An enantiodivergent formal synthesis of paecilomycine A

Article abstract of DOI:10.1016/j.tetlet.2011.12.015

A concise, enantiodivergent formal synthesis of (+)-paecilomycine A and its antipode, involving a 1,4-chirality transfer protocol and an intramolecular Pauson-Khand reaction as the key steps is outlined.

Full text of DOI:10.1016/j.tetlet.2011.12.015

Tetrahedron Letters 53 (2012) 829–832
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An enantiodivergent formal synthesis of paecilomycine A
Goverdhan Mehta a, , Ramesh Samineni a,b, Pabbaraja Srihari b,
⇑
⇑
a School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
b Division of Natural Products Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise, enantiodivergent formal synthesis of (+)-paecilomycine A and its antipode, involving a 1,4-chi-
rality transfer protocol and an intramolecular Pauson–Khand reaction as the key steps is outlined.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 21 November 2011
Revised 1 December 2011
Accepted 4 December 2011
Available online 8 December 2011
Keywords:
1,4-Chirality transfer protocol
Stereoselective Luche reduction
TBS migration
Intramolecular Pauson–Khand reaction
1
O
11
Trichothecenes, based on a tetracyclic sesquiterpenoid frame-
work 1, are a large and diverse family of mycotoxins produced
by various fungal species and are considered important from hu-
man health consideration as they are produced on many edible
grains like wheat, oats, and maize.1 Many functional variations
on the framework 1 are known and verrucarol 2 is a prototype of
this family.2 Over the years, several biosynthetically mediated
structural siblings of trichothecenes like trichotriol 3,3 sambucoin
4,4 and spirotenuipesine A 55 bearing novel skeletons and diverse
bioactivities have been reported. In 2004, a research group led by
Ohima isolated6 a rare class of rearranged tricothecane sesquiterp-
enoids paecilomycine A–C 6–8 from Paecilomyces tenuipes (Isaria
japonica), a common entomopathogenic fungus described in folk
medicine and forming part of health foods in East Asia. The struc-
tures of paecilomycine A–C (6–8) were elucidated on the basis of
extensive 2D NMR analyses and their absolute configuration was
determined by MPA ester protocol.6 Like some of the trichothec-
enes, paecilomycines 6–8 are also bioactive and (+)-paecilomycine
A 6 in particular has been shown to exhibit a novel bioactivity pro-
file by promoting neurite outgrowth in rat pheochromocytoma
(PC-12) cells at 10 nm concentration.6 Indeed, it has been shown
that (+)-6 biosynthesized and released neurotrophic factors that
promoted neuronal differentiation of PC-12 cells and its potency
was estimated to be 1000 times higher than that of another prom-
ising natural product scabronine G,7 thereby marking paecilomy-
cine A 6 as a promising lead toward developing drugs against
neurodegenerative disorders.
H
10
16
O
9
2
3
8
6
12
13
4
O
5
7
15
HO
1
14
OH
verrucarol 2
H
O
O
O
OH
OH
OH
HO
OH
O
O
HO
sambucoin 4
spirotenuipesine A 5
trichotriol 3
H
H
10
9
10
O
O
13 OH
12
16
16
9
13
11
11
6
14
14
OH
8
6
12
8
7
7
R
5
2
5
2
O
4
15
15
4
OH
3
3
O
O
paecilomycine A 6 : R = H
paecilomycine B 7 : R = OH
paecilomycine C 8
The interesting structural attributes of 6–8 and the exceptional
bioactivity of paecilomycine A 6 mark them as attractive targets
for total synthesis and diversity creation. The first total synthesis
of racemic paecilomycine A 6 was accomplished in 2007 by
⇑
Corresponding authors. Tel.: +91 4023010785; fax: +91 4023012460 (G.M.).
