Chemoselective Carbonyl Allylations with Alkoxyallylsiletanes

Article abstract of DOI:10.1021/acs.joc.8b03028

Alkoxyallylsiletanes are capable of highly chemo- and diastereoselective carbonyl allylsilylations. Reactive substrates include salicylaldehydes and glyoxylic acids. Chemoselectivity in these reactions is thought to arise from a mechanism involving first exchange of the alkyoxy group on silicon with a substrate hydroxyl followed by activation of a nearby carbonyl by the Lewis acidic siletane and intramolecular allylation. In this way, substrates containing multiple reactive carbonyl groups (e.g., dialdehyde or triketone) can be selectively monoallylated, even overcoming inherent electrophilicity bias.

Full text of DOI:10.1021/acs.joc.8b03028

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Note
Chemoselective Carbonyl Allylations with Alkoxyallylsiletanes
Paul Spaltenstein, Elizabeth J Cummins, Kelly-Marie Yokuda,
Tim Kowalczyk, Timothy Bryan Clark, and Gregory W. O'Neil
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03028 • Publication Date (Web): 27 Feb 2019
Downloaded from http://pubs.acs.org on March 2, 2019
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Chemoselective Carbonyl Allylations with Alkoxyallylsiletanes
Paul Spaltenstein,1 Elizabeth J. Cummins,1 Kelly-Marie Yokuda,1 Tim Kowalczyk,1Timothy B.
Clark2 and Gregory W. O’Neil1*
1Department of Chemistry, Western Washington University, Bellingham, WA, 98225
2Department of Chemistry, University of San Diego, San Diego, CA, 92110
*Email: oneilg@wwu.edu
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OH
OH
OH
OH
CO
HO
H
O
Si
O
(75%)
OH
H
O
OR
MeCN, 80 ºC
OH
R
n
O
( )
X
H
H
O
H
(88%)
OH
(78%)
Abstract
Alkoxyallylsiletanes are capable of highly chemo- and diastereoselective carbonyl allylsilylations.
Reactive substrates include salicylaldehydes and glyoxylic acids. Chemoselectivity in these
reactions is thought to arise from a mechanism involving first exchange of the alkyoxy group on
silicon with a substrate hydroxyl followed by activation of a nearby carbonyl by the Lewis acidic
siletane and intramolecular allylation. In this way, substrates containing multiple reactive carbonyl
groups (e.g. dialdehyde or triketone) can be selectively monoallylated, even overcoming inherent
electrophilicity bias.
As part of a program investigating activatable silanes for nucleophilic additions,1,2 we
became interested in allylsilacyclobutanes of type 1, inspired by Matsumoto’s report on the use of
siletane 1 for non-catalyzed additions to α-hydroxyketones.3 Our group recently described a novel
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synthesis of this compound by iodine-catalyzed monoetherification of diallylsilacyclobutane
(Scheme 1).4 With reliable access to useful quantities of 1, we now wish to report on its use in a
series of carbonyl allylsilylations. In particular, we have found that reagents of type 1 are capable
of remarkably chemoselective nucleophilic additions to various hydroxyl-substituted carbonyls.
This chemoselectivity is thought to arise from a mechanism involving first exchange of the alkoxy
substituent on silicon with a substrate hydroxyl, followed by intramolecular allylsilylation of a
nearby carbonyl activated by the Lewis acidic silacyclobutane.5-7
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Scheme 1. Synthesis of allylsilacyclobutane 1 by iodine-catalyzed monoetherification and
subsequent intramolecular allylation.
(10 mol%)
I2
Si
Si
OCy
1
CyOH (1 equiv.),
, 35 ºC
CH2Cl2
(30-40%)
O
OH
This work:
R
n
( )
X
CyOH
X = H,H or O
n = 0,1
-
δ+
OH
R
Si
δ
O
chemoselective
allylation
OH
O
n
( )
X
R
n
( )
X
To explore the reactivity of allylsiletane 1, potential substrates were considered that could
exploit this exchangeable siloxane to achieve selective allylation reactions. Previous experiments
in our lab had shown that benzaldehyde was recalcitrant to react with 1. We questioned, however,
if having a nearby hydroxyl group, such as that in salicylaldehyde (2) might promote nucleophilic
addition by allowing for an intramolecular allylation following exchange with the alkoxy
substituent on 1. To test this, the reaction of 2 with 1 was examined in several different solvents
and temperatures.8 Low conversions were generally observed when using less polar solvents like
tetrahydrofuran, dichloromethane, and toluene. However, polar aprotic solvents
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dimethylformamide and acetonitrile gave high conversion to the allylated product 3, perhaps due
to stabilization of a charged transition state such as that depicted in Scheme 1 with coordination
of the aldehyde oxygen to silicon and intramolecular allylation. While DMF gave slightly higher
yield after 6 h at 100 ºC than MeCN at 80 ºC (99% vs 92% respectively), MeCN is generally
preferred in line with recent green chemistry recommendations9 and its easier removal than higher
boiling DMF.
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Scheme 2. Scope of salicylaldehyde allylations with siletane 1.
O
OH
1
, MeCN, 80 ºC, 6 h
H
then TBAF
X
OH
X
OH
2
, X = H
X = H, 3
X = OCH
; (92%)
3; (87%)
no allylation product obtained:
O
O
X = Br; (78%)
X = Cl; (85%)
X = OAc; (75%)
H
CH3
OH
OMe
Other salicylaldehyde derivatives reacted efficiently with 1 including those containing
bromo-, chloro-, and acetyloxy-substituents that might otherwise be incompatible with certain
allylorganometallic reagents (Scheme 2). Interestingly, 2’-hydroxyacetophenone failed to undergo
allylation,10 presumably as a result of the lower electrophilicity of the ketone versus an aldehyde.
Sato et al. had reported the allylation of 2’-hydroxyacetophenone using trifluoro- or
trialkoxysilanes in the presence of triethylamine,11 with triethylamine suggested to act as a
Brønsted base. However the addition of triethylamine failed to promote the allylation of 2’-
hydroxyacetophenone with 1, suggesting some fundamental differences between siletanes and
other electrophilic allylsilanes. Additionally 2-methoxybenzaldehyde proved unreactive,
consistent with a mechanism involving initial exchange at silicon with a substrate hydroxyl.
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To further test the importance of an exchangeable group on the substrate, a competition
experiment was performed using a 1:1 mixture of benzaldehyde and salicylaldehyde (Scheme 3).
When this mixture was treated with 1 in MeCN at 80 ºC, only product 3 derived from
salicylaldehyde was obtained in 90% yield along with unreacted benzaldehyde. Moreover, the
reaction of 1 with the dialdehyde 4-hydroxyisophthalaldehyde (4) selectively produced compound
5 in 78% yield, addition occurring only at the aldehyde ortho- to the hydroxyl group. The
chemoselective monoallylation of 4 to produce 5 has previously been described by Ito and
coworkers using allyltributyltin.12 Those authors explained their result by invoking an
intramolecular hydrogen bond between the phenol and ortho-aldehyde rendering this aldehyde
more electrophilic. While hydrogen bonding may be required to explain Ito's results, we contend
that exchange of hydroxyl groups onto siletane 1 is rapid, and that it is the intramolecularity of the
subsequent allylation that is most responsible for its chemoselectivity.
