Chapter 8 1
CHAPTER 8
1. The initial reaction with BF3 leads to elimination of the methoxy unit with formation of an iminium salt. The
iminium salt reacts with MeMgBr from the less hindered side to give the methylated final product, with the
stereochemistry shown. The stereochemistry is predicted from the conformational model in which path B is
blocked by the bicyclic ring system and the TBDMS protected alcohol. Delivery of the Grignard reagent from the
less hindered path A leads to the product shown.
N CO2EtMeO
t-BuMe 2SiO
Boc
N CO2Et
t-BuMe2SiO
Boc
N CO2EtMe
t-BuMe 2SiO
Boc
B
N BocMe
OSi
HH CO2Et
A
see J. Org. Chem., 1999, 64, 4304
2. This reaction is taken from J. Org. Chem., 2004, 68, 619. Inspection of the model suggests that face A is less
sterically hindered. delivery of the methyl group from that face is consistent with product formation. The acetoxy
group provides the steric hindrance to the bottom face.
O
Me O
H
Me
Cl
OAcHO
Me O
H
Me
Cl
OAc
Me
72 73
MeMgCl , THF
–78°C 0°C
A
B
3. A reasonable mechanism involves formation of a ketone moiety via the alkoxide, with transfer of the negative
charge to the carbon adjacent to the sulfur. An internal Michael addition of this carbanion gives an enolate anion
(see Sec. 9.7.A), which is hydrolyzed to the final product.
OH
SPh
KHO
SPhSPh
O
SPh
O
SPh
O
aq H+ see J. Org. Chem., 1985, 50, 4596
4. See Sec. 4.7.B for a discussion of these models.
(a) All models predict the same incorrect stereochemistry for all nucleophiles since the actual product will have
Copyright © 2011 Elsevier Inc. All rights reserved.
2 Organic Synthesis Solutions Manual
the R and OH stereochemistry reversed (see Sec. 4.7.C).
OH
MeMe
R
HH
O MeMe
H
O
H
Me
MeH
O
H
Me
Me
1 - 5 1 - 5
1 - 5 predicted for all three models
R = (1) Me (2) Ph (3) MeC C:– (4) Et (5) 1,3-dithiylCram Karabatsos Felkin-Ahn
(b) The models predict the same angle of approach for all five nucleophiles. Note that each model predicts a
different product. The Cram and Karabatsos models predict the same diastereomer, but different enantiomers.
Assuming each reaction is not enantioselective, these two models predict the same diastereomer. The Felkin-Anh
model, however, predicts a different diastereomer.
PhMe
HMe
HOR
Me
HPh
HO R
MePh
H Me
Me
R OH
Ph
Me
O
•
Me
H
MeMe
Ph
HO ROH
MeMe
Ph
R
MeMe
Ph
R OH
H
MeO
Me
•
Ph
MeO
Me
•
Ph
H
Cram Karabatsos Felkin-Ahn
approach for all five nucleophilesR = (1) Me (2) Ph (3) MeC C :– (4) Et (5) 1,3-dithiyl
(c) In this molecule, the OMe group can interact with both Grignard reagents but probably not very well with the
sodium or lithium derivatives. The Cram chelation model is used nonetheless. In the other models, the OMe group
is positioned as close as possible to the carbonyl oxygen. The same major product is predicted by all three models.
Unfortunately, the steric hindrance provided by methyl vs. ethyl is minimal, and this lack of facial bias means that
the reaction is predicted to proceed with poor diastereoselectivity.
Me
HOR
O Me
MeEt
MeO
MeEt
HO R
Me
Me
HO RMeO
Et MeOMe
Me
O
•
OMeO
Me
•
MeEt
Et
MeMe
O Me
R OH
Me
Me
Me
R OH
MeO Me
OMe
R OH
MeMe
OMeO
Me
•
Et
Cram Karabatsos Felkin-Ahn
approach for all five nucleophilesR = (1) Me (2) Ph (3) MeC C:– (4) Et (5) 1,3-dithiyl
(d) Both the Cram and Karabatsos models predict the same diastereomer. The Felkin-Anh model predicts the
diastereomer with the opposite stereochemistry of the alcohol moiety.
Copyright © 2011 Elsevier Inc. All rights reserved.
Chapter 8 3
Me
O
Me
•
H
Me
O
Me
•
H H
Me
Me
O
•
Me
HO
Me
R
Me
HO
Me
R
Me
R
Me
OH
Cram Karabatsos Felkin-Ahn
approach for all five nucleophiles
R = (1) Me (2) Ph (3) MeC C:– (4) Et (5) 1,3-dithiyl
(e) All three models predict the same diastereomer.
