Synthesis of N-Acetyl-3-phenylisoserinates of sesquiterpenoid alcohols of Lactarius origin

Article abstract of DOI:10.1135/cccc20020075

Important biological properties of Taxol i.e. 13-N-benzoyl-(2R,3S)-3-phenylisoserinate of baccatin III and also N-benzoyl-(2R,3S)-3-phenylisoserinates of several sesquiterpenoid alcohols of Lactarius origin prompted us to synthesize N-acetyl-3-phenylisose

Full text of DOI:10.1135/cccc20020075

N-Acetyl-3-phenylisoserinates
75
SYNTHESIS OF N-ACETYL-3-PHENYLISOSERINATES
OF SESQUITERPENOID ALCOHOLS OF La cta riu s ORIGIN
a3
Rafał BARYCKIa1, Maria GUMUŁKAa2, Marek MASNYK
,
Włodzimierz M. DANIEWSKIa4,*, MirosławK OBUS and MirosławŁ UCZAK
b1
b2
a
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44, 01-224 Warsaw,
Poland; e-mail: musol@icho.edu.pl, dodas@icho.edu.pl, mamas@icho.edu.pl,
1
2
3
4
daniewsk@icho.edu.pl
b
Department of Medical Microbiology, Medical University of Warsaw, Poland;
e-mail: mkobus@ib.amwaw.edu.pl, mluczak@ib.amwaw.edu.pl
1
2
Received Septem ber 11, 2001
Accepted Decem ber 27, 2001
Dedicated to the memory of Dr Václav Černý.
Im portan t biological properties of Taxol i.e. 13-N-ben zoyl-(2R,3S)-3-ph en ylisoserin ate of
baccatin III an d also N-ben zoyl-(2R,3S)-3-ph en ylisoserin ates of several sesquiterpen oid alco-
h ols of Lactarius origin prom pted us to syn th esize N-acetyl-3-ph en ylisoserin ates of latter al-
coh ols in order to ch eck an d com pare th eir biological properties. Suitably protected
ph en ylisoserin e 5 wh en reacted with sesquiterpen oid alcoh ols in th e presen ce of DCC gave
appropriate esters 7. Th ese, after catalytic h ydrogen ation deprotection produced am in ols 8,
wh ich were acetylated an d gave th e required N-acetyl-3-ph en ylisoserin ates 9a–9g.
Keyw ord s: N-Acetyl-3-ph en ylisoserin e; Sesquiterpen oids; Alcoh ols; Am in o acids; Taxol;
Furan diol; Lactarorufin ; Lactarius origin .
Study of structure an d biological activity of paclitaxel (Taxol ) an d its de-
rivatives revealed th e im portan ce of th e taxol side ch ain 1. It was foun d th at
baccatin III, wh ich is th e diterpen oid part of th e m olecule of taxol does n ot
h ave cytostatic activity2. Sim ilarly our in vestigation of an tifeedan t proper-
ties of N-ben zoyl-(2R,3S)-3-ph en ylisoserin ates of sesquiterpen oid alcoh ols
sh owed a sign ifican t in fluen ce of in troduction of N-ben zoyl-(2R,3S)-3-
ph en ylisoserin e in to th eir m olecules3. Recen tly we reported an tiviral an d
cytostatic activity of N-ben zoyl-(2R,3S)-3-ph en ylisoserin ates sesquiterpen es
of Lactarius origin 4. Havin g con sidered all th ese fin din gs we decided to syn -
th esize N-acetyl derivatives of (2R,3S)-3-ph en ylisoserin ates of various
sesquiterpen oid alcoh ols to see th e in fluen ce of th e sm all am ide group on
biological properties of th ese com poun ds in com parison with th ose possess-
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doi:10.1135/cccc20020075

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Barycki et al.:
in g a bulkier group such as ben zoyl or Boc. Results of biological in vestiga-
tion s will be a subject of future publication s.
Th e first syn th esis th at we h ave attem pted was an alogous to th at de-
scribed for th e syn th esis of N-ben zoyl-(2R,3S)-3-ph en ylisoserin ates of
sesquiterpen oid alcoh ols3. Th is un fortun ately failed an d we h ad to carry
th e syn th esis accordin g to th e Sch em e 1.
