Diversity-Oriented Synthesis of Carbohydrate Scaffolds through the Prins Cyclization of Differently Protected d-Mannitol-Derived Homoallylic Alcohols

Article abstract of DOI:10.1002/ejoc.201701172

A diversity-oriented synthesis of a variety of carbohydrate scaffolds, including sugar-fused isochroman derivatives, bicyclic vinyl halide derivatives, fluorine-substituted tetrahydropyrans, and a furan derivative, is reported. This was achieved through the Prins reaction of d-mannitol-derived homoallylic alcohols in which the allylic alcohol bears a different protecting group, leading to structural variation in the products. Some of the products were also converted into more functionalized scaffolds of wider utility and of possible biological importance. Appropriate mechanisms have been proposed to account for the product formation.

Full text of DOI:10.1002/ejoc.201701172

A Journal of
Accepted Article
Title: Diversity Oriented Synthesis of Carbohydrate Scaffolds Using
the Prins Cyclization of Differently Protected D-Mannitol Derived
Homoallylic Alcohols
Authors: Yashwant D Vankar and Sateesh Dubbu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701172
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701172
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European Journal of Organic Chemistry
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Diversity Oriented Synthesis of Carbohydrate Scaffolds Using the
Prins Cyclization of Differently Protected D-Mannitol Derived
Homoallylic Alcohols
[
a]
[a]
Sateesh Dubbu, and Yashwant D. Vankar *
Dedication ((optional))
Abstract: A diversity oriented synthesis of a variety of carbohydrate
scaffolds such as sugar fused isochroman derivatives, bicyclic vinyl
halide derivatives, fluorine substituted tetrahydropyrans, and a furan
derivative is reported. This has been achieved by using the Prins
reaction on D-mannitol derived homoallylic alcohols in which the
allylic alcohol is differently protected and that causes structural
variations in products. Some of the products have also been
converted into more functionalized scaffolds of wider utility and of
ketals, annulated sugars and C2-branched heptoses. Likewise,
[
9]
more recently we have also utilized a Perlin aldehyde derived
homoallylic alcohol in the Prins reaction to form a variety of
isochroman derivatives by trapping of the initially formed
tetrahydropyranyl carbocation by
intramolecular fashion.
a
phenyl ring in an
possible biological importance. Appropriate mechanisms have been Results and Discussion
proposed to account for the product formation.
In continuation to explore the scope of the Prins reaction in
carbohydrate chemistry we hereby report the chemistry of
differently protected allylic alcohols which are obtained from D-
mannitol derived 1,2,3-triols. This was conceived with a view to
Introduction
[1]
The Prins reaction to form the tetrahydropyran (THP)
rings in a highly stereoselective manner upon reaction of
homoallylic alcohols with a carbonyl compound in the presence
of a Brønsted or a Lewis acid has gained enormous importance
in the last few years. Consequently, synthesis of a number of
[2]
THP ring containing natural products has been reported using
the Prins cyclization. The mechanistic aspects suggest
intermediacy of
a tetrahydropyranyl carbocation that gets
trapped by a nucleophile present in the reaction medium in an
intermolecular fashion to give the observed product. The
trapping of such a tetrahydropyranyl carbocation has also been
[3]
reported in an intramolecular fashion with a suitably appended
nucleophile in the homoallylic alcohol molecule, or sometimes in
the carbonyl compound. Besides, instead of homoallylic alcohols,
homopropargylic alcohols also permit the Prins type reactions to
occur which proceed with the intermediacy of vinyl cations
[4]
followed by trapping with nucleophiles to yield the products.
These reactions lead to a wide variety of highly functionalized
THP ring products, and also fused with a variety of carbocyclic
Scheme 1. Retrosynthetic analysis from differently protected 1, derived from
D-mannitol
[5]
and heterocyclic rings. More recently, the Prins reaction using
carbohydrate derived homoallylic alcohols has also been
[6]
reported to procure interesting chiral molecules. Our interest in
developing carbohydrate based methodologies, especially by
obtain a variety of oxygen heterocycles depending on the nature
of the protecting groups of the allylic hydroxy moiety and
permitting the Prins reaction with the homoallylic alcohol part
while keeping the C1-OH group as pivaloyl protected 1 (Scheme
[
7]
exploring the chemistry of glycals has recently led us to
[8]
report
an
interesting
cascade
Prins-pinacol
type
rearrangement and C4-OBn participation on carbohydrate
substrates. This has allowed an easy access to bridged tricyclic
1).
[
10]
The concept of diversity oriented synthesis (DOS) has
been well utilized over the years in procuring different scaffolds
from similar types of starting materials with minor structural
tuning. This allows an access to a large number of structurally
diverse molecules for possible biological evaluations. In our
present endeavor we wanted to address the importance of the
DOS in utilizing D-mannitol derived homoallylic alcohols with
differently protected allylic hydroxy group. Our aim was to utilize
[
a]
Department of chemistry, Indian Institute of Technology Kanpur,
Kanpur 208016, India.
E-mail: Vankar@iitk.ac.in, ydvankar@gmail.com
http://home.iitk.ac.in/~vankar/
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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European Journal of Organic Chemistry
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this concept and make use of the Prins reaction to procure a
number of structurally diverse and potentially biologically
important carbohydrate derived scaffolds. This included
indication of the formation of products 6 or 7. Increase in the
amount of TMSOTf to 0.5 eq. (entry 6) did raise the yield of 8 to
59% requiring 12 h but again no other product was formed. Use
[
11]
annulated sugars,
which are pharmaceutically important
3 2
of 0.5 eq. of BF ·OEt , on the other hand, at 0 °C-rt gave 53% of
molecules and have the potential to act as enzyme inhibitors.
the product 8 in 5 h which was raised to 72% by using 1.0
equivalent of it in dichloromethane requiring only 20 min at 0 °C-
rt (entries 7, 8). Change of solvent to benzene and acetonitrile
gave lesser yield and required longer time (entries 9, 10). Thus,
there was no effect of solvent or change in catalyst at the
outcome of the selectivity of compound 8 (Table 1).
[
12]
Likewise, we wanted to obtain isochroman derivatives which
are subunits of many important natural products. Besides, some
synthetic isochromans are known to be apoptosis inhibitor of
[13a]
vascular endothelial cells ISO-09
antagonist CJ-17,493.
and neurokinin-1 receptor
Further, they are useful intermediates
in the synthesis of several isocoumarins, benzodiazepine-4-ones
[
13b]
[
14]
and other compounds.
Table 1. Optimization of Prins Friedel-Crafts reaction condition
Scheme 2. Preparation of protected homoallylic alcohols 4 and 5a-5f.
In view of this, we began our work by synthesizing D-
[15]
mannitol derived allylic alcohol 2
(Scheme 2) and protected
as benzyl ether 3a by reacting it with benzyl bromide/NaH. The
cleavage of the acetonide group to the corresponding diol with
[
16]
ethanol-conc. HCl
followed by in situ conversion of the
primary alcohol to the benzyl ether 4 was done by reacting with
Bu SnO/BnBr. We explored the reactivity of this homoallylic
2
alcohol 4 in the Prins reaction using different protic and Lewis
acids. It was expected that 4 could lead to C-aryl glycosides 6 or
We then considered changing the protecting group at C-1
position (primary alcohol) hoping that it could make some
difference at the outcome of the stereoselectivity of compound 8.
Towards this effect we considered incorporating a relatively
bulky and easily removable pivaloyl group. Thus C-1 hydroxyl
group was selectively converted into compound 5a, an O-
pivaloyl protected compound. This was obtained from 3a upon
acetonide deprotection, followed by reaction with pivaloyl
chloride-pyridine in presence of a catalytic amount of DMAP.
Compound 5a was then subjected to Prins-Friedel-Crafts
n
7
arising from the corresponding tetrahydropyranyl carbocation,
generated via the Prins cyclization, by either losing a proton or
by trapping with water respectively. Alternatively, in view of our
[9]
recent experience, we also anticipated that this carbocation
may undergo intramolecular benzyl participation to yield the
corresponding isochroman derivative 8. Thus, homoallylic
alcohol 4 was reacted with p-tolualdehyde in presence of various
reaction by reacting with 1.2 equivalent of p-toualdehyde, 1.0
protic and Lewis acids such as CF
Yb(OTf) , and Cu(OTf) (Table 1) but no product formation was
observed. The use of 0.1 eq. of TMSOTf at 0 °C-rt led to product
as an inseparable mixture of diastereomers (α/β = 0.7:1) albeit
in only 7% yield (entry 5, Table 1) in 12 h and there was no
3
COOH (TFA), FeCl
3
,
o
equivalent of BF
3
·OEt
2
and dichloromethane as solvent at 0 C-rt.
3
2
We were pleased to find that the product 9a was obtained in
86% yield and exclusively as a single stereoisomer (Scheme 3).
8
The structure of 9a was confirmed by COSY, NOE, DEPT
and HETCOR studies, and also by single X-ray crystallography
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European Journal of Organic Chemistry
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(
Figure 1). Thus, NOE correlation studies revealed that
Table 2. Stereoselective synthesis of 2-deoxy-3,4-sugar fused isochroman
irradiation of the H-5 proton at δ = 3.82 ppm resulted in
enhancement of the signals for the H-1 proton at δ = 4.67–4.65
ppm and for the H-3 proton at δ = 3.08–3.04 ppm. This
confirmed that the protons H-5, H-1 and H-3 possess cis
derivatives
[17]
relationship (Figure 1)
and thus the newly generated chiral
center at C-3 was trans to C-4.
This possibly implies that in case of O-pivaloyl protected
homoallylic alcohol 5a, the steric effect and/or remote
participation of the O-piv group possibly induces β-selectivity at
[18]
C-1.
Scheme 3. Stereoselective synthesis of Isochroman derivative from O-pivaloyl
protected compound 5a.
Figure 1. noe correlation and ORTEP diagram of compound 9a
With these results in hand, we pursued our studies with
various other aldehydes and cyclohexanone to obtain sugar
fused isochroman derivatives 9b-9t in good to excellent yields
(Table 2). The substituent present on the aromatic ring showed
some effect on the yield. It was observed that halogenated or
alkyl substituted aromatic aldehydes gave the products in
comparatively higher yields than the corresponding electron
In an effort to utilize such sugar fused isochroman
derivatives to procure some other important molecules, we
converted compound 9q into a carbasugar fused isochroman
derivative as shown in Scheme 6. Thus, O-pivaloyl group in
compound 9q was first deprotected with NaOMe/MeOH to get
deficient aldehydes. These products are devoid of
a C-2
substituent and possess a pivaloyl group at C-6 for further
manipulations, and thus they are different from the isochrmoan
[
9]
3
compound 12 which upon treatment with iodine/Ph P followed
products earlier reported by us. With 1-methylnaphthyl and 2-
methylnaphthyl substituted allylic alcohols 5b and 5c, the
isochroman derivatives 10, and 11a-11c were respectively
formed in excellent yields (Scheme 4). The formation of these
products could be rationalized via a plausible mechanism as
shown in Scheme 5. Thus, 5a upon reaction with a carbonyl
[19]
by reductive cleavage with zinc dust led to compound 13. The
free –OH group was then protected as an actetate and the
resulting molecule 14 was subjected to ring closing metathesis
nd
with Grubbs’ 2 generation catalyst to form the olefin 15.
4
Stereoselective dihydroxylation with OsO /NMO led to a
carbasugar fused isochroman derivative 16 in good yield. The
structures of these molecules were established based on
spectral data and the stereochemistry of these newly generated
stereocenters was confirmed using COSY and NOE
compound in presence of
a
Lewis acid leads to an
oxocarbenium ion intermediate A which on π-participation of the
double bond gives another intermediate B, a tetrahydropyranyl
carbocation, that permits arene participation and forms the
products 9a-9t via intermediate C.
[17]
experiments.
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European Journal of Organic Chemistry
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Scheme 6. Syntheis of carbasugar fused isochroman derivative 16
Scheme 4. Synthesis of sugar fused isochoman derivatives 10, 11a-11c from
1- and 2-methylnapthyl protected compounds 5b and 5c
Figure 2. The syn-dihydroxylation of 15 with an endo approach
Likewise, the O-pivaloyl group of the isochroman derivative
9n was deprotected to obtain alcohol 17 (Scheme 7) which was
converted into the isochroman derivative 18 in two similar steps
as utilized to obtain 13 (vide supra). Oxidative cleavage of the
double bond in 18 gave the corresponding hemiacaetal which
upon acetylation gave 19 as a mixture of two anomers. This
sugar fused isochroman derivative bearing an acetate moiety at
the anomeric carbon can permit further structural variations to
lead to O- and C-glycosylations.
Further, compounds 9q and 9s were converted into an
interesting 2,3-dideoxy-C-glycoside (or
a
tetrahydropyran)
bearing C-3 aryl substituent upon hydrogenation/
hydrogenolysis as shown in Scheme 8.
a
Scheme 5. Plausible mechanism for the formation of 2-deoxy-3,4-sugar fused
isochroman derivatives
The high diastereoselectivity observed in dihydroxylation of 15
could be understood by the transition state as shown in Figure 2.
It is clear that the approach of OsO is less favorable from top
4
than from bottom due to its interaction with the axially oriented
acetate group.
Scheme 7. Synthesis of sugar fused isochroman derivative bearing an acetate
moiety 19
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European Journal of Organic Chemistry
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results are summarized in Table 4. While dichloromethane was
used as a solvent for the preparation of vinyl chlorides, for vinyl
bromides and iodide, dibromomethane and methyl iodide were
used respectively. It is worth mentioning that such solvent
participation in the Prins reaction has been studied in detail by
[20]
Martin et al.
It is expected that such C-aryl glycoside fused
bicyclic vinylic halides could be further functionalized to lead to a
variety of sugar derived molecules. The formation of compound
+
Scheme 8. Synthesis of C-glycoside 20 bearing a C-3 aryl substituent
21a was confirmed by the presence of [M + H] ions at m/z =
3
79.1674 in its mass spectrum and by the appearance of vinylic
After exploring the reactivity of the O-benzyl protected
homoallylic alcohols, we embarked on extending the scope of
this transformation further. In this direction, we carried out the
Prins reaction with the homoallylic alcohol 5d, having the allylic
alcohol protected as propargyl ether, with p-tolualdehyde. Again
a number of protic and Lewis acids, and various solvents were
screened and the results are summarized in Table 3. Use of 1
1
proton at δ = 5.80 ppm in its H NMR spectrum.
Table 4. Stereoselective synthesis of 2-deoxy-3,4-sugar fused bicyclic vinyl
halide derivatives
3 2
eq. of BF ·OEt at -10 °C in dichloromethane was found to be
ideal which led to the corresponding 2-deoxy-3,4-sugar fused
bicyclic vinyl halide in which the nature of the halide part was
dependent on the solvent used. Thus, a number of aldehydes
and cyclohexanone were utilized in the present study and the
corresponding vinyl halide (chloride, bromide and iodide)
derivatives were obtained in very good yields in 40 min-1 h. Our
.
Table 3. Optimization of reaction condition stereoselective synthesis of 2-
deoxy-3,4-sugar fused bicyclic vinyl halide derivatives
The stereochemistry of the products was confirmed by spectral
[17]
data including the COSY and NOE experiments.
To ascertain
the absolute configuration of compound 21a, the signal at δ 3.72
ppm for H-5 was irradiated in an NOE experiment and
enhancement was observed for the H-1 and H-3 peaks in the
region of δ 4.50-4.49 ppm and δ 2.57 ppm respectively. This
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European Journal of Organic Chemistry
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confirms that the three protons H-5, H-3 and H-1 are in cis
orientation (Figure 3).
via normal Prins type reaction, grabs fluorine as a nucleophile
[
21]
from it. The stereochemistry of the newly generated chiral
centers was established based on spectral analysis, including
CH3
OPiv
[17]
OPiv
COSY and NOE experiments. To ascertain the configuration
of compound 22a, the signal at δ 3.49 ppm for H-5 was
irradiated in an NOE experiment and enhancement was
observed for the H-1 and H-3 peaks in the region of δ 4.52–4.49
ppm and δ 1.79–1.76 ppm respectively. Also, irradiation of the
peak at δ 4.69–4.57 ppm for H-8 showed enhancement of H-3
peak in the region of δ 1.79–1.76 ppm. This confirms that the
four protons H-8, H-5, H-3 and H-1 are in cis orientation (Figure
O
5
O
O
R'
Cl
1
H
3
O
H
H
cis cis
Cl
1a
R' =
CH3
2
Figure 3. noe correlation of compound 21a
4).
In view of the fact that fluorinated compounds are
[
22]
medicinally important
we expect that such sugar (C-aryl
Mechanistically, the reaction may proceed via
intermediates X and Y (Scheme 9), similar to intermediates A
and B in Scheme 5, to form vinyl carbocation Z en route to the
products 21a-21p.
glycoside) fused tetrahydropyran derivatives could serve as
useful building blocks.
