A stereoselective oxy-Michael approach to THP*-protected β-hydroxy esters

Article abstract of DOI:10.1055/s-2005-918484

The 'naked' anion of (S)-6-methyl δ-lactol undergoes efficient oxy-Michael addition to α,β-unsaturated methyl sulfones to give the corresponding adducts with excellent (up to 99% de) stereocontrol at the newly formed stereogenic β-centre. The successive r

Full text of DOI:10.1055/s-2005-918484

PAPER
3283
A Stereoselective Oxy-Michael Approach to THP*-Protected b-Hydroxy
Esters
S
a
tereoselectiv
e
e
A
pproac
h
l
to TH
P
i
*-Prot
x
ected
b
-Hydroxy
EA
sters . Hernandez-Juan,a Xin Xiong,b Sarah E. Brewer,a David J. Buchanan,b Darren J. Dixon*b
University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
School of Chemistry, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK
E-mail: darren.dixon@manchester.ac.uk
b
Received 15 September 2005
Dedicated to Professor Steven Ley on the occasion of his 60th birthday
first highly diastereoselective oxy-Michael approach to
THP*-protected b-hydroxy esters following this strategy.
Abstract: The ‘naked’ anion of (S)-6-methyl d-lactol undergoes ef-
ficient oxy-Michael addition to a,b-unsaturated methyl sulfones to
give the corresponding adducts with excellent (up to 99% de) stereo-
control at the newly formed stereogenic b-centre. The successive re-
ductive desulfonylation using excess samarium(II) iodide under
mild reaction conditions affords the THP*-protected b-hydroxy es-
ters as single diastereoisomers after chromatography on silica gel.
b-Alkoxy carbonyl compounds are prone to base-promot-
ed elimination reactions, notably at high temperature.
This coupled with the acid sensitivity of the THP* group
provided us with only a narrow window of choice to dis-
cover an effective and removable activating group. A
number of possible activating groups were considered but
by far the overwhelming favourite was a sulfone moiety
owing to the protodesulfonylation potential of the oxy-
Michael adducts.
Key words: asymmetric synthesis, oxy-Michael additions, samari-
um(II) iodide, protodesulfonylation, b-hydroxy esters
The stereoselective preparation of b-hydroxy esters has
attracted much attention over the last few decades due to
their great value as chiral building blocks for natural prod-
uct synthesis.1 Synthetic access to such compounds in
their optically active form has been widely reported, and
typical strategies include catalytic asymmetric hydroge-
nation of the corresponding b-keto esters,2 asymmetric al-
dol-type reactions3 and other methods.4
A series of a,b-unsaturated phenyl sulfones 29 with either
alkyl or aryl b-substituents were prepared following mod-
ified literature procedures.10 With the Michael acceptors
in hand, a trial oxy-Michael addition to 2a using the ‘na-
ked’ alkoxide of 1 [formed by deprotonation with KH-
MDS (1.0 equiv) and subsequent addition of 18-crown-6
(1.0 equiv)] was performed at –78 °C in THF to ascertain
reactivity and diastereocontrol at the three newly formed
stereocentres on quenching with acetic acid (Scheme 1).
We have recently disclosed a novel d-lactol derived chiral
water equivalent 1, which as its ‘naked’ anion undergoes
highly diastereoselective oxy-Michael additions to b-sub-
stituted nitro olefins.5 The power of this newly developed
method has been verified by applications to the total syn-
thesis of bioactive pharmaceutical compounds and natural
products containing the ethanolamine motif.6 Prompted
by these successful results, we became interested in ex-
ploring a new route to produce optically active b-hydroxy
esters. Studies using Michael acceptors derived from ma-
lonate esters were encouraging and useful for showing the
generality of the stereoselective oxy-Michael reaction.
However, this approach did not provide an alternative
route to protected b-hydroxy esters suitable for polyketide
synthesis as attempted dealkyldecarboxylation led invari-
ably to extensive degradation of the oxy-Michael adducts
owing to the harsh reaction conditions employed.7,8 In or-
der to access such desirable compounds using the oxy-
Michael reaction it was clear that a sacrificial functional
group capable of activating the alkene, but without ad-
versely affecting the reaction stereoselectivity, was re-
quired. Herein we wish to describe the work leading to the
1
Inspection of the crude H NMR spectrum indicated the
presence of four of the eight possible diastereoisomers.
