Chiral phosphoric acid directed regioselective acetalization of carbohydrate-derived 1,2-diols

Article abstract of DOI:10.1002/anie.201304298

In control: A chiral phosphoric acid catalyst (see scheme) significantly enhances or completely overrides the inherent regioselective acetalization profiles exhibited by monosaccharide-derived 1,2-diol substrates. This study represents the first example of chiral-catalyst-directed regio- and enantioselective intermolecular acetalizations, which are complementary to existing methods for substrate-controlled functionalization of polyols. Copyright

Full text of DOI:10.1002/anie.201304298

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DOI: 10.1002/anie.201304298
Organocatalysis
Chiral Phosphoric Acid Directed Regioselective Acetalization of
Carbohydrate-Derived 1,2-Diols**
Enoch Mensah, Nicole Camasso, Will Kaplan, and Pavel Nagorny*
A number of important classes of natural products such as
oligosaccharides or polyketides are polyols, and synthetic
approaches to the regioselective functionalization of such
compounds almost invariably involve multiple protecting
group manipulations.[1]
In contrast, nature utilizes a more direct approach and
relies on enzymes to achieve selective functionalization of less
reactive sites within a complex molecule. Recent findings
suggest that small-molecule-based chiral catalysts could act
similarly to enzymes and enhance or alter the inherent
selectivity profiles exhibited by the substrates.[2] While there is
a wide range of electrophiles that could be activated through
Lewis base catalysis, no catalysts allowing regioselective
trapping of oxocarbenium ions (or their equivalent) have
been reported to date.
accomplishing a CPA-controlled regioselective intermolecu-
lar acetalization reaction represents a significant challenge.
Herein we summarize our studies that demonstrate that CPAs
could significantly enhance or alter the inherent regioselec-
tivity profiles exhibited by various monosaccharide-derived
1,2-diols in CPA-catalyzed reactions with enol ethers
(Scheme 2).
Recent reports indicate that chiral phosphoric acids
(CPAs) could control the course of an intramolecular
enantioselective nucleophilic addition to oxocarbenium
ions.[3,4] Although the precise nature of the catalytic mecha-
nism and intermediates in such transformations has yet to be
clarified,[4i] the existence of an oxocarbenium/chiral phos-
phate ion pair has been invoked (Scheme 1). The chirality of
Scheme 2. Regioselective protection of carbohydrate-derived diols.
PG=protecting group.
This study represents the first example of a chiral-catalyst-
controlled (rather than a substrate- or a reagent-controlled)
regioselective acetalization. Such transformations could be
employed to selectively functionalize/protect adjacent equa-
torial hydroxy groups of monosaccharides[5] in a manner that
is complementary to known substrate-controlled transforma-
tions relying on organotin reagents[1a,6] and organoboron
catalysts developed by the Taylor group.[7] The development
of new protocols for the catalyst-controlled regioselective
protection of saccharides could significantly reduce the
number of steps required for protecting group manipulations
and hence improve the accessibility of complex carbohy-
drates.[8,9]
Our studies commenced with the evaluation of various
Brønsted acid catalysts in the reaction of the galactose
derivative 1a with dihydropyran (Table 1). Typically, sub-
strate-controlled functionalization of b-galactosides such as
1a takes place either at the C3 hydroxy group[10] or non-
selectively.[11] Consistent with these observations, 1a demon-
strated little to no preference for THP-protection at C3 when
achiral acids such as diphenylphosphoric acid (entry 1) or
PPTS (entry 2) were employed as the catalysts. The following
evaluation of both enantiomers of various binol-derived
chiral phosphoric acids 2a–c as the catalysts (entries 3–8)
did not result in a substantial switch in regiocontrol, and
approximately equimolar mixtures of 3a and 3b were
observed in each case. Remarkably, a significantly different
outcome was observed when the chiral phosphoric acid 2d
was employed as the catalyst (entries 9–11). While the
reaction catalyzed by (S)-2d and (Æ)-2d were only weakly
Scheme 1. CPA-catalyzed acetalizations.
the phosphate counterion could, in theory, control not only
stereoselectivity, but also the regioselectivity of a polyol
addition to an oxocarbenium ion. Considering that the
majority of the known enantioselective protocols are based
on the intramolecular trapping of the in situ generated
oxocarbenium with a tethered oxygen-based nucleophile,
[*] Dr. E. Mensah, N. Camasso, W. Kaplan, Prof. Dr. P. Nagorny
Department of Chemistry, University of Michigan
Ann Arbor, MI 48109 (USA)
E-mail: nagorny@umich.edu
[**] We are grateful to the University of Michigan for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304298.
