第 九章

掌握生物碱的结构特点，化学性质和鉴别方法，生物碱的提取分离方法；

了解生物碱的活性。了解生物碱的活性。

第一节、概述

十九世纪德国学者F.W.Sertϋrer从鸦片中

分离出吗啡碱(morphine)

现从自然界中分离得到约10000种

《全国医药产品大全》中收载的药物及其

制剂达六十余种

植物中存在的生物碱大多有明显的生理活

性如：

一、概述

鸦片中的吗啡——镇痛作用

麻黄中的麻黄碱——止喘作用

长春花中的长春碱——抗癌活性

黄连中的小檗碱——抗菌消炎作用黄连中的小檗碱——抗菌消炎作用

山莨菪碱——抗中毒性休克作用

生物碱化学结构的研究为合成药物提供了线

索，如：

植物古柯中的有效成分古柯碱（cocaine）虽有很

强的局部麻醉作用，但是毒性较大，久用容易成瘾

NCOOCH

NO

O

C2H5

C2H5

N

普鲁卡因

procaine(合成品)局麻药

NH

COOCH3

O

O古柯碱cocaine（可卡因）

㈠生物碱的定义 指天然产的一类由氨基酸转变成的胺基及胺基衍生物的有机化合物；

多数具有碱性且能和酸结合生成盐；

大部分为杂环化合物且氮原子在杂环内；

多数有较强的生理活性。多数有较强的生理活性。

㈡分布

存在于一百多个科中如：豆科、茄科、防己科、

罂粟科、毛茛科等植物中。

一、概述

1.游离碱：碱性极弱，以游离碱的形式存在。

2.成 盐：有机酸有：柠檬酸、酒石酸等；特殊的

酸类：乌头酸、绿原酸等.无机酸：硫酸、盐酸等。

㈢存在形式

3.苷 类：以苷的形式存在于植物中；

4.酯 类：多种吲哚类生物碱分子中的羧基，常以

甲酯形式存在。

5.N-氧化物：植物体中的氮氧化物约一百余种。

一、概述

㈣命名规则

1. 类型的命名

⑴基核的化学结构，如吡啶、喹啉、萜类等；

⑵以来源植物命名，如石蒜科生物碱等。⑵以来源植物命名，如石蒜科生物碱等。

2.单体成分的命名

⑴以植物来源的属、种的名称命名；如一叶萩碱

⑵也有以生理活性或药效命名，如：吗啡(使睡眠)

⑶以人名命名的；如：pelletierine

第二节、生物碱的分类、生源关系及其分布

分类方法

1.按植物来源分类；

如：石蒜生物碱，长春花生物碱；

2.按化学结构分类；2.按化学结构分类；

如：异喹啉生物碱、甾体生物碱；

3.按生源结合化学分类；

如：来源于鸟氨酸的吡咯生物碱。

classification

Alkaloids are often classified according to the nature of the nitrogen-containing structure, e.g. pyrrolidine, piperidine, quinoline, isoquinoline, indole, etc, though the structural complexity of some examples rapidly expands the number of some examples rapidly expands the number of subdivisions. The nitrogen atoms in alkaloids originate from an amino acid, and, in general, the carbon skeleton of the particular amino acid precursor is also largely retained intact in the alkaloid structure, though the carboxylic acid carbon is often lost through decarboxylation.

Relatively few amino acid precursors are actually involved in alkaloid biosynthesis, the principal ones being ornithine鸟氨酸, lysine赖氨酸, nicotinic acid烟酸, tyrosine酪氨酸, tryptophan色氨酸, anthranilic acid氨基苯甲酸, and histidine组氨酸. Building blocks from the acetate, shikimate, or deoxyxylulose phosphate pathways are also frequently incorporated into the alkaloid structures.

However, a large group of alkaloids are found to acquire their nitrogen atoms via transamination reactions, incorporating only the nitrogen from an amino acid, whilst the rest of the molecule may be derived from acetate or shikimate, or may be terpenoid or steroid in origin. The term ‘pseudoalkaloid’ is sometimes used to distinguish this group.

1. ALKALOIDS DERIVED FROMORNITHINE 鸟氨酸

L-Ornithine (Figure 6.1) is a non-protein amino acid forming part of the urea cycle in animals, where it is produced from L-arginine(精氨酸）in a reaction catalysed by the enzyme arginase（精氨酸酶）. In plants it is formed mainly from L-glutamate (Figure 6.2).

1.1 Pyrrolidine吡咯类 and Tropane托品烷Alkaloids

Simple pyrrolidine-containing alkaloid structuresare exemplified by hygrine古豆碱 and cuscohygrine红古豆碱, found in those plants of the Solanaceae that

accumulate medicinally valuable tropane alkaloidssuch as hyoscyamine天仙子胺 or cocaine (seeFigure 6.3). The pyrrolidine ring system is formedinitially as a Δ1-pyrrolinium cation (Figure 6.2).

In the first step, the enolate anion from acetyl-CoA acts as nucleophile towards

the pyrrolinium ion in a Mannich-like reaction, which could yield products

with either R or S stereochemistry.

The second addition is then a Claisen condensation extending the side-chain,

and the product is the 2-substituted pyrrolidine, retaining the thioester group

of the second acetyl-CoA.

Hygrine and most of the natural tropane alkaloids lack this particular carbon

atom, which is lost by suitable hydrolysis/decarboxylation reactions. The atom, which is lost by suitable hydrolysis/decarboxylation reactions. The

bicyclic structure of the tropane skeleton in hyoscyamine 天仙子胺 and

cocaine is achieved by a repeat of the Mannich-like reaction just observed.

This requires an oxidation step to generate a new Δ1-pyrrolinium cation, and

removal of a proton α to the carbonyl. The intramolecular Mannich reaction

on the R enantiomer accompanied by decarboxylation generates tropinone,

and stereospecific reduction of the carbonyl yields tropine with a 3α-

hydroxyl.

Hyoscyamine 天仙子胺 is the ester of tropine 托品碱with (S )-tropic acid (Figure 6.4), which is derivedfrom L-phenylalanine. A novel rearrangementprocess occurs in the phenylalanine → tropicacid transformation, in which the carboxylgroup apparently migrates to the adjacent carbon(Figure 6.4). Phenylpyruvic acid and phenyl-lacticacid have been shown to be involved andtropine becomes esterified with phenyl-lactic acid(as the coenzyme-A ester) to form littorinebefore the rearrangement occurs. The mechanismof this rearrangement has yet to be proven,though a free radical process (Figure 6.4) withan intermediate cyclopropane-containing radicalwould accommodate the available data.

Anatoxin变性毒素-a (Figure 6.16) is a toxic tropane－related alkaloid produced by a number of cyanobacteria绿藻类, e.g. Anabaena flos-aquae and Aphanizomenon flos-aquae, species which proliferate in lakes and reservoirs during periods of hot, calm weather. A number of animal deaths have been traced back to consumption of water containing the cyanobacteria绿藻类, and ingestion of the highly potent neurotoxin anatoxin-a, which has been termed Very Fast Death Factor. Anatoxina is a powerful agonist抑制剂 at nicotinic acetylcholine receptors烟碱型乙酰胆碱受体, and has become a useful pharmacological probe. The ring system may be regarded as a homotropane, and it has been suggested that the pyrrolidine ring originates from ornithine via putrescine and Δ1-pyrroline, in a way similar to the tropane alkaloids (Figure 6.16).

Anatoxin变性毒素-a

1.2 Pyrrolizidine(双吡咯烷类,吡咯里西丁类) Alkaloids

Two molecules of ornithine鸟氨酸 are utilized in formationof the bicyclic pyrrolizidine skeleton, thepathway (Figure 6.18) proceeding via the intermediatePutrescine 腐胺. Because plants synthesizingpyrrolizidine alkaloids appear to lack theDecarboxylase脱羧酶 enzyme transforming ornithine intoDecarboxylase脱羧酶 enzyme transforming ornithine intoputrescine, ornithine is actually incorporated byway of arginine精氨酸 (Figure 6.2). Two molecules ofputrescine are condensed in an NAD+-dependentoxidative deamination reaction to give the imine,which is then converted into homospermidine byNADH reduction.

Many pyrrolizidine alkaloids are known to produce hepatic toxicity and there are many recorded cases of livestock（Domestic animals,） poisoning. Potentially toxic structures have 1,2-unsaturation in the pyrrolizidine ring and an ester function on the side-chain. Although themselves non-toxic, these side-chain. Although themselves non-toxic, these alkaloids are transformed by mammalian liver oxidases into reactive pyrrole structures, which are potent alkylating agents and react with suitable cell nucleophiles, e.g. nucleic acids and proteins (Figure 6.19).

