Organocatalytic access to enantioenriched dihydropyran phosphonates via an inverse-electron-demand hetero-Diels-Alder reaction

Article abstract of DOI:10.1021/jo500347a

The enantioselective inverse-electron-demand hetero-Diels-Alder reaction of the remote olefin functionality in dienamines has been developed by the simultaneous activation of α,β-unsaturated aldehydes and acyl phosphonates. The dual activation is based on an organocatalyst that activates both the α,β-unsaturated aldehyde, through dienamine formation, and the acyl phosphonate by hydrogen-bonding. The enantioselective reaction results in the formation of dihydropyran frameworks with three contiguous stereogenic centers. Different substitution patterns are possible for both the heterodiene and the dienophile, and the target products are obtained in good yields and up to 92% ee. The potential of the reaction is demonstrated by transformation of the products into valuable and complex synthons.

Full text of DOI:10.1021/jo500347a

Article
pubs.acs.org/joc
Organocatalytic Access to Enantioenriched Dihydropyran
Phosphonates via an Inverse-Electron-Demand Hetero-Diels−Alder
Reaction
Christian F. Weise, Vibeke H. Lauridsen, Raoní S. Rambo, Eva H. Iversen, Marie-Luise Olsen,
and Karl Anker Jørgensen*
Center for Catalysis, Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark
S
* Supporting Information
ABSTRACT: The enantioselective inverse-electron-demand hetero-Diels−Alder reaction of the remote olefin functionality in
dienamines has been developed by the simultaneous activation of α,β-unsaturated aldehydes and acyl phosphonates. The dual
activation is based on an organocatalyst that activates both the α,β-unsaturated aldehyde, through dienamine formation, and the
acyl phosphonate by hydrogen-bonding. The enantioselective reaction results in the formation of dihydropyran frameworks with
three contiguous stereogenic centers. Different substitution patterns are possible for both the heterodiene and the dienophile,
and the target products are obtained in good yields and up to 92% ee. The potential of the reaction is demonstrated by
transformation of the products into valuable and complex synthons.
Scheme 1. Aminocatalytic H-Bond-Directing Strategy for the
Inverse-Electron-Demand Hetero-Diels−Alder Reaction
INTRODUCTION
■
The Diels−Alder reaction is a powerful tool for carbon−carbon
bond formation and for the generation of complexity in
structural motifs.1 Since its discovery, the reaction has
generated much attention and inspired researchers to develop
it further.2 An important variant constitutes the asymmetric
inverse-electron-demand hetero-Diels−Alder reaction, which
includes the additional incorporation of heteroatoms into the
substrates to give access to optically active, heterocyclic
structures, which are highly important in medicinal chemistry.3
A vast number of heterocyclic structures have been generated
this way applying Lewis-acid catalysis.4,5 During the last years,
organocatalytic alternatives to these hetero-Diels−Alder re-
actions have been developed to address the issue of reaction
conditions applied, enabling a milder access to these
heterocyclic structures.6 In particular, organophosphorus
compounds7 are of great interest due to their versatile
properties.8 Besides the multitude of oxidation states of
phosphorus, changing the property of the molecule, the
possibility to manipulate, or even cleave the phosphorus
moiety, contributes to its versatility. Organophosphorus
compounds show a variety of different bioactiveties, such as
antibiotic, antifungal,9 and HIV-protease inhibiting activity.10
Recently, organocatalysts having dual-activation properties
have been developed. Such catalysts activate both the aldehyde
by enamine/dienamine formation (HOMO raising), as well as
the substrate, having nitro-, nitrile-, and oxoesters-function-
alities, by hydrogen-bond activation (LUMO lowering).11 In
the following, we would like to present a further development
of these activation principles by the organocatalyzed reaction of
acyl phosphonates, via a dienamine intermediate, to give access
to optically active dihydropyran phosphonates with three
contiguous stereocenters (Scheme 1). An attractive feature
with the present reaction is that the phosphonate tether
influences selectivity and increases reactivity, allowing for a
Received: February 13, 2014
Published: March 27, 2014
© 2014 American Chemical Society
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a
Table 1. Optimization Studies of the Inverse-Electron-Demand Hetero-Diels−Alder Reaction
b
c
d
entry
cat.
R (2)
solvent
add.
conv. [%]
yield [%]
dr
ee [%]
1
2
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
Me (2a)
Et (2b)
iPr (2c)
iPr (2c)
iPr (2c)
iPr (2c)
iPr (2c)
iPr (2c)
iPr (2c)
iPr (2c)
THF
DEA
DEA
DEA
MEA
DEA
DEA
DEA
DEA
DEA
DEA
>95
>95
>95
>95
>95
95
72
81
82
86
68
80
75
82
---
---
5.5:1
7:1
86
86
88
86
nd
90
nd
90
---
THF
3
THF
8:1
4
THF
8.5:1
3.5:1
4.5:1
4:1
5
PhMe
CH2Cl2
Et2O
6
7
>95
>95
0
8
MeCN
THF
7.5:1
---
9
10
THF
0
---
---
a
b
c
Reactions performed on a 0.1 mmol scale. Additive: DEA = N,N-diethylacetamide; MEA = N-ethylacetamide. Determined by 31P NMR
d
spectroscopy. Determined by UPC2; see the Supporting Information).
broader scope of substrates. Furthermore, the functionality also
provides the basis for further chemical manipulations.
This highlights the important role of the H-bond activation
mode of the bifunctional aminocatalyst 4a.
With the optimized reaction conditions in hand, the scope of
this methodology was investigated. A selection of α,β-
unsaturated acyl phosphonates 2 with various aryl and alkyl
groups and different electronic properties were successfully
employed, all giving rise to the target dihydropyrans 3 in good
yields and stereoselectivities (Scheme 2).
RESULTS AND DISCUSSION
■
At the outset of the studies, different catalysts and solvents were
evaluated. To explore the feasibility of the organocatalyzed
inverse-electron-demand hetero-Diels−Alder reaction, the
reaction between (E)-4-phenylbut-2-enal (1a) and dimethyl
cinnamoylphosphonate (2a) was performed in THF at room
temperature in the presence of the squaramide catalyst 4a
(Table 1). In the case of the H-bond-directing aminocatalyst
4a, N,N-diethylacetamide (DEA) was used as an additive
influencing the catalytic activity of the system.11,12 Satisfyingly,
the desired [4 + 2]-cycloaddition proceeded with more than
95% conversion, affording the target product 3a in 72% yield
and 86% ee (entry 1). In an attempt to improve the
enantioselectivity, the reaction was run at 4 °C; however, to
reach >95% conversion, the reaction had to stir for 5 d (see the
Supporting Information). It was further found that the reaction
gave the best results using an excess of aldehyde. In the next
stage of the studies, different alkyl groups on the phosphonate
moiety in 2 were screened, revealing that increasing the bulk of
the phosphonate moiety led to improved diastereocontrol of
the reaction (entries 1−3), with diisopropyl phosphonate 2c
giving the best result.
To our delight, phosphonates carrying both electron-
withdrawing and electron-donating substituents on the
Scheme 2. Enantioselective Dienamine-Mediated Inverse-
Electron-Demand Hetero-Diels−Alder Reaction: α,β-
Unsaturated Acyl Phosphonate Scope
Subsequently, a selection of solvents were screened (Table 1,
entries 4−8), with DEA in MeCN or THF proving superior,
giving the desired organophosphorous compound 3c (entries 3
and 8) in 82% yield and with good enantioselectivity as well as
diastereoselectivity. However, owing to slightly higher enantio-
meric excess, MeCN was used as the solvent of choice. A
catalyst survey showed that only the bifunctional squaramide
catalyst 4a promoted the desired asymmetric inverse-electron-
demand hetero-Diels−Alder reaction, whereas, using the steric
shielding catalyst 4b or 4c, no product formation was observed.
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aromatic ring were well tolerated under the optimized reaction
conditions (Scheme 2, 3c−3i). In all cases, good yields, high
diastereoselectivities, and good enantioselectivities were
observed, proving the generality of the reaction. Importantly,
good enantiomeric excesses, ranging from 82% to 92% ee, and
>65% yields, were obtained independent of the substitution
pattern of the aromatic ring. Furthermore, the introduction of
two or three substituents on the aromatic ring did not affect the
yield or the stereoselectivities as demonstrated for 3e and 3i.
Surprisingly, introduction of a meta-nitro substituent on the
aromatic ring of 2 resulted in a slightly lower yield as shown by
the synthesis of 3f. This result suggests that the nitro-group
might coordinate to the catalyst, making the reaction less
efficient. Previous work has demonstrated that β,γ-unsaturated
α-ketoesters having electron-donating substituents on the
aromatic ring were less reactive;11c however, by utilizing the
phosphonate tether, the substrates become much more reactive,
showing a notable decrease in reaction time. All reactions were
completed within 24 h unless otherwise stated.
To further broaden the generality of the developed [4 + 2]-
cycloaddition, aliphatic α,β-unsaturated acyl phosphonates 2
were also applied in the reaction sequence, leading to the
formation of the desired alkyl substituted products 3j and 3k,
albeit in moderate yields and slightly reduced enantiomeric
excesses (Scheme 2). A possible explanation being that π-
stacking interactions between the aromatic moieties of the
formed dienamine intermediate and the phosphonate 2 might
be an important factor influencing the outcome of the reaction.
In the interest of achieving higher substituent diversity, the
α,β-unsaturated aldehyde 1 scope was investigated. The results
are summarized in Scheme 3. Various electron-poor and
electron-rich α,β-unsaturated aldehydes 1 were shown to be
compatible with the developed reaction protocol. Most of the
reactions proceeded in a highly enantio- and diastereoselective
manner, providing 3l−3s in good yields, ranging from 64% to
84% (Scheme 3). However, the introduction of a thiophene
moiety in the 4-position of the starting α,β-unsaturated
aldehyde led to a decrease in yield as well as in selectivity as
indicated by the synthesis of 3s, which might indicate the
importance of π-stacking interactions. It is worth noting that
the obtained stereoselectivities are slightly higher than those for
the α,β-unsaturated phosphonate scope and that the reactions
are completed within 24 h. With respect to the substitution
pattern, introduction of an ortho-methyl or ortho-phenyl
substituent on the aromatic ring led to increased diaster-
eoselectivity. In an attempt to expand the α,β-unsaturated
aldehyde scope, aldehydes bearing different alkyl groups were
tested. However, the results indicated that the presence of an
aromatic substituent in the γ-position of the starting enals was
crucial for obtaining reactivity.
In the final studies, the chiral dihydropyran framework was
used in the construction of more elaborate derivatives. Initial
experiments focused on the stereoselective functionalization of
the enolic moiety of 3 (Scheme 4). Treatment of the
dihydropyran adduct with osmium tetroxide in the presence
of 4-methylmorpholine 4-oxide (NMO) and sodium sulfite
afforded the diastereoselective dihydroxylation product 5 in
54% yield, giving rise to two additionally stereogenic centers.
