Synthetic Routes to (+)-Cassiol and (-)-Cassioside
Maria I. Colombo, and Edmundo A. Rúveda*
Instituto de Química Orgánica de Síntesis (CONICET-UNR), Facultad de Ciencias Bioquímicas y Farmacéuticas, Casilla de Correo 991, 2000 Rosario, Argentina;
e-mail: ruveda@citynet.net.ar
Received: August 10, 1998
Esta revisão sumariza as seqüências desenvolvidas recentemente para a síntese total das substâncias antiulcerogênicas (+)-cassiol e seu glicosídeo (-)-cassiosídeo. A discussão está centrali-zada nas estratégias sintéticas e nas metodologias para a construção de centros carbônicos quaternários.
This review summarizes the sequences recently developed for the total synthesis of the antiulcerogenic compounds (+)-cassiol and its glucoside (-)-cassioside. The discussion is focused on synthetic strategies and on methodologies for the construction of quaternary carbon stereocenters.
Keywords: enantioselective synthesis, construction of quaternary carbon stereocenters
Introduction
As the result of a pharmacological analysis of the aque-ous extract of the dried stem bark of Cinnamomum cassia
Blume, one of the constituents of the traditional chinese prescription ‘‘goreisan’’ (‘‘kennan keihi’’ in Japanese) that displayed a potent antiulcerogenic activity in rats, Fukaya
et al.1 isolated in 1988 three pure compounds responsible for this pharmacological effect. One of these compounds comprised 1 x 10-5% of the stem bark and was named
cassioside (1).
The structure of cassioside (1) {[α]D -25.2 (c 0.5,
MeOH)} was determined by extensive spectroscopic stu-dies. In addition, the enzymatic hydrolysis of 1 with β -D-glucosidase afforded an aglycon named (+)-cassiol (2)
{[α]D 8.6 (c 0.25, MeOH)}, showing more potent antiulcer
activity than cassioside itself.
The absolute configuration of (+)-cassiol (2) was shown to be S by comparison of the CD spectrum of the trimethyl ester 3, prepared by selective hydrogenation, oxidation and methylation of 2, with that of methyl tetrahydrotrisporate C (4), of known absolute configuration. As a consequence
Review
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O
OH OH O
O
OH HO
HO OH
cassioside (1) 1 2
3 4 5 6
1'
2' 3' 4'
O
OH OH OH
cassiol (2)
1 2
3 4 5 6
1'
2' 3'
4'
O
CO Me
CO2Me MeO2C
S
of this comparison, it can be conclude that the absolute configuration at C-4 of (-)-cassioside is also S.
A careful analysis of the structure of (+)-cassiol (2) reveals a rather simple molecular framework that accom-modates a functionalized cyclohexenone moiety with a quaternary stereocenter (C-4) and a 2-ethenyl-1,3-propanediol side chain which is connected at C-3. These structural features and pharmacological activity of cassiol have aroused the interest of synthetic organic chemists and several valuable contributions to its synthesis have ap-peared in the literature in recent years. In this Report we have summarized this body of published material, focusing our attention on synthetic strategies and on new metho-dologies for the construction of quaternary carbon stereo-centers2.
The discussion is organized into three primary sections: 1) strategies based on the assembly of a chiral cyclo-hexenone/cyclohexanone intermediate and its coupling with a side-chain precursor 2) the chiral Diels-Alder
strate-gies and 3) the palladium catalyzed cycloisomerization strategy
Strategies Based on the Assembly of a
Chiral Cyclohexenone/Cyclohexanone
Intermediate and its Coupling with a Side
Chain Precursor
In 1989, Fukaya et al., who had determined the structure of (+)-cassiol (2) just one year earlier, reported also its total synthesis. Fukaya’s strategy3,outlined retrosynthetically in Scheme 1, was based on the selective vinylation of the chiral enone intermediate 6 to furnish the allylic alcohol 5
which, through an 1,3-oxidative rearrangement and depro-tection would afford (+)-(2).
Starting with the commercially available chiral ke-toester 8, of known absolute configuration, and following the degradative sequence described in Scheme 2, the re-quired enone 6 was obtained in enantiomerically pure form {[α]D24 -23.6 (c 1.8, MeOH)}.
