Trans-selective rhodium catalysed conjugate addition of organoboron reagents to dihydropyranones

Article abstract of DOI:10.3390/molecules20046153

The selective synthesis of 2,6-trans-tetrahydropyran derivatives employing the rhodium catalysed addition of organoboron reagents to dihydropyranone templates, derived from a zinc-catalysed hetero-Diels-Alder reaction, is reported. The addition of both arylboronic acids and potassium alkenyltrifluoroborates have been accomplished in high yields using commercially-available [Rh(cod)(OH)]₂ catalyst. The selective formation of the 2,6-trans-tetrahydropyran stereoisomer is consistent with a mechanism involving alkene association and carbometalation on the less hindered face of the dihydropyranone.

Full text of DOI:10.3390/molecules20046153

Molecules 2015, 20, 6153-6166; doi:10.3390/molecules20046153
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Trans-Selective Rhodium Catalysed Conjugate Addition of
Organoboron Reagents to Dihydropyranones
Hannah J. Edwards, Sean Goggins and Christopher G. Frost *
Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK;
E-Mails: han.j.edwards@gmail.com (H.J.E.); sg297@bath.ac.uk (S.G.)
* Author to whom correspondence should be addressed; E-Mail: c.g.frost@bath.ac.uk;
Tel.: +44-(0)1225-386142; Fax: +44-(0)1225-386231.
Academic Editor: John Spencer
Received: 10 March 2015 / Accepted: 1 April 2015 / Published: 8 April 2015
Abstract: The selective synthesis of 2,6-trans-tetrahydropyran derivatives employing the
rhodium catalysed addition of organoboron reagents to dihydropyranone templates, derived
from a zinc-catalysed hetero-Diels-Alder reaction, is reported. The addition of both
arylboronic acids and potassium alkenyltrifluoroborates have been accomplished in high
yields using commercially-available [Rh(cod)(OH)]2 catalyst. The selective formation of the
2,6-trans-tetrahydropyran stereoisomer is consistent with a mechanism involving alkene
association and carbometalation on the less hindered face of the dihydropyranone.
Keywords: boronic acids; conjugate addition; rhodium; tetrahydropyran
1. Introduction
The rhodium-catalysed conjugate addition of organometallic donors has evolved into a versatile tool
for the assembly of complex molecules and intermediates in natural product synthesis [1–6]. The
mechanistic and stereochemical aspects of the reaction have been thoroughly investigated for additions
to prochiral substrates [7] and processes involving enantioselective protonation [8–10]. When the
addition occurs to a chiral acceptor, the diastereoselectivity can be controlled by substrate [11],
ligand [12] or organometallic donor [13]. Tetrahydropyran (THP) rings are a prevalent feature in natural
products and such compounds frequently have important biological activities (Figure 1). In this context,
the selective assembly of the 2,6-trans-tetrahydropyran subunit is a significant challenge [14].

Molecules 2015, 20
6154
A powerful methodology for the construction of 6-membered heterocycles is the hetero-Diels-Alder
(HDA) cycloaddition [15]. This has been a key reaction for the synthesis of many THP containing natural
products [16,17]. In this paper, we describe a general selective synthesis of 2,6-trans-tetrahydropyran
derivatives employing the rhodium-catalysed addition of organoboron reagents to dihydropyranone
templates derived from a HDA reaction.
Me
OMe
O
OMe
OH
OH
N
H
O
H
Me
Me
OH
O
Me
OH
Me
H
Ph
O
Ph
HO
Diospongin B
Psymberin
O
OH
Me
O
O
O
OH
O
O
H
HO
N
O
4
4
OH
(+)-Broussonetine G
Spirolaxine
OMe
HO
MeO
Figure 1. Representative examples of 2,6-trans-tetrahydropyran natural products.
2. Results and Discussion
The required 5,6-dihydro-2H-pyranones, can be accessed using a zinc-catalysed HDA reaction of
Danishefsky’s Diene 1 and an aldehyde heterodienophile [18]. As illustrated in Scheme 1, the use of
benzaldehyde 2 results in an efficient synthesis of rac-2-phenyl-2,3-dihydro-pyran-4-one 3 in 98%
isolated yield. Initial investigations into the rhodium-catalysed addition of phenylboronic acid 4 to 3
were carried out using 3 mol % [Rh(OH)(cod)]2 with additional ligand in dioxane:water (10:1) at 80 °C.
1H-NMR and chiral HPLC analysis of the isolated product indicated the formation of rac-2,6-trans-
diphenyltetrahydropyran 5 in excellent yield.
TMSO
O
+
Ph
H
ZnCl2 (3 mol%)
THF
OMe
1
2
98%
O
O
O
O
Ph B(OH)2
4
[Rh(OH)COD]2 (3 mol%)
Ph
O
Ph
Ph
Ph
Ph
O
3
COD (6 mol%)
KOH (2 equiv)
dioxane:H2O (10:1)
trans-5 94%
cis-5 not isolated
Scheme 1. Catalytic synthesis of 2,6-trans-tetrahydropyran derivatives.
A successful catalytic conjugate addition is dependent on an efficient transmetalation of the
organoboronic acid to rhodium followed by carbometallation to afford an η3-oxa-π-allylrhodium complex
that is protonated to afford the product. A number of detailed mechanistic studies for rhodium-catalysed

Molecules 2015, 20
6155
conjugate addition to cyclic and acyclic, activated alkenyl species have been reported [1–6]. The
selective formation of the 2,6-trans-tetrahydropyran stereoisomer is consistent with a mechanism
involving alkene association and carbometalation on the less hindered face of the dihydropyranone,
which affords the 2,6-trans-tetrahydropyran derivative on protonation of the rhodium oxa-π-allyl species
(Figure 2).
O
O
O
Ar2 B(OH)2
cat. [Rh]
KOH
Ar1
O
Ar2
Ar1
O
Ar1
O
Ar2
trans - product
cis - not observed
[Rh] OH
transmetalation
[Rh] Ar2
[Rh] OH
H2O
protonation
O
O
O
O
O
[Rh]
carbometalation
Ar1
[Rh]
Ar2
[Rh]
Ar2
Ar1
Ar1
O
Ar2
Figure 2. Mechanistic steps and origin of trans-selectivity.
Following these successful initial results, a small range of functionalised 2,3-dihydropyran-4-one
substrates were prepared using the zinc-catalysed HDA reaction (Figure 3). It is interesting to note that
in many of the 2,6-trans-tetrahydropyran natural products, alkyl chains appear more frequently than aryl
groups. Since the use of alkenylboronates in rhodium catalysed additions is well established, this tactical
approach presents a synthetic opportunity to install a broad array of functionality from either HDA or
conjugate addition. To establish useful scope for synthetic applications it was important to establish
whether similar stereocontrol would be maintained in the addition of both aryl- and alkenylboronates.
O
O
O
TBSO
O
O
TBSO
O
MeO
6
7
8
Figure 3. 2,3-Dihydropyran-4-one substrates.
We have previously noted that alkenyltrifluoroborate salts offer practical advantages in terms of
stability and product yield in rhodium-catalysed conjugate addition reactions [19]. This is proposed to
be due to the slow release of alkenylboronic acid and a concommitant reduction in competing
protodeboronation pathways [20]. Therefore, rhodium-catalysed conjugate additions of arylboronic
acids and potassium alkenyltrifluoroborates to the 2,3-dihydropyran-4-one substrates were explored. The
optimised conditions for the addition of both arylboronic acids and potassium alkenyltrifluoroborates
employed commercially-available [Rh(cod)(OH)]2 catalyst with added cycloctadiene ligand to limit
catalyst decomposition. A diverse range of organoboronates were shown to successfully participate in
the conjugate addition to 2,3-dihydropyran-4-ones affording the products 9–17 as the trans isomer
(Scheme 2).

