Stereoselective synthesis of the C13-C28 subunit of (-)-laulimalide utilizing an α-chlorosulfide intermediate

Article abstract of DOI:10.1055/s-0033-1339493

A stereoselective route to the C13-C28 subunit of (-)-laulimalide is described. l-Tartaric acid is the source of the hydroxy groups at C19 and C20. An α-chlorosulfide is employed as the key intermediate for the creation of the C17-C18 bond and the C16-C17 double bond was introduced using the Mislow-Braverman rearrangement and Hutchin's dexoxygenation with concomitant double bond transposition reaction. The C15 and C23 stereogenic centers were created using catalytic asymmetric reactions. The trisubstituted and trans-disubstituted alkenes were created stereoselectively by taking advantage of ring-closing metathesis and the Julia-Kocienski olefination reaction, respectively. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1339493

LETTER
▌1983
lSettteer reoselective Synthesis of the C13–C28 Subunit of (–)-Laulimalide Utilizing
an α-Chlorosulfide Intermediate
Synthesis of the C13–C28 Subunit of (–)-Laulimalide
Sadagopan Raghavan,* Pradip Kumar Samanta
Division of Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: sraghavan@iict.res.in
Received: 03.06.2013; Accepted after revision: 09.07.2013
formation. The retrosynthetic analysis is depicted in
Abstract: A stereoselective route to the C13–C28 subunit of
Scheme 1. The subunits 3 (C3–C12 fragment) and 4
(–)-laulimalide is described. L-Tartaric acid is the source of the hy-
(C13–C28 subunit) were proposed to be united by addi-
tion of the anion from sulfone 3 to the aldehyde derived
droxy groups at C19 and C20. An α-chlorosulfide is employed as
the key intermediate for the creation of the C17–C18 bond and the
C16–C17 double bond was introduced using the Mislow–Braver- from silyl ether 4. Dihydropyran 4 constituting the C13–
man rearrangement and Hutchin’s dexoxygenation with concomi-
tant double bond transposition reaction. The C15 and C23
stereogenic centers were created using catalytic asymmetric reac-
Kocienski reaction.6 Aldehyde 6 can be traced to sulfide 7
tions. The trisubstituted and trans-disubstituted alkenes were creat-
ed stereoselectively by taking advantage of ring-closing metathesis
C28 subunit of laulimalide was envisaged to be obtained
from sulfone 5 and aldehyde 6 taking advantage of Julia–
and alkyne 8 by utilizing a methodology developed re-
cently exploiting α-chlorosulfides as reactive intermedi-
ates.7 Substrates 7 and 8 can be traced back to L-(+)-
tartaric acid and 1,3-propane diol, respectively. Sulfone 5
was envisaged to be obtained from aldehyde 28 utilizing
Keck methallylation and ring-closing-metathesis reac-
tions as key steps.
and the Julia–Kocienski olefination reaction, respectively.
Key words: laulimalide, α-chloro sulfide, Julia–Kocienski olefina-
tion, Mislow–Braverman rearrangement, ring-closing metathesis
Laulimalide (1; Figure 1) and isolaulimalide (2) were iso-
lated in 1988 by Crews et al. from Cacospongia mycofi-
jiensis,1a and at almost the same time by Moore and co-
workers from the marine sponge Hyatella sp.1b Both the
groups also isolated them from the nudibranch predator,
Chromodoris lochi that was feeding on the sponges.1a,b In
1996, Higa and co-workers isolated 1 and 2 along with
neolaulimalide from the sponge Fasciospongia rimosa1c,d
and recently Riccio isolated them from a sponge belong-
ing to the genus Dactylospongia.1e Laulimalide (1) inhib-
its the proliferation of several tumor cell lines with IC50
values in the nanomolar range (KB IC50 = 15 nM, MDA-
MB-435 IC50 = 6–7 nM, P388, A549, HT29, MEL28, IC50
= 10–50 nM). It also exhibits potent activity against cell
lines showing multidrug resistance. Laulimalide binds to
tubulin in a fashion similar to paclitaxel though the bind-
ing site is different.2,3 The structure of 1 was initially as-
signed by NMR analysis1a,b and later confirmed by X-ray
diffraction studies.1c Laulimalide is a 20-membered mac-
rolide wherein its C16–C17-epoxide is susceptible to nu-
cleophilic attack from the C20-hydroxyl group to form
isolaulimalide (2) and the 2,3-cis-enoate readily under-
goes Z/E-isomerization. Owing to its potential as an anti-
cancer lead, its restricted natural supply, and unique
structure, the total synthesis of 1 and the preparation of
analogues has attracted interest.4,5
OH
H
O
O
27 23
20
15
13
17
O
O
OH
H
H11
1
3
28
O
5
9
1
HO
OH
H
15
O
17
H
O
27 23
13
20
11
H
O
O
H
O
5
1
9
28
3
2
Figure 1 Tumor growth inhibitors laulimalide (1) and isolaulimalide
(2)
The synthesis of acetonide 7 began from L-(+)-tartaric
acid (9) that, upon reaction with 2,2-dimethoxypropane in
the presence of PTSA following literature precedent,8 fur-
nished acetonide 10. Reduction of the diester in 10 with
LiAlH4 yielded diol 11. Selective monoprotection of 11
using NaH and benzyl bromide yielded benzyl ether 12.