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Scheme 3. Chemoselective aldehyde allylations using compound 1.
exclusive product
O
O
OH
1
H
H
+
MeCN
3
OH
OH
1 : 1
80 ºC
6 h.
(90%)
O
O
O
OH
1
H
H
H
MeCN
OH
OH
4
80 ºC, 6 h.
OHC
5
via
(78%)
δ+
O
-
δ
Si
O
To better understand the reactivity and selectivity of siletane 1 and the results obtained
with salicylaldehyde, reactions with glyoxylic acids were also investigated (Figure 1). Under the
optimized conditions (MeCN, 80 ºC), phenylglyoxylic acid was fully allylated in 6 hours,
providing analogous reactivity to salicylaldehyde derivatives. As can be seen in Figure 1, aryl,
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heteroaryl, alkyl, and alkenyl glyoxylic acids all react efficiently with 1 to give tertiary α-hydroxy
carboxylic acid products in good isolated yields (60-78%) following a simple basic extraction.
Tertiary α-hydroxy carboxylic acids appear in a number of biologically relevant natural products,
however their synthesis by traditional methods (e.g. organolithium additions to α-oxocarboxylic
acids) can be challenging.13 Wang and coworkers previously reported a similar allylsilylation of
glyoxylic acids,14 however that reaction used moisture-sensitive allyltrichlorosilane (compound 1
can be handled with no special precautions) as well as DMF and HMPA as nucleophilic activators
of the silane. Reactions of glyoxylic acids with 1 were all performed in MeCN and without
additional additives. Accordingly, the mechanism is proposed to involve first exchange of
cyclohexanol on silicon with the carboxylic acid hydroxyl. The bound allylsiletane is then
ambiphilic,15 activating the adjacent ketone due to its Lewis acidity followed by intramolecular
allylation.16 Consistent with this proposal, the methyl ester of phenylglyoxylic acid failed to react
with 1 under these conditions.
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Figure 1. Non-catalyzed glyoxylic acid allylsilylations using allylsilacyclobutane 1.
glyoxylic acid allylations:
HO
HO
HO
Ph
HO
HO
O
Ph
Ph
OH
OH
OH
OH
OH
OH
R
OH
CO2H
O
O
O
O
O
O
Si
R
(79%)
(73%)
(71%
d.r. ~2:1)
(72%)
(60%)
MeCN, 80 ºC
6 h.
1
OCy
HO
HO
HO
Ph
‡
O
O
OH
OH
OMe
O
Ph
-CyOH
Si
O
O
O
O
R
(78%)
(62%)
(--)
In accordance with the proposed glyoxylic acid allylation mechanism, we hypothesized
that certain substrates could be made to undergo highly chemoselective reactions with 1, perhaps
even contrary to general carbonyl electrophilicity trends.17 To that end, aldehyde-containing
ketoacid 618 was prepared and treated with 1 in MeCN at 80 ºC (Scheme 4). Under these conditions,
nucleophilic addition occurred selectively to the ketone giving product 7 in 76% yield.19 This is
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quite remarkable given that compound 6 contains no less than five different electrophilic sites (3
carbonyl groups plus Michael addition and an acidic proton). Moreover, this is one of only a few
examples of direct carbon nucleophile addition to a ketone in the presence of an aldehyde. Otera’s
group reported that ketene silyl acetals will react preferentially with ketones over aldehydes in the
presence of (C6F5)2SnBr2,20 rationalized as due to selective activation of the more electron rich
ketone by the Lewis acid. Other examples generally involve protection and deprotection of the
more electrophilic aldehyde in situ.21-23
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Scheme 4. Chemoselective monoallylation of substrate 6 containing multiple electrophilic sites.
O
OH
1
H
H
CO2
CO2
MeCN,
80 ºC,
6 h.
6
7
(75%)
O
O
To further probe the chemoselectivity, aldehyde-containing ketoacid 824 was also
investigated (Scheme 5). Surprisingly, the reaction of this simpler substrate (i.e. only 4
electrophilic sites) was less chemoselective, giving the desired product 9 along with significant
amounts of aldehyde addition products 10 and 11. It was supposed that aldehyde allylation was
the result of an intermolecular reaction of 8 with allylsilanide 12. Indeed, upon treatment of 8 with
1 the reaction mixture becomes bright orange-colored, which we have ascribed to this charged
1
complex. Additionally, monitoring the reaction by H NMR spectroscopy (in MeCN-d3) shows
rapid (<15 min) release of free cyclohexanol indicating exchange with the substrate hydroxyl prior
to any allylation product formation.
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Scheme 5. First attempts at the chemoselective allylation of aldehyde ketoacid 8.
5
6
7
8
O
OH
CO2
OH
H
CO2
mixture
1
H
H
CO2
+
H
H
MeCN (0.2M)
80 ºC, 6 h.
8
9
10
9
O
O
OH
via
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O
Si
O
H
CO2
8
O
11
H
O
OH
12
O
The ketone in compound 8 is arguably more sterically hindered than in 6 (ref. Scheme 4)
which may slow down the intramolecular process and allow for the intermolecular aldehyde
allylation to compete. To favor intramolecular allylation, the reaction was performed under dilute
conditions (0.02M, Scheme 6). Additionally, compounds 8 and 1 were first reacted at room
temperature to allow for exchange of the alkoxy substituents, followed then by heating to 80 ºC in
order to promote the allylation. Under these conditions, the chemoselectively allylated product 9
was isolated in 65% yield. The use of isopropoxysiletane 13 gave 9 in identical yield as the
cyclohexyloxysilane 1, consistent with a mechanism involving initial loss of this group.
Scheme 6. Successful chemoselective ketone allylation of compound 8 by first alkoxy exchange
followed by heating.
1
13
R = iPr (
R = Cy (
) or
)
O
Si
O
Si
OR
8
H
O
MeCN (0.02M),
rt, 1 h
O
80 oC,
6 h.
OH
H
CO2
H
O
9
(64%)
As a further demonstration of the utility of this method, treatment of cortisone and
hydrocortisone under our standard conditions gave monoallylated products 14 and 15 in 88% and
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90% isolated yields respectively, with no evidence for 1,2- or 1,4-addition at the other ketone(s)
(Scheme 7). The chemoselectivity in this reaction is assumed to arise from first exchange of the 1º
hydroxyl (as opposed to the 3º) followed by intramolecular allylation of the neighboring ketone.
By 1H NMR spectroscopy, only a single diastereomer was formed. Attempts to form X-ray quality
crystals of compounds 14 and 15 or their derivatives (e.g. benzoate esters) for stereochemical
determination were unsuccessful. Adopting Hoye’s protocol for structure assignment through
computation of NMR chemical shifts (Figure S1),25 we have assigned the configuration of the
newly formed stereocenter as (S). Considering the structure of the calculated low-energy
conformer (Figure S2 and Scheme 7 inset), the result suggests preferential allylation past the C17-
hydroxyl. It could be that the pro-(R) face is more sterically hindered by the C16-methylene.
Alternatively the C17-hydroxyl group may direct the addition, for instance by interaction with the
reactive silicon center, akin to other hydroxyl-directed nucleophilic additions.26 Further
experiments are planned to better elucidate the factors controlling the stereochemical course of
this reaction and to demonstrate this process as a new method for chemoselective modification of
steroids and other biomolecules containing multiple carbonyl functional groups.