Molecules 2015, 20
6156
R2 B(OH)2
or
O
O
O
R2 BF3K
[Rh(OH)COD]2 (3 mol%)
R1
R2
O
R1
COD (6 mol%)
KOH (2 equiv)
dioxane:H2O (10:1)
trans-9-17
O
O
O
O
O
F
Me
Me
Ph
Ph
Ph
Ph
O
trans-9 (78%)
trans-10 (77%)
trans-11 (98%)
F
O
O
O
O
O
O
MeO
OMe MeO
trans-12 (58%)
trans-13 (75%)
O
O
Me
TBSO
Ph
O
O
5
trans-14 (81%)
trans-15 (64%)
MeO
O
O
TBSO
O
Ph
HO
O
O
Ph
trans-16 (37%)
trans-17 (81%)
Scheme 2. Catalytic synthesis of racemic 2,6-trans-tetrahydropyran derivatives.
The synthetic potential of this selective process was next explored with an enantiopure acceptor
(Scheme 3). In this context, a suitable asymmetric synthesis of 2-phenyl-2,3-dihydro-pyran-4-one 3 was
required. For catalytic asymmetric HDA reactions, a wide-range of chiral Lewis acid complexes have
been successfully employed [21]. In particular, the use of Ti(OPri)4 in combination with H8-BINOL
offers excellent enantioselectivites and high yields for a wide range of dihydropyrones [22]. Under the
reported conditions (S)-3 was obtained in 85% yield and 90% ee. This would serve as a useful probe for
the stereoselectivity of the catalytic conjugate addition and afford enantioenriched products. Pleasingly,
the optimised conditions were effective for the addition of both arylboronic acids (products 5, 11 and
19) and potassium alkenyltrifluoroborates (products 9, 10 and 18). No erosion of enantiopurity was
observed in the products indicating a highly stereoselective trans addition. The tetrahydropyran
derivatives 5 and 9 were scaled-up and it was possible to recrystallise the products to amplify the ee to
>99%. Confirmation of enantiopurity was established via NMR spectroscopic analysis, by the appearance
of only one set of diastereotopic coupling signals in all environments and via chiral HPLC analysis.

Molecules 2015, 20
6157
O
R2 B(OH)2
or
O
O
O
O
Ph
H
TMSO
2
R2 BF3K
Ti(iOPr)4
(R)-H8-BINOL
[Rh(OH)COD]2 (3 mol%)
Ph
R2
Ph
COD (6 mol%)
KOH (2 equiv)
dioxane:H2O (10:1)
OMe
1
Toluene
trans-product
S-3 90% ee
O
O
O
O
Me
Ph
Ph
Ph
O
Ph
Ph
O
Me
(S,S)-5 (96%)
(S,S)-9 (63%)
(S,S)-10 (77%)
90% ee (>99% ee)
90% ee (>99% ee)
90% ee
O
O
O
O
F
C5H11
Ph
O
Ph
O
Ph
Br
(S,S)-11 (>98%)
(S,S)-18 (72%)
(S,S)-19 (>98%)
F
90% ee
90% ee
90% ee
Scheme 3. Catalytic, stereoselective additions to enantioenriched S-3.
3. Experimental Section
3.1. General Remarks
All reactions were carried out under an atmosphere of nitrogen, in oven-dried glassware unless
otherwise stated. Dichloromethane, tetrahydrofuran (THF) and toluene were dried and degassed by
passing through anhydrous alumina columns using an Innovative Technology Inc. PS-400-7 solvent
purification system and stored under an atmosphere of argon prior to use. Proton, carbon, fluorine and
phosphorus nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance 300 or 400
spectrometer (1H-NMR at 300 or 400 MHz, 13C-NMR at 75.5 or 101 MHz, 19F-NMR at 376.5 MHz and
31P-NMR at 121.5 MHz). Chemical shifts for protons are reported downfield from tetramethylsilane and
are referenced to residual protium in the solvent (1H-NMR: CHCl3 at 7.26 ppm, DMSO at 2.50 ppm,
H2O at 4.79 ppm). Chemical shifts for carbons are reported in parts per million downfield from
tetramethylsilane and are referenced to the carbon resonances of the solvent peak (13C-NMR: CDCl3 at
77.0 ppm, DMSO-d6 at 39.5 ppm). IR spectra were recorded on a Perkin-Elmer 1600 FT IR
spectrophotometer, with absorbencies quoted as ν in cm−1. High resolution mass spectrometry (HRMS)
was performed on a µTOF electrospray time-of-flight (ESI-TOF) mass spectrometer (Bruker Daltonik).
Enantiomeric excesses were determined using HPLC performed on a perkin Elmer IBN series system
using chiralcel columns with a UV detector at 254 nm. Melting points were obtained on a Bibby-Sterilin
SMP10 melting point machine and are uncorrected.
3.2. General Procedure for the Synthesis of Racemic Dihydropyranones
To a flame dried flask under an atmosphere of argon was added ZnCl2 (39 mg, 0.28 mmol, 3 mol %)
and anhydrous diethyl ether (0.4 mL, 3 mol %). Anhydrous THF (100 mL) was added followed by