Subsequently, addition of 4-dimethylaminopyridine (DMAP)
gave 6 in 43% yield. It was also possible to obtain the α-hydroxy
lactone 6 in a one-pot fashion, via the intermediacy of the α,β-
dihydroxy phosphonate 5, in an overall yield of 61%. The α-
hydroxy lactone 6 belongs to a class of compounds, which,
upon reduction, will provide uncommon sugar components of
bacterial lipopolysaccharides (LPS) isolated from various
pathogene microorganisms.13
In this way, tetrahydropyrans having up to five contiguous
stereogenic centers were formed in a highly diastereoselective
manner. A plausible explanation for the high diastereoselectivity
observed in this process might be due to the C-4 aryl
substituent, which affects the stereochemical outcome of the
reaction due to sterical interactions. Assuming that the
dihydropyran ring reacts through its half-chair conformation,
the olefinic moiety will be approached from the site opposite to
the C-4 aryl substituent. This is confirmed by X-ray analysis of
the α-hydroxy lactone 6a (see the Supporting Information).
The synthetic potential of the dihydropyrans 3 was further
demonstrated by the electrophilic addition of N-bromosuc-
cinimide (NBS) to the olefinic moiety in 3 (Scheme 4). The
dihydropyran 3f was converted into the corresponding
bromohydrin 7 in a highly diastereoselective manner (18:1:1)
and with no loss in enantioselectivity. A plausible explanation
for the high diastereoselectivity observed in this case might be
due to the directing effect of the meta-nitro substituent on the
aromatic ring, guiding the bromonium ion to approach from
the top. This might explain the lower diastereoselectivity
observed, when having other substituents on the aromatic ring.
The absolute stereochemistry of the obtained product 3a was
unambiguously determined by X-ray analysis (see the
Supporting Information). This result allowed assignment of
the cis-relationship between the H2 and H3 hydrogen atoms in
7, as elucidated on the basis of 1H NMR and 2D NMR analysis.
Scheme 3. Enantioselective Dienamine-Mediated Inverse-
Electron-Demand Hetero-Diels−Alder Reaction:
α,β‑Unsaturated Aldehyde Scope
3
A relatively small value of the JH2H3 coupling constant was
observed, thus indicating an axial−equatorial alignment of the
H2 and H3 protons in the diastereoisomer obtained according
to the Karplus curve.14
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a
Scheme 4. Product Elaboration
a
Reagents and conditions: (a) tBuOH/H2O (10:1), 2 equiv NMO, 1 equiv Na2SO3, and 10 mol % OsO4, rt, 3−5 h. (b) 4 equiv DMAP, rt,
overnight. (c) (1) tBuOH/H2O (10:1), 2 equiv NMO, 1 equiv Na2SO3, and 10 mol % OsO4, rt, 3−5 h; (2) 4 equiv DMAP, rt, overnight. (d) 2 equiv
NBS, tBuOH/H2O (2:1), rt, 2 h. Yields in parentheses refer to the one-pot reaction.
mass of the charged species). Optical rotations were measured on a
CONCLUSION
■
polarimeter and [α]D values are given in deg·cm·g−1·dm−1
;
In conclusion, by employing a bifunctional squaramide-
containing aminocatalyst, an efficient and highly regio- and
stereoselective methodology for the synthesis of optically active
dihydropyran phosphonates bearing three contiguous stereo-
genic centers has been presented. In general, aliphatic and
aromatic α,β-unsaturated acyl phosphonates having electron-
withdrawing or electron-donating substituents could be
successfully applied in this asymmetric inverse-electron-demand
hetero-Diels−Alder reaction, thereby demonstrating its high
versatility. Furthermore, a range of α,β-unsaturated aldehydes
were shown to be compatible with the presented protocol,
providing good yields ranging from 64% to 84%. The derived
cycloadducts could be transformed into useful chiral and
complex building blocks.
concentration c is listed in g·(100 mL)−1. Analytical thin-layer
chromatography (TLC) was performed using precoated aluminum-
backed plates (Merck Kieselgel 60 F254) and visualized by ultraviolet
irradiation or KMnO4 stain. The enantiomeric excess (ee) of the
products was determined by chiral stationary phase applying UPC2
(Ultra Performance Convergence Chromatography) (Daicel Chir-
alpack IA-3, IB-3, IC-3, and ID-3 columns). Unless otherwise noted,
analytical grade solvents and commercially available reagents were
used without further purification. For flash chromatography (FC),
silica gel (Silica gel 60, 230−400 mesh) or Iatrobeads (Iatrobeads 6RS-
8060) was used.
General Procedure for Preparation of α,β-Unsaturated
Aldehydes 1a−1h. Aldehydes 1a−1g, 1s were prepared according
to the literature procedure, and all spectral data were in accordance
with those previously reported.15 Aldehyde 1h was prepared according
to a modified Oshima’s procedure.16
(E)-4-([1,1′-Biphenyl]-2-yl)but-2-enal (1h). To a solution of
butylmagnesium chloride (7.2 mL, 2.0 M solution in THF, 14.4
mmol) in THF (20 mL) was added BuLi (18 mL, 1.6 M solution in
hexane, 28.8 mmol) at 0 °C, and the mixture was stirred for 10 min. A
solution of 2-bromo-1,1′-biphenyl (12.0 mmol) in THF (20 mL) was
added dropwise. After stirring for 0.5 h at 0 °C, the mixture was cooled
to −78 °C and allyl bromide (3.6 mL, 43.2 mmol) and a catalytic
amount of CuCN·2LiCl were successively added. The resulting
solution was stirred for 0.5 h at −78 °C and was subsequently
quenched with sat. aq. NH4Cl. The mixture was extracted with EtOAc,
and the combined organic layers were dried over Na2SO4 and
concentrated in vacuo. The crude was then filtered through a plug of
silica using a mixture of pentane/Et2O (8:1) as an eluent. The solvent
EXPERIMENTAL SECTION
■
General Methods. NMR spectra were acquired on a spectrometer,
1
running at 400 MHz for H, 100 MHz for 13C, 162 MHz for 31P, and
376 MHz for 19F, respectively. Chemical shifts (δ) are reported in
parts per million (ppm) relative to residual solvent signals of CDCl3:
1
7.26 ppm for H NMR and 77.0 ppm for 13C NMR. Chemical shifts
(δ) for 19F NMR are reported in ppm relative to CFCl3 as external
reference and for 31P NMR relative to H3PO4 as external reference.
Only the signals from the major diastereoisomer are reported. The
following abbreviations are used to indicate the multiplicity in NMR
spectra: s - singlet; bs - broad singlet; d - doublet; t - triplet; q -
quartet; m - multiplet. Mass spectra were recorded on a MICROTOF-
Q spectrometer using electrospray (ES+) ionization (referenced to the
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was evaporated to afford the desired product in quantative yield. The
spectroscopic data are in accordance with those previously reported.16
2-Allyl-1,1′-biphenyl (5.0 mmol) and crotonaldehyde (15.0 mmol)
were dissolved in 25 mL of dry CH2Cl2 under an argon atmosphere.
Hoveyda−Grubbs-II catalyst (0.05 mmol) was added, and the mixture
was degassed with argon and heated to 40 °C. The reaction mixture
MHz, CDCl3): δ = −1.61. HRMS calculated for [C13H17O4P + Na]+:
291.0757; found: 291.0759.
(E)-Diisopropyl Cinnamoylphosphonate (2c). Following the
general procedure, 2c was isolated in 30% yield (0.145 g) as a yellow
oil. 1H NMR (400 MHz, CDCl3): δ = 8.09 (d, J = 16.3 Hz, 1H), 7.65−
7.60 (m, 2H), 7.46−7.40 (m, 3H), 7.12 (dd, J = 16.3, 10.7 Hz, 1H),
4.82 (dq, J = 13.0, 6.3 Hz, 2H), 1.39 (d, J = 6.2 Hz, 12H). 13C NMR
(100 MHz, CDCl3): δ = 199.6 (d, J = 177.8 Hz), 148.3 (d, J = 2.2 Hz),
134.5 (d, J = 1.7 Hz), 131.9, 129.4 (2C), 129.3 (2C), 125.3 (d, J = 65.7
Hz), 73.3 (d, J = 7.2 Hz, 2C), 24.4 (d, J = 3.8 Hz, 2C), 24.2 (d, J = 4.7
Hz, 2C). 31P NMR (162 MHz, CDCl3): δ = −3.17. HRMS calculated
for [C15H21O4P + Na]+: 319.1070; found: 319.1074.
1
was monitored by H NMR spectroscopy until crude NMR analysis
indicated full conversion of 2-allyl-1,1′-biphenyl. The solvent was then
removed by rotatory evaporation, and the crude product was purified
by FC on silica using pentane/Et2O from 12:1−4:1 to afford the
1
desired product as a clear oil in 71% yield (0.785 g). H NMR (400
MHz, CDCl3): δ = 9.38 (d, J = 7.9 Hz, 1H), 7.35−7.16 (m, 9H), 6.75
(dt, J = 15.5, 6.4 Hz, 1H), 5.84 (ddt, J = 15.6, 7.9, 1.6 Hz, 1H), 3.54
(dd, J = 6.4, 1.6 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ = 193.7,
156.9, 142.2, 141.0, 134.4, 133.4, 130.4, 129.8, 129.0 (2C), 128.3 (2C),
127.8, 127.3, 127.0, 36.6. HRMS calculated for [C16H14O + Na]+:
245.0937; found: 245.0937.
(E)-Diisopropyl (3-(p-Tolyl)acryloyl)phosphonate (2d). Following
the general procedure, 2d was isolated in 40% yield (1.24 g) as a
1
yellow oil. H NMR (400 MHz, CDCl3): δ = 8.06 (d, J = 16.2 Hz,
1H), 7.52 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.08 (dd, J =
16.2, 10.9 Hz, 1H), 4.86−4.75 (m, 2H), 2.39 (s, 3H), 1.39 (d, J = 2.2
Hz, 6H), 1.37 (d, J = 2.2 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ =
199.5 (d, J = 177.0 Hz), 148.5 (d, J = 2.2 Hz), 142.7, 131.8 (d, J = 1.6
Hz), 130.2 (2C), 129.4 (2C), 124.4 (d, J = 65.8 Hz), 73.2 (d, J = 7.1
Hz, 2C), 24.4 (d, J = 3.8 Hz, 2C), 24.2 (d, J = 4.7 Hz, 2C), 22.0. 31P
NMR (162 MHz, CDCl3): δ = −2.94. HRMS calculated for
[C16H23O4P + Na]+: 333.1226; found: 333.1229.