Me
Me
OHRH
Me
O
•Me
O
•
Me
Me
H
HO
•
Me
Me
Cram Karabatsos Felkin-Ahn
approach for all five nucleophiles
predicted from all models
R = (1) Me (2) Ph (3) MeC C:– (4) Et (5) 1,3-dithiyl
5. The selectivity is explained by the Cram model. Attack of BuLi over the less steric hindered H, as shown in the
model, leads to the diastereomer indicated as the major product.
OO
CHO
Et Et
BuLi
OO
Et Et
BuH
HO
OO
Et Et
BuHO
H
H
• OH
O
O
EtEt
see Org. Lett., 2000, 2, 207
+
(3 : 1)
via
attack here vialess hindered side
6. Initial reaction with the strong base generates the -carbanion of the sulfoxide. Acyl addition to the ketone
generates the alkoxide as it forms the new C—C bond. The alkoxide regenerates a carbonyl with concomitant
breakage of the bond to generate an ester enolate (see Sec. 9.4.B). In the second step, acetic acid protonates the
carbanion to give the final product.
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4 Organic Synthesis Solutions Manual
O
CO2EtS
O
Ph
O SO
Ph
CO2Et
O
CO2Et
SO
Ph
O
CO2EtS
O
Ph
O SO
Ph
CO2Et
1. LiN(SiMe3)2
2. AcOH
see Tetrahedron Lett., 2000, 41, 377
7.
O Me S Me N
MeO C C-Me
SPh
Me
(a) (b) (c) (d) (e)
8. (a).
MgBrCdCl2
)2Cd
O
Cl PhPh
O2
(b)
OO
Cp2TiMe2 O
(c)
OOH
Bu
BuMgCl , CeCl3
(d)
SPh
O N Li SPh
O
OH
1.
2. 2-butanone
(e) Br CO2H
1. Mg° , THF2. CO
3. H3O+
(f)
Br n-Bu2Cu(CN)Li2
I
n-Bu
1. t-BuLi2. CuCN
-78°C
Copyright © 2011 Elsevier Inc. All rights reserved.
Chapter 8 5
(g)
1. n-BuLi , TMEDA2. allyl bromide
(h) Cl
O
n-Bu
O1. n-BuMgBr , FeCl32. H3O
+
(i)
Br CNNaCN , DMF
(j)
C C-H C C-Me
1. NaNH22. MeI
(k) OBu
O
OBu
OPhPhCu • BF3
(l)
Br
1. Na2Fe(CO)42. EtI
3. COO
(m)
n-Bu n-Bun-Bu n-Bu
CO2H
1. DIBAL-H , heptane 50°C
2. MeLi , ether3. CO2
4. H3O+
(n)
BrPPh3
PPh3 Ph1. n-BuLi
2. PhCHO
(o)
O
P CO2EtEtO
EtO
Ph
CO2Et
PhCHO , NaH
(p)
PMeO
O
OMe
CH3Ph
1. NaH2. PhCHO
Copyright © 2011 Elsevier Inc. All rights reserved.
6 Organic Synthesis Solutions Manual
(q)
DMSOMeI
Me2SOCH3
O
DMSO O
O1. n-BuLi
2.
9.
Ph NOMe
O
Me
Ph NOMe
O
Me
H2O
Ph
O
Ph NOMe
O
Me
HNOMe
Me
CH2=CHMgBr , THF+
Taken from Org. Lett. 2000, 2, 11. Initial acyl substitution of the Weinreb amide generated the conjugated
ketone, along with the amine (MeONHMe). Subsequent Michael addition gave the enolate anion, and workup with
water gave the final -amino ketone product.
10. In reaction (a), the first equivalent of ethyllithium reacts with the more acidic H-O, but the second equivalent
deprotonates at a carbon of the benzene ring, leading to the two dilithio derivatives shown.
see J. Chem. Soc., Chem. Commun., 1980, 87.
In reaction (b), the first equivalent of ethyllithium removes the more acidic H-N, but the second equivalent
deprotonates at the carbon - to the imine moiety.
see J. Organomet. Chem., 1980, 186, 155.
OH
OMe
MeO
NN
H
Ph
OH
EtLi
EtLi
O– Li+
OMe
MeO
NN
H
Ph
O Li
EtLi
O– Li+
OMe
MeO
Li
EtLi NN
Li
Ph
O Li
O– Li+
OMe
MeOLi
(a) +
(b)
11. The following are reasonable reagents for each transformation.
A. 1. DIBAL-H , –78°C 2. H2O
B. 1. aq NaOH 2. pH 7
C. 1. excess PhMgBr 2. H2O
D. 1. aq NaOH 2. pH 7 3. SOCl2 4. n-Pr2Cd
Copyright © 2011 Elsevier Inc. All rights reserved.
