A striking exception to the chelate model for acyclic diastereocontrol: Efficient access to a versatile propargyl alcohol for chemical synthesis

Article abstract of DOI:10.3390/molecules14125216

The four-step, asymmetric synthesis of a chiral propargyl alcohol 1 from (R)-pantolactone is described. A key feature of the synthesis is a diastereoselective acetylide addition to a chiral α-alkoxy-aldehyde 7, in which unusual Felkin selectivity is obser

Full text of DOI:10.3390/molecules14125216

Molecules 2009, 14, 5216-5222; doi:10.3390/molecules14125216
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
A Striking Exception to the Chelate Model for Acyclic
Diastereocontrol: Efficient Access to a Versatile Propargyl
Alcohol for Chemical Synthesis
Sami F. Tlais, Ronald J. Clark and Gregory B. Dudley *
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390,
USA; E-Mails: stlais@chem.fsu.edu (S.F.T); clark@chem.fsu.edu (R.J.C)
* Author to whom correspondence should be addressed; E-Mail: gdudley@chem.fsu.edu.
Received: 26 October 2009; in revised form: 17 November 2009 / Accepted: 30 November 2009 /
Published: 15 December 2009
Abstract: The four-step, asymmetric synthesis of a chiral propargyl alcohol 1 from
(R)-pantolactone is described. A key feature of the synthesis is a diastereoselective
acetylide addition to a chiral α-alkoxy-aldehyde 7, in which unusual Felkin selectivity is
observed, despite the potential for chelation control. Crystalline propargyl alcohol 1 is
valuable for complex molecule synthesis, and is easy to prepare in multi-gram quantities
and high diastereomeric purity.
Keywords: pantolactone; synthesis; Felkin–Anh; acyclic diastereocontrol; chiral building
block
Introduction
The chemical synthesis of complex molecules begins with core building blocks [1]. Chiral,
functionally rich small molecules serve as starting points in the design of synthetic strategies for front-
line molecular targets; knowing which chiral building blocks are readily available is valuable during
retrosynthetic analysis. One such chiral building block is the focus of this article; we describe the
synthesis, large-scale purification, and X-ray crystallographic analysis of propargyl alcohol 1
(Figure 1) from (R)-pantolactone (2). In appreciation of the special thematic issue of Molecules on
Asymmetric Synthesis, a tutorial discussion of steric and stereoelectronic factors that are thought to
influence the outcome of a key diastereoselective 1,2-addition reaction is included.

Molecules 2009, 14
Figure 1. Chiral, functionally rich small molecule building blocks for chemical synthesis.
5217
OH
OH
OH
O
OH
OH
O
O
O
O
O
O
O
TES Bn
PMP
PMP
1
2
3
4
four steps from
commercial material
(this report)
pantolactone
(both enantiomers
commercially available)
five steps from
commercial material
(precursor to paclitaxel)
five steps from
commercial material
(precursor to peloruside)
Propargyl alcohol 1 is an ideal starting point for complex molecule synthesis. Both enantiomers of
pantolactone (2) are commercially available, and 1 offers multiple and orthogonal functional handles
for further manipulation. Propargyl alcohol 1 is highly crystalline, which is convenient for purification,
storage, and handling of large quantities of material. As an indication of the potential utility of 1 in
chemical synthesis, consider that related alcohols 3 and 4 have been converted to the complex natural
products paclitaxel (Taxol) [2] and peloruside [3], respectively. Of particular note is that crystalline
propargyl alcohol 1 can be prepared in high purity via diastereoselective addition to the corresponding
aldehyde (7, vide infra), despite ambiguity in the Felkin–Anh model and the possibility for chelation
control to deliver an alternative diastereomer.
Results and Discussion
The four-step synthesis of 1 from pantolactone (2) is shown in Scheme 1. Reduction of
pantolactone with lithium aluminum hydride and selective protection of the resulting triol using
para-methoxyphenyl (PMP) acetal 5 provides dioxane 6 as reported previously [2]. Primary alcohol 6
is then oxidized to aldehyde 7 under Swern conditions; the unpurified aldehyde is immediately
dissolved in anhydrous THF and treated with a solution of propynylmagnesium bromide.
Scheme 1. Preparation of propargyl alcohol 1 as a mixture of diastereomers from pantolactone (2).
OH
O
CH2OH
1. LiAlH4, Et2O
3. Swern, CH2Cl2
OH
O
O
O
O
O
2. 5, TsOH, CH2Cl2
92% overall (ref 2)
4. CH3CCMgBr, THF
82% overall
6
PMP
PMP
(3:1 dr)
2
O
H
OMe
OMe
O
O
MeO
PMP–CH(OMe)2
(5)
7
PMP
Addition of propynyl Grignard to chiral aldehyde 7 provides a 3:1 mixture of two alcohol
diastereomers (Scheme 1), the relative stereochemistry of which needed to be assigned. The Felkin–
Anh model (Figure 2, inset in oval) does not provide unambiguous guidance in this case, as two groups
—namely, the gem-dimethyl quaternary center and the electronegative oxygen substituent—could
reasonably be designated as the “large” group [4]. Application of the Felkin–Anh model for predicting
acyclic diastereoselection in the addition to aldehyde 7 is discussed below.