E-mail addresses: gmsc@uohyd.ernet.in, gm@orgchem.iisc.ernet.in (G. Mehta),
srihari@iict.res.in (P. Srihari).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.015

830
G. Mehta et al. / Tetrahedron Letters 53 (2012) 829–832
Danishefsky et al.8 As a part of our group’s9 continuing interest and
engagement with the synthesis of neurotrophically active natural
products, we were drawn to paecilomycine natural products and
in a recent Letter10 delineated a concise approach to assemble their
tricyclic framework, albeit in racemic form, employing an intramo-
lecular Pauson–Khand reaction11 as the pivotal step. These studies
impelled us to develop an enantioselective approach to the paecil-
omycine framework and these endeavors have initially led to a for-
mal enantiodivergent synthesis of paecilomycine A 6 which can in
principle provide an access to the natural enantiomer as well as its
antipode. These efforts are outlined in this Letter.
selective with moderate stereoselectivity attributable to 1,4-ste-
reo-induction by the remote secondary methyl group. Relative
stereochemistry at the newly established quaternary carbon center
in 10a and 10b, though predictable on steric considerations, was
secured through stereoselective carbonyl reduction in 10a under
Luche conditions,14 engendered by the 1,3-stereoinduction by the
methyl group, to furnish the diol 11 through concomitant TBS
deprotection. Derivatization of 11 to a crystalline bis-3,5-dib-
romobenzoate 12 and single crystal X-ray structure determina-
tion15 fully secured its formulation (Fig., Scheme 1). Having
established a new chiral quaternary center in 10a and 10b through
chiral induction by the distal methyl group of chiron (R)-9, we pro-
ceeded to erase its original foot print enroute our objective. Toward
this end, both the cyclohexanone diastereomers 10a and 10b were
Our enantioselective approach to paecilomycine natural prod-
ucts emanated from the commercially available (R)-3-methylcy-
clohexanone (99% ee, Aldrich) 9.12
A
sequential one pot
a
-carbomethoxylation with ethyl cyanoformate and hydroxyme-
now individually converted to the corresponding a,b-unsaturated
thylation at ambient temperature with aqueous formaldehyde on
chiron 9 was followed by the TBS protection of the resultant hydro-
xyl group to furnish a readily separable diastereomeric mixture of
10a and 10b in 7:3 ratio, Scheme 1.13 The stereochemical outcome
of the hydroxymethylation could be substantially modulated in fa-
vor of the desired isomer 10a (9:1) when the formaldehyde quench
was carried out at lower temperature (ꢀ78 °C). While the temper-
ature mediated diastereoselection leading to 10a was a welcome
outcome in the context of achieving enantioselective access to
the natural paecilomycine A series, we persisted in the present
study with the conditions that delivered the 7:3 ratio as the intent
was to focus on enantiodivergent access to the paecilomycine
framework. Gratifyingly, the formation of 10a and 10b was regio-
cyclohexenones following the Saegusa protocol16 involving silyl-
enol ether formation and Pd-mediated dehydrosilylation to furnish
enantiomeric enones (+)-1313 and (ꢀ)-13, respectively, Scheme 2.
Enones (+)-13 and (ꢀ)-13 were found to be enantiomerically pure
(>99% ee) by chiral HPLC,17 (Scheme 2). Among the enantiomers
(+)-13 and (ꢀ)-13, the former had the absolute configuration (at
C6) corresponding to the natural paecilomycines.6
Enone (+)-13 was stereoselectively reduced under Luche condi-
tions14 to furnish allylic alcohol (+)-1413 with the bulky –OTBS pro-
tecting group directing the hydride from the opposite b-face. The
resulting allylic hydroxyl group in (+)-14 was protected as an allyl
ether (+)-15 using allylbromide under carefully calibrated condi-
tions to minimize the formation of a frequently encountered
byproduct (<20%) in which TBS and allyl groups have swapped
positions.8,10 The ester moiety in (+)-15 was reduced with DIBAL
and the resulting primary alcohol was oxidized with IBX to furnish
aldehyde 16. Aldehyde 16 was smoothly elaborated to enyne (+)-
17 using Ohira–Bestmann reagent 18.18 The stage was now set
for the key intramolecular Pauson–Khand reaction and exposure
of (+)-17 to Co2(CO)8 furnished the tricyclic enone (ꢀ)-18 as a sin-
gle diastereomer in moderate yield, Scheme 3. Chiral (ꢀ)-18, so ob-
tained, was found to be spectroscopically identical13 with the
racemic 18 reported by Danishefsky et al.8 Since, racemic 18 has
been converted to paecilomycine A 6 during its first synthesis,8
our preparation of chiral (ꢀ)-18 constitutes a formal enantioselec-
tive synthesis of the natural product.