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Table 1: Optimization of the reaction conditions for the regioselective
tetrahydropyranylation of the d-galactose derivative 1a.
Table 2: The scope of regioselective tetrahydropyranylation.[a]
Entry
1
Product
Catalyst
Yield [%][b]
(conv.)
C2/C3[c]
(R)-2d
(S)-2d
(PhO)2PO2H
78 (81)
n.d. (59)
48 (57)
8:1
1.7:1
1:1.8
(R)-2d
(S)-2d
(PhO)2PO2H
74 (85)
n.d. (62)
69 (70)
8.4:1
2.9:1
1.3:1
2[d]
Entry
Catalyst
Conv. [%][b]
3a (d.r.)
3b (d.r.)
3a/3b[c]
1
2
3
4
5
6
7
8
(PhO)2PO2H
PPTS
57
95
73
42
59
78
62
90
78
89
90
>95:5
4.2:1
1.3:1
1.9:1
2.1:1
1.7:1
>95:5
5.5:1
1:1
3.1:1
2.9:1
5.2:1
1.1:1
1.3:1
3.2:1
1.4:1
2:1
1:1.1
1:1
1:2.7
1:1
1.3:1
2.4:1
1.1:1
1:2.6
1.7:1
8:1
(R)-2d
(S)-2d
(PhO)2PO2H
(R)-2d
(S)-2d
(PhO)2PO2H
54 (58)
n.d. (31)
31 (n.d.)
86 (87)
n.d. (15)
43 (48)
6:1
1:2.6
1:1
11:1
1:2
3[e]
(S)-2a
(R)-2a
(S)-2b
(R)-2b
(S)-2c
(R)-2c
(S)-2d
(R)-2d
(Æ)-2d
4
1:2.2
(R)-2d
(S)-2d
(PhO)2PO2H
82 (91)
n.d. (11)
41 (46)
6:1
1:1
1.6:1
5
6
9
10
11
1:1
1.3:1
1.4:1
1.6:1
1.3:1
3.5:1
(R)-2d
(S)-2d
(PhO)2PO2H
77 (96)
n.d. (18)
37 (55)
10:1
1.6:1
1:1.4
[a] 1a was found to be insoluble in the majority of other organic solvents.
[b] Performed on 0.05 mmol scale (0.04m solution) for 5 h. [c] Deter-
mined by 1H NMR analysis of the crude reaction mixtures and
comparison of the spectra to those of the independently prepared 3a and
3b. M.S.=molecular sieves, PMP=para-methoxyphenyl, PPTS=pyridi-
nium para-toluenesulfonate, THP=tetrahydropyran.
[a] Reactions were performed on 0.05 mmol scale (0.04m solution, 5 h).
[b] Yield of isolated product; conversion values are given in parentheses.
[c] Determined by H NMR analysis of the crude reaction mixtures and
1
comparison of the spectra to those of the independently prepared
regioisomeric THP ethers. [d] Performed on 1.1 mmol scale. [e] Warmed
from 0 to 108C during the course of the reaction.
selective for the formation of 3a (3a/3b = 1.7:1 and 3.5:1,
respectively), the reaction catalyzed by the R enantiomer of
this catalyst was found to be substantially more selective
(3a/3b=8:1). In all of these cases (entries 3–11) only minor
quantities (ca. 3–5%) of the bis(protected) product 3c were
formed.
C3 products in low yield. The diol precursor to 4c was
significantly more soluble, and the reaction catalyzed by (R)-
2d could be conducted at lower temperature (À208C) to
provide 4c in good yield and selectivity (86% yield, C2/C3 =
11:1). In contrast, reactions with (S)-2d and (PhO)2PO2H
resulted in protection of the C3 position and were signifi-
cantly slower. To investigate the influence of the C4,C6
protecting group on the reaction selectivity, cyclohexylidene-
and isopropylidene-containing d-glucose derivatives were
synthesized and evaluated (entries 5 and 6). The (R)-2d-
catalyzed reactions of these substrates resulted in THP
protection at C2 in good yields and good to excellent
selectivities (4d: C2/C3 = 6:1; 4e: C2/C3 = 10:1).