(E)-Diisopropyl (3-(3,4,5-Trimethoxyphenyl)acryloyl)phos-
phonate (2e). Following the general procedure, 2d was isolated in
10% yield (0.386 g) as a yellow thick oil. 1H NMR (400 MHz,
CDCl3): δ = 8.05 (d, J = 16.2 Hz, 1H), 7.03 (dd, J = 16.1, 11.5 Hz,
1H), 6.85 (s, 2H), 4.84−4.76 (m, 2H), 3.90 (s, 9H), 1.38 (dd, J = 6.2,
2.4 Hz, 12H). 13C NMR (100 MHz, CDCl3): δ = 198.9 (d, J = 176.3
Hz), 153.5 (2C), 148.4 (d, J = 1.9 Hz), 141.3, 129.5 (d, J = 1.7 Hz),
124.3 (d, J = 69.1 Hz), 106.2 (2C), 73.1 (d, J = 7.2 Hz, 2C), 61.0, 56.2
(2C), 24.0 (d, J = 4.1 Hz, 2C), 23.9 (d, J = 4.4 Hz, 2C). 31P NMR
(162 MHz, CDCl3): δ = −3.23. HRMS calculated for [C18H27O7P +
Na]+: 409.1392; found: 409.1390.
(E)-4-(4-Methoxyphenyl)but-2-enal (1e). Following the general
1
procedure, 1e was isolated in 71% (1.49 g) yield as an orange oil. H
NMR (400 MHz, CDCl3): δ = 9.53 (d, J = 7.89 Hz, 1H), 7.10 (d, J =
8.5 Hz, 2H), 6.95 (dt, J = 15.5, 6.7, 6.7 Hz, 1H), 6.87 (d, J = 8.6 Hz,
2H), 6.09 (dd, J = 15.5, 7.89 Hz, 1H), 3.80 (s, 3H), 3.60 (d, J = 6.6 Hz,
2H).). 13C NMR (100 MHz, CDCl3): δ = 193.8, 158.6, 156.9, 133.2,
129.8 (2C), 128.9, 114.2 (2C), 55.3, 38.1. HRMS calculated for
[C11H12O2 + Na]+: 199.0730; found: 199.0730.
(E)-4-(3,5-Dimethylphenyl)but-2-enal (1f). Following the general
1
procedure, 1f was isolated in 52% yield (0.453 g) as a yellow oil. H
NMR (400 MHz, CDCl3): δ = 9.54 (d, J = 7.91 Hz, 1H), 6.99−6.91
(m, 2H), 6.81 (s, 2H), 6.13 (dd, J = 15.5, 7.9 Hz, 1H), 3.58 (d, J = 6.7
Hz, 2H), 2.32 (d, J = 9.3 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ =
193.9, 156.8, 138.4, 136.8, 133.3 (2C), 128.5, 126.6 (2C), 38.9, 21.2
(2C). HRMS calculated for [C12H14O + Na]+: 197.0937; found:
197.0937.
General Procedure for Preparation of (E)-Cinnamoyl/
enoylphosphonates 2a−2k. A 12 mmol (1.2 equiv) portion of
acid was suspended in 5 mL of anhydrous CH2Cl2 (in the case where
the acid was liquid, no solvent was used) and cooled to 0 °C.
Oxalylchloride (1.02 mL, 12 mmol, 1.2 equiv) was added dropwise,
followed by the addition of ca. 2 drops of DMF. The reaction was
cooled another 10 min and then stirred at rt until it became a clear
solution and gas evolution ceased (ca. 2−3 h), after which crude NMR
analysis indicated full conversion to the acid chloride. The reaction was
cooled to 0 °C, and 10 mmol (1.0 equiv) of the respective phosphite
was added over 1 h, upon which the reaction became yellow. The
reaction was stirred at rt overnight, and the solvent was removed under
vacuum. The crude reaction mixture was purified by FC on Iatrobeads
using pentane/EtOAc from 9:1 to 2:1. To make sure to collect only
clean product, 31P NMR spectra were taken of several individual
fractions. In the case where the product contained some acid starting
material, indicated by NMR analysis, it could be removed by extraction
with sat. aq. NaHCO3. All products were stored in the freezer and did
not show decomposition during the development of this project.
(E)-Dimethyl Cinnamoylphosphonate (2a). Following the general
procedure, 2a was isolated in 14% yield (0.246 g) as a yellow oil (93%
(E)-Diisopropyl (3-(3-Nitrophenyl)acryloyl)phosphonate (2f). Fol-
lowing the general procedure, 2f was isolated in 28% yield (0.962 g) as
a yellow oil. 1H NMR (400 MHz, CDCl3): δ = 8.46 (s, 1H), 8.28 (dd,
J = 8.2, 1.1 Hz, 1H), 8.10 (d, J = 16.3 Hz, 1H), 7.91 (d, J = 6.8 Hz,
1H), 7.62 (t, J = 8.0 Hz, 1H), 7.18 (dd, J = 16.3, 10.0 Hz, 1H), 4.82
(dq, J = 12.6, 6.3 Hz, 2H), 1.38 (d, J = 7.0 Hz, 12H). 13C NMR (100
MHz, CDCl3): δ = 199.6 (d, J = 180.7 Hz), 149.1, 144.9 (d, J = 1.9
Hz), 136.2 (d, J = 1.8 Hz), 134.6, 130.5, 127.5 (d, J = 65.7 Hz), 125.8,
123.5, 73.7 (d, J = 7.3 Hz, 2C), 24.4 (d, J = 3.8 Hz, 2C), 24.2 (d, J =
4.7 Hz, 2C). 31P NMR (162 MHz, CDCl3): δ = −3.89. HRMS
calculated for [C15H20NO6P + Na]+: 364.0920; found: 364.0923.
(E)-Diisopropyl (3-(2-Fluorophenyl)acryloyl)phosphonate (2g).
Following the general procedure, 2g was isolated in 36% yield
(1.127 g) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ = 8.18 (d, J
= 16.4 Hz, 1H), 7.61 (dd, J = 10.8, 4.3 Hz, 1H), 7.45−7.37 (m, 1H),
7.21−7.09 (m, 3H), 4.82 (dq, J = 12.7, 6.3 Hz, 2H), 1.39 (d, J = 6.2
Hz, 12H). 13C NMR (100 MHz, CDCl3): δ = 199.8 (d, J = 179.4 Hz),
162.2 (d, J = 255.9 Hz), 140.4, 133.3 (d, J = 8.9 Hz), 129.6 (d, J = 2.5
Hz), 127.4 (d, J = 6.3 Hz), 126.7 (d, J = 6.1 Hz), 124.9 (d, J = 3.7 Hz),
116.7 (d, J = 21.9 Hz), 73.3 (d, J = 7.3 Hz, 2C), 24.4 (d, J = 3.7 Hz,
2C), 24.2 (d, J = 4.8 Hz, 2C). 19F NMR (376 MHz, CDCl3) δ =
−112.9. 31P NMR (162 MHz, CDCl3): δ = −3.21. HRMS calculated
for [C15H20FO4P + Na]+: 337.0981; found: 337.0974.
1
clean). H NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 16.3 Hz, 1H),
7.64−7.62 (m, 2H), 7.49−7.40 (m, 3H), 7.08 (dd, J = 16.3, 12.9 Hz,
1H), 3.91 (d, J = 10.8 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ =
198.2 (d, J = 175.2 Hz), 149.5 (d, J = 1.8 Hz), 134.3 (d, J = 1.6 Hz),
132.2 (2C), 129.5 (3C), 125.5 (d, J = 66.3 Hz), 54.4 (d, J = 7.2 Hz,
2C). 31P NMR (162 MHz, CDCl3): δ = 0.38. HRMS calculated for
[C11H13O4P + Na]+: 263.0444; found: 263.0444.
(E)-Diisopropyl (3-(4-Chlorophenyl)acryloyl)phosphonate (2h).
Following the general procedure, 2h was isolated in 10% yield
1
(0.331 g) as a yellow oil that solidified upon cooling. H NMR (400
MHz, CDCl3): δ = 8.03 (d, J = 16.2 Hz, 1H), 7.56 (d, J = 8.5 Hz), 7.40
(d, J = 8.5 Hz, 2H), 7.07 (dd, J = 16.3, 10.5 Hz, 1H), 4.86−4.76 (m,
2H), 1.38 (d, J = 7.6 Hz, 12H).). 13C NMR (100 MHz, CDCl3): δ =
199.6 (d, J = 178.5 Hz), 146.7 (d, J = 2.1 Hz), 137.9, 133.0, 130.5
(2C), 129.8 (2C), 125.6 (d, J = 65.8 Hz), 73.4 (d, J = 7.2 Hz, 2C),
24.4 (d, J = 3.8 Hz, 2C), 24.2 (d, J = 4.7 Hz, 2C). 31P NMR (162
MHz, CDCl3): δ = −3.56. HRMS calculated for [C15H20ClO4P +
Na]+: 353.0680; found: 353.0683.
(E)-Diethyl Cinnamoylphosphonate (2b). Following the general
1
procedure, 2b was isolated in 27% yield (0.607 g) as a yellow oil. H
NMR (400 MHz, CDCl3): δ = 8.11 (d, J = 16.3 Hz, 1H), 7.64−7.61
(m, 2H), 7.47−7.39 (m, 3H), 7.09 (dd, J = 16.3, 11.9 Hz, 1H), 4.25
(dq, J = 14.2, 7.1 Hz, 4H), 1.33 (t, J = 7.1 Hz, 6H).). 13C NMR (100
MHz, CDCl3): δ = 199.0 (d, J = 175.7 Hz), 148.9 (d, J = 1.9 Hz),
134.4 (d, J = 1.6 Hz), 132.0, 129.4 (2C), 129.4 (2C), 125.4 (d, J = 66.0
Hz), 64.2 (d, J = 7.1 Hz, 2C), 16.8 (d, J = 5.7 Hz, 2C). 31P NMR (162
(E)-Diisopropyl (3-(4-Bromo-2-fluorophenyl)acryloyl)phos-
phonate (2i). Following the general procedure, 2i was isolated in
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Article
1
30% yield (1.1768 g) as a yellow oil that solidified upon cooling. H
NMR (400 MHz, CDCl3): δ = 8.08 (d, J = 16.5 Hz, 1H), 7.48 (t, J =
8.2 Hz, 1H), 7.35−7.30 (m, 2H), 7.16 (dd, J = 16.4, 9.5 Hz, 1H),
4.87−4.75 (m, 2H), 1.31 (d, J = 6.2 Hz, 12H). 13C NMR (100 MHz,
CDCl3): δ = 199.7 (d, J = 180.1 Hz), 161.7 (d, J = 260.3 Hz), 139.1 (t,
J = 2.7 Hz), 130.4 (d, J = 3.1 Hz), 128.5 (d, J = 3.7 Hz), 127.3 (dd, J =
65.4, 6.2 Hz), 126.3 (d, J = 9.9 Hz), 121.8 (dd, J = 11.6, 1.9 Hz), 120.4
(d, J = 25.0 Hz), 73.4 (d, J = 7.3 Hz, 2C), 24.4 (d, J = 3.7 Hz), 24.2 (d,
J = 4.8 Hz). 19F NMR (376 MHz, CDCl3) δ = −110.6. 31P NMR (162
MHz, CDCl3): δ = −3.41. HRMS calculated for [C15H19BrFO4P +
Na]+: 415.0081; found: 415.0083.
