Asymmetric synthesis of 3-hydroxyl-2-alkanones via tandem organocatalytic aminoxylation of aldehydes and chemoselective diazomethane homologation

Article abstract of DOI:10.1016/j.tetlet.2009.03.057

Asymmetric synthesis of 3-hydroxyl-2-alkanones is achieved via one-pot, tandem organocatalytic aminoxylation of aldehydes and chemoselective CH₂N₂-induced homologation. Accelerating effect of water is observed in α-aminoxylation. MgC

Full text of DOI:10.1016/j.tetlet.2009.03.057

Tetrahedron Letters 50 (2009) 2628–2631
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Asymmetric synthesis of 3-hydroxyl-2-alkanones via tandem organocatalytic
aminoxylation of aldehydes and chemoselective diazomethane homologation
c
c
Li Yang a,b, Run-Hua Liu a, Bing Wang a, , Ling-Ling Weng , Hu Zheng
*
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
b State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
c Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Asymmetric synthesis of 3-hydroxyl-2-alkanones is achieved via one-pot, tandem organocatalytic amin-
oxylation of aldehydes and chemoselective CH2N2-induced homologation. Accelerating effect of water is
Received 9 February 2009
Revised 3 March 2009
Accepted 6 March 2009
Available online 14 March 2009
observed in
a-aminoxylation. MgCl2, a Lewis acid additive, improves the chemoselectivity of the diazo-
methane homologation to 6:1 in favor of ketone.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalysis
Asymmetric synthesis
Oxygenations
Diazo compounds
Rearrangements
Optically active
a
-hydroxyketones (acyloins) are versatile inter-
ity was undermined by
a
-hydroxyamination, and the regioselec-
mediates in organic synthesis (Fig. 1). For example, they are poten-
tial precursors to chiral 1,2-diols and 1,2-aminoalcohols, which are
common structural features found in numerous chiral ligands, aux-
iliaries, and biologically active compounds.1 However, methods for
the asymmetric synthesis of this type of compounds are rather lim-
ited. Notable examples include Rubottom–type oxidation of ke-
tone-derived enolates by Davis’ oxazirine reagent,2 asymmetric
epoxidation followed by hydrolysis,3 and Sharpless asymmetric
dihydroxylation of enol ethers.4 However, the level of stereocontrol
in these protocols is very sensitive toward the structure of sub-
strates, and varies widely (68% up to 95% ee). In addition, pre-for-
mation of enolate or its equivalent is required, which not only
raises the issue of regioselectivity for non-symmetric substrates,
but also excludes the presence of many base-sensitive functions.
On the other hand, organocatalysis has made enormous progress
in the past decade,5 and highly enantioselective organocatalytic
tivity was low.9b Consequently, direct
a
-aminoxylation of
ketones, at its present stage, cannot provide an efficient and gen-
eral access to chiral non-cyclic
-hydroxyketones.10 As our contin-
uing interest in vicinally functionalized chiral alcohol and
amines,11 we envisioned that an alternative tandem aldehyde
aminoxylation–homologation sequence could circumvent such
limitations, and would afford the desired 3-hydroxyl-2-alkanones
with a wider substrate scope. Herein we describe the preliminary
results of this study.
The tandem sequence was investigated step by step, first with
the aminoxylation using 3-phenylpropanal 1a as a model sub-
strate. Surprisingly, this was not as smooth as we expected. It
was found that in dry DMSO (re-distilled from CaH2, and stored
over 4 Å MS under Ar), the reaction was considerably slower than
that reported, and after reductive treatment (NaBH4/EtOH/0 °C),
a
a
-aminoxylation of aldehydes using nitrosobenzene has been
developed.6 The products have been utilized in subsequent reduc-
tion,6 Horner–Wadsworth–Emmons olefination,7 and allylation8
reactions in a tandem manner to afford diverse chiral building
OH
R2
NH2
R2
Me4NBH(OAc)3
(via oxime)
R1
R1
Red-Al
O
a a
-aminoxylation,9
OH(SiR3)
OH
blocks. Although ketones also undergo such
R1
R2
survey of the literature revealed that open-chain non-symmetric
ketones were generally not ideal substrates, as the chemoselectiv-
OH
NH2
R2
OH
R1
R1
Zn(BH4)2
(via imine)
Zn(BH4)2
R2
OH
OH
a-hydroxy ketones.