Molecules 2015, 20
6158
freshly-purified aldehyde (9.42 mmol, 1.0 eq). The reaction was stirred for 10 min before dropwise
addition of Danishefsky’s Diene (1) (2.7 mL, 14.13 mmol, 1.5 eq). The reaction was stirred overnight at
room temperature and then filtered through celite and concentrated. The crude product was purified by
flash column chromatography to afford the respective dihydropyranones.
3.3. Synthesis of Racemic 2-Phenyl-2,3-dihydropyran-4-one (3)
Freshly distilled benzaldehyde (0.96 mL, 9.42 mmol) was reacted under the standard procedure and
the crude product purified by flash column chromatography (eluting with petrol:ethyl acetate 8:2) to
afford the title compound as a red oil (1.2 g, 73% yield).
Rf (petrol:ethyl acetate, 7:3); 0.29; νmax (CH2Cl2)/cm−1; 3063 (C-H), 1722 (C=O), 1670 (C=C), 1593,
1583 (C=C), 1268, 1037 (C-O); δH (300 MHz; CDCl3); 7.48 (1H, dd, J = 6.0, 0.5 Hz, OCH), 7.44–7.35
(5H, m, ArH), 5.52 (1H, dd, J = 6.0 Hz, 1.3 Hz, CHCO), 5.43 (1H, dd, J = 14.4, 3.5 Hz, CH2CHAr),
2.91 (1H, dd, J = 16.9, 14.3 Hz, COCHH), 2.66 (ddd, J = 16.9, 3.5, 1.3 Hz, COHH); δC (75.5 MHz;
CDCl3); 192.1, 163.2, 137.9, 129.0, 128.9, 126.2, 107.4, 81.1, 43.4; HRMS (ESI+) calcd for C11H10NaO2
[M+Na+] m/z 197.0579 found: m/z 197.0590.
All data in accordance with literature values [22].
3.4. Synthesis of Racemic 2-[2-(4-Methoxyphenyl)vinyl]-2,3-dihydropyran-4-one (6)
Recrystallised 4-methoxycinnamaldehyde (1.0 g, 6.17 mmol) was reacted under the standard
procedure and the crude product purified by flash column chromatography (eluting with petrol:ethyl
acetate 8:2) to afford the title compound as an orange solid (0.28g, 20% yield).
Rf (petrol:ethyl acetate, 4:1); 0.29; δH (300 MHz; CDCl3); 7.40 (2H, d, J = 6.0 Hz, ArH), 7.34 (1H, d,
J = 8.5 Hz, OCHCH), 6.87 (2H, d, J = 8.5 Hz, ArH), 6.70 (1H, d, J 15.9 Hz, ArCHCH), 6.16 (1H, dd,
J = 15.9, 6.8 Hz, ArCHCH), 5.46 (1H, d, J = 6.0 Hz, COCH), 5.07–5.00 (1H, m, CH2CHO), 3.81 (3H,
s, OCH3), 2.78–2.56 (2H, m, CH2CO); δC (75.5 MHz; CDCl3); 192.2, 163.2, 150.0, 133.6, 128.2, 128.1,
122.7, 114.1, 107.3, 80.1, 55.4, 42.1; HRMS (CI+) calcd for C14H15O3 [M+H]+ /z 231.1016 found:
m/z. 231.1059.
All data in accordance with literature values [22].
3.5. Synthesis of Racemic 2-[5-(tert-Butyldimethylsilanyloxy)pentyl]-2,3-dihydropyran-4-one (7)
6-(tert-Butyldimethylsilanyloxy)hexanal (1.0 g, 4.09 mmol) was reacted under the standard
procedure and the crude product purified by flash column chromatography (eluting with petrol:ethyl
acetate 9:1) to afford the title compound as a yellow oil (0.990 g, 81% yield).
Rf (petrol:ethyl acetate, 4:1); 0.56; δH (300 MHz; CDCl3); 7.35 (1H, d, J = 5.9 Hz, CHCHO), 5.39 (1H,
dd, J = 5.9, 1.0 Hz, CHCHO), 4.39 (1H, ddt, J = 12.7, 7.7, 4.6 Hz, CH2CHCH2), 3.61 (2H, t, J = 6.3 Hz,
CH2OSi), 2.52 (1H, dd, J = 16.7, 12.9 Hz, COCHH), 2.42 (1H, ddd, J = 16.7, 4.3, 1.0 Hz, COCHH),
1.89–1.64 (2H, m, CHCH2CH2), 1.58–1.49 (2H, m, CH2CH2OSi), 1.48–1.33 (4H, m, (CH2)2(CH2)2OSi),

Molecules 2015, 20
6159
0.89 (9H, s, SiC(CH3)3), 0.04 (6H, s, Si(CH3)2); δC (75.5 MHz; CDCl3); 192.9, 163.4, 107.0, 79.6, 63.0,
41.9, 34.5, 32.7, 26.0, 25.7, 24.7, 18.4, −5.2; HRMS (ESI+) calcd for C16H30O3Si [M+H]+ m/z 299.2037
found: m/z 299.2052.
All data in accordance with literature values [23].
3.6. Synthesis of Racemic 2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-2,3-dihydropyran-4-one (8)
3-(tert-butyldimethylsilanyloxy)propionaldehyde (1.0 g, 9.336 mmol) was reacted under the standard
procedure and the crude product purified by flash column chromatography (eluting with petrol:ethyl
acetate 4:1) to afford the title compound as a yellow oil (0.400 g, 39% yield).
Rf (petrol:ethyl acetate, 4:1); 0.51; δH (300 MHz; CDCl3); 7.35 (1H, d, J = 6.0 Hz, OCH), 5.41 (1H, dd,
J = 6.0, 1.0 Hz, CHCO), 4.67–4.57 (1H, m, OCHCH2), 3.85–3.71 (2H, m, OCH2), 2.63–2.43 (2H, m,
COCH2), 2.07–1.96 (1H, m, CHCHHCH2), 1.90–1.79 (1H, m, CHCHHCH2), 0.89 (9H, s, SiC(CH3)3),
0.05 (6H, s, Si(CH3)2); δC (75.5 MHz; CDCl3); 192.7, 163.2, 107.2, 58.4, 42.1, 37.4, 26.0, 18.4, −5.32,
−5.36; HRMS (ESI+) calcd for C13H25O3 [M+H]+ m/z 257.1572 found: m/z 257.1536.
All data in accordance with literature values [23].
3.7. Synthesis of (S)-2-Phenyl-2,3-dihydropyran-4-one ((S)-3)
A mixture of (R)-H8-BINOL (0.610 g, 2.07 mmol) and Ti(OiPr)4 (0.56 mL, 1.884 mmol) with
activated 4 Å molecular sieves (4.54 g) in anhydrous toluene (38 mL) under an inert atmosphere was
heated at 35 °C for 1 h. The yellow mixture was cooled to room temperature and freshly distilled
benzaldehyde (0.96 mL, 9.42 mmol, 1.0 eq) added. After stirring for 10 min the mixture was cooled to
0 °C and Danishefsky’s diene (11.3 mmol, 1.2 eq) was added. The reaction was stirred at 0 °C for 24 h
and then treated with trifluoroacetic acid (0.1 mL). After stirring for a further 15 min at 0 °C, NaHCO3
(10 mL) was added and the reaction stirred for 10 min and then filtered through a plug of celite. The
organic layer was then separated and the aqueous extracted with diethylether (3 × 25 mL). The combined
organic extracts were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by
flash chromatography (eluting with petrol:ethyl acetate 8:2) to afford the title compound as a red oil (1.2 g,
73% yield). The chromatographed material was determined to be in 90% ee by chiral HPLC analysis
(Chiralcel OD, 9:1 Hexanes: propan-2-ol, 1.0 mL·min−1, tR = 11.22 min (major) and 13.23 min (minor).
[α]20
Rf (petrol:ethyl acetate, 7:3); 0.29;
= +81° (c = 0.8, CHCl3); νmax (CH2Cl2)/cm−1; 3063 (C-H), 1722
D
(C=O), 1670 (C=C), 1593, 1583 (C=C), 1268, 1037 (C-O)δH (300 MHz; CDCl3); 7.48 (1H, dd, J = 6.0,
0.6 Hz, OCHCH), 7.44–7.38 (5H, m, ArH), 5.53 (1H, dd, J = 6.0 Hz, 1.2 Hz, CHCO), 5.43 (1H, dd,
J = 14.4, 3.5 Hz, CH2CHAr), 2.91 (1H, dd, J = 17.0, 14.4 Hz, COCHH), 2.66 (ddd, J = 17.0, 3.5, 1.3
Hz, COHH); δC (75.5 MHz; CDCl3); 192.2, 163.2, 137.9, 129.0, 128.9, 126.2, 107.5, 81.2, 43.5; HRMS
(ESI+) calcd for C11H10NaO2 [M+Na]+ m/z 197.0579 found: m/z 197.0590.
All data in accordance with literature values [22].

