3
preparation of 2a-k was adapted from a protocol already reported
by us18 – where the work-up was adapted to isolate the sodium
sulfonate salts (see ESI).
Having identified the best carbonyl reduction conditions (1.1
eq NaBH4, THF, 0 °C, NaOH aq.), we explored the reaction
scope by submitting sulfonates 2a-k to the optimised conditions
(Table 3). It is possible to notice that a variety of substituents on
the aromatic rings were tolerated, affording compounds 3a-k
with consistently good diastereoselectivities.
several Lewis bases, including: amines,21 phosphines,22 and N-
heterocyclic carbenes.23 The latter have been shown capable of
forming discrete sulfonate borohydrides.23 The reaction of 2a
with commercially available 1M BH3THF provided desired 3a
in similar (79: 21) diastereomeric ratio, demonstrating that for the
formation of intramolecular charge transfer complexes of borane,
the solvent media is crucial. Seven membered transition states are
unusual compared to the most common Zimmerman Traxler (six
membered); however these have been precedented in a number of
reports.24
Table 3. Scope of the reaction for the reduction of 2a-k to 3a-k.
Conv.
(%)a
Yield
(%)b
Entry Product
X
Y
dra
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
98
89
81
92
96
94
99
78
91
98
82
1
2
3a
3b
3c
3d
3e
3f
H
4-F
H
H
H
84:16
80:20
83:17
76:24
76:24
85:15
85:15
79:21
85:15
81:19
91:9
3
2-NO2
4-F
4
H
Scheme 3. Proposed mechanism explaining the formation of the
major anti diastereomer 2a via charge-transfer complex 5.
5
H
4-OMe
4-OMe
2,4-Cl
4-NO2
4-Cl
6
4-F
H
In conclusion, we have developed a convenient synthetic
strategy to access α,γ-substituted γ-hydroxy sulfonates in good
yield and stereoselectivity by reduction of γ-keto-sulfonates. The
interaction of the sulfonate group to boron was able to direct the
hydride attack predominantly at the Si face of the carbonyl, thus
affording predominantly the anti γ-hydroxy sulfonates. The use
of sulfonate as a directing group in reduction of carbonyls and in
other reactions is hitherto unreported. This new reaction and the
diastereoselectivity provided will be of interest for those studying
the preparation of hydroxy sulfonic acids and their use in organic
synthesis and medicinal chemistry.
7
3g
3h
3i
8
H
9
H
11
12
3j
4-Cl
H
H
3k
2-Br
a Conversion and diastereoselective ratio (dr) was calculated via 1H NMR
analysis of the crude reaction material. b Isolated yield.
The absolute configuration of the hydroxyl stereocenter was
determined by single crystal X-ray analysis of the N-(2-
bromobenzyl)-N,N,N-triethylammonium salt 4, derived from 3k,
as shown in Figure 1.
Acknowledgement
We acknowledge support from Science Foundation Ireland (SFI-
11/RFP/CHS/3122), for supporting Noel McLaughlin and from
IRC (EPSPG/2017/287) for support to Francesco Alletto.
Supplementary Material
Experimental procedures for the preparation of compounds
2a-l, 3a-l and compound 4 and their characterisation; copies of
representative 1H/13C NMR spectra can be found in the
supplementary information.
References and notes
(1)
(2)
Noyori, R.; Ohkuma, T. Angew. Chemie Int. Ed. 2001, 40, 40.
Kolodiazhnyi, O. I.; Gryshkun, E. V.; Andrushko, N. V.; Freytag,
M.; Jones, P. G.; Schmutzler, R. Tetrahedron: Asymmetry 2003, 14,
181.
Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191.
Gung, B. W. Tetrahedron 1996, 52, 5263.
Ager, D. J.; East, M. B. Tetrahedron 1992, 48, 2803.
Reetz, M. T. Angew. Chemie Int. Ed. 1984, 23, 556.
Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560.
Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. J.
Am. Chem. Soc. 2001, 123, 9535.
Figure 1. ORTEP plot for ammonium salt 4, derived from γ-
hydroxy sulfonate 3k
The relative proximity of the ion pair revealed by the X-ray
crystal structure of 4 may provide information regarding the
reduction mechanism (Scheme 3). Our mechanistic hypothesis
reasons that the reaction of NaBH4 and water may form borane
(BH3) in situ, which could in turn form a charge-transfer complex
with the sulfonate anion, producing intermediate 5. Nucleophilic
hydride can attack either the Si or the Re face of the carbonyl
group due to the rotation around the C1-C2 or C2-C3 axis.
However, Si-attack is thought to predominate as the major
product of the reduction is the anti γ-hydroxy sulfonate.20
Charge-transfer complexes with borane have been noted with
(3)
(4)
(5)
(6)
(7)
(8)
(9)
Paterson, I.; Delgado, O.; Florence, G. J.; Lyothier, I.; O’Brien, M.;
Scott, J. P.; Sereinig, N. J. Org. Chem. 2005, 70, 150.
Chen, K. M.; Hardtmann, G. E.; Prasad, K.; Repič, O.; Shapiro, M.
J. Tetrahedron Lett. 1987, 28, 155.
(10)