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Scheme 7. Selective cortisone and hydrocortisone monoallylation using siletane 13.
low-energy conformation
O
HO
OH
HO
HO
OH
δ-
X
X
20
Si
17
+
O
OH
δ
H
H
O
OH
13
MeCN,
(S)
OH
H
H
H
H
OH
80 ºC
O
O
16
= 63º
φ
88%
X = O; cortisone
X = H, OH; hydrocortisone
14
X = O;
(d.r. > 10:1)
H
15
, 90%
X = H, OH;
H
Conclusion
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In summary, our investigations have revealed that alkoxyallylsiletanes react efficiently
with both salicylaldehydes and glyoxylic acids based on a mechanism involving initial ligand
exchange at silicon followed by intramolecular allylation of a proximal carbonyl that has been
activated by the Lewis acidic siletane. Consistent with this mechanism, highly chemoselective
allylations were achieved. For instance, the reaction of dialdehyde 4-hydroxyisophthalaldehyde
with 1 resulted in selective nucleophilic addition to the aldehyde ortho- (as opposed to para) to
the hydroxyl group. We also demonstrated one of only a few examples involving the selective
addition of a carbon nucleophile to a ketone in the presence of an aldehyde. Overall, the results
suggest that allylsiletanes may be of great utility to target-oriented synthesis campaigns, perhaps
as a means of avoiding protecting groups for sequential carbonyl additions. Additionally,
biomolecules such as steroids containing multiple carbonyl groups can be selectively modified
which may aid in our understanding of their function.
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Experimental Section
General Information. All reactions were carried out under N2 in flame-dried glassware. The
solvents used were dried by passing the solvent through a column of activated alumina under
nitrogen immediately prior to use. All reagents were purchased and used as received unless
otherwise mentioned. Heating of reaction mixtures was accomplished using hot plate stirrers
equipped with a thermocouple (accuracy ± 2 °C) and aluminum heating block. TLC analysis
used 0.25 mm silica layer fluorescence UV254 plates. Flash chromatography: silica gel (230-400
mesh). NMR: Spectra were recorded on a 300 or 500 spectrometer in the solvents indicated;
chemical shifts (δ) are given in ppm, coupling constants (J) in Hz. The solvent signals were used
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as references (CDCl3: δc ≡ 77.0 ppm; residual CHCl3 in CDCl3: δH ≡ 7.26 ppm; C6D6: δc ≡ 128.0
5
6
7
8
ppm; residual C6H6 in C6D6: δH ≡ 7.16 ppm; residual CHD2CN in CD3CN: δH ≡ 1.94 ppm).
1-Allyl-1-cyclohexyloxysiletane (1). To a Schlenk flask containing diallylsiletane (1.1 g, 6.9
mmol, 1.0 eq.) in DCM (35 mL) was added I2 (180 mg, 10 mol %) at room temperature, and the
resulting red solution was stirred for 10 min. Cyclohexanol (0.72 mL, 6.9 mmol, 1.0 eq.) was
then added and the solution was heated to 35 °C for 30 min. After 30 min. a drop of pyridine was
added, and the solution was concentrated in vacuo. Purification by chromatography on silica
(20:1 to 10:1 Hex:EtOAc) gave 1 as a pale yellow oil (0.44 g, 30%, Rf = .98 in 10:1
9
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Hex:EtOAc). Spectral data for 1 matched that previously reported by Matsumoto:3 1H NMR
(500 MHz, CDCl3) δ 5.85 (ddt, J = 17.1, 10.2, 8.0 Hz, 1H), 4.94 (ddt, J = 17.1, 2.0, 2.0 Hz, 1H),
4.90 (ddt, J = 10.1, 2.0, 1.0 Hz, 1H), 3.87 (tt, J = 9.6, 4.0 Hz, 1H), 2.04 (m, 2H), 2.1 – 1.65 (m,
8H), 1.63 – 1.42 (m, 2H), 1.42 – 1.10 (m, 8H).
1-Allyl-1-isopropoxysiletane (13). To a Schlenk flask containing 1,1-dichlorosilacyclobutane
(1.0 mL, 8.4 mmol, 1.0 eq.) at 0 °C was added allylmagnesium bromide (1.0 M in diethyl ether,
8.4 mL, 8.4 mmol, 1.0 eq.) dropwise over 15 min. The solution was stirred for 1 h at 0 °C and then
filtered under N2 using Et2O (20 mL) to rinse. The solution was cooled back to 0 °C, and
diisopropylethylamine (Hünig’s base, 2.2 mL, 13 mmol, 1.5 eq.) was added, followed by
isopropanol (0.68 mL, 8.9 mmol, 1.1 eq.). The solution was stirred and warmed to room
temperature over 3 h and then filtered through cotton using Et2O and concentrated in vacuo. The
resulting mixture was triturated with Et2O followed by purification by chromatography on silica
(20:1 to 10:1 Hex:EtOAc) giving 13 (0.8 g, 56%) as an oil. IR (ATR) 2970, 2920, 1630, 1388,
1154, 1120, 894, 766 cm-1. 1H NMR (500 MHz, CDCl3) δ 5.86 (ddt, J = 17.3, 10.0, 7.9 Hz, 1H),
4.97 (dq, J = 16.9, 1.5 Hz, 1H), 4.91 (ddt, J = 8.8, 2.1, 1.1 Hz, 1H), 4.18 (sept, J = 6.1 Hz, 1H),
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1.96 (m, 1H), 1.75 (dt, J = 8.1, 1.1 Hz, 2H), 1.54 (m, 1H), 1.34-1.22 (m, 4H), 1.21 (d, J = 6.0 Hz,
6H). 13C{1H} NMR (125 MHz, CDCl3) δ 133.0, 113.9, 65.9, 25.7, 23.3, 17.8, 13.4. HRMS-TOF
(ESI+) Calcd for C9H18NaOSi (M + Na): 193.1025. Found 193.1020.
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General Procedure for Allylations of Salicylaldehydes (2-hydroxybenzaldehydes, Scheme 2).
To a Schlenk flask containing a 2-hydroxybenzaldehyde (1.0 eq.) in MeCN was added 1 (1.5 eq.)
and the solution was heated to 80 °C for 6 h. The mixture was then cooled to 0 °C before adding
TBAF (4.5 eq) and stirring for 15 min. The reaction was quenched with aq. NH4Cl and the product
was extracted twice with EtOAc. The combined organic layers were dried of MgSO4, filtered, and
concentrated in vacuo and the residue purified by chromatography on silica.
