Preparation and application of 2-(arylmethoxy)isopinocampheols for the asymmetric aldol reaction of 3,3,3-trifluoropropionates

Article abstract of DOI:10.1016/j.tetlet.2011.08.034

The preparation of 2-(arylmethoxy)isopinocampheols from pinanediol via the DIABL-H reduction of the corresponding aryl aldehyde acetals has been described. A systematic examination of the asymmetric aldol reaction of 3,3,3-trifluoropropionates led to the double diastereoselective aldol reaction of 2-(arylmethoxy)isopinocampheyl 3,3,3-trifluoropropionates providing anti-α-trifluoromethyl-β-hydroxy esters in 63-85% yields, ≥99% anti-selectivity and 80-96% de for the anti-isomer.

Full text of DOI:10.1016/j.tetlet.2011.08.034

Tetrahedron Letters 52 (2011) 5359–5362
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Preparation and application of 2-(arylmethoxy)isopinocampheols for the
asymmetric aldol reaction of 3,3,3-trifluoropropionates
⇑
P. Veeraraghavan Ramachandran , Gowrisankar Parthasarathy, Pravin D. Gagare
Herbert C. Brown Center for Borane Research, Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907-2084, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of 2-(arylmethoxy)isopinocampheols from pinanediol via the DIABL-H reduction of the
corresponding aryl aldehyde acetals has been described. A systematic examination of the asymmetric
aldol reaction of 3,3,3-trifluoropropionates led to the double diastereoselective aldol reaction of
Received 8 June 2011
Revised 3 August 2011
Accepted 7 August 2011
Available online 11 August 2011
2-(arylmethoxy)isopinocampheyl 3,3,3-trifluoropropionates providing anti-a-trifluoromethyl-b-hydroxy
esters in 63–85% yields, P99% anti-selectivity and 80–96% de for the anti-isomer.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Aldol
Trifluoropropionates
Boron enolates
Isopinocampheols
Diisopinocampheylboron triflate
Enantioselective synthesis of partially-fluorinated molecules is
often challenging1 and contributes to the success of agrochemicals
and pharmaceuticals.2 Over the past two decades, as part of our
program on fluoroorganic synthesis via boranes,3 we have devel-
oped several protocols involving hydroboration,4 allylboration,5,6
reduction,7 and homologation.8 We recently reported a highly
anti-selective enolboration–aldolization of 3,3,3-trifluoropropio-
nates using dialkylboron triflates.9 In continuation, both the
reagent-10 and substrate-controlled11 asymmetric variants of the
reaction failed, necessitating the development of a synergistic ap-
proach. Described herein are the details of the systematic investiga-
tion that led to the double asymmetric aldol reaction of
diisopinocampheylboron enolates of 2-(arylmethoxy)isopinocamp-
heyl-3,3,3-trifluoropropionates.12
Taking cue from the diisopinocampheylboron triflate [(ꢀ)-Ipc2-
BOTf, (ꢀ)-1]-controlled aldol reaction of non-fluorinated propio-
nates in excellent ee,10 benzaldehyde (2a) was initially aldolized
with diisopinocampheylboron enolates of methyl-(3a), ethyl-(3b),
isopropyl-(3c), benzyl-(3d), and tert-butyl 3,3,3-trifluoropropio-
nates (3e).13 Contrary to the non-fluorinated derivatives, the
triflate (Nrb2BOTf, 5),9 followed by aldolization of benzaldehyde
provided reasonableanti:syn selectivity (73:27 and 94:6, respectively)
and low diastereoselectivity (14% and 58%, respectively) for the
anti-isomers 6af and 6ag, respectively (Table 1).
Aldol reaction of bis-exo-norbornylboron enolates of (ꢀ)-isopi-
nocampheyl- (3h), (+)-menthyl- (3i), and (ꢀ)-8-phenylmenthyl
(3j) trifluoropropionates with benzaldehyde provided the corre-
sponding aldol products (6ah–j) in 96–98% anti-selectivity and
20–68% de (Table 1).