Chapter 8 7
12. (a) In general, exo attack is preferred in bicyclic systems such as this (see Sec. 4.7.E). If the exo face is the
lowest energy face for approach of the organocuprate, the major product will be the exo methyl derivative shown.
O
Me
Me
Me2CuLi O
Me
Me
Me
H
(b) Initial addition of the cuprate occurs from the less sterically hindered exo face (see answer in a). This
conjugate addition leads to an enolate anion (see Sec. 9.7.A). Since the bromide moiety is on a face easily
accessible by the enolate, displacement of the bromide is facile, leading to a five-membered ring and the tricyclic
ketone shown.
OMe
H
Br
Me2CuLi
OMe
H
Br
Me
Me
Me
OH
(c) The epoxidation of the alkene occurs from the face opposite the sterically blocking methyl group to give A.
Once the epoxide stereochemistry is set, reaction with butylmagnesium bromide occurs from the less hindered face,
and at the less hindered carbon (distal to the bridgehead carbon bearing the methyl group).
Me
Me
HO
H Me
Me
HO
H
OA
Me
Me
HO
H
HO n-BuB
13.
(a)
Me
O
i-Pr Me
for a spirodecane derivative,see Bull. Chem. Soc. Jpn., 1978, 51, 3590
(b)
O
SiMe3
t-BuO2CH
HO
O
O
J. Am. Chem. Soc., 2002, 124, 5380
(c)
H
CO2Me
Org. Lett., 2003, 5, 991
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8 Organic Synthesis Solutions Manual
(d)
CO2Me
OTBSOHC
Org. Lett. 2003, 5, 4641
(e)
OMeO
NMe
OH
see J. Org. Chem., 1998, 63, 1704
(f)
OH
see Org. Lett., 2000, 2, 4169
S
S
(g)
N O
H
HO2COMe
Org. Lett. 2003, 5, 269
(h)
N
O
Org. Lett. 2003, 5, 1115
(i)
NO
O
Boc
J. Am. Chem. Soc., 2002, 124, 4716
(j)
O
O
OMe
Me
OTBDPS
HMeMe
Angew. Chem. Int. Ed., 2004, 43, 739
(k)
OH
OSiMe3
SPh
see Tetrahedron: Asymmetry, 1999, 10, 1877
(l)
O
OBu
NH2
see Tetrahedron Lett., 2000, 41, 2369
(m)
OH
Ph
MeJ. Org. Chem., 2002, 67, 3134
(n)
N
OMe
CH2Cbz
see J. Org. Chem., 1999, 64, 1410
(o)
Me
O
Me
see J. Am.Chem. Soc., 1980, 102, 4274
(p)
OH
CO2H
J. Org. Chem., 2003, 68, 10030
(q)
O
O
OAc
H
H
H
HO
O
O
J. Org. Chem., 2003, 68, 6905
(r)
N
(s)
S S
OBnBnO
OHt-BuMe2SiO
J. Am. Chem. Soc., 2003, 125, 14435
(t)
OH
OTIPS
O
OTIPS
J. Am. Chem. Soc., 2003, 125, 5415
(u)
NH
N
O
PhMe
see J. Chem. Soc., Perkin Trans. 1, 1992, 2851
via Sommelet-Hauser rearrangement
Copyright © 2011 Elsevier Inc. All rights reserved.
Chapter 8 9
(v)
N NHO2C CO2H
see Tetrahedron Lett., 2000, 41, 2203
(w)
OSEM
J. Org. Chem., 2003, 68, 6096
(x)
N
N
HO (CH2)12CH=CH2
Org. Lett. 2003, 5, 765
(y)
H HO
CO2HPhO2S
Eur. J. Org. Chem. 2003, 848
(z)
NHO2C
see J. Org. Chem., 2000, 65, 2824
(aa)
MeO
O O
see J. Org. Chem., 1992, 57, 1047
(ab)
N Boc
OTBS
Ph
Me
O
Ph
J. Org. Chem., 2002, 67, 9192
(ac)
O
Br
OTIPS
Me
Me
CO2Me
J. Am. Chem. Soc., 2002, 124, 11616
(ad)
O
see Tetrahedron Lett.,1984, 25, 5501
(ae)
CO2Me
OMOMO
see Tetrahedron Lett., 1987, 28, 731
(af)
O
Tetrahedron, 2002, 58, 1647
(ag)
N
O
O
Ph
OOMe
OMe
MeO
NO2
J. Org. Chem. 2003, 68, 8162
(ah)
OH
J. Org. Chem., 1992, 57, 1047
HO
(ai)
CHO
OEt
OJ. Am. Chem. Soc., 2003, 125, 5642
(aj)
SS
TBDMSO
C3H7
O CO2H
see J. Org. Chem., 1999, 64, 6610
(ak)
HO
O
(al)
O O
Phsee Synthesis, 1993, 137
(am)
NPh CH2
see Tetrahedron Lett., 2000, 41, 1975
Copyright © 2011 Elsevier Inc. All rights reserved.