2-(1-hydroxybut-3-en-1-yl)phenol (3). The general procedure was followed with salicylaldehyde
(2) (50 mg, 0.41 mmol). Purification by chromatography on silica (4:1 to 1:1 Hex:MTBE) gave 3
as a clear oil (60 mg, 89%). (Rf = 0.26 in 4:1 Hex:MTBE). Spectral data matched that previously
reported by Franco:27 IR (ATR) 3315, 2927, 1587, 1490, 1456, 1237, 1043, 751 cm-1. 1H NMR
(500 MHz, CDCl3) δ 7.98 (bs, 1H), 7.18 (m, 1H), 6.98 (dd, J = 7.6, 1.6 Hz, 1H), 6.88 (dd, J = 8.2,
1.0 Hz, 1H), 6.84 (td, J = 7.6, 1.2 Hz, 1H), 5.85 (ddt, J = 21.0, 7.9, 6.4 Hz, 1H), 5.25-5.20 (m, 2H),
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4.88 (dd, J = 8.6, 5.2 Hz, 1H), 2.68-2.55 (m, 2H). C{1H} NMR (125 MHz, CDCl3) δ 155.5,
133.9, 129.0, 127.1, 126.3, 119.8, 119.5, 117.3, 74.7, 42. HRMS-TOF (ESI+) Calcd for
C10H12NaO2 (M + Na): 187.0729. Found 187.0722.
2-(1-hydroxybut-3-en-1-yl)-5-methoxyphenol. The general procedure was followed with 4- 2-
hydroxy-4-methoxybenzaldehyde (50 mg, 0.33 mmol). Purification by chromatography on silica
(4:1 to 1:1 Hex:EtOAc) gave the allylated product as an oil (56 mg, 87%). IR (ATR) 3370, 2983,
1736, 1709, 1373, 1239, 1041, 734 cm-1. 1H NMR (500 MHz, CDCl3) δ 8.09 (s, 1H), 6.86 (d, J =
8.4 Hz, 1H), 6.44 (d, J = 2.6 Hz, 1H), 6.39 (dd, J = 8.4, 2.6 Hz, 1H), 5.83 (dddd, J = 17.7, 9.7, 8.0,
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6.3 Hz, 1H), 5.23 – 5.19 (m, 2H), 4.83 (dd, J = 8.4, 5.1 Hz, 1H), 3.76 (s, 3H), 2.74 (bs, 1H), 2.64
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– 2.54 (m, 2H). C{1H} NMR (125 MHz, CDCl3) δ 160.4, 156.8, 133.9, 127.7, 119.3, 118.7,
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105.8, 102.6, 74.3, 55.2, 42.2. HRMS-TOF (ESI+) Calcd for C11H14NaO3 (M + Na): 217.0835.
Found 217.0835.
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5-bromo-2-(1-hydroxybut-3-en-1-yl)phenol. The general procedure was followed with 4-
bromo-2-hydroxybenzaldehyde (50 mg, 0.25 mmol). Purification by chromatography on silica
(4:1 to 1:1 Hex:EtOAc) gave the allylated product as a yellow oil (47 mg, 78%). IR (ATR) 3275,
1705, 1591, 1578, 1484, 1374, 1244, 1224, 1042, 880 cm-1. 1H NMR (500 MHz, CDCl3) δ 8.17
(s, 1H), 7.05 (d, J = 1.9 Hz, 1H), 6.96 (dd, J = 8.3, 2.1 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 5.82
(dddd, J = 16.9m 10.4, 7.9, 6.5 Hz, 1H), 5.25 (m, 1H), 5.23 (ddd, J = 10.0, 2.6, 0.9 Hz, 1H), 4.85
(ddd, J = 7.9, 5.3, 2.3 Hz, 1H), 2.66 (d, J = 2.6 Hz, 1H), 2.63 – 2.54 (m, 2H). 13C{1H} NMR (125
MHz, CDCl3) δ 156.5, 133.3, 128.2, 125.1, 122.8, 122.0, 120.5, 120.0, 74.3, 42.1. HRMS-TOF
(ESI+): Calcd for C10H10BrO (M – H2O + H): 224.9910. Found 224.9911.
5-chloro-2-(1-hydroxybut-3-en-1-yl)phenol. The general procedure was followed with 4-
formyl-3-hydroxyphenyl acetate (50 mg, 0.28 mmol). Purification by chromatography on silica
(4:1 to 1:1 Hex:EtOAc) gave the allylated product as a yellow oil (47 mg, 85%). IR (ATR) 3258,
2977, 1581, 1488, 1046, 988, 901, 735 cm-1. 1H NMR (500 MHz, CDCl3) δ 8.18 (s, 1H), 6.89 (s,
1H), 6.88 (d, J = 9.7 Hz, 1H), 6.81 (dd, J = 8.0, 1.9 Hz, 1H), 5.83 (dddd, J = 10.7, 3.0, 1.5 Hz,
1H), 4.87 (ddd, J = 7.7, 5.2, 1.8 Hz, 1H), 2.63 (d, J = 2.3 Hz), 2.61 – 2.56 (m, 2H). 13C{1H} NMR
(125 MHz, CDCl3) δ 156.4, 134.2, 133.4, 127.9, 124.7, 119.92, 119.89, 117.6, 74.3, 42.1. HRMS-
TOF (ESI+): Calcd for C10H10ClO (M – H2O + H): 181.0415. Found 181.0415.
3-hydroxy-4-(1-hydroxybut-3-en-1-yl)phenyl acetate. The general procedure was followed with
4-chloro-2-hydroxybenzaldehyde (50 mg, 0.32 mmol). Purification by chromatography on silica
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(4:1 to 1:1 Hex:EtOAc) gave the allylated product as a yellow oil (53 mg, 75%). IR (ATR) 3332,
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2916, 2848, 1736, 1604, 1431, 1370, 1207, 1147, 975, 908 cm-1. H NMR (500 MHz, CDCl3) δ
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8.17 (s, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 2.3 Hz, 1H), 6.58 (dd, J = 8.2, 2.3 Hz, 1H), 5.84
(dddd, J = 17.6, 9.6, 7.9, 6.4 Hz, 1H), 5.26 – 5.20 (m, 2H), 4.87 (dd, J = 8.4, 5.1 Hz, 1H), 2.72 (bs,
1H), 2.65 – 2.55 (m, 2H), 2.28 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 169.4, 156.6, 151.1,
133.7, 127.6, 123.9, 119.7, 112.8, 110.8, 74.3, 42.1, 21.1. HRMS-TOF (ESI+) Calcd for
C12H14NaO4 (M + Na): 245.0784. Found 245.0787.
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4-Hydroxy-3-(1-hydroxybut-3-en-1-yl)benzaldehyde (5). The general procedure was followed
with 4-hydroxyisophthalaldehyde (4) (0.10 g, 0.67 mmol). Purification by chromatography on
silica (10:1 Hex:MTBE to 0:1 Hex:MTBE; Rf = 0.33 in 1:1 Hex:MTBE) giving 5 as a yellow
solid (0.1 g, 78%). IR (ATR) 3177, 2925, 2848, 2753, 1659, 1583, 1433, 1385, 1282, 1201, 1042,
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911, 867 cm-1. H NMR (500 MHz, CDCl3) δ 9.81 (s, 1H), 7.70 (dd, J = 8.5, 2.2 Hz, 1H), 7.54 (d,
J = 2.1 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 5.84 (ddt, J = 17.0, 10.3, 7.2 Hz, 1H), 5.26-5.20 (m, 2H),
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4.99 (t, J = 7.1 Hz, 1H), 2.64-2.60 (m, 2H). C{1H} NMR (125 MHz, CDCl3) δ 190.9, 161.7,
133.1, 132.0, 129.0, 128.9, 126.8, 120.1, 17.9, 74.3, 42.3. HRMS-TOF (ESI+) Calcd for
C11H12NaO3 (M + Na): 215.0678. Found 215.0678.