The b-selectivity was an impressive 96% de and the a-se-
lectivity in the major b-stereoisomer was 3:1. Purification
by column chromatography on silica gel afforded 3a as a
mixture of diastereoisomers. Recrystallisation of this mix-
ture allowed isolation of the major diastereoisomer and its
unambiguous stereochemical determination by single
crystal X-ray diffraction (Scheme 1). Gratifyingly, the
stereochemical outcome was in agreement with all of our
previous studies on the stereoselective oxy-Michael reac-
tion of 1 and arises from addition of the nucleophile to the
Re-face of the Michael acceptor. After repetition of the re-
action, attempted protodesulfonylation reactions of crude
oxy-Michael adduct 3a were attempted. However, this re-
duction proved to be a significant challenge owing to the
relative ease of the competing retro oxy-Michael reaction.
Capricious promises were made by sodium/mercury
amalgams but, finally, freshly prepared samarium(II) io-
dide efficiently desulfonylated 3a in THF at –78 °C.11
Quenching and the usual work up gave crude THP*-pro-
tected b-hydroxy ester 4a in 96% de. Purification allowed
easy isolation of isomerically pure major product in 67%
yield.
SYNTHESIS 2005, No. 19, pp 3283–3286
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x
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Advanced online publication: 14.11.2005
DOI: 10.1055/s-2005-918484; Art ID: C07605SS
© Georg Thieme Verlag Stuttgart · New York

3284
F. A. Hernandez-Juan et al.
PAPER
Table 1 Scope of the Stereoselective Oxy-Michael Addition to a,b-
Unsaturated Phenyl Sulfones 2 and Successive Protodesulfonylation
Entry
R1
R2
Product Yield (%)a de (%)b
1
2
3
4
5
6
7
8
i-Pr
Ph
Et
4a
4b
4c
4d
4e
4f
67
56
76
54
59
63
66
43
96
68
74
68
86
98
56
54
Me
Et
Ph
Ph
t-Bu
Me
Et
c-Hex
c-Hex
c-Hex
i-Pr
t-Bu
t-Bu
4g
4h
Scheme 1
a Isolated yield of isomerically pure major diastereomer over two
steps after silica gel chromatography.
b Measured by analysis of the 1H NMR (500 MHz) spectra of the
crude reaction product after protodesulfonylation.
The preliminary experiments for the successive stereose-
lective oxy-Michael reaction and protodesulfonylation
process were very pleasing. Thus, the scope of this ap-
proach was probed by performing additions to a variety of
a,b-unsaturated phenyl sulfones 2. Owing to the general
lack of stereocontrol at the redundant a-centre on quench-
ing with acetic acid, the crude oxy-Michael adducts 3
were subjected directly to the samarium(II) iodide pro-
todesulfonylation conditions (Scheme 2). The results are
presented in Table 1. All the reactions proceeded with
moderate to good overall yields (43–76%). However, sig-
nificant variations in the reaction de were observed and
were dependent on the nature of the b-substituent and the
ester group. Thus, with a b-phenyl group, only moderate
diastereomeric excesses of 68–74% were obtained regard-
less of the steric demand of the ester group (entries 2–4).
However, with b-cyclohexyl and b-isopropyl groups, high
diastereoselectivities were observed only with the ethyl
ester derivatives (entry 6, 98% de and entry 1, 96% de). In
the presence of a bulky tert-butyl ester, a lower reaction
de of 56% (entry 7) and 54% (entry 8) was recorded.
that all these reactions proceeded efficiently (53% to 78%
yield over two steps) with uniformly excellent diastereo-
control (90 to 99% de) (Table 2, Scheme 3). It is notewor-
thy that in the cases where the methyl sulfone contained
an isopropyl b-substituent (entry 1) or a tert-butyl ester
group (entry 4) that the samarium(II) iodide mediated pro-
todesulfonylation was sluggish and unreacted intermedi-
ates 6a and 6d were recovered from the respective
reaction mixtures.
1) KHMDS, 18-C-6,
THP*O
R1
THP*O
R1
THF, –78 °C
SmI2
CO2R2
SO2Me
CO2R2
1
SO2Me
CO2R2
3) AcOH
THF,
–78 °C
R1
2)
4
6
5
Scheme 3
Table 2 Scope of the Stereoselective Oxy-Michael Addition to a,b-
Unsaturated Methyl Sulfones 2 and Successive Protodesulfonylation
1) KHMDS, 18-C-6,
THF, –78 °C
THP*O
R1
THP*O
R1
SmI2
R1
R2
Product Yield (%)a de (%)b
CO2R2
SO2Ph
CO2R2
1
Entry
THF,
–78 °C
SO2Ph
CO2R2
R1
4
1
2
3
4
5
6
i-Pr
Ph
Ph
Ph
Et
4a
4b
4c
4d
4i
54c
78
98
97
98
99
97
90
3
2)
3) AcOH
2
Me
Et
Scheme 2
67
t-Bu
53d
66
We believed that the disappointing substrate-dependent
diastereoselectivities were a result of the bulky phenyl
group of the sulfone moiety. Accordingly we reasoned
that replacement of phenyl sulfone derived acceptors 2
with sterically less demanding methyl sulfones could give
rise to improved diastereoselectivities. Thus, a range of
a,b-unsaturated methyl sulfones 5 were prepared follow-
ing modified literature procedures.10 These were submit-
ted to the successive oxy-Michael reaction and
protodesulfonylation process. We were delighted to find
4¢-MeOC6H4 Me
4¢-BrC6H4 Et
4j
64
a Isolated yield of isomerically pure major diastereomer over two
steps after silica gel chromatography.