Chiral esters 3g and 3j were selected for a synergistic double dia-
stereoselection study due to the high de achieved in the substrate-
controlled reactions. The corresponding diisopinocampheylboron
enolates were too slow to react (5% conversion) under the standard
conditions. However, the enolization of 3f, with either (+)- or (ꢀ)-1,
followed by the reaction with benzaldehyde provided an anti:syn
selectivity of 68:32 and 71:29, respectively, and a de of 12% and
14%, respectively, for the anti-isomer of the product 6af. The esters
)2BOTf
1.
enantioselectivities for the
a-trifluoromethyl-b-hydroxy esters
1
(-)-
4aa–ae14 were disappointingly poor (14–30%), although the diaste-
reoselectivities were good, ranging from 82% to 94% (Scheme 1).
The substrate-controlled asymmetric ester aldol reaction11 of
(ꢀ)-norephedrine-derived 3,3,3-trifluoropropionates 3f and 3g
was then pursued. Enolization with bis-exo-2-norbornylboron
OH
O
Et3N, CH2Cl2
OR
F3C
OR
-78 oC, 1.5 h
2. PhCHO (2a)
-78 oC, 8 h
O
-
CF3
4aa ae
3a e
-
R = Me, Et, i-Pr, t-Bu, Bn
82-94% de, 14-30% ee
⇑
Corresponding author.
E-mail address: chandran@purdue.edu (P.V. Ramachandran).
Scheme 1. Examination of the reagent-controlled aldol reaction of
trifluoropropionates.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.034

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P. Veeraraghavan Ramachandran et al. / Tetrahedron Letters 52 (2011) 5359–5362
Table 1
Table 2
Comparison of 1 and 5 for the enolboration–aldolization of chiral 3,3,3-trifluoropro-
Examination of substrate-controlled aldol reaction
pionates
Ar
Ar
O
1. Nrb2BOTf, Et3N
OH
O
R2BOTf, Et3N
CF3
CH2Cl2, -78 oC, 1.5 h
O
O
OR*
CH2Cl2, -78 °C, 1.5 h
O
Ph
F3C
Ph
OR*
CF3
2. PhCHO
O
3
PhCHO
-78 °C, 8 h
CF3
O
-78 oC, 1 h, 0 °C, 1 h
O
OH
6
11
10
O
Aldolb
Ester
Ar
Aldol
anti:synb
F3C
OR*
R2BOTf
10
11a
% de of antib
c
3
R.OH
6a
anti:sync % de of anti
1
2
3
4
5
10a
10b
10c
10d
10e
Ph
11aa
91:9
98:2
96:4
98:2
97:3
20
26
24
22
22
2-MeO–C6H4
3,5-Me2–C6H3
1-Naphthyl
2-Naphthyl
11ab
11ac
11ad
11ae
OH Me
N
Mes
1
3f
5
6af
73:27
14
S
O
O
2
3
3f
3f
’’
’’
(ꢀ)-1
(+)-1
6af
6af
71:29
68:32
14
12
a
See footnote 14.
anti:syn ratios and
b
%
de of anti-isomer were determined by 19F NMR
OH Bn
N
spectroscopy.
Mes
4
5
3g
5
6ag 94:6
6ag
58
d
S
O
O
3g ’’
(ꢀ)-1
d
(9c), (+)-2-(1-naphthylmethoxy)- (9d), and (+)-2-(2-naphthylmeth-
oxy)isopinocampheols (9e) in near quantitative yields (Scheme 2).16
The substrate-controlled aldol reactions of 2-(arylmethoxy)iso-
pinocampheyl 3,3,3-trifluoropropionates 10a–e with 5 provided
only ꢁ20% de for the anti-isomers (Table 2).
OH
6
7
3h
5
6ah 96:4
20
50
3h ’’
3i
(ꢀ)-1
6ah 90:10
HO
The double diastereoselection approach was necessary for opti-
mal results. Using the antipodes of 1, (ꢀ)-Ipc2BOTf was determined
to be the matched reagent for the bulky (ꢀ)-isopinocampheol es-
ters17 derived from (ꢀ)-pinanediol. While esters 10a and 10b pro-
vided anti:syn selectivity of ꢁ70:30 range, 10c–e provided
essentially pure anti-aldols (Table 3).