2. ALKALOIDS DERIVED FROM LYSINE赖氨酸

L-Lysine is the homologue of L-ornithine（鸟氨酸）, and it too functions as an alkaloid precursor, using pathways analogous to those noted for ornithine. The extra methylene group in lysine means this amino acid participates in forming six-membered piperidine rings, just as ornithine provided fivemembered pyrrolidine rings. As with ornithine, the carboxyl group is lost, the ε-amino nitrogen rather than the α-amino nitrogen is retained, and lysine thus supplies a C5N building nitrogen is retained, and lysine thus supplies a C5N building block (Figure 6.21).

N-Methylpelletierine (Figure 6.22) is an alkaloidal constituent of the bark of pomegranate (Punica granatum; Punicacae), where it cooccurs with pelletierine and pseudopelletierine (Figure 6.22), the mixture of alkaloids having activity against intestinal tapeworms. NMethylpelletierine and pseudopelletierine are homologues of hygrine and tropinone respectively, and a pathway similar to Figure 6.3 using the diamine cadaverine (Figure 6.22) may be proposed. (The rather distinctive names cadaverine and putrescine reflect early isolations of these compounds from decomposing animal flesh.) In practice, the Mannich reaction involving the Δ1-piperidinium salt practice, the Mannich reaction involving the Δ1-piperidinium salt utilizes the more nucleophilic acetoacetyl-CoA rather than acetyl-CoA, and the carboxyl carbon from acetoacetate appears to be lost during the reaction by suitable hydrolysis/decarboxylation reactions (Figure 6.22). Anaferine (Figure 6.22) is an analogue of cuscohygrine in which a further piperidine ring is added via an intermolecular Mannich reaction.

The alkaloids found in the antiasthmatic plant Lobelia inflata

(Campanulaceae) contain piperidine rings with alternative C6C2

side-chains derived from phenylalanine via cinnamic acid. These

alkaloids are produced as in Figure 6.23, in which benzoylacetyl-

CoA, an intermediate in the β-oxidation of cinnamic苯乙烯 acid

provides the nucleophile for the Mannich reaction.

Oxidation in the piperidine ring gives a new iminium species, and this

can react further with a second molecule of benzoylacetyl-CoA, can react further with a second molecule of benzoylacetyl-CoA,

again via a Mannich reaction. Naturally, because of the nature of the

side-chain, the second intramolecular Mannich reaction, as involved

in pseudopelletierine biosynthesis, is not feasible. Alkaloids such as

lobeline and lobelanine from Lobelia inflata, or sedamine from

Sedum acre (Crassulaceae), are products from further N-

methylation and/or carbonyl reduction reactions (Figure 6.23).

The pungency（辣素） of the fruits of black pepper (Piper nigrum; Piperaceae), a widely used condiment调味品, is mainly due to the piperidine哌啶 alkaloid piperine (Figure 6.24). In this structure, the piperidine ring forms part of a tertiary amide structure, and is incorporated via piperidine itself, the reduction product of Δ1-piperideine (Figure 6.22).

2.1 Quinolizidine（喹嗪，奎诺里西丁类）Alkaloids

The lupin羽扇豆 alkaloids, found in species of Lupinus (Leguminosae/Fabaceae), and responsible for the toxic properties associated with lupins, are characterized by a quinolizidine skeleton (Figure 6.25). This bicyclic ring system is closely related to the ornithine-derived pyrrolizidine system, but is formed from two molecules of lysine. Lupinine from Lupinus luteus is a relatively simple structure very comparable to the basic ring system of the pyrrolizidine alkaloid comparable to the basic ring system of the pyrrolizidine alkaloid retronecine (see page 305), but other lupin alkaloids, e.g. lupanine and sparteine (Figure 6.25) contain a tetracyclic bis-quinolizidine ring system, and are formed by incorporation of a third lysine molecule.

2.2 Indolizidine（吲哚联啶生物碱）Alkaloids

Indolizidine alkaloids (Figure 6.26) are characterized by fused six- and five-membered rings, with a nitrogen atom at the ring fusion, e.g. swainsonine from Swainsona canescens (Leguminosae/ Fabaceae) and castanospermine from the Moreton Bay chestnut Castanospermum australe (Leguminosae/Fabaceae). In this respect, they appear to be a hybrid between the pyrrolizidine and quinolizidine alkaloids described above. Although they are derived from lysine, their origin deviates from the more common lysine-derived structures in that L-pipecolic acid is an intermediate in the pathway. Two routes to pipecolic acid are known in intermediate in the pathway. Two routes to pipecolic acid are known in nature as indicated in Figure 6.26, and these differ with respect to whether the nitrogen atom originates from the α- or the ε-amino group of lysine. For indolizidine alkaloid biosynthesis, pipecolic acid is formed via the aldehyde and Schiff base with retention of the α-amino group nitrogen. The indolizidinone may then be produced by incorporating a C2 acetate unit by simple reactions, though no details are known. This compound leads to castanospermine by a sequence of hydroxylations, but is also a branchpoint compound to alkaloids such as swainsonine, which have the opposite configuration at the ring fusion. Involvement of a planar iminium ion could account for the change in stereochemistry.

3.ALKALOIDS DERIVED FROMNICOTINIC ACID

1. Pyridine AlkaloidsThe alkaloids found in tobacco (Nicotiana tabacum; Solanaceae) include nicotine and anabasine 新烟碱(Figure 6.28). The structures contain a pyridine ring together with a pyrrolidine ring (in nicotine) or contain a pyridine ring together with a pyrrolidine ring (in nicotine) or a piperidine unit (in anabasine), the latter rings arising from ornithine and lysine respectively. The pyridine unit has its originsin nicotinic acid (vitamin B3) (Figure 6.28), the vitamin sometimes called niacin, which forms an essential component of coenzymessuch as NAD+ and NADP+

The nicotinic acid component of nicotinamideis synthesized in animals by degradation ofL-tryptophan through the kynurenine犬尿酸

pathway and 3-hydroxyanthranilic acid (Figure 6.29) (see also dactinomycin, the pyridine ring being formed by oxidative cleavage of the benzene ring and subsequent inclusion of the amine nitrogen (Figure 6.29).

However, plants such as Nicotiana 烟草use a different pathway employing glyceraldehyde 3-phosphate and L-aspartic acid precursors (Figure 6.30)

In the formation of nicotine, a pyrrolidine ring derived from ornithine鸟氨酸, most likely as the N-methyl-Δ1-pyrrolinium cation (see Figure 6.2) is attached to the pyridine ring of nicotinic acid, displacing the carboxyl during the sequence (Figure 6.31). A dihydronicotinic acid intermediate is likely to be involved allowing decarboxylation to the enamine 1,2-dihydropyridine. This allows an aldol-type reaction with the N-methylpyrrolinium cation, and finally dehydrogenation of the dihydropyridine ring back to a pyridine gives nicotine.

Nornicotine原烟碱 is derived by oxidative demethylation of nicotine. Anabasine is produced from nicotinic acid and lysine via the Δ1-piperidinium cation in an essentially analogous manner (Figure 6.32).

A subtle anomaly has been exposed in that a further Nicotiana alkaloid anatabine appears to be derived bycombination of two nicotinic acid units, and the Δ3-piperideine ring is not supplied by lysine (Figure 6.33).

Nicotinic acid undoubtedly provides the basic skeleton for some other alkaloids. Ricinine (Figure 6.35) is a 2-pyridone structure and contains a nitrile grouping, probably formed by dehydration of a nicotinamide derivative. This alkaloid is a toxic constituent of castor oil seeds (Ricinus communis; Euphorbiaceae), though the toxicity of the seeds results mainly from the polypeptide ricin (see page 434).

蓖麻碱

4. ALKALOIDS DERIVED FROMTYROSINE 酪氨酸

4.1. Phenylethylamines and SimpleTetrahydroisoquinoline四氢异喹啉 Alkaloids

PLP-dependent decarboxylation of L-tyrosine gives the simple phenylethylamine derivativetyramine, which on di-N-methylation yields hordenine, a germination inhibitory alkaloid from barley (Hordeum vulgare; Graminae/ Poaceae) (Figure 6.37).

Closely-related alkaloids cooccurring withmescaline酶斯卡灵(一种致幻剂) are anhalamine老头掌胺 , anhalonine老头掌碱 , and

anhalonidine甲基老头掌胺 (Figure 6.40), which are representativesof simple tetrahydroisoquinoline derivatives.The additional carbon atoms, two in the case ofanhalonidine and anhalonine, and one for anhalamine,are supplied by pyruvate and glyoxylaterespectively. In each case, a carboxyl group islost from this additional

precursor. The keto acidpyruvate reacts with a suitable phenylethylamine,pyruvate reacts with a suitable phenylethylamine,in this case the dimethoxy-hydroxy derivative,giving a Schiff base (Figure 6.40).