General Procedure for Allylations of Glyoxylic Acids (α-oxocarboxylic acids, Figure 1). To a
Schlenk flask containing a glyoxylic acid (1.0 eq.) in MeCN was added 1 (1.5 eq.) and the solution
was heated to 80 °C for 6 h. MeCN was removed in vacuo and the products were redissolved in
Et2O. The solution was extracted with 1 M NaOH (15 mL x 2). The combined aqueous layers were
then acidified to pH 1 with 1 M HCl, and extracted with EtOAc (20 mL x 3). The combined organic
layers were dried with MgSO4, filtered, and concentrated in vacuo.
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2-Hydroxy-2-methyl-4-pentenoic acid. The general procedure was followed with pyruvic acid
(100 mg, 1.1 mmol) as starting material giving the allylated product as an oil (89 mg, 60%).
Spectral data matched that previously reported by Kaur:28 1H NMR (500 MHz, CDCl3) δ 5.80
(ddt, J = 18.1, 9.3, 7.3 Hz, 1H), 5.20-5.13 (m, 1H), 4.97-4.86 (m, 1H), 2.57 (dd, J = 13.6, 7.7 Hz,
1H), 2.43 (dd, 13.9, 7.3 Hz, 1H), 1.47 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 180.9, 131.6,
119.9, 74.5, 44.3, 25.0.
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2-Ethyl-2-hydroxy-4-pentenoic acid. The general procedure was followed with 2-oxobutyric
acid (50 mg, 0.49 mmol). For easier purification and characterization purposes, the product was
converted to its corresponding methyl ester: To a round bottom containing MeOH (2 mL) was
added the crude allylated product and pTSA (7 mg, 0.03 mmol, 0.1 eq.). The solution was refluxed
for 4 h, then cooled and diluted with EtOAc (10 mL), washed with NaHCO3 (10 mL x 3) and brine
(10 mL x 1). The organic phase was dried with MgSO4, filtered, and concentrated in vacuo.
Purification by chromatography on silica (10:1 to 0:1 Hex:EtOAc; Rf = 0.24 in 10:1 Hex:EtOAc)
afforded the methyl ester as an oil (56 mg, 72%). Spectral data for the methyl ester matched that
previously reported by Seto:29 1H NMR (500 MHz, C6D6) δ 5.88 (m, 1H), 5.05 – 4.98 (m, 2H),
3.24 (s, 3H), 2.36 (d, J = 7.2 Hz, 2H), 1.78 – 1.50 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H). 13C{1H} NMR
(125 MHz, CDCl3) δ 176.5, 132.3, 118.4, 77.9, 51.9, 44.0, 32.1, 8.0.
2-hydroxy-2-phenylpent-4-enoic acid. The general procedure was followed with phenyl
glyoxylic acid (50 mg, 0.33 mmol) as starting material giving the allylated product as an oil (51
mg, 78%). Spectral Data matched that previously reported by Howard:30 1H NMR (500 MHz,
CDCl3) δ 7.64 (d, J = 7.6 Hz, 2H), 7.37 (t, J = 7.8 Hz, 2H), 7.32 (t, J = 7.3 Hz, 1H), 5.79 (ddt, J =
17.2, 10.3, 7.0 Hz, 1H), 5.23 (d, J = 17 Hz, 1H), 5.18 (d, J = 10.0 Hz, 1H), 3.02 (dd, J = 13.8 Hz,
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7.1 Hz, 1H), 2.81 (dd, J = 14.3, 6.7 Hz, 1H). C{1H} NMR (125 MHz, CDCl3) δ 178.9, 140.3,
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131.8, 128.4, 128.0, 125.6, 120.1, 44.0.
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2-benzyl-2-hydroxypent-4-enoic acid. The general procedure was followed with phenyl pyruvic
acid (50 mg, 0.30 mmol) as starting material giving the allylated product as an oil (46 mg, 73%).
For characterization purposes, the product was converted to its corresponding methyl ester: To a
round bottom containing MeOH (1 mL) was added the allylated product (46 mg, 0.22 mmol, 1.0
eq.) and pTSA (4 mg, 0.02 mmol, 0.1 eq.). The solution was refluxed for 4 hr, then cooled and
diluted with EtOAc (10 mL), washed with NaHCO3 (10 mL x 3) and brine (10 mL x 1). The
organic phase was dried with MgSO4, filtered, and concentrated in vacuo. Purification by
chromatography on silica (20:1 to 10:1 Hex:EtOAc) gave the methyl ester as a pale yellow oil (Rf
= 0.31 in 10:1 Hex:EtOAc). Spectral data for the methyl ester: IR (ATR) 2954, 1731, 1602, 1436,
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1213, 1053, 974, 812, 701 cm-1. H NMR (500 MHz, CDCl3) δ 7.30-7.23 (m, 3H), 7.18 (m, 2H),
5.82 (dddd, J = 17.1, 10.3, 7.7, 6.8 Hz, 1H), 5.16-5.11 (m, 2H), 3.72 (s, 3H), 3.06 (d, J = 13.2 Hz,
1H), 2.95 (d, J = 13.6 Hz, 1H), 2.62 (ddt, J = 13.9, 7.6, 1.0 Hz, 1H), 2.50 (ddt, J = 13.8, 7.1, 1.4
Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 175.5, 135.6, 132.3, 129.9, 128.2. 126.9, 118.9, 78.2,
52.5, 45.1, 43.5. HRMS-TOF (ESI+) Calcd for C12H14NaO3 (M + Na): 229.0835. Found 229.0835.
2-hydroxy-2-(1-phenylethyl)pent-4-enoic acid. The general procedure was followed with 2-oxo-
3-phenylbutanoic acid as starting material (50 mg, 0.28 mmol) and gave the allylated product as
an oil (45 mg, 71%; d.r. 2.1). For characterization purposes, the product was converted to its
corresponding methyl ester: To a round bottom containing MeOH (1 mL) was added the allylated
product (32 mg, 0.14 mmol, 1.0 eq.) and pTSA (3 mg, 0.02 mmol, 0.1 eq.). The solution was
refluxed for 4 h, then cooled and diluted with EtOAc (10 mL), washed with NaHCO3 (10 mL x 3)
and brine (10 mL x 1). The organic phase was dried with MgSO4, filtered, and concentrated in
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vacuo. Purification by chromatography on silica (20:1 to 10:1 Hex:EtOAc) gave the methyl ester
as a pale yellow oil (Rf = 0.35 in 10:1 Hex:EtOAc). Spectral data for the mixture of diastereomeric
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methyl esters: IR (ATR) 2955, 1732, 1606, 1436, 1265, 1170, 830, 734 cm-1. H NMR (500 MHz,
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CDCl3) δ 7.35-7.18 (m, 10H), 5.76 (ddt, J = 21.3, 8.4, 6.4 Hz, 1H), 5.66 (ddt, J = 20.6, 8.3, 6.5
Hz, 1H), 5.15-5.07 (m, 2H), 5.04-4.96 (m, 2H), 3.81 (s, 3H), 3.57 (s, 3H), 3.16-3.10 (m, 2H), 2.69
(ddt, J = 13.8, 6.3, 1.5 Hz, 1H), 2.49 (ddq, J = 13.9, 8.3, 1.1 Hz, 1H), 2.35 (ddd, J = 13.9, 8.3, 0.81
Hz, 1H), 2.03 (ddt, J = 13.9, 6.3, 1.4 Hz, 1H), 1.40 (d, J = 7.2 Hz, 3H), 1.24 (d, J = 7.1 Hz, 3H).