(E)-Diisopropyl But-2-enoylphosphonate (2j). Following the
general procedure, 2j was isolated in 31% yield (0.218 g) as a light
yellow oil (91% clean). 1H NMR (400 MHz, CDCl3): δ = 7.48 (tt, J =
13.9, 6.9 Hz, 1H), 6.44 (dd, J = 15.4, 14.4 Hz, 1H), 4.75 (dq, J = 12.5,
6.3 Hz, 2H), 1.99 (dt, J = 7.0 Hz, 1.2 Hz, 3H), 1.35 (d, J = 6.2 Hz,
12H). 13C NMR (100 MHz, CDCl3): δ = 199.5 (d, J = 174.7 Hz),
150.5, 131.6 (d, J = 65.0 Hz), 73.1 (d, J = 7.3 Hz, 2C), 24.4 (d, J = 3.8
Hz, 2C), 24.2 (d, J = 4.8 Hz, 2C), 19.4 (d, J = 1.6 Hz). 31P NMR (162
MHz, CDCl3): δ = −3.20. HRMS calculated for [C10H19O4P + Na]+:
257.0913; found: 257.0913.
NMR (CDCl3): δ = 145.4 (d, J = 227.8 Hz), 141.2, 139.7 (d, J = 1.1
Hz), 128.7 (2C), 128.6, 128.5, 128.2, 128.1, 127.7, 127.0, 126.8 (2C),
119.7 (d, J = 23.1 Hz), 79.6 (d, J = 8.2 Hz), 62.8 (t, J = 5.3 Hz, 2C),
60.3, 52.6 (d, J = 2.0 Hz), 47.1 (d, J = 12.9 Hz), 35.3, 16.3 (d, J = 1.4
Hz), 16.4 (d, J = 1.5 Hz). 31P NMR (CDCl3): δ = 8.53. HRMS
calculated for [C23H29O5P + Na]+: 439.1645; found: 439.1651. [α]2D0
−102.1 (c = 0.99, MeCN).
=
Diisopropyl ((2R,3R,4S)-2-(2-Hydroxyethyl)-3,4-diphenyl-3,4-di-
hydro-2H-pyran-6-yl)phosphonate (3c). Following the general
procedure (reaction time 24 h), 3c was isolated by FC on silica in
82% yield (0.0732 g) as a light yellow oil (dr = 8:1). 1H NMR
(CDCl3): δ = 7.23−7.17 (m, 3H), 7.13−7.11 (m, 3H), 6.91−6.90 (m,
2H), 6.84 (dd, J = 6.6, 2.9 Hz, 2H), 6.03 (dd, J = 10.8, 2.3 Hz, 1H),
4.84−4.72 (m, 2H), 4.37 (td, J = 9.7, 3.3 Hz, 1H), 3.73−3.68 (m, 3H),
2.73 (t, J = 10.4 Hz, 1H), 2.18 (bs, 1H), 1.68−1.57 (m, 2H), 1.41−
1.36 (m, 12H). 13C NMR (CDCl3): δ = 146.3 (d, J = 227.6 Hz), 140.6
(d, J = 152.2 Hz), 128.7 (2C), 128.5, 128.2 (2C), 128.1, 128.1, 127.8
(2C), 127.1, 126.8, 119.2 (d, J = 23.1 Hz), 79.9 (d, J = 8.0 Hz), 71.6
(d, J = 5.9 Hz), 71.5 (d, J = 5.9 Hz), 60.2, 52.7 (d, J = 1.8 Hz), 47.1 (d,
J = 12.8 Hz), 35.3, 24.1 (d, J = 4.1 Hz, 2C), 23.9 (d, J = 4.7 Hz, 2C).
31P NMR (CDCl3): δ = 6.16. HRMS calculated for [C25H33O5P +
Na]+: 467.1958; found: 467.1960. [α]2D0 = −100.8 (c = 1.00, MeCN).
Diisopropyl ((2R,3R,4S)-2-(2-Hydroxyethyl)-3-phenyl-4-(p-tolyl)-
3,4-dihydro-2H-pyran-6-yl)phosphonate (3d). Following the general
procedure (reaction time 48 h), 3d was isolated in 87% yield (0.0801
(E)-Diisopropyl Pent-2-enoylphosphonate (2k). Following the
general procedure, 2k was isolated in 12% yield (0.299 g) as a light
yellow oil (90% clean). 1H NMR (400 MHz, CDCl3): δ = 7.46 (dt, J =
16.0, 6.3 Hz, 1H), 6.38 (ddt, J = 15.5, 13.6, 1.7 Hz, 1H), 4.80−4.64
(m, 2H), 2.38−2.18 (m, 2H), 1.31 (dd, J = 6.2, 1.3 Hz, 12H), 1.06 (t, J
= 7.4 Hz, 3H).). 13C NMR (100 MHz, CDCl3): δ = 199.6 (d, J =
174.6 Hz), 156.4, 128.8 (d, J = 65.0 Hz), 73.0 (d, J = 7.2 Hz, 2C), 26.6
(d, J = 1.5 Hz), 24.3 (d, J = 3.7 Hz, 2C), 24.1 (d, J = 4.8 Hz, 2C), 12.0.
31P NMR (162 MHz, CDCl3): δ = −3.17. HRMS calculated for
1
g) as a light yellow oil (dr = 8:1). H NMR (CDCl3): δ = 7.24−7.17
(m, 3H), 6.93−6.90 (m, 4H), 6.72 (d, J = 8.0 Hz, 2H), 6.01 (dd, J =
10.8, 2.2 Hz, 1H), 4.81−4.73 (m, 2H), 4.34 (td, J = 9.8, 3.0 Hz, 1H),
3.71−3.65 (m, 3H), 2.71 (t, J = 10.4 Hz, 1H), 2.23 (s, 3H), 1.84 (bs,
1H), 1.69−1.53 (m, 2H), 1.42−1.36 (m, 12H).13C NMR (CDCl3): δ
= 146.1 (d, J = 227.9 Hz), 139.9 (d, J = 0.9 Hz), 138.2 (d, J = 0.8 Hz),
136.2, 128.9 (2C), 128.7 (2C), 128.1 (2C), 127.6 (2C), 127.0, 119.6
(d, J = 22.9 Hz), 79.9 (d, J = 8.0 Hz), 71.5 (d, J = 5.7 Hz), 71.4 (d, J =
5.7 Hz), 60.2, 52.6 (d, J = 1.7 Hz), 46.6 (d, J = 12.7 Hz), 35.3, 24.1 (d,
J = 4.1 Hz, 2C), 23.9 (d, J = 4.4 Hz, 2C), 21.0. 31P NMR (CDCl3): δ =
6.26. HRMS calculated for [C26H35O5P + Na]+: 481.2114; found:
481.2122. [α]2D9 = −125.0 (c = 0.51, MeCN).
[C11H21O4P + Na]+: 271.1070; found: 271.1069.
General Procedure for Preparation of Dihydropyran
Phosphonates 3a−3k. An ordinary screw-cap vial was charged
with a magnetic stirring bar and 0.2 mmol (1.0 equiv) of phosphonate
2. After addition of 0.8 mL of a stock solution of N,N-diethylacetamide
(DEA) in MeCN (1 equiv DEA), 52 μL (0.4 mmol, 2 equiv) of 1a was
added, followed by the addition of 16 mg (0.032 mmol, 0.16 equiv) of
catalyst 4a. The reaction mixture was stirred at rt and monitored by 1H
and 31P NMR spectroscopy. After the reaction time given, the reaction
was cooled to 0 °C and 15.1 mg (0.4 mmol, 2 equiv) of NaBH4 was
added, followed by the addition of ca. 5 drops of MeOH. The reaction
was stirred for 2 h at rt, diluted with 30 mL of Et2O, and extracted 6−8
times with 8 mL of water to remove the additive. The organic phase
was dried over Na2SO4, the solvent was removed under reduced
pressure, and the crude product was purified by FC on silica (CH2Cl2/
MeOH 100:0 → 200:1 → 200:2 → 200:3 → 200:4) to afford products
3. The dr after purification was determined by 31P NMR spectroscopy.
Dimethyl ((2R,3R,4S)-2-(2-Hydroxyethyl)-3,4-diphenyl-3,4-dihy-
dro-2H-pyran-6-yl)phosphonate (3a). Following the general proce-
dure (reaction time 24 h), 3a was isolated by FC on silica in 72% yield
(0.0562 g) as a light yellow solid with a mp 137.7−139.1 °C. (dr =
Diisopropyl ((2R,3R,4S)-2-(2-Hydroxyethyl)-3-phenyl-4-(3,4,5-tri-
methoxyphenyl)-3,4-dihydro-2H-pyran-6-yl)phosphonate (3e). Fol-
lowing the general procedure (reaction time 24 h), 3e was isolated by
FC on silica in 70% yield (0.0752 g) as a pale yellow oil (dr = 9:1). 1H
NMR (CDCl3): δ = 7.23−7.18 (m, 3H), 6.92 (d, J = 6.9 Hz, 2H), 6.05
(dd, J = 10.7, 2.0 Hz, 1H), 5.97 (s, 2H), 4.83−4.72 (m, 2H), 4.37 (td, J
= 9.9, 3.2 Hz, 1H), 3.81 (s, 1H), 3.75 (s, 5H), 3.60 (s, 6H), 2.66 (t, J =
10.5 Hz, 1H), 2.20 (bs, 1H), 1.67−1.60 (m, 2H), 1.42−1.37 (m, 12H).
13C NMR (CDCl3): δ = 152.7 (2C), 146.8 (d, J = 227.9 Hz), 140.0
(2C), 136.8 (d, J = 25.6 Hz), 128.7 (2C), 128.2 (2C), 127.0, 118.6 (d,
J = 22.9 Hz), 104.6 (2C), 79.7 (d, J = 7.8 Hz), 71.5 (d, J = 2.3 Hz),
71.4 (d, J = 2.2 Hz), 60.5 (d, J = 64.0 Hz, 2C), 55.8 (2C), 52.6 (d, J =
1.5 Hz), 47.2 (d, J = 12.9 Hz), 35.3, 24.1 (d, J = 2.0 Hz), 24.0 (d, J =
2.1 Hz), 23.9 (d, J = 4.7 Hz), 23.8 (d, J = 4.5 Hz). 31P NMR (CDCl3):
δ = 6.03. HRMS calculated for [C28H39O8P + Na]+: 557.2275; found:
557.2279. [α]2D0 = −110.4 (c = 1.00, MeCN).
