0RGANI[ [HEMl5TRY
`Structure and Function
`
`FIFTH EDITION
`
`K. PETER C. VOLLHARDT
`University of California at Berkeley
`
`NEIL E. SCHORE
`University of California at Davis
`
`I • W. H. FREEMAN AND COMPANY
`
`New York
`
`•
`
`Luitpold Pharmaceuticals, Inc., Ex. 2018, p. 1
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`

`
`ABOUT THE COVER
`Taxol, a brand name for the generic drug paclitaxel, emerged through years of setbacks and controversy to become, by the
`end of the twentieth century, the best-selling anticancer drug in the world, saving and improving the quality of countless
`thousands of Jives. The front cover shows a model of the three-dimensional structure of the molecule, superimposed on a
`picture of the magnificent Pacific yew tree, from the bark of which the first samples of Taxol were isolated. During the last
`decade, the medicinal importance of this molecule enticed several research groups to tackle its total synthesis, applying new
`synthetic methodologies and strategies to assemble its complicated structure. First, in what turned out to be a veritable race,
`were the teams of K. C. Nicolaou at The Scripps Research Institute and the University of California, San Diego (who pro(cid:173)
`vided the idea for the cover picture), and R. A. Holton at Florida State University (in 1994). These syntheses were followed
`by those of S. J. Danishefsky (Sloan-Kettering Institute for Cancer Research and Columbia University), P. A. Wender
`(Stanford University), T. Mukaiyama (Science University of Tokyo), and I. Kuwajima (Tokyo Institute of Technology), each
`featuring its own unique approach. Synthetic strategies used to construct complex molecules are discussed in Chapter 8 and
`subsequently throughout the text. The biological and medicinal context of organic molecules is addressed in many Chemical
`Highlights, in the general text (for example p. 152 for Taxol), and in numerous problems.
`
`Publishers: Susan Finnemore Brennan, Craig Bleyer
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`
`Library of Congress Cataloging-in-Publication Data
`
`Vollhardt, K. Peter C.
`Organic chemistry : structure and function.- 5th ed. I K. Peter C. Vollhardt, Neil E. Schore.
`p. cm.
`Includes index.
`ISBN-13: 978-0-7167-9949-8
`ISBN-10: 0-7167-9949-9
`1. Chemistry, Organic-Textbooks. I. Schore, Neil Eric, 1948- II. Title.
`QD251.3.V65 2007
`547-dc22
`
`2005025107
`
`©2007
`All rights reserved
`
`Printed in the United States of America
`
`Third printing
`
`W. H. Freeman and Company
`41 Madison Avenue
`New York, NY 10010
`Houndmills, Basingstoke RG21 6XS, England
`
`www.whfreeman.com
`
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`

`
`CARBOHYDRATES
`Polyfunctional Compounds in Nature
`
`In everyday life, when we say the word "sugar" we
`usually refer to sucrose, the most widely occurring
`disaccharide in nature. Obtained from sugar beet and
`sugar cane (illustrated here), sucrose is prepared
`commercially in pure form in greater quantities than
`any other chemical substance.
`
`T ake a piece of bread and place it in your mouth. After a few minutes it will
`
`begin to taste distinctly sweet, as if you had added sugar to it. Indeed, in a
`way, this is what happened. The acid and enzymes in your saliva have cleaved
`the starch in the bread into its component units: glucose molecules. You all know glu(cid:173)
`cose as dextrose or grape sugar. The polymer, starch, and its monomer, glucose, are
`two examples of carbohydrates.
`Carbohydrates are most familiar to us as major contributors to our daily diets, in
`the form of sugars, fibers, and starches, such as bread, rice, and potatoes. In this ca(cid:173)
`pacity, they function as chemical energy-storage systems, being metabolized to wa-
`ter, carbon dioxide, and heat or other energy. Members of this class of compounds
`give structure to plapts, flowers, vegetables, and trees. They also serve as building
`units of fats (Sections 19-13 and 20-5) and nucleic acids (Section 26-9). All are con(cid:173)
`sidered to be polyfunctiOnal, because they possess multiple functional groups. Glu(cid:173)
`cose, C6(H20)6' and many related simple members of this compound class form the
`building blocks of the complex carbohydrates and have the empirical formulas
`Cn(H20)m essentially hydrated carbon.
`
`.
`'
`
`1096 ~··
`
`Luitpold Pharmaceuticals, Inc., Ex. 2018, p. 3
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`

`
`24-1 Names and Structures of Carbohydrates 1097
`
`We shall first consider the structure and naming of the simplest carbohydrates-the
`sugars. We then tum our attention to their chemistry, which is governed by the pres(cid:173)
`ence of carbonyl and hydroxy functions along carbon chains of various lengths. We
`have already seen an example of the biosynthesis of carbohydrates (Chemical Highlight
`18-1). Here we examine several methods for sugar synthesis and structural analysis. Fi(cid:173)
`nally, we describe a sampling of the many types of carbohydrates found in nature.