HCl·NH2
C6H5CH2OCON
O
O
C6H5CH2OCONH
O
O
(ii)
(iii)
OCH3
OR
OR
OH
OH
3
1, R = H
4, R = CH3
5, R = H
(i)
(iv)
2, R = CH3
(i) MeOH, SOCl2; (ii) C6H5CH2OCOCl, NaHCO3; (iii) 2-methoxypropene, pyridinium 4-toluenesulfonate;
(iv) LiOH / H2O
SCHEME 1
Th e (2R,3S)-3-ph en ylisoserin e h ydroch loride (1) was tran sform ed in to its
m eth yl ester 2 in quan titative yield. Subsequen tly th e am ide derivative 3
was prepared by th e reaction of th e ester 2 with ben zyl ch loroform ate in
presen ce of sodium h ydrogen carbon ate. Th e h ydroxy group of th e am ide 3
was protected with 2-m eth oxypropen e with th e form ation of oxazolidin e 4.
Alkalin e h ydrolysis of th e ester group in 4 followed by acidification gave
th e acid 5 ready for esterification with various sesquiterpen oid alcoh ols in
presen ce of DCC an d DMAP. Esters 7 were deprotected by h ydrogen olysis
usin g 10% palladium catalyst an d gave th e ph en ylisoserin e esters 8. Th e
deprotection step reaction con dition s m ust be m ild en ough to preven t th e
decom position of th e sesquiterpen oid part of th e m olecule. Esters 8 are
ready for acylation , wh en acetic an h ydride was used th e required N-Acetyl-
3-ph en ylisoserin ates 9a–9g were prepared from followin g sesquiterpen oid
alcoh ols: furan diol (6a), 8-epi,9-epi-furan diol (6b ), lactarorufin A (6c),
8-epi,9-epi-lactarorufin A (6d ), 3-O-eth yllactarorufin A (6e), 3-O-eth yl-
8-epi-lactarorufin A (6f), 5-deoxylactarolide B (6g) (Sch em e 2).
EXPERIMENTAL
All m eltin g poin ts were m easured on a Kofler h ot plate an d are un corrected. 1H an d
13C NMR spectra (ppm , δ-scale, couplin g con stan ts J in Hz) were run at 500 an d 125 MHz,
respectively (Bruker 500 MHz spectrom eter) in CDCl3 un less oth erwise n oted, usin g TMS as
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

N-Acetyl-3-phenylisoserinates
77
in tern al stan dard. All sign als of carbon s were iden tified by DEPT, 2D 1H an d 13C correlation ,
an d 1H an d 13C lon g ran ge correlation . IR spectra (ν in cm –1) were recorded on a Perkin –
Elm er 1680 FT spectrom eter. Mass spectra were obtain ed on an AMD 604 m ass spectrom eter.
Colum n ch rom atograph y (CC) was carried out usin g silica gel, an d TLC an alyses were con -
ducted on silica gel or RP-18 TLC plates.
Th e ph en ylisoserin ates were prepared from sesquiterpen oid alcoh ols isolated from m ush -
room s (Lactarius rufus, Lactarius vellereus, vouch er n um bers 33550 an d 32260, respectively,
specim en deposited at th e Departm en t of System atics an d Geograph y of Plan ts of th e Un i-
versity of Warsaw) or syn th esized by tran sform ation of n atural products. Th e referen ces of
R1NH
O
C6H5CH2OCON
O
O
(i)
(ii)
5
+
6a-6g
OR
OR
OH
8, R1 = H
7
(iii)
9a-9g, R1 = Ac
(i) DCC, DMAP/CH2Cl2; (ii) H2, 10% Pd-C/MeOH; (iii) Ac2O, NaHCO3/CH2Cl2
2
O
O
O
O
O
O
1
3
9a
3a
9
R2O
4
4a
R2O
R2O
R2O
8
H
H
OH
H
H
OH
OH
H
OH
7a
5
H
H
H
7
6
6a, 9a
6b, 9b
6c, 9c
6d, 9d
O
O
O
O
O
O
R2O
R2O
R2O
H
OEt
H
H
OEt
OH
H
H
H
6e, 9e
6f, 9f
6g, 9g
CH3CONH
O
6: R2 = H
9: R2 =
OH
SCHEME 2
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

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Barycki et al.:
th e procedures of isolation or preparation of all th e sesquiterpen es 6a–6g used for th e prepa-
ration of esters 9a–9g can be foun d in th e recen t review5.