1
5.5:1). H NMR (CDCl3): δ = 7.23−7.17 (m, 3H), 7.13−7.11 (m,
3H), 6.90 (d, J = 6.9 Hz, 2H), 6.85−6.83 (m, 2H), 6.02 (dd, J = 11.0,
2.3 Hz, 1H), 4.43−4.38 (m, 1H), 3.85 (t, J = 10.5 Hz, 6H), 3.72−3.69
(m, 3H), 2.75 (t, J = 10.4 Hz, 1H), 2.25 (bs, 1H), 1.69−1.60 (m, 2H).
13C NMR (CDCl3): δ = 144.4 (d, J = 228.9 Hz), 141.0 (d, J = 0.9 Hz),
Diisopropyl ((2R,3R,4S)-2-(2-Hydroxyethyl)-4-(3-nitrophenyl)-3-
phenyl-3,4-dihydro-2H-pyran-6-yl)phosphonate (3f). Following the
general procedure (reaction time 24 h), 3f was isolated in 65% yield
139.6 (d, J = 1.1 Hz), 128.7 (2C), 128.2 (2C), 128.1 (2C), 127.7
(2C), 127.1, 126.8, 120.4 (d, J = 23.0 Hz), 79.3 (d, J = 8.1 Hz), 59.6,
53.3 (d, J = 2.5 Hz), 53.2 (d, J = 2.3 Hz), 52.6 (d, J = 1.9 Hz), 47.1 (d,
J = 12.8 Hz), 35.3. 31P NMR (CDCl3): δ = 11.47. HRMS calculated
for [C21H25O5P + Na]+: 411.1332; found: 411.1336. [α]2D0 = −139.5 (c
= 1.03, MeCN).
Diethyl ((2R,3R,4S)-2-(2-Hydroxyethyl)-3,4-diphenyl-3,4-dihydro-
2H-pyran-6-yl)phosphonate (3b). Following the general procedure
(reaction time 24 h), 3b was isolated by FC on silica in 81% yield
(0.0671 g) as a colorless oil (dr = 7:1). 1H NMR (CDCl3): δ = 7.24−
7.18 (m, 3H), 7.13−7.12 (m, 3H), 6.91 (d, J = 7.1 Hz, 2H), 6.86−6.83
(m, 2H), 6.03 (dd, J = 11.0, 2.2 Hz, 1H), 4.40 (td, J = 9.4, 3.1 Hz, 1H),
4.25−4.17 (m, 4H), 3.76−3.69 (m, 3H), 2.76 (t, J = 10.4 Hz, 1H),
2.00−1.97 (m, 1H), 1.64−1.56 (m, 2H), 1.43−1.37 (m, 6H). 13C
1
(0.064 g) as a yellow oil (dr = >20:1). H NMR (CDCl3): δ = 7.99
(dd, J = 8.3, 1.1 Hz, 1H), 7.74 (t, J = 2.0 Hz, 1H), 7.31−7.13 (m, 5H),
6.90 (d, J = 6.4 Hz, 2H), 5.98 (dd, J = 10.7, 2.2 Hz, 1H), 4.86−4.72
(m, 2H), 4.40 (td, J = 9.7, 3.2 Hz, 1H), 3.84 (dt, J = 10.7, 2.8 Hz, 1H),
3.75 (t, J = 5.7 Hz, 2H), 2.71 (t, J = 10.4 Hz, 1H), 2.13 (bs, 1H),
1.70−1.59 (m, 2H), 1.45−1.37 (m, 12H). 13C NMR (CDCl3): δ =
148.1, 147.6 (d, J = 226.7 Hz), 143.6, 138.7, 134.1, 129.2, 129.0, 128.0
(2C), 127.6 (2C), 122.6, 122.1, 117.1 (d, J = 23.3 Hz), 79.5 (d, J = 8.0
Hz), 71.9 (d, J = 5.7 Hz), 71.7 (d, J = 5.7 Hz), 59.8, 52.6 (d, J = 1.9
Hz), 46.8 (d, J = 12.9 Hz), 35.3, 24.1 (d, J = 4.2 Hz, 2C), 23.9 (d, J =
4.5 Hz, 2C).31P NMR (CDCl3): δ = 5.51. HRMS calculated for
[C25H32NO7P + Na]+: 512.1809; found: 512.1817. [α]2D6 = −96.6 (c =
0.60, MeCN).
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Article
Diisopropyl ((2R,3R,4S)-4-(2-Fluorophenyl)-2-(2-hydroxyethyl)-3-
phenyl-3,4-dihydro-2H-pyran-6-yl)phosphonate (3g). Following the
general procedure (reaction time 24 h), 3g was isolated in 70% yield
7.4 Hz, 2H), 6.00 (d, J = 11.1 Hz, 1H), 4.74−4.66 (m, 2H), 4.11 (t, J =
6.7 Hz, 1H), 3.69 (t, J = 5.8 Hz, 2H), 2.45 (d, J = 5.9 Hz, 2H), 2.26
(bs, 1H), 1.64−1.55 (m, 1H), 1.50−1.45 (m, 1H), 1.37−1.33 (m,
12H), 1.13−1.06 (m, 1H), 1.02−0.94 (m, 1H), 0.82 (t, J = 7.3 Hz,
3H). 13C NMR (CDCl3): δ = 145.2 (d, J = 227.4 Hz), 140.6, 128.9,
128.5, 128.4, 128.1, 127.1, 119.5 (d, J = 22.3 Hz), 80.0 (d, J = 8.0 Hz),
71.4 (d, J = 5.5 Hz), 71.3 (d, J = 5.5 Hz), 60.4, 49.4 (d, J = 1.8 Hz),
41.1 (d, J = 12.3 Hz), 35.4, 24.6, 24.0 (d, J = 2.5 Hz), 24.0 (d, J = 2.6
Hz), 23.8 (d, J = 4.7 Hz), 23.8 (d, J = 5.0 Hz), 10.3. 31P NMR
(CDCl3): δ = 6.74. HRMS calculated for [C21H33O5P + Na]+:
419.1958; found: 419.1961. [α]2D8 = −18.3 (c = 0.535, MeCN).
General Procedure for Preparation of Dihydropyran Phos-
phonates 3l−3s. An ordinary screw-cap vial was charged with a
magnetic stirring bar and 59.3 mg (0.2 mmol, 1.0 equiv) of
phosphonate 2a. After addition of 0.8 mL of a stock solution of
N,N-diethylacetamide (DEA) in MeCN (1 equiv DEA), 0.4 mmol (2
equiv) of 1 was added, followed by the addition of 16 mg (0.032
mmol, 0.16 equiv) of catalyst 4a. The reaction mixture was stirred at rt
1
(0.0651 g) as a pale yellow oil (dr = 7:1). H NMR (CDCl3): δ =
7.21−7.15 (m, 3H), 7.09−7.01 (m, 2H), 6.98−6.93 (m, 3H), 6.83−
6.78 (m, 1H), 5.95 (dd, J = 10.8, 2.2 Hz, 1H), 4.82−4.69 (m, 2H),
4.38 (td, J = 9.7, 3.2 Hz, 1H), 4.05 (d, J = 10.7, Hz, 1H), 3.75−3.72
(m, 2H), 2.89 (t, J = 10.4 Hz, 1H), 2.32 (bs, 1H), 1.68−1.57 (m, 2H),
1.41−1.35 (m, 12H). 13C NMR (CDCl3): δ = 160.6 (d, J = 246.6 Hz),
146.0 (d, J = 227.0 Hz), 139.3, 129.4 (d, J = 4.4 Hz), 128.6 (2C),
128.5, 128.4 (d, J = 6.7 Hz), 128.1, 127.9, 127.1, 124.1 (d, J = 3.6 Hz),
118.6 (d, J = 23.1 Hz), 115.3 (d, J = 22.5 Hz), 79.9 (d, J = 8.2 Hz),
71.5 (d, J = 5.5 Hz), 71.4 (d, J = 5.6 Hz), 60.0, 50.7, 40.5 (d, J = 13.2
Hz), 35.3, 24.0 (d, J = 4.2 Hz, 2C), 23.8 (t, J = 4.9 Hz, 2C). 31P NMR
(CDCl3): δ = 6.13. 19F NMR (CDCl3): δ = −115.3. HRMS calculated
for [C25H32FO5P + Na]+: 485.1864; found: 485.1870. [α]2D9 = −99.4 (c
= 0.827, MeCN).
Diisopropyl ((2R,3R,4S)-4-(4-Chlorophenyl)-2-(2-hydroxyethyl)-3-
phenyl-3,4-dihydro-2H-pyran-6-yl)phosphonate (3h). Following the
general procedure (reaction time 30 h), 3h was isolated in 67% yield
1
and monitored by H and 31P NMR spectroscopy. After the reaction
time given, the reaction was cooled to 0 °C and 15.1 mg (0.4 mmol, 2
equiv) of NaBH4 was added, followed by the addition of ca. 5 drops of
MeOH. The reaction was stirred for 2 h at rt, diluted with 30 mL of
Et2O, and extracted 6−8 times with 8 mL of water to remove the
additive. The organic phase was dried over Na2SO4, the solvent was
removed under reduced pressure, and the crude product was purified
by FC (CH2Cl2/MeOH 100:0 → 200:1 → 200:2 → 200:3 → 200:4)
to afford products 3. The dr after purification was determined by 31P
NMR spectroscopy.
1
(0.0641 g) as a pale yellow oil (dr = 11:1). H NMR (CDCl3): δ =
7.22−7.18 (m, 3H), 7.08 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 6.6 Hz, 2H),
6.75 (d, J = 8.4 Hz, 2H), 5.95 (dd, J = 10.8, 2.2 Hz, 1H), 4.81−4.70
(m, 2H), 4.35 (dt, J = 9.3, 3.1 Hz, 1H), 3.74−3.71 (m, 2H), 3.69−3.65
(m, 1 H), 2.65 (t, J = 10.4 Hz, 1H), 2.31 (bs, 1H), 1.64−1.56 (m, 2H),
1.41−1.35 (m, 12H). 13C NMR (CDCl3): δ = 146.7 (d, J = 227.7 Hz),
139.6 (d, J = 47.3 Hz), 132.5 (2C), 129.0 (2C), 128.8 (2C), 128.4
(2C), 128.1 (2C), 127.2, 118.3 (d, J = 22.9 Hz), 79.5 (d, J = 8.1 Hz),
71.6 (d, J = 5.8 Hz), 71.5 (d, J = 5.7 Hz), 59.9, 52.6 (d, J = 1.9 Hz),
46.5 (d, J = 12.8 Hz), 35.3, 24.1 (d, J = 1.5 Hz), 24.0 (d, J = 1.4 Hz),
23.9 (d, J = 1.9 Hz), 23.8 (d, J = 1.9 Hz). 31P NMR (CDCl3): δ = 5.92.