For the crucial selective vinylation reaction of (-)-6, the (E)-vinyllithium reagent 7 was generated in situ by the transmetalation of 14 with butyllithium, following the methodology previously described by Corey et al.4, to
afford the allylic alcohol 5 in 94% yield (see next page). The vinylstannane 14 was, in turn, prepared in 29% overall yield starting with bis (trimethylsilyl)-acetylene (12) and following the sequence outlined in Scheme 3.
OTBDPS O
O OH O
OH OH OH
O
OTBDPS O
O Li
5
2 6
7
+
Scheme 1.
O
MeO2C
O O
OH
OTBDPS O
OTBDPS O
8
1) HOCH2CH2OH, TsOH, PhH, reflux 2) Lithium N-isopropylcyclohexylamine, PhSeBr, THF, -70 °C
3) H2O2, CH2Cl2, 0 °C, 66%
(three steps) 10
1) TBDPSCl, imidazole, DMF 2) TsOH, H2O, THF, reflux
78% (two steps) 11
1) LDA, THF, HMPA, MeI, -78 °C 2) TMSOTf, Et3N
3) PhSeCl
4) H2O2, 67%, (four steps) (-)-6 MeO2C
9
O O
1) OsO4, Py, PhH, rt 2) NaIO4, Et2O, rt 3) NaBH4, EtOH, 0 °C, 74% (three steps)
Scheme 2.
O
MeO2C
S
OAc
Finally, the oxidative rearrangement of the allylic alco-hol 5, induced by pyridinium dichromate, gave the ex-pected enone 15 which, by deprotection, afforded (+)-cassiol (2) {[α]D28.5 8.63 (c 0.35, MeOH)} of more than
98% optical purity.
By following a strategy conceptually similar to that outlined in Scheme 1, several authors developed sequences towards cassiol (2), using, however, a variety of interesting methodologies for the construction of the quaternary stere-ocenter present in the required cyclohexenone/cyclohex-anone intermediate.
In 1990, Mori et al.5 reported the enantioselective syn-thesis of the vinylogous ester 21, and its transformation into (+)-cassiol (2), starting with the chiral β-hydroxyester 16. By two successive alkylations of 16 with methyl iodide and with 3,3-dimethoxypropyl iodide (17) respectively, the es-ter 18, with the required stereochemistry at the quaternary stereocenter, was obtained in excellent yield.
That the configuration of this ester is the one shown in
18, was deduced on the basis of previous observationsthat the alkylation of the dianion of 16 (or its methylated pro-duct) gives preferentially the anti-product6. The ester 18
was then transformed into the vinylogous ester 21 by the sequence of functional group interconversions followed by Claisen condensation, esterification and column chroma-tography, as described in Scheme 4.
Finally, addition of 7, generated from 14, to 21 followed by cleavage of the protecting groups gave (+)-2 in 5.6% overall yield and 99.2% ee.
S
S TM
TM
OAc OAc O
O O
TMS
O O
Bu3Sn
12
1) MeLi, THF, rt
2) , THF, -78 °C
MsCl, -78 °C
3) LiAlH4, Et2O, 15 °C, then
Me2C(OMe)2, Me2CO, H2SO4 13
1) Bu4NF, THF, rt
2) Bu3SnH, AIBN, 80 °C
14
Scheme 3.
O
O O OTBDPS
15 5
PDC, CH2Cl2 rt, 75%
70% HF-Py, Py MeCN, 72%
(+)-2
CO2Me
OH
I OMe
OMe
CO2Me OH
OMe
OMe
OH MeO2C
OMe
MeO
OH OMe
MeO
OTBDMS
MeO2C
OTBDMS O
OEt
O
OTBDMS
O
OEt
OTBDMS
1) LDA, MeI, THF, HMPA, 97%
2) LDA, THF, HMPA, 16
18
1) LiAlH4, Et2O, 85%
2) TBDMSCl, imidazole, DMF
19
1) H2CrO4, Me2CO
2) CH2N2, Et2O
61% (two steps) 20
1) NaH, PhH, reflux, 3 h
2) EtI, K2CO3, DMF 2 h, rt, 80%
21 22
+
9 : 1
17 , 97%
OTBDPS
O Bu3Sn
O O
OTBDPS O
O OH
(-)-6
14
BuLi, THF, -50 °C to -78 °C to 0 °C
94%
A similar strategy to that described by Mori et al.5 for the synthesis of (+)-cassiol (2) was reported in 1996 by Taber et al.7 However, a completely different approach was used by these authors for the construction of the vinylogous ester 23, with a defined absolute configuration, as illus-trated in retrosynthetic format in Scheme 5. The key trans-formation in this approach is the stereospecific conversion of an acyclic stereocenter into a cyclic quaternary one (26 →25) by an intramolecular alkylidene carbene methine insertion reaction8.
