Achieving high selectivity and facile displacement with a new thiol auxiliary for boron-mediated aldol reactions

Article abstract of DOI:10.1021/ol0614774

(Chemical Equation Presented) Synthesis of a new thiol auxiliary (1) is readily achieved (in five or six steps, >74% overall yield from norephedrine) and is shown to give high diastereoselectivity in boron-mediated anti-aldol reactions with a range of aldehydes. This new thiol auxiliary may be directly displaced by a range of nucleophiles under very mild conditions, to give the corresponding phosphonate esters, alcohols, acids, SNAC thiolesters, and methyl esters.

Full text of DOI:10.1021/ol0614774

ORGANIC
LETTERS
2006
Vol. 8, No. 19
4219-4222
Achieving High Selectivity and Facile
Displacement with a New Thiol Auxiliary
for Boron-Mediated Aldol Reactions
Sandra Fanjul, Alison N. Hulme,* and John W. White
School of Chemistry, The UniVersity of Edinburgh, West Mains Road,
Edinburgh EH9 3JJ, U.K.
alison.hulme@ed.ac.uk
Received June 15, 2006
ABSTRACT
Synthesis of a new thiol auxiliary (1) is readily achieved (in five or six steps, >74% overall yield from norephedrine) and is shown to give high
diastereoselectivity in boron-mediated anti-aldol reactions with a range of aldehydes. This new thiol auxiliary may be directly displaced by a
range of nucleophiles under very mild conditions, to give the corresponding phosphonate esters, alcohols, acids, SNAC thiolesters, and
methyl esters.
Despite recent advances in the catalytic aldol and organo-
catalytic aldol reactions,1 auxiliary-controlled aldol reactions
have maintained their place as one of the principle means
through which the aldol reaction finds application in
synthesis.2 This is primarily due to the high yields and high
diastereoselectivities which may be attained in auxiliary-
controlled reactions and the facile separation of diastereo-
meric aldol adducts which allows the subsequent isolation
of enantiopure species. Two auxiliaries currently have
predominance in the field:2 the Evans’ oxazolidinone3a-c and
its oxazolidinethione and thiazolidinethione counterparts for
syn-aldol reactions and the Abiko-Masamune norephedrine-
derived auxiliary for a range of anti-aldol reactions.3d,e
However, for an auxiliary-based strategy to be truly useful,
the auxiliary must be removable under a range of conditions.4
Although this has clearly been demonstrated for the Evans’
oxazolidinone, and to a lesser extent for the Abiko-
Masamune auxiliary, there are still some nucleophilic
displacement reactions which (though highly desirable
synthetically) are unachieveable, or very low yielding, with
either of these auxiliaries because of competitive retro-aldol
or elimination reactions. In the course of synthetic studies
directed toward the synthesis of the marine natural product
octalactin A,5 we have encountered these problems first
hand.6 Direct displacement by a phosphonate anion of the
norephedrine-derived auxiliary in an anti-aldol adduct re-
sulted in extensive decomposition of the aldol adduct through
a retro-aldol mechanism, such that the acylated auxiliary was
(1) For recent reviews, see: (a) Sodeoka, M.; Hamashima, Y. Bull. Chem.
Soc. Jpn. 2005, 78, 941-956. (b) Denmark, S. E.; Heemstra, J. R., Jr.;
Beutner, G. L. Angew. Chem., Int. Ed. 2005, 44, 4682-4698. (c) Kazmaier,
U. Angew. Chem., Int. Ed. 2005, 44, 2186-2188. (d) Seayad, J.; List, B.
Org. Biomol. Chem. 2005, 3, 719-724. (e) Saito, S.; Yamamoto, H. Acc.
Chem. Res. 2004, 37, 570-579. (f) Alcaide, B.; Almendros, P. Angew.
Chem., Int. Ed. 2003, 42, 858-860.
(2) (a) Palomo, C.; Oiarbide, M.; Garc´ıa, J. M. Chem. Soc. ReV. 2004,
33, 65-75. (b) Arya, P.; Qin, H. Tetrahedron 2000, 56, 917-947.
(3) (a) Evans, D. A.; Bartroli, J. A.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127-2129. (b) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 77-
91. (c) Evans, D. A.; Shaw, J. T. Actual. Chim. 2003, 35-38. (d) Abiko,
A.; Liu, J. F.; Masamune, S. J. Am. Chem. Soc. 1997, 119, 2586-2587. (e)
Abiko, A. Acc. Chem. Res. 2004, 37, 387-395.
(4) For a recent review of auxiliary-mediated reactions, see: Gnas, Y.;
Glorius, F. Synthesis 2006, 1899-1930.
(5) Tapiolas, D. M.; Roman, M.; Fenical, W.; Stout, T. J.; Clardy, J. J.
Am. Chem. Soc. 1991, 113, 4682-4683.
(6) Hulme, A. N.; Howells, G. E. Tetrahedron Lett. 1997, 38, 8245-
8248.
10.1021/ol0614774 CCC: $33.50
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Published on Web 08/25/2006