`
`24· 1 Names and Structures of Carbohydrates
`
`The simplest carbohydrates are the sugars, or saccharides. As chain length increases,
`the increasing number of stereocenters gives rise to a multitude of diastereomers. For(cid:173)
`tunately for chemists, nature deals mainly with only one of the possible series of enan(cid:173)
`tiomers. Sugars are polyhydroxycarbonyl compounds and many form stable cyclic
`hemiacetals, which affords additional structural and chemical variety.
`
`Sugars are classified as aldoses and ketoses
`Carbohydrate is the general name for the monomeric (monosaccharides), dimeric
`(disaccharides), trimeric (trisaccharides), oligomeric (oligosaccharides), and poly(cid:173)
`meric (polysaccharides) forms of sugar (saccharum, Latin, sugar). A monosaccha(cid:173)
`ride, or simple sugar, is an aldehyde or ketone containing at least two additional
`hydroxy groups. Thus, the two simplest members of this class of compounds are
`2,3-dihydroxypropanal (glyceraldehyde) and 1,3-dihydroxyacetone. Complex sugars
`(Section 24-11) are those formed by the linkage of simple sugars through ether bridges.
`Aldehydic sugars are classified as aldoses; those with a ketone function are called
`ketoses. On the basis of their chain length, we call sugars trioses (three carbons),
`tetroses (four carbons), pentoses (five carbons), hexoses (six carbons), and so on.
`Therefore, 2,3-dihydroxypropanal (glyceraldehyde) is an aldotriose, whereas 1,3-
`dihydroxyacetone is a ketotriose.
`Glucose, also known as dextrose, blood sugar, or grape sugar (glykys, Greek,
`sweet), is a pentahydroxyhexanal and hence belongs to the class of aldohexoses. It
`occurs naturally in many fruits and plants and in concentrations ranging from 0.08 to
`0.1 % in human blood. A corresponding isomeric ketohexose is fructose, the sweet(cid:173)
`est natural sugar (some synthetic sugars are sweeter), which also is present in many
`fruits (jructus, Latin, fruit) and in honey. Another important natural sugar is the al(cid:173)
`dopentose ribose, a building block of the ribonucleic acids (Section 26-9).
`
`CHO
`I
`H-C-OH
`I
`C1f20H
`
`2,3-Dihydroxy propanal
`(Glyceraldehyde)
`(An aldotrilse)
`
`CHO
`I
`H-C-OH
`I
`HO-C-H
`I
`H-C-OH
`I
`H-C-OH
`I
`CH20H
`
`CH20H
`I
`C=O
`I
`HO-C-H
`I
`H-C-OH
`I
`H-C-OH
`I
`CHzOH
`
`1,3-Dihydroxy acetone
`(A ketotrilse)
`
`CHO
`I
`H-C-OH
`I
`H-C-OH
`I
`H-C-OH
`I
`CHzOH
`
`Glucose
`(An al do heIDse)
`
`Fructose
`(A ketoheIDse)
`
`Ribose
`(An aldopentose)
`
`Luitpold Pharmaceuticals, Inc., Ex. 2018, p. 4
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`

`
`1098 Chapter 24 CARBOHYDRATES
`
`EXERCISE 24-1
`
`To which classes of sugars do the following monosaccharides belong?
`
`CHO
`I
`(a) HCOH
`I
`HCOH
`I
`CH20H
`Erythrose
`
`CHO
`I
`HOCH
`I
`(b) HOCH
`I
`HCOH
`I
`CH20H
`Lyxose
`
`CH20H
`I
`C=O
`I
`(c) HOCH
`I
`HCOH
`I
`CH20H
`Xylulose
`
`A disaccharide is derived from two monosaccharides by the formation of an
`ether (usually, acetal) bridge (Section 17-7). Hydrolysis regenerates the monosac(cid:173)
`charides. Ether formation between a mono- and a disaccharide results in a trisac(cid:173)
`charide, and repetition of this process eventually produces a natural polymer (poly(cid:173)
`saccharide ). Polysaccharides constitute the framework of cellulose and starch
`(Section 24-12).
`
`Most sugars are chiral and optically active
`With the exception of 1,3-dihydroxyacetone, all the sugars mentioned so far contain
`at least one stereocenter. The simplest chiral sugar is 2,3-dihydroxypropanal (glycer(cid:173)
`aldehyde ), with one asymmetric carbon. Its dextrorotatory form is found to be R and
`the levorotatory enantiomer S, as shown in the Fischer projections of the molecule.
`Recall that, by convention, the horizontal lines in Fischer projections represent bonds
`to atoms above the plane of the page (Section 5-4 ).