* Corresponding author. Tel./fax: +86 21 54237570.
E-mail address: wangbing@fudan.edu.cn (B. Wang).
Figure 1. Selected synthetic utilities of chiral
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.057

L. Yang et al. / Tetrahedron Letters 50 (2009) 2628–2631
2629
Table 2
OH
Effect of Lewis acid in CH2N2-induced rearrangement
2a 30~40%
3a 10%
ONHPh
1) PhNO (1.0 eq.)
L-proline (0.1 eq.)
DMSO, RT, 10 min
O
CHO
OH
O
CHO
CH2N2-Et2O
2) NaBH4, EtOH, 0 o
C
OH
ONHPh additive, RT
ONHPh
ONHPh
5a
1a (1.2 eq.)
OH
>60%
4a
4aa (%)
eeb (%)
5a (%)
drc (%)
Scheme 1. Preliminary results using anhydrous DMSO.
Entry
Additive
1
None
None
23
13
17
0
30
60
50
97
Nd
95
—
Nd
97
97
23
40
35
0
17
10
16
1.2:1
Nd
1.1:1
—
Nd
1.2:1
Nd
2d
3
large amounts of 3-phenylpropanol were formed. The yield of the
expected product 2a was only 30–40% after extended reaction
time,12 along with up to 10% of 3a which might result from the
decomposition of 2a (Scheme 1). Shifting to other organocata-
lysts6e,13 or solvents (CHCl3 and MeCN) did not improve the results.
On the other hand, when we accidentally used DMSO from an old
bottle, both the reaction rate and the yield were significantly im-
proved. This prompted us to examine the effect of water14 more
closely than that revealed in the literature (Table 1).
MeOH
BF3ꢁOEt2
CeCl3
MgCl2
MgBr2
4
5
6
7
a
Isolated yields for two steps.
Determined by chiral HPLC.
Determined by NMR, relative stereochemistry not assigned.
b
c
d
Reaction run at –10 °C.
The water content of our re-distilled DMSO was determined to
be 0.02% by Karl Fischer method, while that of the unfresh solvent
was ꢀ2.2%. It turned out that water did accelerate the reaction, and
1.0% (v/v) water in DMSO was optimal, providing the highest reac-
tion rate and yield (entry 3). The solvent effect was especially pro-
nounced in the range below 1.0%, where less water corresponded
to slower reaction and unpredictable yields (entries 1–3). Presum-
ably, the dependence on water was due to that it facilitated the
increased the chemoselectivity to a useful level of 6:1 with en-
hanced yields of ketone (up to 60%). Protic additive (MeOH)
showed the opposite selectivity, favoring the epoxide. Thus inex-
pensive MgCl2 was chosen as the key modulator to be introduced
before addition of CH2N2.
The role of MgCl2 could be rationalized as outlined in Figure 2.
The metal counterion trapped the alkoxide anion, so that only the
lone pair electron of the oxygen, rather than a negative charge,
could be used to displace N2. Thus path B was considerably im-
peded, while path A, which involved 1,2-hydrogen shift, was
unaffected.
With the optimized conditions in hand, the tandem aminoxyla-
tion–homologation of various aldehydes was examined (Table 3).
The sequential reactions were carried out conveniently in one
pot, without isolation of the intermediates, in moderate to good
yields over two steps.17 b-Branched aldehyde showed slightly bet-
ter yields (entry 6). b-Alkylthio substitution was well tolerated (en-
hydrolysis of the iminium salt intermediate to
a-aminoxyalde-
hyde, regenerating the proline catalyst. Although initial enamine
formation produced 1 equiv of water, it seemed that this was not
sufficient to maintain a smooth catalytic cycle and certain amounts
of added water were required. Interestingly, this has not been
noted in previous reports. Thus DMSO containing 1.0% water was
used throughout our subsequent study.
The next step was homologation of aldehyde to methyl ketone.