HRMS calculated for [C25H32ClO5P + Na]+: 501.1568; found:
501.1574. [α]2D9 = −109.3 (c = 0.58, MeCN).
Diisopropyl ((2R,3R,4S)-3-(4-Fluorophenyl)-2-(2-hydroxyethyl)-4-
phenyl-3,4-dihydro-2H-pyran-6-yl)phosphonate (3l). Following the
general procedure (reaction time 24 h), 3l was isolated in 82% yield
1
(0.0839 g) as a pale yellow oil (dr = 10:1). H NMR (CDCl3): δ =
7.47 (d, J = 8.1 Hz, 2H), 7.14−7.13 (m, 3H), 7.03 (d, J = 7.9 Hz, 2H),
6.82 (dd, J = 6.5, 3.0 Hz, 2H), 6.01 (dd, J = 10.8, 2.2 Hz, 1H), 4.83−
4.71 (m, 2H), 4.39 (td, J = 9.9, 2.8 Hz, 1H), 3.74 (t, J = 5.5 Hz, 2H),
3.68 (dt, J = 11.1, 2.6 Hz, 1H), 2.82 (t, J = 10.4 Hz, 1H), 2.35 (bs,
1H), 1.66−1.51 (m, 2H), 1.41−1.35 (m, 12H). 13C NMR (CDCl3): δ
= 146.5 (d, J = 228.2 Hz), 144.1, 140.7, 129.4 (q, J = 32.6 Hz), 128.5,
128.4 (2C), 127.6 (2C), 127.1, 125.3 (q, J = 3.6 Hz, 2C), 123.9 (q, J =
271.1 Hz), 118.7 (d, J = 22.9 Hz, 2C), 78.9 (d, J = 8.3 Hz), 71.7 (d, J =
5.8 Hz), 71.6 (d, J = 5.8 Hz), 59.6, 52.6 (d, J = 1.9 Hz), 47.2 (d, J =
12.7 Hz), 35.3, 24.1 (d, J = 4.1 Hz, 2C), 23.9 (d, J = 4.6 Hz, 2C). 31P
NMR (CDCl3): δ = 5.92. 19F NMR (376 MHz, CDCl3): δ = −62.5.
HRMS calculated for [C26H32F3O5P + Na]+: 535.1832; found:
535.1835. [α]2D5 = −87.3 (c = 1.15, MeCN).
Diisopropyl ((2R,3R,4S)-3-(4-Fluorophenyl)-2-(2-hydroxyethyl)-4-
phenyl-3,4-dihydro-2H-pyran-6-yl)phosphonate (3m). Following
the general procedure (reaction time 24 h), 3m was isolated in 77%
yield (0.0712 g) as a light yellow oil (dr = 8:1). 1H NMR (CDCl3): δ
= 7.14−7.12 (m, 3H), 6.93−6.89 (m, 6H), 6.01 (dd, J = 10.8, 2.3 Hz,
1H), 4.83−4.71 (m, 2H), 4.33 (td, J = 9.6, 3.4 Hz, 1H), 3.74 (t, J = 5.2
Hz, 2H), 3.63 (dt, J = 10.7, 3.6 Hz, 1H), 2.72 (t, J = 10.4 Hz, 1H), 2.25
(bs, 1H), 1.64−1.56 (m, 2H), 1.42−1.36 (m, 12H). 13C NMR
(CDCl3): δ = 161.8 (d, J = 245.8 Hz), 146.4 (d, J = 227.8 Hz), 141.1,
135.6 (d, J = 3.0 Hz), 129.5 (d, J = 7.7 Hz), 128.8, 128.3 (2C), 128.0,
127.7, 126.9, 118.9 (d, J = 22.9 Hz, 2C), 115.6 (d, J = 21.4 Hz), 79.5
(d, J = 8.1 Hz), 71.6 (d, J = 5.8 Hz), 71.5 (d, J = 5.7 Hz), 59.9, 52.0 (d,
J = 1.9 Hz), 47.3 (d, J = 12.6 Hz), 35.3, 24.1 (d, J = 4.1 Hz, 2C), 23.9
(d, J = 4.5 Hz, 2C). 31P NMR (CDCl3): δ = 6.06. 19F NMR (376
MHz, CDCl3): δ = −115.30. HRMS calculated for [C25H32FO5P +
Na]+: 485.1864; found: 485.1872. [α]2D8 = −100.3 (c = 0.52, MeCN).
Diisopropyl ((2R,3R,4S)-2-(2-Hydroxyethyl)-4-phenyl-3-(o-tolyl)-
3,4-dihydro-2H-pyran-6-yl)phosphonate (3n). Following the general
procedure (reaction time 24 h), 3n was isolated in 84% yield (0.0773
g) as a pale yellow oil (dr = 15:1). 1H NMR (CDCl3): δ = 7.23 (t, J =
7.6 Hz, 1H), 7.14−7.05 (m, 5H), 6.93 (d, J = 7.6 Hz, 1H), 6.82−6.80
(m, 2H), 6.07 (dd, J = 10.8, 2.3 Hz, 1H), 4.86−4.72 (m, 2H), 4.35 (t, J
= 9.9 Hz, 1H), 3.73 (bs, 2H), 3.66 (d, J = 10.5 Hz, 1H), 3.05 (t, J =
10.3 Hz, 1H), 2.22 (bs, 1H), 1.65−1.57 (m, 5H), 1.40 (dt, J = 13.9, 6.3
Hz, 12H). 13C NMR (CDCl3): δ = 146.7 (d, J = 228.2 Hz), 141.2,
Diisopropyl ((2R,3R,4S)-4-(4-Bromo-2-fluorophenyl)-2-(2-hy-
droxyethyl)-3-phenyl-3,4-dihydro-2H-pyran-6-yl)phosphonate (3i).
Following the general procedure (reaction time 24 h), 3i was isolated
1
in 78% yield (0.0842g) as a light yellow oil (dr = 8:1). H NMR
(CDCl3): δ = 7.24−7.18 (m, 3H), 7.13 (dd, J = 8.3, 1.9 Hz, 1H), 7.00
(dd, J = 9.7, 1.9 Hz, 1H), 6.95−6.90 (m, 3H), 5.90 (dd, J = 10.7, 2.2
Hz, 1H), 4.79−4.70 (m, 2H), 4.38 (td, J = 9.7, 3.1 Hz, 1H), 4.02 (dt, J
= 10.8, 3.0 Hz, 1H), 3.75 (t, J = 5.7 Hz, 2H), 2.84 (t, J = 10.4 Hz, 1H),
2.06 (bs, 1H), 1.71−1.57 (m, 2H), 1.41−1.35 (m, 12H). 13C NMR
(CDCl3): δ = 160.4 (d, J = 251.4 Hz), 146.6 (d, J = 227.1 Hz), 138.9,
130.5 (d, J = 5.1 Hz), 128.8, 128.5, 127.9, 127.5, 127.5, 127.4, 127.3,
120.7 (d, J = 9.7 Hz), 119.0 (d, J = 25.9 Hz), 117.6 (d, J = 23.2 Hz),
79.8 (d, J = 8.2 Hz), 71.6 (d, J = 5.7 Hz), 71.5 (d, J = 5.7 Hz), 59.9,
50.7, 40.2 (d, J = 13.3 Hz), 35.3, 24.0 (d, J = 4.2 Hz, 2C), 23.8 (t, J =
4.2 Hz, 2C). 19F NMR (CDCl3): δ = −114.9. 31P NMR (CDCl3): δ =
5.80. HRMS calculated for [C25H31BrFO5P + Na]+: 563.0969; found:
563.0977. [α]2D9 = −112.7 (c = 0.538, MeCN).
Diisopropyl ((2R,3R,4S)-2-(2-Hydroxyethyl)-4-methyl-3-phenyl-
3,4-dihydro-2H-pyran-6-yl)phosphonate (3j). Following the general
procedure (reaction time 48 h), 3j was isolated in 52% yield (0.0397
1
g) as a yellow oil (dr = 8:1). H NMR (CDCl3): δ = 7.33−7.30 (m,
2H), 7.24−7.22 (m, 1H), 7.09−7.07 (m, 2H), 5.88 (dd, J = 10.9, 2.1
Hz, 1H), 4.75−4.65 (m, 2H), 4.13 (td, J = 9.8, 3.1 Hz, 1H), 3.69 (t, J =
5.8 Hz, 2H), 2.55 (bs, 1H), 2.30 (t, J = 10.2 Hz, 2H), 1.60−1.50 (m,
2H), 1.36−1.32 (m, 12H), 0.87 (d, J = 7.0 Hz, 3H). 13C NMR
(CDCl3): δ = 144.9 (d, J = 227.8 Hz), 140.6, 128.9, 128.5, 128.4,
128.0, 127.1, 121.7 (d, J = 22.1 Hz), 79.9 (d, J = 8.0 Hz), 71.4 (d, J =
5.7 Hz), 71.3 (d, J = 5.5 Hz), 60.2, 52.1 (d, J = 1.8 Hz), 35.3, 34.9 (d, J
= 12.8 Hz), 24.0 (dd, J = 4.1, 2.5 Hz, 2C), 23.8 (dd, J = 4.6, 2.9 Hz,
2C), 18.6 (d, J = 1.5 Hz). 31P NMR (CDCl3): δ = 6.90. HRMS
calculated for [C20H31O5P + Na]+: 405.1801; found: 405.1805. [α]2D9
−13.4 (c = 1.07, MeCN).
=
Diisopropyl ((2R,3R,4S)-4-Ethyl-2-(2-hydroxyethyl)-3-phenyl-3,4-
dihydro-2H-pyran-6-yl)phosphonate (3k). Following the general
procedure (reaction time 48 h), 3k was isolated in 66% yield
1
(0.0523 g) as a dark yellow oil (dr = 7:1). H NMR (CDCl3): δ =
7.34−7.30 (t, J = 7.3 Hz, 2H), 7.25−7.23 (m, 1H),7.09−7.08 (d, J =
3543
dx.doi.org/10.1021/jo500347a | J. Org. Chem. 2014, 79, 3537−3546

The Journal of Organic Chemistry
Article
137.9 (d, J = 146.4 Hz), 130.1, 128.1, 127.7 (3C), 126.8, 126.7, 126.5
(2C), 125.9, 119.2 (d, J = 23.0 Hz), 80.6 (d, J = 7.9 Hz), 71.5 (dd, J =
9.7, 5.8 Hz, 2C), 60.5, 47.6 (d, J = 12.9 Hz), 47.0, 34.8, 24.1 (d, J = 4.2
Hz, 2C), 23.9 (d, J = 4.6 Hz, 2C), 19.4. 31P NMR (CDCl3): δ = 6.24.