The chemical synthesis of tetrahydroisoquinolines by the Pictet–Spengler reaction does not usually employ keto acids like pyruvate or aldehyde acids like glyoxylate. Instead, simple aldehydes, e.g. acetaldehyde or formaldehyde, could be used (Figure 6.41, a), giving the same product directly without the need for a decarboxylation step to convert the intermediate tetrahydroisoquinolinecarboxylic acid (Figure 6.41, b). In nature, both routes are in fact found to operate, depending on the complexity of the R group. Thus, the keto acid (route b) is used for relatively simple substrates (R = H, Me) whilst more complex for relatively simple substrates (R = H, Me) whilst more complex precursors (R = ArCH2, ArCH2 CH2, etc) are incorporated via the corresponding aldehydes (route a). The stereochemistry in the product is thus controlled by the condensation/Mannich reactions (route a), or by the final reduction reaction (route b). Occasionally, both types of transformation have been demonstrated in the production of a single compound,an example being the Lophophora schotti alkaloid lophocerine (Figure 6.42).

Incorporation of a phenylethyl unit into the phenylethylamine gives rise to a benzyltetrahydroisoquinoline skeleton (Figure 6.44), which can undergo further modifications to produce a wide range of plant alkaloids, many of which feature as important drug materials. Fundamental changes to the basic skeleton increase the diversity of structural types as described under ‘modified benzyltetrahydroisoqinolines’. Most examples of benzyltetrahydroisoquinoline alkaloids and modified structures contain ortho di-oxygenation in each aromatic ring, which pattern is potentially derivable aromatic ring, which pattern is potentially derivable from the utilization of two DOPA molecules. Although two tyrosine molecules are used in the biosynthetic pathway, only the phenylethylamine fragment of the tetrahydroisoquinoline ring system is formed via DOPA, the remaining carbons coming from tyrosine via 4-hydroxyphenylpyruvic acid and 4-hydroxyphenylacetaldehyde (Figure 6.45).

吗啡烷

Structures in which two (or more) benzyltetrahydroisoquinoline units are linked together are readily explained by a phenolic oxidative coupling mechanism (see page 28). Thus, tetrandrine (Figure 6.46), a bis-benzyltetrahydroisoquinoline alkaloid isolated from Stephania tetrandra (Menispermaceae) is easily recognized as a coupling product from two molecules of (S )-N-methylcoclaurine (Figure 6.46).

Tetrandrine is currently of interest for its abilityto block calcium channels, and may have applicationsin the treatment of cardiovascular disorders. Bya similar mechanism, tubocurarine (Figure 6.47),the principal active component in the arrow poisoncurare from Chondrodendron tomentosum(Menispermaceae), can be elaborated by a differentcoupling of one molecule each of (S )- and (R)-Nmethylcoclaurinecoupling of one molecule each of (S )- and (R)-Nmethylcoclaurine(Figure 6.47).

4.2. Modified BenzyltetrahydroisoquinolineAlkaloids修饰的苄基四氢异喹啉类生物碱

The principal opium alkaloids morphine吗啡, codeine可代因, and thebaine地

巴因 (Figure 6.50) are derived by this type of coupling, though the

subsequent reduction of one aromatic ring to some extent disguises their

benzyltetrahydroisoquinoline origins.

4.3. Phenethylisoquinoline Alkaloids苯乙基异喹啉生物碱

Several genera（属） in the lily family (Liliaceae百合科 ) are found to

synthesize analogues of the benzyltetrahydroisoquinoline alkaloids,

e.g. autumnaline (Figure 6.65), which contain an extra carbon

between the tetrahydroisoquinoline and the pendant aromatic rings.

This skeleton is formed in a similar way to that in the This skeleton is formed in a similar way to that in the

benzyltetrahydroisoquinolines from a phenylethylamine and an

aldehyde (Figure 6.65), but a whole C6C3 unit rather than a C6C2

fragment functions as the reacting aldehyde.

多巴胺

苛丽碱

(S )-Autumnaline has also been found to actas a precursor for colchicine 秋水仙碱(Figure 6.66), analkaloid containing an unusual tropolone ring.Colchicine is found in species of Colchicum , e.g.Colchicum autumnale (Liliaceae/Colchicaceae), aswell as many other plants in the Liliaceae.Colchicine no longer has its nitrogen atom ina ring system, and extensive reorganization ofthe autumnaline structure is thus necessary. Theseven-membered tropolone ring was shown bylabelling experiments to originate by ring expansionof the tyrosine-derived aromatic ring takingof the tyrosine-derived aromatic ring takingin the adjacent benzylic carbon (Figure 6.66).Prior to these remarkable rearrangements, oxidativecoupling of autumnaline in the para–parasense features in the pathway giving the dienoneisoandrocymbine, which has a homomorphinanskeleton (compare salutaridine, Figure 6.50). Theisomer androcymbine (Figure 6.66) had beenisolated from Androcymbium melanthioides (Liliaceae/Colchicaceae), thus giving a clue to thebiosynthetic pathway.

4.4. Amaryllidaceae Alkaloids石蒜生物碱

Various types of alkaloid structure are encountered in the daffodil(水仙） family, the Amaryllidaceae, and they can be rationalized better through biosynthesis than by structural type. The alkaloids arise by alternative modes of oxidative coupling of precursors related to norbelladine (Figure 6.69), which is formed through combination of 3,4- dihydroxybenzaldehyde with tyramine 酪胺(β-氨基乙基苯酚的俗名), these two preursors arising from phenylalanine and tyrosine respectively. Three structural types of alkaloid can be related to 4-O-methylnorbelladine by different alkaloid can be related to 4-O-methylnorbelladine by different alignments of the phenol rings, allowing coupling para–ortho (A), para–para (B), or ortho–para (C) as shown in Figure 6.69. For galanthamine, the dienone formed via oxidative coupling (C) undergoes nucleophilic addition from the phenol group, forming an ether linkage (compare opium alkaloids, page 328), and the sequence is completed by reduction and methylation reactions. For lycorine（石蒜碱） and crinine, although details are not given in Figure 6.69, it is apparent that the nitrogen atom acts as a nucleophile towards the dienone system in a similar manner, generating the new heterocyclic ring systems.

加兰他敏

5.ALKALOIDS DERIVED FROMTRYPTOPHAN

L-Tryptophan色氨酸 is an aromatic amino acid containing an indole

ring system, having its origins in the shikimate pathway via

anthranilic acid（邻氨基苯甲酸）. It acts as a precursor of a wide

range of indole alkaloids, but there is also definite proof that major

rearrangement reactions can convert the indole ring system into a rearrangement reactions can convert the indole ring system into a

quinoline ring, thus increasing further the ability of this amino acid

to act as an alkaloid precursor .

5.1 Simple Indole AlkaloidsTryptamine色胺,β-吲哚基乙胺and its N-methyl and N,N-

dimethyl derivatives (Figure 6.70) are widely distributed in plants, as are simple hydroxylated derivatives such as 5-hydroxytryptamine (serotonin). These are formed (Figure 6.70) by a series of decarboxylation, methylation, and hydroxylation reactions, though the sequences of these reactions are found to vary according to final product and/or organism involved. 5-Hydroxytryptamine is also found in mammalian tissue, where it acts as a neurotransmitter in the central nervous system. It is formed from tryptophan by hydroxylation and then decarboxylation, paralleling the tyrosine → dopamine pathway (see page 316). In the formation of psilocin (Figure 6.70), decarboxylation precedes N-methylation, and hydroxylation occurs last. Phosphorylation of the hydroxyl in psilocin gives psilocybin

5.2 Simple β-Carboline咔啉 Alkaloids

Alkaloids based on a β-carboline system (Figure 6.73) exemplify the formation of a new six membered heterocyclic ring using the ethylamine side-chain of tryptamine in a process analogous to generation of tetrahydroisoquinoline alkaloids . Position 2 of the indole system is nucleophilic due to the adjacent nitrogen, and can participate in a Mannich/Pictet–Spengler type reaction, and can participate in a Mannich/Pictet–Spengler type reaction, attacking a Schiff base generated from tryptamine and an aldehyde (or keto acid) (Figure 6.73). Aromaticity is restored by subsequent loss of the C-2 proton. (It should be noted that the analogous chemical reaction actually involves nucleophilic attack from C-3, and then a subsequent rearrangement occurs to give bonding at C-2; there is no evidence yet for this type of process in biosynthetic pathways.)

5.3 Terpenoid Indole Alkaloids萜吲哚类生物碱

More than 3000 terpenoid indole alkaloids are recognized,making this one of the major groupsof alkaloids in plants. They are found mainly ineight plant families, of which the Apocynaceae夹竹桃科,the Loganiaceae马钱科, and the Rubiaceae茜草科 provide thebest sources. In terms of structural complexity,many of these alkaloids are quite outstanding, andit is a tribute to the painstaking experimental studiesof various groups of workers that we are ableto rationalize these structures in terms of theirto rationalize these structures in terms of theirbiochemical origins. In virtually all structures, aTryptamine色胺 portion can be recognized. The remainingfragment is usually a C9 or C10 residue, andthree main structural types are discernable. Theseare termed the Corynanthe type, as in ajmalicine阿马里新and akuammicine阿枯米辛碱 , the Aspidosperma type, as intabersonine水甘草碱 , and the Iboga type, exemplified bycatharanthine长春花碱 (Figure 6.75).