13C{1H} NMR (125 MHz, CDCl3) δ 176.5, 175.7, 142.1, 141.5, 132.9, 132.8, 130.1, 129.2, 128.6,
128.3, 128.1, 127.6, 127.5, 127.0, 126.9, 118.7, 118.6, 80.3, 80.2, 52.9, 52.3, 46.7, 46.6, 42.8, 41.7,
16.5, 14.6. HRMS-TOF (ESI+) Calcd for C14H18NaO3 (M + Na): 257.1154. Found 257.1158.
2-Allyl-2-hydroxy-4-phenyl-3-butenoic acid. The general procedure was followed with (E)-2-
oxo-4-phenylbut-3-enoic acid (50 mg, 0.28 mmol) as starting material. For easier purification, the
crude product was converted to the corresponding methyl ester: To a solution of the crude product
in MeOH/DCM (3 mL, 1:1) at room temperature was added TMSCHN2 (0.6 M, 0.56 mL, 0.34
mmol, 1.2 eq.) dropwise over 10 min. After stirring for 20 min, additional TMSCHN2 (0.6 M, 0.28
mL, 0.17 mmol, 0.6 eq.) was added.After stirring for an additional 10 min the reaction was
quenched with AcOH (0.10 mL) and diluted with toluene (0.5 mL) and the solvent was removed
in vacuo. Purification by chromatography on silica (10:1 to 4:1 Hex:EtOAc) gave the methyl ester
as an oil (51 mg, 78%). Spectral data for the methyl ester: IR (ATR) . 1H NMR (500 MHz, CDCl3)
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δ. C{1H} NMR (125 MHz, CDCl3) δ. HRMS-TOF (ESI+) Calcd for C14H16NaO3 (M + Na):
255.0992. Found 255.0994.
2-Allyl-[4-(2-Furanyl)]-2-hydroxy-3-butenoic acid. The general procedure was followed with
(E)-4-(furan-2-yl)-2-oxobut-3-enoic acid (50 mg, 0.30 mmol). For easier purification and
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characterization purposes, the product was converted to its corresponding tert-butyl diphenyl silyl
ester: To a Schlenk flask was added DCM (3 mL) and the crude allylated product at 0 °C. Hünig’s
base (0.13 mL, 0.75 mmol, 2.5 eq.) was added followed by tert-butyl(chloro)diphenylsilane (165
mg, 0.19 mmol, 2.0 eq.) and the solution was allowed to warm to room temperature with stirring
for 15 h. The reaction was quenched with H2O (10 mL) and extracted with DCM (10 mL x 3).
Purification by chromatography on silica (20:1 to 10:1 Hex:EtOAc; Rf = 0.68 in 10:1 Hex:EtOAc)
gave the silyl ether/ester as a clear oil (127 mg, 62%). Spectral data for the bis-silyl derivative: IR
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(ATR) 2930, 2857, 1742, 1427, 1259, 1106, 734, 697 cm-1. H NMR (500 MHz, CDCl3) δ 7.67
(d, J = 6.6 Hz, 2H), 7.63 (d, J = 6.6 Hz, 2H), 7.57 (d, J = 6.8 Hz, 2H), 7.55 (d, J = 6.7 Hz, 2H),
7.43 – 7.38 (m, 3H), 7.35 – 7.26 (m, 6H), 7.22 (d, J = 7.4 Hz, 2H), 7.20 (d, J = 7.5 Hz, 2H), 6.32
(dd, J = 3.3, 1.9 Hz, 1H), 6.28 (d, J = 16.1 Hz, 1H), 6.23 (d, J = 16.0 Hz, 1H), 6.00 (d, J = 3.3 Hz,
1H), 5.95 (m, 1H), 5.11 – 5.04 (m, 2H), 2.73 (dd, J = 14.1, 7.5 Hz, 1H), 2.62 (dd, J = 14.1, 6.4 Hz,
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1H), 1.04 (s, 9H), 1.02 (s, 9H). C{1H} NMR (125 MHz, CDCl3) δ 170.7, 152.1, 142.2, 136.3,
136.1, 135.4, 135.32, 135.29, 135.26, 135.1, 132.7, 131.6, 131.5, 129.9, 129.0, 128.7, 127.71,
127.69, 127.66, 127.58, 127.57, 126.99, 126.96, 119.8, 118.8, 111.2, 108.5, 81.0, 44.0, 27.5, 26.9,
19.9, 19.1. HRMS-TOF (ESI+) Calcd for C43H48NaO4Si2 (M + Na): 707.2989. Found 707.2978.
(3E)-2-Allyl-4-(4-formylphenyl)-2-hydroxy-3-butenoic acid (7). The general procedure was
followed with 6 (0.10 g, 0.49 mmol). For easier purification, compound 7 was converted to its
corresponding methyl ester: To a solution of crude 7 in MeOH/DCM (8.4 mL, 1:1) at room
temperature was added TMSCHN2 (0.51 mL, 1.02 mmol, 1.2 eq.) dropwise over 10 min. After
stirring for 20 min, additional TMSCHN2 (0.25 mL, 0.51 mmol, 0.6 eq.) was added. After stirring
for an additional 10 min, a third addition of TMSCHN2 (0.13 mL, 0.25 mmol, 0.3 eq.) was added,
and the solution stirred for 5 min. The reaction was quenched with AcOH (0.10 mL) and diluted
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with toluene (0.38 mL) and the solvent was removed in vacuo. Purification by chromatography on
silica (10:1 to 4:1 Hex:EtOAc; Rf = 0.28 in 4:1 Hex:EtOAc) gave the methyl ester as a pale yellow
oil (96 mg, 75%). Spectral data for the methyl ester: IR (ATR) 2954, 1731, 1697, 1602, 1436,
1213, 1053, 974, 812, 701 cm-1. 1H NMR (500 MHz, CDCl3) δ 9.97 (s, 1H), 7.83 (d, J = 8.7 Hz,
2H), 7.53 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 15.5 Hz, 1H), 6.49 (d, J = 14.6 Hz, 1H), 5.79 (dddd, J
= 14.5, 9.7, 7.7, 6.8 Hz, 1H), 5.19-5.13 (m, 2H), 3.82 (s, 3H), 2.68 (ddt, J = 13.9, 7.9, 1.1 Hz, 1H),
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2.54 (ddt, J = 13.5, 6.9, 1.2 Hz, 1H). C{1H} NMR (125 MHz, CDCl3) δ 191.7, 174.5, 142.3,
135.6, 132.9, 131.6, 130.1, 129.2, 127.2, 119.7, 53.3, 44.0. HRMS-TOF (ESI+) Calcd for
C15H17O4 (M + H): 261.1121. Found 261.1120.