Molecules 2015, 20
6160
3.8. General Procedure for the Rhodium-Catalysed Conjugate Additions to Dihydropyranones
An oven dried, 24 mL screw-capped vial equipped with a rubber septum was charged with
organoboron reagent (0.228 mmol, 2.0 eq), [Rh(OH)(cod)]2 (0.0016 g, 0.00342 mmol, 3 mol %),
cyclooctadiene (0.007 g, 0.00684 mmol) and potassium hydroxide (0.009 g, 0.228 mmol). The reaction
vessel was purged with argon and dioxane (0.5 mL) and water (0.05 mL) were subsequently added by
syringe. The red solution was stirred for 15 minutes at room temperature, before the addition of
dihydropyranone (0.114 mmol, 1.0 eq). The reaction was transferred to a preheated hotplate at 80 °C for
20 h. Upon completion, the crude reaction mixture was taken up in diethyl ether (5 mL) and filtered
through a short plug of silica (elution; diethyl ether) and the solvent removed in vacuo. The crude residue
was purified by flash column chromatography on silica gel to afford the desired compounds.
3.9. Synthesis (2S,6S)-Diphenyltetrahydropyran-4-one (5)
Phenylboronic acid (0.210 g, 1.72 mmol) was treated with (S)-2-phenyl-2,3-dihydropyran-4-one ((S)-3)
(0.150 g, 0.86 mmol) under the standard conditions. The crude residue was purified by flash column
chromatography on silica gel (eluting with petrol:ethyl acetate 9:1) to afford the title compound as a
white solid (0.207 g, 96% yield).
[α]20
Rf (petrol:ethyl acetate, 4:1); 0.47;
= −16° (c = 1, CHCl3); νmax (CH2Cl2)/cm−1; 3067, 3066, 2974,
D
2886 (C-H), 1714 (C=O), 1601 (C=C aryl), 1133 (C-O); δH (300 MHz; CDCl3); 7.27–7.26 (5H, m, ArH),
7.05 (2H, m, CHOCH), 6.87 (2H, dd, J = 14.6, 6.6 Hz, CHHCOCHH), 6.81 (2H, dd, J = 15.0, 5.0 Hz,
CHHCOCHH); δC (75.5 MHz; CDCl3); 206.8, 139.9, 128.8, 128.2, 126.8, 73.6, 46.4; HRMS (ESI+)
calcd for C17H16NaO2 [M+Na]+ m/z 275.1048 found: m/z. 275.1029; HPLC (Chiralcel ODH, 97:3
Hexanes:propan-2-ol, 0.5 mL·min−1, tR = 11.07 min (major) and 13.11 min (minor).
3.10. Synthesis of (2S,6S)-2-Phenyl-6-styryltetrahydropyran-4-one (9)
Potassium (E)-styryltrifluoroborate (0.907 g, 4.32 mmol) was reacted with (S)-2-phenyl-2,3-
dihydropyran-4-one ((S)-3) (0.20 g, 1.148 mmol) under the standard conditions. The crude residue was
purified by flash column chromatography on silica gel (eluting with petrol:ethyl acetate 9:1) to afford
the title compound as a white solid (0.20 g, 63% yield).
[α]20
Rf (petrol:ethyl acetate, 4:1); 0.5;
= −77° (c = 1, CHCl3), νmax (neat)/cm−1; 3035, 2979, 2882 (C-H),
D
1720 (C=O), 1658 (C=C), 1600, 1579 (C=C aryl), 1231, 1048 (C-O); δH (300 MHz; CDCl3); 7.34–7.17
(10H, m, ArH), 6.53 (1H, dd, J = 16.3, 1.4 Hz, ArCH), 6.23 (1H, dd, J = 16.3, 5.0, ArCHCH), 5.12 (1H,
dd, J = 7.4, 5.0 Hz, ArCHO), 4.83 (1H, ddd, J = 10.7, 5.2, 1.4 Hz, CHCHO), 2.79–2.63 (4H, m,
CH2COCH2); δC (75.5 MHz; CDCl3); 206.5, 140.3, 136.0, 133.5, 128.8, 128.7, 128.3, 128.2, 127.8,
126.7, 126.5, 73.6, 72.9, 47.8, 45.4; HRMS (ESI+) calcd for C19H18NaO2 [M+Na]+ m/z 301.1204 found:
m/z. 301.1177; HPLC (Chiralcel ODH; 95.5 Hexanes:propan-2-ol, 1.0 mL·min−1, tR = 13.37 min (major)
and 21.93 min (minor).