`
`~'Model
`~ildinq
`CHO
`
`Fischer Projections of the Two Enantiomers
`of 2,3-Dihydroxypropanal (Glyceraldehyde)
`
`CHO
`
`CHO
`
`is the same as
`
`I
`I
`I
`
`H-C-OH
`
`I
`I
`I
`
`H+ OH
`CH20H
`CH 20H
`(R)-( + )-2,3-Dihydroxypropanal
`[D-( + )-Glyceraldehyde]
`([a]fic = +8.7)
`
`Ho-c-H
`
`CHO
`
`I
`I
`I
`
`I
`I
`I
`
`CH20H
`
`is the same as
`
`HO+H
`CH20H
`(S)-( - )-2,3-Dihydroxypropanal
`[L-(-)-Glyceraldehyde]
`([a];;'°c = -8.7)
`
`Even though R and S nomenclature is perfectly satisfactory for naming sugars, an
`older system is still in general use. It was developed before the absolute configuration
`of sugars was established, and it relates all sugars to 2,3-dihydroxypropanal (glycer(cid:173)
`aldehyde ). Instead of Rand S, it uses the prefixes D for the ( +) enantiomer of glyc(cid:173)
`eraldehyde and L for the (-) enantiomer (Chemical Highlight 5-2). Those monosac(cid:173)
`charides whose highest-nambered stereocenter (i.e., the one farthest from the aldehyde
`or keto group) has the same absolute configuration as that of D-( + )-2,3-dihydroxy(cid:173)
`propanal [D-( + )-glyceraldehyde] are then labeled D; those with the opposite config(cid:173)
`uration at that stereocenter are named L. Two diastereomers that differ only at one
`stereocenter are also called epimers.
`
`Luitpold Pharmaceuticals, Inc., Ex. 2018, p. 5
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`

`
`24-1 Names and Structures of Carbohydrates 1099
`
`Designation of a D and an L Sugar
`
`CHO
`
`I
`
`11~1-~H
`
`H-,-OH
`
`I
`
`H~OH
`Highest-numbered_/,,/CH20H
`stereocenter
`o-Aldose
`
`CH,OH
`
`II r~H
`
`H+OH
`HO~~H
`CH20H
`L-Ketose
`
`The D,L n<?menclature divides the sugars into two groups. As the number of stereo(cid:173)
`centers increases, so does the number of stereoisomers. For example, the aldotetrose
`2,3,4-trihydroxybutanal has two stereocenters and hence may exist as four stereoiso(cid:173)
`mers: two diastereomers, each as a pair of enantiomers. The next higher homolog,
`2,3,4,5-tetrahydroxypentanal, has three stereocenters, and therefore eight stereoisomers
`are possible: four diastereomeric pairs of enantiomers. Similarly, 16 stereoisomers
`(as eight enantiomeric pairs) may be formulated for the corresponding pentahy(cid:173)
`droxyhexanal.
`Like many natural products, these diastereomers have common names that are of(cid:173)
`ten used, mainly because the complexity of these molecules leads to long systematic
`names. This chapter will therefore deviate from our usual procedure of labeling mol(cid:173)
`ecules systematically. The isomer of 2,3,4-trihydroxybutanal with 2R,3R configuration
`is called erythrose; its diastereomer, threose. Note that each of these isomers has two
`enantiomers, one belonging to the family of the o sugars, its mirror image to the L
`sugars. The sign of the optical rotation is not correlated with the o and L label (just
`as in the R,S notation: ( - ) Does not necessarily correspond to S, and ( +) does not
`necessarily correspond to R; see Section 5-3). For example, o-glyceraldehyde is dex(cid:173)
`trorotatory, but o-erythrose is levorotatory.
`
`Diastereomeric 2,3,4-Trihydroxybutanals:
`Erythrose and Threose
`
`~h1 Model
`~ildinq
`
`CHO
`H~H
`H+OH
`CH20H
`2R,3R
`
`CHO
`
`HO+H
`
`HO+H
`CH20H
`2S,3S
`
`CHO
`
`HO+H
`
`H+OH
`CH20H
`2S,3R
`
`CHO
`H~H
`HO+H
`CH 20H
`2R,3S
`
`D-(-)·Eryth- r L·(+)-Eryth(cid:173)
`
`Mirror
`plane
`
`D-(-)·Th- 1 L-{+)·Th(cid:173)
`
`Mirror
`plane
`
`Luitpold Pharmaceuticals, Inc., Ex. 2018, p. 6
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`
`

`
`1100 Chapter 24 CARBOHYDRATES
`
`CHO
`
`=+~=
`
`CH20H
`o-( - )-Erythrose
`
`CHO
`
`H*OH
`
`H
`
`H
`
`OH
`
`OH
`
`CHO
`
`HO*H
`
`H
`
`H
`
`OH
`
`OH
`
`CH20H
`o-( - )-Ribose
`
`CH20H
`o-( - )-Arabinose
`
`CHO
`
`H+OH
`CHc()H
`o-( + )-Glyceraldehyde
`
`CHO
`
`H:+~H
`
`CH20H
`o-( - )-Threose
`
`CHO
`
`H~±~H
`
`H=t=OH
`CH20H
`o-( + )-Xylose
`
`CHO
`
`:~±:
`
`H=t=OH
`CH20H
`o-(- )-Lyxose
`
`CHO
`
`CHO
`
`CHO
`
`CHO
`
`CHO
`
`CHO
`
`CHO
`
`H
`
`H
`
`H
`
`OH H
`
`OH H
`
`H
`
`H
`
`OH H
`
`OH
`
`OH H
`
`H
`
`H
`
`OH
`
`H
`
`H
`
`H
`
`H
`
`OH
`
`OH H
`
`H
`
`H
`
`OH HO
`
`OH
`
`H
`
`OH H
`
`H
`
`H
`
`H
`
`HO
`
`HO
`
`CHO
`
`H
`
`H
`
`OH H
`OH H
`
`H
`
`H
`
`H
`
`H
`
`OH
`
`OH
`
`H
`
`OH
`
`H
`
`H
`
`OH
`
`H
`
`H
`
`OH
`
`H
`
`H
`
`OH
`
`H
`
`H
`
`OH
`
`CH20H
`o-( + )-Allose
`
`CH20H
`o-( + )-Altrose
`
`CH 20H
`D-( +)-Glucose
`
`CH20H
`o-( + )-Mannose
`
`CH20H
`D-( - )-Gulose
`
`CH20H
`n-(-)-Idose
`
`CH20H
`n-( + )-Galactose
`
`CH20H
`n-( + )-Talose
`
`Figure 24-1 o-Aldoses
`(up to the aldohexoses), their
`signs of rotation, and their
`common names.