10 Organic Synthesis Solutions Manual
(an)
O O
OBn
Org. Lett. 2002, 4, 643 (ao)
TBDPSO
J. Am. Chem. Soc., 2003, 125, 1712 (ap)
MeO OMe
CHO
Org. Lett. 2003, 5, 3931
14. In each case, a possible synthesis is presented. Other solutions are possible for each problem.
(a) This sequence is taken from the cited paper.
C8H17
(CH2)7COOH
C8H17
N OMe
O
Me
C8H17
C11H23
OC8H17 C18H35
O
C8H17C18H35
a , b c
d , e
f
(a) SOCl2 (b) MeNHOMe (c) C11H23MgBr , THF (d) TsNHNH2 (e) NaBH4 (f) m-CPBA
Weinreb amide
(b) All reagents are taken from J. Am. Chem. Soc., 2003, 125, 4048. Initial deprotection of the acetate group
(7.3.A.ii) was followed by a tetrapropylammonium perruthenate oxidation (3.2.F.i) to give the aldehyde. Wittig
olefination (8.8.A.i) and reduction of the ester with Dibal (4.6.C), gave the alcohol. Deprotection of the O-silyl
group with tetrabutylammonium fluoride (7.3.A.i) allowed "switching" of the protecting groups, with the more
reactive allylic alcohol being converted to the triisopropylsilyl ether (7.3.A.i). A second TPAP oxidation to the
aldehyde, was followed by a Grignard reaction (8.4.C.i) to give the target.
O O
OAc
OSiMe2t-Bu
O OOSiMe2t-Bu
OH
O O
OH
OSiMe2t-Bu
O OOH
OH
O O
CHO
OSiMe2t-Bu
O OOH
OTIPS
O OOH
OTIPS
O OCHO
OTIPS
O OOSiMe2t-Bu
CO2Et
a b cd
e f gh
(a) K2CO3 , MeOH (b) TPAP , NMO (c) Ph3P=CHCO2Et , toluene , 100°C (d) Dibal-H , CH2Cl2 , –78°C(e) TBAF , THF (f) TIPS-Cl , imidazole (g) TPAP , NMO (h) allylMgbr , ether , –78°C
Copyright © 2011 Elsevier Inc. All rights reserved.
Chapter 8 11
(c) This sequence is taken from J. Org. Chem., 2003, 68, 9533. Initial protection of the alcohol as the
triisopropylsilyl ether (7.3.A.i) was followed by a Wittig reaction (8.8.A.i), which gave a 4:1 Z:E mixture of the
alkene. Deprotection of the alcohol (7.3.A.i) allowed oxidation to the aldehyde with the Dess-martin reagent
(3.2.D). A second Wittig reaction gave a vinyl ether, and hydrolysis liberated the ketone product.
CHO
OH
OMeMeO
MeO
MeO
MeO
OMe
CHO
OTIPS
OMeMeO
MeO
MeO
MeO
OMe
OTIPS
OMeMeO
MeO
MeO
MeO
OMe
OMeMeO
MeO
MeO
MeO
OMe
O
CHO
OMeMeO
MeO
MeO
MeO
OMeOMe
MeO
MeO
MeO
MeO
OMe
OMe
a b
c,d
e f
(a) TIPSCl , DMAP , imidazole (b) Ph3PCH2CH3 , KN(TMS)2 , THF (c) TBAF , THF (d) Dess-Martin periodinane, CH2Cl2 (e) Ph3PCH(OMe)Me , BuLi , THF (f) p-TsOH , THF
(d) All reagents are taken from J. Am. Chem. Soc., 2003, 125, 12836. Initial protection of the alcohol as the benzyl
ether (7.3.A.i) allowed the Grignard reaction (8.4.C) to form the homoallylic alcohol. This alcohol was protected
as the triethylsilyl ether (7.3.A.i), and ozonolysis (3.7.B) generated the ketone.