Molecules 2015, 20
6161
3.11. Synthesis of (2S, 6S)-2-(5-Methylhex-1-enyl)-6-phenyltetrahydropyran-4-one (10)
Potassium (E)-trifluoro(5-methyl-hex-1-enyl)borate (0.047 g, 0.23 mmol) was reacted with
(S)-2-phenyl-2,3-dihydropyran-4-one ((S)-3) (0.020 g, 0.115 mmol) under the standard conditions. The
crude residue was purified by flash column chromatography on silica gel (eluting with petrol:ethyl
acetate 9:1) to afford the title compound as a yellow oil (0.024 g, 77% yield).
Rf (petrol:ethyl acetate, 4:1); 0.78; νmax (neat)/cm−1; 3068, 2955, 2870 (C-H), 1706 (C=O), 1648 (C=C),
1602 (C=C aryl), 1268, 1069 (C-O); δH (300 MHz; CDCl3); 7.38–7.27 (5H, m, ArH), 5.69 (1H, dtd,
J = 15.7, 6.3, 0.9 Hz, CH2CHCH), 5.57 (1H, ddt, J = 15.7, 5.0, 1.0 Hz, CH2CHCH), 5.11 (1H, dd,
J = 7.4, 5.3 Hz, ArCHO), 4.70 (1H, dd, J = 9.7, 4.8 Hz, CHCHO), 2.76 (1H, dd, J = 14.4, 5.7,
CHHCOCHH), 2.70 (2H, d, J = 5.4 Hz, CHHCOCHH), 2.60 (1H, ddd, J = 14.4, 4.6, 1.0 Hz,
CHHCOCHH), 2.10–2.03 (2H, m, CH2CH2CH), 1.53 (1H, nonet, J = 6.6 Hz, (CH3)2CH), 1.29–1.24
(2H, m, (CH3)2CHCH2), 0.88 (6H, d, J = 6.6 Hz, (CH3)2CH); δC (75.5 MHz; CDCl3); 206.9, 140.5, 136.1,
128.1, 126.4, 73.1, 72.9, 48.0, 45.4, 38.1, 30.4, 27.6, 22.5; HPLC (Chiralcel AD; 98:2 Hexanes:propan-2-ol,
1.0 mL·min−1, tR = 6.85 min (major) and 15.91 min (minor).
3.12. Synthesis of (2S,6S)-2-(3,5-Difluorophenyl)-6-phenyltetrahydropyran-4-one (11)
3,5-difluorophenylboronic acid (0.045 g, 0.287 mmol) was reacted with (S)-2-phenyl-2,3-
dihydropyran-4-one ((S)-3) (0.025 g, 0.144 mmol) under the standard conditions. The crude residue was
purified by flash column chromatography on silica gel (eluting with petrol:ethyl acetate 9:1) to afford
the title compound as a yellow solid (0.038 g, 98% yield).
Rf (petrol:ethyl acetate, 4:1); 0.6; δH (300 MHz; CDCl3); 7.42–7.30 (5H, m, ArH), 6.90 (2H, ddd,
J = 8.2, 2.2, 0.7 Hz, FCCHCCHCF), 6.75 (1H, tt, J = 8.8, 2.3 Hz, CFCHCF), 5.34 (1H, t, J = 5.7 Hz,
OCH), 4.97 (1H, dd, J = 6.82, 5.64 Hz, OCH), 2.93 (2H, ddd, J = 14.5, 5.7, 0.9 Hz, CHHCOCHH),
2.85–2.72 (2H, m, CHHCOCHH); δC (75.5 MHz; CDCl3); 205.7, 144.2, 139.2, 128.9, 128.5, 127.0,
109.7, 109.3, 103.5, 74.2, 72.3, 46.8, 45.8; HPLC (Chiralcel AD: 99:1 Hexanes:propan-2-ol,
0.5 mL·min−1, tR = 37.30 min (major) and 48.68 min (minor).
3.13. Synthesis of trans-2-(4-Methoxyphenyl)-6-[2-(4-methoxyphenyl)-vinyl]-tetrahydropyran-4-one (12)
4-methoxyphenylboronic acid (0.026 g, 0.174 mmol) was reacted with 2-[2-(4-Methoxyphenyl)-
vinyl]-2,3-dihydropyran-4-one (6) (0.020 g, 0.0869 mmol) under the standard conditions. The crude
residue was purified by flash column chromatography on silica gel (eluting with petrol:ethyl acetate 8:2)
to afford the title compound as a yellow oil (0.017 g, 58% yield).
Rf (petrol:ethyl acetate, 4:1); 0.26; δH (300 MHz; CDCl3); 7.32 (4H, dd, J 8.8, 2.2 Hz, ArH, 6.88 (4H,
dd, J = 11.6, 8.8 Hz, ArH), 6.52 (1H, d, J = 16.2, 5.3 Hz, ArCH), 6.15 (1H, d, J = 16.2 Hz, 5.3 Hz,
ArCHCH), 5.17 (1H, dd, J = 7.2, 4.9, ArCHO), 4.81 (1H, ddd, J = 9.4, 5.3, 1.4, CHCHO), 3.81 (6H, s,
OCH3, OCH3), 2.87–2.63 (4H, m, CH2COCH2); HRMS (ESI+) calcd for C21H22NaO4 [M+Na]+ m/z
361.1416 found: m/z. 361.1404.