Condensation of secologanin裂环马钱子碱 with tryptamine in a Mannich-like reaction generates the tetrahydro- β-carboline system and produces strictosidine (Figure 6.76).

Carbocyclic variants related to ajmalicine such as yohimbine are likely to arise from dehydrogeissoschizine by the mechanism indicated in Figure 6.77.

Reserpine利血平 and deserpidine(Figure 6.78) are trimethoxybenzoyl esters ofyohimbine-like alkaloids, whilst rescinnamine萝芙木碱 is a

trimethoxycinnamoyl ester. Both reserpine andrescinnamine contain an additional methoxyl substituenton the indole system at position 11, theresult of hydroxylation and methylation at a latestage in the pathway. A feature of these alkaloidsis that they have the opposite stereochemistry atposition 3 to yohimbine and strictosidine. Rauwolfiaposition 3 to yohimbine and strictosidine. Rauwolfiaserpentina also contains significant amountsof ajmalicine (Figure 6.76), emphasizing the structuraland biosynthetic relationships between thetwo types of alkaloid.

The structural changes involved in converting the Corynanthe type skeleton into those of the Aspidosperma and Iboga groups are quite complex, and are summarized in Figure 6.79.

Further variants on the terpenoid indole alkaloid skeleton (Figure 6.82)

士的宁碱

二甲马钱子碱

5.4 Quinoline喹啉 Alkaloids§ Some of the most remarkable examples of terpenoid indole alkaloid

modifications are to be found in the genus Cinchona 金鸡纳树, 金鸡纳皮(Rubiaceae), in the alkaloids quinine 奎宁quinidine, cinchonidine, and cinchonine (Figure 6.88), long prized for their antimalarial 抗疟的properties.

These structures are remarkable in that the indole nucleus is no longer present, having been rearranged into a quinoline system (Figure 6.89). The relationship was suspected quite early on, however, since the indole derivative cinchonamine (Figure 6.90) was known to co-occur with these quinoline alkaloids. An outline of the pathway from the Corynanthe-type indole alkaloids to cinchonidine is shown in Figure 6.90. The conversion is dependent on the reversible processes by which amines plus aldehydes or ketones, imines (Schiff bases), and their reduction products are imines (Schiff bases), and their reduction products are related in nature.

Camptothecin 喜树碱(Figure 6.93) from Camptothecaacuminata (Nyssaceae) is a further example ofa quinoline-containing structure that is actuallyderived by modification of an indole system. Themain rearrangement process is that the original β-carboline 6–5–6 ring system becomes a 6–6–5pyrroloquinoline by ring expansion of the indoleheterocycle (Figure 6.92). In camptothecin, theiridoid portion from strictosidine is effectivelystill intact, the original ester function being utilizedstill intact, the original ester function being utilizedin forming an amide linkage to the secondaryamine. This occurs relatively early, inthat strictosamide is an intermediate. Pumiloside(also isolated from C. acuminata) and deoxypumilosideare potential intermediates. Stepsbeyond are not yet defined, but involve relativelystraightforward oxidation and reduction processes(Figure 6.93).

5.5 Pyrroloindole AlkaloidsBoth C-2 and C-3 of the indole ring can be regarded as nucleophilic, but

reactions involving C-2 appear to be the most common in alkaloid biosynthesis. There are examples where the nucleophilic character of C-3 is exploited, however, and the rare pyrroloindole skeleton typified by physostigmine毒扁豆碱 (eserine) (Figure 6.95) is a likely case.

5.6 Ergot麦角 AlkaloidsErgot is a fungal disease commonly found onmany wild and cultivated grasses, and is causedby species of Claviceps. The disease is eventuallycharacterized by the formation of hard, seedlike‘ergots’ instead of normal seeds, these structures, called

sclerotia, forming the resting stage of thefungus. The poisonous properties of ergots in grain,fungus. The poisonous properties of ergots in grain,especially rye黑麦, for human or animal consumptionhave long been recognized, and the causativeagents are known to be a group of indole alkaloids,referred to collectively as the ergot alkaloidsor ergolines麦角灵 (Figure 6.99).

The building blocks for lysergic acid are tryptophan (less the carboxyl group) and an isoprene unit (Figure 6.100).

Alkylation of tryptophan with dimethylallyl diphosphate gives 4-dimethylallyl Ltryptophan色氨酸, which then undergoes N-methylation (Figure 6.101).

麦角胺

6. ALKALOIDS DERIVED FROMANTHRANILIC ACID

Anthranilic acid 邻胺基苯甲酸 (Figure 6.106) is a key intermediate in the biosynthesis of L-tryptophan and so contributes to the elaboration of indole alkaloids. During this conversion, the anthranilic acid residue is decarboxylated, so anthranilic acid residue is decarboxylated, so that only the C6N skeleton is utilized. However, there are also many examples of where anthranilic acid itself functions as an alkaloid precursor, using processes which retain the full skeleton and exploit the carboxyl (Figure 6.106).

6.1 Quinazoline 喹唑啉 alkaloids

Peganine 骆驼蓬碱或瓦丝素(Figure 6.107) is a quinazoline alkaloid found in Peganum harmala (Zygophyllaceae), where it co-occurs with the β-carboline alkaloid.

6.2 Quinoline and Acridine （吖啶, 氮蒽）Alkaloids

anthraniloyl-CoA (Figure 6.108) can act as a starter unit for chain extension via

one molecule of malonyl-CoA, and amide formation generates the

heterocyclic system, which will adopt the more stable 4-hydroxy-2-quinolone

form (Figure 6.108). Position 3 is highly nucleophilic and susceptible to

alkylation, especially via dimethylallyl diphosphate in the case of these alkylation, especially via dimethylallyl diphosphate in the case of these

alkaloids.

7. ALKALOIDS DERIVED FROMHISTIDINE（组氨酸）

7.1 Imidazole咪唑 AlkaloidsThe amino acid L-histidine (Figure 6.110) contains an imidazole ring,

and is thus the likely precursor of alkaloids containing this ring system. There are relatively few examples, however, and definite evidence linking them to histidine is often lacking. Histamine 组胺(Figure 6.110) is the decarboxylation product from histidine and is often involved in human allergic responses, e.g. to insect bites or pollens. Stress stimulates the action of the enzyme histidine decarboxylase and histamine is released from mast cells (Figure decarboxylase and histamine is released from mast cells (Figure 6.110).

Histidine is a proven precursor of dolichotheline (Figure 6.111) in Dolichothele sphaerica (Cactaceae), the remaining carbon atoms originating from leucine via isovaleric acid.

匹鲁卡品,毛果芸香碱(一种眼科缩瞳药)

异毛果芸香碱

Pilocarpine is valuable in ophthalmic work as a miotic and as a treatment for glaucoma. Additional carbon atoms may originate from acetate or perhaps the amino acid threonine in the case of pilocarpine, whilst pilosine incorporates a phenylpropane C6C3 unit (Figure 6.113).

8. ALKALOIDS DERIVED BY AMINATIONREACTIONS

The majority of alkaloids are derived from aminoacid precursors by processes that incorporate intothe final structure the nitrogen atom together withthe amino acid carbon skeleton or a large proportionof it. Many alkaloids do not conform with this

description, however, and are synthesized primarily from non-amino acid precursors, with the

nitrogen atom being inserted into the structure at anitrogen atom being inserted into the structure at arelatively late stage. Such structures are frequentlybased on terpenoid or steroidal skeletons, thoughsome relatively simple alkaloids also appear tobe derived by similar late amination processes. Inmost of the examples studied, the nitrogen atomis donated from an amino acid source through atransamination reaction with a suitable aldehydeor ketone.

8.1 Acetate-derived AlkaloidsThe poison hemlock毒芹 (Conium maculatum ; Umbelliferae/Apiaceae) accumulates a range of simple piperidine alkaloids, e.g.

coniine毒芹碱 and γ- coniceine (Figure 6.115). A study of their biosynthetic origins excluded lysine as a precursor, and demonstrated the sequence shown in Figure 6.115 to be operative.

Pinidine (Figure 6.116) from Pinus species is found to have a rather similar origin in acetate, and most likely a poly-β-keto acid. During the sequence outlined in Figure 6.116, the carboxyl group is lost. Note that an alternative folding of the poly-β-keto acid and loss of carboxyl might be formulated.

8.2 Phenylalanine苯丙氨酸-derived Alkaloids

Whilst the aromatic amino acid L-tyrosine is a common and extremely important precursor of alkaloids ， L-phenylalanine is less frequently utilized, and usually it contributes only carbon atoms, e.g. C6C3, C6C2, or C6C1 units, without providing a nitrogen atom from its amino group . Ephedrine麻黄碱 (Figure 6.117), the main alkaloid in species of Ephedra∗ (Ephedraceae) and a valuable nasal decongestant鼻腔充血and bronchial 支气管dilator, is a prime example.