Molecules 2009, 14
Figure 2. Alternative Felkin–Anh models for predicting/assigning stereochemistry.
5218
OH
OH
O
O
O
H
PMP
PMP
Mg2+
O
O
O
H
H
O
O
O
O
7a
7b
H
C3H3
PMP
PMP
1
8
Felkin–Anh model with
quaternary carbon as large group
and Cram chelation with –OR group
predicts syn- stereochemistry
Felkin–Anh model with
–OR as large group
C3H3
O
H
M
S
predicts anti- stereochemistry
L
(A)
(B)
Nu–
To apply the Felkin-Anh model (Figure 2), the three substituents on the aldehyde α-carbon (H, OR,
and the quaternary carbon bearing the gem-dimethyl group) must be designated as “small” (S),
“medium” (M), and “large” (L). Typically this designation is made based on the relative sizes of the
three substituents (sterics), although there is a stereoelectronic preference for electronegative atoms to
act “large” by creating local regions of high electron density that result in negative Coulombic
interactions with the incoming nucleophile. Lewis basic substituents typically assume the “medium”
position when chelating metal salts are present [5]. Whichever is the relevant substrate conformation,
–
the nucleophile (C3H5 ) attacks along the Bürgi–Dunitz trajectory, passing closest to the “small” group
and opposite from the “large” group [6].
The reaction path represented in Figure 2B (chelation control, 7b → 8) appears quite reasonable,
although it proved to be the minor pathway (vide infra). Approach of the nucleophile from the side
opposite the bulky quaternary center is consistent with steric considerations, and a five-membered ring
chelation of magnesium(II) salts may provide a conformational bias in favor of 7b. The chelation-
control model (i.e., Figure 2B) is generally a good predictor of diastereoselectivity in the addition of
Grignard reagents to α-alkoxy aldehydes and ketones. For example, allylic alcohol 4 (Figure 1, vide
supra) is prepared by chelation-controlled hydride addition (reduction) of an α-benzyloxy ketone [3].
The reaction path represented in Figure 2A (7a → 1) is favored (in the absence of chelation) on
stereoelectronic grounds, as approach of the nucleophile from the side opposite the oxygen substituent
minimizes Coulombic interactions between regions of high electron density surrounding the oxygen
atom and the electron-rich nucleophile. For the reaction to proceed along this pathway, the five-
membered ring chelation of magnesium(II) salts must be disrupted, and the stereoelectronic
(Coulombic) shield provided by the electron-rich oxygen substituent must outweigh steric advantages
of approaching opposite the bulky quaternary center.
The major diastereomer produced in the reaction of propynylmagnesium bromide with aldehyde 7
was shown by X-ray crystallography to be 1 (Figure 3), which is the result of Felkin addition in the
absence of chelation [7]. This unpredicted result could prove quite useful for chemical synthesis.
Aldehyde 7 is available by oxidation of known pantolactone derivative 6 (Scheme 1) [2]. After clean
addition of propynylmagnesium bromide, crystallization of the crude product mixture from ether
provides monoprotected anti-1,2-diol 1 in 40% yield as a single diastereomer (Scheme 2) as measured
by 1H- NMR spectroscopy [8]. Slow evaporation of a dichloromethane solution of 1 provided crystals
suitable for X-ray diffraction analysis (the result of which is shown in Figure 3).

