), 66.0 (C-3), 72.4 (C-5), 72.9 (C-1), 76.1
(C-4), 109.0 (Cisoprop:), 176.1 (C@O); HRMS (IE): m=z
found 313.1588, m=z calcd for 3b 313.1889.
Phosphorus oxychloride (freshly distilled, 0.045 mL,
0.48 mmol) was added via a syringe to a solution of 4
(0.15 g, 0.48 mmol) in anhydrous pyridine (10 mL) and
the mixture was stirred at room temperature for 25 h.
Ethyl ether (20 mL) and saturated aq NH4Cl solution
(15 mL) were added and the aq layer was separated and
extracted two times with ethyl ether (10 mL). The com-
bined organic layers were washed with water (2 · 10 mL)
and brine (10 mL), separated and dried with MgSO4.
After filtration, the solvent was concentrated and
the residue was purified by preparative TLC (0.5%
(b) A50-mL microwave vessel (for reactions up to
6 bar) containing a mixture of 4,5-O-isopropylidene

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L. H. B. Baptistella, G. Cerchiaro / Carbohydrate Research 339 (2004) 665–671
CH2Cl2–MeOH) to give 5 in 85% yield (0.12 g); ½aŠ
1536 cmÀ1; 1H NMR (300 MHz, CDCl3): d 1.36 and 1.54
(2 · s, 2 · 3H, 2 · CH3), 1.10–1.98 (m, 10H, cyclohexyl.),
D
)14.7ꢁ (c 1.16, CHCl3); IR (KBr): mmax 3406, 3338, 3060,
1
1683, 1649, 1531 cmÀ1; H NMR (300 MHz, CDCl3): d
1.86 (dd, 1H, J4;5 6, Jgem 14 Hz, H-5), 2.51 (dd, 1H, J4;5 8,
0
1.33 and 1.40 (2 · s, 2 · 3H, 2 · CH3), 1.10–2.00 (m, 10H,
cyclohex.), 3.01 (ddd, 1H, J2;6eq 2.5, J5;6eq 5, Jgem 20 Hz,
H-6eq), 3.14 (br d, 1H, Jgem 20 Hz, H-6ax), 3.77–3.89 (m,
1H, CHcyclohex:), 4.30 (d, 1H, J4;5 5 Hz, H-4), 4.69 (td, 1H,
J5;6ax 2, J4;5 ¼ J5;6eq 5 Hz, H-5), 5.97 (d, 1H, J 7 Hz, NH),
6.35 (d, 1H, J2;6eq 2.5 Hz, H-2); 13C NMR (75 MHz,
CDCl3): d 24.7, 25.3, 27.1, 32.7 (Ccyclohex:), 25.8 and 27.4
(2 · CH3), 32.8 (C-6), 48.8 (CHcyclohex:), 72.4 (C-5), 75.0
(C-4), 109.5 (Cisoprop:), 125.6 (C-2), 150.6 (C-1), 165.4
(C@O), 197.4 (C-3); HRMS (IE): m=z found 293.1627,
m=z calcd for 5 293.1626.
Jgem 14 Hz, H50), 3.65–3.84 (m, 2H, CHcyclohex: and OH),
4.08 (dd, 1H, J2;3 1.5, J3;4 6 Hz, H-3), 4.39 (dt, 1H,
0
J3;4 ¼ J4;5 6, J4;5 8 Hz, H-4), 4.74 (s, 1H, H-2), 5.39 (s,
1H, H-1), 6.66 (d, 1H, J 6.5 Hz, NH); 13C NMR
(75 MHz, CDCl3): d 24.7, 25.4, 32.6, 32.7 (Ccyclohex:), 25.9
and 27.7 (2 · CH3), 35.3 (C-5), 48.0 (CHcyclohex:), 69.9 (C-
4), 70.9 (C-3), 82.0 (C-2), 95.4 (C-1), 105.1 (C-6), 110.3
(Cisoprop:), 165.8 (C@O amide); HRMS (EI): m=z found
327.1682, m=z calcd for 7b 327.1681.
Acknowledgements
3.7. N-Cyclohexyl (3S,4S,5R)-3-hydroxy-4,5-O-isopro-
pylidene-1-cyclohexene-1-carboxamide (6)
We are grateful to Prof. S. Hanessian for the initial ideas
of this work, to Prof. P. M. Imamura for his helpful
discussions and Prof. C. Collins for revising this man-
uscript. G.C. thanks CNPq for a fellowship and our
thanks are also due to FAPESP for financial support.
Asuspension of 5 (0.070 g, 0.24 mmol) and NaBH4
(0.010 g, 0.26 mmol) in anhydrous MeOH (20 mL) was
stirred at 0 ꢁC (ice bath) for 20 min. Asaturated aq
solution of NH4Cl (1 drop) was added and the solvent
was evaporated. Purification of the residue by column
chromatography (1% CH2Cl2–MeOH) gave 6 in 77%
References
yield (0.054 g); ½aŠ +23.8ꢁ (c 0.74, CHCl3); IR (KBr):
D
mmax 3330, 3071, 1652, 1615, 1534 cmÀ1
;
1H NMR
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(500 MHz, CDCl3): d 1.33 (s, 6 H, 2 x CH3), 1.09–1.95
(m, 10H, cyclohex.), 1.99–2.02 (m, 1H, H-6eq), 2.83 (dd,
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D
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