OHO
OBn
O OTESOBn
OOBn
OH
OBn
OTESa b c d
(a) NaH , BnBr , DMF (b) isopropenylmagnesium bromide , Li2CuCl4 , THF (c) TESCl , imidazole, DMF(d) 1. O3 , NaHCO3 , MeOH (2. Me2-S
(e) All reagents are taken from J. Am. Chem. Soc., 2002, 124, 9718. Asymmetric dihydroxylation (3.5.B.ii),
followed by protection of the diol as an acetonide (7.3.A.iii), allowed removal of the para-methoxyphenyl
protecting group with ceric ammonium nitrate (7.3.A.ii). TPAP oxidation (3.2.F.i) and reaction with
ethylmagnesium bromide (8.4.C.i) was followed by a second TPAP oxidation to the ketone, and reaction with
vinylmagnesium bromide. Deprotection liberated the diol.
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12 Organic Synthesis Solutions Manual
OPMP
O HO
O
CHOO
OO PMP
H O
H O
O HO
O OHHO
HO
OPMPO
O
OO
O
OHO
O
(a) AD-mix- , t-BuOH , H2O (b) Me2C(OMe)2 , TsOH (c) CAN (d) TPAP , NMO(e) EtMgBr (f) TPAP , NMO (g) CH2=CHMgBr (h) Dowex 50 (H+) , MeOH
a b cd
ef g h
(f) Reaction d will generate ortho and para isomers. The para isomer must be separated chromatographically. A
milder Lewis acid may be used for this Friedel-Crafts acylation since phenol is highly activated (12.4.D).
N O2
OH
O H
O H
NH2
OH
OTs
OH
O
Cl
O
OH
O
a b c d e
f gh
(a) HNO3 , H2SO4 (b) H2 , Ni(R) (c) NaNO2 , HCl ; H2O , reflux (d) (e) Zn(Hg) , HCl (f) 1. 9-BBN 2. H2O2 , NaOH
(g) TsCl , pyridine (h) t-BuOK , t-BuOH , reflux
, AlCl3
(g) All reagents are taken from the J. Am. Chem. Soc., 2003, 125, 15433. Protection of the alcohol as the t-
butyldimethylsilyl ether (7.3.A.i) allowed ozonolysis to the aldehyde (3.7.B). Wittig reaction (8.4.C) gave the
conjugated ester, which was reduced to the alcohol with diisobutylaluminum hydride (4.6.C) and then oxidized to
the aldehyde with tetrapropylammonium perruthenate (3.2.F.i). Horner-Wadsworth-Emmons olefination (8.8.A.i)
gave a new conjugated ester, which was reduced and then oxidized as above. A second Horner-Wadsworth-
Emmons olefination (8.8.A.iii) gave the requisite triene unit, and both the alcohol and the alkyne were deprotected
with tetrabutylammonium fluoride (7.3.A.i).
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Chapter 8 13
Et3Si
OTBS
CO 2E t
CO2Et
TBSO
Et3Si
Et3Si
O H
E t3Si
OTBS
Et3Si
OTBS OHTBSO
Et3Si
H O
Et3Si
CHO
OTBS
Et3Si
OTBS
CHO
CHO
TBSO
Et3Si
CO2Me
TBSO
CO2Me
HO
a b c d
ef g h
i
j(a) t-Bu<e2SiOTf , 2,6-lutidine (b) O3 ; PPh3 (c) PPh3=CMeCO2Et , toluene , 100°C (d) Dibal-H , toluene, –78°C (e) TPAP , NMO (f) NaH , (EtO)2P(=O)CHMeCO2Et (g) Dibal-H , toluene, –78°C (h) TPAP , NMO (i) NaH , (EtO)2P(=O)CHMeCO2Et (j) 4 eq TBAF
(h) This sequence is taken from J. Org. Chem.., 2003, 68, 9983. Initial oxidation with tetrapropylammonium
perruthenate (3.2.F.i) was followed by addition of the sulfone anion (8.6.A) to the aldehyde. Deprotection of
pivaloyl group (7.3.A.ii) and a second oxidation to the aldehyde with the Dess-Martin reagent (3.2.D) was followed
by addition of the alkyne anion (8.3.C) to give the propargyl alcohol. Lindlar hydrogenation provided the cis-
alkene (4.8.B) and a final Dess-Martin oxidation to the ketone completed the sequence.