The sulfide 7 was obtained cleanly from 12 following
Hata’s protocol,9 using tri-n-butyl phosphine and diphe-
nyl disulfide (Scheme 2).
Herein, we describe the synthesis of the C13–C28 subunit
3 of laulimalide utilizing catalytic asymmetric reactions
and an α-chlorosulfide as key intermediate for C–C bond
The synthesis of propargyl ether 8 commenced with the
selective monoprotection of 1,3-propanediol (13) into si-
lyl ether 14. Oxidation using Swern conditions10 furnished
aldehyde 15 that, on reaction with trimethylsilylacetylene
SYNLETT 21709013, 2415, 1983–1987
Advanced online publication: 07.08.2013
DOI: 10.1055/s-0033-1339493; Art ID: ST-2013-D0512-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1984
S. Raghavan, P. K. Samanta
LETTER
sulfone anion
aldehyde addition
OH
H
O
O
O
O
TBSO
+
H
20
22
27
23
SO2Ph
12
15
17
13
O
3
H
H
O
O
OH
O
21
H
H 11
1
28
3
O
Julia–Kocienski
MOMO
13
9
5
OTBDPS
4
1
3
H
chlorosulfide
OTBDPS
22
18
O
N
N
SO2PT
27
O
+
PT =
N
O
O
N
OMOM
Keck methallylation
5
Ph
RCM
6
OMOM
O
O
13
OBn
PhS
23
25
O
TBDPSO
+
SnBu3
+
PMBO
17
18
21
28
7
Pu's protocol
8
Scheme 1 Retrosynthetic disconnection of (–)-laulimalide
OMe
OMe
OH
,
O
O
O
O
CO2H
LiAlH4, THF
HO2C
OH
HO
70 °C, 2 h, 89%
CO2Me
cat. PTSA, MeOH
70 °C, 12 h, 84%
MeO2C
OH
11
10
9
O
O
O
O
PhSSPh, Bu3P
THF, r.t., 16 h, 95%
NaH, BnBr
DMF, 2 h, 60%
OBn
HO
OBn
PhS
12
7
Scheme 2 Preparation of sulfide 7
(16) following the protocol of Lin Pu,11 yielded propar- with an excess of alkynylzinc bromide 21, obtained by se-
gylic alcohol 17 (92% ee)12 probably via chiral complex quential treatment of 8 with i-PrMgCl·LiCl and ZnBr2, to
18. Removal of TMS moiety in 17 proceeded cleanly on afford propargyl sulfide 22 diastereoselectively. Sulfide
treatment with K2CO3 in methanol to furnish propargyl al- 22 was proposed to be transformed into alkene 26 by tak-
cohol 19. Protection of the hydroxy group in 19 using ing advantage of the Mislow–Braverman rearrangement13
MOMCl under standard conditions yielded compound 8 and reductive deoxygenation (Scheme 4). Thus selective
(Scheme 3).