Meth yl (2R,3S)-3-Ph en ylisoserin ate Hydroch loride (2)
Ph en ylisoserin e h ydroch loride6 (1; 16.0 g, 73.6 m m ol) was dissolved in m eth an ol (120 m l)
an d th e sollution ch illed to 0 °C. Subsequen tly th ion yl ch loride (11.0 m l, 130 m m ol) was
added dropwise. Th e reaction m ixture was stirred durin g 3 h an d th e volatiles were rem oved
by evaporation on rotary evaporator leavin g a residue wh ich con tain ed th e required ester 2
in quan titative yield. Oil, [α ]D20 –19.7 (c 1.0, H2O). UV (EtOH): λm ax 205 n m , εm ax 9 020. IR
(film ), νm ax: 3 429, 2 955, 1 742, 1 615. 1H NMR (400 MHz, D2O): 3.68 s, 3 H (OCH3); 4.70 ABq,
2 H, JAB = 6.9 (H-2, H-3); 7.45–7.49 m , 2 H (arom . H); 7.50–7.54 m , 3 H (arom . H). 13C NMR
(100 MHz, D2O): 53.21 (OCH3); 57.12 (C-3); 72.06 (C-2); 127.52, 129.49, 130.06, 132.69
(arom . C); 172.40 (C-1). For C10H14ClNO3 (231.7) calculated: 51.79% C, 6.04 % H, 6.04% N;
foun d: 51.84% C, 5.98 % H, 6.21% N.
Meth yl N-(Ben zyloxycarbon yl)-(2R,3S)-3-ph en ylisoserin ate (3)
Ester 2 (2.00 g, 0.96 m m ol) dissolved in dich lorom eth an e (40 m l) was treated with groun d
sodium h ydrogen carbon ate (20 g, 0.23 m ol). Subsequen tly to th e suspen sion ben zyl ch loro-
form ate (1.50 m l, 1.07 m m ol) was added dropwise with stirrin g. Th e reaction m ixture was
stirred for addition al 2 h , th e solids were filtered off, an d th e filtrate was con cen trated in
vacuo. Pure product (3; 2.57 g, 86%) was obtain ed by recrystallisation of th e residue from di-
ch lorom eth an e–h exan e, m .p. 120–121 °C, [α ]2D0 –3.79 (c 1.0, CHCl3). IR (CHCl3 ), νm ax: 3 435
(OH), 1 734 (C=O). 1H NMR (200 MHz, CDCl3): 3.35 d, 1 H, J1 = 4.3 (OH); 3.80 s, 3 H
(OCH3); 4.48 dd, 1 H, J = 4.3, J2 = 1.4 (H-2); 5.29 dd, 1 H, J1 = 9.6, J2 = 1.4 (H-3); 5.07 s,
(Ph CH2); 5.09 s (Ph CH2); 5.90 d, 1 H, J = 9.6 (NH); 7.29–7.40 m , 10 H (arom . H). 13C NMR
(50 MHz, CDCl3): 53.0 (OCH3); 56.5 (C-3); 67.6 (Ph CH2O); 73.4 (C-2); 126.7, 127.8, 128.0,
128.1, 128.4, 128.6, 136.1, 138.8 (arom . C); 155.6 ( CONH); 173.1 (C-1). LSIMS, m/z: 352
(M + Na)+. HR-MS: for C18H19NNaO5 calculated 352.11609, foun d 352.11781.
Meth yl (4S,5R)-3-(Ben zyloxycarbon yl)-2,2-dim eth yl-4-ph en yloxazolidin e-5-carboxylate (4)
Am ide (3) (2.12 g, 6.44 m m ol) dissolved in toluen e (50 m l) was treated with 2-m eth oxy-
propen e (2.12 m l, 22.2 m m ol) in presen ce of pyridin ium 4-toluen esulfon ate (126 m g,
0.50 m m ol). Th e reaction m ixture was stirred at am bien t tem perature for 20 m in an d subse-
quen tly at 90 °C durin g 1.5 h . Th e reaction m ixture was cooled to room tem perature an d
th e n ext portion of 2-m eth oxypropen e (1.06 m l, 11.1 m m ol) was added. Heatin g was carried
out as with th e previous portion . Solven t was rem oved in vacuo, an d th e product 4 (1.61 g,
68%) was isolated by ch rom atograph y on silica gel usin g h exan e–eth yl acetate 9 : 1. Oil,
[α ]2D0 –14.81 (c 1.0, CHCl3). IR (CHCl3), νm ax: 1 703, 1 753 (C=O). 1H NMR (200 MHz,
CDCl3): 1.71 s, 3 H (CH3); 1.80 s, 3 H (CH3); 3.80 s, 3 H (OCH3); 4.55 d, 1 H, J = 4.7 (H-5);
