anti-1,2-diols via Ni-catalyzed reductive coupling of alkynes and α-oxyaldehydes

Article abstract of DOI:10.1021/ol050881k

(Chemical Equation Presented) Ni-catalyzed reductive coupling of aryl alkynes (1) and enantiomerically enriched α-oxyaldehydes (2) afford differentiated anti-2,2-diols (3) with high diastereoselectivity and regioselectivity, despite the fact that the meth

Full text of DOI:10.1021/ol050881k

ORGANIC
LETTERS
2005
Vol. 7, No. 14
2937-2940
anti-1,2-Diols via Ni-Catalyzed Reductive
Coupling of Alkynes and
r
-Oxyaldehydes
Torsak Luanphaisarnnont, Chudi O. Ndubaku, and Timothy F. Jamison*
Department of Chemistry, Massachusetts Institute of Technology,
77 Massachusetts AVe., Cambridge, Massachusetts 02139
tfj@mit.edu
Received April 21, 2005
ABSTRACT
Ni-catalyzed reductive coupling of aryl alkynes (1) and enantiomerically enriched
r-oxyaldehydes (2) afford differentiated anti-1,2-diols (3) with
high diastereoselectivity and regioselectivity, despite the fact that the methoxymethyl (MOM) and para-methoxybenzyl (PMB) protective groups
typically favor syn-1,2-diol formation in carbonyl addition reactions of this family of aldehydes.
Enantiomerically pure 1,2-diols are important and commonly
occurring functional group patterns in natural products such
as carbohydrates and polyketides and in chiral ligands used
in asymmetric catalysis. Consequently, much effort has been
invested in the development of stereoselective methods for
1,2-diol synthesis. A very powerful one for preparing syn-
1,2-diols is the Sharpless asymmetric dihydroxylation of
trans-disubstituted olefins.1 However, the diastereomeric anti-
1,2-diols are not as easily accessed using this transforma-
tion, because the corresponding dihydroxylations of cis-
disubstituted olefins typically proceed with diminished
enantioselectivity.1c
continues to be actively investigated. Recently, MacMillan
and List reported catalytic asymmetric aldol reactions that
afford the anti-1,2-diol architecture.3 Aldolases,4 catalytic
antibodies,5 and a heteropolymetallic catalyst6 also have been
used to favor anti addition in related reactions.
A contrasting approach to the synthesis of 1,2-diols
involves nucleophilic addition to aldehydes bearing protected
hydroxyl groups adjacent to the carbonyl.7 Cram’s rule, after
(3) (a) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386-7387. (b)
Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew.
Chem., Int. Ed. 2004, 43, 2152-2154. (c) Northrup, A. B.; MacMillan, D.
W. C. Science 2004, 305, 1752-1755.
(4) (a) Bednarski, M. D.; Simon, E. S.; Bishofberger, N.; Fessner, W.-
D.; Kim, M.-J.; Lees, W.; Saito, T.; Waldmann, H.; Whitesides, G. M. J.
Am. Chem. Soc. 1989, 111, 627-635. (b) Fessner, W.-D.; Sinerius, G.;
Schneider, A.; Dreyer, M.; Schulz, G. E.; Badia, J.; Aguilar, J. Angew.
Chem., Int. Ed. Engl. 1991, 30, 555-558.
(5) (a) List, B.; Shabat, D.; Barbas, C. F., III; Lerner, R. A. Chem.s
Eur. J. 1998, 4, 881-885. (b) Hoffmann, T.; Zhong, G.; List, B.; Shabat,
D.; Anderson, J.; Gramatikova, S.; Lerner, R. A.; Barbas, C. F., III J. Am.
Chem. Soc. 1998, 120, 2768-2779.
(6) Yoshikawa, N.; Suzuki, T.; Shibasaki, M. J. Org. Chem. 2002, 67,
2556-2565.
Auxiliary-based, anti-selective glycolate aldol addition
reactions have been developed to address this limitation.2
Nevertheless, these methods are much less common than
those for analogous syn-selective addition, and this area
(1) (a) Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schro¨der, G.;
Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968-1970. (b) Kolb, H.
C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994, 94, 2483-
2547. (c) Johnson, R. A., Sharpless, K. B. In Catalytic Asymmetric Synthesis,
2nd ed.; Ojima, I., Ed.; VCH: New York, 2000; pp 357-398.
(2) (a) Mukaiyama, T.; Iwasawa, N. Chem. Lett. 1984, 753-756. (b)
Evans, D. A.; Gage, J. R.; Leighton, J. L.; Kim, A. S. J. Org. Chem. 1992,
57, 1961-1963. (c) Crimmins, M. T.; McDougall, P. J. Org. Lett. 2003, 5,
591-594.
(7) Reviews: (a) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23,
556-569. (b) Reetz, M. T. Acc. Chem. Res. 1993, 26, 462-468. (c) Eliel,
E. L. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic: New York,
1983; Vol. 2, Part A; pp 125-155.
10.1021/ol050881k CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/04/2005