8
9
5
6ai
6ai
95:5
97:3
20
50
3i
’’
(ꢀ)-1
HO
Ph
10 3j
11 3j
5
6aj
6aj
98:2
d
68
d
’’
(ꢀ)-1
A series of aldehydes was then screened for the aldol reaction
under the optimized conditions with the most favorable ester
10d. The anti-a-trifluoromethyl-b-hydroxy esters, which were ob-
a
b
c
See footnote 14.
The yields of the aldol products were 58–69%.
anti:syn ratios and
de of anti-isomers were determined by 19F NMR
%
tained in 63–85% yield, P99% anti-selectivity and 80–90% de, dis-
play the generality of the reaction (Table 4).18
spectroscopy.
Only ꢁ5–6% conversion was observed by 19F NMR spectroscopy.
d
It was now incumbent upon us to determine the relative and
absolute stereochemistry of the aldol products. We resorted to
comparing the optical rotation of a known derivative since none
of the derivatives could be crystallized for X-ray crystallographic
structure determination. Thus, aldol 11ed was reduced to diol,
which was followed by TBS protection of the primary hydroxyl
3h and 3i disclosed an improved 50% de for the anti-isomers (anti-
selectivity of 90% and 97% for 6ah and 6ai, respectively), when com-
pared to the substrate-controlled reaction (Table 1). The synergistic
effect of two pinane moieties prompted the preparation and exam-
ination of bulkier isopinocampheols.
The formation of an inseparable mixture of products during the
attempted preparation of trifluoropropionate from (+)-3-O-
benzylpinanediol15 motivated the design of new chiral auxiliaries,
(+)-2-arylmethoxyisopinocampheols (9). Accordingly, (ꢀ)-(1R, 2R, 3S,
Table 3
Examination of the double diastereoselection in aldol reaction
Ar
Ar
1
1. Ipc2BOTf ( ), Et3N
5R)-pinane-2,3-diol (7), derived from (ꢀ)-
a-pinene, was converted
CF3
CH2Cl2, -78 oC, 1.5 h
2. PhCHO, -78 oC, 8 h
O
O
to the acetals 8a–e with the corresponding aromatic aldehydes
and reduced with DIBAL-H to provide (+)-2-(benzyloxy)- (9a), (+)-
2-(2-methoxybenzyloxy)- (9b), (+)-2-(3,5-dimethylbenzyloxy)-
O
O
Ph
CF3
O
O
OH
10
11
Ester 10
Ipc2BOTf
Aldol
11a
Yieldb (%)
anti:sync
% de of antic
Ar
OH
O
1
2
3
4
5
6
7
8
10a
10b
10c
10c
10d
10d
10e
10e
(ꢀ)-1
(ꢀ)-1
(ꢀ)-1
(+)-1
(ꢀ)-1
(+)-1
(ꢀ)-1
(+)-1
11aa
11ab
11ac
11ac
11ad
11ad
11ae
11ae
62
64
61
60
65
60
65
63
76:24
70:30
94:6
P99:61
P99:61
P99:61
P99:61
P99:61
86
54
86
75
90
60
90
62
OH
Ar
OsO4
O
ArCHO, cat. PPTS
Toluene, reflux
5 h, 98%
NMO/Py
7
8a-e
O
a
b
c
d
e
: Ar = Ph
OH
DIBAL-H, CH2Cl2
: Ar = 2-methoxyphenyl
: Ar = 3,5-dimethylphenyl
: Ar = 1-naphthyl
a
b
c
-78 oC to rt, 12 h
95%
See footnote 14.
% Isolated yield.
anti:syn ratios and
9a-e
: Ar = 2-naphthyl
%
de of anti-isomer were determined by 19F NMR
spectroscopy.