Schlotterbeck and Arndt have reported this transformation via
reaction with diazomethane.15a,b However, the literature prece-
dences also indicated that the chemoselectivity was profoundly
influenced by the structure of the parent aldehydes, those bearing
try 7). Finally,
x-oxygenated aldehydes were also suitable
substrates, providing the opportunity for further elaboration. The
ee’s of all products were excellent, indicating that no racemization
occurred during the CH2N2-induced rearrangement. The absolute
configuration of the product was established by single-crystal X-
ray diffraction of compound 4b (Fig. 3).18
eletron-withdrawing
a
-substituents tend to give the undesired
-aminoxyaldehyde
epoxide.15b In our preliminary trial, when the
a
was treated in situ with an ethereal solution of CH2N2, the desired
ketone 4a was obtained along with equimolar epoxide 5a in low
yields (23%). Indeed, compared with unbranched aldehydes, the
Synthetic application of the 3-phenylaminoxyl-2-alkanone
products was demonstrated by a highly enantioselective synthesis
of compound 9 (Scheme 2), the C12–C21 chiral building block for
Epothilones.19 The N–O bond in ent-4h was easily cleaved by CuSO4
in MeOH or hydrogenolysis (H2, cat. PtO2). The crude alcohol was
protected with TBS to afford the known ketone 6 (70%). Wittig olef-
ination constructed the tri-substituted double bond in a highly
stereoselective manner, and selective removal of the terminal
TBS protection afforded 9 (85%). Chiral HPLC analysis of alcohol 9
confirmed that its optical purity was almost completely preserved
(97% ee).20 In our hands, this is a more convenient route with high-
er ee, compared with other methods such as enzymatic resolution
(88–90% ee) or asymmetric allylation (90–95% ee).
a-aminoxy substitution did exhibit a significant adverse effect.
Lowering the reaction temperature only aggrevated the situation,
with an even lower yield of 4a and worse selectivity (entry 2). In-
spired by Yamamoto’s Lewis acid–catalyzed homologation,16 we
turned our attention to simple Lewis acid additives in an attempt
to overcome the unfavorable intrinsic preference for epoxide (Ta-
ble 2). The use of borontrifluoride etherate led to intractable mix-
tures, while lanthanides afforded only moderate ketone to epoxide
ratio (entries 3 and 4). To our delight, anhydrous magnesium salts
Table 1
Effect of water in proline-catalyzed
a-aminoxylation
Entry
H2O% (v/v)
Time (min)
2a (%)
eea (%)
O
N2CH2
0.02b
0.2c
40
20
5
10
10
30–40
50
64
60
60
98
98
98
98
98
A
path A
path B
1
2
3
4
5
H
N2
B
R
R
H
-Cl-
1.0c
ONHPh
O
R
O
R
O
2.2b
10.0c
O
O
PhHN
PhHN
Mg
Mg Cl
Cl
Cl
a
Determined by chiral HPLC.
Determined by Karl Fischer method.
Obtained by adding calculated amounts of water to dry DMSO.
ONHPh
b
c
Figure 2. Plausible role of Mg(II) additives.

2630
L. Yang et al. / Tetrahedron Letters 50 (2009) 2628–2631
Table 3
TBSO
TBSO
CuSO4
One-pot tandem a-aminoxylation and regioselective CH2N2-induced rearrangement
TBSCl
MeOH, 0oC
O
DMF, Im
70%
O
1) PhNO (1.0 eq.)
L-proline (0.1 eq.)
DMSO, RT, 10 min
O
ONHPh
OTBS
R
R
CHO
ent-4h (99% ee)
6
ONHPh
2) CH2N2 (1.5 eq.)
Et2O, MgCl2, RT
S
1 (3 eq.)
TBSO
4
S
ClBu3P
10-CSA
N
7
N
DCM-MeOH
85%
Entry
1
1
Ketone 4,a (%)
4a, 60
eeb (%)
97
t-BuOK, THF
90%
OTBS
CHO
CHO
8
1a
12
HO
S
S
Lit.
I
21
N
N
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
4b, 57
4c, 40
4d, 46
4e, 46
4f, 55
4g, 43
4h, 42
4i, 41
98
97
98
98
98
97
99
95
OTBS
OTBS
Br
9 (97% ee)
10
Scheme 2. Synthesis of a chiral building block (9) for Epothilone.