Starting with (-)-norcitronellol (27) prepared from gera-niol by a known procedure9, and by a series of functional group manipulations, enantiomerically pure 26 was ob-tained (Scheme 6).
The cyclization of 26 into 25 was carried out with the lithium derivative of (trimethylsilyl)-diazomethane (29), generated in situ, and by α-elimination at the vinyl chlo-rides 30 according to Scheme 7. The yield of the two-step route was similar to that of the one-pot procedure with 29. For the preparation of 23, cyclopentene 25 was first submitted to ozonolysis followed by oxidation to the methyl ester 24 which, upon Claisen condensation and esterification with 2-diazopropane, afforded a mixture of regioisomers (23 and 31) separable by column chromato-graphy (Scheme 8).
The catalytic hydrogenation of 23 gave alcohol 32
which, by vinylation, under essentially the same conditions OEt
O OTBDMS
21
Bu3Sn
O O
14
BuLi, THF, -70 °C to 0 °C 2) 10% HF, MeCN, 33% (two steps) 1)
(+)-2
O
O OBn
23
CO2Me O
OBn
24
OBn
25
H O
OBn
26
Scheme 5.
H CHO
OBn
28
OH
Ref. 9 OH
geraniol 27
1) NaH, BnBr, DME, 95% 2) O3, CH2Cl2, -78 °C Ph3P, 82%
1) EtMgBr, THF 2) DMSO, (COCl)2,
Et3N, CH2Cl2 -78 °C, 66% (two steps)
H O
OBn 26
Scheme 6.
H O
OBn OBn
H CHCl
OBn
26
N2CHSiMe3(29), BuLi (hexane), DME, -68 °C, 82%
25
Ph3P=CHCl, THF NaHMDS, -78 °C 97%
30
KHMDS Et2O, 89%
Scheme 7.
OBn
CO2Me O
OBn
O
O
OBn
O
O
OBn
25
1) O3, CH2Cl2, -78 °C, Ph3P, 74% 2) Ca(OCl)2, MeCN, MeOH
AcOH, 4A MS, rt, 61%
24
23 31
+
4 : 1
1) KHMDS, DME
2) (CH3)2C=N2, Et2O, 0 °C
74% (two steps)
previously described, and cleavage of the protecting groups moiety, afforded (+)-cassiol (2) {[α]D 9.1 (c 4.5, MeOH)}.
Also in 1996, Shishido and coworkers10 took advantage of the highly diasteroselective intramolecular [3+2] dipolar cycloaddition of the nitrile oxide 34, generated from oxime
33, for the construction of isoxazoline 35, a precursor of intermediate 36, with a defined stereochemistry at the quaternary stereocenter, to be transformed into (+)-cassiol (2) (Scheme 9).
These authors envisioned, on the basis of molecular mechanic calculations, that the stereochemistry of the two contiguous chiral centers of oxime 33 was crucial to cons-traint the conformation of the transition state of the dipolar cycloaddition reaction to the more favorable chair-like one leading, consequently, to the diasteroselective formation of
35 (Fig. 1).
The preparation of oxime 33 with the required relative and absolute stereochemistry was carried out following the asymmetric aldol methodology of Evans11 and further functional group interconversions, as shown in Scheme 10. The nitrile oxide intermediate 34, generated from oxime 33, on treatment with sodium hypochlorite afforded, as expected, exclusively the isoxazoline 35 in 88% yield. That the stereochemistry of the newly generated center is
S as depicted in 35, was established by NOE experiments
on the free alcohol 41a and further, by analysis of the
1H-NMR spectrum of the corresponding MTPA ester 41b,
it was shown that the optical purity of 35 was more than 99%.
The isoxazoline ring of 35 was smoothly cleaved by hydrogenolysis to afford 36 in good yield. By protection of the free hydroxyl group of 36 followed by vinylation, the intermediate 42 was obtained. Starting with 42 and follo-wing the sequence depicted in Scheme 11, the synthesis of (+)-cassiol (2) was completed.