oxidation of 22 using mCPBA yielded an epimeric mix-
ture of sulfoxides 23 which was directly heated in toluene
in the presence of 2-mercapto-1-methylimidazole14 to fur-
The reaction of sulfide 7 with NCS in benzene7 furnished
chlorosulfide 20 which, without isolation, was reacted
OH
1. TBDPSCl, NaH, DMF
r.t., 12 h, 75%
16
H
TMS
H
Et2Zn, (R)-BINOL, Ti(Oi-Pr)4
OTBDPS
OH OP
2. (COCl)2, DMSO, Et3N
CH2Cl2, 15 min, 98%
O
OTBDPS
CH2Cl2, HMPA, r.t., 12 h
80%, 92% ee
TMS
17
13, P = H
14, P = TBDPS
15
OTBDPS
TMS
OP
1. K2CO3, MeOH
r.t., 1 h, 90%
2. MOMCl, DIPEA
CH2Cl2, r.t., 4 h, 85%
Zn
O
H
O
OTBDPS
Ti
O
O
19, P = H
8, P = MOM
O
chiral complex 18
Scheme 3 Preparation of alkyne 8
Synlett 2013, 24, 1983–1987
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of the C13–C28 Subunit of (–)-Laulimalide
1985
i-PrMgCl⋅LiCl, THF
–10 °C, 1 h
OMOM
OMOM
TBDPSO
TBDPSO
then ZnBr2, THF
–10 °C, 1 h
8
21
ZnBr
O
O
O
O
O
O
OMOM
21
TBDPSO
NCS, PhH
r.t., 15 min
OBn
PhS
OBn
PhS
OBn
r.t., 12 h, 83%
SPh
7
20
Cl
22
S
O
O
Me
OMOM
TBDPSO
TBDPSO
HN
N
OMOM
O
O
MCPBA, CHCl3
–45 °C, 15 min
OBn
OBn
SPh
toluene, 60 °C
2 h, 85%
O
O
23
24
1. o-NsNHNH2, AcOH
r.t., 1 h
2. NaCNBH3, 0 °C to r.t.
1 h, 87%
TBDPSO
OMOM
OMOM
O
O
O
O
TBDPSO
IBX [O]
O
OP
3. Li, C10H8, THF
–78 °C, 20 min, 70%
CH2Cl2, DMSO
r.t., 2 h, 85%
6
H
26, P = Bn
27, P = H
TBDPSO
OMOM
OH
O
O
o-NsNHNH2
NaBH4, CeCl3⋅6H2O
26
24
OBn
Ph3P, DEAD, THF
MeOH, –50 °C, 15 min
96%
–15 °C to r.t., 1 h, 20%
25
Scheme 4 Synthesis of alcohol 6
OPMB
SnBu3
Br
OH
O
O
Ti(Oi-Pr)4, (S)-BINOL, CH2Cl2
PMBO
PMBO
NaH, THF, 30 min, 94%
H
60 h, –20 °C, 86%
96% ee
28
30
29
Ph
Ph
N
N
N
N
N
N
OP
Ph
N
O
H
N
S
N
S
O
O
1. cat. 31, toluene
SH
H
N
O
O
110 °C, 6 h, 92%
22
34
(NH4)6Mo7O24, H2O2
0 °C, 18 h, 97%
N
N
27
2. DDQ, CH2Cl2/H2O
r.t., 1 h, 85%
Ph3P, DEAD, THF
0 °C to r.t., 20 min, 94%
5
35
32, P = PMB
33, P = H
Ph
N
N
N
O
P
N
S
H
O
H
O
1. DDQ, CH2Cl2/H2O
O
(NH4)6Mo7O24, H2O2
0 °C, 36 h, 75%
cat. 39, CH2Cl2, r.t.
r.t., 30 min, 85%
30
5
4 h, 85%
2. 34, Ph3P, DEAD, THF
0 °C, 30 min, 94%
38
36, P = OH
N
N
N
N
PCy3
Ru
S
37, P =
N
N
Cl Ph
Mes
Mes
Cl
Ph
Ru
Cl
Cl
Ph
PCy3
PCy3
cat. 31
cat. 39
Scheme 5 Preparation of sulfone 5
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1983–1987

1986
S. Raghavan, P. K. Samanta
LETTER
1. KHMDS, DMF, HMPA
–60 °C, 15 min, then add
–78 °C to r.t., 12 h, 75%
OMOM
O
O
N
6
N
H
H
13
O
27
O
N
OTBDPS
S
N
O
2. TBAF, AcOH, THF
r.t., 5 h, 87%
O
Ph
5
4
28
Scheme 6 Synthesis of C13–C28 fragment 4
nish α,β-unsaturated ketone 24. In the first approach, the
α,β-unsaturated ketone 24 was reduced diastereoselec-
tively utilizing the Luche protocol15 to furnish allyl alco-
hol 25 as the sole isomer. Since the newly created carbinol
centre was to be destroyed, the configuration was not es-
tablished. Attempted reductive deoxygenation with dou-
ble bond transposition using Myer’s protocol16 afforded
alkene 26, although in poor yield (20%). Therefore, in the
second approach, ketone 24 was deoxygenated using
Hutchins’s protocol.17 The o-nitrobenzenesulfonyl hydra-
zone obtained from 24 was subjected to reduction with so-
dium cyanoborohydride in the presence of acetic acid to
yield alkene 26 in excellent yield.18 Debenzylation of 26
using lithium naphthalinide19 yielded alcohol 27 that,
when subjected to IBX oxidation, afforded aldehyde 6.