Molecules 2015, 20
6162
3.14. Synthesis of trans-2-Benzo[1,3]dioxol-5-yl-6-[2-(4-methoxyphenyl)vinyl]-tetrahydropyran-4-one (13)
Benzo-[1,3]dioxol-5-ylboronic acid (0.029 g, 0.174 mmol) was reacted with 2-[2-(4-
methoxyphenyl)-vinyl]-2,3-dihydropyran-4-one (6) (0.020 g, 0.0869 mmol) under the standard
conditions. The crude residue was purified by flash column chromatography on silica gel (eluting with
petrol:ethyl acetate 8:2) to afford the title compound as a yellow oil (0.032 g, 75% yield).
Rf (petrol:ethyl acetate, 4:1); 0.38; νmax (neat)/cm−1; 2906, 2862 (C-H), 1715 (C=O), 1641 (C=C), 1606,
1577, 1511 (C=C aryl), 1246, 1033 (C-O); δH (300 MHz; CDCl3); 7.33 (3H, d, J 8.8 Hz, ArH), 6.89 (2H,
d, J = 11.7 Hz, ArH), 6.82 (2H, d, J = 11.5 Hz, ArH), 6.53 (1H, d, J = 16.2 Hz, ArCHCH), 6.14 (1H, dd,
J = 16.4, 5.5 Hz, ArCHCH), 5.96 (2H, s, OCH2O), 5.10 (1H, dd, J = 7.0, 5.4 Hz, ArCHO), 4.84 (1H,
ddd, J = 10.6, 5.3, 1.2 Hz, CHCHO), 3.81 (3H, s, ArOCH3), 2.83–2.65 (4H, m, CH2COCH2); HRMS
(ESI+) calcd for C21H20NaO5 [M+H]+ m/z 375.1208 found: m/z. 375.1192.
3.15. Synthesis of trans-2-Dec-1-enyl-6-[2-(4-methoxyphenyl)vinyl]-tetrahydropyran-4-one (14)
Potassium decenyl trifluoroborate (0.043 g, 0.174 mmol) was reated with 2-[2-(4-methoxyphenyl)-
vinyl]-2,3-dihydropyran-4-one (6) (0.020 g, 0.0869 mmol) under the standard conditions. The crude
residue was purified by flash column chromatography on silica gel (eluting with petrol:ethyl acetate 8:2)
to afford the title compound as a yellow oil (0.026 g, 81% yield).
Rf (petrol:ethyl acetate, 4:1); 0.5; νmax (CH2Cl2)/cm−1; 2925, 2855 (C-H), 1718 (C=O), 1610, 1514 (C=C
aryl), 1250 (C-O); δH (300 MHz; CDCl3); 7.32 (2H, d, J = 8.7 Hz, ArH), 6.85 (2H, d, J = 8.7 Hz, ArH),
6.53 (1H, d, J = 16.1 Hz, ArCHCH), 6.12 (1H, dd, J = 16.1, 5.6 Hz, ArCHCH), 5.71 (1H, dt, J = 16.0,
6.6 Hz, CH2CHCH), 5.55 (1H, dd, J = 15.7, 5.5 Hz, CH2CHCH), 4.80 (1H, dd, J = 10.7, 5.1 Hz, CHO),
4.67 (1H, dd, J = 10.7, 5.6 Hz, CHO), 3.08 (3H, s, OCH3), 2.69–2.47 (4H, m, CH2COCH2), 2.05 (2H, q,
J = 6.9 Hz, CH2CHCH), 1.37–1.26 (12H, m, CH3(CH2)6), 0.88 (3H, t, J = 6.6 Hz, CH3(CH2)6); δC (75.5
MHz; CDCl3); 206.7, 159.9, 135.4, 132.4, 128.6, 127.9, 126.0, 125.7, 114.1, 72.6, 72.5, 55.4, 46.3, 32.5,
32.0, 29.5, 29.3, 29.3, 29.0, 22.8, 14.2; HRMS (ESI+) calcd for C24H35O3 [M+H]+ m/z 371.2586 found:
m/z 371.2588.
3.16. Synthesis of trans-2-[5-(tert-Butyl-dimethylsilanyloxy)-pentyl]-6-phenyltetrahydropyran-4-one (15)
Phenylboronic acid (0.021 g, 0.168 mmol) was reacted with (S)-2-[5-(tert-Butyl-dimethylsilanyloxy)-
pentyl]-2,3-dihydropyran-4-one (7) (0.025 g, 0.0838 mmol) under the standard conditions. The crude
residue was purified by flash column chromatography on silica gel (eluting with petrol:ethyl acetate 9:1)
to afford the title compound as a colourless oil (0.020 g, 64% yield).
Rf (petrol:ethyl acetate, 4:1); 0.72; δH (300 MHz; CDCl3); 7.41–7.28 (5H, m, ArH), 5.21 (1H, t, J = 5.7
Hz, ArCHO), 3.98–3.90 (1H, m, OCHCH2), 3.57 (2H, t, J = 1.56 Hz, CH2OSi), 2.88–2.74 (2H, m,
COCH2), 2.57 (1H, ddd, J = 14.4, 4.5, 1.1 Hz, COCHH), 2.34 (1H, dd, J = 14.4, 7.3, 1.1 Hz, COCHH),
1.54–1.40 (4H, m, CH2CH2), 1.37–1.27 (4H, m, CH2CH2), 0.88 (9H, s, C(CH3)3), 0.03 (6H, s, Si(CH3)2);
δC (75.5 MHz; CDCl3); 207.3, 140.2, 128.6, 128.0, 126.8, 63.1, 47.2, 46.2, 34.55, 32.72, 25.9, 25.6, 25.1,
18.4, −5.26.