More recently, in 1998, Banerjee et al.12 reported a short and efficient synthesis of (-)-6, the key intermediate O
O
OH
O O
Br , t-BuLi
32 23
H2, Pd-C
EtOH, 81%
Et2O, -78 °C to 0 °C to rt 2) 10% aq. HCl, 2.5h, 60% (two steps) 1)
(+)-2
OTHP
N-OH
OTHP
N O
OTHP
O OTHP
N
O OH
33 34
+
-36 35
(+)-2
Scheme 9.
THPO
N O
THPO
N O _
35
+
Figure 1.
O N
O O
Ph 37
H O
38
CH2Cl2, Bu2BOTf i-Pr2NEt, -78 °C, 99%
O N
O O
Ph 39 OH
1) DHP, PPTS CH2Cl2, reflux
2) LiAlH4, THF
60% (two steps) OH
OTHP
33
40
1) Swern oxidation 2) H2N-OH.HCl
AcONa, MeOH rt, 89% (two steps)
33
7% aq. NaOCl CH2Cl2, rt, 88%
41a, R=H
41b, R=(S)-MTPA OR
N O PPTS, EtOH
reflux, 75%
MTPCl, Et3N
CH2Cl2, 89%
enone which had been prepared by Fukaya an co-workers in the first synthesis of (+)-cassiol (2)3.
The approach used by Banerjee et al. for the generation of the quaternary stereocenter of (-)-6 was based on the asymmetric Michael addition of chiral imines /secondary enamines under neutral conditions to electrophilic alkenes, recently developed by d’Angelo and co-workers13.
Condensation of β-ketoester 44 with (S)-(-)-α-methyl benzylamine furnished the chiral enamine 45 in excellent yield. The Michael addition of 45 to acrolein followed by hydrolysis and cyclization of the crude product afforded (+)-46. Finally, a sequence involving reduction, selective oxidation and protection gave enantiomerically pure (-)-6
{[α]D25 -22.75 (c 1.65, MeOH)}, this work represents a
formal total synthesis of (+)-cassiol (2) (Scheme 12).
The Chiral Diels-Alder Strategies
Two conceptually related enantioselective synthesis of (+)-cassiol (2) and (-)-cassioside (1) involving a chiral Diels-Alder reaction as the key step, have appeared in the literature.
In 1994, Corey and co-workers14 demonstrated the syn-thetic power of their oxazaborolidine-catalyzed enantiose-lective Diels-Alder reaction15 by the development of a remarkable short and efficient route to (+)-cassiol (2). After an appropriate choice of protecting groups for the diene, small structural modifications in the catalyst and an experi-mentally oriented selection of reaction solvents, Corey et al. discovered that the cycloaddition reaction of the elec-tron-rich triene 51, prepared as depicted in Scheme 13, and 2-methylacrolein in the presence of the chiral oxaza-borolidine derived from tryptophan (54) afforded 52 in 83% yield and 97% ee (see next page).
Finally, by the four-step sequence also described in Scheme 13, (+)-cassiol (2) {[α]D20 8.5(c 0.27, MeOH)}
was obtained in ca. 40% overall yield.
35
H2, Raney-Ni, B(OMe)3 H2O, MeOH, rt, 88%
42
1) TBSCl, imidazole DMF, rt, 97% 2) 14,BuLi, THF -78 °C to 0 °C
HF-Py, MeCN, Py, 73% OTHP
OTBS OH
O O
43
OTBS OH
O O O
36
1) PPTS, EtOH, reflux 2) Me2C(OMe)2, CH2Cl2, rt
3) Swern oxidation, 48% (three steps)
(+)-2
Scheme 11.
OEt O O
OEt O N H Ph Me
H
O
OTBDPS
O MeO2C
O
OH
44
45
(-)-6
(+)-46
(-)-47
(S)-(-)-a-methyl benzyl amine TsOH, PhH reflux, 92%
acrolein, PhH hydroquinone (cat.) 10 °C to rt, pyrrolidine AcOH, EtOH, reflux, 49%
1) LiAlH4, THF, 0 °C 2) MnO2, CH2Cl2, rt, 92%
(two steps)
TBDPSCl, imidazole DMF
Scheme 12.