Molecules 2009, 14
Figure 3. Ball-and-stick representation of propargyl alcohol 1 from X-ray analysis.
5219
Scheme 2. The major diastereomer (1) is highly crystalline.
O
OH
BrMg
THF; then
H
O
O
O
O
recrystallize
>95% de
Felkin product
PMP
PMP
7
1
(not chelation control)
Several factors may be involved in overriding the general tendency for chelation-controlled addition
to α-alkoxy aldehydes in this specific case (acetylide addition to aldehyde 7). Polar coordinating
solvents like THF often erode the diastereoselectivity of chelation-controlled additions, although we
observed similar diastereoselectivities when conducting this particular reaction in other solvents.
Hyperconjugative interactions (n → σ*) between the acetal oxygens attenuate their Lewis basicity as
compared to typical ether linkages, resulting in weaker chelation from acetals, but chelation-controlled
addition to α-(alkoxyalkyl)oxy aldehydes is known [9–10] Perhaps the best explanation comes from
analysis of an alternative illustration of the potential chelate (Figure 4), which reveals a 1,3-diaxial
interaction between the metal cation (with its associated ligands, not shown) and one of the two
β-methyl substituents. Such a 1,3-diaxial interaction may disfavor and disrupt chelation.
Figure 4. A diaxial interaction that may disrupt chelation in aldehyde 7.
1,3-diaxial interaction?
OH
Mg2+
O
O
O
O
H
O
PMP
PMP
In the absence of chelation control, selectivity between the competing pathways (cf. Figure 2A and
2B) arises from the balance of steric (favoring syn-isomer 8) and stereoelectronic (favoring anti-isomer
1) factors. Our study focused on the acetylide nucleophile derived from propyne [11]. The steric
profile of acetylide nucleophiles is minimal, which minimizes the impact of steric shielding from the
large quaternary center [12–14]. Meanwhile, the greater ionic character of acetylide organometallic
reagents (sp-hybridized carbanions) as compared to most sp2- and sp3-hybridized carbanions probably

Molecules 2009, 14
5220
translates into greater Coulombic interactions, which repel the electron-rich nucleophile from regions
of high electron density. In summary, we attribute the observed stereochemistry to (a) a substrate that
is ill-suited to chelation of metal salts, and (b) a small, electron-rich nucleophile that is more sensitive
to stereoelectronic factors than steric factors.
Experimental
General
1H-NMR and 13C-NMR spectra were recorded on a 600 MHz spectrometer and 150 MHz
respectively using CDCl3 as the deuterated solvent. The chemical shifts (δ) are written in parts per
1
million (ppm) relative to the residual CHCl3 peak (7.26 ppm for H-NMR and 77.0 ppm for
13C-NMR). The coupling constants (J) were reported in Hertz (Hz). Mass spectra were acquired using
electro-spray ionization (ESI+). Melting points were determined on a Mel-Temp apparatus.
1-(2-(4-Methoxyphenyl)-5,5-dimethyl-1,3-dioxan-4-yl)but-2-yn-1-ol (1): Oxalyl chloride (64 mmol,
5.5 mL) was added dropwise at –78 °C to a mixture of dry DMSO (85 mmol, 6.0 mL) in methylene
chloride (72 mL). After 10 min, a solution of alcohol 6 (42.0 mmol, 10.6 g) in methylene chloride
(39 mL) was added dropwise. After 30 min, triethylamine (30 mL) was added to the reaction mixture,
which was warmed to ambient temperature over 15 min. The reaction was quenched with H2O
(100 mL) and extracted with methylene chloride (200 mL × 2). The combined organic layers were
washed with saturated aqueous NaHCO3 (100 mL). Evaporation of the organic solvent under reduced
pressure afforded a pale yellow oil, which was mixed with ether (20 mL) and filtered through a small
plug of silica gel with ether (100 mL). Evaporation of the volatile components under reduced pressure
afforded 10.2 g of a pale yellow solid (consisting primarily of aldehyde 7), which was used without
further purification in the next step.
The aforementioned crude mixture containing aldehyde 7 was dissolved in anhydrous THF
(200 mL) cooled at 0 °C, and treated with a solution of propynylmagnesium bromide (0.5 M, 150 mL,
75 mmol). The reaction mixture was warmed to room temperature over 1.5 h. The reaction was
quenched with saturated aqueous NH4Cl (200 mL) and then extracted with ethyl acetate (300 mL).
Evaporation of the volatile components under reduced pressure afforded a yellow oil, which was
subsequently diluted with ether (15 mL). Shortly thereafter (within 5 min), white crystals began to
form. The crystalline precipitate was collected by filtration, washed with hexane (150 mL), and dried
under reduced pressure to furnish 4.89 g (40% from 6) of alcohol 1 as a single diastereomer.
1
(mp = 105 °C). H-NMR (CDCl3), δ 0.92 (s, 3H); 1.29 (s, 3H); 1.85 (d, 3H, J = 2.0); 2.27 (d, 1H,
J = 7.7 Hz); 3.58 (d, 1H, J = 11.1 Hz); 3.63 (d, 1H, J = 11.1 Hz); 3.65 (d, 1H, J = 4.4 Hz); 3.80 (s,
3H); 4.46 (m, 1H); 6.89 (apparent t, 1H, J = 2.1, 2.8 Hz); 6.90 (apparent t, 1H, J = 2.1, 2.8 Hz); 7.44
(apparent t, 1H, J = 2.1, 2.8 Hz); 7.46 (apparent t, 1H, J = 2.1, 2.8 Hz); 13C-NMR (CDCl3) δ 3.7, 19.5,
22.0, 32.6, 55.3, 62.9, 77.6, 79.6, 83.1, 87.0, 102.0, 113.6, 113.7, 127.6, 131.0, 160.1; HRMS (ESI+):
calcd. for C17H22O4Na 313.1416, found 313.1426.