`
`Figure 24-2 o-Ketoses
`(up to the ketohexoses ), their
`signs of rotation, and their
`common names.
`
`CHDH
`
`~o
`
`CH20H
`1,3-Dihydroxyacetone
`
`CH,OH
`
`H+~H
`
`CH20H
`n-( - )-Erythrulose
`
`HO_f ~H
`
`H+OH
`CH20H
`n-( + )-Xylulose
`
`CH,OH
`
`:i~:
`
`CH20H
`n-( + )-Ribulose
`
`CH,OH
`
`CH 20H
`
`H!~~ HO!:
`
`H
`
`OH
`
`H
`
`OH
`
`H
`
`OH
`
`H
`
`OH
`
`HO
`
`H
`
`Hi~H H1:
`
`CH,OH
`
`CH.OH
`
`H
`
`OH
`
`HO
`
`H
`
`H
`
`OH
`
`CH20H
`n-( + )-Psicose
`
`CH20H
`n-(-)-Fructose
`
`CH20H
`n-( + )-Sorbose
`
`CH20H
`n-(- )-Tagatose
`
`Luitpold Pharmaceuticals, Inc., Ex. 2018, p. 7
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`
`

`
`24-2 Conformations and Cyclic Forms of Su~ars 1101
`As mentioned previously, an aldopentose has three stereocenters and hence 23 =
`8 stereoisomers. There are 24 = 16 such isomers in the group of aldohexoses. Why
`then use the D,L nomenclature even though it designates the absolute configuration
`of only one stereocenter? Probably because almost all naturally occurring sugars
`have the D con.figuration. Evidently, somewhere in the structural evolution of the sugar
`molecules, nature "chose" only one configuration for one end of the chain. The amino
`acids are another example of such selectivity (Chapter 26).
`Figure 24-1 shows Fischer projections of the series of o-aldoses up to the aldohexoses.
`To prevent confusion, chemists have adopted a standard way to draw these projections:
`The carbon chain extends vertically and the aldehyde terminus is placed at the top. In
`this convention, the hydroxy group at the highest-numbered stereocenter (at the bottom)
`points to the right in all o sugars. Figure 24-2 shows the analogous series of ketoses.
`
`Give a systematic name for (a) o-(-)-ribose and (b) o-( +)-glucose. Remember to assign
`the R and S configuration at each stereocenter.
`
`Redraw the dashed-wedged line structure of sugar A (shown in the margin) as a Fischer
`projection and find its common name in Figure 24-1.
`
`IN SUMMARY The simplest carbohydrates are sugars, which are polyhydroxy alde(cid:173)
`hydes (aldoses) and ketones (ketoses). They are classified as o when the highest numbered
`stereocenter is R, L when it is S. Sugars related to each other by inversion at one stereo(cid:173)
`center are called epimers. Most of the naturally occurring sugars belong to the o family.
`
`24-2 Conformations and Cyclic Forms of Su~ars
`
`Sugars are molecules with multiple functional groups and multiple stereocenters. This
`structural complexity gives rise to a variety of chemical properties. To enable chemists
`to focus on the portion of a sugar molecule involved in any given chemical process,
`several ways of depicting sugars have been developed. We have seen the Fischer rep(cid:173)
`resentation in Section 24-1; this section shows us how to interconvert Fischer and
`dashed-wedged representations. In addition, it introduces the cyclic isomers that exist
`in solutions of simple sugars.