Other types of mixed-acetal protecting groups such as 2-
methoxy-2-propyl (MOP) and 1-methoxy-1-cyclohexyl ace-
tals have been used as alternatives to tetrahydropyrans.[13–15]
Therefore, regioselective catalyst-controlled introduction of
such protecting groups was investigated next (Table 3). As
before, (R)-2d could significantly alter or enhance the
inherent regioselectivity profiles exhibited by the substrates,
and excellent to good levels of regiocontrol (up to 25:1) were
observed in these transformations. In contrast, the reactions
catalyzed by (S)-2d or diphenylphosphoric acid were signifi-
cantly less selective, which indicates that the chirality of (R)-
The regioselective tetrahydropyranylation of various d-
galactose- and d-glucose-derived 2,3-diols catalyzed by (R)-
2d was evaluated next (Table 2). More soluble than 1a,
a thioglycoside substrate (entry 2) underwent a regioselective
reaction on a 1.1 mmol scale at À208C and resulted in the
predominant formation of the C2-protected derivative 4a
(74% yield, C2/C3 = 8.4:1). Both the reaction catalyzed by
the enantiomeric catalyst (S)-2d as well as by (PhO)2PO2H
resulted in lower levels of regiocontrol. The (R)-2d-catalyzed
reactions of pseudo-C2-symmetrical d-glucose-derived diols
(entries 3–6) all resulted in the selective protection of the C2
position of the glucose. In contrast, functionalization of the
C3 position has been observed for the substrate-controlled
reactions of the b-d-glucose-derived 2,3-diols.[12] Because of
the low solubility of the precursor to 4b, its reaction with
dihydropyran was significantly slower than those leading to
3a and 4a, even at 08C. While the reaction catalyzed by (R)-
2d provided 4b (entry 3, C2/C3 = 6:1), the reaction catalyzed
by (S)-2d was sluggish and favored formation of the C3-
protected isomer (C2/C3 = 1:2.6). A control experiment using
(PhO)2PO2H provided an equimolar mixture of the C2 and
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Table 3: The scope of regioselective protection with 2-methoxypropene and 1-
clohexene catalyzed by (R)-2d was executed on a gram scale
without any erosion in yield or selectivity (0.05 mmol scale:
25:1, 65% yield, 2.78 mmol scale: > 25:1, 95% yield). The
protection of the methyl a-d-glucose-derived 2,3-diol
(entry 4) resulted in the formation of the C3-protected
products 6d.
methoxycyclohexene.[a]
Considering that organotin-mediated protections of a-d-
glucopyranosides are known to proceed at the C2 position,
our method is complementary to the known organotin
methods.[1a,10a] At the same time, the protection of the
unsymmetrical a-d-mannose-derived diol (Table 3, entry 7)
proceeded at the equatorial C3 rather than the axial C2
position to provide the derivative 6g. This outcome is
consistent with other methods which rely on substrate
control.[1a,7] However, it is noteworthy that the use of (R)-
2d resulted in significant enhancement of the selectivity
(C2/C3=1:12.6) in comparison with the reaction catalyzed by
achiral (PhO)2PO2H (C2/C3 = 1:2.6). Finally, to demonstrate
that this methodology could be used to functionalize simple
alkylpyranosides, acetalization of a 1-pentanol-derived b-
glucose derivative was investigated (entry 8). Consistent with
the prior observations for the similar substrate (entry 3), the
formation of 5h was observed in good yields and excellent
selectivities when (R)-2d was employed as a catalyst.
The CPA-controlled derivatization of the commercially
available a-l-fucose derivative 7 was also investigated
[Eq. (1)]. The control reaction catalyzed by the achiral
(PhO)2PO2H resulted in the formation of the bis(protected)
derivative 8c (35% yield) and only minor amounts of 8a and
Entry
Product
PG
Catalyst
Yield [%][b] 5/6[c]
(conv.)