over fifty years, remains a good predictor of the stereochem-
ical outcome of additions to these chiral R-oxyaldehydes
(Figure 1).8
aldehydes proceed with high regioselectivity and enantio-
selectivity when a chiral phosphine such as neomenthyl-
diphenylphosphine (NMDPP) is utilized (Scheme 1).11,12 We
Scheme 1. Catalytic Asymmetric Reductive Coupling of
Alkynes and Aldehydes
now disclose that the corresponding reaction with chiral
R-oxyaldehydes preferentially affords 1,2-diol products of
the anti relative configuration.
Figure 1. Models for stereoselective nucleophilic additions to
R-oxyaldehydes. (A) The cyclic “Cram-chelate” model predicts syn-
1,2-diols. (B) The “dipolar” model predicts anti-1,2-diols.
We began our studies by investigating the role of the
ligand in catalytic reductive coupling reactions of 1-phenyl-
1-propyne (1a) and the known aldehyde 2a13 (eq 1).
A high level of substrate control was observed with both
(+)- and (-)-NMDPP providing the coupling product 3a as
predominantly the anti diastereomer (Table 1, entries 1 and
For R-alkoxy groups that have the ability to coordinate
(such as MeO-, MOMO-, BnO-, or PMBO-, among others),
the “Cram-chelate” model typically applies, and syn-1,2-diols
are favored (Figure 1, A).8b,9 When larger groups (such as
tBuMe2SiO- or Ph3CO-) are employed, the “dipolar” model
is invoked to account for the general preference for anti-
1,2-diol products (Figure 1, B). However, because of the
greater degree of flexibility in the latter process (σ-bond
rotation), nucleophilic additions of this type usually proceed
with moderate selectivity and therefore are not always viable
means to access anti-1,2-diols.
Table 1. Ni/NMDPP-Catalyzed Reductive Coupling of
1-Phenyl-1-propyne (1a) and MOM-Protected R-Oxyaldehyde
2a
In rare instances, R-oxyaldehydes bearing chelating groups
adjacent to the carbonyl afford anti-1,2-diols with >95:5
diastereoselectivity.10 This unusual preference is particularly
interesting from a mechanistic point of view, because it
suggests that even in the presence of highly coordinating
groups such as MOMO- or BnO-, the nucleophilic addition
occurs instead via the “dipolar” model. This phenomenon
may be observed when reagents lacking the ability to chelate
are utilized10a,c or when a reagent that imparts complete
stereocontrol is employed.10d
entrya phosphine time (h) temp (°C) d.r.b yield (%) (d.r.)c
1
(+)-NMDPP
(-)-NMDPP
(+)-NMDPP
(+)-NMDPP
(+)-NMDPP
(+)-NMDPP
6
6
0
0
84:16
77:23
89:11
90:10
89:11
88:12
61 (90:10)
32 (80:20)
62 (90:10)
37 (90:10)
77 (90:10)
87 (90:10)
2
3
4
5d
6d
6
6
6
20
-10
-20
-10
-10
We have previously reported that nickel-catalyzed reduc-
tive coupling reactions of aryl-substituted alkynes and
a See Supporting Information for experimental procedures. 100 mol %
of alkyne and 100 mol % of aldehyde were used, unless otherwise noted.
All reactions proceeded with >95:5 regioselectivity. b Ratio of anti/syn
determined by 1H NMR analysis of crude reaction mixtures. c Yield and
d.r. of the isolated reaction product. d Conducted using 150 mol % of
aldehyde.
(8) (a) Cram, D. J.; Abd Elhafez, R. A. J. Am. Chem. Soc. 1952, 74,
5828-5835. (b) Gawley, R. E.; Aube, J. Principles of Asymmetric Synthesis;
Tetrahedron Organic Chemistry Series, Vol. 14; Pergamon Press, Elsevier:
Oxford, 1996; pp 121-160.
(9) Of particular interest is the NMR observation of a chelate as an
intermediate in the addition of dimethylmagnesium to R-alkoxy alde-
hydes: Chen, X.; Hortelano, E. R.; Eliel, E. L.; Frye, S. V. J. Am. Chem.
Soc. 1992, 114, 1778-1784.
(10) (a) Banfi, L.; Bernardi, A.; Colombo, L.; Gennari, C.; Scolastico,
C. J. Org. Chem. 1984, 49, 3784-3790. (b) Tio, H.; Mizobuchi, T.;
Tsukamoto, M.; Tokoroyama, T. Tetrahedron Lett. 1986, 27, 6373-6376.
(c) Marumoto, S.; Kogen, H.; Naruto, S. Chem. Commun. 1998, 2253-
2254. (d) An example of highly reagent-controlled nucleophilic addition to
a MOMO-aldehyde: Corey, E. J.; Yu, C.-M.; Kim, S. S. J. Am. Chem.
Soc. 1989, 111, 5495-5496.
2).14 (+)-NMDPP was selected for further studies because
it provided the anti product in higher yield and selectivity
(Table 1, entry 1). The diastereoselectivity and yield were
further improved by careful examination of reaction tem-
perature. At -10 °C, nearly 9:1 diastereoselectivity was
obtained without compromising the reaction yield (Table 1,
entry 3). On further cooling, however, the yield diminished
2938
Org. Lett., Vol. 7, No. 14, 2005