2-(4-formylphenyl)-2-hydroxypent-4-enoic acid (9). To a Schlenk flask containing MeCN (14
mL) was added siletane 13 (0.11 g, 0.31 mmol, 1.1 eq.) and 8 (50 mg, 0.28 mmol, 1.0 eq.) and the
resulting mixture was allowed to stir for 1 h at room temperature before being heated to 80 °C for
6 h. The reaction was then cooled to room temperature and solvent was removed by rotary
evaporator. The resulting product was redissolved in THF (2.8 mL) and TBAF (0.90 mL, 0.90
mmol, 3.0 eq.) was added and the mixture was stirred at room temperature for 30 min. The reaction
was quenched with aq. NH4Cl (20 mL) and extracted with EtOAc (2 x 15 mL). The combined
organic layers were dried over MgSO4, filtered, and concentrated in vacuo. For easier purification
and characterization purposes, 9 was converted to its corresponding methyl ester: To a solution of
crude 9 in DCM/MeOH (3.0 mL, 1:1) at room temperature was added TMSCHN2 (0.56 mL, 0.34
mmol, 1.2 eq.) dropwise over 10 min. After stirring for 20 min, additional TMSCHN2 (0.28 mL,
0.17 mmol, 0.60 eq.) was added. After stirring for an additional 10 min, a third addition of
TMSCHN2 (0.17 mL, 0.085 mmol, 0.30 eq.) was added, and the solution stirred for 5 min. The
reaction was quenched with AcOH (0.03 mL), and diluted with toluene (0.01 mL) before
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concentrating in vacuo. Purification by chromatography on silica (4:1 to 1:1 Hex:EtOAc; Rf = 0.6
in 1:1 Hex:EtOAc) gave the methyl ester as a clear oil (42 mg, 64%). Spectral data for the methyl
ester: IR (ATR) 3496, 2955, 1732, 1699, 1606, 1436, 1265, 1170, 830, 734 cm-1. 1H NMR (500
MHz, CDCl3) δ 10.02 (s, 1H), 7.89-7.86 (m, 2H), 7.81-7.78 (m, 2H), 5.76 (ddt, J = 20.5, 7.5, 6.8
Hz, 1H), 5.20-5.13 (m, 2H), 3.8 (s, 3H), 2.98 (dd, J = 14.3, 7.2 Hz, 1H), 2.77 (ddt, J = 11.7, 6.9,
1.1 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 191.8, 174.3, 147.6, 135.8, 131.6, 129.6, 126.4,
119.9, 78.1, 53.6, 44.3. HRMS-TOF (ESI+) Calcd for C13H14NaO4 (M + Na): 257.0784. Found
257.0779.
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(8S,9S,10R,13S,14S,17R)-17-(1,2-dihydroxypent-4-en-2-yl)-17-hydroxy-10,13-dimethyl-
1,6,7,8,9,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3,11(2H)-dione
(14). To a solution of cortisone (100 mg, 0.28 mmol, 1 eq.) in MeCN (2.8 mL) was added siletane
13 (190 mg, 0.55 mmol, 2.0 eq.) and the mixture was heated to 80 ºC for 6 h. The solution was
then cooled to room temperature and concentrated in vacuo. Purification by column
chromatography on silica (5% MeOH/DCM) gave 14 (99 mg, 88%) as a white solid (mp. 88.6 –
89.5 ºC). [α]D20 = 97.25 (c 0.8, MeOH). IR (ATR) 3383, 2930, 1697, 1645, 1632, 1231, 987, 972
cm-1. 1H NMR (500 MHz, CDCl3) δ 5.75 (ddt, J = 16.0, 10.0, 7.9 Hz, 1H), 5.72 (s, 1H), 4.97 (dq,
J = 17.0, 1.6 Hz, 1H), 4.92 (ddt, 0.9, 1.7, 10.0 Hz, 1H), 3.96 (dd, J = 10.9, 1.1 Hz, 1H), 3.87 (d, J
= 10.9 Hz, 1H), 2.85 (d, J = 12.7 Hz, 1H), 2.78 (ddd, J = 13.7, 5.1, 3.2 Hz, 1H), 2.49 (dd, J = 14.8,
5.0 Hz, 1H), 2.46 (dd, J = 14.3, 4.7 Hz, 1H), 2.44 (J = 11.9 Hz, 1H), 2.41 – 2.25 (m, 2H), 2.00 –
1.80 (m, 6H), 1.74 – 1.59 (m, 3H), 1.41 (s, 3H), 1.35 – 1.20 (m, 2H), 0.94 (s, 3H), 0.79 (dtd, J =
13
18.0, 10.2, 4.2 Hz, 1H). C{1H} NMR (125 MHz, CDCl3) δ 211.0, 199.9, 169.1, 131.4, 124.5,
115.7, 90.4, 75.9, 70.6, 62.5, 53.3, 52.4, 49.5, 45.7, 38.1, 36.3, 34.8, 33.7, 22.8, 21.5, 19.6, 17.2,
16.9, 14.1. HRMS-TOF (ESI+) Calcd for C24H35O5 (M + H): 403.2484. Found 403.2482.
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(8S,9S,10R,11S,13S,14S,17R)-17-(1,2-dihydroxypent-4-en-2-yl)-11,17-dihydroxy-10,13-
dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-
3-one (15). To a solution of hydrocortisone (100 mg, 0.28 mmol, 1 eq.) in MeCN (5.5 mL) was
added siletane 13 (120 mg, 0.55 mmol, 2.0 eq.) and the mixture was heated to 80 ºC for 8 h. The
solution was then cooled to room temperature and concentrated in vacuo. Purification by column
chromatography on silica (5% MeOH/DCM) gave 15 (100 mg, 90%) as a white solid (mp. 249.5
– 251.0 ºC). [α]D20 = 47.20 (c 1.0, MeOH). IR (ATR) 3430, 2927, 1651, 1108, 1040, 948 cm-1. 1H
NMR (500 MHz, CDCl3) δ 5.72 (ddt, J = 17.1, 10.1, 7.6 Hz, 1H), 5.67 (s, 1H), 4.96 (dq, J = 17.0,
1.0 Hz, 1H), 4.92 (d, J = 10.0 Hz, 1H), 4.44 (m, 1H), 4.02 (dd, J = 10.2, 1.2 Hz, 1H), 3.92 (d, J =
10.3 Hz, 1H), 2.54 – 2.43 (m, 2H), 2.41 – 2.30 (m, 2H), 2.30 – 2.16 (m, 2H), 2.12 (dd, J = 14.0,
2.5 Hz, 1H), 2.10 – 1.96 (m, 2H), 1.92 – 1.83 (m, 2H), 1.81 – 1.53 (m, 3H), 1.47 (s, 3H), 1.37 –
1.05 (m, 4H), 1.25 (s, 3H), 1.05 – 0.92 (m, 2H), 0.79 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3)
δ 199.8, 172.7, 131.6, 122.3, 115.4, 91.1, 76.5, 71.0, 68.8, 56.2, 51.5, 48.0, 45.1, 42.7, 39.2, 35.0,
33.8, 31.1, 23.2, 21.7, 20.9, 19.7, 18.9, 14.4. HRMS-TOF (ESI+) Calcd for C24H37O5 (M + H):
405.2636. Found 405.2628.
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1
NMR Calculations. The evaluation of Boltzmann-averaged 13C and H magnetic shielding
tensors and isotropic chemical shifts from density functional theory (DFT) followed Hoye’s
protocol25 adapted as follows. For the two candidate diastereomers, we applied the ETKDG
conformational search algorithm31 as implemented in RDKit32 to obtain nine low-energy
conformations of each structure which were then optimized at the B3LYP/6-31G* level of theory33
together with the PCM implicit solvent model34 with dielectric constant ε = 4.81 as implemented
in Q-Chem 5.1.35 NMR shielding tensors were evaluated using gauge-including atomic orbitals
(GIAOs)36,37 at the same B3LYP/6-31G*/PCM level for each optimized conformer, and shielding
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tensors were Boltzmann-averaged to obtain 1H and 13C isotropic chemical shifts relative to those
predicted for TMS at the same level of theory. Further discussion of the stereocenter assignment
based on these data is provided in the Supporting Information.