b Measured by analysis of the 1H NMR (500 MHz) spectra of the
crude reaction product after protodesulfonylation.
c 21% unreacted intermediate 6a was recovered.
d 24% unreacted intermediate 6d was recovered.
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PAPER
Stereoselective Approach to THP*-Protected b-Hydroxy Esters
3285
reaction product de was determined as 68% by inspection of the
crude 500 MHz NMR spectrum. Purification by flash column chro-
matography eluting with petroleum ether (bp 40–60 °C)–Et2O (9:1)
gave the major diastereoisomer 4b (104 mg, 56%, de >98%) and the
minor 4b¢ (16 mg, 9%, de >98%) as an oil.
Finally, in order to demonstrate the accessibility of our
method towards optically pure b-hydroxy esters, exposure
of 4j (>98 de) to Amberlyst 15 ion exchange resin in eth-
anol at room temperature led to quantitative THP* remov-
al (Scheme 4). The enantiomeric excess of b-hydroxy
ester 7 was determined as >98% ee by chiral HPLC and
confirmed that no racemisation was occurring in the
deprotection step. Comparison of the specific rotation of
4b
[a]D20 –20.7 (c = 0.44, CHCl3).
IR (film): 1738, 1160, 1068, 1024, 995, 760, 697 cm–1.
22
prepared 7 {[a]D –27.6 (c = 1.49, CHCl3)} to literature
1H NMR (500 MHz, CDCl3): d = 7.41 (d, J = 7.2 Hz, 2 H), 7.33 (t,
J = 7.2 Hz, 2 H), 7.27 (t, J = 7.2 Hz, 1 H), 5.13 (dd, J = 8.7, 5.1 Hz,
1 H), 4.55 (dd, J = 9.6, 2.1 Hz, 1 H), 3.68 (s, 3 H), 3.42 (ddq,
J = 12.4, 6.2, 2.0 Hz, 1 H), 2.93 (dd, J = 15.5, 8.7 Hz, 1 HA), 2.70
(dd, J = 15.5, 5.1 Hz, 1 HB), 1.80 (m, 2 H), 1.53–1.10 (m, 4 H), 1.09
(d, J = 6.2 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 171.5, 141.7, 128.2, 127.5, 126.6,
102.0, 76.6, 72.3, 51.6, 42.5, 32.2, 30.7, 22.3, 21.5.
MS-EI: m/z (%) = 296 ([M + NH4]+, 65), 206 (97), 163 (100), 121
(26).
reported data of (R)-7 {[a]D25 +33.1 (c = 1.46, CHCl3)}2c
confirmed the absolute stereochemistry as S. This, in con-
junction with the X-ray structure of 3a, allowed the S-ste-
reochemistry of all THP*-protected b-hydroxy esters 4 to
be assigned by analogy.
OH
Amberlyst 15
EtOH, r.t.
CO2Et
O
O
CO2Et
Br
HRMS-EI: m/z calcd for C16H26O4N (M + NH4): 296.1856; found:
296.1859.
Br
(S)-7 (ee 98%)
4j (de 98%)
4b¢
[a]D20 +112.9 (c = 0.24, CHCl3).
Scheme 4
IR (film): 1738, 1251, 1160, 1068, 995, 760, 698 cm–1.