O
OTBDPS
More recently, in 1996, Boeckman et al.16 reported the construction of the quaternary carbon stereocenter present in (-)-cassioside (1) by an asymmetric Diels Alder reaction of the oxygenated triene 55, identical to triene 51, pre-viously described by Corey et al.14 except by the protecting group, and the chiral dienophile 58.
O O
H O
48
O
50
+ O
PPh3
49
O O
51
O O OTIPS
25% mol of catalyst 54
1:1 CH2Cl2-PhCH3
-78 °C, 42h, 83%, 97% ee
+
CHO
OTIPS
H
O O O
H
52
O
O O HO
53
5 mM HCl, MeOH 23 °C, 30 min, 96% 1) ∆
2) I2, chromatography, 90%
LDA, TIPSOTf 99%
1) NaBH4, THF, H2O, 0 °C, 15 min
2) DDQ, CH2Cl2, HMDS (2 eq.), 23 °C, 3 h
3) Bu4NF, THF, 23 °C, 15 min, 65% (three steps)
(+)-2
Scheme 13.
O
O O
H C=PPh3
CH3
CH3CO
O
O O
OTIPS OTIPS OTIPS
N O
Cl O NH
O
O
48
1) Ph3P=CHO, PhH, reflux
2) , PhH, reflux,
60% (two steps) 50 55
58 BuLi, THF, 0 °C
57 , rt, 2 h 56
1) SiO2, CH2Cl2, H2O, rt
2) Et3N, TIPSOTf, CH2Cl2, rt
99% (two steps)
OTIPS
H
OTIPS OTIPS O
A OTIPS
H
OTIPS OTIPS O
A
O
H
O O O
A
N O
TiCl4, CH2Cl2,
-20 °C to -78 °C, SbPh3
Me3Al, hexane,
CH2Cl2, 48 h, 89%
60 59
+
11 : 1
1) Bu4NF, THF, 18 °C, 12 h
2) Me2C(OMe)2, H2SO4,
Me2CO, rt, 18 h
3) crystallization
61
A =
55 + 58
HN
N H
B O O
O H Ts
The preparation of 55, carried out by two consecutive Wittig reactions, is described in Scheme 14, together with the preparation of the chiral dienophile 58.
To avoid decomposition of the acid-sensitive triene 55, under the usual conditions of the Lewis acid-catalyzed cycloaddition reaction, the TiCl4-SbPh3 complex was
em-ployed as promoter and further, one equivalent of trimethy-lalminum was added as proton scavenger. Under these conditions a 11:1 mixture of two diasteroisomeric cycload-ducts 59 and 60, endo and exo respectively, was obtained in 89% yield. The X-ray analysis of the crystalline ace-tonide derivative 61, prepared as described also in Scheme 14, confirmed the structure and absolute stereochemistry of the major diastereoisomer.
The reduction of the mixture of cycloadducts 59 and 60
followed by column chromatography, allowed the isolation of the major alcohol 62 and recovery of the chiral auxiliary (56). Finally, glycosidation of the hydroxyl group of 62 following
Kahne’s procedure gave intermediate 64 which, by genera-tion of the enone moiety and deprotecgenera-tion afforded (-)-1
{[α]D25 -25.1 (c 0.6, MeOH)}, this work represents the first
total synthesis of (-)-cassioside (1) (Scheme 15).
The Palladium Catalyzed
Cycloisomerization Strategy
Also in 1996, based on the strategy outlined retrosyn-thetically in Scheme 16, Trost et al.17 reported a new total synthesis of (+)-cassiol (2). The key features of Trost’s cassiol synthesis are the new palladium catalyzed cycloi-somerization of enyne 66 in an ene type fashion to the cyclohexanone derivative 65, the elaboration of the side chain present in cassiol by a palladium (0) catalyzed reac-tion (68→67) and the generation of the quaternary carbon stereocenter by an enzymatic process.