4.94 ABq, 2 H, J = 10.9 (Ph CH2O); 5.26 d, 1 H, J = 4.7 (H-4); 6.82–7.35 m , 10 H (arom . H).
13C NMR (50 MHz, CDCl3): 25.8 (CH3); 26.4 (CH3); 52.6 (OCH3); 63.3 (C-4); 66.7 (Ph CH2);
81.1 (C-5); 97.1 (C-2); 126.3, 127.6, 127.7, 128.2, 128.6, 135.8 (arom . C); 152.1 (NC=O);
170.6 (CO2CH3). HR-MS: for C21H23NO5 calculated 369.15762, foun d 369.15780.
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N-Acetyl-3-phenylisoserinates
79
(4S,5R)-3-Ben zyloxycarbon yl-2,2-dim eth yl-4-ph en yloxazolidin e-5-carboxylic acid (5)
Oxazolidin e 4 (1.88 g, 5.10 m m ol) dissolved in m eth an ol (30 m l) was treated with 0.5
M
aqueous lith ium h ydroxide (10 m l). After 10 m in , th e reaction solution was n eutralized with
0.1 M h ydroch loric acid (50 m l). Th e precipitated acid 6 was filtered an d dried (1.67 g, 92%),
m .p. 58–60 °C, [α ]2D0 –7.41 (c 1.0, CHCl3). IR (CHCl3), νm ax: 1 708 (C=O). 1H NMR (200 MHz,
CDCl3): 1.73 s, 3 H (CH3); 1.79 s, 3 H (CH3); 4.57 d, 1 H, J = 4.9 (H-5); 4.92 s, 1 H
(Ph CH2O); 4.98 s, 1 H (Ph CH2O); 5.26 d, 1 H, J = 4.9 (H-4); 6.82–7.31 m , 10 H (arom . H).
13C NMR (50 MHz, CDCl3): 26.5 (CH3); 26.6 (CH3); 63.5 (C-4); 67.1 (Ph CH2); 80.8 (C-5);
97.4 (C-2); 126.3, 127.7, 127.8, 128.2, 128.7, 135.6, 140.2 (arom . C); 152.3 (NC=O); 174.0
(CO2H). HR-MS: for C19H18NO5 (M+ – CH3) calculated 340.11850, foun d 340.11803.
Gen eral Procedure for Preparation of N-Acetyl Derivatives 9a–9g
Sesquiterpen oid alcoh ol 6a–6g (2 m m ol), th e acid 5 (0.852 g, 2.40 m m ol), DMAP (0.035 g,
0.28 m m ol) an d DCC (0.650 g, 3.60 m m ol) were dissolved in dich lorom eth an e (50 m l). Th e
reaction m ixture was stirred durin g 15 m in , an d th e N,N′-dicycloh exyl urea form ed durin g
th e reaction was filtered off. Th e filtrate was con cen trated in vacuo, an d th e product 7 was
isolated by filtration th rough silica gel in dich lorom eth an e–dieth yl eth er 93 : 7. An ester 7
(0.65 m m ol) was dissolved in m eth an ol (10 m l), an d th e resultin g solution was treated with
palladium on ch arcoal (10%, 30 m g). Th e ester was deprotected with stoich iom etric am oun t
of h ydrogen at atm osph eric pressure an d room tem perature. Th e reaction was followed by
TLC. Th e catalyst was filtered off an d th e filtrate evaporated on rotary evaporator leavin g a
residue wh ich was dissolved in dich lorom eth an e (25 m l). To th e resultin g solution , groun d
sodium h ydrogen carbon ate was added to form a th ick suspen sion an d subsequen tly to th e
reaction m ixture acetic an h ydride (0.105 m l, 0.85 m m ol) wh ile stirrin g. After 10 m in th e re-
action m ixture was treated with water (50 m l) an d th e product was extracted with dich loro-
m eth an e (3 × 50 m l). Th e extract was dried over an h ydrous MgSO4, wh ich was filtered off,
an d th e filtrate evaporated in vacuo leavin g a residue, from wh ich th e N-acetyl-3-ph en yl-
isoserin ates 9a–9g were isolated by colum n ch rom atograph y in solven ts in dicated separately
for each com poun d.