severely, and no appreciable improvement in diastereo-
selectivity was observed (Table 1, entry 4).15 On the other
hand, by increasing the amount of the aldehyde and extending
the reaction time, a balance of yield and selectivity for the
reductive coupling of 1a and 2a was achieved (Table 1, entry
6).
Table 2. Extension of the anti-Selective Reductive Coupling to
a Variety of Aryl Alkynes and R-Oxyaldehydesa
The relative stereochemistry of 3a was determined by
removal of the MOM protective group and conversion to
the corresponding cyclic carbonate 4 (Scheme 2). A large
Scheme 2. Assignment of the Relative Configuration of 3A
a All reactions were conducted with 100 mol % of alkyne and 150 mol
% of aldehyde. All reactions proceeded with >95:5 regioselectivity. b Ratio
of anti/syn determined by 1H NMR analysis of crude reaction mixtures.
c Yield and diastereoselectivity of the isolated reaction product. d The syn
product was also isolated in 18% yield (>95:5 d.r.).
The simplest interpretation of the observed sense of
induction is that, because of the absence of any chelating
metal in the reaction, the preferred mode of addition can be
rationalized by the “dipolar” model (Figure 2, B).
nOe was observed between the carbinol protons, suggesting
a cis relationship between them in 4, that is, of the anti
configuration in 3a. Further confirmation of the relative
configuration involved conversion of 3a to ketodiol 5 whose
data were consistent with those previously reported (Scheme
2).3a
The scope of this novel, anti-selective reductive coupling
is shown in Table 2. Placing a larger substituent on the side
of the alkyne where C-C bond formation occurs (e.g., Me
to Et or cyclopropyl, Table 2, entries 1, 3, and 4), dramati-
cally improved the selectivity, albeit with a depreciation in
yield. Notably, heteroatom-substituted alkynes are tolerated
and do not affect the anti selectivity (Table 2, entry 5). Also,
changing the protective group on the aldehyde to PMB
improves the chemical yield while maintaining excellent
diastereoselectivity (Table 2, entry 6 vs entry 3). However,
changing the cyclohexyl substituent on the aldehyde to either
a phenyl group (Table 2, entry 7) or an n-hexyl group (Table
2, entry 8) resulted in lowered selectivity, likely due to a
reduced conformational bias in the aldehyde.
Figure 2. Schematic representation of divergent pathways leading
to syn- and anti-1,2-diols.
(11) (a) Miller, K. M.; Huang, W.-S.; Jamison, T. F. J. Am. Chem. Soc.
2003, 125, 3442-3443. See also: (b) Huang, W.-S.; Chan, J.; Jamison, T.