On the other hand, with 3,3-disubstituted allyl ether
derivative 5f, the reaction resulted in the formation of a sugar
[
23]
fused furan derivative 23.
Mechanistically, the reaction should proceed via the typical
Prins type oxocarbenium ion intermediate A (Scheme 11) in
both the cases. In case of 5e (R = H), A should lead to
carbocation B which undergoes further cyclization through π-
interaction followed by the fluoride ion attack on another
carbocation C to form products 22a-22d. On the other hand,
OPiv
O
OPiv
O
OPiv
O
O
O
R'
R'
O
R'
X
solvent
Z
Y
2
1a-21p
3
intermediate D, resulting from A (when R = CH ), undergoes π-
cation cyclization to form a tertiary carbocation E followed by
proton loss to form the observed product 23. The structure
elucidation of 23 was done using NOE correlation studies, which
revealed that the H-4 and H-7 protons had a trans relationship,
as we did not observe any NOE effect from H-7 at δ = 2.89 ppm
when H-4 was irradiated at δ = 3.42–3.41 ppm (Figure 4).
Furthermore, irradiation of H-3 proton at δ = 2.11–2.04 ppm
resulted in an enhancement of in the signal for the H-5 protons
at δ = 3.72 ppm and in an enhancement of in the signal for the
H-1 protons at δ = 4.39 ppm. Which confirmed that the H-5, H-3,
and H-1 protons had a cis relationship (Figure 4).
Scheme 9. Plausible mechanism for the formation of 2-deoxy-3,4-sugar fused
bicyclic vinyl halide derivatives
Interestingly, reaction of homoallylic alcohol 5e, having the
allylic alcohol protected as allyl ether, with different aldehydes
using BF ·OEt as a promoter yielded sugar fused fluorine
3 2
substituted tetrahydropyrans 22a-22d (Scheme 10). The
formation of compound 22a was confirmed by the presence of
+
[
M + Na] ions at m/z = 289.1216 in its mass spectrum and by
1
the appearance of multiplet at δ = 4.71–4.53 ppm in its H NMR
spectrum. Clearly, here BF ·OEt is also acting as a reactant,
3
2
possibly because the ensuing secondary carbocation, formed
Scheme 11. Plausible mechanism for the formation of 22a-22d and 23
Scheme 10. Synthesis of sugar fused fluorine substituted tetrahydropyran
derivatives 22a-22d and sugar fused furan derivative 23
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European Journal of Organic Chemistry
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General experimental procedures for the preparation of stating
materials
General procedure A (Alkylation of –OH):
To a stirred suspension of NaH (60%) (6.32 mmol, 2.0 eq) in dry DMF (5
mL) was added dropwise allyl alcohol (3.16 mmol) in dry DMF (5 mL) at 0
o
C. After completion of addition, the reaction mixture was stirred at the
same temperature for 30 min. followed by addition of an alkyl halide (3.47
mmol) and the reaction brought to room temperature. After stirring for the
respective time (1 h-6 h), the reaction mixture was quenched by pouring
in crushed ice, and the extracted with ethyl acetate (3 x 25 mL). The
combined organic extracts were washed with water (2 x 30 ml), brine
Figure 4. noe correlation of compound 22a and 23
Conclusions
2 4
solution (1 x 20 mL) and dried over Na SO . Evaporated under reduced
vacuo gave crude product which was purified through column
chromatography to afford the product.
a
In summary, we have converted a number of D-mannitol derived
homoallylic alcohols having an appropriate protection of the –OH
group of the allylic alcohol part leading to
a range of
General procedure B (acetonide deprotection followed by pivaloyl
protection of selective primary hydroxyl group):
carbohydrate scaffolds such as sugar fused isochroman
derivatives, bicyclic vinyl halide derivatives, fluorine substituted
tetrahydropyrans, a furan derivative. One of the sugar fused
In a round bottom flask, acetonide protected compound (3a-3f) (0.50 g)
was dissolved in a solution of dilute hydrochloric acid in 30 mL of ethanol
(1 mL of concentrated HCl per 100 mL of ethanol). The progress of
reaction was monitored by thin layer chromatography. Upon completion
isochroman derivatives was utilized in the synthesis of
a
carbasugar fused isochroman derivative and also in the
synthesis of a sugar fused isochroman derivative bearing an
acetate moiety at the anomeric carbon for further O- or C-
3
(1h), the reaction was neutralized by adding 1 mL of aq. NH and the
solvent was removed in vacuo and the crude product was used for next
step without purification.
glycosylations. Also,
a
2,3-dideoxy-C-glycoside (or
a
tetrahydropyran) bearing a C-3 aryl substituent was prepared
from the same sugar fused isochroman derivative. Clearly such
a diversity oriented synthesis of fused carbohydrate scaffolds
will be useful in procuring further derivatives/analogues for
possible biological evaluations.
To a solution of the diol (2.40 mmol) in CH
2 2
Cl (6 mL) was added pyridine
o
(0.23 mL, 2.88 mmol) and pivaloyl chloride (0.29 mL, 2.40 mmol) at 0 C.
A catalytic amount of 4-dimethylaminopyridine (DMAP) (0.02 g, 0.24
mmol) was added. The mixture was stirred at ambient temperature for
the respective time (4–24 h) and then diluted with CH Cl2 (30 mL). The
2
organic layer was washed with aqueous 5% HCl (15 mL), saturated
aqueous NaHCO
anhydrous Na SO
crude homoallylic alcohol which was purified by column chromatography.
3
(15 mL), and brine (20 mL). The extract was dried over
2
4
, filtered, and concentrated in vacuo to obtain the
Experimental Section
General procedures
(2R,3S)-1,3-bis(benzyloxy)pent-4-en-2-ol (4):
All the solvents were distilled prior to use. Dry solvents were prepared
according to the standard procedures. All other reagents were used as
received from either Aldrich, Spectrochem Pvt. Ltd. (Mumbai), Sd fine-
chem Ltd. (Mumbai) and Lancaster chemical companies. Reactions
requiring inert atmosphere were carried out under nitrogen atmosphere.
Melting points were determined on a micro hot-stage (Yanako MP-S3).
IR spectra were recorded with FT-IR as a thin film and are expressed in
[15]
Compound 3a was prepared as per the literature proceudre. The crude
diol (0.50 g, 2.40 mmol) was dissolved in dry toluene (5 mL) and reacted
n
o
with Bu
apparatus, for 6 h. The reaction mixture was then cooled to room
temperature and Et N (0.31 mL, 2.40 mmol) TBAI (1.06 g, 2.88 mmol)
2
SnO (0.89 g, 3.60 mmol) at 140 C using a Dean-Start
3
and benzyl bromide (0.28 mL, 2.40 mmol) were added in succession.
The resulting solution was heated to 120 C for 2 h and then poured into
N HCl (10 mL) and extracted with ethyl acetate (3 x 10 ml). Etracted
material was washed with brine (1 x 20 mL), dried over Na SO , and
concentrated under vacuum. The residue was purified by column
chromatography to afford product 4 (0.16 g, 69%) as a pale yellow liquid.
= +42.18° (c = 1.43, CH
νmax/cm ) 3453, 3064, 3031, 2867, 1585, 1496, 1453, 1274, 1070,
o
-1
1
13
cm . H (500 MHz or 400 MHz) and C (125 MHz or 100 MHz) NMR
spectra were recorded using CDCl as a solvent. Chemical shifts are
1
3
2
4
reported in ppm downfield to tetramethylsilane. Coupling constants are
reported and expressed in Hz; splitting patterns are designated as br
(
(
broad), s (singlet), d (doublet), dd (double doublet), m (multiplet), td
triplet of doublet), dt (doublet of triplet). Optical rotations were measured
R
(
1
1
4
f
= 0.5 (9/1 hexane/EtOAc);
2 2
Cl ); IR
−1
using a polarimeter (AUTOPOL II) at 28 °C. The visualization of spots on
TLC plates was effected by exposure to iodine or spraying with 10%
H SO and charring. Column chromatography was performed over silica
2 4
gel (100−200 Mesh) using hexane and ethyl acetate as eluents. Mass
spectra were obtained from high resolution ESI mass spectrometer using
Q−TOF analyser.
1
3
090; H NMR (400 MHz, CDCl ) δ 7.35–7.25 (m, 10H), 5.89–5.80 (m,
H), 5.40–5.30 (m, 2H), 4.61 (d, J = 11.92 Hz, 1H), 4.56–4.50 (m, 2H),
.36 (d, J = 11.92 Hz, 1H), 3.92–3.84 (m, 2H), 3.62–3.53 (m, 2H), 2.33
bs, 1H); C NMR (100 MHz, CDCl ) δ 138.26, 138.11, 135.11, 128.51,
3
28.48, 127.92, 127.88, 127.83, 127.73, 120.11, 81.02, 73.51, 72.37,
13
(
1
7
3
+
0.88, 70.54; HRMS calcd for C19
21.1462.
3
H22NaO [M + Na] 321.1467, found
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European Journal of Organic Chemistry
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+
(2R,3S)-3-(benzyloxy)-2-hydroxypent-4-enyl pivalate (5a):
70.70, 66.91, 26.67, 25.41; HRMS calcd for C19
H
22
O
3
[M] 298.1569,
found 298.1562.
[
15]
Compound 3a was prepared as per the literature proceudre.
It was
subjected to acetonide deprotection followed by pivaloyl protection of
selective primary hydroxyl group using general procedure B within 4 h
and compound 5a was obtained as a colorless liquid; Yield 0.51 g, 86%;
(2R,3S)-2-hydroxy-3-(naphthalen-2-ylmethoxy)pent-4-enyl pivalate
(5c):
−
1
f
R = 0.5 (9/1 hexane/EtOAc); IR (νmax/cm ) 3427, 2982, 1729, 1371,
Compound 3c (0.50 g, 1.67 mmol) was subjected to acetonide
deprotection followed by selective pivaloyl protection of primary hydroxyl
group using general procedure B with pivaloyl chloride (0.20 mL, 1.67
mmol), pyridine (0.16 mL, 2.01 mmol) and DMAP (0.02 g, 0.16 mmol).
Compound 5c was obtained in 4 h as a colorless liquid; Yield 0.52 g,
1
1
211, 1207, 1101;
CDCl ) δ 7.34–7.24 (m, 5H), 5.89–5.80 (m, 1H), 5.42–5.31 (m, 2H), 4.62
d, J = 11.92 Hz, 1H), 4.36 (d, J = 11.88 Hz, 1H), 4.21–4.12 (m, 2H),
2 2
= +38.11° (c = 1.73, CH Cl ); H NMR (400 MHz,
3
(
3
1
3
.92–3.80 (m, 2H), 2.57 (d, J = 4.56 Hz, 1H), 1.17 (s, 9H); C NMR (100
) δ 178.72, 137.97, 134.55, 128.52, 127.95, 127.84, 120.58,
0.99, 71.82, 70.55, 65.07, 38.88, 27.24; HRMS calcd for C17 [M +
MHz, CDCl
8
H] 293.1753, found 293.1759.
3
9
1%; R
f
= 0.5 (9/1 hexane/EtOAc);
= +27.22° (c = 0.41, CH
2
Cl
max/cm ) 3458, 2981, 1727, 1440, 1227, 1111; H NMR (500 MHz,
CDCl ) δ 7.83–7.74 (m, 4H), 7.48–7.44 (m, 3H), 5.93–5.86 (m, 1H),
.46–5.37 (m, 2H), 4.79 (d, J = 12 Hz, 1H), 4.54 (d, J = 12 Hz, 1H), 4.24–
4.16 (m, 2H), 3.95 (d, J = 2.85 Hz, 1H), 3.90–3.87 (m, 1H), 2.48 (br s,
2
); IR
H
25
O
4
−1
1
(ν
+
3
5
2
,2-dimethyl-4-((S)-1-(naphthalen-1-ylmethoxy)allyl)-1,3-dioxolane
1
3
(3b):
1H), 1.15 (s, 9H); C NMR (125 MHz, CDCl
3
) δ 178.80, 135.39, 134.51,
33.33, 133.11, 128.39, 127.97, 127.80, 126.7, 126.2, 126.07, 125.94,
20.80, 80.96, 71.91, 70.68, 65.10, 38.89, 27.22; HRMS calcd for
1
1
Compound
bromomethyl)naphthalene (0.76 g, 3.47 mmol), NaH (0.15 g, 6.32 mmol)
using general procedure A in 6 h to obtain 3b as a colorless liquid; Yield
.84 g, 89%; R = 0.9 (9/1 hexane/EtOAc); = +39.88° (c = 0.53,
CH Cl ); IR (νmax/cm ) 2936, 1453, 1368, 1054, 994; H NMR (400 MHz,
CDCl ) δ 8.28–8.07 (m, 2H), 7.73–7.54 (m, 4H), 7.31–7.29 (m, 1H),
.91–5.82 (m, 1H), 5.46–5.36 (m, 2H), 5.06 (d, J = 11.88 Hz, 1H), 4.76 (d,
J = 12.40 Hz, 1H), 4.10 (dd, J = 12.36, 5.96 Hz, 1H), 4.00–4.96 (m, 1H),
2
(0.50 g, 3.16 mmol) was reacted with 1-
+
21 27 4
C H O [M + H] 343.1909, found 343.1902.
(
0
f
(R)-2,2-dimethyl-4-((S)-1-(prop-2-ynyloxy)allyl)-1,3-dioxolane (3d):
−
1
1
2
2
3
Compound 2 (0.50 g, 3.16 mmol) was subjected to alkylation using
general procedure A with propargyl bromide (0.31 mL, 3.47 mmol) and
NaH (0.15 g, 6.32 mmol) needing 2 h to obtain 3d as a pale yellow liquid;
5
1
3
3
δ
1
2
3
.81–3.73 (m, 2H), 1.39 (s, 3H), 1.33 (s, 3H); C NMR (100 MHz, CDCl )
Yield 0.57 g, 92%; R
f
= 0.7 (9/1 hexane/EtOAc);
= +8.99° (c = 0.53,
135.04, 133.70, 133.02, 132.19, 129.36, 127.89, 127.31, 127.11,
27.05, 124.61, 123.48, 120.41, 109.63, 81.15, 77.55, 68.56, 66.81,
−1
1
CH
MHz, CDCl
4
1
2
Cl
2
); IR (νmax/cm ) 2942, 2873, 1561, 1323, 1113; H NMR (400
) δ 5.75–5.65 (m, 1H), 5.37–5.30 (m, 2H), 4.21–4.16 (m, 1H),
.08–4.01 (m, 3H), 3.87–3.84 (m, 2H), 2.39–2.38 (m, 1H), 1.38 (s, 3H),
3
+
6.64, 25.33; HRMS calcd for C19
H
22
O
3
[M] 298.1569, found 298.1562.
13
3
.30 (s, 3H). C NMR (100 MHz, CDCl ) δ 134.01, 120.80, 109.67,
(
(
2R,3S)-2-hydroxy-3-(naphthalen-1-ylmethoxy)pent-4-enyl pivalate
5b):
80.40, 79.66, 77.26, 74.51, 66.90, 55.56, 26.56, 25.26; HRMS calcd for
C H O [M] 196.1099, found 196.1091.
11 16 3
+
Compound 3b (0.50 g, 1.67 mmol) was subjected to acetonide
deprotection followed by selective pivaloyl protection of the primary
hydroxyl group using pivaloyl chloride (0.20 mL, 1.67 mmol), pyridine
(2R,3S)-2-hydroxy-3-(prop-2-ynyloxy)pent-4-enyl pivalate (5d):
Compound 3d (0.50 g, 2.54 mmol) was subjected to acetonide
deprotection followed by pivaloyl protection with pivaloyl chloride (0.31
mL, 2.54 mmol), pyridine (0.24 mL, 3.05 mmol) and DMAP (0.03 g, 0.16
mmol) using general procedure B requiring 6 h. Compound 5d was
(
0.16 mL, 2.01 mmol), DMAP (0.02 g, 0.16 mmol), using general
procedure B. It required 4 h to obtain 5b as a colorless liquid; Yield 0.51
g, 89%; R = 0.5 (9/1 hexane/EtOAc); = +20.48° (c = 0.21, CH Cl ); IR
max/cm ) 3483, 2973, 1728, 1480, 1284; H NMR (400 MHz, CDCl ) δ
f
1
2
2
−
1
(ν
3
obtained as
hexane/EtOAc);
a
colorless liquid; Yield 0.39 g, 86%;
= +21.98° (c = 0.43, CH Cl ); IR (νmax/cm ) 3483,
293, 2975, 2116, 1728, 1481, 1286; H NMR (400 MHz, CDCl ) δ 5.79–
f
R = 0.5 (9/1
8
1
4
9
1
8
.27–8.25 (m, 1H), 8.07–8.04 (m, 1H), 7.71–7.54 (m, 4H), 7.28–7.24 (m,
H), 5.93–5.84 (m, 1H), 5.48–5.37 (m, 2H), 5.04 (d, J = 11.88 Hz, 1H),
.72 (d, J = 11.92 Hz, 1H), 4.18–4.06 (m, 2H), 3.89–3.84 (m, 2H), 1.11 (s,
−1
2
2
1
3
5
4
9
7
3
.70 (m, 1H), 5.41–5.34 (m, 2H), 4.23–4.17 (m, 1H), 4.16–4.08 (m, 2H),
13
H); C NMR (100 MHz, CDCl
32.20, 129.33, 127.94, 127.37, 127.22, 127.18, 124.42, 123.61, 121.10,
1.00, 71.88, 68.55, 64.92, 38.84, 27.18; HRMS calcd for C21 [M +
3
) δ 178.75, 134.45, 133.46, 133.01,
.05–3.98 (m, 2H), 3.91–3.87 (m, 1H), 2.39 (t, J = 2.28 Hz, 1H), 1.18 (s,
13
H); C NMR (125 MHz, CDCl
3
) δ 178.74, 133.27, 121.45, 80.33, 79.51,
20NaO [M
27 4
H O
4.62, 71.67, 64.99, 55.61, 38.90, 27.24; HRMS calcd for C13
H
4
+
H] 343.1909, found 343.1902.