CHO
In summary, we have developed a general method for the synthe-
sis of 3-hydroxyl-2-alkanones via tandem organocatalytic aminoxy-
lation of aldehydes and chemoselective diazomethane
homologation. An accelerating effect of water was observed for the
aminoxylation, while MgCl2 served as an effective Lewis acid addi-
CHO
CHO
9
tive for the chemoselective homologation of
a-aminoxyaldehyde
to ketone. A key intermediate for the synthesis of Epothilones was
prepared using this approach in high ee. Studies on chemoselective
epoxide formation and utilization of this byproduct via regioselec-
tive C–2 ring-opening of the epoxide are under investigation.
CHO
Acknowledgments
CHO
1g
1h
1i
S
Financial support from the NSFC (20602008, 20832005) and
Chinese Academy of Sciences (KSCX2-YW-R-23) is gratefully
acknowledged. We thank Dr. Xiao-Di Yang for X-ray analysis.
TBSO
CHO
References and notes
9
BnO
CHO
1. For leading reviews, see: (a) Bergmeier, S. C. Tetrahedron 2000, 56, 2561; (b)
Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835.
2. (a) Davis, F. A.; Haque, M. S.; Ulatowski, T. G.; Towson, J. C. J. Org. Chem. 1986,
51, 4083; (b) Davis, F. A.; Sheppard, A. C. J. Org. Chem. 1987, 52, 954; (c) Davis, F.
A.; Weismiller, M. C. J. Org. Chem. 1990, 55, 3715; (d) Davis, F. A.; Chen, B.-C.
Chem. Rev. 1992, 92, 919.
a
Isolated yields for two steps.
Determined by chiral HPLC.
b
3. (a) Zhu, Y.; Tu, Y.; Yu, H.; Shi, Y. Tetrahedron Lett. 1998, 39, 7819; (b) Reddy, D.
R.; Thornton, E. R. J. Chem. Soc., Chem. Commun. 1992, 172; (c) Fududa, T.;
Katsuki, T. Tetrahedron Lett. 1996, 37, 4389; (d) Adam, W.; Fell, R. T.; Stegmann,
V. R.; Saha-Möller, C. R. J. Am. Chem. Soc. 1998, 120, 708; (e) Adam, W.; Fell, R.
T.; Saha-Möller, C. R.; Zhao, C.-G. Tetrahedron: Asymmetry 1998, 9, 397.
4. Hashiyama, T.; Morikawa, K.; Sharpless, K. B. J. Org. Chem. 1992, 57, 5067.
5. For reviews, see: (a) Berkessel, A.; Gröger, H. Asym. Organocatal.; Wiley-VCH:
Weinheim, 2005; (b) Organocatalysis; Reetz, M. T., List, B., Jaroch, S., Weinmann,
H., Eds.; Springer: Berlin, 2008; (c) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed.
2001, 40, 3726; (d) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138.
6. For seminal publications, see: (a) Momiyama, N.; Yamamoto, H. J. Am. Chem.
Soc. 2003, 125, 6038; (b) Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2003, 125, 10808; (c) Zhong, G. Angew. Chem., Int. Ed. 2003,
42, 4247; (d) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M. Tetrahedron Lett.
2003, 44, 8293; (e) Momiyama, N.; Torii, H.; Saito, S.; Yamamoto, H. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5374.
7. Zhong, G.; Yu, Y. Org. Lett. 2004, 6, 1637.
8. Zhong, G. Chem. Commun. 2004, 606.
9. For seminal publications, see: (a) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Shoji,
M. Angew. Chem., Int. Ed. 2004, 43, 1112; (b) Hayashi, Y.; Yamaguchi, J.; Sumiya,
T.; Hibino, K.; Shoji, M. J. Org. Chem. 2004, 69, 5966; (c) Bøgevig, A.; Sundén, H.;
Córdova, A. Angew. Chem., Int. Ed. 2004, 43, 1109.
10. Only the following three examples of open-chain non-symmetric ketone have
been reported to give meaningful results so far, see Ref. 9c.