Scheme 2. Preparation of (+)-2-(arylmethoxy)isopinocampheols.

P. Veeraraghavan Ramachandran et al. / Tetrahedron Letters 52 (2011) 5359–5362
5361
Table 4
Generality of the reaction
References and notes
1. Enantiocontrolled Synthesis of Fluoro-organic Compounds: Stereochemical
Challenges and Biomedical Targets; Soloshonok, V. A., Ed.; Wiley: Chichester,
UK, 1999.
2. (a) Fluorine in Medicinal Chemistry and Chemical Biology; Ojima, I., Ed.; Wiley-
Blackwell: West Sussex, UK, 2009; (b) O’Hagan, D. J. Fluorine Chem. 2010, 131,
1071; (c) Hagmann, W. K. J. Med. Chem. 2008, 51, 4360.
3. Ramachandran, P. V.; Brown, H. C. In Asymmetric Fluoroorganic Chemistry:
Synthesis, Applications, and Future Directions In ACS Symposium Series 746;
Ramachandran, P. V., Ed.; American Chemical Society: Washington, DC, 2000;
pp 22–37.
4. For fluoroorganic synthesis via hydroboration, see: (a) Brown, H. C.; Chen, G.
M.; Jennings, M. P.; Ramachandran, P. V. Angew. Chem., Int. Ed. 1999, 38, 825;
(b) Ramachandran, P. V.; Jennings, M. P.; Brown, H. C. Org. Lett. 1999, 1, 1399;
(c) Ramachandran, P. V.; Jennings, M. P. Org. Lett. 2001, 3, 3789.
5. For fluoroorganic synthesis via allylboration, see: (a) Kumar, D.; Madhavan, S.;
Ramachandran, P. V.; Brown, H. C. Tetrahedron: Asymmetry 2000, 22, 4629; (b)
Ramachandran, P. V.; Padiya, K. J.; Rauniyar, V.; Reddy, M. V. R.; Brown, H. C. J.
Fluorine Chem. 2004, 125, 615; (c) Ramachandran, P. V.; Padiya, K. J.; Reddy, M.
V. R.; Brown, H. C. J. Fluorine Chem. 2004, 125, 579.
6. For difluoroallylborations, see: (a) Ramachandran, P. V.; Tafelska-Kaczmarek,
A.; Sakavuyi, K.; Chatterjee, A. Org. Lett. 2011, 13, 1302; (b) Ramachandran, P.
V.; Chatterjee, A. J. Fluorine Chem. 2009, 130, 144; (c) Ramachandran, P. V.;
Chatterjee, A. Org. Lett. 2008, 10, 1195.
7. For fluoroorganic synthesis via reduction, see: (a) Ramachandran, P. V.;
Teodorovic´, A. V.; Brown, H. C. Tetrahedron 1993, 49, 1725; (b)
Ramachandran, P. V.; Teodorovic´, A. V.; Brown, H. C. Tetrahedron: Asymmetry
1994, 5, 1075; (c) Ramachandran, P. V.; Gong, B.; Brown, H. C. J. Org. Chem.
1995, 60, 41.
8. For fluoroorganic synthesis via homologation, see: Ramachandran, P. V.;
Jennings, M. P. J. Fluorine Chem. 2007, 28, 827.
9. Ramachandran, P. V.; Parthasarathy, G.; Gagare, P. Org. Lett. 2010, 12, 4474.
10. Ramachandran, P. V.; Pratihar, D. Org. Lett. 2009, 11, 1467.
11. (a) Abiko, A.; Liu, J.-F. J. Org. Chem. 1996, 61, 2590; (b) Abiko, A. Acc. Chem. Res.
2004, 37, 387.