`
`Fischer projections depict all-eclipsed conformations
`Recall (Section 5-4) that the Fischer projection represents the molecule in an all-eclipsed
`arrangement. It can be translated into an all-eclipsed dashed-wedged line picture.
`
`Fischer Projection and Dashed-Wedged Line Structures
`for D-( +)-Glucose
`
`HO H H OH
`
`HOH2CVCHO
`H OH
`A
`
`.;;Jn Model
`'1"'eu ii din q
`
`CHO
`
`CHO
`
`H
`HO
`H
`
`H
`
`OH
`H
`OH
`
`OH
`CH20H
`
`Fischer
`projection
`
`H
`HO
`H
`
`H
`
`OH
`
`H
`
`OH
`
`OH
`CH20H
`
`1CHO
`I zc~H
`--oH
`I
`3C<<fr
`I H
`4C<oH
`I H
`sc<oH
`I
`6CH20H
`
`OH
`
`I H \ s r,
`--C-CH,OH
`I
`-
`HO,
`--c 4
`1cHo
`H' \ 3 2 I
`c-c
`w7
`\;-H
`OH HO
`
`All-eclipsed
`dashed-wedged
`line structure
`
`180°
`rotation
`ofC3
`andC5
`
`H OHHO H
`\ /
`' \ /
`I
`/c"--- 4 /c---._ 2 /CHO
`3 C
`5 C
`HOCH,
`l'\
`/'\
`6
`-
`HO H HO H
`
`All-staggered
`dashed-wedged
`line structure
`
`Luitpold Pharmaceuticals, Inc., Ex. 2018, p. 8
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`
`

`
`1102 Chapter 24 CARBOHYDRATES
`
`~a Model
`~Buildinq
`
`-~ ANIMATED MECHANISM:
`Jiila Cyclic hemiacetal forma(cid:173)
`tion by ylucose
`
`KEDIR LIKK
`
`A molecular model can help you see that the all-eclipsed form actually possesses
`a roughly circular shape. Notice that the groups on the right of the carbon chain in
`the original Fischer projection now project downward in the dashed-wedged line struc(cid:173)
`ture. Rotation of two alternate internal carbons by 180° (C3 and C5 in this example)
`gives the all-staggered conformation.
`
`Sugars form intramolecular hemiacetals
`Sugars are hydroxycarbonyl compounds that should be capable of intramolecu(cid:173)
`lar hemiacetal formation (see Section 17-7). Indeed, glucose and the other
`hexoses, as well as the pentoses, exist as an equilibrium mixture with their cyclic
`hemiacetal isomers, in which the hemiacetals strongly predominate. In principle,
`any one of the five hydroxy groups could add to the carbonyl group of the
`aldehyde. However, three- and four-membered rings are too strained and, although
`five-membered ring formation is known, six-membered rings are usually the
`preferred product.
`To depict a sugar correctly in its cyclic form, draw the dashed-wedged line rep(cid:173)
`resentation of the all-eclipsed structure. Rotation of C5 -places its hydroxy group in
`position to form a six-membered cyclic hemiacetal by addition to the Cl aldehyde
`carbon. Similarly, a five-membered ring can be made by rotation of C4 to place its
`OH group in position to bond to Cl. This procedure is general for all sugars in the
`D series.
`
`Cyclic Hemiacetal Formation by Glucose
`
`Rotate CS by
`120° around
`C4--C5 bond
`
`CH20H I
`
`0
`
`6
`s I
`Ho-17 ~ /H
`C4 OH H
`1C
`~~ 13
`21 /\"'OH
`c-c \
`I
`I
`H
`OH
`o-Glucofuranose
`(Less stable)
`
`New
`stereocenter
`
`?H,OH
`\
`H/c-s -o"'
`I
`I
`"" H
`C4 H
`1C/
`~~ ?~ 2~/\"'oH
`~ c-c \
`AH
`bOH
`New
`~ ~ stereocenter
`
`o-Glucopyranose
`(More stable)
`(Groups on the right in the original
`Fischer projection [circled] point downward
`in the cyclic hemiacetal except at CS, which
`has been rotated)
`
`Draw the Fischer projection of L-( - )-glucose and illustrate its transformation into the cor(cid:173)
`responding six-membered cyclic hemiacetal.
`
`Luitpold Pharmaceuticals, Inc., Ex. 2018, p. 9
`Pharmacosmos A/S v. Luitpold Pharmaceuticals, Inc., IPR2015-01495
`
`

`
`The six-membered ring structure of a monosaccharide is called a pyranose,
`a name derived from pyran, a six-membered cyclic ether (see Sections 9-6 and
`25-1). Sugars in the five-membered ring form are called furanoses, from Juran
`(Section 25-3). In contrast with glucose, which exists primarily as the pyranose,
`fructose forms both fructopyranose and fructofuranose in a rapidly equilibrating
`68: 32 mixture.