Acknowledgment
P.K.S. is thankful to the CSIR, New Delhi, for a fellowship. Finan-
cial assistance from the DST, New Delhi, is gratefully acknow-
ledged. We thank Dr. B. Jagadeesh, Head, NMR center, for
acquiring the NMR spectra and Dr. R. Srinivas, Head, NCMS divi-
sion, for acquiring the mass spectra.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
References and Notes
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53, 3642. (b) Corley, D. G.; Herb, R.; Moore, R. E.; Scheuer,
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1996, 255. (d) Higa, T.; Tanaka, J.-I.; Garcia Gravalos, D.
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Riccio, R. Eur. J. Org. Chem. 2001, 775.
(2) (a) Mooberry, S. L.; Tien, G.; Hernandez, A. H.; Plubrukarn,
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review, see: Gallagher, B. M. Jr. Curr. Med. Chem. 2007, 14,
2959.
(3) (a) Pryor, D. E.; Brate, A. O.; Bilcer, G.; Diaz, J. F.; Wang,
Y. F.; Wang, Y.; Kabaki, M.; Jung, M. K.; Andreu, J. M.;
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(4) For the total synthesis of 1, see: (a) Ghosh, A. K.; Wang, Y.
J. Am. Chem. Soc. 2000, 122, 11027. (b) Ghosh, A. K.;
Wang, Y.; Kim, J. T. J. Org. Chem. 2001, 66, 8973.
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Savi, C.; Tudge, M. Org. Lett. 2001, 3, 3149. (e) Mulzer, J.;
Enev, V. S.; Kaehlig, H. J. Am. Chem. Soc. 2001, 123,
10764. (f) Wender, P. A.; Hegde, S. G.; Hubbard, R. D.;
Zhang, L. J. Am. Chem. Soc. 2002, 124, 4956. (g) Williams,
D. R.; Liang, M.; Mullins, R. J.; Stites, R. E. Tetrahedron
Lett. 2002, 43, 4841. (h) Mulzer, J.; Ahmed, A.;
The synthesis of sulfone 5 began with the methallylation
of the aldehyde20 28 using Keck’s protocol21 to furnish ho-
moallyl alcohol 29 (ee = 96%).22 Allyl ether formation us-
ing standard conditions yielded compound 30 that was
subjected to ring-closing metathesis reaction using
Grubbs’ catalyst23 31 to furnish pyran derivative 32. De-
protection of PMB ether using DDQ24 followed by reac-
tion of the resulting alcohol 33 with thiol 34 under
Mitsunobu conditions25 yielded sulfide 35. Oxidation us-
ing ammonium molybdate and H2O2 yielded sulfone 5.
Alternatively, the ether 30 was deprotected with DDQ to
furnish alcohol 36 that, on reaction with thiol 34, yielded
sulfide 37. Oxidation to sulfone 38 using ammonium mo-
lybdate and H2O2 proceeded more readily in this instance
in comparison to sulfide 35 where oxidation to sulfoxide
was rapid but further oxidation to sulfone 5 proved to be
slow. RCM using Grubbs’ catalyst23 39 yielded 5
(Scheme 5).
The coupling of fragments 5 and 6 was accomplished us-
ing the Kocienski-modified Julia-olefination procedure.6
Deprotonation of sulfone 5 with KHMDS in DMF fol-
lowed by addition of aldehyde 6 furnished stereoselec-
tively diene derivative 426 constituting the C13–C28
subunit of laulimalide (Scheme 6).