(R)-2d
(S)-2d
(PhO)2PO2H 40 (45)
(R)-2d
(S)-2d
(PhO)2PO2H 79 (88)
(R)-2d
(S)-2d
(PhO)2PO2H 40 (57)
(R)-2d
(S)-2d
(PhO)2PO2H 57 (90)
(R)-2d
(S)-2d
(PhO)2PO2H 62 (67)
(R)-2d
(S)-2d
(PhO)2PO2H 39 (79)
(R)-2d
(S)-2d
(PhO)2PO2H 70 (77)
(R)-2d
(S)-2d
(PhO)2PO2H 53 (66)
76 (83)
10:1
n.d. (30)
2.3:1
1:2.3
20:1
1
93 (95)
n.d. (95)
12:1
1:2.3
>25:1
1:1
51 (55)
n.d. (10)
1:2.3
20:1
2
3
4
5
84 (95)
n.d. (95)
3.5:1
1:4.1
>25:1[d]
1:1.7
1:1.3
>25:1
1:2.7
1:1.7
1:8.8
1:2.4
2.2:1
1:6.3
1:1.7
2.4:1
5:1
95 (97)
n.d. (79)
72 (95)
n.d. (69)
79 (80)
n.d. (93)
69 (96)
n.d. (97)
(R)-2d
(S)-2d
(PhO)2PO2H 66 (72)
79 (88)
n.d. (83)
1:1.3
2:1
(R)-2d
(S)-2d
88 (>95) 7:1
n.d. (74)
2.7:1
(PhO)2PO2H 68 (>95) 1:1.2
(R)-2d
(S)-2d
78 (93)
n.d. (55)
7:1
2.5:1
6
7
8
(PhO)2PO2H 64 (n.d.) 1.3:1
(R)-2d
(S)-2d
(PhO)2PO2H 18 (39)
(R)-2d
(S)-2d
(PhO)2PO2H 45 (71)
60 (84)
n.d. (81)
1:12.6
1:7.2
1:2.6
>25:1
1:1.7
1:1
8b (4% and 6% correspondingly) were observed after
24 hours. In contrast, the reaction catalyzed by (S)-2d
resulted in the selective formation of 8a (> 20:1:1, 53%
conversion, 52% yield). The corresponding reaction with (R)-
2d was sluggish (10% of 8c, and 7% of 8a conversions and
7% of 8b were observed after 24 h). Although the function-
alization of the C3 position of a-l-fucose could be accom-
plished using organoboron and organotin chemistry, the
chirality of the CPA is clearly important for the selective
formation of 8a.
80 (82)
n.d. (65)
[a] Reactions were performed on 0.05 mmol scale (0.04m solution, 18–24 h)
at À558C (1-methoxycyclohexene) or À788C (2-methoxypropene). [b] Yield of
isolated product; conversion values are given in parentheses. [c] Determined
by 1H NMR analysis of the crude reaction mixtures. [d] Performed on
2.78 mmol (1.0 g) scale. TBS=tert-butyldimethylsilyl.
Our preliminary results suggest that the acetalization
reactions take place under kinetic control. Thus, no isomer-
ization of the product acetals was observed under the reaction
conditions, and the observed selectivity for the formation of
5c catalyzed by (R)-2d remained constant throughout the
reaction progression at À558C (see the Supporting Informa-
tion). To rationalize the observations, both a concerted
mechanism[4j,16,17] or a more traditional stepwise mechanism
proceeding through a carbocationic intermediate might be
proposed. Thus, chiral phosphate is involved in the formation
2d is essential for attaining high levels of regiocontrol. The
protection of the b-(d)-glucose-derived 2,3-diols (entries 3, 5,
and 6) and the b-(d)-galactose-derived 2,3-diols (entries 1 and
2) resulted in the formation of the C2-protected products 5.
This method seems to be tolerant to changes in the C4 and C6
protecting groups, and the use of the conformationally locked
substrates is not essential (entries 5 and 6). Importantly, the
reaction of the precursor to 5c (entry 3) and 1-methoxycy-
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Kawabata, W. Muramatsu, T. Nishio, T. Shibata, H. Schedel, J.
of a hydrogen bond with the diol, and the observed
regioselectivities likely result from a more favored coordina-
tion of the catalyst to the substrate (see the Supporting
Information). Achiral counterion-directing effects have been
previously observed for the 4-(N,N-dimethylamino)pyridine-
catalyzed acetylation of b-d-glucopyranosides,[18] and our
observations summarized herein indicate that the chirality of
the anion also plays an important role in differentiating the
site of the reaction with the electrophile.
The carbohydrate-derived substrates tested in acetaliza-
tion reactions (Tables 1–3) possess pseudo-C2 symmetry axes
and therefore similar chirality of the diol stereocenters.
However, because of the presence of other stereocenters, the
steric environment around each alcohol functionality is
different, and thus the C2-symmetric catalyst (R)-2d could
stereodifferentiate between the hydroxy groups. Considering
that the chiral catalyst could recognize rather subtle differ-
ences in the steric environment of substrates such as 5c
(Table 3), other types of stereoselective processes such as
intermolecular desymmetrization of meso diols such as 9
could be envisioned (Scheme 3). In accordance with this
proposal, the exposure of 9 to 2-methoxypropene catalyzed
by (R)-2d (unoptimized) resulted in the formation of
enantioenriched product 10 (e.r. = 86:14).
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In conclusion, this study represents the first example of
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Received: May 19, 2013
Revised: July 29, 2013
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Published online: October 9, 2013
Keywords: carbohydrates · organocatalysis · protecting groups ·
.
regioselectivity · synthetic methods
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