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Conformational Analysis. To better understand the chemoselectivity highlighted in Scheme 7, a
relaxed potential energy scan on a model cortisone compound was performed at the B3LYP/6-
31G*/PCM level of theory in Q-Chem 5.1.34 In the model compound, the C and D rings were
preserved to retain the integrity of steric interactions near the new stereocenter while the A and B
rings were replaced with simpler cyclohexane units. Along this scan, the C16-C17-C20-C21 dihedral
angle was constrained in increments of 10° while allowing all other degrees of freedom to relax
through geometry optimization.
Acknowledgements
Financial support from the National Institutes of Health (R15 GM119034) and Gelest Inc.
(Fellowship to P.S) is gratefully acknowledged. TK acknowledges support from the Research
Corporation for Science Advancement through a Cottrell Scholar Award.
Supporting Information Available: Copies of 1H NMR and 13C{1H} NMR spectra; comparison
of experimental and simulated NMR chemical shifts; potential energy scan of model cortisone
compound. This material is available free of charge via the internet at http://pubs.acs.org
References and Footnotes
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(10) By NMR, release of the alkoxy group on silicon was observed that we have interpreted as
exchange with the hydroxyl group of o-hydroxyacetophenone (see the Supporting Information).
However, no evidence for subsequent allylation was observed.
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(17) Dickens, T. K.; Warren, S. Chemistry of the Carbonyl Group. John Wiley & Sons Ltd,
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(18) Sello, G.; Di Gennaro, P. “Aldol Reactions of the trans-o-Hydroxybenzylidenepyruvate
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(19) For comparison, the allylation of compound 6 with allylmagnesium bromide was investigated
using 0.5, 1.0, and 2.0 equivalents of the Grignard reagent at 0 and -78 ℃. In all cases evidence
for allylation of both the aldehyde and ketone was observed.
(20) Chen, J-x.; Sakamoto, K.; Orita, A.; Otera, J. “Unusual Preference for Ketone and Reversal
of Chemoselectivity in Lewis Acid-Catalyzed Aldol Reaction of Ketene Silyl Acetal” J. Org.
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(25) Willoughby, P. H.; Jansma, M. J.; Hoye, T. R. “A guide to small-molecule structure
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reactions” Chem. Rev. 1993, 93, 1307-1370.
(27) Franco, D.; Wenger, K.; Antonczak, S.; Cabrol-Bass, D.; Dunach, E.; Rocamora, M.; Gomez,
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Experimental and Theoretical Studies” Chem-Eur. J. 2002, 8, 664-672.
(28) Kaur, P.; Singh, P.; Kumar, S. “Regio- and stereochemical aspects in synthesis of 2-allyl
derivatives of glycolic, mandelic and lactic acids and their iodocyclisations to 3-hydroxy-3,4-
dihydrofuran-2(5H)-ones” Tetrahedron 2005, 61, 8231-8240.
(29) Seto, M.; Roizen, J. L.; Stoltz, B. M. “Catalytic Enantioselective Alkylation of Substituted
Dioxanone Enol Ethers. Ready Access to C(α)-Tetrasubstituted Hydroxyketones, Acids, and
Esters” Angew. Chem. Int. Ed. 2008, 47, 6873-6876.
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(34) Lange, A. W.; Herbert, J. M. “A smooth, nonsingular, and faithful discretization scheme for
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(35) Shao, Y.; Gan, Z.; Epifanovsky, E.; Gilbert, A. T. B.; Wormit, M.; Kussmann, J.; Lange, A.
W.; Behn, A.; Deng, J.; Feng, X.; Ghosh, D.; Goldey, M.; Horn, P. R.; Jacobson, L. D.; Kaliman,
I.; Khaliullin, R. Z.; Kuś, T.; Landau, A.; Liu, J.; Proynov, E. I.; Rhee, Y. M.; Richard, R. M.;
Rohrdanz, M. A.; Steele, R. P.; Sundstrom, E. J.; Woodcock, H. L.; Zimmerman, P. M.; Zuev, D.;
Albrecht, B.; Alguire, E.; Austin, B.; Beran, G. J. O.; Bernard, Y. A.; Berquist, E.; Brandhorst, K.;
Bravaya, K. B.; Brown, S. T.; Casanova, D.; Chang, C.-M.; Chen, Y.; Chien, S. H.; Closser, K.
D.; Crittenden, D. L.; Diedenhofen, M.; DiStasio, R. A.; Do, H.; Dutoi, A. D.; Edgar, R. G.; Fatehi,
S.; Fusti-Molnar, L.; Ghysels, A.; Golubeva-Zadorozhnaya, A.; Gomes, J.; Hanson-Heine, M. W.
D.; Harbach, P. H. P.; Hauser, A. W.; Hohenstein, E. G.; Holden, Z. C.; Jagau, T.-C.; Ji, H.; Kaduk,
B.; Khistyaev, K.; Kim, J.; Kim, J.; King, R. A.; Klunzinger, P.; Kosenkov, D.; Kowalczyk, T.;
Krauter, C. M.; Lao, K. U.; Laurent, A.; Lawler, K. V.; Levchenko, S. V.; Lin, C. Y.; Liu, F.;
Livshits, E.; Lochan, R. C.; Luenser, A.; Manohar, P.; Manzer, S. F.; Mao, S.-P.; Mardirossian,
N.; Marenich, A. V.; Maurer, S. A.; Mayhall, N. J.; Neuscamman, E.; Oana, C. M.; Olivares-
Amaya, R.; O’Neill, D. P.; Parkhill, J. A.; Perrine, T. M.; Peverati, R.; Prociuk, A.; Rehn, D. R.;
Rosta, E.; Russ, N. J.; Sharada, S. M.; Sharma, S.; Small, D. W.; Sodt, A.; Stein, T.; Stück, D.; Su,
Y.-C.; Thom, A. J. W.; Tsuchimochi, T.; Vanovschi, V.; Vogt, L.; Vydrov, O.; Wang, T.; Watson,
M. A.; Wenzel, J.; White, A.; Williams, C. F.; Yang, J.; Yeganeh, S.; Yost, S. R.; You, Z.-Q.;
Zhang, I. Y.; Zhang, X.; Zhao, Y.; Brooks, B. R.; Chan, G. K. L.; Chipman, D. M.; Cramer, C. J.;
Goddard, W. A.; Gordon, M. S.; Hehre, W. J.; Klamt, A.; Schaefer, H. F.; Schmidt, M. W.; Sherrill,
C. D.; Truhlar, D. G.; Warshel, A.; Xu, X.; Aspuru-Guzik, A.; Baer, R.; Bell, A. T.; Besley, N. A.;
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