O
O
O
Figure 3. X-ray structure of 4b.

L. Yang et al. / Tetrahedron Letters 50 (2009) 2628–2631
2631
122.4, 127.0, 128.7, 128.9, 129.6, 136.6, 147.8, 208.7 ppm; HR-MS Calcd for
11. (a) Liu, R.-H.; Fang, K.; Wang, B.; Xu, M.-H.; Lin, G.-Q. J. Org. Chem. 2008, 73,
3307; (b) Wang, B.; Fang, K.; Lin, G.-Q. Tetrahedron Lett. 2003, 44, 7981; (c)
Wang, B.; Yu, X.-M.; Lin, G.-Q. Synlett 2001, 904; (d) Liu, D.-G.; Wang, B.; Lin,
G.-Q. J. Org. Chem. 2000, 65, 9114; (e) Wang, B.; Liu, R.-H. Eur. J. Org. Chem.
2009, doi:10.1002/ejoc.200900231.
12. It should be noted that the reaction time cannot be extended indefinitely, for
the product tends to be decomposed by PhNO or undergo other side reactions,
see: Ramachary, D. B.; Barbas, C. F., III Org. Lett. 2005, 7, 1577.
13. (a) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Sumiya, T.; Urushima, T.; Shoji, M.;
Hashizume, D.; Koshino, H. Adv. Synth. Catal. 2004, 346, 1435; (b) Wang, W.;
Wang, J.; Li, H.; Liao, L. Tetrahedron Lett. 2004, 45, 7235.
14. For an excellent review of water effects in organocatalysis, see: (a)
Gruttadauria, M.; Giacalone, F.; Noto, R. Adv. Synth. Catal. 2009, 351, 33; For a
general survey of water acceleration in organic synthesis, see: (b) Ribe, S.;
Wipf, P. Chem. Commun. 2001, 299.
C16H17NO2 255.1259. Found 255.1265. Compound 4d: ½a D27
ꢃ
+54.6 (c 0.85,
CHCl3) for 97.9% ee; HPLC: Chiralcel OD column; detected at 214 nm; eluent: n-
hexane/2-propanol = 95/5 (v/v), flow rate: 0.8 ml/min, t1 = 8.63 min (minor),
t2 = 9.28 min (major); 1H NMR (300 MHz, CDCl3): d 0.92 (t, 3H, J = 6.6 Hz),
1.27–1.41 (m, 4H), 1.60–1.43 (m, 2H), 1.70–1.80 (m, 2H), 2.20 (s, 3H), 4.36 (t,
1H, J = 6.0 Hz), 6.91–7.00 (m, 3H), 7.27 (t, 2H, J = 7.8 Hz), 7.37 (s, 1H) ppm; 13C
NMR (CDCl3, 100 MHz): d 13.8, 22.2, 25.0, 25.7, 30.2, 30.4, 88.5, 114.4, 122.1,
128.7, 128.7, 147.9, 209.1 ppm; HR-MS (ESI) Calcd for C14H22NO2 236.1645,
Found 236.1645. Compound 4h: ½a D24
ꢃ
+53.6 (c 1.36, CHCl3) for 99% ee; HPLC:
Chiralpak AD-H column; detected at 214 nm; eluent: n-hexane/2-
propanol = 95/5 (v/v), flow rate: 0.7 ml/min, t1 = 8.7 min (minor),
t2 = 17.7 min (major); 1H NMR (300 MHz, CDCl3): d 0.08 (s, 3H), 0.10 (s, 3H),
0.91 (s, 9H), 1.84–2.08 (m, 2H), 2.21 (s, 3H), 3.76–3.94 (m, 2H), 4.61 (dd, 1H,
J = 8.4, 4.2 Hz), 6.94–7.00 (m, 3H), 7.22–7.30 (m, 2H), 7.41 (s, 1H) ppm; 13C
NMR (CDCl3, 75 MHz): d ꢄ5.4,ꢄ5.3, 18.3, 25.9, 26.3, 33.5, 58.7, 85.3, 114.6,
122.4, 128.9, 148.0, 208.9 ppm.