+
+
Na] 263.1259, found 263.1260.
2
,2-dimethyl-4-((S)-1-(naphthalen-2-ylmethoxy)allyl)-1,3-dioxolane
(R)-4-((S)-1-(allyloxy)allyl)-2,2-dimethyl-1,3-dioxolane (3e):
(3c):
Compound 2 (0.50 g, 3.16 mmol) was subjected to alkylation using
general procedure A with allyl chloride (0.31 mL, 3.47 mmol) and NaH
Compound 2 (0.50 g, 3.16 mmol) was subjected to alkylation using
general procedure A with 2-(bromomethyl)naphthalene (0.76 g, 3.47
mmol) and NaH (0.15 g, 6.32 mmol) in 6 h to obtain 3c as a colorless
(
1
0.15 g, 6.32 mmol) in 30 min to obtain 3e as a pale yellow liquid; Yield
.18 g, 94%; R = 0.7 (9/1 hexane/EtOAc); = +32.14° (c = 0.31,
CH Cl ); IR (νmax/cm ) 2986, 2876, 1380, 1370, 1252; H NMR (400
MHz, CDCl ) δ 5.90–5.70 (m, 2H), 5.33–5.13 (m, 4H), 4.09–4.01 (m, 3H),
.90–3.83 (m, 2H), 3.69 (t, J = 6.40 Hz, 1H), 1.39 (s, 3H), 1.32 (s, 3H);
f
liquid; Yield 0.84 g, 89%; R
f
1
= 0.9 (9/1 hexane/EtOAc);
= +17.83° (c =
); IR (νmax/cm ) 2972, 1480, 1289, 1145; H NMR (400 MHz,
) δ 7.84–7.76 (m, 4H), 7.48–7.44 (m, 3H), 5.91–5.82 (m, 1H),
.45–5.35 (m, 2H), 4.82–4.79 (m, 1H), 4.56 (d, J = 11.88 Hz, 1H), 4.19–
−1
1
2
2
−
1
0
2 2
.11, CH Cl
3
CDCl
3
3
5
4
13
3
C NMR (100 MHz, CDCl ) δ 135.27, 134.71, 119.46, 117.17, 109.57,
1
3
.06 (m, 2H), 3.92–3.79 (m, 2H), 1.43 (s, 3H), 1.36 (s, 3H); C NMR
) δ 135.70, 135.24, 135.08, 133.35, 135.22, 128.29,
27.96, 127.81, 126.70, 126.21, 126.00, 120.01, 109.65, 81.07, 77.70,
+
8
1.01, 77.65, 69.73, 66.79, 26.62, 25.38; HRMS calcd for C11
18 3
H O [M]
(100 MHz, CDCl
3
198.1256, found 198.1259.
1
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201701172
FULL PAPER
(2R,3S)-3-(allyloxy)-2-hydroxypent-4-enyl pivalate (5e):
Typical Procedure ‘D’ for the Prins reaction:
Compound 3e (0.50 g, 2.52 mmol) was subjected to acetonide
deprotection followed by reaction with pivaloyl chloride (0.31 mL, 2.52
mmol), pyridine (0.23 mL, 3.02 mmol) and DMAP (0.03 g, 0.25 mmol) to
selectively protect the primary hydroxyl group using general procedure B.
It needed 4 h and compound 5e was obtained as a colorless liquid; Yield
To a stirred solution of propargyl and pivaloyl protected homollaylic
alcohol 5d (0.62 mmol), an aldehyde (0.74 mmol, 1.2 equiv.) and 4 Å
molecular sieve (200 mg), in anhydrous specified halogenated solvent (3
3 2
mL), was added BF ·OEt (0.62 mmol, 1.0 equiv., which was previously
dissolved in 1 mL of anhydrous specified halogenated solvent under
o
0
.50 g, 82%; R
f
= 0.5 (9/1 hexane/EtOAc);
= +11.41° (c = 1.29,
nitrogen atmosphere) slowly drop by drop at -10 C. The resulting mixture
−
1
CH Cl ); IR (νmax/cm ) 3414, 2934, 2853, 1492, 1452, 1375, 1032, 966,
7
4
CDCl
8.80, 27.17; HRMS calcd for C13H O [M] 242.1518, found 242.1516.
22 4
2
2
was allowed to stir at the same temperature for the specified time (Table
4). After completion of the reaction as indicated by TLC, the mixture was
quenched with saturated NaHCO solution (2 mL), diluted with water (5
3
mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic
phases were washed with brine (1 × 5 mL), dried over anhydrous
1
48; H NMR (500 MHz, CDCl
.18–4.05 (m, 3H), 3.89–3.78 (m, 3H), 1.18 (s, 9H); C NMR (100 MHz,
) δ 178.60, 134.49, 120.05, 117.16, 80.92, 71.63, 69.48, 64.01,
3
) δ 5.89–5.73 (m, 2H), 5.36–5.14 (m, 4H),
13
3
+
3
2 4
Na SO and concentrated in vacuo. The resulting crude product was
purified by silica gel column chromatography (100−200 mesh) using ethyl
acetate/hexane gradients to afford the pure product 21 (Table 4).
(
(
R)-2,2-dimethyl-4-((S)-1-(3-methylbut-2-enyloxy)allyl)-1,3-dioxolane
3f):
(
4R,4aS,10bS)-4-(benzyloxymethyl)-2-p-tolyl-1,2,4,4a,6,10b-
Compound 2 (0.50 g, 3.16 mmol), 1-bromo-3-methylbut-2-ene (0.40 mL,
.47 mmol) and NaH (0.15 g, 6.32 mmol) was subjected to alkylation
using general procedure A in 1 h to obtain 3f as a colorless liquid; Yield
.61 g, 86%; R = 0.5 (9/1 hexane/EtOAc); = +11.41° (c = 1.29,
CH Cl ); IR (νmax/cm ) 2985, 2933, 1454, 1379, 1370, 1251, 1158, 1076;
H NMR (500 MHz, CDCl ) δ 5.81–5.74 (m, 1H), 5.35–5.27 (m, 3H),
.07–4.02 (m, 3H), 3.89–3.83 (m, 2H), 3.63 (t, J = 6.87 Hz, 1H), 1.73 (s,
hexahydropyrano[3,4-c]isochromene (8):
3
0
f
Following the typical procedure ‘C’ for the Prins reaction, compound 8
was isolated as a white solid; m.p. = 92–94 C; Yield 0.092 g, 72%; R
0.7 (9/1 hexane/EtOAc); IR (νmax/cm ) 2970, 2869, 1540, 1480, 1366,
1285, 1039;
diastereomers) δ 7.38–6.99 (m, 20H, both isomers), 5.06 (s, 1H, major
isomer), 4.92 (s, 1H, minor isomer), 4.77–4.60 (m, 6H, both isomers),
4.45 (d, J = 11.88 Hz, 1H, major isomer), 4.15 (d, J = 10.08 Hz, 1H,
minor isomer), 4.00 (dd, J = 10.56, 4.12 Hz, 1H, major isomer), 3.93–
−
1
o
2
2
f
=
1
−1
3
1
4
3
3
H NMR (400 MHz, CDCl , (α/β = 0.7:1) mixture of
13
H), 1.63 (s, 3H), 1.41 (s, 3H), 1.33 (s, 1H); C NMR (125 MHz, CDCl
3
)
δ 137.22, 135.63, 120.91, 119.18, 109.47, 81.03, 77.56, 67.04, 65.16,
+
2
6.61, 25.77, 25.24, 18.04; HRMS calcd for C13
23 3
H O [M + H] 227.1647,
found 227.1641.
3.88 (m, 1H, minor isomer), 3.83–3.79 (m, 2H, both isomers), 3.44 (t, J =
9
.4 Hz, 1H, minor isomer), 3.09–2.99 (m, 2H, both isomers), 2.62–2.57
(
(
2R,3S)-2-hydroxy-3-(3-methylbut-2-enyloxy)pent-4-enyl
5f):
pivalate
(m, 1H, minor isomer), 2.53–2.46 (m, 2H, both isomers), 2.35 (s, 3H,
minor isomer), 2.33 (s, 3H, major isomer), 1.71–1.58 (m, 4H, both
13
isomers); C NMR (100 MHz, CDCl
3
) δ 139.29, 138.84, 137.84, 137.59,
Compound 3f (0.50 g, 2.21 mmol) upon acetonide deprotection was
treated with pivaloyl chloride (0.27 mL, 2.21 mmol), pyridine (0.21 mL,
1
1
1
37.44, 137.29, 136.21, 134.34, 129.14, 129.10, 128.55, 128.36, 128.14,
27.83, 127.69, 127.48, 126.66, 126.40, 126.16, 126.08, 124.49, 124.31,
07.99, 83.14, 82.86, 80.13, 79.45, 74.39, 73.58, 72.23, 69.85, 68.89,
2
.65 mmol) and DMAP (0.02 g, 0.22 mmol) following general procedure
B to obtain 5f as a colorless liquid in 4 h; Yield 0.54 g, 91%; R = 0.5 (9/1
f
−
1
68.32, 51.60, 39.83, 39.76, 36.76, 29.80, 21.24; HRMS calcd for
C H O [M + H] 401.2117, found 401.2119.
27 29 3
hexane/EtOAc);
= +18.22° (c = 0.53, CH
2
Cl
2
); IR (νmax/cm ) 2986,
) δ
+
1
2
5
2
9
1
876, 1380, 1370, 1252, 1155, 1076, 927; H NMR (400 MHz, CDCl
.81–5.72 (m, 1H), 5.34–5.24 (m, 3H), 4.17–3.98 (m, 3H), 3.84–3.79 (m,
3
H), 3.73 (dd, J = 7.76, 5.48 Hz, 1H), 1.69 (s, 3H), 1.60 (s, 3H), 1.17 (s,
13
H); C NMR (100 MHz, CDCl
3
) δ 178.70, 137.41, 134.92, 120.82,
19.95, 80.61, 71.74, 65.13, 65.09, 38.85, 27.21, 25.81, 18.10; HRMS
Following typical procedure ‘C’ for the Prins reaction, compounds
9a-9t were prepared:
+
22 4
calcd for C13H O [M] 242.1518, found 242.1516.
((2R,4R,4aS,10bS)-2-p-tolyl-1,2,4,4a,6,10b-hexahydropyrano[3,4-
c]isochromen-4-yl)methyl pivalate (9a):
Representative General Procedures for the Prins reactions
Typical Procedure ‘C’ for the Prins reaction:
o
White solid; m.p. = 137–139 C; Yield 0.11 g, 84%; R
f
= 0.7 (9/1
−
1
hexane/EtOAc);
= + 42.88° (c = 0.23, CH
869, 1729, 1480, 1366, 1285, 1039; H NMR (500 MHz, CDCl
.00 (m, 8H, ArH), 4.94 (d, J = 15.45 Hz, 1H, H-7), 4.90 (d, J = 15.45 Hz,
H, H-7′), 4.67 (dd, J = 11.45, 2.30 Hz, 1H, H-1), 4.49 (dd, J = 11.45,
.30 Hz, 1H, H-6), 4.35 (dd, J = 11.45, 4.60 Hz, 1H, H-6′), 3.84–3.81 (m,
H, H-5), 3.41 (t, J = 9.70 Hz, 1H, H-4), 3.09–3.04 (m, 1H, H-3), 2.63–
.59 (m, 1H, H-2′), 2.34 (s, 3H, -CH
.21 (s, 9H, Piv); C NMR (100 MHz, CDCl ) δ 178.47, 139.04, 137.39,
35.94, 134.28, 129.14, 126.73, 126.52, 125.85, 124.54, 124.40, 79.22,
7.94, 76.78, 74.44, 68.38, 63.58, 39.69, 38.99, 36.64, 27.36, 21.23;
2
Cl
2
); IR (νmax/cm ) 2970,
) δ 7.35–
1
2
7
1
2
1
2
1
1
7
3
To a stirred solution of a homoallylic alcohol (0.51 mmol), aldehyde (0.61
mmol, 1.2 equiv.) and 4 Å molecular sieve (200 mg), in anhydrous
dichloromethane (4 mL) at 0 °C was added BF ·OEt (0.51 mmol, 1.0
3 2
equiv.) under nitrogen atmosphere. The resulting mixture was allowed to
stir at room temperature for the specified time (Tables 2, Schemes 3 and
3
), 1.63 (q, J =12.36 Hz, 1H, H-2),
1
3
3
1
0). After completion of the reaction as indicated by TLC, the mixture
was quenched with saturated NaHCO solution (2 mL), diluted with water
5 mL) and extracted with dichloromethane (3 × 5 mL). The combined
organic phases were washed with brine (1 × 5 mL), dried over anhydrous
Na SO and concentrated in vacuo. The resulting crude product was
3
(
+
HRMS calcd for C25
H
31
O
4
[M + H] 395.2222, found 395.2220.
2
4
purified by silica gel column chromatography (100−200 mesh) using ethyl
acetate/hexane gradients to afford the pure product.
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201701172
FULL PAPER
o
(
(2R,4R,4aS,10bS)-2-(4-isopropylphenyl)-1,2,4,4a,6,10b-
Pale solid; m.p. = 129–131 C; Yield 0.12 g, 78%;
hexane/EtOAc); = +48.01° (c = 0.29, CH Cl ); IR (νmax/cm ) 2957,
869, 1729, 1531, 1480, 1350, 1284, 1164, 1104, 1071, 738; H NMR
500 MHz, CDCl ) δ 8.22–7.02 (m, 8H), 4.95 (d, J = 14.85 Hz, 1H), 4.91
f
R = 0.4 (9/1
−
1
hexahydropyrano[3,4-c]isochromen-4-yl)methyl pivalate (9b):
2
2
1
2
(
Pale yellow liquid; Yield 0.11 g, 81%; R
+
1
f
1
= 0.7 (9/1 hexane/EtOAc);
=
3
−
(d, J = 14.9 Hz, 1H), 4.81 (d, J = 10.9 Hz, 1H), 4.53 (dd, J = 12, 1.7 Hz,
1H), 4.39 (dd, J = 11.45, 5.15 Hz, 1H), 3.87–3.84 (m, 1H), 3.41 (t, J =
14.22° (c = 0.21, CH
Cl
2 2
); IR (νmax/cm ) 2959, 2869, 1729, 1479, 1284,
) δ 7.33–7.01 (m, 8H), 4.94
1
164, 1104, 1010; H NMR (400 MHz, CDCl
3
9
.42 Hz, 1H), 3.13–3.09 (m, 1H), 2.69–2.67 (m, 1H), 1.55 (q, J = 12.21
(
1
1
d, J = 15.56 Hz, 1H), 4.90 (d, J = 15.56 Hz, 1H), 4.67 (d, J = 10.47 Hz,
H), 4.99–4.47 (m, 1H), 4.36 (dd, J = 11.92, 4.6 Hz, 1H), 3.84–3.81 (m,
H), 3.42 (t, J = 9.86 Hz, 1H), 3.10–3.03 (m, 1H), 2.90 (septet, J = 6.84
13
Hz, 1H), 1.21 (s, 9H); C NMR (125 MHz, CDCl
3
) δ 178.40, 149.20,
47.40, 135.25, 134.52, 134.20, 126.85, 126.78, 126.46, 124.52, 124.40,
23.76, 78.06, 74.17, 68.38, 63.24, 39.56, 39.01, 36.67, 27.34; HRMS
1
1
Hz, 1H), 2.64–2.61 (m, 1H), 1.66 (q, J = 12.36 Hz, 1H), 1.25–1.23 (m,
+
13
calcd for C24H27NNaO [M + Na] 448.1736, found 448.1731.