As shown in Scheme 17, the conjugate addition of the anion of dimethyl methylmalonate 70 to
N,N-dimethy-OTIPS
H
OTIPS OTIPS
59 + 60 LiBH4, THF, rt, 48 h, 72%
O
OMPM S MPMO
MPMO MPMO
O
Ph
63
Tf2O, 2,6-di-tert-butyl-4-methyl-pyridine, 4A MS, CH2Cl2, -90 °C, 50% OTIPS
H
OTIPS OTIPS OH
62
O
OMPM O MPMO
MPMO MPMO
1) Pd(OAc)2, AgOTf, I2, MeCN, CH2Cl2
2) Et3N, NaI, Me2CO, rt, 60% (two steps) 3) CAN, MeCN, H2O, 80%
(-)-1
-+
64
Scheme 15.
O
OH OH OH
(+)-2
O
66 OTBDMS
TMS
O
MeO2C
67
CO2Me
CO2Me OTBDMS
OTBDMS
NMe2
OTBDMS OTBDMS 65
O TBDMS
TMS O
O
MeO2C
68 NMe2
OAc
CO2H O
MeO2C
69 NMe2
CO2Me CO2Me
70
CO2Me CO2Me
70
1) NaH, THF,
CH2 CHCONMe2
2) PLE, phosphate buffer pH7, rt, 75% (two steps)
CO2H O
MeO2C
69
NMe2 1) 1-Hydroxybenzotriazole, H2O
DCC, THF then NaBH4, 64%
O
MeO2C
72
NMe2 OH
CH2 CHMgBr, THF, -78 °C
then Ac2O, 76% (two steps)
O
66
OTBDMS
O
MeO2C
67
CO2Me CO2Me
OTBDMS OTBDMS
NMe2 O
MeO2C
68
NMe2 OAc
CH2(CO2M)2, NaH
2% (η3-C3H5PdCl)2
Ph3P, THF, 80%
1) NaBH4, THF:EtOH (10:1), 90%
2) TBDMSCl, imidazole, DMF, 80 °C, 94% 3) TMS Li , BF3.OEt2, 74%
TMS 1) DMSO, (COCl)2, CH2Cl2
Et3N, -78 °C to rt
2)
Scheme 17.
O
66
OTBDMS
OTBDMS OTBDMS TMS
OTBDMS OTBDMS
65
O TBDMS
TMS O
OTBDMS OTBDMS
73
O TBDMS
TMS O
OTBDMS OTBDMS
74
O TBDMS
TMS O
(dab)3 Pd3.CHCl3
HCO2H, rt, 3 h, 83%
3 : 1
1) Et3SiH, [(H2C CHSiMe)2O]2Pt
PhMe, 70 °C
2) DDQ, CH2Cl2, rt
Bu4NF, THF, rt +
lacrylamide and desymmetrization of the resulting disubs-tituted malonate by pig liver esterase (PLE) catalyzed hydrolysis led to 69 of 92% ee after recrystallization. Although the absolute configuration of 69 was only tenta-tively assigned at this juncture, it was confirmed as S after completion of the synthesis.
Chemoselective reduction of the carboxylic acid group of 69 furnished alcohol 72 which, by oxidation and addition of vinylmagnesium bromide followed by acetylation gave
68, the substrate required for the elaboration of the side chain of (+)-2. In fact, the Pd (0) catalyzed allylic alkylation of 68 with dimethyl malonate afforded triester 67 in good yield. Starting with 67 and by a sequence involving reduc-tion of the ester groups and protecreduc-tion of the resulting triol, followed by conversion of the N,N-dimethylamide group into an alkynyl ketone, the cyclization precursor 66 was obtained in 18% overall yield in nine steps.
The key cycloisomerization reaction of 66, under the conditions described in Scheme 18, afforded a 3:1 mixture of the diastereisomeric cyclization products 73 and 65 in 83% yield. Finally, by a two-step sequence involving a net double bond migration (74) followed by O and C desilyla-tion (+)-cassiol (2) {[α]D25 16.1 (c 0.15, MeOH)} was
obtained in 42% overallyield for the last three steps.
Concluding Remarks
The application of a variety of synthetic strategies and different methodologies for the construction of quaternary carbon stereocenters can be observed in the description of the sequences towards the synthesis of (+)-cassiol and its glucoside (-)-cassioside. The scarcity of (+)-cassiol to-gether with its promising pharmacological activity and the interesting structural features are likely to stimulate a se-cond generation of short and economical synthetic routes that will soon appear in the literature.
Acknowledgments
We wish to thank CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas) and Universidad Nacional de Rosario (UNR) for financial support.
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