O
O
O
a, b
+
CO2Et
CO2Et
TBSO
10b
TBSO
10a
9
Br
c, d
O
Br
OH
e
O
Having accessed the advanced precursor (ꢀ)-18 of (+)-paecil-
omycine A in the natural series, it was of interest to pursue the
same objective in the antipodal series. Availability (Scheme 1) of
enantiomerically pure (ꢀ)-13 paved the way toward such an enter-
prise. Thus, stereoselective reduction of (ꢀ)-13 to the allylic alco-
hol (ꢀ)-14, protection as the O-allylether (ꢀ)-15, and elaboration
of the ester moiety to aldehyde ent-16 were accomplished rou-
tinely, Scheme 4. Execution of the Ohira–Bestmann reaction18 led
to the enyne (ꢀ)-17, the key precursor for the intramolecular Pau-
son–Khand reaction. Exposure of (ꢀ)-17 to Co2(CO)8 led to the
CO2Et
CO2Et
O
Br
HO
11
O
Br
O
O
a, b
CO2Et
CO2Et
TBSO
TBSO
(+)-13
10a
O
O
a, b
Fig: ORTEP of 12 with 30% probability
CO2Et
CO2Et
TBSO
TBSO
(-)-13
Scheme 1. Reagents and conditions: (a) CNCO2Et, LiHMDS, THF, ꢀ78 °C to rt, 2 h,
followed by aq HCHO (37–41% w/v), KHCO3, 2 h, 78%; (b) TBSCl, imidazole, CH2Cl2,
3 h, 92%; (c) NaBH4, CeCl3ꢁ7H2O, MeOH, 15 min, 87%; (d) TBAF, THF, 1 h, 92%;
(e) 3,5-dibromobenzoic acid, DCC, DMAP, CH2Cl2, 0 °C to rt, 8 h, 85%.
10b
Scheme 2. Reagents and conditions: (a) TMSCl, LiHMDS, THF, ꢀ78 °C to rt, 1 h;
(b) Pd(OAc)2, O2, DMSO, 55 °C, 72 h, 87% (br sm).

G. Mehta et al. / Tetrahedron Letters 53 (2012) 829–832
831
paecilomycine framework augurs well for exploring the therapeu-
tic potential of their novel scaffold.
H
H
O
O
OH
b
a
CO2Et
CO2Et
(+)-13
Acknowledgments
CO2Et
TBSO
c
TBSO
TBSO
(+)-15
(+)-14
This research was carried out under the Indo-French joint labo-
ratory for sustainable chemistry. R.S. thanks the CSIR for the award
of a Research fellowship. G.M. wishes to thank Eli Lilly and the
Jubilant Bhartia Foundations for the research support and the Gov-
ernment of India for the award of National Research Professorship.
We acknowledge the help of Dr. Balasubramanian Sridhar in solv-
ing the X-ray crystal structures at the CCD facility of the Indian
Institute of Chemical Technology, Hyderabad.
H
H
O
O
d
O
O
CHO
OMe
OMe
P
TBSO
TBSO
(+) 17
16
N2
References and notes
e
1. (a) Grove, J. F. Nat. Prod. Rep. 1988, 5, 187–209; (b) Grove, J. F. Nat. Prod. Rep.
1993, 10, 429–448; (c) Jarvis, B. B.; Stahly, G. P.; Pavanasasivam, G.; Midiwo, J.
O.; DeSilva, T.; Holmlund, C. E.; Mazolla, E. P.; Geoghegan, R. F., Jr. J. Org. Chem.
1982, 47, 1117–1124; (d) Jarvis, B. B.; Vrudhula, V. M.; Midiwo, J. O.; Mazzola,
E. P. J. Org. Chem. 1983, 48, 2576–2578; (e) Corley, D. G.; Rottinghaus, G. E.;
Tempesta, M. S. Tetrahedron Lett. 1986, 27, 427–430; (f) Mohr, P.; Tamm, C.;
Zucher, W.; Zehnder, M. Helv. Chim. Acta 1984, 67, 406–412.
H
O
H
O
OH
OH
ref 8
H
O
TBSO
O
2. Gutzwiller, J.; Mauli, R.; Sigg, H. P.; Tamm, C. Helv. Chim. Acta 1964, 47, 2234–
2262.