6
1
7
H), 1.22 (s, 1H); C NMR (100 MHz, , CDCl
3
) δ 178.43, 148.41, 139.34,
6
35.96, 134.29, 126.76, 126.53, 125.95, 124.56, 124.40, 79.31, 77.98,
4.42, 68.38, 63.58, 39.71, 38.99, 36.55, 33.95, 27.38, 24.09; HRMS
((2R,4R,4aS,10bS)-2-(4-cyanophenyl)-1,2,4,4a,6,10b-
hexahydropyrano[3,4-c]isochromen-4-yl)methyl pivalate (9g):
+
calcd for C27
H
35
O
4
[M + H] 423.2535, found 423.2532.
o
(
(2R,4R,4aS,10bS)-2-(4-(trifluoromethyl)phenyl)-1,2,4,4a,6,10b-
White solid; m.p. = 149–151 C; Yield 0.10 g, 76%; R
f
= 0.4 (9/1
−
1
hexahydropyrano[3,4-c]isochromen-4-yl)methyl pivalate (9c):
hexane/EtOAc);
= +12.01° (c = 0.54, CH
869, 2227, 1727, 1479, 1284, 1164, 1103, 1018; H NMR (400 MHz,
Cl
2 2
); IR (νmax/cm ) 2958,
1
2
3
CDCl ) δ 7.65–7.00 (m, 8H), 4.94 (d, J = 15.56 Hz, 1H), 4.89 (d, J =
15.56 Hz, 1H), 4.76–4.73 (m, 1H), 4.51 (dd, J = 11.88, 2.28 Hz, 1H), 4.37
(dd, J = 11.92, 5.04 Hz, 1H), 3.86–3.82 (m, 1H), 3.39 (t, J = 9.84 Hz, 1H),
Pale yellow liquid; Yield 0.13 g, 90%; R
f
1
= 0.8 (9/1 hexane/EtOAc);
=
−
+
59.11° (c = 0.32, CH
Cl
2 2
); IR (νmax/cm ) 2971, 2870, 1730, 1480, 1326,
) δ 7.62–7.01 (m, 8H), 4.95
1
1
164, 1125, 1067; H NMR (400 MHz, CDCl
3
3
9
1
.12–3.05 (m, 1H), 2.67–2.62 (m, 1H), 1.53 (q, J = 12.36 Hz, 1H), 1.20 (s,
(
d, J = 15.56 Hz, 1H), 4.90 (d, J = 15.56 Hz, 1H), 4.76 (d, J = 10.56 Hz,
1
3
H); C NMR (125 MHz, CDCl
3
) δ 178.40, 147.24, 135.32, 134.20,
1
1
1
1
1
H), 4.53–4.50 (m, 1H), 4.37 (dd, J = 11.88, 5.04 Hz, 1H), 3.87–3.83 (m,
H), 3.41 (t, J = 9.84 Hz, 1H), 3.12–3.06 (m, 1H), 2.68–2.63 (m, 1H),
32.35, 128.64, 126.83, 126.75, 126.39, 124.51, 124.42, 118.89, 111.42,
13
78.25, 78.03, 74.19, 68.37, 63.28, 39.56, 39.00, 36.61, 27.34; HRMS
calcd for C25H27NNaO [M + Na] 428.1838, found 428.1837.
4
3
.58 (q, J = 12.8 Hz, 1H), 1.21 (s, 9H); C NMR (100 MHz, CDCl ) δ
+
78.43, 145.93, 135.50, 134.23, 126.81, 126.69, 126.04, 125.59, 125.46,
24.47, 78.49, 78.00, 74.24, 68.38, 63.35, 39.59, 39.00, 36.71, 27.35;
+
HRMS calcd for C25
H
28
F
3
O
4
[M + H] 449.1940, found 449.1947.
((2R,4R,4aS,10bS)-2-(3-bromophenyl)-1,2,4,4a,6,10b-
hexahydropyrano[3,4-c]isochromen-4-yl)methyl pivalate (9h):
((2R,4R,4aS,10bS)-2-(4-bromophenyl)-1,2,4,4a,6,10b-
hexahydropyrano[3,4-c]isochromen-4-yl)methyl pivalate (9d):
Pale yellow liquid: Yield 0.14 g, 90%; R
f
1
= 0.8 (9/1 hexane/EtOAc);
=
−
+
8.18° (c = 0.41, CH
2 2
Cl ); IR (νmax/cm ) 2971, 2869, 1728, 1479, 1284,
1
1164, 1105, 1071, 749; H NMR (400 MHz, CDCl ) δ 7.55–7.00 (m, 8H),
3
Pale yellow liquid; Yield 0.14 g, 90%; R
f
1
= 0.8 (9/1 hexane/EtOAc);
=
−
4.92 (d, J = 15.08 Hz, 1H), 4.89 (d, J = 15.56 Hz, 1H), 4.66 (dd, J = 11.44,
2.28 Hz, 1H), 4.51 (dd, J = 11.88, 2.28 Hz, 1H), 4.35 (dd, J = 11.88, 5.04
Hz, 1H), 3.84–3.80 (m, 1H), 3.39 (t, J = 9.6 Hz, 1H), 3.09–3.02 (m, 1H),
+
1
8
1
3
9
1
7
38.22° (c = 0.28, CH
284, 1164, 1011, 820, 557; H NMR (500 MHz, CDCl
2 2
Cl ); IR (νmax/cm ) 2957, 2928, 2854, 1730, 1488,
1
3
) δ 7.43–6.96 (m,
H), 4.97–4.83 (m, 2H), 4.62–4.60 (m, 1H), 4.45 (dd, J = 9.16, 1.36 Hz,
H), 4.33–4.29 (m, 1H), 3.79–3.76 (m, 1H), 3.48 (t, J = 7.78 Hz, 1H),
.04–2.99 (m, 1H), 2.58–2.54 (m, 1H), 1.52 (q, J = 9.76 Hz, 1H), 1.16 (s,
13
2
(
.65–2.60 (m, 1H), 1.57 (q, J = 12.36 Hz, 1H), 1.22 (s, 9H); C NMR
100 MHz, CDCl ) δ 178.44, 144.28, 135.57, 134.22, 130.69, 130.05,
129.02, 126.79, 126.65, 124.51, 124.44, 124.38, 122.61, 78.33, 77.93,
4.27, 68.37, 63.34, 39.55, 39.01, 36.64, 27.37; HRMS calcd for
3
13
3
H); C NMR (100 MHz, CDCl ) δ 178.43, 141.03, 135.61, 134.23,
7
31.56, 127.55, 126.78, 126.63, 124.48, 124.44, 121.45, 78.53, 77.96,
+
24 4
C H28BrO [M + H] 459.1171, found 459.1176.
4.31, 68.37, 63.42, 39.57, 38.99, 36.62, 27.35; HRMS calcd for
+
C
24
H
28BrO
4
[M + H] 459.1171, found 459.1172.
((2R,4R,4aS,10bS)-2-(3-fluorophenyl)-1,2,4,4a,6,10b-
hexahydropyrano[3,4-c]isochromen-4-yl)methyl pivalate (9i):
((2R,4R,4aS,10bS)-2-(4-fluorophenyl)-1,2,4,4a,6,10b-
hexahydropyrano[3,4-c]isochromen-4-yl)methyl pivalate (9e):
Pale yellow liquid; Yield 0.12 g, 91%; R
f
1
= 0.8 (9/1 hexane/EtOAc);
=
−
+
2 2
9.10° (c = 0.42, CH Cl ); IR (νmax/cm ) 2970, 2869, 1728, 1512, 1225,
Pale yellow liquid; Yield 0.12 g, 90%; R
f
1
= 0.8 (9/1 hexane/EtOAc);
=
1
−
1164, 1106, 1070; H NMR (400 MHz, CDCl ) δ 7.36–6.94 (m, 8H), 4.94
+
58.78° (c = 0.29, CH
Cl
2 2
); IR (νmax/cm ) 2970, 2869, 1729, 1512, 1225,
) δ 7.37–7.01 (m, 8H), 4.95
3
1
(d, J = 15.6 Hz, 1H), 4.89 (d, J = 15.56 Hz, 1H), 4.71–4.68 (m, 1H), 4.51
1
162, 1106, 1074; H NMR (500 MHz, CDCl
3
(dd, J = 11.92, 2.28 Hz, 1H), 4.39–4.34 (m, 1H), 3.85–3.81 (m, 1H), 3.40
(d, J = 14.85 Hz, 1Hz), 4.90 (d, J = 14.85 Hz, 1H), 4.68 (dd, J = 10.9,
(
1
t, J = 9.6 Hz, 1H), 3.10–3.04 (m, 1H), 2.66–2.61 (m, 1H), 1.58 (q, J =
2.36 Hz, 1H), 1.22 (s, 9H); C NMR (125 MHz, CDCl ) δ 178.43,
3
1
3
2
.75 Hz, 1H), 4.50 (dd, J = 12, 2.3 Hz, 1H), 4.37 (dd, J = 12, 4.55 Hz, 1H),
.85–3.82 (m, 1H), 3.41 (t, J = 9.72 Hz, 1H), 3.10–3.04 (m, 1H), 2.64–
13
1
3
164.97, 162.02, 144.64, 144.59, 135.64, 134.25, 129.98, 129.92, 126.79,
1
7
.60 (m, 1H), 1.60 (q, J = 12.21 Hz, 1H), 1.22 (s, 9H); C NMR (125
) δ 178.43, 163.26, 161.32, 137.81, 137.80, 135.73, 134.26,
27.55, 127.48, 126.77, 126.61, 124.50, 124.44, 115.37, 115.20, 78.66,
8.02, 76.86, 74.38, 68.38, 63.47, 39.63, 38.99, 36.73, 27.35; HRMS
26.64, 124.50, 124.45, 121.35, 121.33, 114.55, 114.38, 112.95, 112.77,
MHz, CDCl
1
7
3
8.48, 77.96, 74.30, 68.38, 63.39, 39.59, 39.00, 36.64, 27.36; HRMS
+
calcd for C24
H28FO
4
[M + H] 399.1972, found 399.1978.
+
4
calcd for C24H28FO [M + H] 399.1972, found 399.1978.
((2R,4R,4aS,10bS)-2-(3-nitrophenyl)-1,2,4,4a,6,10b-
hexahydropyrano[3,4-c]isochromen-4-yl)methyl pivalate (9j):
o
Yellow solid; m.p. = 116–118 C; Yield 0.11 g, 78%; R
f
= 0.4 (9/1
(
(2R,4R,4aS,10bS)-2-(4-nitrophenyl)-1,2,4,4a,6,10b-
−
1
hexane/EtOAc);
= +22.08° (c = 0.58, CH
869, 1729, 1531, 1480, 1350, 1284, 1164, 1104, 1071, 738; H NMR
Cl
2 2
); IR (νmax/cm ) 2957,
hexahydropyrano[3,4-c]isochromen-4-yl)methyl pivalate (9f):
1
2
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European Journal of Organic Chemistry
10.1002/ejoc.201701172
FULL PAPER
(
500 MHz, CDCl
3
) δ 8.27–7.51 (m, 4H), 7.55–7.02 (m, 4H), 4.95 (d, J =
J = 15.45 Hz, 1H), 4.70 (dd, J = 11.45, 2.3 Hz, 1H), 4.50 (dd, J = 12, 2.3
Hz, 1H), 4.39–4.35 (m, 1H), 3.85–3.82 (m, 1H), 3.42 (t, J = 9.75 Hz, 1H),
3.10–3.05 (m, 1H), 2.66–2.62 (m, 1H), 1.64 (q, J = 12.4 Hz), 1.22 (s, 9H);
C NMR (125 MHz, CDCl ) δ 178.55, 142.02, 135.88, 134.28, 128.48,
3
128.35, 127.68, 126.74, 126.55, 125.86, 124.54, 124.40, 79.32, 78.04,
1
1
3
5.5 Hz, 1H), 4.91 (d, J = 15.45 Hz, 1H), 4.82–4.80 (m, 1H), 4.55 (dd, J =
2.5, 2.3 Hz, 1H), 4.37 (dd, J = 12.05, 5.15 Hz, 1H), 3.89–3.86 (m, 1H),
.42 (t, J = 9.45 Hz, 1H), 3.14–3.09 (m, 1H), 2.73–2.69 (m, 1H), 1.59 (q,
) δ 178.45,
48.41, 144.10, 135.28, 134.20, 131.85, 129.47, 126.85, 126.76, 124.51,
24.47, 122.64, 120.93, 78.06, 77.91, 74.16, 68.39, 63.22, 39.50, 39.03,
6.61, 27.35; HRMS calcd for
48.1731.
13
13
J = 12.4 Hz, 1H), 1.23 (s, 9H); C NMR (125 MHz, CDCl
3
1
1
3
4
77.97, 74.42, 68.38, 63.53, 39.70, 38.99, 36.72, 27.36; HRMS calcd for
+
C
24
H
29
O
4
[M + H] 381.2066, found 381.2064.
+
24 6
C H27NNaO [M + Na] 448.1736, found
((2R,4R,4aS,10bS)-2-(naphthalen-2-yl)-1,2,4,4a,6,10b-
hexahydropyrano[3,4-c]isochromen-4-yl)methyl pivalate (9o):
((2R,4R,4aS,10bS)-2-(2-bromophenyl)-1,2,4,4a,6,10b-
hexahydropyrano[3,4-c]isochromen-4-yl)methyl pivalate (9k):
o
White solid; m.p. = 102–104 C: Yield 0.12 g, 84%; R
f
= 0.6 (9/1
−
1
hexane/EtOAc);
= +32.11° (c = 0.42, CH
2868, 1728, 1479, 1284, 1164, 1105, 745; H NMR (500 MHz, CDCl
7.86–7.83 (m, 4H), 7.53–7.38 (m, 3H), 7.25–7.03 (m, 4H), 4.98 (d, J =
14.9 Hz, 1H), 4.93 (d, J = 14.9 Hz, 1H), 4.89–4.86 (m, 1H), 4.57 (dd, J =
12, 2.25 Hz, 1H), 4.42 (dd, J = 12, 5.15 Hz, 1H), 3.93–3.90 (m, 1H), 3.48
Cl
2 2
); IR (νmax/cm ) 2969,
) δ
1
Pale yellow liquid; Yield 0.14 g, 90%; R
f
1
= 0.8 (9/1 hexane/EtOAc);
=
3
−
+
1
4
30.82° (c = 0.42, CH
284, 1165, 1011, 820, 557; H NMR (400 MHz, CDCl
H), 7.24–7.00 (m, 4H), 5.00–4.88 (m, 3H), 4.51–4.37 (m, 2H), 3.89–3.85
2
Cl
2
); IR (νmax/cm ) 2957, 2928, 2854, 1731, 1479,
1
3
) δ 7.55–7.29 (m,
(
m, 1H), 3.42 (t, J = 9.62 Hz, 1H), 3.13–3.07 (m, 1H), 2.85–2.80 (m, 1H),
(t, J = 9.45 Hz, 1H), 3.17–3.11 (m, 1H), 2.76–2.72 (m, 1H), 1.73 (q, J =
12.4 Hz, 1H), 1.25 (s, 9H); C NMR (125 MHz, CDCl ) δ 178.49, 139.44,
3
135.87, 134.29, 133.38, 133.05, 128.63, 128.20, 127.76, 126.76, 126.59,
126.20, 125.94, 124.55, 124.44, 124.15, 79.32, 78.04, 74.53, 68.41,
1
3
13
1
1
1
3
.41 (q, J = 12.36 Hz, 1H), 1.22 (s, 9H); C NMR (100 MHz, CDCl
3
) δ
78.45, 141.22, 135.76, 134.24, 132.60, 129.01, 127.87, 127.49, 126.73,
26.58, 124.62, 124.39, 121.58, 78.35, 78.05, 74.32, 68.39, 63.42, 39.53,
+
9.00, 34.93, 27.38; HRMS calcd for
C
24
H28BrO
4
[M + H] 459.1171,
63.58, 39.75, 39.04, 36.67, 27.40; HRMS calcd for
NH ] 448.2488, found 448.2485.
4
28 4
C H34NO [M +
+
found 459.1172.