`
`Cyclic Hemiacetal Formation by Fructose
`
`24-2 Conformations and Cyclic Forms of Su~ars 1103
`
`0 Pyran
`
`I~
`~o/
`
`Fu ran
`
`~Hodel
`'1"Buildinq
`
`HQ,,
`/
`H.,.... "'4
`'cs
`
`CH2 -0H
`0
`6
`\\
`3/2C-CH20H
`C-C
`I
`! '
`HO/ A
`H HOH
`o-Fructose
`
`/
`
`0
`6
`HOCH2 / ~ CH OH
`I /
`~/I 2
`cs H HO
`2C
`3 1 /f'oH
`~~ 14
`c-c I
`I
`I
`0 H
`H
`
`New
`stereocenter
`
`CH-0
`2
`CH OH
`H / 6
`""
`2
`I
`"'/1
`TZ H Ho/
`2 c~"
`31
`HO "" 14
`c-c
`I
`I
`OH H
`
`New
`stereocenter
`
`OH
`
`32%
`o-Fructofuranose
`
`68%
`o-Fructopyranose
`
`Note that, upon cyclization, the carbonyl carbon turns into a new stereocenter.
`As a consequence, hemiacetal formation leads to two new compounds, two diastere(cid:173)
`omers differing in the configuration of the hemiacetal group. If that configuration is
`S in a o-series sugar, that diastereomer is labeled a; when it is R in a o sugar, the
`isomer is called {3.* Hence, for example, o-glucose may form a- or {3-o-glucopyra(cid:173)
`nose or -furanose. Because this type of diastereomer formation is unique to sugars,
`such isomers have been given a separate name: anomers. The new stereocenter is
`called the anomeric carbon.
`
`The anomers a- and {3-glucopyranose should form in equal amounts because they are enan(cid:173)
`tiomers. True or false? Explain your answer.
`
`WORKING WITH THE CONCEPTS False! Anomers differ in configuration at only the anomeric car(cid:173)
`bon (Cl). The configurations at the remaining stereocenters (C2 through C5) are the same
`in a-glucopyranose as they are {3-glucopyranose. Anomers are therefore diastereomers(cid:173)
`not enantiomers-and should not form in equal amounts. Enantiomers differ from each
`other in configuration at every stereocenter.
`
`*The situation is reversed for L-series sugars. For instance, a-L-glucopyranose is the enantio(cid:173)
`mer of a-D-glucopyranose. Therefore, every carbon in a-L-glucopyranose has the opposite
`configuration of the corresponding carbon in a-n-glucopyranose. Thus the anomeric carbon in
`a-L-glucopyranose is R, the opposite of that in the D enantiomer.
`
`Luitpold Pharmaceuticals, Inc., Ex. 2018, p. 10
`Pharmacosmos A/S v. Luitpold Pharmaceuticals, Inc., IPR2015-01495
`
`

`
`1104 Chapter 24 CARBOHYDRATES
`
`Fischer, Haworth, and chair cyclohexane projections help depict
`cyclic sugars
`How can we represent the stereochemistry of the cyclic forms of sugars? One ap(cid:173)
`proach uses Fischer projections. We simply draw elongated lines to indicate the bonds
`formed upon cyclization, preserving the basic "grid" of the original formula.
`
`Adapted Fischer Projections of Glucopyranoses
`
`s
`
`R
`
`}.~ \
`
`H
`
`OH
`
`HO-C-H
`H
`OH
`
`In the ~her projection
`of the 0t form of a
`D sugar, the anomeric
`OH points toward the
`right. In the Fischer
`projection of the /j form,
`the anomeric OH
`is on the left.
`
`o~
`"'c-H
`
`H
`
`HO
`
`H
`
`H
`
`OH
`
`H
`
`OH
`
`OH
`CH20H
`
`Cyclization
`
`HO
`
`H
`
`H
`
`H
`
`OH
`
`0
`
`HO
`
`H
`
`H
`
`0
`
`H
`
`OH
`
`CH20H
`CH20H
`a-D·( + )-Glucopyranose P·»·( + )-Glucopyranose
`(m.p. 150°C)
`(m.p. 146°C)
`
`Haworth* projections more accurately represent the real three-dimensional
`structure of the sugar molecule. The cyclic ether is written in line notation as a pen(cid:173)
`tagon or a hexagon, the anomeric carbon (in a I5 sugar) placed on the right, and the
`ether oxygen put on top. The substituents located above or below the ring are at(cid:173)
`tached to vertical lines. In relating the Haworth projection to a three-dimensional
`structure, we interpret the ring bond at the bottom (between C2 and C3) to be in
`front of the plane of the paper, and the ring bonds containing the oxygen are un(cid:173)
`derstood to be in back.
`
`Haworth Projections
`
`Groups on the right in
`the Fischer projection
`point downward in the
`Haworth formula.
`
`Y:O){H
`
`i~c
`OH OH
`a-D-(- )-Erythrofuranose
`
`H
`OH
`a-D-( + )-Glucopyranose
`
`OH
`H
`{3-D·( + )-Glucopyranose
`
`In a Haworth projection, the a anomer has the OH group at the anomeric carbon
`pointing down, whereas the f3 anomer has it pointing up.