OH
OPiv
CHO
OPiv OPiv
OH
SOPh
OH
OH
SOPh
O
SOPh
O
MeO2C
HO
OH
SOPh
CO2Me
CHO
OH
SOPh
HO
OH
SOPh
MeO2C
a b c d e
f g
(a) TPAP , NMO , CH2Cl2 (b) PhSOMe , LDA, THF (c) NaOMe , MeOH (d) Dess-Martin(e) HC CCO2Me , LDA , THF (f) H2 , Lindlar catalyst (g) Dess-Martin , pyridine
(i) All reagents in this sequence are taken from Org. Lett., 2002, 4, 1715. Conjugate addition of divinyl cuprate
(8.7.A.vi) was followed by reduction of the ester with Super hydride (4.5.B). The resulting alcohol was oxidized to
the aldehyde with the Swern oxidation (3.2.C.i), followed by Wittig olefination (8.8.A.i), and catalytic
Copyright © 2011 Elsevier Inc. All rights reserved.
14 Organic Synthesis Solutions Manual
hydrogenation of both vinyl groups (4.8.B). The silyl protecting group was removed with tetrabutylammonium
fluoride (7.3.A.i), and a Swern oxidation to the aldehyde (3.2.C.i), followed by NaClO2 oxidation to the acid, and
esterification with diazomethane (2.5.C; 13.9.C), was followed by introduction of the phenylselenide via the
enolate anion (9.2) and syn elimination (2.9.C.vi). A second conjugate addition with divinyl cuprate (8.7.A.vi) and
reduction of the ester with Super hydride (4.5.B), allowed formation of the alkoxide with sodium hydride. The
alkoxide attacked the carbamate unit, and acyl substitution (2.5.C) led to the oxazolidinone product shown.
N
R' OR
N
R'
CO2Me
NMeO2C
R' OR
N
R'
OH
N
R'
CO2Me
NMeO2C
R' ORN
R' OROH
N
R'
CHO
N
R'
OH
NOHC
R' OR
N
R'
CO2Me
N
OO
N
R' OR
a b c d e
f gh i
j k l
(a) (vinyl)2CuLi (b) Super Hydride (c) Swern oxidation (d) Ph3PEt+Br– , BuLI (e) H2 , 5% Pd-C(f) TBAF (g) Swern oxidation (h) 1. NaClO2 , NaH2PO4 2. CH2N2 (i) LiN(TMS)2 ; PhSeCl(j) (vinyl)2CuLi (k) Super hydride (l) NaH
R' = CO2Me; OR = OSiPh2t-Bu
(j)
OH O
SPh2
O
OH
Et
a
bc d
(a) Hg(OAc)2 , H2O ; NaBH4 (b) CrO3 (c) , LDA ; HBF4
(d) EtC CNa ; H3O+
(k) All reagents are taken from the cited reference. Wittig olefination gives the conjugated ester, allowing
conjugate addition with the higher order cuprate, in the presence of the trapping agent chlorotrimethylsilane.
DIBAL-H reduction of the ester gives an aldehyde, which reacts with the alkyne anion to give the diastereomeric
mixture of alcohols shown.
Copyright © 2011 Elsevier Inc. All rights reserved.
Chapter 8 15
O
OHC
O
EtO2C
O
EtO2CCMe3
O
OHCCMe3
O
CMe3OH
EtO2C
see J. Am. Chem. Soc., 2000, 122, 8453
a b c
d
(a) Ph3P=CHCO2Et, CH2Cl2 (b) t-Bu2CuCNLi , ether , TMSCl (c) DIBAL-H, PhMe , -78°C (d) EtO2C CLi, THF, -78°C
(l) All reagents are taken from J. Am. Chem. Soc., 2003, 125, 4680. This sequence includes a "cheat", in that
phosphonate ester is used, containing the Weinreb's amide unit. Horner-Wadsworth-Emmons olefination with a
(8.8.A.iii) leads to the conjugated amide, and reduction to the aldehyde with diisobutylaluminum hydride (4.6.C)
was followed by a Wittig reaction (8.8.A.i) to give the diene. Deprotection of the trityl group (7.3.A.i) and
iodination (2.8.A) gave the target.
TrOCHO
HO
TrO O
NMe OMe
APO
NMe OMe
O
EtOOEt
I
TrO O
HTrO
ab c
d e
(a) NaH + A (b) Dibal-H , THF , –78°C (c) Ph3P=CHMe (d) BCl3 (e) I2 , PPh3 , imidazole
(m) All reagents in this sequence are taken from J. Am. Chem. Soc., 2002, 124, 9682. Reduction of the ester with
LiAlH4 (4.2.B) was followed by PCC oxidation (3.2.B.ii) to the aldehyde. Wittig olefination (8.8.A.i) gave the
vinyl group, and hydroboration generated the anti-Markovnikov alcohol (5.4.A). Reaction with thionyl chloride
converted the alcohol to the chloride (2.8.A).