(
(2R,4R,4aS,10bS)-2-(3,5-dichlorophenyl)-1,2,4,4a,6,10b-
((2R,4R,4aS,10bS)-2-styryl-1,2,4,4a,6,10b-hexahydropyrano[3,4-
c]isochromen-4-yl)methyl pivalate (9p):
hexahydropyrano[3,4-c]isochromen-4-yl)methyl pivalate (9l):
Colorless liquid; Yield 0.14 g, 92%; R
f
−
= 0.8 (9/1 hexane/EtOAc);
=
Pale yellow liquid; Yield 0.09 g, 68%; R
f
= 0.7 (9/1 hexane/EtOAc);
=
); IR (νmax/cm ) 2971, 2869, 1728, 1479, 1285,
1165, 1102, 1040; H NMR (400 MHz, CDCl ) δ 7.40–7.00 (m, 9H), 6.66
1
−1
–
1
4
1
17.01° (c = 0.53, CH
163, 1103, 793, 748; H NMR (400 MHz, CDCl
.94 (d, J = 15.12 Hz, 1H), 4.89 (d, J = 15.6 Hz, 1H), 4.64 (dd, J = 11,
.84 Hz, 1H), 4.53 (dd, J = 11.92, 2.28 Hz, 1H), 4.34 (dd, J = 11.92, 5.04
2
Cl
2
); IR (νmax/cm ) 2926, 2853, 1730, 1568, 1283,
2 2
+28.11° (c = 0.33, CH Cl
1
1
3
) δ 7.27–7.00 (m, 7H),
3
(d, J = 16.04 Hz, 1H), 6.27 (dd, J = 16.04, 5.96 Hz, 1H), 4.92 (d, J =
15.12 Hz, 1H), 4.88 (d, J = 15.12 Hz, 1H), 4.50 (dd, J = 11.92, 2.28 Hz,
1H), 4.34–4.29 (m, 2H), 3.78–3.74 (m, 1H), 3.32 (t, J = 9.62 Hz, 1H),
3.02–2.95 (m, 1H), 2.54–2.50 (m, 1H), 1.53 (q, J = 12.22 Hz, 1H), 1.22 (s,
Hz, 1H), 3.83–3.79 (m, 1H), 3.37 (t, J = 9.64 Hz, 1H), 3.08–3.02 (m, 1H),
1
3
2
(
1
6
NH
.65–2.60 (m, 1H), 1.53 (q, J = 12.37 Hz, 1H), 1.22 (s, 9H); C NMR
100 MHz, CDCl ) δ 178.42, 145.34, 135.31, 135.03, 134.18, 127.66,
26.83, 126.72, 124.47, 124.37, 124.41, 77.94, 77.69, 74.17, 68.36,
3.21, 39.46, 39.00, 36.49, 27.35; HRMS calcd for NO [M +
1
3
3
3
9H); C NMR (100 MHz, CDCl ) δ 178.50, 136.77, 135.87, 134.26,
130.68, 129.26, 128.63, 127.78, 126.76, 126.60, 126.55, 124.53, 124.41,
24
C H
30Cl
2
4
77.75, 77.65, 74.55, 68.34, 63.70, 39.38, 38.99, 34.72, 27.36; HRMS
+
+
4
]
466.1552, found 466.1550.
calcd for C26
31
H O
4
[M + H] 407.2222, found 407.2220.
((2R,4R,4aS,10bS)-2-(2,3-dichlorophenyl)-1,2,4,4a,6,10b-
((2R,4R,4aS,10bS)-2-((E)-prop-1-enyl)-1,2,4,4a,6,10b-
hexahydropyrano[3,4c] isochromen -4-yl)methyl pivalate (9m):
hexahydropyrano[3,4-c]isochromen-4-yl)methyl pivalate (9q):
Colorless liquid: Yield 0.14 g, 92%; R
f
= 0.8 (9/1 hexane/EtOAc);
=
); IR (νmax/cm ) 2970, 2870, 1729, 1479, 1283,
164, 1106, 1040; H NMR (400 MHz, CDCl ) δ 7.48–7.01 (m, 7H), 5.06–
Pale yellow liquid; Yield 0.08 g, 70%; R
f
= 0.8 (9/1 hexane/EtOAc);
=
−
1
−1
+
1
5
4
3
30.92 ° (c = 0.41, CH
2
Cl
2
+26.00° (c = 0.21, CH
1256, 1113; H NMR (400 MHz, CDCl
2
Cl
2
); IR (νmax/cm ) 2949, 2921, 2847, 1728, 1361,
) δ 7.25–6.98 (m, 4H), 5.81–5.73
1
1
3
3
.03 (m, 1H), 4.95 (d, J = 15.12 Hz, 1H), 4.90 (d, J = 15.12 Hz, 1H),
.52–4.90 (m, 1H), 4.40 (dd, J = 92, 5.04 Hz, 1H), 3.89–3.85 (m, 1H),
.42 (t, J = 9.84 Hz, 1H), 3.13–3.07 (m, 1H), 2.85–2.80 (m, 1H), 1.39 (q,
(m, 1H), 5.58–5.52 (m, 1H), 4.90 (d, J = 15.56 Hz, 1H), 4.84 (d, J = 15.56
Hz, 1H), 4.44 (dd, J = 11.88, 2.28 Hz, 1H), 4.28–4.23 (m, 1H), 4.10–4.05
(m, 1H), 3.70–3.65 (m, 1H), 3.26 (t, J = 9.64 Hz, 1H), 2.94–2.88 (m, 1H),
2.41–2.36 (m, 1H), 1.71 (d, J = 6.40 Hz, 3H), 1.47–1.38 (m, 1H), 1.19 (s,
1
3
J = 12.21 Hz, 1H), 1.22 (s, 9H); C NMR (100 MHz, CDCl
3
) δ 178.42,
42.08, 135.56, 135.56, 134.21, 132.91, 129.62, 129.36, 127.80, 126.79,
26.65, 125.36, 124.59, 124.42, 78.13, 76.51, 74.30, 68.40, 63.37, 39.50,
1
3
1
1
3
9H); C NMR (100 MHz, CDCl
3
) δ 178.47, 136.04, 134.26, 131.14.
127.82, 126.70, 126.46, 124.52, 124.35, 78.01, 74.52, 68.30, 63.79,
39.29, 38.95, 34.56, 27.33, 17.93; HRMS calcd for C21
+
+
9.00, 34.67, 27.20; HRMS calcd for
24
C H
27Cl
2
O
4
[M + H] 449.1286,
29 4
H O [M + H]
found 449.1283.
345.2066, found 345.2069.
((2R,4R,4aS,10bS)-2-cyclohexyl-1,2,4,4a,6,10b-hexahydropyrano[3,4-
c]isochromen-4-yl)methyl pivalate (9r):
((2R,4R,4aS,10bS)-2-phenyl-1,2,4,4a,6,10b-hexahydropyrano[3,4-
c]isochromen-4-yl)methyl pivalate (9n):
Colorless liquid; Yield 0.09 g, 70%; R
f
−
= 0.9 (9/1 hexane/EtOAc);
=
1
+
17.09° (c = 0.43, CH
2
Cl
2
); IR (νmax/cm ) 2931, 2855, 1730, 1450, 1284,
) δ 7.32–6.97 (m, 4H), 4.87
1
1152, 1099, 746; H NMR (400 MHz, CDCl
3
Pale yellow liquid: Yield 0.10 g, 82%; R
f
1
= 0.6 (9/1 hexane/EtOAc);
=
−
(d, J = 15.56 Hz, 1H), 4.84 (d, J = 16 Hz, 1H), 4.47–4.44 (m, 1H), 4.17
(dd, J = 11.44, 6.4 Hz, 1H), 3.61–3.57 (m, 1H), 3.32–3.28 (m, 1H), 3.18 (t,
J = 9.6 Hz, 1H), 2.86–2.79 (m, 1H), 2.39–2.35 (m, 1H), 1.95–1.43 (m,
+
1
7
2 2
28.88° (c = 0.20, CH Cl ); IR (νmax/cm ) 2958, 2869, 1730, 1480, 1165,
1
105, 1066, 748, 559; H NMR (500 MHz, CDCl
3
) δ 7.40–7.32 (m, 4H),
.30–7.20 (m, 4H), 7.02–7.01 (m, 1H), 4.95 (d, J = 15.45 Hz, 1H), 4.90 (d,
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201701172
FULL PAPER
1
3
6
H), 1.34–1.22 (m, 3H), 1.19 (s, 9H), 1.18–0.99 (m, 3H); C NMR (125
3H), 6.96–6.91 (m, 1H), 5.05 (dd, J = 15.56, 1.84 Hz, 1H), 4.91–4.85 (m,
2H), 4.54 (dd, J = 11.88, 2.28 Hz, 1H), 4.44 (dd, J = 11.92, 4.56 Hz, 1H),
MHz, CDCl
3
) δ 178.48, 136.45, 134.30, 126.64, 126.37, 124.50, 124.32,
8
2
1.63, 77.68, 75.16, 68.27, 64.04, 42.74, 39.43, 38.92, 30.99, 29.07,
4.09–4.05 (m, 1H), 3.66 (t, J = 10.52 Hz, 1H), 3.58 (t, J = 9.34 Hz, 1H),
+
13
7.33, 26.64, 26.31, 26.18; HRMS calcd for C24
H
35
O
4
[M + H] 387.2535,
3.08 (dt, J = 14.24, 2.28 Hz, 1H), 1.58–1.41 (m, 1H), 1.26 (s, 9H);
C
found 387.2533.
NMR (125 MHz, CDCl ) δ 178.39, 163.93, 161.98, 144.38, 144.32,
3
1
1
7
33.68, 133.17, 131.64, 130.47, 129.98, 129.91, 129.17, 127.40, 125.75,
25.21, 124.25, 122.73, 121.57, 121.55, 114.66, 114.49, 113.15, 112.97,
(
(2S,4R,10bS)-2-propyl-1,2,4,4a,6,10b-hexahydropyrano[3,4-
8.97, 77.82, 70.28, 63.48, 40.12, 39.48, 39.06, 27.42; HRMS calcd for
c]isochromen-4-yl)methyl pivalate (9s):
+
C
28
H
30FO
4
[M + H] 449.2128, found 449.2125.
Pale yellow liquid; Yield 0.08 g, 70%; R
f
1
= 0.9 (9/1 hexane/EtOAc);
=
−
((2R,4R,12cS)-2-(3,5-dichlorophenyl)-1,2,4,4a,6,12c-
hexahydrobenzo[f]pyrano[3,4-c]isochromen-4-yl)methyl
+
1
4
1
21.12° (c = 0.39, CH
285, 1167, 1142, 1095, 747; H NMR (400 MHz, CDCl
H), 4.89 (d, J = 15.6 Hz, 1H), 4.85 (d, J = 15.68 Hz, 1H), 4.49–4.45 (m,
H), 4.17 (dd, J = 11.44, 6.4 Hz, 1H), 3.67–3.55 (m, 2H), 3.19 (t, J = 9.68
2 2
Cl ); IR (νmax/cm ) 2959, 2870, 1730, 1459, 1480,
1
pivalate
3
) δ 7.20–6.97 (m,
(11b):
o
Hz, 1H), 2.89–2.83 (m, 1H), 2.36–2.31 (m, 1H), 1.59–1.40 (m, 4H), 1.38–
Compound 11b was isolated as a white solid; m.p. = 93–95 C; Yield
0.11 g, 80%; R = 0.7 (9/1 hexane/EtOAc); = –9.06° (c = 1.22,
CH Cl ); IR (νmax/cm ) 2950, 2924, 1729, 1569, 1283, 1164, 1105, 1073;
H NMR (400 MHz, CDCl ) δ 8.31–7.57 (m, 5H), 7.53–7.08 (m, 4H),
13
1
.24 (m, 1H), 1.20 (s, 9H), 0.93 (t, J = 6.84 Hz, 3H); C NMR (100 MHz,
CDCl ) δ 178.47, 136.31, 134.27, 126.65, 126.39, 124.47, 124.32, 77.63,
5.17, 68.27, 64.15, 39.49, 38.92, 37.96, 34.25, 27.31, 18.96, 14.12;
f
−
1
3
2
2
1
7
3
+
HRMS calcd for C21
H
31
O
4
[M + H] 347.2222, found 347.2226.
5.07–5.02 (m, 1H), 4.97 (d, J = 1.84 Hz, 1H), 4.88–4.82 (m, 2H), 4.56 (dd,
J = 11.88, 2.28 Hz, 1H), 4.42 (dd, J = 11.92, 4.6 Hz, 1H), 4.07–4.03 (m,
1
H), 3.64 (t, J = 10.32 Hz, 1H), 3.55 (t, J = 9.38 Hz, 1H), 3.05 (dt, J =
(
1
(4'R,10b'S)-4',4a',6',10b'-tetrahydro-1'H-spiro[cyclohexane-
,2'pyrano[3,4c] isochromene-4'-yl)methyl pivalate (9t):
13
1
4.2, 2.28 Hz, 1H), 1.44 (q, J = 11.44 Hz, 1H), 1.26 (s, 9H); C NMR
) δ 178.40, 145.08, 137.08, 134.99, 133.67, 133.16,
32.26, 131.55, 130.14, 129.22, 128.26, 128.06, 127.80, 127.61, 127.49,
(100 MHz, CDCl
3
1
Colorless liquid; Yield 0.08 g, 68%; R
f
= 0.9 (9/1 hexane/EtOAc);
= –
); IR (νmax/cm ) 2931, 2855, 1730, 1450, 1284,
152, 1099, 746; H NMR (400 MHz, CDCl ) δ 7.20–7.15 (m, 4H), 6.98–
.96 (m, 1H), 4.91–4.83 (m, 2H), 4.49 (dd, J = 11.92, 2.28 Hz, 1H), 4.09
−
1
127.03, 126.66, 126.06, 125.88, 125.26, 124.62, 124.16, 122.70, 78.20,
77.77, 77.67, 70.28, 65.99, 63.28, 40.00, 39.29, 39.06, 29.79, 27.42;
HRMS calcd for C28
7
1
6
2 2
.88° (c = 0.43, CH Cl
1
3
+
H
2
29Cl O
4
[M + H] 499.1443, found 499.1447.
(
dd, J = 11.88, 7.32 Hz, 1H), 3.83–3.78 (m, 1H), 3.12–3.03 (m, 2H),
(
(2S,4R,4aS,12cS)-2-propyl-1,2,4,4a,6,12c-
hexahydrobenzo[f]pyrano[3,4-c]isochromen-4-yl)methyl
11c):
2
1
1
3
.27–2.21 (m, 1H), 1.72–1.35 (m, 6H), 1.32–1.24 (m, 4H), 1.21–1.18 (m,
13
pivalate
3
0H); C NMR (100 MHz, CDCl ) δ 178.52, 136.75, 134.45, 126.60,
(
26.30, 124.36, 124.31, 76.04, 73.05, 70.25, 68.24, 64.77, 39.87, 38.91,
8.81, 34.80, 30.36, 29.77, 27.35, 26.26, 21.79, 21.25; HRMS calcd for
+
C
23
H
33
O
4
[M + H] 373.2379, found 373.2371.
f
Compound 11c was isolated as a colorless liquid; Yield 0.06 g, 53%; R =
0
2
−
1
.8 (9/1 hexane/EtOAc);
= +10.01° (c = 1.11, CH
2
Cl
2
); IR (νmax/cm
)
1
949, 2870, 1729, 1469, 1470, 1285, 1167, 1142, 1075, 749; H NMR
(
(1R,3R,4aS,12aS)-3-p-tolyl-1,3,4,4a,11,12a-
hexahydrobenzo[h]pyrano[3,4-c]isochromen-1-yl)methyl
10):
(400 MHz, CDCl
3
) δ 7.95–7.65 (m, 3H), 7.49–7.40 (m, 2H), 7.07 (d, J =
pivalate
8
.4 Hz, 1H), 5.01 (dd, J = 15.36, 2.16 Hz, 1H), 4.81 (dd, J = 15.4, 1.12
(
Hz, 1H), 4.52 (dd, J = 11.72, 2.2 Hz, 1H), 4.26 (q, J = 5.84 Hz, 1H), 3.90–
.85 (m, 1H), 3.82–3.77 (m, 1H), 3.47 (t, J = 10.24 Hz, 1H), 3.37 (t, J =
9.52 Hz, 1H), 2.81 (dd, J = 13.92, 2.16 Hz, 1H), 1.55–1.37 (m, 5H), 1.23
3
Following the typical procedure C for the Prins reaction, compound 8 was
o
isolated as a white solid; m.p. = 156–158 C; Yield 0.09 g, 73%; R
f
= 0.7
); IR (νmax/cm ) 2924,
853, 1729, 1457, 1284, 1159, 1113, 811; H NMR (400 MHz, CDCl ) δ
.83–7.46 (m, 4H), 7.37–7.17 (m, 6H), 5.44 (d, J = 12.36 Hz, 1H), 5.30 (d,
13
−
1
(s, 9H), 0.92 (t, J = 6.76 Hz, 3H); C NMR (125 MHz, CDCl
3
) δ 178.47,
(9/1 hexane/EtOAc);
2 2
= +2.89° (c = 0.23, CH Cl
1
133.61, 133.15, 131.75, 131.14, 129.08, 127.14, 125.51, 125.11, 124.47,
2
7
3
1
22.74, 78.76, 77.47, 70.21, 64.15, 39.46, 38.98, 37.89, 27.36, 18.93,
+
33 4
14.16; HRMS calcd for C25H O [M + H] 397.2379, found 397.2376.