the major recovered product at the end of the reaction.7
Following our earlier success in the achiral manifold with
the use of thiolesters to address this displacement problem,8
we therefore set out to develop a high-yielding route to a
thiol alternative of the Abiko-Masamune auxiliary (Scheme
1).
Scheme 1. Synthesis of the Thiol Analogue of the
Abiko-Masamune Auxiliary
Figure 1. Crystal structure of thiopropionate 6.
reaction of the norephedrine-derived auxiliary through the
appropriate choice of reagents, thus leading to either anti-
or syn-aldol adducts.3d,e With the classical oxygenated
auxiliary, the formation of anti-aldol adducts is controlled
by the presence of bulky ligands on the boron [(cHex)2BOTf]
and the addition of Et3N at low temperatures to form the
kinetic E(O)-enolate. We therefore set out by using these
Table 1. anti-Aldol Reaction of Thiopropionate 6
(1S,2R)-(+)-Norephedrine was converted into its mesity-
lene sulfonamide,3d,e and subsequent treatment with thionyl
chloride gave alkyl chloride 2 with net retention of stereo-
chemistry.9 The chloride was converted into aziridine 3,10
which was opened regio- and stereoselectively (>95:5) with
thiolbenzoic acid in the presence of catalytic PBu3.11 Treat-
ment of thiolbenzoate 4 with benzyl bromide and sodium
hydride gave benzyl sulfonamide 5 exclusively.12 Reduction
of the benzoate using LiAlH4 gave the thiol auxiliary 1 in
excellent yield. Thiol 1 could also be accessed through
saponification with NaOMe, thus avoiding the need for
tedious purification from aluminum salts (five or six steps
from norephedrine, >74% overall yield). The thiol was
converted into its propionate derivative 6, to allow the
determination of the levels of diastereoselectivity that it could
confer in a range of aldol reactions. The X-ray crystal
structure of 6 has confirmed the overall net retention of
stereochemistry of this synthetic sequence (Figure 1).
It has been reported by Abiko and Masamune that selective
enolization may be achieved in the boron-mediated aldol
(7) Howells, G. E.; Hulme, A. N.; White, J. W. Unpublished results.
(8) Hulme, A. N.; Howells, G. E.; Walker, R. E. Synlett 1998, 828-
830.
(9) Flores-Parra, A.; Suarez-Moreno, P.; Sanchez-Ruiz, S. A.; Tlahuextl,
M.; Jaen-Gaspar, J.; Tlahuext, H.; Salas-Coronado, R.; Cruz, A.; Noth, H.;
Contreras, R. Tetrahedron: Asymmetry 1998, 9, 1661-1672.
(10) On a small scale, direct conversion of the sulfonamido alcohol to
aziridine 3 was achieved through in situ generation of the mesylate (MsCl,
Et3N, 87%).
(11) Fan, R.-H.; Hou, X.-L. J. Org. Chem. 2003, 68, 726-730.
(12) Significant levels of benzoate migration and concomitant thiol
benzylation were observed when benzylation was attempted in the presence
of other bases.
a Isolated yield of the major diastereomer. b Diastereomeric ratio deter-
mined by H NMR integration.
1
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Org. Lett., Vol. 8, No. 19, 2006