(-) 18
6
3. Corley, D. G.; Rottinghaus, G. E.; Tempesta, M. S. J. Org. Chem. 1987, 52, 4405–
4408.
4. Fort, D. M.; Barnes, C. L.; Tempesta, M. S. J. Nat. Prod. 1993, 56, 1890–1897.
5. Kikuchi, H.; Miyagawa, Y.; Sahashi, Y.; Inatomi, S.; Haganuma, A.; Nakahata, N.;
Oshima, Y. J. Org. Chem. 2004, 69, 352–356.
Scheme 3. Reagents and conditions: (a) NaBH4, CeCl3ꢁ7H2O, MeOH, 15 min, 86%;
(b) allylbromide, NaH, HMPA, TBAI, ꢀ15 °C, 3 h, 89%; (c) (i) DIBAL-H, CH2Cl2, 0 °C,
1 h, quant; (ii) IBX, THF/DMSO (5:1), 87% (crude); (d) K2CO3, MeOH, 6 h, 81%;
(e) Co2(CO)8, 4 Å ms, toluene, reflux, 24 h, 34%.
6. Kikuchi, H.; Miyagawa, Y.; Sahashi, Y.; Inatomi, S.; Haganuma, A.; Nakahata, N.;
Oshima, Y. Tetrahedron Lett. 2004, 45, 6225–6228.
7. (a) Kita, T.; Takaya, Y.; Oshima, Y.; Ohta, T.; Aizawa, K.; Hirano, T.; Inakuma, T.
Tetrahedron 1998, 54, 11877–11886; (b) Obara, Y.; Kobayashi, H.; Ohta, T.;
Ohizumi, Y.; Nakahata, N. Mol. Pharmacol. 2001, 59, 1287–1297.
H
H
O
OH
O
b
a
8. Min, S.-J.; Danishefsky, S.-J. Angew. Chem., Int. Ed. 2007, 46, 2199–2202.
9. For related work from our group, see: (a) Mehta, G.; Singh, R. Tetrahedron Lett.
2005, 46, 2079–2082; (b) Mehta, G.; Singh, R. Angew. Chem., Int. Ed. 2006, 45,
953–955; (c) Mehta, G.; Shinde, H. M. Tetrahedron Lett. 2007, 48, 8297–8300; (d)
Mehta, G.; Maity, P. Tetrahedron Lett. 2007, 48, 8865–8868; (e) Mehta, G.; Bhat,
B. A. Tetrahedron Lett. 2009, 50, 2474–2477; (f) Mehta, G.; Maity, P. Tetrahedron
Lett. 2011, 52, 1749–1752; (g) Mehta, G.; Maity, P. Tetrahedron Lett. 2011, 52,
1753–1756; (h) Mehta, G.; Maity, P. Tetrahedron Lett. 2011, 52, 5161–5165.
10. Mehta, G.; Samineni, R.; Srihari, P. Tetrahedron Lett. 2011, 52, 1663–1666.
11. For some reviews on Pauson–Khand reactions see: (a) Brummnod, K. M.; Kent,
J. L. Tetrahedron 2000, 56, 3263–3283; (b) Gibson, S. E.; Stevenazzi, A. Angew.
Chem., Int. Ed. 2003, 42, 1800–1810.
CO2Et
(-)-13
CO2Et
CO2Et
TBSO
TBSO
TBSO
(-)-15
(-)-14
c
H
H
O
O
d
O
O
P
OMe
OMe
CHO
12. Preparation of (9): (a) Adams, R.; Smith, C. M.; Loewe, S. J. Am. Chem. Soc. 1942,
2087–2089; (b) Djerassi, C.; Krakower, G. W. J. Am. Chem. Soc. 1958, 237–242.