J = 11.44 Hz, 1H), 4.72 (d, J = 8.36 Hz, 1H), 4.55–4.53 (m, 1H), 4.43 (dd,
J = 9.04, 3.92 Hz, 1H), 3.92–3.89 (m, 1H), 3.50 (t, J = 7.56 Hz, 1H), 3.23
(
(2R,4R,4aS,10bS)-2-((E)-prop-1-enyl)-1,2,4,4a,6,10b-
(
t, J = 9.26 Hz, 1H), 2.73–2.70 (m, 1H), 2.35 (s, 3H), 1.66 (q, J = 9.81 Hz,
H), 1.23 (s, 9H); C NMR (125 MHz, CDCl ) δ 178.46, 139.07, 137.42,
3
33.18, 131.96, 129.25, 129.16, 128.83, 128.78, 127.20, 126.68, 125.87,
13
hexahydropyrano[3,4-c]isochromen-4-yl)methanol (12):
1
1
1
3
4
25.70, 122.59, 121.62, 79.36, 77.91, 74.52, 67.15, 63.57, 39.88, 39.01,
Compound 9q (1.00 g, 2.90 mmol) was dissolved in dry MeOH (15 mL)
and cooled to 0 °C. To this solution was added a catalytic amount of
NaOMe (0.01 g, 0.29 mmol) at 0 °C. The mixture was stirred for 12 h at
room temperature and after completion of reaction (monitoring by TLC)
methanol was evaporated, extracted with ethyl acetate (2 x 15 mL) and
washed with water (1 x 10 mL) and brine (1 x 10 mL). Evaporation of the
solvent followed by purification using silica gel column chromatography
+
7.00, 27.38, 21.23; HRMS calcd for C29
H
33
O
4
[M + H] 445.2379, found
45.2370.
Following the typical procedure ‘C’ for the Prins reaction
compounds ‘11a-11c’ were prepared.
gave 12 as a colorless liquid. Yield 0.70 g, 93%;
hexane/EtOAc); = +17.18° (c = 1.03, CH Cl ); IR (νmax/cm ); 2949,
921, 2848, 1361, 1216, 1103; H NMR (400 MHz, CDCl ) δ 7.22–6.97
m, 4H), 5.84–5.75 (m, 1H), 5.59–5.53 (m, 1H), 4.92 (d, J = 16.96 Hz,
f
R = 0.3 (9/1
(
(2R,4R,4aS,12cS)-2-(3-fluorophenyl)-1,2,4,4a,6,12c-
hexahydrobenzo[f]pyrano[3,4-c]isochromen-4-yl)methyl
11a):
−
1
2
2
pivalate
1
2
(
3
(
1
3
2
3
H), 4.88 (d, J = 15.6 Hz, 1H), 4.13–4.09 (m, 1H), 3.94–3.89 (m, 1H),
.81–3.75 (m, 1H), 3.57–3.53 (m, 1H), 3.28 (t, J = 9.62 Hz, 1H), 2.95–
Compound 11a was isolated as a pale yellow liquid; Yield 0.10 g, 80%; R
0.7 (9/1 hexane/EtOAc); +51.62° (c 0.49, CH Cl ); IR
max/cm ) 2957, 2925, 1730, 1592, 1284, 1166, 1104, 1068; H NMR
400 MHz, CDCl ) δ 7.98–7.67 (m, 3H), 7.51–7.24 (m, 3H), 7.16–7.09 (m,
f
=
=
=
2
1
2
.88 (m, 1H), 2.42–2.37 (m, 1H), 2.25 (bs, 1H), 1.72 (dd, J = 6.4, 0.92 Hz,
−
1
(ν
13
3
H), 1.43 (q, J = 12.37 Hz, 1H); C NMR (100 MHz, CDCl ) δ 135.92,
(
3
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201701172
FULL PAPER
1
1
7
34.16, 131.15, 128.19, 126.70, 126.45, 124.48, 124.34, 79.16, 78.11,
5.36, 68.21, 63.18, 39.10, 34.58, 17.93; HRMS calcd for 20NaO
3
2833, 1731, 1492, 1370, 1240, 1097, 901; H NMR (400 MHz, CDCl ) δ
16
C H
3
7.27–6.99 (m, 4H), 6.11 (d, J = 10.08 Hz, 1H), 5.88–5.83 (m, 1H), 5.38 (t,
J = 4.34 Hz, 1H), 5.02–4.94 (m, 2H), 3.90–3.86 (m, 1H), 3.02 (t, J = 11
Hz, 1H), 2.68–2.55 (m, 1H), 2.07 (s, 3H), 1.78–1.70 (m, 1H); C NMR
125 MHz, CDCl ) δ 170.66, 136.10, 135.06, 134.78, 126.64, 126.47,
25.98, 124.51, 124.40, 75.66, 69.05, 66.59, 34.58, 29.95, 21.40; HRMS
+
[
M + Na] 283.1310, found 283.1312.
13
(
3
(R,E)-1-((3R,4S)-3-vinylisochroman-4-yl)pent-3-en-2-ol (13):
1
+
17 3
calcd for C15H O [M + H] 245.1178, found 245.1179.
A solution of 12 (0.30 g, 1.15 mmol) in dry toluene (5 mL), under nitrogen
atmosphere, was treated with triphenylphosphine (0.72 g, 2.76 mmol),
imidazole (0.18 g, 2.76 mmol) and iodine (0.43 g, 1.72 mmol) at reflux.
After 30 min the mixture was cooled, and the mixture was washed with
(
2R,3R,4S,4aS,10bS)-3,4-dihydroxy-2,3,4,4a,6,10b-hexahydro-1H-
benzo[c]chromen-2-yl acetate (16):
1
0% aq solution of NaHCO
3
(1 x 3 mL) and brine (1 x 3 mL). The organic
SO and the solvent
t
phase was separated, dried over anhydrous Na
2
4
The diene 15 (0.10 g, 0.40 mmol) was dissolved in BuOH/acetone/H
solvent system (1:3:1, 5 mL), and N-methyl morpholine N-oxide (0.07 g,
0.61 mmol) followed by OsO (0.04 mmol) were added in succession,
and the resulting mixture was stirred at room temperature for 18 h. Then
saturated Na solution (5 mL) was added, and the mixture stirred for
1 h. Compound was extracted with EtOAc (3 × 5 mL), and the extracts
were dried (Na SO ) and concentrated. The residue was purified by
column chromatography to obtain 16 as a colorless liquid: Yield 0.09 g,
0.3 (5/5 hexane/EtOAc); +30.03 (c = 1.20, CH Cl ); IR
(νmax/cm ) 3543, 2931, 2884, 1729, 1567, 1454; H NMR (500 MHz,
CDCl ) δ 7.23–6.98 (m, 4H), 5.23 (q, J = 2.85 Hz, 1H), 4.96–4.90 (m, 2H),
2
O
evaporated. The crude product was filtered through silica gel and used
without any further purification. The crude iodo compound (0.30 g, 1.15
mmol) in dry EtOH (5 mL) was added zinc dust (1.39 g, 23.06 mmol).
The mixture was refluxed for 2 h and cooled to room temperature.
Addition of solid NH Cl (0.20 g) and diethyl ether (2 mL) followed by
4
stirring for 10 min gave a gray suspension. The suspension was filtered
through a pad of celite and the filtrate concentrated and purified through
silica gel column chromatography to give 13 as a colorless liquid; Yield
0
4
2 2 5
S O
2
4
®
R
f
=
=
2
2
−
1
1
.20 g, 72%; R
f
= 0.2 (9/1 hexane/EtOAc);
= +11.21° (c = 0.41,
−
1
CH Cl ); IR (νmax/cm ) 3414, 2934, 2853, 1492, 1452, 1375, 1032, 966,
2
2
3
1
7
5
1
4
1
48; H NMR (400 MHz, CDCl
3
) δ 7.30–6.94 (m, 4H), 5.91–5.83 (m, 1H),
4.13 (t, J = 2.85 Hz, 1H), 3.95–3.92 (m, 1H), 3.63 (t, J = 10.02 Hz, 1H),
3.01–2.96 (m, 1H), 2.43 (dt, J = 14.6, 2.85 Hz, 1H), 2.09 (s, 3H), 1.91–
3
) δ 169.96, 135.54, 134.23,
126.86, 126.40, 125.27, 124.34, 77.83, 71.79, 71.17, 70.01, 68.64, 33.96,
.66–5.46 (m, 2H), 5.28 (dt, J = 17.4, 1.36 Hz, 1H), 5.18 (dt, J = 10.56,
.33 Hz, 1H), 4.80 (d, J = 15.12 Hz, 1H), 4.74 (d, J = 15.56 Hz, 1H),
.35–4.32 (m, 1H), 4.18–4.13 (m, 1H), 2.97–2.93 (m, 1H), 1.99–1.92 (m,
1
3
1.85 (m, 1H); C NMR (125 MHz, CDCl
13
+
H), 1.87–1.80 (m, 1H), 1.66 (dd, J = 6.4, 0.92 Hz, 3H); C NMR (125
) δ 136.69, 136.00, 134.42, 134.12, 129.28, 127.04, 126.46,
26.18, 124.20, 118.43, 77.81, 70.89, 63.90, 42.55, 37.81, 17.73; HRMS
27.53, 21.27; HRMS calcd for
279.1226.
15 19 5
C H O [M + H] 279.1232, found
MHz, CDCl
1
calcd for C16
3
+
2
H20NaO [M + Na] 267.1361, found 267.1363.
(
(2R,4R,4aS,10bS)-2-phenyl-1,2,4,4a,6,10b-hexahydropyrano[3,4-
c]isochromen-4-yl)methanol (17):
(R,E)-1-((3R,4S)-3-vinylisochroman-4-yl)pent-3-en-2-yl acetate (14):
Following the same procedure as was used for 12, compound 9n (1.00 g,
2.63 mmol) gave 17 as a colorless liquid; Yield 0.65 g, 83%; R = 0.3 (9/1
To a solution of alcohol 13 (0.10 g, 0.40 mmol) in dry dichloromethane
1.5 mL) at 0 °C was added triethylamine (69 µL, 0.49 mmol), acetic
anhydride (42 µL, 0.45 mmol), and catalytic amount of 4-
f
−
1
(
hexane/EtOAc);
= +8.18° (c = 1.43, CH
2
Cl
2
); IR (νmax/cm ) 3467,
) δ 7.41–
1
a
2917, 2854, 1492, 1302, 1200, 1090; H NMR (400 MHz, CDCl
3
dimethylaminopyridine (0.05 g, 0.04 mmol). The reaction mixture was
stirred for 1 h and after completion of reaction, quenched with aq.
NaHCO solution (5 mL) and extracted with ethyl acetate (2 x 10 mL).
3
The extract was washed with water (1 x 10 mL) followed by brine (10 mL)
and the solvent concentrated under reduced pressure to afford a residue
which was purified by column chromatography to furnish the
corresponding acetylated compound 14 as colorless liquid; Yield 0.10 g,
7.28 (m, 5H),7.21–7.00 (m, 4H), 4.99–4.91 (m, 2H), 4.71 (dd, J = 11.48,
2.28 Hz, 1H), 3.99 (dd, J = 11.44, 3.68 Hz, 1H), 3.85 (dd, J = 11.44, 5.52
Hz, 1H), 3.74–3.69 (m, 1H), 3.41 (t, J = 9.64 Hz, 1H, ), 3.11–3.05 (m, 1H),
13
2.64–2.59 (m, 1H), 1.68 (q, J = 12.32 Hz, 1H); C NMR (100 MHz,
CH Cl ) δ 141.73, 135.69, 134.06, 128.52, 127.92, 126.68, 126.49,
126.27, 124.43, 124.33, 79.70, 79.61, 75.30, 68.22, 63.21, 39.50, 36.50;
2
2
+
3 4
HRMS calcd for C19H24NO [M+NH ] 314.1756, found 314.1755.
9
2%; R
f
= 0.5 (9/1 hexane/EtOAc);
= +32.12° (c = 0.32, CH
max/cm ) 2936, 2853, 1736, 1493, 1450, 1371, 1240, 1019, 931;
NMR (400 MHz, CDCl ) δ 7.19–6.94 (m, 4H), 5.91–5.83 (m,1H), 5.73–
.65 (m, 1H), 5.44–5.28 (m, 2H), 5.21 (dt, J = 10.56, 1.36 Hz, 1H), 4.78
2 2
Cl ); IR
−
1
1
(ν
H
3
5
(
(
d, J = 15.12 Hz, 1H), 4.74 (d, J = 15.12 Hz, 1H), 4.34–4.30 (m, 1H), 2.78
q, J = 5.34 Hz, 1H), 2.20–2.07 (m, 1H), 1.95 (s, 3H), 1.95 (s, 3H), 1.92–
(
R)-1-phenyl-2-((3R,4S)-3-vinylisochroman-4-yl)ethanol (18):
1
1
7
.83 (m, 1H), 1.66 (dd, J = 6.88, 1.36 Hz, 3H), 1.27–1.20 (m, 1H); 170.39,
36.61, 135.71, 134.61, 129.68, 128.85, 126.68, 126.24, 124.24, 118.62,
Following the same procedure as was used for 13, compound 17 (0.70 g,
2.49 mmol) gave 18 as a colorless liquid; Yield 0.65 g, 68%; R = 0.4 (9/1
hexane/EtOAc);
7.94, 77.69, 73.15, 69.25, 64.33, 39.54, 37.94, 21.34, 17.80; HRMS
+
calcd for C18
H
23
O
3
[M + H] 287.1647, found 287.1649.
f
−
1
= +7.72° (c = 0.42, CH
923, 2853, 1492, 1453, 1375, 1204, 1059; H NMR (400 MHz, CDCl ) δ
2
Cl
2
); IR (νmax/cm ) 3418,
1
2
7
1
4
1
1
7
3
3
(2R,4aR,10bS)-2,4a,6,10b-tetrahydro-1H-benzo[c]chromen-2-yl
.34–7.22 (m, 5H), 7.18–6.96 (m, 4H), 5.90–5.82 (m, 1H), 5.25 (dt, J =
7.4, 1.36 Hz, 1H), 5.18 (dt, J = 10.52, 1.36 Hz, 1H), 4.81–4.71 (m, 3H),
acetate (15):
.33–4.31 (m, 1H), 3.02–2.97 (m, 1H), 2.27–2.20 (m, 1H), 2.06–2.00 (m,
The diene 14 (0.15 g , 0.52 mmol) was dissolved in dry CH
2
Cl
2
(4 mL),
13
2 2
H); C NMR (100 MHz, CH Cl ) δ 144.86, 136.56, 135.81, 134.11,
and Grubbs’ second generation catalyst (0.02 g, 0.05 mmol) was added
to it. The solution was refluxed for 4 h, and the solvent removed under
vacuum. The crude residue was purified by column chromatography
gave 15 (0.10 g, 83%) as
hexane/EtOAc); = +16.10 (c = 1.20, CH
29.28, 128.65, 127.80, 126.51, 126.28, 126.01, 124.29, 118.57, 77.67,
+
2.44, 63.81, 44.50, 38.10; HRMS calcd for
03.1361, found 303.1367.
19 2
C H20NaO [M + Na]
a
pale yellow liquid;
f
R = 0.4 (9/1
−
1
2
Cl ); IR (νmax/cm ) 2930,
2
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201701172
FULL PAPER
(
2R,4aS,10bS)-2-phenyl-1,2,4,4a,6,10b-hexahydropyrano[3,4-
Pale yellow liquid; Yield 0.13 g, 80%; R
f
= 0.5 (only hexane);
); IR (νmax/cm ) 2961, 2834, 1731, 1480, 1365,
284, 1164; H NMR (400 MHz, CDCl ) δ 7.26–7.18 (m, 4H), 5.81–5.80
m, 1H), 4.52–4.50 (m, 1H), 4.43 (dd, J = 11.92, 2.28 Hz, 1H), 4.28–4.20
(m, 3H), 3.75–3.71 (m, 1H), 3.25 (t, J = 9.6 Hz, 1H), 2.92–2.85 (m, 1H),
=
−
1
c]isochromen-4-yl acetate (19):
2 2
+31.11° (c = 0.42, CH Cl
1
1
3
(
Following the same procedure as was used for 16, the crude diol was
dissolved in THF:H
o
2
O (2:1, 3 mL) and cooled to 0 C. To this cooled
2
6
1
3
.61–2.55 (m, 1H), 2.06–2.02 (m, 1H), 1.59–1.49 (m, 1H), 1.25–1.23 (m,
solution was added NaIO
the mixture was filtered, extracted with dichloromethane (2 x 10 mL) and
washed with brine (10 mL). Extract was evaporated and the crude
product was acetylated following
acetylating 14, gave 19 as a white solid (m.p. = 169–171 C); Yield 0.08
4
in two portions. After completion of reaction,
1
3
H), 1.24 (s, 9H); C NMR (100 MHz, CDCl
29.89, 126.51, 125.84, 125.56, 79.02, 77.31, 74.79, 69.26, 63.43, 39.65,
8.98, 38.16, 33.93, 27.38, 24.11, 24.08; HRMS calcd for C23 32ClO [M
3
) δ 178.30, 148.41, 138.80,
H
4
a procedure, as was used for
+
o
+ H] 407.1989, found 407.1982.