1. (-)-(Ipc)2BOTf, Et3N
-78 oC, 1.5 h
CF3
O
O
O
CH2Cl2
O
R
CF3 2. RCHO ( ), -78 oC, 8 h
2
O
O
OH
10d
11
RCHO
Aldol
2
R
11a
Yieldb (%)
anti:sync
% de of antic
1
2
3
4
5
6
7
8
9
10
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
11ad
11bd
11cd
11dd
11ed
11fd
11gd
11hd
11id
11jd
65
77
65
73
64
63
71
72
68
85
P99:61
P99:61
P99:61
P99:61
P99:61
P99:61
P99:61
P99:61
P99:61
P99:61
90
88
80
88
86
80
86
80
82
96
p-F–C6H4
p-NO2–C6H4
p-MeO–C6H4
E-PhCH@CH
i-Pr
Chx
PhCH2
2-Thiophene
TBSOCH2CH2
2j
a
b
c
See footnote 14.
Isolated yield,%.
anti:syn ratios and
%
de of anti-isomer were determined by 19F NMR
spectroscopy.
12. For the asymmetric aldolization of 3,3,3-trifluoropropanimides via: Silyl
enolates, see: (a) Shimada, T.; Yoshioka, M.; Konno, T.; Ishihara, T. Org. Lett.
2006, 8, 1129. , and; titanium enolates , see: (b) Franck, X.; Seon-Meniel, B.;
Figadere, B. Angew. Chem., Int. Ed. 2006, 45, 5174.
CF3
1. NaBH4
2. TBSCl, Im
TBSO
Ph
11ed
13. The trifluoropropionates were prepared as described in ref. 9 and in Komata, T.;
Akiba, S.; Hosoi, K.; Ogura, K. J. Fluorine Chem. 2008, 129, 35.
14. The first letter of the product aldol number refers to the aldehyde and the
second letter refers to the ester.
15. Pinheiro, S.; Gonçalves, C. B. S. S.; de Lima, M. B.; de Farias, F. M. C. Tetrahedron:
Asymmetry 2000, 11, 3495.
16. For the optical rotations of 9a–e, see Supplementary data.
17. For the optical rotation 10a–e, see Supplementary data.
18. Optimal ee was achieved by using 3.5 equiv. of reagent 1. The yield and ee
decreases by 5–8% when 2.5 equiv of the reagent is used.
3. NaH, CH3I
OMe
12
CF3
1. O3, MeOH
2. NaBH4
HO
OH
OMe
3. TBAF
13
[α]20D + 6.8° (c 0.9 CHCl3)
Scheme 3. Determination of absolute stereochemistry.
19. Konno, T.; Umetani, H.; Kitazume, T. J. Org. Chem. 1997, 62, 137.
20. Observed rotation for (2R, 3R)-13: ½a 2D0 +6.8° (c = 0.9, CHCl3); Lit.17 rotation for
ꢂ
(2S, 3S): ½a 2D0
-6.4° (c = 1.1, CHCl3).
ꢂ
21. Following is a representative procedure for the preparation of 9d.
Preparation of 8d: A solution of (1R,2R,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]-
heptane-2,3-diol (7) (12.76 g, 75 mmol), 1-naphthaldehyde (11.7 g, 75 mmol)
and catalytic pyridinium p-toluenesulfonate (0.1 g, 0.4 mmol) in toluene
(100 mL) was refluxed for 5 h in a 250 mL round-bottom flask connected to a
Dean Stark apparatus. Toluene was removed in vaccuo to obtain 24 g of the
crude acetal 8d, which was used without further purification for the reduction
with DIBAL-H.
and methylation of the secondary hydroxyl to 12. Ozonolysis,
reduction, and TBS-cleavage afforded the known diol 13 (Scheme
3).19 Comparison of the PMR spectrum of the diol, confirmed the
relative stereochemistry and the optical rotation20 revealed the
configuration to be 2R, 3R.