CO2Et OHOH ClCHO
a b c d e
(a) LiAlH4 (b) PCC (c) Ph3P=CH2 (d) Bh3•THF; H2O2 , NaOH (e) SOCl2 , LiCl , Py
(n) All reagents are taken from J. Org. Chem., 2003, 68, 6905. Oxidation of the secondary alcohol with the Dess-
Martin periodinane (sec 3.2.D) was followed by mild basic hydrolysis of the acetate. Oxidation of the resulting
alcohol with tetrapropylammoniumperruthenate (TPAP - sec 3.2.F.i) gave a ketone. Ozonolysis under reductive
conditions led to the aldehyde unit, and intramolecular aldol condensation gave the targeted compound as a mixture
Copyright © 2011 Elsevier Inc. All rights reserved.
16 Organic Synthesis Solutions Manual
of diastereomeric alcohols.
O
O
OAc
H
HO
H
H
O
O
O
H
O
H
H
O
O
OAc
H
O
H
H
O
O
CHO
O
H
O
H
H
O
O
OH
H
O
H
H
O
O
O
HH
H
O
OH
a b c
d e
(a) Dess-Martin periodinane, Py , CH2Cl2 (b) K2CO3 , aq MeOH (c) TPAP , NMO , MS 4Å , CH2Cl2(d) O3 , Py , CH2Cl2 MeOH, Me2S (e) NaOH , MeOH
(o) All reagents are taken from J. Org. Chem., 2003, 68, 2376. Asymmetric reduction of the ketone unit by
hydrogenation (sect 4.8.C, 4.8.G) using a chiral catalyst was followed by protection of the resulting alcohol and an
SN2 displacement (sect 2.6.A) of the chloride to give the azide. DIBAL-H reduction (sect 4.6.C) of the ester
stopped at the aldehyde, and a simple Wittig olefination (sect 8.8.A) gave the alkene unit. Dihydroxylation using
osmium tetroxide (sect 3.5.B) gave the final product.
Cl
CO2Et
O
N3
CHO
TBDMSO
Cl
CO2Et
OH
N3
TBDMSO
Cl
CO2Et
TBDMSO
N3
OH
TBDMSO OH
N3
CO2Et
TBDMSOa b c
d e f
(a) H2 , Ru(OAc)2/BINAP (b) TBDMS-Cl , imidazole (c). NaN3 , DMF (d) Dibal(e) Ph3P=CH2 (f) K3[Fe(CN)6] , K2CO3 , 10% aq OsO4
(p) All reagents are taken from Org. Lett. 2002, 4, 2125. Reduction of both ester units with LiAlH4 gave the diol
(4.2.B), and the symmetry of the molecule allowed on hydroxyl to be protected as the OTBDMS ether (7.3.A.i).
Swern oxidation (3.2.C.i), followed by Wittig olefination (8.8.A.i) gave the conjugated ester, which was reduced
with diisobutylaluminum hydride (4.6.C) to the allylic alcohol. Another Swern oxidation gave the aldehyde, and
this was followed by a second Wittig olefination and Dibal reduction of the ester. Final Swern oxidation to the
conjugated aldehyde completed the synthesis.
Copyright © 2011 Elsevier Inc. All rights reserved.
Chapter 8 17
EtCO2Et
CO2Et
EtOTBS
CO2Et
EtOH
OH
EtOTBS
OH
OTBS
OH
EtOH
OSiMe2t-Bu
EtOTBS
CHO
OHC
OTBS
EtCHO
OTBS
EtO2C
OTBS
a b c d
e f g
h i
(a) LiAlH4 , THF (b) Me2t-BuSiCl , NaH , THF (c) (COCl)2 , DMSO , –78°C (d) Ph3P=CHCO2Et , PhH(e) Dibal-H , THF (f) (COCl)2 , DMSO , –78°C (g) Ph3P=CHCO2Et , toluene(h) Dibal-H , THF (i) (COCl)2 , DMSO , –78°C
(q) This sequence is taken from J. Am. Chem. Soc., 2002, 124, 6981. Swern oxidation (3.2.C.i) of the primary
alcohol unit was followed by a Wittig reaction(8.8.A.i). Dibal reduction of the ester (4.6.C) to the primary alcohol,
allowed an allylic manganese dioxide oxidation (3.2.F.iii) to the aldehyde. Subsequent Horner-Wadsworth-
Emmons olefination (8.8.A.iii) and deprotection of the O-silyl group with tetrabutylammonium fluoride (7.3.A.i)
gave the target.