In summary, we have developed a facile two-step process
involving a highly diastereoselective oxy-Michael addi-
tion of the naked anion of 6-methyl d-lactol to a,b-unsat-
urated methyl sulfone derived acceptors and successive
samarium(II) iodide mediated protodesulfonylation. This
1H NMR (500 MHz, CDCl3): d = 7.39–7.29 (m, 5 H), 5.30 (t, J = 7.1
Hz, 1 H), 4.22 (dd, J = 9.1, 2.2 Hz, 1 H), 3.62 (s, 3 H), 3.38 (ddq,
J = 12.6, 6.2, 2.1 Hz, 1 H), 3.02 (dd, J = 15.2, 7.1 Hz, 1 HA), 2.72
(dd, J = 15.2, 7.1 Hz, 1 HB), 1.78–1.14 (m, 6 H), 1.24 (d, J = 6.2 Hz,
3 H).
method provides a useful way to prepare isomerically 13C NMR (125 MHz, CDCl3): d = 171.0, 140.9, 128.4, 128.0, 127.1,
99.2, 74.7, 72.0, 51.5, 43.2, 32.3, 30.9, 22.2, 21.6.
pure protected b-hydroxy esters. The applications of this
approach in synthesis are in progress and will be reported
in due course.
MS-EI: m/z (%) = 296 ([M + NH4]+, 66), 277 (12), 205 (11), 163
(100), 121 (23).
HRMS-EI: m/z calcd for C16H26O4N (M + NH4): 296.1856; found
296.1857.
Two-Step Asymmetric Synthesis of THP*-Protected b-Hydroxy
Esters; (S)-Methyl 3-[(2R,6S)-6-Methyltetrahydro-2H-pyran-2-
yloxy]-3-phenylpropanoate (4b) and (R)-Methyl 3-[(2R,6S)-6-
Methyltetrahydro-2H-pyran-2-yloxy]-3-phenylpropanoate
(4b¢); Typical Procedure
Acid-Mediated Removal of THP* Group; (S)-Ethyl 3-Hydroxy-
3-(4-bromophenyl)propanoate [(S)-7]; Typical Procedure
To a stirred solution of (S)-ethyl 3-[(2R,6S)-6-methyltetrahydro-
2H-pyran-2-yloxy]-3-(4-bromophenyl)propanoate (4j; 111 mg, 0.3
mmol) in EtOH (3 mL) at r.t. was added Amberlyst 15 ion exchange
resin (600 mg). The mixture was stirred at r.t. for 1 h. The mixture
was then filtered through a short silica gel plug washing with Et2O
(15 mL). The filtrate was evaporated in vacuo to give (S)-7 (81 mg,
99%) as a pale yellow oil; [a]D22 –27.6 (c = 1.49, CHCl3).
To a stirred solution of (S)-6-methyltetrahydropyran-2-ol (1; 116
mg, 1 mmol) in THF (15 mL) at –78 °C was added KHMDS (2 mL,
1 mmol, 0.5 M solution in toluene) dropwise. The mixture was then
stirred for 15 min at –78 °C before a solution of 18-crown-6 (6.49
mL, 2.04 M in toluene) was added dropwise. Stirring was main-
tained for a further 30 min before methyl 3-phenyl-2-(phenylsulfo-
nyl)acrylate (2b; 202 mg, 0.67mmol) in THF (5 mL) was added
dropwise. Stirring was maintained for 30 min at –78 °C. The reac-
tion was then quenched with glacial AcOH (0.12 mL, 2 mmol) via
syringe and the resulting mixture was allowed to warm to r.t. Et2O
(15 mL) and H2O (15 mL) were added and the aqueous layer was
separated and extracted with Et2O (3 × 15 mL). The combined or-
ganic layers were washed with brine (15 mL), dried (MgSO4), fil-
tered through a pad of silica gel and concentrated in vacuo. The
crude was treated with freshly prepared SmI2 (0.1 M, 67 mL, 6.7
mmol) in THF at –78 °C for 12 h, quenched with a sat. aq solution
of NH4Cl and slowly warmed up to r.t. The mixture was extracted
with Et2O (3 × 20 mL) and the combined organic layers were
washed with brine, dried (MgSO4) and concentrated in vacuo. The
1H NMR (500 MHz, CDCl3): d = 7.42 (d, J = 8.5 Hz, 2 H), 7.19 (d,
J = 8.2 Hz, 2 H), 5.03 (m, 1 H), 4.12 (q, J = 7.2 Hz, 2 H), 3.31 (br
s, 1 H), 2.63 (m, 2 H), 1.20 (t, J = 7.2 Hz, 3 H).
Acknowledgment
We gratefully acknowledge GlaxoSmithKline (to D.J.B), EPSRC
(to X.X.), the EU (Marie Curie Fellowship to F.A.H.-J.) for fun-
ding. We are indebted to Dr J. E. Davies for X-ray crystallography
and EPSRC National Mass Spectrometry Service Centre, Swansea
for analysis and Prof S. V. Ley for support. D.J.D. would like to
thank Paul Berg for contributing to some of the preliminary studies.
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F. A. Hernandez-Juan et al.
PAPER
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components.
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Synthesis 2005, No. 19, 3283–3286 © Thieme Stuttgart · New York