HRMS calculated for [C26H35O5P + Na]+: 481.2114; found: 481.2113.
[α]2D8 = −95.1 (c = 0.445, MeCN).
Diisopropyl ((2R,3R,4S)-2-(2-Hydroxyethyl)-3-(4-methoxyphenyl)-
4-phenyl-3,4-dihydro-2H-pyran-6-yl)phosphonate (3o). Following
the general procedure (reaction time 24 h), 3o was isolated in 74%
yield (0.0701 g) as a pale yellow oil (dr = 10:1). 1H NMR (CDCl3): δ
= 7.14−7.12 (m, 3H), 6.85−6.80 (m, 4H), 6.75 (d, J = 8.7 Hz, 2H),
6.01 (dd, J = 10.8, 2.3 Hz, 1H), 4.83−4.71 (m, 2H), 4.34−4.28 (m,
1H), 3.74 (s, 5H), 3.65 (ddd, J = 10.5, 3.7, 2.4 Hz, 1H), 2.67 (t, J =
10.4 Hz, 1H), 2.24 (bs, 1H), 1.65−1.57 (m, 2H), 1.42−1.36 (m, 12H).
13C NMR (CDCl3): δ = 158.5, 146.2 (d, J = 227.5 Hz), 141.4, 131.7,
Diisopropyl ((2R,3S,4R)-2-(2-Hydroxyethyl)-4-phenyl-3-(thio-
phen-2-yl)-3,4-dihydro-2H-pyran-6-yl)phosphonate (3s). Following
the general procedure (reaction time 24 h), 3s was isolated in 64%
1
yield (0.0573 g) as a yellow oil (dr = 4:1). H NMR (CDCl3): δ =
7.19−7.14 (m, 4H), 6.95−6.92 (m, 2H), 6.83 (dd, J = 5.1, 3.5 Hz,
1H), 6.57 (d, J = 3.5 Hz, 1H), 5.97 (dd, J = 10.7, 2.3 Hz, 1H), 4.85−
4.69 (m, 2H), 4.31−4.26 (m, 1H), 3.77−3.68 (m, 3H), 3.11 (t, J =
10.3 Hz, 1H), 2.27 (bs, 1H), 1.76−1.67 (m, 2H), 1.42−1.36 (m,
12H).13C NMR (CDCl3): δ = 146.4 (d, J = 227.6 Hz), 142.5 (d, J =
1.3 Hz), 141.2, 128.7, 128.3, 128.2, 127.7, 127.0, 126.8, 125.7, 124.4,
118.6 (d, J = 22.9 Hz), 80.2 (d, J = 8.1 Hz), 71.6 (d, J = 6.4 Hz), 71.5
(d, J = 5.9 Hz), 60.0, 48.5 (d, J = 12.7 Hz), 48.3 (d, J = 2.0 Hz), 35.3,
24.1 (d, J = 4.2 Hz, 2C), 23.9 (d, J = 4.5 Hz, 2C). 31P NMR (CDCl3):
δ = 5.99. HRMS calculated for [C23H31O5PS + Na]+: 473.1522; found:
473.1523. [α]2D9 = −87.3 (c = 0.83, MeCN).
General Procedure for the Formation of Dihydroxy Pyrans.
An ordinary screw-cap vial was charged with 0.14 mmol (1 equiv) of
compound 3d or 3o and 1.4 mL of tBuOH/H2O solution (10:1).
Then, 0.28 mmol (2 equiv) of NMO was added, followed by 0.14
mmol (1 equiv) of Na2SO3 and 100 μL of 2.5% (w/w) solution of
OsO4 in tBuOH/H2O. The reaction mixture was stirred at rt and
129.0 (2C), 128.2 (2C), 127.8 (2C), 126.7, 119.2 (d, J = 22.9 Hz),
114.1 (2C), 80.0 (d, J = 8.0 Hz), 71.5 (d, J = 5.7 Hz), 71.4 (d, J = 5.7
Hz), 60.2, 55.1, 51.8 (d, J = 1.8 Hz), 47.1 (d, J = 12.8 Hz), 35.3, 24.1
(d, J = 4.2 Hz, 2C), 23.9 (d, J = 4.6 Hz, 2C). 31P NMR (CDCl3): δ =
6.23. HRMS calculated for [C26H35O6P + Na]+: 497.2063; found:
497.2069. [α]2D8 = −122.5 (c = 0.72, MeCN).
1
Diisopropyl ((2R,3R,4S)-3-(3,5-Dimethylphenyl)-2-(2-hydroxy-
ethyl)-4-phenyl-3,4-dihydro-2H-pyran-6-yl)phosphonate (3p). Fol-
lowing the general procedure (reaction time 24 h), 3p was isolated in
72% yield (0.0682 g) as a pale yellow oil (dr = 9:1). 1H NMR
(CDCl3): δ = 7.16−7.09 (m, 3H), 6.86−6.84 (m, 2H), 6.80 (s, 1H),
6.50 (s, 2H), 6.02 (dd, J = 10.8, 2.3 Hz, 1H), 4.84−4.72 (m, 2H),
4.34−4.28 (m, 1H), 3.75 (t, J = 5.8 Hz, 2H), 3.69 (dt, J = 10.4, 3.0 Hz,
1H), 2.65 (t, J = 10.3 Hz, 1H), 2.28 (s, 1H), 2.20 (s, 6H), 1.66−1.60
(m, 2H), 1.42−1.36 (m, 12H). 13C NMR (CDCl3): δ = 146.2 (d, J =
228.9 Hz), 140.6 (d, J = 193.5 Hz), 138.1 (3C), 128.7 (2C), 128.1
(2C), 127.8, 126.7 (2C), 125.9, 119.5 (d, J = 22.9 Hz), 80.15 (d, J =
8.0 Hz), 71.45 (d, J = 5.8 Hz), 71.35 (d, J = 5.6 Hz), 60.4, 52.4 (d, J =
1.8 Hz), 46.75 (d, J = 12.5 Hz), 35.4, 24.1 (d, J = 4.2 Hz), 23.9 (d, J =
3.5 Hz, 2C), 23.8 (d, J = 3.3 Hz), 21.3 (2C). 31P NMR (CDCl3): δ =
6.24. HRMS calculated for [C27H37O5P + Na]+: 495.2271; found:
495.2275. [α]2D9 = −128.1 (c = 0.54, MeCN).
monitored by H and 31P NMR spectroscopy. After the reaction time
given (3−5 h), the reaction was diluted with Et2O (20 mL) and
washed with brine (3 × 10 mL) and water (6 × 10 mL). The organic
phase was dried over Na2SO4, the solvent was removed under reduced
pressure, and the crude product was purified by FC on silica (eluent:
DCM/MeOH 100:0 → 200:1 → 200:2 → 200:3 → 200:4) to afford
compounds 5a,5b.
Diisopropyl ((2R,3R,4R,5R,6R)-2,3-Dihydroxy-6-(2-hydroxyethyl)-
5-phenyl-4-(p-tolyl)tetrahydro-2H-pyran-2-yl) (5a). Following the
aforementioned procedure, 5a was isolated in 50% yield (0.0342 g) as
a white solid (dr = 17:1). 1H NMR (CDCl3): δ = 7.13−6.92 (m, 9H),
5.88 (bs, 1H), 4.91−4.82 (m, 2H), 4.57−4.51 (m, 1H), 4.16 (dd, J =
10.4, 4.9 Hz, 1H), 3.80−3.76 (m, 1H), 3.61−3.56 (m, 1H), 3.46 (bs,
1H), 3.33 (t, J = 11.1 Hz, 1H), 3.20 (bs, 1H), 2.84 (t, J = 11.2 Hz,
1H), 2.18 (s, 3H), 1.51−1.47 (m, 2H), 1.44 (d, J = 6.2 Hz, 3H), 1.38
(t, J = 6.0 Hz, 9H). 13C NMR (CDCl3): δ = 138.8 (d, J = 1.6 Hz),
136.5 (d, J = 1.5 Hz), 135.9, 128.8 (4C), 128.3 (2C), 128.0 (2C),
126.6, 95.9 (d, J = 207.9 Hz), 73.5 (d, J = 6.9 Hz), 72.9 (d, J = 7.9 Hz),
72.1 (d, J = 9.1 Hz), 71.9 (d, J = 6.4 Hz), 59.6, 53.8 (d, J = 1.7 Hz),
48.9 (d, J = 8.9 Hz), 35.2, 24.4 (d, J = 2.5 Hz), 24.1 (d, J = 3.6 Hz),
23.9 (d, J = 4.8 Hz), 23.6 (d, J = 5.5 Hz), 21.0. 31P NMR (CDCl3): δ =
15.59. HRMS calculated for [C26H37O7P + Na]+: 515.2169; found:
515.2175. [α]2D5 = −29.9 (c = 1.00, MeCN).
Diisopropyl ((2R,3R,4R,5R,6R)-2,3-Dihydroxy-6-(2-hydroxyethyl)-
5-(4-methoxyphenyl)-4-phenyltetrahydro-2H-pyran-2-yl)phos-
phonate (5b). Following the aforementioned procedure, 5b was
isolated in 54% yield (0.0384 g) as a white solid (dr = 15:1). 1H NMR
(CDCl3): δ = 7.16−7.12 (m, 2H), 7.07−7.06 (m, 3H), 6.94−6.88 (m,
2H), 6.64 (d, J = 8.2 Hz, 2H), 4.91−4.81 (m, 2H), 4.52−4.47 (m,
1H), 4.19 (dd, J = 10.4, 4.9 Hz, 1H), 3.81−3.71 (m, 2H), 3.67 (s, 3H),
3.12−3.57 (m, 1H), 3.30 (t, J = 11.1 Hz, 2H), 2.79 (t, J = 11.2 Hz,
1H), 1.51−1.47 (m, 2H), 1.43 (d, J = 6.2 Hz, 3H), 1.39−1.36 (m,
10H). 13C NMR (CDCl3): δ = 158.1, 139.9, 130.7 (d, J = 1.5 Hz),
128.3 (2C), 128.1 (4C), 126.5, 113.7 (2C), 95.9 (d, J = 207.8 Hz),
73.5 (d, J = 6.9 Hz), 72.9 (d, J = 8.0 Hz), 72.4 (d, J = 10.8 Hz), 71.9
(d, J = 8.4 Hz), 59.8, 55.0, 53.0 (d, J = 1.7 Hz), 49.6 (d, J = 8.9 Hz),
35.1, 24.4 (d, J = 2.4 Hz), 24.0 (d, J = 3.8 Hz, 2C), 23.6 (d, J = 5.4
Hz). 31P NMR (CDCl3): δ = 15.50. HRMS calculated for [C26H37O8P
+ Na]+: 531.2118; found: 531.2121. [α]2D5 = −36.2 (c = 1.41, MeCN).