15. (a) Schlotterbeck, F. Chem. Ber. 1907, 40, 479; (b) Arndt, F.; Eistert, B. Chem. Ber.
1928, 61, 1118; For a recent example, see: (c) Davis, J. T. J. Org. Chem. 1997, 62,
8243; For an alternative reagent to diazomethane, see: (d) Aoyama, T.; Shioiri,
T. Synthesis 1988, 228; For a review, see: (e) Gutsche, C. D. Org. React. 1954, 8,
364.
18. Crystallographic data for 4b (C16H16BrNO2): T = 293(2) K; wavelength:
0.71073 Å; crystal system: monoclinic; space group: C2; unit cell
dimensions: a = 32.049(16) Å, b = 5.537(3) Å, c = 8.889(4) Å,
= 90°; V = 1576.6(13) Å3; Z = 4; calcd = 1.408 Mg/m3; F(000) = 680; final R
indices [I > 2 (I)]: R1 = 0.0454, wR2 = 0.1145; R indices (all data), R1 = 0.0740,
a = 90°, b = 90°,
c
q
16. Maruoka, K.; Concepcion, A. B.; Yamamoto, H. Synlett 1994, 521.
17. General procedures: To a solution of
L-proline (12 mg, 0.1 mmol) in DMSO–H2O
r
wR2 = 0.1430; 3306 reflections measured, 2480 were unique (R(int) = 0.0400).
CCDC 719767 contains the supplementary crystallographic data for this
compound. These data can be obtained free of charge from the Cambridge
Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif.
19. For reviews on the synthesis of Epothilones, see: (a) Nicolaou, K. C.;
Roschangar, F.; Vourloumis, D. Angew. Chem., Int. Ed. 1998, 37, 2014; (b)
Zhang, R.; Liu, Z. Curr. Org. Chem. 2004, 8, 267.
(99:1) were added PhNO (107 mg, 1.0 mmol) and aldehyde (3 mmol)
successively under fast stirring. After the color of the solution turned into
orange, MgCl2 (ꢀ500 mg) was added, followed by CH2N2 (10 mL, 0.5–0.6 M in
Et2O), and the mixture was stirred at rt for 2 h, purged with N2, quenched with
aq NH4Cl, and diluted with ether (50 mL). The aqueous phase was extracted
with ether (2ꢂ50 mL), the combined organic layer was dried (MgSO4),
concentrated under reduced pressure and purified by flash column
20. Compound 9: ½a D22
ꢄ28.6 (c 0.39, CHCl3) for 97% ee; HPLC: Chiralcel OD column;
ꢃ
chromatography. Compound 4a: ½a D24
ꢃ
+63.7 (c 0.80, CHCl3) for 98% ee; HPLC:
detected at 230 nm; eluent: n-hexane/2-propanol = 80/20 (v/v), flow rate:
0.7 ml/min, t1 = 6.3 min (major), t2 = 14.5 min (minor); 1H NMR (300 MHz,
CDCl3): d 0.04 (s, 3H), 0.11 (s, 3H), 0.92 (s, 9H), 1.75–1.95 (m, 2H), 2.02 (s, 3H),
2.32 (br s, 1H), 2.72 (s, 3H), 3.76 (m, 2H), 4.40 (dd, 1H, J = 6.9, 4.5 Hz), 6.53 (s,
1H), 6.94 (s, 1H).
Chiralpak AD-H column; detected at 214 nm; eluent: n-hexane/2-
propanol = 80/20 (v/v), flow rate: 0.7 ml/min, t1 = 11.2 min (minor),
t2 = 14.6 min (major); 1H NMR (300 MHz, CDCl3): d 2.18 (s, 3H), 2.98 (AB-d,
1H, JAB = 14.1, J = 9.0 Hz), 3.10 (AB-d, 1H, JAB = 14.1, J = 4.2 Hz), 4.56 (dd, J = 9.3,
4.2 Hz), 6.65 (d, 2H, J = 7.8 Hz), 6.91(t, 2H, J = 7.5 Hz), 7.15 (t, 2H, J = 8.1 Hz),
7.23–7.38 (m, 6H) ppm; 13C NMR (CDCl3, 75 MHz): d 26.8, 36.9, 89.4, 114.5,