8.3 Terpenoid AlkaloidsA variety of alkaloids based on mono-, sesqui-, di-,and tri-terpenoid skeletons have been characterized,but information about their formation in nature isstill somewhat sparse.Monoterpene alkaloids are in

themain structurally related to iridoidmaterials (seethemain structurally related to iridoidmaterials (seepage 187), the oxygen heterocycle being replacedby a nitrogen-containing ring. β-Skytanthine fromSkytanthus acutus (Apocynaceae) and actinidinefrom Actinidia polygama (Actinidiaceae) serve asexamples (Figure 6.122).

Gentianine 龙胆宁(Figure 6.123) is probably the mostcommon of the monoterpene alkaloids, but it issometimes formed as an artefact when a suitableplant extract is treated with ammonia, the basecommonly used during isolation of alkaloids.

Perhaps the most important examples of

terpenoid alkaloids from a pharmacological point

of view are those found in aconite （乌头, 从乌头的根提炼出的强心止痛剂）or wolfsbane (Aconitum species; Ranunculaceae) and species of Delphinium (Ranunculaceae). Whilst Aconitum napellus has had some medicinal uses, plants of both genera owe their highly toxic nature to diterpenoid alkaloids. Aconite in particular is regarded as extremely toxic, due to the presence of aconitine乌头碱 (Figure 6.124) and related C19 norditerpenoid alkaloids. 碱 (Figure 6.124) and related C19 norditerpenoid alkaloids. Species of Delphinium accumulate diterpenoid alkaloids such as atisine (Figure 6.124), which tend to be less toxic than aconitine.

阿替素，异叶乌头碱,阿替素，异叶乌头碱,阿提辛(退热药)

8.4 Steroidal Alkaloids甾体类生物碱

Many plants in the Solanaceae accumulate steroidal alkaloids based on a

C27 cholestane skeleton, e.g. solasodine and tomatidine (Figure C27 cholestane skeleton, e.g. solasodine and tomatidine (Figure

6.126).

As with the sapogenins, this group of steroidalalkaloids is derived from cholesterol, with appropriateside-chain modifications during the sequence(Figure 6.127). Amination appears to employL-arginine as the nitrogen source, probably via asubstitution process on 26-hydroxycholesterol. Asecond substitution allows 26-amino-22-hydroxycholesterolto cyclize, generating a piperidine ring.to cyclize, generating a piperidine ring.After 16β-hydroxylation, the secondary amine isoxidized to an imine, and the spiro-system canbe envisaged as the result of a nucleophilicaddition of the 16β-hydroxyl on to the imine(or iminium via protonation). Whether the 22R(as in solasodine) or 22S (as in tomatidine)configuration is established may depend on thisreaction.

condensed ring system appears to be produced by a branch from the main pathway to solasodine/tomatidine structures. Thus, a substitution process will allow generation of the new ring system (Figure 6.128).

9. PURINE嘌呤 ALKALOIDS

The purine derivatives caffeine , theobromine ,and theophylline (Figure 6.135) are usuallyreferred to as purine alkaloids. As alkaloids theyhave a limited distribution, but their origins arevery closely linked with those of the purine basesadenine and guanine, fundamental components ofnucleosides, nucleotides, and the nucleic acids.nucleosides, nucleotides, and the nucleic acids.

9.1 Saxitoxin and Tetrodotoxin（贝类毒素&河豚毒素）

The structure of saxitoxin (Figure 6.136) contains a reduced purine ring system, but it is not biosynthetically related to the purine alkaloids described above. Not all features of its biosynthetic origin have been established, but the amino acid supplying most of the ring system is known to be L-arginine (Figure 6.136).

macrocyclic alkaloid 大环生物碱类

Cl

N

MeO

O

O

N

Me

O

Me

H MeMeO

OH Me

N

O

O

O

Me

HMe

OMeO

Me

美登碱maytansine

高效低毒、安全幅度大的抗癌活性成分

其他类型生物碱

N

NMe Me

MeMe

O O

OMeCH3O

H

四甲基吡嗪（川芎嗪）

O OCl

O

MeON

OMeMe

O

N

CH3O

O

O

H

N H

莲氏花烷hasubanane

间千金藤碱metaphanine

短防已碱acutumine

本章内容

一、概述

二、生物合成途径

F

三、分类和分布

四、理化性质

五、提取与分离

六、结构鉴定

第四节生物碱的理化性质

（一）性状

1.形态——多为结晶固体，少为粉末；有熔点。

少数常温下——液体（多不含氧，若含多成酯键）

COOCH

N

N

N

N

MeN

Me

COOCH3

毒藜碱dl-anabasine

菸碱nicotine

槟榔碱arecoline

三、理化性质（一）一般性质

2.颜色——多为无色或白色，少数有色。

N

O

N

O

Zn+NO

OMe

OMe

NO

OMe

OMe

Zn

H2SO

4

+

小檗碱 四氢小檗碱

（ 黄色） （ 无色）

三、理化性质（一）一般性质

O

O

一叶萩碱成盐后则无色。

N

一叶萩碱（黄色）

三、理化性质（一）一般性质

3.味 觉——多具苦味。

4.挥发性——多无挥发性，少数具挥发性。

5.旋光性——多为左旋光性。

有的产生变旋现象。

如：菸碱 中性溶液——左旋光性

酸性溶液——右旋光性

多数左旋体呈显著生理活性。

三、理化性质（一）一般性质

6.溶解度(1)游离碱

类别 极性 溶解性 H2O CHCl3 H+ OH-

非酚性 较弱 脂溶性 — + + —

季铵碱 强 水溶性 + — + +

*酸、碱均为1%。

氮氧化物 半极性中等水溶 + ± + +

两性: Ar-OH 较弱 脂溶性 — + + +-COOH 强 水溶性 + — + +

三、理化性质（一）一般性质

6.溶解度

(1)游离碱

少数酚性碱，由于各种原因而导致不溶碱水中。

如：

NO

Me

OMe

OMe

O

N Me

MeO

O

去甲 基粉 防 已碱

由于空间位阻 且能

所以不溶于碱水

Ar-OH

形成分 子 内氢键

三、理化性质（一）一般性质

6.溶解度

(2)成盐Alk

多易溶于水，不溶或难溶有机溶剂。

含氧酸盐的水溶性往往较大。含氧酸盐的水溶性往往较大。

与大分子有机酸所形成的盐水溶性差

与小分子有机酸或无机酸成盐水溶性较好。

五、化学性质和反应

（一）碱性

1.碱性的来源

N: N:H+ H++

生物碱 生物碱盐生物碱 生物碱盐

2.碱性强弱的表示方法

BH H3O+ B++

Ka[B] [H3O]

[BH ]

+

+

三、理化性质（二）碱性

2.碱性强弱的表示方法

[BH ]

[B]pKa pH lg

+——

游离碱浓 度

成盐碱浓 度

pKa = - lgKa；pKb = - lgKb；pKa + pKb = 14

pKa: < 2 2 ~ 7 7 ~ 11 > 11

极弱碱 弱 碱 中强碱 强碱

三、理化性质（二）碱性

3.影响碱性强弱的因素

（1）杂化方式

N -N C C NSP3 ( ) > SP2 ( ) > SP ( )

pKa ~ ~ ~ pKa 10~ 5 ~ 6 0 ~ 1

N N

吡啶 胡椒 啶

pka= 5.2 ( SP2 ) pka = 11.2 ( SP3 )

三、理化性质（二）碱性

3.影响碱性强弱的因素

（2）电子效应

N Me N N MeMe Me N Me

MeMe

仲胺 叔胺伯胺胺

pka9.3 10.6 10.7 9.74

连接供电基团则使碱性增强。

三、理化性质（二）碱性

3.影响碱性强弱的因素

（2）电子效应

pKa : 11.2 10.1 11.3 10.4

N N N N

A B a b

三、理化性质（二）碱性

3.影响碱性强弱的因素

（2）电子效应

氮原子附近若有吸电基团，碱性减弱。

NH

COOCH3

O C

O

NH

O C

O可卡 因 托哌可卡 因

pKa = 8.31 pKa = 9.88

三、理化性质（二）碱性

3.影响碱性强弱的因素

（2）电子效应

氮原子孤电子对处于P~π共轭体系时，碱性减弱。

N C O

R

..

酰胺 结构

O

O

N

O

N

N

O

N

N

Me

Me

O

Me胡椒 碱 咖 啡 因

（ pKa=1.22）（ pKa=1.42）

三、理化性质（二）碱性

3.影响碱性强弱的因素

（2）电子效应

诱导——场效应：碱性降低。

N

N

N2

N1

1

2

菸碱

=8.2

=3.4

pKa

NN

pKa=5.2 pKa=10.4

三、理化性质（二）碱性

3.影响碱性强弱的因素

（3）立体因素

叔胺分子——碱性降低

但如：苦参碱——使碱性增强但如：苦参碱——使碱性增强

N

N

O

16

1

苦参碱

N..