−
1
g, 71%; R
f
= 0.7 (9/1 hexane/EtOAc); IR (νmax/cm ) 2915, 1753, 1372,
1
1
226, 1104; H NMR (400 MHz, CDCl
3
, 1:1 ) δ 7.42–7.00 (m, 18H, both
((4aS,6R,8R,8aS)-3-chloro-6-(4-(trifluoromethyl)phenyl)-2,4a,5,6,8,8a
hexahydropyrano [3,4-b]pyran-8-yl)methyl pivalate (21c):
isomers), 6.51 (d, J = 3.24 Hz, 1H, one isomer), 5.96 (d, J = 7.8 Hz, 1H,
another isomer), 5.10 (dd, J = 11.92, 2.32 Hz, 1H, one isomer), 5.00–
4
.92 (m, 4H, both isomers), 4.88 (dd, J = 11.44, 1.84 Hz, 1H, another
Pale yellow liquid; Yield 0.15 g, 88%; R
f
= 0.5 (only hexane);
); IR (νmax/cm ) 2973, 2873, 1730, 1480, 1325;
H NMR (400 MHz, CDCl ) δ 7.58–7.41 (m, 4H), 5.79 (d, J = 2.08 Hz,
=
isomer), 3.73 (dd, J = 10.52, 3.24 Hz, 1H, one isomer), 3.52–3.44 (m, 2H,
both isomers), 3.21–3.14 (m, 1H, one isomer), 2.68–2.59 (m, 2H, both
isomers), 2.19 (s, 3H, one isomer), 2.18 (s, 3H, another isomer), 1.79–
1
1
1
9
3
3
−1
+
2 2
53.68° (c = 0.41, CH Cl
1
3
1
1
3
2
H), 4.60–4.57 (m, 1H), 4.44 (dd, J = 11.92, 2.28 Hz, 1H), 4.27 (dd, J =
1.92, 5.04 Hz, 1H), 4.20 (d, J = 1.84 Hz, 1H), 4.19 (d, J = 1.84 Hz, 1H),
.76–3.72 (m, 1H), 3.24 (t, J = 9.16 Hz, 1H), 2.63–2.56 (m, 1H), 2.09–
13
2 2
.66 (m, 2H, both isomers); C NMR (100 MHz, CH Cl ) δ 169.75,
40.97, 140.39, 135.48, 135.06, 134.08, 133.99, 128.58, 128.12, 127.98,
26.87, 126.73, 126.60, 126.24, 126.12, 124.79, 124.65, 124.43, 94.42,
13
.04 (m, 1H), 1.50–1.40 (m, 1H), 1.21 (s, 9H); C NMR (100 MHz,
0.78, 78.31, 76.26, 75.31, 73.67, 68.66, 68.2138.68, 36.51, 35.70,
3
CDCl ) δ 178.31, 145.41, 130.11, 129.97, 125.92, 125.40, 125.37,
+
3.06, 21.34; HRMS calcd for C20
47.1264.
H
20NaO
4
[M + Na] 347.1259, found
1
25.10, 78.16, 77.32, 74.53, 69.22, 63.14, 39.46, 38.96, 38.29, 27.29;
+
3 4
HRMS calcd for C21H25ClF O [M + H] 433.1393 found 433.1397.
((2R,3S,4S,6S)-3-hydroxy-6-propyl-4-o-tolyltetrahydro-2H-pyran-2-
((4aS,6R,8R,8aS)-6-(4-bromophenyl)-3-chloro-2,4a,5,6,8,8a-
yl)methyl pivalate (20):
hexahydropyrano[3,4-b]pyran-8-yl)methyl pivalate (21d):
A solution of 9s/9q (0.10 g, 0.28 mmol) in dry methanol was stirred under
Pale yellow liquid; Yield 0.16 g, 89%; R
f
= 0.5 (only hexane);
); IR (νmax/cm ) 3483, 3293, 2975, 2116, 1728, 1481,
286; H NMR (400 MHz, CDCl ) δ 7.44–7.16 (m, 4H), 5.78 (d, J = 1.84
Hz, 1H), 4.50–4.47 (m, 1H), 4.41 (dd, J = 11.92, 2.28 Hz. 1H), 4.25 (dd, J
11.92, 5.04 Hz, 1H), 4.19 (d, J = 1.84 Hz, 1H), 4.18 (d, J = 1.84 Hz, 1H),
.74–3.70 (m, 1H), 3.23–3.19 (m, 1H), 2.60–2.53 (m, 1H), 2.04–1.99 (m,
= +8.26°
H
2
atmosphere in the presence of 10% Pd/C (0.01 g) for 15 h. After
−1
(
1
2 2
c = 0.26, CH Cl
completion of reaction, the reaction mixture was filtered through a pad of
1
3
®
celite and the filtrate concentrated. The residue was purified through
silica gel chromatography to give pure compound 20 as a pale yellow
=
liquid; Yield 0.08 g, 81%; R
f
1
= 0.2 (9/1 hexane/EtOAc);
= –12.01° (c =
3
1
1
7
−
0
1
4
.15, CH
170, 1097; H NMR (400 MHz, CDCl
.12 Hz, 2H), 3.61–3.48 (m, 3H), 3.10–3.04 (m, 1H), 2.37 (s, 3H), 2.11 (d,
2
Cl
2
1
); IR (νmax/cm ) 3473, 2932, 2871, 1729, 1480, 1367, 1286,
13
3
H), 1.49–1.39 (m, 1H), 1.20 (s, 9H); C NMR (125 MHz, CDCl ) δ
78.30, 140.49, 131.53, 130.05, 127.42, 125.21, 121.48, 78.24, 77.31,
3
) δ 7.20–7.10 (m, 4H), 4.36 (d, J =
4.65, 69.24, 63.23, 39.49, 38.97, 38.25, 27.32; HRMS calcd for
J = 2.11 Hz, 1H), 1.79–1.74 (m,1H), 1.56–1.34 (m, 4H), 1.23 (s, 9H), 0.90
+
C
20
H
25BrClO
4
[M + H] 443.0625, found 443.0624.
13
(
t, J = 7.1 Hz, 3H); C NMR (125 MHz, CDCl
3
) δ 179.00, 140.12, 137.01,
1
3
3
30.75, 126.67, 126.63, 125.62, 79.78, 77.35, 71.41, 64.67, 44.73, 38.96,
(
(4aS,6R,8R,8aS)-3-chloro-6-o-tolyl-2,4a,5,6,8,8a-
+
7.73, 27.31, 19.89, 18.90, 14.10; HRMS calcd for C21
49.2379, found 349.2376.
33 4
H O [M + H]
hexahydropyrano[3,4-b]pyran-8-yl)methyl pivalate (21e):
Pale yellow liquid; Yield 0.12 g, 81%; R
f
= 0.5 (only hexane);
); IR (νmax/cm ) 2971, 2871, 1729, 1480, 1285, 1165,
082; H NMR (400 MHz, CDCl ) δ 7.39–7.13 (m, 4H), 5.82 (d, J = 1.4
Hz, 1H), 4.68 (dd, J = 11, 1.84 Hz, 1H), 4.43 (dd, J = 11.92, 2.28 Hz, 1H),
= +5.41°
Following the typical procedure ‘D’ for the Prins reaction,
compounds ‘21a-21p’ were prepared.
−1
(
1
2 2
c = 0.26, CH Cl
1
3
(
(4aS,6R,8R,8aS)-3-chloro-6-p-tolyl-2,4a,5,6,8,8a-
4
2
9
.26–4.20 (m, 3H), 3.78–3.74 (m, 1H), 3.27 (t, J = 9.16 Hz, 1H), 2.63–
hexahydropyrano[3,4-b]pyran-8-yl)methyl pivalate (21a):
.56 (m, 1H), 2.37 (s, 3H), 2.03–1.98 (m, 1H), 1.65–1.56 (m,1H), 1.23 (s,
1
3
3
H); C NMR (100 MHz, CDCl ) δ 178.36, 139.02, 135.17, 130.57,
Pale yellow liquid; Yield 0.13 g, 83%; R
f
= 0.5 (only hexane);
); IR (νmax/cm ) 3483, 3293, 2975, 2116, 1728,
481, 1286; H NMR (500 MHz, CDCl ) δ 7.21–7.12 (m, 4H, ArH), 5.79
=
129.92, 127.80, 126.25, 125.62, 125.53, 77.53, 74.80, 69.28, 63.63,
−
1
+
+
1
32.21° (c = 0.42, CH
Cl
2 2
4
39.77, 38.96, 36.20, 27.38, 19.26; HRMS calcd for C21H28ClO [M + H]
1
3
379.1676 found 379.1678.
(
d, J = 1.7 Hz, 1H, H-7), 4.51–4.90 (m, 1H, H-1), 4.42 (dd, J = 14.9, 2.85
Hz, 1H, H-6), 4.25 (dd, J = 14.85, 6.3 Hz, 1H, H-6′), 4.20–4.19 (m, 2H, H-
,8′), 3.75–71 (m, 1H, H-5), 3.26–3.22 (m, 1H, H-4), 2.60–2.55 (m, 1H,
H-3), 2.32 (s, 3H, -CH ), 2.04–2.00 (m, 1H, H-2′), 1.56–1.47 (m, 1H, H-2),
.22 (s, 9H, Piv); C NMR (100 MHz, CDCl ) δ 178.37, 138.48, 137.43,
29.87, 129.11, 125.74, 125.51, 78.96, 77.25, 74.77, 69.26, 63.41, 39.62,
((4aS,6R,8R,8aS)-6-(2-bromophenyl)-3-chloro-2,4a,5,6,8,8a-
8
hexahydropyrano[3,4-b]pyran-8-yl)methyl pivalate (21f):
3
13
1
1
3
3
3
Pale yellow liquid; Yield 0.16 g, 89%; R
f
= 0.5 (only hexane);
); IR (νmax/cm ) 3489, 3296, 2975, 2116, 1728,
480; H NMR (400 MHz, CDCl ) δ 7.49–7.08 (m, 4H), 5.78 (d, J = 1.8
Hz, 1H), 4.82–4.79 (m, 1H), 4.41 (dd, J = 11.92, 2.28 Hz, 1H), 4.20 (d, J
1.84 Hz, 1), 4.19 (d, J = 1.84 Hz, 1), 3.78–3.74 (m, 1H), 3.25 (t, J =
.64 Hz, 1H), 2.63–2.57 (m, 1H), 2.25–2.20 (m, 1H), 1.32–1.78 (m, 1H),
=
−1
+
1
2 2
19.33° (c = 0.51, CH Cl
+
8.98, 38.26, 27.34, 21.21; HRMS calcd for
79.1676, found 379.1674.
C
21
H28ClO
4
[M
+
H]
1
3
=
((4aS,6R,8R,8aS)-3-chloro-6-(4-isopropylphenyl)-2,4a,5,6,8,8a-
9
1
hexahydropyrano[3,4-b]pyran-8-yl)methyl pivalate (21b):
13
3
.21 (s, 9H); C NMR (100 MHz, CDCl ) δ 178.42, 140.65, 132.58,
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201701172
FULL PAPER
1
6
+
29.90, 129.08, 127.85, 127.34, 125.3, 121.50, 78.14, 77.35, 74.62,
Pale yellow liquid; Yield 0.15 g, 89%; R
f
= 0.5 (only hexane);
); IR (νmax/cm ) 2941, 2831, 1731, 1280, 1161;
3
) δ 7.29–6.91 (m, 4H), 6.01–6.00 (s, 1H), 4.53–
=
−
1
9.27, 63.26, 39.40, 39.01, 36.61, 27.3; HRMS calcd for C20
H
25BrClO
4
[M
+52.88° (c = 0.32, CH
2
Cl
H NMR (400 MHz, CDCl
2
+
1
H] 443.0625, found 443.0627.
4
3
1
1
1
.51 (m, 1H), 4.42 (dd, J = 12.36, 2.28 Hz, 1H), 4.29–4.22 (m, 3H), 3.74–
.70 (m, 1H), 3.26 (t, J = 9.16 Hz, 1H), 2.60–2.55 (m, 1H), 2.06–2.02 (m,
(
(4aS,6R,8R,8aS)-3-chloro-6-phenyl-2,4a,5,6,8,8a-
13
3
H), 1.52–1.37 (m, 1H), 1.21 (s, 9H); C NMR (100 MHz, CDCl ) δ
hexahydropyrano[3,4-b]pyran-8-yl)methyl pivalate (21g):
78.34, 164.16, 161.72, 144.04, 143.97, 129.96, 129.89, 129.26, 121.22,
21.19, 120.09, 114.61, 114.40, 112.86, 112.63, 78.14, 77.31, 74.37,
Colorless liquid; Yield 0.12 g, 80%; R
f
= 0.5 (only hexane);
); IR (νmax/cm ) 2971, 2871, 1729, 1479, 1284, 1164,
110; H NMR (400 MHz, CDCl ) δ 7.34–7.25 (m, 5H), 5.80–5.79 (m, 1H),
= +22.01°
−
1
70.83, 63.16, 40.91, 38.98, 38.16, 27.3; HRMS calcd for C20
+ H] 427.0920, found 427.0921.
H
25BrFO
4
[M
2 2
(c = 0.46, CH Cl
+
1
1
4
1
1
1
1
6
3
.53 (dd, J = 11, 2.28 Hz, 1H), 4.44 (m, 1H), 4.27 (dd, J = 11.92, 5.04 Hz,
H), 4.20 (d, J = 1.84 Hz, 1H), 4.19 (d, J = 1.84 Hz, 1H), 3.76–3.71 (m,
H), 3.24 (t, J = 9.16 Hz, 1H), 2.62–2.55 (m, 1H), 2.07–2.02 (m, 1H),
((4aS,6R,8R,8aS)-3-bromo-6-(2,3-dichlorophenyl)-2,4a,5,6,8,8a-
hexahydropyrano[3,4-b]pyran-8-yl)methyl pivalate (21l):
1
3
.56–1.46 (m, 1H), 1.21 (s, 9H); C NMR (100 MHz, CDCl
41.44, 129.91, 128.45, 127.72, 125.73, 125.44, 79.03, 77.27, 74.73,
9.27, 63.34, 39.61, 38.98, 38.33, 27.34; HRMS calcd for C20 29ClNO
3
) δ 178.36,
o
White solid; m.p. = 81– 82 C; Yield 0.17 g, 86%; R
f
= 0.6 (only hexane);
); IR (νmax/cm ) 2960, 2861, 1730, 1244,
1013, 738; H NMR (400 MHz, CDCl ) δ 7.42–7.17 (m, 3H), 5.99 (d, J =
.84 Hz, 1H), 4.87–4.84 (m, 1H), 4.42–4.38 (m, 1H), 4.32–4.18 (m, 3H),
.79–3.74 (m, 1H), 3.27 (t, J = 9.64 Hz, 1H), 2.64–2.57 (m, 1H), 2.24–
−
1
H
4
2 2
= +38.81° (c = 0.41, CH Cl
+
1
[
M + NH
4
]
382.1785, found 382.1788.
3
1
3
2
(
(4aS,6R,8R,8aS)-3-chloro-6-((E)-prop-1-enyl)-2,4a,5,6,8,8a-
13
.20 (m, 1H), 1.32–1.23 (m, 1H), 1.20 (s, 9H); C NMR (100 MHz,
178.31, 141.49, 132.90, 129.55, 129.40, 129.36, 129.24,
27.73, 125.19, 120.05, 77.52, 76.30, 76.24, 75.29, 74.39, 70.85, 63.26,
hexahydropyrano[3,4-b]pyran-8-yl)methyl pivalate (21h):
3
CDCl ) δ
1
Pale yellow liquid; Yield 0.09 g, 72%; R
f
= 0.6 (only hexane);
); IR (νmax/cm ) 2971, 2871, 1730, 1480, 1285,
160, 1094; H NMR (400 MHz, CDCl ) δ 5.75 (d, J = 1.84 Hz, 1H),
= –
−
1
63.13, 40.83, 38.98, 36.85, 36.27, 27.33; HRMS calcd for C20
[M + H] 477.0235, found 477.0231.
H24BrCl
2
O
4
1
1
5
4
9
3
1
7
2
2 2
3.08° (c = 0.33, CH Cl
+
1
3
.72–5.63 (m, 1H), 5.47–5.41 (m, 1H), 4.34 (dd, J = 11.92, 2.28 Hz, 1H),
.17–4.08 (m, 3H), 3.92–3.87 (m, 1H), 3.59–3.50 (m, 1H), 3.08 (t, J =
.16 Hz, 1H), 2.43–2.38 (m, 1H), 1.80–1.69 (m, 1H), 1.66 (d, J = 6.4 Hz,
((4aS,6R,8R,8aS)-3-bromo-6-(3-nitrophenyl)-2,4a,5,6,8,8a-
hexahydropyrano[3,4-b]pyran-8-yl)methyl pivalate (21m):
13
3
H), 1.34–1.22 (m, 1H), 1.18 (s, 9H); C NMR (100 MHz, CDCl ) δ
78.35, 130.62, 129.72, 127.89, 125.7,0 125.57, 77.80, 76.81, 75.01,
4.82, 73.55, 69.17, 63.69, 63.57, 39.34, 39.22, 38.93, 37.79, 36.32,
Pale yellow liquid; Yield 0.14 g, 78%; R
f
= 0.2 (only hexane);
); IR (νmax/cm ) 2929, 2856, 1730, 1288, 1169;
H NMR (400 MHz, CDCl ) δ 8.19–7.47 (m, 4H), 6.01 (d, J = 1.84 Hz,
1H), 4.64 (dd, J = 12.84, 1.84 Hz, 1H), 4.46 (dd, J = 11.96, 2.28 Hz, 1H),
.27–4.23 (m, 3H), 3.78–3.74 (m, 1H), 3.28 (t, J = 9.6 Hz, 1H), 2.66–2.58
=
−
1
2 2
+51.82° (c = 0.42, CH Cl
+
1
7.29, 21.24, 17.89; HRMS calcd for C17
H
25ClNaO
4
[M + Na] 351.1339,
3
found 351.1339.