13. All new compounds were characterized on the basis of their spectroscopic data
(IR, 1H, 13C, mass, HRMS). Spectral data for some of the key compounds are as
TBSO
TBSO
(-)-17
ent-16
N2
e
follows: 10a: ½a D20
ꢂ
+64.80 (c 1.65, CHCl3); IR (neat): 2953, 2861, 1714, 1648,
1519, 1461, 1252, 1098, 839, 778. 1H NMR (500 MHz, CDCl3) d: 4.13 (q,
J = 7.0 Hz, 2H), 4.02 (d, J = 10.0 Hz, 1H), 3.64 (d, J = 10.0 Hz, 1H), 2.59–2.57 (m,
1H), 2.31 (d, J = 13.0 Hz, 1H), 2.03 (t, J = 13.0 Hz, 1H), 1.80–1.71 (m, 2H), 1.51–
1.40 (m, 2H), 1.20 (t, J = 7.0 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H), 0.80 (s, 9H), ꢀ0.02
(s, 3H), ꢀ0.03 (s, 3H). 13C NMR (75 MHz, CDCl3) d: 206.4, 169.8, 66.0, 61.6, 61.1,
49.3, 35.0, 32.5, 30.8, 25.6 (3C), 22.2, 18.0, 14.0, ꢀ5.8 (2C). MS (ESI) m/z 351
(M+Na)+; HRMS (ESI) m/z calcd for C17H32O4SiNa (M+Na)+ = 351.1967, found
H
H
O
O
ref 8
H
O
OH
OH
TBSO
351.1954. Compound 10b: ½a D20
ꢀ11.0 (c 0.60, CHCl3); IR (neat): 2932, 1712,
ꢂ
1518, 1462, 1249, 1102, 839, 778. 1H NMR (500 MHz, CDCl3) d: 4.19–4.13 (m,
2H), 4.00 (d, J = 10.0 Hz, 1H), 3.82 (d, J = 10.0 Hz, 1H), 2.52 (dd, J = 13.5, 5.0 Hz,
1H), 2.39–2.35 (m, 1H), 2.21 (br s, 1H), 2.10 (dd, J = 14.0, 5.5 Hz, 1H), 1.98–1.91
(m, 2H), 1.54–1.49 (m, 1H), 1.23 (t, J = 8.0 Hz, 3H), 0.95 (d, J = 7.0 Hz, 3H), 0.84
(s, 9H), 0.03 (s, 3H), 0.02 (s, 3H). 13C NMR (75 MHz, CDCl3) d: 207.1, 170.5, 65.1,
62.6, 61.1, 47.8, 32.2, 28.7, 28.3, 25.6 (3C), 19.8, 18.1, 14.0, ꢀ5.7, ꢀ5.8. MS (ESI)
m/z 351 (M+Na)+; HRMS (ESI) m/z calcd for C17H32O4SiNa (M+Na)+ = 351.1967,
O
(+)-18
ent-
6
Scheme 4. Reagents and conditions: (a) NaBH4, CeCl3ꢁ7H2O, MeOH, 15 min, 82%;
(b) allylbromide, NaH, HMPA, TBAI, ꢀ15 °C, 3 h, 85%; (c) (i) DIBAL-H, CH2Cl2, 0 °C,
1 h, quant; (ii) IBX, THF/DMSO (5:1), 84% (crude); (d) K2CO3, MeOH, 6 h, 79%; (e)
Co2(CO)8, 4 Å ms, toluene, reflux, 24 h, 32%.
found 351.1953. Compound (+)-13: ½a D20
ꢂ
+27.7 (c 1.0, CHCl3); IR (neat): 2950,
2890, 2863, 2361, 1737, 1682, 1519, 1250, 1110, 842. 1H NMR (300 MHz,
CDCl3) d: 5.83 (s, 1H), 4.12 (q, J = 7.0 Hz, 2H), 4.03 (d, J = 9.6 Hz, 1H), 3.84 (d,
J = 9.6 Hz, 1H), 2.62–2.44 (m, 2H), 2.29–2.19 (m, 1H), 2.15–2.04 (m, 1H), 1.94
(s, 3H), 1.22 (t, J = 7.0 Hz, 3H), 0.84 (s, 9H), 0.02 (s, 6H). 13C NMR (75 MHz,
CDCl3) d: 193.6, 169.7, 161.8, 126.1, 65.3, 61.0, 57.9, 28.6, 27.9, 25.9 (3C), 24.3,
18.3, 14.2, ꢀ5.5 (2C). MS (ESI) m/z 349 (M+Na)+; HRMS (ESI) m/z calcd for
tricyclic (+)-18, spectroscopically identical with the enantiomer
(ꢀ)-18 described above and the racemic 18 reported by Danishef-
sky.8 Thus, arrival at (+)-18 can be construed as a formal synthesis
of ent-paecilomycine A 6.