I OH
Me Me
OSiMe2t-Bu
Me
I
Me Me
OSiMe2t-Bu
Me Me
OH
ICHO
Me Me
OSiMe2t-Bu
Me
I
Me Me
OSiMe2t-Bu
Me Me
CHO
I
Me Me
OSiMe2t-Bu
Me Me
CO2Me
I
Me Me
OH
Me Me OMe
CO2MeI
Me Me
OSiMe2t-Bu
Me Me OMe
CO2Me
a b
c d e
f
(a) DMSO , (COCl)2 , NEt3 (b) Ph3P=C(Me)CO2Me (c) Dibal , –78°C (d) MnO2 , CH2Cl2(e) (i-PrO)2POCH(OMe)CO2Me , KN(TMS)2 , THF , 18-crown-6 (f) TBF , THF
15. In each case a synthesis is shown. There are other syntheses based on other starting materials. In each of the
provided solutions, the source of starting material was the 2000-2001 Aldrich Chemical catalog. There are,
obviously, other sources of organic chemicals. Other synthetic routes are available based on other starting
materials.
(a) This is a very simple synthesis. Disconnection to the commercially available cyclopentane carboxaldehyde
Copyright © 2011 Elsevier Inc. All rights reserved.
18 Organic Synthesis Solutions Manual
(Aldrich, $50.00/10g). Cyclopentanecarbonitrile (Aldrich, $154.40/10g) is another obvious starting material.
O
CHO CHO
O1. i-PrMgBr
2. H3O+ , heat3. PCC , CH2Cl2
(b)
O O
O O
a b(a) Me2SOCH2
– (b) Me2C=PPh3
The cyclohexenone starting material is available from Aldrich, $60.40/100 mL.
(c)
Bu
Et
Bu
EtO
Bu
CHO
Bu
EtHO
Bu
EtO
Bu
CHO
Bu
Et
a b c
(a) n-PrMgBr ; H3O+ (b) CrO3 (c) Ph3P=CH2
The hexanal starting material is available from Aldrich, $42.90/500 mL.
Copyright © 2011 Elsevier Inc. All rights reserved.
Chapter 8 19
(d)
O
n-Pr
Et
O
On-Bu
n-BuSPh
Et
n-Pr
O
SPh
n-Pr
Et
n-Bu
O
SPh
n-Pr
Et
n-Bu
n-Pr
Et
O
OSPh
Et
n-Pr
SPh
O
n-Pr
Et
O
On-Bu
CHn-PrSPh
Et
n-Pr
O
ab c d
e f g
(a) 1. LiN(i-Pr)2 2. PhSCl (b) NBS , h ; KOH , EtOH (c) (n-Pr)2CuLi ; EtI(d) Ph3P=CHn-Pr (e) HN=NH (f) NaIO4 ; 120°C (g) O3 ; Me2S
Cyclohexanone is available from Aldrich ($19.70/L). The enolate chemistry used here is described in greater
detail in Section 9.4.A.ii. Reduction of the alkene(step e) used diimide, described in Section 4.10.B, and was
chosen to be compatible with the SPh moiety which is known to poison many hydrogenation catalysts and is itself
subject to hydrogenolysis.
(e)
O
CHOOH
CHO
Oa b
(a) n-C6H13MgBr ; H3O+ (b) CrO3
Pentanal is available as valeraldehyde from Aldrich, $33.80/L
(f)
O
CO2H
O
O
CO2H
CO2H
O
O O
a b c d
(a) AlCl3 , succinic anhydride (b) Zn(Hg) , HCl (c) PPA (d) Me2S=CH2
Friedel-Crafts acylation is described in Sections 12.4.D, 12.4.E. Benzene is available from Aldrich, $28.80/L.
Copyright © 2011 Elsevier Inc. All rights reserved.
20 Organic Synthesis Solutions Manual
(g)
O
Me
CHCH2Ph
Me
OH
Me
O
Me
CN
Me
CN
Me
O
Me
OH
Me
CHCH2Ph
O
a b c d
(a) MeMgBr ; H3O+ (b) 1. TsCl , pyridine 2. NaCN , DMF (c) n-PrMgBr ; H3O+ , heat (d) Ph3P=CHCH2Ph
Cyclopentene oxide is available from Aldrich, $118.60/25g.
(h)
O
CHO
CHOO O
a b
SPh2(a) [ / n-BuLi ] (b) HClO4
The hexanal starting material is available from Aldrich, $42.90/500 mL.
Copyright © 2011 Elsevier Inc. All rights reserved.