4
13
(m, 1H), 2.14–2.09 (m, 1H), 1.54–1.44 (m, 1H), 1.22 (s, 9H); C NMR
((4aS,6S,8R,8aS)-3-chloro-6-propyl-2,4a,5,6,8,8a-
(100 MHz, CDCl
3
) δ 178.33, 148.41, 143.51, 131.68, 129.43, 128.93,
hexahydropyrano[3,4-b]pyran-8-yl)methyl pivalate (21i):
1
22.67, 120.81, 120.30, 77.59, 74.22, 70.84, 62.99, 40.79, 38.99, 38.11,
+
6
27.31; HRMS calcd for C20H24BrNNaO [M + Na] 476.0685, found
Pale yellow liquid; Yield 0.09 g, 69%; R
f
= 0.6 (only hexane);
); IR (νmax/cm ) 2960, 2873, 1731, 1480, 1285,
168; H NMR (400 MHz, CDCl ) δ 5.75 (s, 1H), 4.38–4.35 (m, 1H),
= –
−
1
476.0687.
3
1
4
1
2 2
7.11° (c = 0.23, CH Cl
1
3
((4aS,6R,8R,8aS)-3-bromo-6-phenyl-2,4a,5,6,8,8a-
.14–4.13 (m, 2H), 4.10–4.05 (m, 1H), 3.35–3.49 (m, 1H), 3.42–3.38 (m,
H), 3.04–3.00 (m, 1H), 2.40–2.34 (m, 1H), 1.75–1.71 (m, 1H), 1.50–1.23
hexahydropyrano[3,4-b]pyran-8-yl)methyl pivalate (21n):
1
3
(
m, 5H), 1.18 (s, 9H), 0.87 (t, J = 6.42 Hz, 3H); C NMR (100 MHz,
CDCl ) δ 178.37, 129.54, 125.80, 76.77, 75.46, 69.16, 63.89, 39.42,
8.90, 37.57, 36.13, 27.27, 18.86, 14.04; HRMS calcd for C17 28ClO [M
3
Pale yellow liquid; Yield 0.14 g, 84%; R
f
= 0.5 (only hexane);
); IR (νmax/cm ) 2930, 2855, 1731, 1284, 1163; H NMR
) δ 7.34–7.25 (m, 5H), 6.01–6.00 (m, 1H), 4.54–4.51 (m,
H), 4.41 (dd, J = 11.88, 2.28 Hz, 1H), 4.27–4.23 (m, 3H), 3.75–3.71 (m,
H), 3.28 (t, J = 9.64 Hz, 1H), 2.63–2.55 (m, 1H), 2.06–2.02 (m, 1H),
= –9.12°
−
1
1
3
+
H
4
(c = 0.26, CH
(400 MHz, CDCl
2 2
Cl
+
H] 331.1676, found 331.1675.
3
1
1
1
1
6
13
.57–1.48 (m, 1H), 1.21 (s, 9H); C NMR (125 MHz, CDCl
41.42, 129.50, 128.45, 127.72, 125.74, 119.98, 79.00, 74.53, 70.85,
3.31, 41.07, 38.98, 38.86, 27.34; HRMS calcd for C20 29BrNO [M +
3
) δ 178.35,
((4aS,6R,8R,8aS)-3-bromo-6-p-tolyl-2,4a,5,6,8,8a-
H
4
hexahydropyrano[3,4-b]pyran-8-yl)methyl pivalate (21j):
+
4
NH ] 426.1280, found 426.1283.
Pale yellow liquid; Yield 0.15 g, 86%; R
f
= 0.5 (only hexane);
); IR (νmax/cm ) 2963, 2861, 1730, 1479, 1289,
171, 1121; H NMR (400 MHz, CDCl ) δ 7.21–7.12 (m, 4H), 6.01–6.00
=
−
1
((4a'S,8'R,8a'S)-3'-bromo-4a',5',8',8a'-tetrahydro-2'H
spiro[cyclohexane-1,6'-pyrano[3,4-b]pyran]-8'-yl)methyl
21o):
+
1
2 2
56.10° (c = 0.54, CH Cl
1
pivalate
3
(
(
(
(
(
m, 1H), 4.50–4.47 (m, 1H), 4.41 (dd, J = 11.76, 2.12 Hz, 1H), 4.28–4.22
m, 3H), 3.74–3.70 (m, 1H), 3.29–3.24 (m, 1H), 2.61–2.55 (m, 1H), 2.32
s, 3H), 2.03–1.99 (m, 1H), 1.57–1.48 (m, 1H), 1.21 (s, 9H); C NMR
1
3
Colorless liquid; Yield 0.11 g, 68%; R = 0.7 (only hexane);
= +7.18° (c
f
−
1
1
=
0.44, CH
NMR (400 MHz, CDCl
2.28 Hz, 1H), 4.20–4.18 (m, 2H), 4.02–3.97 (m, 1H), 3.70–3.65 (m, 1H),
2
Cl
2
); IR (νmax/cm ) 2933, 2861, 1729, 1470, 1290, 1168;
H
125 MHz, CDCl
3
) δ 178.33, 138.48, 137.40, 129.59, 129.12, 125.74,
3
) δ 5.91 (d, J = 1.4 Hz, 1H), 4.37 (dd, J = 11.44,
1
2
19.94, 78.92, 77.31, 74.60, 70.86, 63.39, 41.10, 38.98, 38.18, 27.35,
1.20; HRMS calcd for C21H28BrO [M + H] 423.1171, found 423.1173.
4
+
2
.99 (t, J = 9.64 Hz, 1H), 2.61–2.54 (m, 1H), 2.09 (d, J = 13.76 Hz, 1H),
13
1.70–1.44 (m, 5H), 1.42–1.20 (m, 6H), 1.19 (s, 9H); C NMR (100 MHz,
) δ 178.41, 130.24, 119.45, 76.24, 72.93, 70.77, 69.80, 64.44,
((4aS,6R,8R,8aS)-3-bromo-6-(3-fluorophenyl)-2,4a,5,6,8,8a-
CDCl
3
hexahydropyrano[3,4-b]pyran-8-yl)methyl pivalate (21k):
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European Journal of Organic Chemistry
10.1002/ejoc.201701172
FULL PAPER
4
0.46, 39.59, 38.89, 36.27, 30.14, 27.32, 26.14, 21.76, 21.21; HRMS
NMR (470 MHz, CDCl
3
) δ –38.81, –50.00, –118.96; HRMS calcd for
+
+
calcd for C19
H
30BrO
4
[M + H] 401.1327, found 401.1326.
C
15
H
17
C
l2FNaO
3
[M + Na] 357.0436, found 357.0434.
((4aS,6R,8R,8aS)-3-iodo-6-p-tolyl-2,4a,5,6,8,8a-hexahydropyrano[3,4-
((3R,4aS,6R,8R,8aS)-3-fluoro-6-(naphthalen-2-
b]pyran-8-yl)methyl pivalate (21p):
yl)octahydropyrano[3,4-b]pyran-8-yl)methyl pivalate (22d):
Colorless liquid; Yield 0.16 g, 86%; R
f
= 0.6 (only hexane);
= +42.18°
Following the typical procedure ‘C’ for the Prins reaction, compound 20d
−
1
(
c = 0.33, CH
2
Cl
100; H NMR (400 MHz, CDCl
Hz, 1H), 4.48 (dd, J = 11, 1.84 Hz, 1H), 4.40 (dd, J = 11.88, 2.28 Hz, 1H),
2
); IR (νmax/cm ) 2955, 2854, 1732, 1461, 1284, 1163,
f
was isolated as a colorless liquid; Yield 0.18 g, 72%; R = 0.7 (9/1
1
−1
1
3
) δ 7.21–7.12 (m, 4H), 6.27 (d, J = 1.84
hexane/EtOAc);
= –32.11° (c = 0.12, CH
2
Cl
2
); IR (νmax/cm ) 3056,
1
2970, 2866, 1728, 1479, 1285, 1148, 1099, 1017; H NMR (400 MHz,
4
2
9
1
3
.30–4.17 (m, 3H), 3.73–3.68 (m, 1H), 3.30 (t, J =9.60 Hz, 1H), 2.67–
3
CDCl ) δ 7.82–7.80 (m, 4H), 7.47–7.42 (m, 3H), 4.72–4.57 (m, 2H),
4.48–4.45 (m, 1H), 4.31–4.19 (m, 2H), 3.69–3.66 (m, 1H), 3.32–3.26 (m,
.61 (m, 1H), 2.32 (s, 3H), 2.02–1.97 (m, 1H), 1.57–1.48 (m, 1H), 1.21 (s,
13
H); C NMR (100 MHz, CDCl
3
) δ 178.38, 138.47, 137.67, 137.42,
1H), 3.02 (t, J = 9.16 Hz, 1H), 2.29–2.27 (m, 1H), 2.03–1.99 (m, 1H),
13
29.13, 125.76, 94.90, 78.84, 77.40, 74.30, 74.24, 63.33, 42.70, 38.98,
1.80–1.78 (m, 1H), 1.60–1.41 (m, 2H), 1.24 (s, 9H); C NMR (100 MHz,
CDCl 178.45, 139.02, 133.32, 132.98, 128.12, 128.08, 127.75,
126.22, 125.94, 124.32, 124.00, 86.83, 85.07, 78.88, 77.69, 77.48, 70.00,
+
8.07, 27.37, 21.25; HRMS calcd for C21
H
27INaO
4
[M + Na] 493.0852,
3
) δ
found 493.0859.
19
6
(
C
9.71, 63.66, 39.22, 39.00, 38.28, 38.18, 36.54, 36.36, 27.36; F NMR
470 MHz, CDCl –38.81, –50.00, –118.96; HRMS calcd for
[M + Na] 423.1948, found 423.1942.
3
) δ
Following the typical procedure ‘C’ for the Prins reaction, followed
by deprotection of the O-Pivaloyl group, as was used to get
compound 12, compounds ‘22a-22c’ were prepared.
+
24 4
H29FNaO
((3S,3aS,5R,7R,7aS)-3-(prop-1-en-2-yl)-5-p-tolylhexahydro-2H-
furo[2,3-c]pyran-7-yl)methyl pivalate (23):
((3R,4aS,6R,8R,8aS)-3-fluoro-6-phenyloctahydropyrano[3,4-b]pyran-
8
-yl)methanol (22a):
Following the typical procedure ‘C’ for the Prins reaction, compound 23
was isolated as a pale yellow liquid; Yield 0.17 g, 76%; R
hexane/EtOAc); = +28.31° (c = 1.21, CH Cl ); IR (νmax/cm ) 2967,
2843, 1732, 1561, 1347; H NMR (500 MHz, CDCl ) δ 7.22–7.12 (m, 4H,
f
= 0.7 (9/1
Colorless liquid; Yield 0.08 g, 53%; R
f
−
= 0.5 (8/2 hexane/EtOAc);
=
−
1
1
+
42.81° (c = 0.43, CH
Cl
2 2
); IR (νmax/cm ) 3451, 2987, 2876, 1523, 1423;
) δ 7.35–7.26 (m, 5H, ArH), 4.72–4.53 (m, 1H,
2
2
1
1
H NMR (400 MHz, CDCl
3
3
2 2
ArH), 4.96 (s, 1H, C=CH ), 4.78 (s, 1H, C=CH ), 4.43–4.39 (m, 2H, H-1
and H-6’), 4.26 (dd, J = 12.00, 5.75 Hz, 1H, H-6), 4.11 (dd, J = 9.20, 6.90
Hz, 1H, H-8’), 3.99 (dd, J = 9.15, 2.25 Hz, 1H, H-8), 3.74–3.71 (m, 1H, H-
(
(
H-8)), 4.50 (dd, J = 11.44, 2.28 Hz, 1H, H-1), 4.20–4.15 (m, 1H), 3.88
dd, J = 11.92, 3.64 Hz, 1H), 3.76–3.72 (m, 1H), 3.52–3.47 (m, 1H),
3
1
1
3
–
.35–3.28 (m, 1H), 3.01 (t, J = 9.84 Hz, 1H), 2.30–2.24 (m, 1H), 1.94–
.89 (m, 1H), 1.83–1.72 (m, 1H), 1.59–1.37 (m, 2H), 141.38, 128.51,
27.93, 125.98, 86.65, 85.23, 79.53, 79.34, 78.03, 69.89, 69.66, 63.08,
5
2
), 3.44–3.40 (m, 1H, H-4), 2.91–2.88 (m, 1H, H-7), 2.32 (s, 3H, -CH
.13–2.09 (m, 1H, H-3), 2.08–2.01 (m, 1H, H-2), 1.72 (s, 3H, -CH
3
),
),
3
13
1
9
1.48–1.40 (m, 1H, H-2), 1.20 (s, 9H, Piv); C NMR (125 MHz, CDCl ) δ
9.22, 38.19, 38.11, 36.45, 36.32; F NMR (470 MHz, CDCl
3
+
) δ –38.81,
3
178.32, 144.60, 139.03, 137.20, 129.02, 125.79, 112.12, 79.46, 79.36,
3
50.00, –118.96; HRMS calcd for C15H19FNaO [M + Na] 289.1216,
7
5.62, 73.27, 64.44, 47.40, 47.17, 38.92, 36.02, 27.29, 24.43, 21.19;
found 289.1216.
+
33 4
HRMS calcd for C23H O [M + H] 373.2379, found 373.2373.
((3R,4aS,6R,8R,8aS)-3-fluoro-6-p-tolyloctahydropyrano[3,4-b]pyran-
8
-yl)methanol (22b):
Acknowledgements
Colorless liquid, Yield 0.10 g, 58%; R
f
−
= 0.5 (8/2 hexane/EtOAc);
=
1
+
1
4
3
3
38.62° (c = 0.32, CH
145; H NMR (400 MHz, CDCl
2
Cl
2
); IR (νmax/cm ) 3463, 2934, 2863, 1516, 1367,
) δ 7.23–7.13 (m, 4H), 4.71–4.52 (m, 1H),
We thank the Department of Science and Technology, New
Delhi, India, for a J. C. Bose National Fellowship (No. SR/S2/
JCB-26/2010) to Y.D.V., S.D. thanks the Council of Scientific
and Industrial Research, New Delhi for a Senior Research
Fellowship.
1
3
.47 (dd, J = 11.44, 2.28 Hz, 1H), 4.20–4.15 (m, 1H), 3.87–3.71 (m, 2H),
.50–3.46 (m, 1H), 3.34–3.28 (m, 1H), 3.00 (t, J = 9.64 Hz, 1H), 2.33 (s,
H), 2.31–2.21 (m, 1H), 1.91–1.86 (m, 1H), 1.78–1.71 (m, 1H), 1.60–1.36
13
(m, 2H); C NMR (125 MHz, CDCl
3
) δ 138.42, 137.68, 129.18, 126.02,
8
3
–
3
6.68, 85.28, 79.54, 79.25, 78.05, 69.89, 69.66, 63.06, 39.10, 38.20,
19
3
8.12, 36.49, 36.35, 21.21; F NMR (470 MHz, CDCl ) δ –38.81, –50.00,
Keywords: D-Mannitol • Prins reaction • 2-Deoxy-3,4-fused
+
118.96; HRMS calcd for C16
3
H21FNaO [M + Na] 303.1372, found
sugars • Isochroman • Vinyl halide
73.2371.
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European Journal of Organic Chemistry
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Entry for the Table of Contents
FULL PAPER
Text for Table of Contents
Carbohydrates*
Sateesh Dubbu, Yashwant D. Vankar*
Page No. – Page No.
Diversity Oriented Synthesis of
Carbohydrate Scaffolds Using the
Prins Cyclization of Differently
Protected
D-Mannitol
Derived
Homoallylic Alcohols
Differently protected D-mannitol derived homoallylic alcohols were reacted with carbonyl compounds in the presence of
BF ·OEt to form a variety of carbohydrate scaffolds. Application in the synthesis of biologically important carbasugar fused
isochroman derivative and other useful compounds are reported.
3
2
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