In conclusion, we have herein reported the synthesis21 and the
development of 2-(arylmethoxy)isopinocampheols as novel chiral
auxiliaries for the double asymmetric aldol reaction22 of 3,3,3-triflu-
oropropionates with diisopinocampheylboron triflates. The syner-
gistic combination of (ꢀ)-2-(1-naphthylmethoxy)isopinocampheyl
esters and the (ꢀ)-isomer of the boron triflate provided P99%
anti-selectivity and 80–96% de for the aldols. We believe that this
Preparation of 9d: DIBAL-H (3.7 g, 26.1 mmol) was added, dropwise, to
a
solution of acetal 8d (2.3 g, 7.4 mmol) in CH2Cl2 (100 mL) at ꢀ78 °C. The
reaction mixture was slowly warmed to room temperature, stirred for 24 h and
the excess DIBAL-H was quenched with dropwise addition of 3 M aq NaOH
solution until hydrogen evolution ceased. Dichloromethane (100 mL) was
added to the resulting thick mass and stirred for 30 min. The reaction mixture
was filtered through celite, concentrated and purified by silica coulmn
chromatography to obtain 2.17 g (95%) of the pure alcohol 9d. 1H NMR
(300 MHz, CDCl3) d 8.03 (d, J = 7.6 Hz, 1H), 7.90–7.77 (m, 2H), 7.58–7.39 (m,
4H), 4.96 (d, J = 10.9 Hz, 1H), 4.64 (d, J = 10.9 Hz, 1H), 4.19–4.06 (m, 1H), 3.54
(d, J = 8.3 Hz, 1H), 2.55–2.35 (m, 2H), 2.30–2.17 (m, 1H), 2.01–1.90 (m, 1H),
1.66 (ddd, J = 13.8, 6.3, 2.0 Hz, 1H), 1.56–1.49 (m, 1H), 1.52 (s, 3H), 1.36 (s, 3H),
1.03 (s, 3H); 13C NMR (75 MHz, CDCl3) d 134.2, 133.6, 131.6, 128.6, 128.32 (s),
126.19 (s), 125.97 (s), 125.67 (s), 125.31 (s), 123.55 (s), 78.16 (s), 70.33 (s),
61.32 (s), 50.75 (s), 40.46 (s), 38.55 (s), 28.62 (s), 28.29 (s), 23.96 (s), 23.61 (s);
HRMS (ESI) calcd for C21H26O2Na+ 333.1830, found. 333.1832.
new protocol will find applications for the introduction of a-hydro-
xy-b-trifluoromethyl moieties in organic molecules.
Acknowledgment
Financial support from the Herbert C. Brown Center for Borane
Research is gratefully acknowledged.
22. Following is a representative procedure for the enolboration–aldolization of
10d.
Preparation of 10d: DCC (2.88 g, 14 mmol) and DMAP (0.37 g, 3 mmol) were
added to a solution of alcohol (9d) (3.1 g, 10 mmol) in CH2Cl2 (50 mL) at 0 °C,
followed by the dropwise addition of 3,3,3-trifluoromethylpropionic acid
(1.66 g, 13 mmol). The reaction mixture was warmed to room temperature and
stirred for 12 h, diluted with CH2Cl2, washed with sat. aqueous NaHCO3
solution, dried over anhyd. Na2SO4, and the solvent was evaporated in vacuo.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.08.034.