In summary, we have described a new route to the C13–
C28 fragment (14.49% overall yield in 12 steps by the
longest linear sequence) from 1,3-propanediol (13). The
key steps include substrate-controlled asymmetric trans-
formations, enantioselective propargylation using Pu’s
protocol, C–C bond formation using α-chlorosulfide in-
termediate, Mislow–Braverman rearrangement, reductive
deoxygenation with alkene transposition and Julia–
Kocienski olefination.
Hoegenauer, E. K.; Enev, V. S.; Hanbauer, M.; Kaehlig, H.;
Ohler, E. J. Org. Chem. 2003, 68, 3026. (i) Crimmins, M. T.;
Stanton, M. G.; Allen, S. P. J. Am. Chem. Soc. 2002, 124,
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Hilfiker, M. A. J. Am. Chem. Soc. 2003, 125, 13654.
(k) Gallagher, B. M.; Fang, F. G. Jr.; Johannes, C. W.;
Pesant, M.; Tremblay, M. R.; Zhao, H.; Akasaka, K.; Li, X.
Y.; Liu, J.; Littlefield, B. A. Bioorg. Med. Chem. Lett. 2004,
14, 575. (l) Uenishi, J.; Ohmi, M. Angew. Chem. Int. Ed.
Synlett 2013, 24, 1983–1987
© Georg Thieme Verlag Stuttgart · New York

LETTER
2005, 44, 2756; Angew. Chem. 2005, 117, 2816. (m) For a
Synthesis of the C13–C28 Subunit of (–)-Laulimalide
1987
of our knowledge this is the first report on the use of
o-nitrobenzenesulfonyl hydrazine for reductive
deoxygenation.
review, see: Mulzer, J.; Ohler, E. Chem. Rev. 2003, 80, 3753.
(n) Gollner, A.; Altmann, K.-H.; Gertsch, J.; Mulzer, J.
Chem. Eur. J. 2009, 15, 5979. (o) Trost, B. M.; Amans, D.;
Seganish, W. M.; Chung, C. K. J. Am. Chem. Soc. 2009, 131,
17087.
(19) Alonso, E.; Ramón, D. J.; Yus, M. Tetrahedron 1997, 53,
14355.
(20) Aldehyde 28 was obtained by ozonolysis of the di-OPMB
ether of cis-1,4-butenediol. See: Supporting Information for
a detailed experimental protocol.
(5) For the synthesis of analogues of 1, see: (a) Wender, P. A.;
Hegde, S. G.; Hubbard, R. D.; Zhang, L.; Mooberry, S. L.
Org. Lett. 2003, 5, 3507. (b) Paterson, I.; Bergmann, H.;
Menche, D.; Berkessel, A. Org. Lett. 2004, 6, 1293.
(c) Mooberry, S. L.; Randall-Hlubek, D. A.; Leal, R. M.;
Hegde, S. G.; Hubbard, R. D.; Zhang, L.; Wender, P. A.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 8803. (d) Gallagher,
B. M. Jr.; Zhao, H.; Pesant, M.; Fang, F. G. Tetrahedron
Lett. 2005, 46, 923. (e) Paterson, I.; Menche, D.; Hakansson,
A. E.; Longstaff, A.; Wong, D.; Barasoain, I.; Buey, R. M.;
Diaz, J. F. Bioorg. Med. Chem. Lett. 2005, 15, 2243.
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(22) The enantiomeric ratio was determined by HPLC of the
alcohol. CYCLOBOND® [(0.46 cm I.D. × 25 cm L),
isocratic 3% MeCN in H2O, flow rate: 1.0 mL/min, 25 °C];
R-isomer tR = 9.658 min and S-isomer tR = 11.153 min.
(23) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 5426.