optimized conditions with thiol auxiliary 1. Gratifyingly, we
found that we could obtain anti-aldol adducts with a range
of aldehydes (vinyl, alkyl, and aromatic) in high yield and
with high selectivity using the thiol auxiliary 1 (Table 1).13
In all cases, our yields were comparable to that of the
established Abiko-Masamune auxiliary, and only a minor
erosion of diastereoselectivity was observed. As with the
classic auxiliary, the minor diastereomer is thought to be
the other anti diastereomer, rather than the syn diastereomer.3d,e
This confirms the high selectivity of enolate formation in
these reactions but suggests a minor erosion of facial
selectivity of the resultant enolate in switching from the ester
to the thiolester.
The main focus for the synthesis of the thiol auxiliary 1
was its potentially facile displacement with a range of
nucleophiles. Of most immediate synthetic relevance to us
was the displacement of the auxiliary by phosphonate
nucleophiles (Table 2), which might then allow direct
extension of the aldol adduct using a Horner-Wadsworth-
Emmons (HWE) reaction.14 Treatment of protected aldol
adducts 8 with the lithium anion of diethyl ethane phospho-
nate was shown to give the desired phosphonate esters 9 in
high yield (78-91%) and with varying diastereoselectivity
adjacent to the phosphonate (3:2 to 4:1 ratio of diastereo-
mers). However, the diastereomeric phosphonate esters were
not separated, as previous studies have shown that both give
equal selectivity in the HWE reaction.6 In all cases, the
auxiliary 1 was also recovered in excellent yield (79-91%).
After the successful displacement of auxiliary 1 was
achieved with a phosphonate anion, we decided to investigate
the displacement reaction with other mild nucleophiles
(Scheme 2). Initially, we examined reduction of the aldol
Scheme 2. Nucleophilic Displacement Reactions of anti-Aldol
Adducts 7
Table 2. Phosphonate Displacement of Auxiliary 1
adducts to give the diol, a reaction which is typically
achieved with rather harsh conditions (LiAlH4, DIBALH)
with the classic Abiko-Masamune auxiliary.15 In contrast,
we found that upon treatment of 7c with NaBH4 diol 10 was
obtained in high yield in only 1 h (99%). We then decided
to investigate the hydrolysis reactions of aldol adducts 7,
the counterparts of which have been shown to be quite
sluggish with the classic auxiliary. LiOH-mediated hydrolysis
of the thiolester 7c was complete in only 30 min (as opposed
to the typical 24-48 h reaction times required for hydrolysis
of the Abiko-Masamune auxiliary)16 and gave an excellent
yield of the corresponding acid 11 (99%, Scheme 2).17
(13) Optimum conditions for aldol coupling with thiol auxiliary 1 were
found to be: 3.0 equiv of Et3N [cf. 2.4 equiv reported in ref 3e] and 2.0
equiv of (cHex)2BOTf [cf. 2.0 equiv reported in ref 3e]. When conducting
milligram scale reactions, an excess of aldehyde (3.0+ equiv) was used.
(14) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863-927.
(15) For recent synthetic examples, see: (a) Fraunhoffer, K. J.; Bacho-
vchin, D. A.; White, M. C. Org. Lett. 2005, 7, 223-226. (b) Lafontaine, J.
A.; Provencal, D. P.; Gardelli, C.; Leahy, J. W. J. Org. Chem. 2003, 68,
4215-4234. (c) Maleczka, R. E., Jr.; Terrell, L. R.; Geng, F.; Ward, J. S.,
III. Org. Lett. 2002, 4, 2841-2844. (d) Amarasinghe, K. K. D.; Montgom-
ery, J. J. Am. Chem. Soc. 2002, 124, 9366-9367.
(16) For recent synthetic examples, see: (a) Kiho, T.; Nakayama, M.;
Kogen, H. Tetrahedron 2003, 59, 1685-1697. (b) Andrus, M. B.; Meredith,
E. L.; Simmons, B. L.; Sekhar, B. B. V. S.; Hicken, E. J. Org. Lett. 2002,
4, 3549-3552.
Org. Lett., Vol. 8, No. 19, 2006
4221

Similarly, transthiolesterification of 7c was achieved under
the extremely mild conditions reported by Raines et al. (N-
acetylcysteamine, iPr2NEt)18 in only 1 h, to give an excellent
yield of the SNAC thiolester 12 (88%). This latter procedure
is notable because it avoids the need for a two-step
hydrolysis/thiolesterification process which is typically used
in the case of polyketide starter units derived from the Evans
oxazolidinone.19 [The use of trimethylaluminum in these
transthiolesterification reactions as reported by Willis et al.
(N-acetylcysteamine, Me3Al, THF, 0 °C)20 was not viable.21]
Finally, transesterification of aldol adduct 7f was very readily
achieved by treatment with sodium methoxide, giving methyl
ester 13 in 94% yield in only 30 min. In all of the successful
displacement reactions, auxiliary 1 was recovered in high
yield (84-99%).
In conclusion, we have developed an auxiliary which
promotes highly selective anti-aldol adduct formation, while
also offering facile displacement with a range of nucleophiles.
The high yields associated with these reactions, relative ease
of synthesis of the thiol auxiliary 1, and its excellent bench
stability make it an attractive alternative for use in synthesis.
Acknowledgment. We thank the EPSRC (DTA student-
ships to S.F. and J.W.W.) for financial support of this work
and the Royal Society of Edinburgh/Scottish Executive
(Research Fellowship to A.N.H.).
(17) If the hydrolysis reactions were left for extended time periods, partial
degradation of the thiol auxiliary 1 was observed.
(18) Nilsson, B. L.; Kiessling, L. L.; Raines, R. T. Org. Lett. 2000, 2,
1939-1941.
Supporting Information Available: Experimental pro-
cedures for the synthesis of thiol auxiliary 1, for the synthesis
of thiopropionate 6 and an anti-aldol reaction to give 7c,
and for the displacement reactions to give compounds 9c
and 10-13. Spectroscopic data for compounds 7b and 7e.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(19) For recent examples of the two-step synthesis of SNAC thiolesters,
see: (a) Wu, J.; Zaleski, T. J.; Valenzano, C.; Khosla, C.; Cane, D. E. J.
Am. Chem. Soc. 2005, 127, 17393-17404. (b) Aldrich, C. C.; Venkatraman,
L.; Sherman, D. H.; Fecik, R. A. J. Am. Chem. Soc. 2005, 127, 8910-
8911. (c) Hartung, I. V.; Rude, M. A.; Schnarr, N. A.; Hunziker, D.; Khosla,
C. J. Am. Chem. Soc. 2005, 127, 11202-11203.
(20) Le Sann, C.; Mun˜oz, D. M.; Saunders, N.; Simpson, T. J.; Smith,
D. I.; Soulas, F.; Watts, P.; Willis, C. L. Org. Biomol. Chem. 2005, 3, 1719-
1728.
(21) Complex mixtures were obtained under these conditions including
the products of elimination and retroaldol reactions.
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