`
`Draw Haworth projections of (a) a-o-fructofuranose; (b) J3-o-glucofuranose; and
`(c) J3-o-arabinopyranose._
`
`*Sir W. Norman Haworth (1883-1950), University of Birmingham, England, Nobel Prize 1937
`(chemistry).
`
`Luitpold Pharmaceuticals, Inc., Ex. 2018, p. 11
`Pharmacosmos A/S v. Luitpold Pharmaceuticals, Inc., IPR2015-01495
`
`

`
`24-3 Anomers of Simple Su~ars: Mutarotation of Glucose 1105
`
`Haworth projections are used extensively in the literature, but here, to make use of
`our knowledge of conformation (Sections 4-3 and 4-4), the cyclic forms of sugars will
`be presented mostly as envelope (for furanoses) or chair (for pyranoses) conformations.
`As in Haworth notation, the ether oxygen will be placed usually top right and the
`anomeric carbon at the right vertex of the envelope or chair.
`
`CH)OH
`I -
`HOCH
`
`Conformational Pictures of Glucofuranose and -pyranose
`
`H
`
`H
`
`HO
`
`OH
`
`HO
`
`H
`
`OH
`
`H
`
`H
`
`H
`
`OH
`
`H
`
`H
`
`p-o-Glucofuranose
`
`a-o-Glucopyranose
`
`P-o-Glucopyranose
`
`Although there are exceptions, most aldohexoses adopt the chair conformation
`that places the bulky hydroxymethyl group at the C5 terminus in the equatorial po(cid:173)
`sition. For glucose, this preference means that, in the a form, four of the five sub(cid:173)
`stituents can be equatorial, and one is forced to lie axial; in the f3 form, all substituents
`can be equatorial. This situation is unique for glucose; the other seven D aldohexoses
`(see Figure 24-1) contain one or more axial substituents.
`
`Using the values in Table 4-3, estimate the difference in free energy between the all(cid:173)
`equatorial conformer of {3-o-glucopyranose and that obtained by ring flip (assume that
`~GcH20H = ~GcH3 = 1.7 kcal mol- 1 and that the ring oxygen mimics a CH2 group).
`
`IN SUMMARY Hexoses and pentoses can take the form of five- or six-membered
`cyclic hemiacetals. These structures rapidly interconvert through the open-chain poly(cid:173)
`hydroxyaldehyde or ketone, with the equilibrium usually favoring the six-membered
`(pyranose) ring.
`
`24-3 Anomers of Simple Sugars: Mutarotation of Glucose
`
`Glucose precipitates from concentrated solutions at room temperature to give crys(cid:173)
`tals that melt at 146°C. Structural analysis by X-ray diffraction reveals that these
`crystals contain only the a-o-( + )-glucopyranose anomer (Figure 24-3). When
`
`Luitpold Pharmaceuticals, Inc., Ex. 2018, p. 12
`Pharmacosmos A/S v. Luitpold Pharmaceuticals, Inc., IPR2015-01495
`
`

`
`1106 Chapter 24 CARBOHYDRATES
`
`Figure 24-3 Structure
`of a-D-( + )-glucopyranose,
`with selected bond lengths and
`angles.
`
`uo2 A H
`
`H"' 0
`I
`l-\2)A ~
`~
`y~
`
`o.97tA~ O
`
`ll0.6°
`
`crystalline a-D-( + )-glucopyranose is dissolved in water and its optical rotation mea(cid:173)
`sured immediately, a value [a]~ 50c = + 112 is obtained. Curiously, this value decreases
`with time until it reaches a constant + 52. 7. The process that gives rise to this effect
`is the interconversion of the a and f3 anomers.
`In solution, the a-pyranose rapidly establishes an equilibrium (in a reaction that
`is catalyzed by acid and base; see Section 17-7) with a small amount of the open(cid:173)
`chain aldehyde, which in tum undergoes reversible ring closure to the f3 anomer.
`
`Interconversion of Open-Chain and Pyranose Forms of o-Glucose
`
`HO
`
`HO
`
`0
`
`H+ or Ho-
`___,.
`
`H
`
`OH
`
`36.4%
`a·D·( + )-Glucopyranose
`([aJ:r" = +112)
`
`H
`HO
`H
`H
`
`CHO
`OH
`H
`OH
`OH
`CH20H
`0.003%
`Aldehyde form
`
`H+ or Ho-
`
`HO
`
`OH
`
`H
`
`63.6%
`/J·D·( + )-Glucopyranose
`([a];,'"c = + 18.7)
`
`The f3 form has a considerably lower specific rotation ( + 18.7) than its anomer;
`therefore, the observed a value in solution decreases. Similarly, a solution of the pure
`f3 anomer (m.p. 150°C, obtainable by crystallizing glucose from acetic acid) gradually
`increases its specific rotation from+ 18.7 to +52.7. At this point, a final equilibrium
`has been reached, with 36.4% of the a anomer and 63.6% of the f3 anomer. The
`change in optical rotation observed when a sugar equilibrates with its anomer is called
`mutarotation (mutare, Latin, to change). Interconversion of a and f3 anomers is a
`general property of sugars. This includes all monosaccharides capable of existing as
`cyclic herniacetals.