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(26) Compound 4: To a solution of sulfone 5 (54 mg, 0.17 mmol,
1.5 equiv) in anhyd DMF (0.2 mL) and HMPA (64 μL)
cooled at –60 °C was added KHMDS (192 μL, 15% in
toluene, 1.2 equiv) via syringe. The reaction was stirred for
15 min and cooled to –78 °C. A solution of aldehyde 6 (80
mg, 0.12 mmol, 1 equiv) in anhyd DMF (0.2 mL) and
HMPA (64 μL) was added dropwise. The reaction was
stirred at the same temperature for 1 h and allowed to warm
to ambient temperature for over a period of 12 h. The
reaction mixture was quenched by adding sat. aq NH4Cl
solution (2 mL), the layers were separated and the aqueous
layer was extracted with CH2Cl2 (3 × 15 mL). The combined
organic layers were washed with brine, dried over anhyd
Na2SO4, filtered and concentrated under reduced pressure to
furnish the crude product. Purification of the crude residue
via flash chromatography on silica gel using 12% EtOAc–
hexane as the eluent afforded 4 as a colorless oil (56 mg, 0.09
mmol) in 75% yield. TLC (SiO2): Rf 0.6 (EtOAc–hexane,
3:7); [α]25D –21° (c = 0.98 in CHCl3). 1H NMR (500 MHz,
CDCl3): δ = 7.58–7.70 (m, 4 H), 7.24–7.34 (m, 6 H), 5.74
(dt, J = 14.8, 5.0 Hz, 1 H), 5.52–5.64 (m, 2 H), 5.23–5.38 (m,
2 H), 4.56 (d, J = 7.0 Hz, 1 H), 4.37 (d, J = 7.0 Hz, 1 H),
4.08–4.16 (m, 1 H), 4.00–4.09 (m, 2 H), 3.87–3.96 (m, 1 H),
3.67–3.74 (m, 1 H), 3.62–3.66 (m, 1 H), 3.56–3.61 (m, 1 H),
3.20 (s, 3 H), 2.13–2.31 (m, 2 H), 1.91–2.04 (m, 1 H), 1.69–
1.87 (m, 2 H), 1.60–1.68 (m, 4 H), 1.30 (s, 6 H), 0.98 (s, 9
H). 13C NMR (75 MHz, CDCl3): δ = 135.6, 134.8, 133.9,
133.1, 131.2, 129.6, 128.9, 127.7, 127.0, 119.9, 108.6, 93.5,
81.1, 80.1, 73.4, 72.7, 65.6, 60.4, 55.3, 38.7, 35.8, 34.3, 27.3,
27.0, 23.1, 19.3. IR (neat): 2930, 2858, 1155, 1106, 1033,
704 cm–1. MS (ESI): m/z = 643 [M + Na]+. HRMS (ESI): m/z
[M + Na]+ calcd for C37H52SiO6Na: 643.3430; found:
643.3444.
(6) (a) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley,
A. Synlett 1998, 26. (b) For a review, see: Blakemore, P. R.
J. Chem. Soc., Perkin Trans. 1 2002, 2563.
(7) Raghavan, S.; Kumar, V. V.; Chowhan, L. R. Synlett 2010,
1807.
(8) Mash, E. A.; Nelson, K. A.; Van Deusen, S.; Hemperly, S.
B. Org. Synth. 1990, 68, 92.
(9) Nakagawa, I.; Hata, T. Tetrahedron Lett. 1975, 1409.
(10) (a) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(b) Huang, S. L.; Omura, K.; Swern, D. Synthesis 1978, 297.
(11) (a) Pu, L. Tetrahedron 2003, 5, 9873. (b) Gao, G.; Xie, R.
G.; Pu, L. PNAS 2004, 101, 5417.
(12) The enantiomeric ratio was determined by HPLC of the
alcohol. CHIRALPAK®IA-3 [(0.46 cm I.D. × 25 cm L),
isocratic hexane, flow rate: 1.0 mL/min, 25 °C]; S-isomer tR
= 12.739 min and R-isomer tR = 12.946 min. The ‘S’
configuration at the newly created carbinol stereocentre was
unambiguously established by comparison of the 1H NMR
spectra of esters of 17 and racemic 17 prepared using
(S)-methoxymandelic acid.
(13) (a) Miller, E. G.; Rayner, D. R.; Mislow, K. J. Am. Chem.
Soc. 1966, 88, 3139. (b) Braverman, S.; Stabinsky, Y. Chem.
Commun. 1967, 270. (c) Evans, D. A.; Andrews, G. C. Acc.
Chem. Res. 1974, 7, 147.
(14) Baudin, J. B.; Julia, S. A.; Lorne, R. Synlett 1991, 509.
(15) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226.
(16) Myers, A. G.; Zheng, B. Tetrahedron Lett. 1996, 28, 4841.
(17) Hutchins, R. O.; Kacher, M.; Rua, L. J. Org. Chem. 1975,
40, 923.
(18) The hydrazone formation and subsequent reductive
deoxygenation steps proceeded more efficiently using
o-nitrobenzenesulfonyl hydrazine (o-NsNHNH2) rather than
using p-toluenesulfonyl hydrazine (TsNHNH2). To the best
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