In conclusion, we have outlined a concise, enantiodivergent
strategy that leads to the formal synthesis of (+)-paecilomycine
A and its antipode from a single, commercial chiral pool precur-
sor. Considering the important connect between chirality and bio-
activity profile, access to both the enantiomeric series related to
C
17H30O4SiNa (M+Na)+ = 349.1806, found 349.1813. Compound (ꢀ)-13: ½a 2D0
ꢂ
ꢀ31.7 (c 1.0, CHCl3); (+)-14: ½a D20
ꢂ
+51.36 (c 0.88, CHCl3); IR (neat): 2930, 2857,
1726, 1516, 1464, 1249, 1096, 840, 777. 1H NMR (300 MHz, CDCl3) d: 5.48 (br
d, J = 2.1 Hz, 1H), 4.48 (br d, J = 2.1 Hz, 1H), 4.11 (q, J = 7.2 Hz, 2H), 3.88 (d,
J = 10.0 Hz, 1H), 3.72 (d, J = 10.0 Hz, 1H), 1.92 (t, J = 6.0 Hz, 2H), 1.85–1.69 (m,
2H), 1.67 (s, 3H), 1,24 (t, J = 7.2 Hz, 3H), 0.85 (s, 9H), 0.01 (s, 6H). 13C NMR
(75 MHz, CDCl3) d: 174.8, 137.4, 122.7, 67.0, 65.3, 60.5, 51.2, 27.3, 25.6 (3C),

832
G. Mehta et al. / Tetrahedron Letters 53 (2012) 829–832
23.5, 23.1, 18.0, 14.1, ꢀ5.7, ꢀ5.8. MS (ESI) m/z 351 (M+Na)+; HRMS (ESI) m/z
(M+Na)+ = 371.2018, found 371.2028. Compound (+)-18: ½a 2D0
ꢂ
+75.32 (c 0.16,
calcd for C17H32O4SiNa (M+Na)+ = 351.1967, found 351.1952. Compound (ꢀ)-
CHCl3).
14: ½a 2D0
ꢂ
ꢀ47.63 (c 1.0, CHCl3); (+)-15: ½a D20
ꢂ
+137.23 (c 1.0, CHCl3); IR (neat):
14. Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226–2227.
15. Single crystal X-ray diffraction data were collected on a Bruker AXS SMART
APEX CCD diffractometer at 294 K using graphite monochromated Mo K
2931, 2858, 2363, 1738, 1516, 1464, 1250, 1172, 1095, 842, 776. 1H NMR
(300 MHz, CDCl3) d: 5.87 (ddd, J = 16.0, 11.0, 6.0 Hz, 1H), 5.63 (br d, J = 3.0 Hz,
1H), 5.22 (dd, J = 17.0, 1.5 Hz, 1H), 5.10 (dd, J = 10.2, 1.2 Hz, 1H), 4.14–4.04 (m,
4H), 4.02–3.96 (m, 1H), 3.91 (d, J = 9.0 Hz, 1H), 3.60 (d, J = 9.0 Hz, 1H), 1.96–
1.91 (m, 2H), 1.83–1.76 (m, 1H), 1.73–1.69 (m, 1H), 1.67 (s, 3H), 1.22 (t,
J = 7.0 Hz, 3H), 0.85 (s, 9H), 0.01 (s, 6H). 13C NMR (75 MHz, CDCl3) d: 173.9,
138.1, 135.5, 121.0, 116.3, 71.8, 71.1, 65.9, 60.1, 52.0, 27.7, 25.7 (3C), 23.4, 23.1,
18.0, 14.1, ꢀ5.6, ꢀ5.8. MS (ESI) m/z 391 (M+Na)+; HRMS (ESI) m/z calcd for
a
radiation (k = 0.7107Å). The data were reduced by SAINTPLUS; the crystal
structures were solved by direct methods using SHELXS97 and refined by full-
matrix least-squares method using SHELXL97. Crystal data for 3,5-
dibromobenzoate 12:
a = 9.3505(15), b = 14.166(2), c = 20.060(3) Å, V = 2657.2(7) Å3, Z = 4,
calcd = 1.850 mg mꢀ3, 23,303 reflections measured, 4669 unique, 3471 with
I > 2 (I). Full-matrix least-squares refinement led to a final R = 0.0519 and
C25H24Br4O6, M = 740.08, orthorhombic, P212121,
q
C
20H36O4SiNa (M+Na)+ = 391.2280, found 391.2281. Compound (ꢀ)15: ½a 2D0
ꢂ
r
ꢀ140.10 (c 1.0, CHCl3); (+)17: ½a D20
ꢂ
+132.30 (c 0.8, CHCl3); IR (neat): 3308,
wR = 0.0997 and GOF = 0.971. CCDC 844353.