三、理化性质（二）碱性

3.影响碱性强弱的因素

（4）分子内氢键

若能形成稳定的分子内氢键，可使碱性增强。

（指成盐时接受的质子能形成稳定的分子内氢键）（指成盐时接受的质子能形成稳定的分子内氢键）

C C

H

O

H

NHCH3

C C

O

H

H

NHCH3

麻黄碱 伪 麻黄碱

三、理化性质（二）碱性

3.影响碱性强弱的因素

（4）分子内氢键

O H

NHMeH2

Me

H

H1

H1

OH

NHMeH2

Me

H+

+

伪 麻黄碱麻黄碱

MeMe

三、理化性质（二）碱性

3.影响碱性强弱的因素

（4）分子内氢键

O H

NHMeH2

Me

H

H1

H1

OH

NHMeH2

Me

H+

+

伪 麻黄碱麻黄碱

pKa=9.74pKa=9.58

三、理化性质（二）碱性

3.影响碱性强弱的因素

（5）分子内互变异构

NN

O

Me

MeOOC

1

4

蛇根碱

三、理化性质（二）碱性

3.影响碱性强弱的因素

（5）分子内互变异构

NN

O

Me

MeOOC

1

4

蛇根碱

三、理化性质（二）碱性

3.影响碱性强弱的因素

（5）分子内互变异构

NN

O

Me

MeOOCO

Me

MeOOC

NN+

_1

4

蛇根碱

异构化

pKa=10.8

三、理化性质（二）碱性

3.影响碱性强弱的因素

（5）分子内互变异构

O

N

O

OO

OMe

OMe醇胺 型小檗碱 pKa=11.53

N

O

O

OMe

OMe

+.OH-

季铵 型

异构化

三、理化性质（二）碱性

3.影响碱性强弱的因素

（5）分子内互变异构

N:O

N

N:

OO新番 木鳖 碱 pKa=3.8

NN

Me

O

H

pKa=8.15阿 马林碱

N原子处在稠环的“桥头”——张力较大

三、理化性质（二）碱性

3.影响碱性强弱的因素

（5）分子内互变异构

互变异构的条件：

①环叔胺分子，氮原子的α、β位有双键；①环叔胺分子，氮原子的α、β位有双键；

②环叔胺分子，氮原子的α位有-OH；

③处于稠环桥头的N，不能异构化。

三、理化性质（二）碱性

3.影响碱性强弱的因素

碱性强弱：

Ar-NH2N

+OH N H NH2 N

O

NH

->>>>>

H季铵 仲胺 伯胺 叔胺 芳胺 酰胺

供电--碱性↑

共轭、诱导吸电--碱性↓

三、理化性质（二）碱性

比较碱性强弱：

N Me3

NN O1 2 N

H CONHCH

MeCH

2OH

Me3

N

NN

MeH

1 2

brevicolline

A

3 > 2 > 1

NN

N

O

MeH

1 2

3

evodiamine

吴茱萸碱

B

1 > 3 > 2

N

N

Me

HC

1

2

麦角新碱ergonovine

2 > 1 > 3

三、理化性质

（三）成盐

生物碱与酸成盐，对质子化来说，仲胺、叔胺

生物碱成盐时，质子多结合于氮原子。

季胺碱、氮杂缩醛、烯胺以及具有涉及氮原子

的跨环效应形式存在的生物碱，质子化则往往并非

发生在氮原子上。

三、理化性质

（三）成盐

1.季胺碱的成盐

N OHOH

N+ - H X

-+ X

. - + H OH

季胺 碱 盐 水

质子与OH-结合成水

三、理化性质

（三）成盐

2.含氮杂缩醛Alk的成盐

HHH X +

质子与RO-结合成H-OR(醇或水）

N C4

H

OR N C11 H

H OH X

OH 或 HOR

+X-

+ R

氮杂缩醛生物碱 亚胺 盐 醇或水

三、理化性质

（三）成盐

2.含氮杂缩醛Alk的成盐

N

N

O

OO CH2CH3

N

N

O CH2CH3

COOH

H

OH

++

-

斯米 生 （ 亚胺 盐）

（内脂环开裂，质子与COO 结合）-

三、理化性质

（三）成盐

3.具有烯胺结构Alk的成盐

+

N C C N C C

H.. α β +H+

烯胺 亚胺 盐

Alk质子化多在β碳上，而非氮原子

三、理化性质

（三）成盐

3.具有烯胺结构Alk的成盐

N

O

N

H

MeOOC

N

O

N

H

MeOOC

H

+HCl

OH-

二氢奥 斯冬宁 亚胺 盐

三、理化性质

（三）成盐

*稠环桥头N原子不能形成亚胺形式的盐。

NH

O

N

N

OHH

H

HO

有烯胺结构

新士的宁

NN

Me

O

O

H

含氮杂缩醛结构阿马林碱

三、理化性质

（三）成盐

4.涉及氮原子跨环效应Alk的成盐

N N C+H+

N O

N C

O

+

OH-

H

具有酮基的Alk 成盐

N原子孤电子对空间上靠近酮基时，则产生跨环效应

三、理化性质

（三）成盐

4.涉及氮原子跨环效应Alk的成盐

MeO MeO

N

O

N

MeOOC

O

Me

MeO

MeO

O

N

MeOOC

Me

MeO

MeON

O

H +..+

产生跨环效应生成的盐二甲氧基皮拉菲林

dimethoxy picraphylline

三、理化性质

（四）沉淀反应－生物碱的鉴识

用途：

鉴别——试管、TLC或PPC显色剂；

提取分离——检查是否提取完全。

主要内容： 1.沉淀试剂主要内容： 1.沉淀试剂

2.反应原理

3.反应条件

4.结果判断

三、理化性质

（五）沉淀反应

1.沉淀试剂

金属盐类

碘-碘化钾（Wagner）KI-I2 棕褐色沉淀

⋅碘化铋钾（Dragendoff）BiI3⋅KI 红棕色沉淀

碘化汞钾（Mayer试剂）HgI2⋅2KI 类白色沉淀

若加过量试剂，沉淀又被溶解

氯化金(3%)（Suric chloride）HAuCl4 黄色晶形沉淀

三、理化性质

（五）沉淀反应

1.沉淀试剂

酸类——硅钨酸(Bertrand试剂)SiO2⋅12WO3乳白色

酚酸类——苦味酸(Hager试剂) 2,4,6-三硝基苯酚黄色

复盐——

雷氏铵盐(Ammoniumreineckate)硫氰酸铬铵试剂

生成难溶性复盐 紫红色

三、理化性质

（五）沉淀反应

2.反应原理：生成更大多分子复盐和络盐

NH KBiI4

NH BiI4

+ + + - + K+

生物碱盐 碘化铋钾

NH

O

NO2

NO2O

2N

O

O2N

NO2

O2N

NH+

生物碱盐

++ -

苦味酸

三、理化性质

（五）沉淀反应

3.沉淀反应条件

（1）通常在酸性水溶液中生物碱成盐状态下进行；

（若在碱性条件下则试剂本身将产生沉淀）

（2）在稀醇或脂溶性溶液中时，含水量>50%；

（当醇含量>50%时可使沉淀溶解）

（3）沉淀试剂不易加入多量。

（如：过量的碘化汞钾可使产生的沉淀溶解）

三、理化性质

（五）沉淀反应

4.结果的判断

（1）鉴别时每种Alk需采用三种以上沉淀试剂；

（沉淀试剂对各种Alk的灵敏度不同）

（2）直接对中药酸提液进行沉淀反应，则

阳性结果——不能判定Alk的存在

阴性结果可判断无Alk存在

氨基酸、蛋白质、多糖、鞣质等 + 沉淀试剂——沉淀

三、理化性质

（六）显色反应

◆Labat反应

5%没食子酸的醇溶液

具有亚甲二氧基结构呈翠绿色

◆Vitali反应

发烟硝酸和苛性碱醇溶液

结构中有苄氢存在则呈阳性反应

深紫—暗红—最后颜色消失

本章内容

一、概述

二、生物合成途径

F

三、分类和分布

四、理化性质

五、提取与分离

六、结构鉴定

第五节生物碱的提取与分离

一、总生物碱的提取

（一）提取溶剂提取，离子交换和沉淀法

1.酸水提取法

2.醇类溶剂提取法

3.与水不相混溶的有机溶剂提取法

四、提取分离（一）提取

1.酸水提取法：冷提法（渗漉法、冷浸法）

酸性水——0.1% ~ 1%H2SO4、HCl、HOAc等

生药H+/H2O

生药H+/H2O

生药H+/H2O

生药H+/H2O

生药H+/H2O

生药H+/H2O

H+/H2O药渣

Alk ↓OH-/H2O

OH-弱碱及杂质

亲水性Alk

H+/H2O药渣

Alk ↓OH-/H2O

OH-弱碱及杂质

亲水性Alk

H+/H2O药渣

Alk ↓OH-/H2O

OH-弱碱及杂质

亲水性Alk

H+/H2O药渣

Alk ↓OH-/H2O

OH-弱碱及杂质

亲水性Alk

H+/H2O药渣

Alk ↓OH-/H2O

OH-弱碱及杂质

亲水性Alk

H+/H2O药渣

Alk ↓OH-/H2O

OH-弱碱及杂质

亲水性Alk

四、提取分离（一）提取

1.酸水提取法

此法缺点：

提取液体积较大（浓缩困难）

提取液中水溶性杂质多

解决方法：

（1）离子交换树脂法

（2）沉淀法

(3)膜浓缩

四、提取分离（一）提取

1.酸水提取法

（1）离子交换树脂法

NH RSO NH H+-+

+ ++ +RSO3HNH RSO

3NH H

NH4OH

RSO3

NH4 N O

+-+

+ ++ +

+-+ +

氢离子 型阳 生物碱盐

阳离子 交换树 脂的铵 盐游离生物碱

OH- 如：

有机溶剂提取Alk

离子 交换树 脂

• 离子交换树脂阳离子交换树脂R-与阳离子胺盐结合吸附

原料

酸溶液浸提

酸液

离子交换树脂柱吸附水洗

然后洗脱得到总生物碱或生物碱部位----实际生产常用方法

优点：不用浓缩，不用有机溶剂（少用）

水洗溶剂洗脱

非生物碱

生物碱部位1

生物碱部位2

生物碱部位3

四、提取分离（一）提取

1.酸水提取法

（2）沉淀法

①酸提碱沉法用于弱碱性生物碱

药 材H+/H O提取；

药 材H+/H O提取；

药 材

沉 淀 H2O

H+/H2O提取；加碱碱化

水溶性Alk、杂质不溶或难溶性Alk

药 材

沉 淀 H2O

H+/H2O提取；加碱碱化

水溶性Alk、杂质不溶或难溶性Alk

四、提取分离（一）提取

1.酸水提取法

（2）沉淀法

②盐析法：适用中等弱碱。

黄藤1%H SO 水溶液黄藤1%H SO 水溶液黄藤1%H SO 水溶液黄藤1%H SO 水溶液黄藤1%H SO 水溶液黄藤1%H SO 水溶液黄藤1%H SO 水溶液黄藤1%H2SO4水溶液

H2O沉淀

碱化至pH=9；加NaCl达饱和

掌叶防已碱

黄藤1%H2SO4水溶液

沉淀 H2O

黄藤1%H2SO4水溶液

沉淀 H2O

黄藤1%H2SO4水溶液

沉淀 H2O

黄藤1%H2SO4水溶液

沉淀

黄藤1%H2SO4水溶液

H2O沉淀

黄藤1%H2SO4水溶液

四、提取分离（一）提取

1.酸水提取法

（2）沉淀法

③雷氏铵盐沉淀法 适用于季铵碱

B+ + NH4[Cr(NH3)2(SCN)4] (B[Cr(NH3)2(SCN)4])4 3 2 4 3 2 4

Ag2SO4

B2SO4 + Ag[Cr(NH3)2(SCN)4]

BaCl2

BaSO4 + B . Cl

四、提取分离（一）提取

季铵碱的水溶液季铵碱的水溶液

水溶液沉淀(雷氏复盐)

加酸水调至弱酸性加新配制的雷氏铵盐饱和/H2O

溶丙酮（乙醇）中

水溶液水溶液水溶液水溶液

雷氏铵盐沉淀

沉 淀 滤 液

滤液 (B2SO4)

硫酸钡沉淀 季铵碱的盐酸盐

溶丙酮（乙醇）中加Ag2SO4饱和水溶液

加入氯化钡（BaCl2）

雷氏铵盐沉淀 滤液 (B2SO4)雷氏铵盐沉淀

沉 淀

滤液 (B2SO4)雷氏铵盐沉淀

滤 液沉 淀

滤液 (B2SO4)雷氏铵盐沉淀

四、提取分离（一）提取

2.醇类溶剂提取法 生药

药渣醇液

醇或酸性醇

挥醇；加酸水

H+ / H2O

OH-/H2O

挥醇；加酸水

碱性较弱的碱

亲水性AlkCHCl3

沉淀

Alk

OH-/H2O CHCl3

四、提取分离（一）提取

3. 有机溶剂(与水不相混溶者)提取法

生 药碱化（如石灰乳、Na2CO3溶液或10%NH4OH）（使Alk游离），后有机溶剂渗滤（或浸渍）（如CHCl3等）

残 渣 CHCl3

CHCl3 H+/H2O

H+/H2O

OH-/H2O

Alk沉淀

亲水性Alk

碱性较弱的Alk

四、提取分离

(二）Separation of akloids

溶解性——重结晶法

碱性强弱——pH梯度萃取碱性强弱——pH梯度萃取

色谱法

四、提取分离

（二）系统分离法分离

生物碱的分离

系统分离 特定分离

多用于基础研究 侧重于生产实用

总 碱

单体Alk的分离

类别指酸碱性强弱

部位指极性不同

依据Alk的理化性质

类别Alk的一般分离流程如下图

总 生物碱

H+/H2O(2%H2SO4、2%酒石酸等)

H+/H2O不溶物

有机溶剂萃取(CHCl3、苯 等)

有机溶剂 H+/H2O

(弱碱性Alk) (中强、强碱性Alk)

1~2%NaOH萃取 氨 水调 pH=9~10

有机溶剂萃取

OH-/H2O 有机溶剂OH /H2O 有机溶剂

NH4Cl/有机溶剂

有机溶剂

酚 性弱碱性Alk

非 酚 性弱碱性Alk

有机溶剂 OH-/H2O

1~2%NaOH萃取

OH-/H2O 有机溶剂

NH4Cl/CHCl3

CHCl3

pH > 12n-BuOH萃取

酚 性叔胺 Alk

非 酚 性叔胺 Alk

n-BuOH

水溶性Alk

酸化加生物碱沉淀剂过滤

沉淀

两种途径

四、提取分离（二）分离

1.根据Alk及其盐的溶解度不同进行分离

（1）已知成分——查文献选择结晶溶剂

（2）未知成分——色谱方法进行溶剂的选择

2.Alk碱性不同——pH梯度萃取法2.Alk碱性不同——pH梯度萃取法

首先考虑的问题：

所选溶剂pH值多少为宜？

萃取几次能完全？

萃取溶剂的最佳体积？

四、提取分离（二）分离

2.Alk碱性不同——pH梯度萃取法

（1）确定pH值的方法

1 2 3 4 5 6 7 8

pH值 低 稿高

1 2 3 5 6 7 8

组分A+B

氯仿萃取

四、提取分离（二）分离

2.Alk碱性不同——pH梯

度萃取法

（1）确定pH值的方法

选择最佳pH的缓冲溶液进行萃取

（1）确定pH值的方法

碱性

B > A1 2 3 4 5 6 7 8

pH值 低 稿高

组分A+B

氯仿萃取

此时，低pH值有利于A的萃取。pH=2-3,可以得到纯A。

四、提取分离（二）分离

2.Alk碱性不同——pH梯度萃取法

（1）确定pH值的方法

1 2 3 4 5 6 7 8

pH值 低 稿高

1 2 3 4 5 6 7 8

组分A+B+C

氯仿萃取

此时，pH 2.5得到A，。余下液体调制pH3-4，萃取得到C。余液调制pH大于5，可萃取得到B萃取得到B

四、提取分离（二）分离

3.色谱法

⑴吸附剂：柱色谱法常用氧化铝（偶用硅胶）；

⑵展开剂：游离Alk常以苯、乙醚、氯仿等溶剂洗脱

⑶化合物极性判断：⑶化合物极性判断：

①相似结构：双键多、含氧官能团多——则极性大

②在含氧官能团中：

-COOH Ar-OH R-OH -CHO R=O> > > >

-COOR R-O-R' C=C C-C> > >

四、提取分离

提取分离实例——长春碱与长春新碱

N

O

N

H

COOMe

N

N

OCOMeH

R

MeOCOOMeO

R= - CH3

R= - CHO

长 春碱

醛基长 春碱

长春花，又名日日春、天天开等。夹竹桃科，常绿直立亚灌木。株高30-60厘米，叶对生，长椭圆形，深绿具光译。花腋生，花冠高脚碟状，裂片5，呈轮状排列，花径3-4厘米，白色、粉红色或紫红色。

原产西印度，早在宋代以前就传入我国。性喜高温高湿，耐半阴。多采用播种繁殖。长春花不仅姿态忧美，花期特长，还是一种防治癌症的良药。据研究，长春是一种防治癌症的良药。据研究，长春花中含55种生物碱。其中长春碱和长春新碱对治疗绒癌等恶性神瘤、淋巴肉瘤及儿童急性白血病等都有一定疗效，是目前国际上应用最多的抗癌植物药源。

四、提取分离

长春花全草 (干粉80目)