`
`An alternative mechanism for mutarotation bypasses the aldehyde intermediate and pro(cid:173)
`ceeds through oxonium ions. Formulate it.
`
`Luitpold Pharmaceuticals, Inc., Ex. 2018, p. 13
`Pharmacosmos A/S v. Luitpold Pharmaceuticals, Inc., IPR2015-01495
`
`

`
`24-4 Polyfunctional Chemistry of Su~ars: Oxidation to Carboxylic Acids 1107
`
`EXERCISE 24-9
`
`Calculate the equilibrium ratio of a- and {3-glucopyranose (which has been given in the
`text) from the specific rotations of the pure anomers and the observed specific rotation at
`mutarotational equilibrium.
`
`WORKING WITH THE CONCEPTS We are given the specific rotation data for the pure a form
`(+112), the pure f3 form (+18.7), and the equilibrium mixture (+52.7). The specific
`rotation of the equilibrium mixture is the average of the rotations of the contributing iso(cid:173)
`mers, weighted by their respective mole fractions in the mixture:
`
`+52.7 = ( + l 12)(mole fraction of a)+ ( + 18.7)(mole fraction of {3)
`If we designate the mole fraction of a as x"' and the mole fraction of f3 as x13, we have (by
`the definition of mole fraction) x" + x13 = 1 and can therefore substitute one for the other
`in the equation above. Solving gives x" = 0.364 and x13 = 0.636. So the equilibrium ratio
`X13/Xa = (0.636)/(0.364) = 1.75.
`
`By using Table 4-3, estimate the difference in energy between a- and {3-glucopyranose at
`room temperature (25°C). Then calculate it by using the equilibrium percentage.
`
`EXERCISE 24-11
`The pure a and f3 forms of o-galactose exhibit [a] 0 values of + 150.7 and +52.8,
`respectively. The equilibrium mixture after mutarotation in water shows a specific rota(cid:173)
`tion of + 80.2. Calculate the composition of the equilibrium mixture.
`
`IN SUMMARY The hemiacetal carbon (anomeric carbon) can have two configura(cid:173)
`tions: a or f3. In solution, the a and f3 forms of the sugars are in equilibrium with
`each other. The equilibration can be followed by starting with a pure anomer and
`observing the changes in specific rotation, a phenomenon also called mutarotation.
`
`24-4 Polyfunctional Chemistry of Su~ars: Oxidation to
`Carboxylic Acids
`Simple sugars exist as isomers: the open-chain structure and the a and /3 anomers of
`various cyclic forms. Because all of these isomers equilibrate rapidly, the relative rates
`of their individual reactions with various reagents determine the product distribution
`of a particular transformation. We can therefore divide the reactions of sugars into
`two groups, those of the linear form and those of the cyclic forms, because the two
`structures contain different functional groups. Although the two forms may some(cid:173)
`times react competitively, we see in this section that reactions of aldoses with oxidizing
`agents take place at the aldehyde moiety of the open-chain form, not the hemiacetal
`function of the cyclic isomers.
`
`Fehling's and Tollens's tests detect reducing sugars
`Because they are polyfunctional compounds, the open-chain monosaccharides un(cid:173)
`dergo the reactions typical of each of their functional groups. For example, aldoses
`contain the oxidizable formyl group and therefore respond to the standard oxidation
`tests such as exposure to Fehling's or Tollens's solutions (Section 17-14). The
`a-hydroxy substituent in ketoses is similarly oxidized.
`
`Luitpold Pharmaceuticals, Inc., Ex. 2018, p. 14
`Pharmacosmos A/S v. Luitpold Pharmaceuticals, Inc., IPR2015-01495
`
`

`
`1108 Chapter z4 CARBOHYDRATES
`
`Results of Fehling's and Tollens's Tests on Aldoses and Ketoses
`
`CHO
`
`H
`
`HO
`
`H
`
`OH
`
`H
`
`OH
`
`H
`
`OH
`CH20H
`D-Glucose
`
`Blue Cu' complex, HO-, H,O
`(Fehling's solution)
`
`+
`
`Cu20
`Brick-red
`precipitate
`
`COOH
`
`OH
`
`H
`
`OH
`
`OH
`
`H
`
`HO
`
`H
`
`H
`
`CH20H
`o-Gluconic acid
`(An aldonic acid)
`
`Ag-, NH,•-oH, H,O
`(Tollens's solution)
`
`OOH
`111
`RCCHR
`Ketose
`
`Ag
`Silver mirror
`
`+
`
`00
`1111
`RCCR
`a-Dicarbonyl
`compound
`
`In these reactions, the aldoses are tra