Molecules 2015, 20
6163
3.17. Synthesis of trans-2-[5-(tert-Butyldimethylsilanyloxy)pentyl]-6-styryltetrahydropyran-4-one (16)
Potassium (E)-styryl trifluoroborate (0.028 g, 0.13 mmol) was reacted with (S)-2-[5-(tert-Butyl-
dimethyl-silanyloxy)-pentyl]-2,3-dihydropyran-4-one (7) (0.020 g, 0.067 mmol) under the standard
conditions. The crude residue was purified by flash column chromatography on silica gel (eluting with
petrol:ethyl acetate 9:1) to afford the title compound as a colourless oil (0.010 g, 37% yield).
Rf (petrol:ethyl acetate, 4:1); 0.62; νmax (neat)/cm−1; 2931, 2858 (C-H), 1713 (C=O), 1623 (C=C), 1579,
1569 (C=C aryl), 1251, 1049 (C-O); δH (300 MHz; CDCl3); 7.40–7.27 (5H, ArH), 6.56 (1H, dd,
J = 16.1, 1.2, ArCH), 6.23 (1H, dd, J = 11.2, 5.2, ArCHCH), 4.87 (1H, dd, J = 9.6, 4.5 Hz, CHCHO),
4.12–4.03 (1H, m, OCHCH2), 3.59 (2H, t, J = 6.4 Hz, CH2OTBS), 2.68 (2H, qd, J = 14.3, 5.4 Hz,
COCH2), 2.49 (1H, ddd, J = 14.2, 4.0, 1.2 Hz, COCHH), 2.29 (1H, dd, J = 13.9, 8.2Hz, COCHH),
1.55–1.46 (4H, m, CH2CH2), 1.43–1.34 (4H, m, CH2CH2), 0.88 (9H, s, C(CH3)3), 0.03 (6H, s, Si(CH3)2).
3.18. Synthesis of trans-2-(4-Benzyloxybut-1-enyl)-6-(2-hydroxyethyl)tetrahydropyran-4-one (17)
Potassium (E)-(4-(-benzyloxy)but-1-en-1-yl)trifluoroborate (0.105 g, 0.39 mmol) was reated with
2-[2-(tert-Butyldimethylsilanyloxy)ethyl]-2,3-dihydropyran-4-one (8) (0.050 g, 0.195 mmol) under the
standard conditions. The crude residue was treated with TBAF (0.43 mL, 1M in THF) in THF (2 mL).
After stirring for 1 h, a saturated solution of NH4Cl was added and the mixture extracted with Et2O
(3 × 10 mL). Combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel (eluting with CH2Cl2:methanol 9:1) to afford
the title compound as a yellow oil (0.048 g, 81% yield).
Rf (CH2Cl2:methanol 9:1); 0.46; νmax (neat)/cm−1; 3342 (O-H), 2930, 2858 (C-H), 1472, 1463 (C=C),
1254, 1094 (C-O); δH (300 MHz; CDCl3); 7.37–7.27 (5H, m, ArH), 5.71 (1H, dt, J = 15.8, 6.4 Hz,
CH2CHCH), 5.58 (1H, dd, J = 15.8, 4.7 Hz, CH2CHCH), 4.75 (1H, dd, J = 9.7, 4.7 Hz, CHCHO), 4.49
(2H, s, ArCH2O), 4.26 (1H, m, OCHCH2), 3.73 (1H, br.s, OH), 3.50 (2H, t, J = 6.6 Hz, OCH2CH2), 2.67
(1H, dd, J = 14.5, 6.2 Hz, CHHCOCHH), 2.52 (1H, ddd, J = 14.6, 3.8, 1.4 Hz, CHHCOCHH),
2.43–2.28 (4H, m, CHHCOCHH, CH2CHCH), 1.91–1.62 (2H, m, OCHCH2); δC (75.5 MHz; CDCl3);
206.5, 138.3, 132.2, 130.3, 128.4, 127.7, 127.6, 73.0, 72.9, 70.5, 69.2, 60.3, 47.6, 44.9, 37.5, 32.9.
3.19. Synthesis of (2S,6S)-2-Dec-1-enyl-6-phenyltetrahydropyran-4-one (18)
Potassium decenyl trifluoroborate salt (0.057 g, 0.23 mmol) was reacted with (S)-2-phenyl-2,3-
dihydropyran-4-one ((S)-3) (0.020 g, 0.115 mmol) under the standard conditions. The crude residue was
purified by flash column chromatography on silica gel (eluting with petrol:ethylacetate 9:1) to afford the
title compound as a yellow oil (0.027 g, 72% yield).
Rf (petrol:ethyl acetate, 4:1); 0.69; νmax (CH2Cl2)/cm−1; 3037, 2924, 2854 (C-H), 1720 (C=O), 1667
(C=C), 1603 (C=C aryl), 1249, 1052 (C-O); δH (300 MHz; CDCl3); 7.38–7.29 (5H, m ArH), 7.00 (1H,
dt, J = 15.7, 6.3 Hz, CH2CH), 5.57 (1H, dd, J = 15.7, 4.9 Hz, CH2CHCH), 5.11 (1H, dd, J = 7.4 Hz, 5.4
Hz, ArCHO, 5.71 (1H, dd, J = 9.6, 4.7 Hz, CHCHO), 2.74 (1H, dd, J = 14.4, 5.9 Hz, CHHCOCHH),
2.70 (2H, d, J = 6.6 Hz, CHHCOCHH), 2.60 (1H, dd, J = 14.4, 4.6 Hz, CHHCOCHH), 2.06 (2H, q,

Molecules 2015, 20
6164
J = 6.9 Hz, CH2CH), 1.35 (2H, dd, J = 13.0, 5.9 Hz, CH2CH2CH), 1.30–1.22 (10H, m, CH3(CH2)8),
0.87 (3H, t, J = 6.6 Hz, CH3); δC (75.5 MHz; CDCl3); 206.9, 140.0, 136.0, 128.8, 128.3, 128.1, 126.5,
73.1, 72.9, 48.0, 45.4, 32.5, 31.9, 29.5, 29.4, 29.2, 29.0, 22.8, 14.2; HPLC (Chiralcel ODH: 98:2
Hexanes:propan-2-ol, 1.0 mL·min−1, tR = 19.43 min (minor) and 21.42 min (major).
3.20. Synthesis of (2S,6S)-2-(4-Bromophenyl)-6-phenyltetrahydropyran-4-one (19)
4-Bromophenylboronic acid (0.058 g, 0.287 mmol) was reacted with (S)-2-phenyl-2,3-dihydropyran-
4-one ((S)-3) (0.025 g, 0.144 mmol) under the standard conditions. The crude residue was purified by
flash column chromatography on silica gel (eluting with petrol:ethylacetate 9:1) to afford the title
compound as a colourless oil (0.044 g, 93% yield).
Rf (petrol:ethyl acetate, 4:1); 0.61; νmax (neat)/cm−1; 2983, 2896 (C-H), 1719 (C=O), 1596, 1494 (C=C
aryl), 1245, 1231 (C-O); δH (300 MHz; CDCl3); 7.41 (2H, d, J = 7.9 Hz, ArH), 7.30–7.24 (5H, m, ArH),
7.17 (2H, d, J = 8.3 Hz, ArH), 5.04 (1H, t, J = 5.8 Hz, ArCHO), 4.98 (1H, t, J = 5.9 Hz, ArCHO), 2.85
(1H, dd, J = 14.8, 6.5 Hz, CHHCOCHH), 2.76 (1H, dd, J = 14.8, 5.8 Hz, CHHCOCHH), 2.75 (2H,
J = 6.8 Hz, CHHCOCHH); δC (75.5 MHz; CDCl3); 206.3, 139.6, 139.0, 131.9, 128.8, 128.5, 128.3,
126.8, 122.2, 73.8, 72.9, 46.9, 46.3; HRMS (ESI+) calcd for C17H15BrNaO2 [M+Na]+ m/z 353.0153
found: m/z 252.0124; HPLC (Chiralcel OJ, 9:1 Hexanes:propan-2-ol, 1.0 mL·min−1, tR = 20.36 min
(minor) and 28.61 min (major).
4. Conclusions
In summary, the catalytic conjugate addition of both aryl- and alkenylboronates to dihydropyranone
templates have been accomplished in high yields, leading to the selective synthesis of
2,6-trans-tetrahydropyran derivatives. The selective formation of the 2,6-trans-tetrahydropyran
stereoisomer is consistent with a mechanism involving alkene association and carbometalation on the
less hindered face of the dihydropyranone. This methodology has simultaneously expanded the limited
precedent for metal-catalysed addition of organoboron reagents to enantioenriched substrates and
demonstrated the utility of sequential catalysis in the construction of “natural product-like” molecules.
Acknowledgments
We are grateful to the University of Bath and Atlas Genetics (http://www.atlasgenetics.com) for
funding. We acknowledge the valuable assistance of Anneke Lubben (Mass Spectrometry) and
John Lowe (NMR).
Author Contributions
H. J. Edwards and S. Goggins performed the research and C. G. Frost wrote the manuscript. All
authors have approved the final content of the manuscript.
Conflicts of Interest
The authors declare no conflict of interest.