Molecules 2009, 14
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Conclusions
Alcohol 1 is a versatile chiral building block for chemical synthesis. Based on the observations
described in this paper—Alcohol 1 is highly crystalline and accessible by simple Felkin addition of
propyne to aldehyde 7—Monoprotected anti-1,2-diol 1 is now readily available for the construction of
complex molecular targets.
Acknowledgments
This research is supported by a grant from the National Science Foundation (NSF CHE 0749918).
References and Notes
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one’s feet.” The more common translation of the proverb is, “The journey of a thousand miles
begins with a single step.”
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of chiral polyoxy 8-membered ring enone corresponding to the B ring of taxol. Bull. Chem. Soc.
Jpn. 2001, 74, 113–122.
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synthesis of (+)-peloruside a, a potent microtubule stabilizing agent. J. Am. Chem. Soc. 2009, 131,
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Sons: New York, NY, USA, 1994.
5. Electronegative atoms (e.g., oxygen) are often good Lewis bases, so manipulation of the system in
either direction (–OR as “large” or “medium” group) is frequently possible by promoting or
disrupting chelation of metal salts; see reference [4] for discussion.
6. The products arising from the alternative conformations are sometimes referred to as “Felkin” and
“anti-Felkin” products, although the Felkin–Anh model accounts for either possibility. In this
paper we use the term “chelation control” to indicate products arising from the electron-rich
Lewis basic substituent occupying the “medium” position in the Felkin–Anh model.
7. CCDC 748703 contains the supplementary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html/ or from the CCDC, 12
Union Road, Cambridge CB2 1EZ, UK; Fax: +44 1223 336033; E-Mail: deposit@ccdc.cam.ac.uk.
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Chem. 1997, 62, 6041–6045.
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discussion see: Kagawa, N.; Ihara, M.; Toyota, M. Convergent Total Synthesis of (+)-
Mycalamide A. J. Org. Chem. 2006, 71, 6796–6805, and references cited therein.
11. Addition of a vinyl Grignard nucleophile to aldehyde 7 produced a complex mixture of products
for which purification was not attempted.

Molecules 2009, 14
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12. Our lab has documented and exploited the minimal steric profile of acetylide nucleophiles in the
olefination of hindered aldehydes and ketones; see: Engel, D.A.; Dudley, G.B. Olefination of
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Sample Availability: Samples of compound 1 are available from the authors.
© 2009 by the authors; licensee Molecular Diversity Preservation International, 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/3.0/).