F. Org. Lett. 2000, 2, 4221-4223. (c) Colby, E. A.; Jamison, T. F. J. Org.
Chem. 2003, 68, 156-166.
(12) Reviews of Ni-catalyzed reductive couplings: (a) Miller, K. M.;
Molinaro, C.; Jamison, T. F. Tetrahedron: Asymmetry 2003, 14, 3619-
3625. (b) Ikeda, S.-i. Angew. Chem., Int. Ed. 2003, 42, 5120-5122. (c)
Montgomery, J. Angew. Chem., Int. Ed. 2004, 43, 3890-3908.
(13) Racemic 2a: Paquette, L. A.; Mitzel, T. M. J. Am. Chem. Soc. 1996,
118, 1931-1937.
(14) We found no achiral phosphine that was as efficient as NMDPP,
thus preventing a meaningful estimation of the “inherent selectivity” of
these aldehydes in these catalytic coupling reactions: Masamune, S.; Choy,
W.; Peterson, J. S.; Sita, L. R. Angew Chem., Int. Ed. Engl. 1985, 24, 1-30.
(15) Further cooling to -40 °C resulted in improved diastereoselectivity
(>95:5) but also severely reduced conversion (<10%).
In conclusion, a nickel-catalyzed reductive coupling of
alkynes and easily accessible, enantiomerically enriched
R-oxyaldehydes has been developed. These coupling reac-
tions provide efficient access to a variety of differentially
protected anti-1,2-diols, despite the fact that additions to
methoxymethyl- (MOM) and p-methoxybenzyl-protected
(PMB) 2-hydroxyaldehydes typically display a preference
for syn-1,2-diols. Currently, we are investigating the utility
of this novel method for preparing these useful intermediates
as a catalytic, stereoselective fragment coupling reaction in
target-oriented synthesis.
Org. Lett., Vol. 7, No. 14, 2005
2939

Acknowledgment. Support for this work was provided
by the National Institute of General Medical Sciences (GM-
063755). T.L. thanks the MIT Undergraduate Research
Opportunities Program, and C.O.N. thanks the Pfizer Di-
versity in Organic Chemistry Program for fellowship support.
We also thank the NIGMS (GM-072566), NSF (CAREER
CHE-0134704), the Sloan Foundation, Amgen, Boehringer-
Ingelheim, Bristol Myers-Squibb, GlaxoSmithKline, Johnson
& Johnson, Merck Research Laboratories, Wyeth, and the
Deshpande Center (MIT) for generous financial support of
our program. We are grateful to Dr. Li Li for obtaining mass
spectrometric data for all compounds (MIT Department of
Chemistry Instrumentation Facility, which is supported in
part by the NSF (CHE-9809061 and DBI-9729592) and the
NIH (1S10RR13886-01)).
Supporting Information Available: Experimental
procedures and data for all new compounds. These ma-
terials are available free of charge via the Internet at
http://pubs.acs.org.
OL050881K
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Org. Lett., Vol. 7, No. 14, 2005