Molecules 2015, 20
6165
References
1. Tian, P.; Dong, H.-Q.; Lin, G.-Q. Rhodium-catalyzed asymmetric arylation. ACS Catal. 2012, 2,
95–119.
2. Berthon, G.; Hayashi, T. Rhodium- and palladium-catalyzed asymmetric conjugate additions. In
Catalytic Asymmetric Conjugate Reactions; Cordova, A., Ed.; Wiley-VCH: Weinheim, Germany,
2010; Chapter 1, pp. 1–70.
3. Edwards, H.J.; Hargrave, J.D.; Penrose, S.D.; Frost, C.G. Synthetic applications of rhodium
catalysed conjugate addition. Chem. Soc. Rev. 2010, 39, 2093–2105.
4. Hargrave, J.D.; Allen, J.C.; Frost, C.G. Alternatives to organoboron reagents in rhodium-catalyzed
conjugate additions. Chem. Asian J. 2010, 5, 386–396.
5. Hayashi, T.; Yamasaki, K. Rhodium-catalyzed asymmetric 1,4-addition and its related asymmetric
reactions. Chem. Rev. 2003, 103, 2829–2844.
6. Fagnou, K.; Lautens, M. Rhodium-catalyzed carbon-carbon bond forming reactions of
organometallic compounds. Chem. Rev. 2003, 103, 169–196.
7. Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. Catalytic cycle of rhodium-catalyzed
asymmetric 1,4-addition of organoboronic acids. Arylrhodium, oxa-π-allylrhodium, and
hydroxorhodium intermediates J. Am. Chem. Soc. 2002, 124, 5052–5058.
8. Filloux, C.M.; Rovis, T. Rh(I)–bisphosphine-catalyzed asymmetric, intermolecular
hydroheteroarylation of α-substituted acrylate derivatives. J. Am. Chem. Soc. 2015, 137, 508–517.
9. Navarre, L.; Martinez, R.; Genet, J.; Darses, S. Access to enantioenriched α-amino esters via
rhodium-catalyzed 1,4-addition/enantioselective protonation. J. Am. Chem. Soc. 2008, 130,
6159–6169.
10. Moss, R.J.; Wadsworth, K.J.; Chapman, C.J.; Frost, C.G. Rhodium-catalysed tandem conjugate
addition-protonation: An enantioselective synthesis of 2-substituted succinic esters. Chem. Commun.
2004, 1984–1985.
11. Ramnauth, J.; Poulin, O.; Bratovanov, S.S.; Rakhit, S.; Maddaford, S.P. Stereoselective C-glycoside
formation by a rhodium(I)-catalyzed 1,4-addition of arylboronic acids to acetylated enones derived
from glycals. Org. Lett. 2001, 3, 2571–2573.
12. Zoute, L.; Kociok-Kohn, G.; Frost, C.G. Rhodium-catalyzed 1,4-additions to enantiopure acceptors:
Asymmetric synthesis of functionalized pyrrolizidinones. Org. Lett. 2009, 11, 2491–2494.
13. Hargrave, J.D.; Bish, G.; Frost, C.G. Switching stereoselectivity in rhodium-catalysed 1,4-additions:
The asymmetric synthesis of 2-substituted pyrrolizidinones. Chem. Commun. 2006, 4389–4391.
14. Clarke, P.A.; Santos, S. Strategies for the formation of tetrahydropyran rings in the synthesis of
natural products. Eur. J. Org. Chem. 2006, 9, 2045–2053.
15. Pellissier, H. Asymmetric hetero-Diels–Alder reactions of carbonyl compounds. Tetrahedron 2009,
65, 2839–2877.
16. Tietze, L.F.; Kettschau, G.; Gewert, J.A.; Schuffenhauer, A. Hetero-Diels–Alder reactions of
1-oxa-1,3-butadienes. Curr. Org. Chem. 1998, 2, 19–62.
17. Kumaraswamy, G.; Ramakrishna, G.; Naresh, P.; Jagadeesh, B.; Sridhar, B. A flexible enantioselective
total synthesis of Diospongins A and B using catalytic hetero-Diels–Alder/Rh-catalyzed 1,4-addition
and asymmetric transfer hydrogenation reactions as key steps. J. Org. Chem. 2009, 74, 8468–8471.

Molecules 2015, 20
6166
18. Danishefsky, S.; Kerwin, J.F.; Kobayashi, S. Lewis acid catalyzed cyclocondensations of
functionalized dienes with aldehydes. J. Am. Chem. Soc. 1982, 104, 358–360.
19. Frost, C.G.; Penrose, S.D.; Gleave, R. Rhodium catalysed conjugate addition of a chiral
alkenyltrifluoroborate salt: The enantioselective synthesis of hermitamides A and B. Org. Biomol.
Chem. 2008, 6, 4340–4347.
20. Lennox, A.J.J.; Lloyd-Jones, G.C. Organotrifluoroborate hydrolysis: Boronic acid release
mechanism and an acid-base paradox in cross-coupling. J. Am. Chem. Soc. 2012, 134, 7431–7441.
21. Jørgensen, K.A. Catalytic asymmetric hetero-Diels–Alder reactions of carbonyl compounds and imines.
Angew. Chem. Int. Ed. 2000, 39, 3558–3588.
22. Wang, B.; Feng, X.; Huang, Y.; Liu, H.; Cui, X.; Jiang, Y. A highly enantioselective
hetero-Diels–Alder reaction of aldehydes with Danishefsky’s Diene catalyzed by chiral
titanium(IV) 5,5',6,6',7,7',8,8'-octahydro-1,1'-bi-2-naphthol complexes. J. Org. Chem. 2002, 67,
2175–2182.
23. Smith, A.B., III; Fox, R.J.; Vanecko, J.A. (+)-Sorangicin a synthetic studies. Construction of the
C(1–15) and C(16–29) subtargets. Org. Lett. 2005, 7, 3099–3102.
Sample Availability: Samples of the compounds are not available from the authors.
© 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/4.0/).