5362
P. Veeraraghavan Ramachandran et al. / Tetrahedron Letters 52 (2011) 5359–5362
The crude product was purified by silica coulmn chromatography to obtain
same temperature for 8 h. The reaction was quenched by the addition of pH 7
buffer solution (2 mL). The mixture was diluted with MeOH (2 mL), followed
by the careful addition of 30% hydrogen peroxide (2 mL) and stirred vigorously
for 5–6 h. The reaction mixture was partitioned between water (4 mL) and
CH2Cl2 (15 mL). The aqueous layer was extracted with CH2Cl2 and the
combined organics were washed with brine (5 mL), dried (anhydrous
Na2SO4), filtered, concentrated, and purified by silica gel chromatography to
obtain 160 mg (65%) of the pure anti-aldol 11ad. 1H NMR (300 MHz, CDCl3) d
8.07–8.02 (m, 1H), 7.90–7.87 (m, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.6–7.49 (m, 3H),
7.48–7.42 (m, 1H), 7.19–7.05 (m, 3H), 7.01–6.90 (m, 2H), 5.35 (dd, J = 9.5,
6.3 Hz, 1H), 4.87 (d, J = 11.4 Hz, 1H), 4.82–4.76 (m, 1H), 4.72 (d, J = 11.4 Hz, 1H),
3.52–3.42 (m, 1H), 3.42 (d, J = 8.0 Hz, 1H), 2.50–2.40 (m, 1H), 2.39 (t, J = 5.7 Hz,
1H), 2.35–2.22 (m, 1H), 2.02–1.93 (m, 1H), 1.68 (d, J = 10.0 Hz, 1H), 1.59 (ddd,
J = 13.8, 6.3, 2.2 Hz, 1H), 1.51 (s, 3H), 1.36 (s, 3H), 1.06 (s, 3H); 19F NMR
(282 MHz, CDCl3) d ꢀ65.87 (d, J = 8.5 Hz); 13C NMR (75 MHz, CDCl3) d 165.92,
140.20, 134.29, 133.61, 131.50, 128.69, 128.22, 127.87, 126.24, 125.99, 125.82,
125.58, 123.76 (q, J = 279.8 Hz), 125.48, 123.55, 78.86, 74.40, 70.25, 70.23,
61.73, 56.75 (q, J = 22.5 Hz), 51.92, 40.05, 38.51, 34.05, 28.38, 28.15, 24.23,
3.98 g (95%) of the pure ester 10d. 1H NMR (300 MHz, CDCl3) d 8.04–7.98 (m,
1H), 7.86 (dd, J = 6.4, 3.0 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.55–7.40 (m, 4H),
5.35 (dd, J = 9.7, 5.3 Hz, 1H), 4.88 (d, J = 11.1 Hz, 1H), 4.63 (d, J = 11.1 Hz, 1H),
3.02–2.69 (m, 2H), 2.51–2.36 (m, 2H), 2.32–2.20 (m, 1H), 2.07–1.96 (m, 1H),
1.86 (ddd, J = 14.0, 5.3, 2.6 Hz, 1H), 1.67–1.53 (m, 1H), 1.61 (s, 3H), 1.38 (s, 3H),
1.06 (s, 3H); 13C NMR (100 MHz, CDCl3) d 164.4, 134.9, 133.6, 131.5, 128.5,
127.9, 125.8, 125.6, 125.4, 123.4 (q, J = 275 Hz), 123.7, 78.2, 73.7, 61.4, 51.1,
39.9, 39.2 (q, J = 30.7 Hz), 38.4, 33.9, 28.1, 27.2, 24.6, 24.1; 19F NMR (282 MHz,
CDCl3) d ꢀ65.03 (t, J = 10.2 Hz); HRMS (ESI) calcd for C24H27F3O3Na+ 443.1810,
found 443.1813.
Enolboration–aldolization of 10d: Trifluoromethanesulfonic acid (TfOH,
0.146 mL, 1.64 mmol) was added dropwise at 0 °C to freshly prepared (ꢀ)-
Ipc2BH (450 mg, 1.57 mmol) suspended in CH2Cl2 (3.5 mL) and stirred for 1 h.
The clear, yellowish red solution of Ipc2BOTf [(ꢀ)-1] was cooled to -78 °C, and
triethylamine (0.279 mL, 2.01 mmol) was added dropwise, followed by the
dropwise
ylmethoxy)bicyclo[3.1.1]heptan-3-yl
addition
of
(1R,2R,3S,5R)-2,6,6-trimethyl-2-(1-naphth-
3,3,3-trifluoropropanoate (190 mg,
0.45 mmol) in CH2Cl2 (1 mL). The resulting solution was stirred at ꢀ78 °C for
1.5 h. Benzaldehyde (71 mg, 0.67 mmol) in CH2Cl2 (1 mL) (pre-cooled to -
78 °C) was added dropwise to the above enolate solution and stirred at the
24.17; ½a 2D4
ꢂ
+20.3 (c 0.61, CHCl3); HRMS (ESI) calcd for C31H33F3O4Na 549.2229,
found 549.2226.