2930, 2858, 1741, 1693, 1516, 1464, 1253, 1112, 841, 777, 633. 1H NMR
(300 MHz, CDCl3) d: 5.92 (ddd, J = 16.2, 10.5, 5.7 Hz, 1H), 5.57–5.56 (m, 1H),
5.25 (dd, J = 17.1, 1.5 Hz, 1H), 5.14 (d, J = 10.0 Hz, 1H), 4.21–4.10 (m, 2H), 3.85
(d, J = 4.8 Hz, 1H), 3.80 (d, J = 9.6 Hz, 1H), 3.54 (d, J = 9.0 Hz, 1H), 2.28–2.17 (m,
1H), 1.99 (s, 1H), 1.92 (br s, 1H), 1.77–1.68 (m, 1H), 1.72 (s, 3H), 1.48 (m, 1H),
0.92 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H). 13C NMR (75 MHz, CDCl3) d: 139.0, 135.6,
120.1, 116.4, 87.4, 74.6, 71.4, 69.2, 66.6, 41.4, 27.7, 25.9 (3C), 25.1, 23.5, 18.4,
ꢀ5.3 (2C). MS (ESI) m/z 343 (M+Na)+; HRMS (ESI) m/z calcd for C19H32O2SiNa
16. Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
17. Chiral HPLC: Column: chiral pak IC 250X4.6 mm, 5microns, mobile phase: 3%
IPA-HEXANE, flow rate: 1.0 ml/min.
Racemic 13
(+)-13
(-)-13
mV
mV
mV
400
300
200
100
0
300
250
200
150
100
50
250
200
150
100
50
(M+Na)+ = 343.2069, found 343.2076. Compound (ꢀ)-17: ½a 2D0
ꢀ134.14 (c 1.0,
ꢂ
CHCl3); (ꢀ)-18: ½a D20
ꢀ73.61 (c 0.16, CHCl3); IR (neat): 2927, 2856, 2364, 1741,
ꢂ
1707, 1647, 1516, 1463, 1094, 841. 1H NMR (300 MHz, CDCl3) d: 5.83 (br s, 1H),
5.28 (br s, 1H), 4.35 (dd, J = 10.0, 6.3 Hz, 1H), 3.96 (d, J = 10.5 Hz, 1H), 3.76 (d,
J = 10.5 Hz, 1H), 3.71 (br s, 1H), 3.31–3.26 (m, 1H), 3.18 (dd, J = 21, 10.8 Hz, 1H,
2.45 (dd, J = 18.6, 6.6 Hz, 1H), 2.27 (dd, J = 12.6, 5.7 Hz, 1H), 2.16–2.00 (m, 2H),
1.88 (dd, J = 18.3, 1.8 Hz, 1H), 1.70 (s, 3H), 1.66–1.51 (m, 1H), 0.82 (s, 9H), 0.01
(s, 3H), ꢀ0.03 (s, 3H). 13C NMR (75 MHz, CDCl3) d: 206.7, 186.0, 136.3, 126.5,
121.1, 81.4, 75.1, 60.6, 46.4, 38.6, 37.7, 27.6, 25.9 (3C), 24.5, 22.9, 18.3, ꢀ5.4
(2C). MS (ESI) m/z 371 (M+Na)+; HRMS (ESI) m/z calcd for C20H32O3SiNa
0
0
10.0 11.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0m
10.011.012.013.014.015.016.017.018.019.0 m
10.0 11.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 m
18. (a) Ohira, S. Synth. Commun. 1989, 19, 561–564; (b) Muller, S.; Liepold, B.; Roth,
G. J.; Bestmann, H. J. Synlett 1996, 521–552; (c) Seyferth, D.; Marmor, R. S.;
Hibert, P. J. Org. Chem. 1971, 36, 1379–1386; (d) Gilbert, J. C.; Weerasooriya, U.
J. Org. Chem. 1979, 44, 4997–4998.