苯渗漉液 药 渣

苯渗漉

6%酒石酸水溶液萃取

除水杂

除脂杂

苯 液 H+/H2O pH=4

6%酒石酸水溶液萃取

过滤，氨水碱化至pH=6~7 CHCl3提

除脂杂

除碱性较强的成分

四、提取分离

H2OCHCl3 弱碱

回收氯仿，蒸干溶于无水乙醇除脂杂

Alk硫酸盐

溶于无水乙醇H2SO4调pH=3.8~4.1Alk沉淀

溶于H2O，氨水碱化至pH=8~9 CHCl3萃取

除脂杂

除水杂

精

制

四、提取分离

H2OCHCl3

游离Alk回收氯仿

长春碱 醛基长春碱

溶于苯:氯仿(1:2)液中通过Al2O3吸附柱

用苯:氯仿(1:2)洗脱

色谱分离

MeO MeO

O[ ] + -

提取分离实例——延胡索乙素

NMeO

OMe

OMe

NMeO

OMe

OMe

O

H

OH[ ]

[ ]

+ -

四氢巴 马亭 （ 无色） 巴 马亭 （ 黄色） 黄藤

黄藤（粗粉）

用1%醋酸浸渍；酸提

H+/H2O药渣

加OH-调pH=9

酸提碱沉

滤液 沉淀

（巴马亭粗品）

加OH调pH=9（ 7%NaCl 和 NaOH )

放置，过滤

巴 马 亭 粗 品

8 0 - 9 0 % E t O H回 流

不 溶 物 E t O H液

加 H C l调 p H = 2 - 3

放 置 ， 过 滤

析 晶 滤 液（ 盐 酸 巴 马 亭 ）

加 硫 酸 、 锌 粉 ， 加 热 （ 干 燥 、 氢 化 ）

不 溶 物 热 滤 液

冷 却 ， 过 滤

四 氢 巴 马 亭 硫 酸 盐

热 溶 7 5 % E t O H中 ， 趁 热 过 滤

不 溶 物 滤 液

加 氨 水 调 p H = 8 . 5 - 9， 过 滤

四 氢 巴 马 亭

金鸡纳树皮粉末

Ca（OH）2溶液湿润苯提

苯提液

稀H2SO4酸洗

酸溶液

NaOH溶液调PH值至6.5温热放置析晶、过滤

硫酸奎宁晶体

溶于稀硫酸中加氨水碱化

母液

碱化

加氨水碱化

奎宁

沉淀 滤液

乙醚萃提

不溶物（金鸡宁）

乙醚液稀盐酸

乙醚液

酸液酒石酸钾钠

母液

酒石酸金鸡纳丁

碱化

金鸡纳丁

KI

氢碘酸奎宁丁晶体

碱化

奎宁丁

母液

新鲜浙贝母地上部分（8.7kg）甲醇(25升）浸提

浸膏（610g）

水溶，弃不溶物

水层液

乙醚萃取

乙醚液 水层正丁醇萃取

正丁醇层 水层

浓缩

Bu fraction 67g

1升5％醋酸溶液溶解、过滤

酸液

BuOH萃取

BuOH萃取液 酸水层

硅胶（500克）柱分离chloroform：methanol：water=14:6:1

fraction 1 f2 f3 f4 f5 f6氧化铝柱C:M=9:1至4：1

硅胶柱C:M:W=7:12:8下相

产物41（131mg）42（6.7mg)

硅胶柱

BuOH萃取液 酸水层

浓氨水碱化至PH9后BuOH萃取

水层BuOH层浓缩

提取物21g

水溶，XAD-2（11）大孔树脂吸附，后水洗

水层 树脂

80％甲醇洗脱、浓缩

洗脱物9克

硅胶（500克）柱分离chloroform：methanol：water=14:6:1

fraction 1 f2 f3 f4 f5 f6

本章内容

一、概述

二、生物合成途径

F

三、分类和分布

四、理化性质

五、提取与分离

六、结构鉴定

五、结构鉴定

（一）色谱法

测定理化常数（如：熔点），与文献报道的

数据进行对照，与对照品共薄层，测定其衍生物

的理化数据等。的理化数据等。

1.薄层色谱法

2.纸色谱法

五、结构鉴定

（二）谱学法

紫外光谱、红外光谱、质谱、核磁共振

UV——反映分子中所含共轭系统情况；

IR——利用特征吸收峰，鉴定结构中主要官能团；IR——利用特征吸收峰，鉴定结构中主要官能团；

NMR——各种技术图谱测定结构；

MS——依据文献，结合主要生物碱类型的质谱特

征进行解析。

1.难于裂解或由取代基或侧链的裂解产生特征离子

五、结构鉴定

生物碱MS的一般规律：

特点：M+或M+-1多为基峰或强峰。

一般观察不到由骨架裂解产生的特征离子。

主要包括两大类：

①芳香体系组成分子的整体或主体结构；

如喹啉类、吖啶酮类等

②具有环系多、分子结构紧密的生物碱；

如苦参碱类、秋水仙碱类等

• 核磁共振谱应用一维NMR和二维NMR，可以解决大部分化合物的结构解析分化合物的结构解析

本章需要掌握的关键问题本章需要掌握的关键问题

生物碱的理化性质

生物合成的基本原料

生物碱的特性检测方法

生物碱总碱的提取方法-通用法、生物碱特性提取法，生物碱的纯化法

练习试题

一、选择判断题

二、是非题

三、化学鉴别题

四、分析比较碱性大小

五、提取分离

一、选择判断题

◆生物碱的盐若从酸水中游离出来，pH应为（ ）

A. pH < Pka B. pH > Pka C. pH = PKa

◆某生物碱碱性很弱，几乎呈中性，氮原子的存

在状态可能为( )。A.伯胺 B.仲胺 C.酰胺 D.叔胺

一、选择判断题

◆季铵型生物碱分离常用( )。

A.水蒸汽蒸馏法 B.雷氏铵盐法

C.升华法 D.聚酰胺色谱法

◆生物碱沉淀反应是利用大多数生物碱在( )条件◆生物碱沉淀反应是利用大多数生物碱在( )条件

下，与某些沉淀试剂反应生成不溶性复盐或络合物

沉淀。

A.酸性水溶液 B.碱性水溶液

C.中性水溶液 D.亲脂性有机溶剂

一、选择判断题

◆将混合生物碱溶于有机溶剂中，以酸液pH由大→小

顺次萃取，可依次萃取出( )。

A.碱性由强→弱的生物碱A.碱性由强→弱的生物碱

B.碱性由弱→强的生物碱

C.极性由弱→强的生物碱

D.极性由强→弱的生物碱

一、选择判断题

◆生物碱的碱性强弱可与下列( )情况有关。

A.生物碱中N原子具有各种杂化状态

B.生物碱中N原子处于不同的化学环境

C.以上两者均有关 D.以上两者均无关

一、选择判断题

◆pH梯度萃取法分离生物碱时，生物碱在酸水层，

应顺次调pH（ ）用氯仿萃取。

A.pH=3~8 B.pH=8~13 C.pH=1~7 D.pH=7~1

◆对生物碱进行分离常用的吸附剂为( )。

A.活性炭 B.硅胶 C.葡聚糖凝胶 D.碱性氧化铝

二、是非判断题

◆自然界所发现的生物碱都是氨基酸的代谢产物。

◆季铵型生物碱可溶于水，它是各类生物碱中碱性

最强的一类生物碱。

◆阴离子交换树脂适用于分离生物碱类物质。

◆所有含N的化合物，其质谱上的分子离子峰m/z均

为奇数。

◆生物碱一般是以游离碱的状态存在于植物体内。

二、是非判断题

◆某一中药的粗浸液，用生物碱沉淀试剂检查结果

为阳性，可说明该中药中肯定含有生物碱。

◆某生物碱PKa=7.6，若用足够的雷氏铵盐使该生物

碱完全沉淀，该溶液的pH值应调节到大于PKa两

个单位（即pH=9.6)。

◆生物碱都能被生物碱沉淀试剂所沉淀。

三、化学方法鉴别下列各组化合物

NN

Me

OMe

OMe

MeO

O

Me

H3COOCCOOH

A B

三、化学方法鉴别下列各组化合物

NH

COOH

O

NHMeMe

NH2N

O

A B C

三、化学方法鉴别下列各组化合物

N

O

ON

Me

MeO

MeO

OMe

MeO

OMe

MeO

A B

五、提取分离

一中药材中主要含有生物碱类成分，

且已知在其总碱中含有如下成分：

季铵碱、酚性叔胺碱、非酚性叔胺季铵碱、酚性叔胺碱、非酚性叔胺

碱、水溶性杂质、脂溶性杂质

现有下列分离流程，试将每种成分

可能出现的部位填入括号中。

总 碱的酸性水溶液

NH4 调 至pH 9~10

CHCl3 萃取

碱水层 层CHCl3

酸化

雷 氏铵 盐1%NaOH

雷 氏铵 盐

水液沉淀

经分 解1%HClNH4Cl 处理

提取酸水层

碱水层 CHCl3 层

CHCl3层CHCl3 层CHCl3( )

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