General Procedure for the Formation of α-Hydroxy
Lactones from Dihydroxy Pyrans. An ordinary screw-cap vial
was charged with 0.17 mmol (1 equiv) of compound 5a or 5b, 0.68
mmol (4 equiv) of DMAP, and CH2Cl2 (1.7 mL). The reaction was
stirred overnight at rt. Then, the reaction mixture was diluted with
Et2O (10 mL) and washed with 0.5 M HCl (3 × 10 mL) and water (3
× 10 mL). The organic layer was dried over Na2SO4, the solvent was
removed under reduced pressure, and the crude product was purified
by FC on silica (eluent: CH2Cl2/MeOH 100:0 → 200:1 → 200:2 →
200:3 → 200:4) to afford compounds 6a,6b.
Diisopropyl ((2R,3R,4S)-3-(Benzo[d][1,3]dioxol-5-yl)-2-(2-hy-
droxyethyl)-4-phenyl-3,4-dihydro-2H-pyran-6-yl)phosphonate (3q).
Following the general procedure (reaction time 24 h), 3q was isolated
1
in 80% yield (0.0783 g) as a pale yellow oil (dr = 11:1). H NMR
(CDCl3): δ = 7.17−7.13 (m, 3H), 6.89−6.87 (m, 2H), 6.63 (d, J = 7.9
Hz, 1H), 6.44 (d, J = 1.6 Hz, 1H), 6.33 (dd, J = 7.9, 1.7 Hz, 1H), 6.00
(dd, J = 10.8, 2.3 Hz, 1H), 5.91 (d, J = 6.9 Hz, 2H), 4.77−4.71 (m,
2H), 4.26−4.23 (m, 1H), 3.75 (s, 2H), 3.63 (dt, J = 10.5, 3.0 Hz, 1H),
2.66 (t, J = 10.4 Hz, 1H), 2.24 (bs, 1H), 1.64−1.61 (m, 2H), 1.41−
1.34 (m, 12H). 13C NMR (CDCl3): δ = 147.4 (d, J = 146.7 Hz),
147.3, 145.2, 141.3, 133.5, 128.7, 128.3, 128.0, 127.8, 126.8, 121.5,
119.1 (d, J = 22.9 Hz), 108.4, 107.9, 101.0, 79.1 (d, J = 8.1 Hz), 71.5
(d, J = 5.7 Hz), 71.4 (d, J = 5.8 Hz), 60.2, 52.3 (d, J = 2.0 Hz), 47.1 (d,
J = 12.7 Hz), 35.3, 24.1 (d, J = 4.2 Hz, 2C), 23.9 (d, J = 4.5 Hz, 2C).
31P NMR (CDCl3): δ = 6.14. HRMS calculated for [C26H33O7P +
Na]+: 511.1856; found: 511.1859. [α]2D5 = −114.9 (c = 1.65, MeCN).
Diisopropyl ((2R,3R,4S)-3-([1,1′-Biphenyl]-2-yl)-2-(2-hydroxy-
ethyl)-4-phenyl-3,4-dihydro-2H-pyran-6-yl)phosphonate (3r). Fol-
lowing the general procedure (reaction time 24 h), 3r was isolated in
1
70% yield (0.0732 g) as a pale yellow oil (dr = > 20). H NMR
(CDCl3): δ = 7.45−7.41 (m, 1H), 7.35−7.31 (m 2H), 7.26−7.12 (m,
7H), 7.02 (d, J = 7.2 Hz, 2H), 6.72 (d, J = 8.1 Hz, 2H), 5.99 (dd, J =
10.8, 2.3 Hz, 1H), 4.87−4.68 (m, 2H), 4.27−4.21 (m, 1H), 3.80−3.76
(m, 1H), 3.67 (bs, 2H), 2.84 (t, J = 10.3 Hz, 1H), 2.17 (bs, 1H), 1.54−
1.49 (m, 2H), 1.36−1.29 (m, 12H). 13C NMR (CDCl3): δ = 146.58
(d, J = 228.7 Hz), 143.7, 140.9 (d, J = 63.5 Hz), 137.7, 130.1, 129.2
(2C), 128.3 (2C), 128.2 (2C), 128.1, 127.5 (2C), 126.9, 126.6, 126.3,
126.1 (2C), 119.1 (d, J = 22.9 Hz), 80.9 (d, J = 7.7 Hz), 71.5 (d, J =
4.6 Hz), 71.4 (d, J = 4.4 Hz), 60.6, 47.2 (d, J = 12.7 Hz), 46.9, 34.9,
24.1 (d, J = 4.3 Hz), 24.0 (d, J = 4.4 Hz), 23.9 (d, J = 4.7 Hz), 23.7 (d,
J = 4.5 Hz). 31P NMR (CDCl3): δ = 6.17. HRMS calculated for
[C31H37O5P + Na]+: 543.2271; found: 543.2273. [α]2D5 = −70.3 (c =
1.6, MeCN).
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General Procedure for One-Pot Formation of α-Hydroxy
Lactones. An ordinary screw-cap vial was charged with 0.14 mmol (1
equiv) of compound 3d or 3o and 1.4 mL of tBuOH/H2O solution
(10:1). Then, 0.28 mmol (2 equiv) of NMO was added, followed by
0.14 mmol (1 equiv) of Na2SO3 and 100 μL of 2.5% (w/w) solution of
OsO4 in tBuOH/H2O. The reaction mixture was stirred at rt and
ASSOCIATED CONTENT
* Supporting Information
■
S
Screening of temperature and equivalents of aldehyde;
calculation of the dihedral angle; X-ray structures of
1
compounds 6a and 3a; H and 13C NMR spectra of aldehydes
1
1h, 1e, and 1f; H, 31P, and 13C NMR of α,β-unsaturated acyl
1
monitored by H and 31P NMR spectroscopy. After the reaction time
1
given (3−5 h), 0.56 mmol (4 equiv) of DMAP was added and the
reaction was stirred overnight at rt. The reaction was diluted with Et2O
(20 mL) and washed with 0.5 M HCl (3 × 10 mL), brine (3 × 10
mL), and water (6 × 10 mL). The organic phase was dried over
Na2SO4, the solvent was removed under reduced pressure, and the
crude product was purified by FC on silica (eluent: CH2Cl2/MeOH
100:0 → 200:1 → 200:2 → 200:3 → 200:4) to afford compounds
6a,6b.
(3R,4R,5R,6R)-3-Hydroxy-6-(2-hydroxyethyl)-5-phenyl-4-(p-tolyl)-
tetrahydro-2H-pyran-2-one (6a). Following the aforementioned
procedures, 6a was isolated as a single diastereoisomer in 44% yield
(0.0243 g) (method A) and 49% yield (0.0226 g) (method B) as a
white solid with a mp 137.4−138.7 °C. 1H NMR (CDCl3): δ = 7.20−
7.10 (m, 3H), 7.03 (d, J = 7.5 Hz, 2H), 6.98−6.94 (m, 4H), 4.84 (ddd,
J = 11.7, 9.0, 3.2 Hz, 1H), 4.45 (d, J = 11.0 Hz, 1H), 3.82−3.71 (m,
2H), 3.41 (t, J = 11.5 Hz, 1H), 3.28−3.22 (m, 2H), 2.20 (s, 3H),
1.88−1.72 (m, 2H), 1.66 (bs, 1H). 13C NMR (CDCl3): δ = 173.4,
137.0, 136.7, 134.9, 129.2 (2C), 128.8 (2C), 128.3 (2C), 127.5 (3C),
83.4, 72.0, 58.7, 51.9, 51.2, 36.4, 21.0. HRMS calculated for [C20H22O4
+ Na]+: 349.1410; found: 349.1413. [α]2D5 = −30.9 (c = 0.493,
MeCN).
phosphonates; H, 31P, and 13C NMR of the dihydropyran
phosphonates; and 1H, 31P, and 13C NMR of the dihydropyran
derivatives. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: kaj@chem.au.dk.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was made possible by grants from Aarhus University,
FNU, and the Carlsberg Foundation. Thanks are expressed to
Ph.D. Espen Eikeland (Department of Chemistry, Aarhus
University) for performing X-ray analysis. R.S.R. thanks CNPq/
CsF for a fellowship.
REFERENCES
(1) Diels, O.; Alder, K. Liebigs Ann. 1928, 460, 98.
■
(3R,4R,5R,6R)-3-Hydroxy-6-(2-hydroxyethyl)-5-(4-methoxy-
phenyl)-4-phenyltetrahydro-2H-pyran-2-one (6b). Following the
aforementioned procedures, 6b was isolated as a single diaster-
eoisomer in 43% yield (0.0252 g) (method A) and 61% yield (0.0293
g) (method B) as a white solid. 1H NMR (CDCl3): δ = 7.18 (t, J = 7.4
Hz, 2H), 7.12 (d, J = 7.2 Hz, 1H), 7.09−7.05 (m, 2H), 6.93 (d, J = 8.6
Hz, 2H), 6.69 (d, J = 8.6 Hz, 2H), 4.82−4.77 (m, 1H), 4.46 (d, J =
11.1 Hz, 1H), 3.81−3.73 (m, 2H), 3.70 (s, 3H), 3.39 (t, J = 11.5 Hz,
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P
NMR spectroscopy) at rt. The reaction mixture was diluted with Et2O
(10 mL) and washed with brine (3 × 10 mL) and water (6 × 10 mL).
The organic layer was dried over Na2SO4, the solvent was removed
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1
isolated in 71% yield (0.0671 g) as a white solid (dr = 18:1:1). H
NMR (CDCl3): δ = 8.10 (s, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.51 (d, J =
7.8 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.24 (s, 1H), 7.15 (d, J = 4.4 Hz,
3H), 7.08−7.03 (m, 1H), 4.94−4.79 (m, 2H), 4.62−4.56 (m, 1H),
4.45 (d, J = 11.5 Hz, 1H), 4.31 (d, J = 2.8 Hz, 1H), 3.97−3.82 (m,
2H), 3.51−3.46 (m, 2H), 1.65−1.55 (m, 2H), 1.50 (d, J = 6.1 Hz,
3H), 1.47 (d, J = 6.2 Hz, 3H), 1.44 (s, 1H), 1.40 (d, J = 6.1 Hz, 3H),
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1.4 Hz), 138.0 (d, J = 1.4 Hz), 135.7, 128.8 (3C), 128.6 (2C), 127.1,
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