(4S,4aR,7aS,8S)-6,6,8-Trimethyl-4,4a,5,6,7,7a,8,9-octahydrocyclopenta[4,5]cyclohepta[1,2-c]-
furan-4,8-diol 4-(N-acetyl-(2R,3S)-3-phenylisoserinate) (9a). Ch rom atograph y dich lorom eth an e–
2-propan ol 49 : 1. Yield 31%, oil, [α ]D +12.8 (c 1.05, CHCl3). IR (CHCl3), νm ax: 3 432 (OH),
1 734 (C=O), 1 680 (C=O). 1H NMR (CD3OD): 1.03 s, 3 H (CH3-6); 1.06 s, 3 H (CH3-6);
1.27 s, 3 H (CH3-8); 1.32 dd, 1 H, J(4a,5α) = 5.3, J(4a,5β) = 13.5 (H-5β); 1.46–1.54 m , 2 H
(H-5α, H-7α); 1.63 dd, 1 H, J(7α,7β) = 12.6, J(7β,7a) = 7.0 (H-7β); 1.96 s, 3 H (CH3CO);
2.40–2.55 m , 3 H (H-4a, H-7a, OH-8); 2.62 d, 1 H, J(9α,9β) = 15.4 (H-9α); 2.84 dd, 1 H,
J(9α,9β) = 15.4, J(1,9β) = 1.4 (H-9β); 3.62 bs, 1 H (OH-2′); 4.52 d, 1 H, J(2′,3′) = 2.6 (H-2′);
5.54 dd, 1 H, J(3′,NH) = 9.1, J(3′,2′) = 2.6 (H-3′); 6.01 d, 1 H, J(4,4a) = 8.6 (H-4); 6.65 d, 1 H,
J(NH,3′) = 9.1 (NH); 7.11 s, 1 H (H-3); 7.23 bs, 1 H (H-1); 7.27–7.39 m , 5 H (arom . H).
13C NMR (CD3OD): 23.2 (CH3CO); 30.7 (CH3-8); 30.8 (CH3-6); 31.1 (CH3-6); 32.5 (C-9); 35.6
(C-6); 43.5 (C-7); 43.6 (C-5); 44.2 (C-4a); 52.9 (C-7a); 54.6 (C-3′); 71.6 (C-4); 72.1 (C-8); 73.7
(C-2′); 118.6 (C-9a); 124.0 (C-3a); 126.9, 127.9, 128.6, 138.7 (arom . C); 140.3 (C-3); 141.8
(C-1); 169.6 (CH3CO); 171.7 (C-1′). LSIMS, m/z: 478 (M + Na)+. HR-MS: for C26H33NNaO6
calculated 478.22056, foun d 478.22203.
(4R,4aS,7aS,8S)-6,6,8-Trimethyl-4,4a,5,6,7,7a,8,9-octahydrocyclopenta[4,5]cyclohepta[1,2-c]-
furan-4,8-diol 4-(N-acetyl-(2R,3S)-3-phenylisoserinate) (9b). Ch rom atograph y dich lorom eth an e–
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

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Barycki et al.:
2-propan ol 99 : 1. Yield 52%, m .p. 180–182 °C, [α ]D +44.9 (c 1.02, MeOH). IR (CHCl3), νm ax
:
1 732 (C=O), 1 679 (C=O). 1H NMR (CD3OD): 0.96 s, 3 H (CH3-6); 1.02 s, 3 H (CH3-6);
1.06 s, 3 H (CH3-8); 1.31 dd, 1 H, J(5α,5β) = 12.7, J(4a,5β) = 10.7 (H-5β); 1.54 dd, 1 H, J(7α,7β) =
13.2, J(7α,7a) = 10.7 (H-7α); 1.74 dd, 1 H, J(5a,5β) = 12.7, J(4a,5α) = 7.0 (H-5α); 1.82 dd, 1 H,
J(7α,7β) = 13.2, J(7β,7a) = 8.06 (H-7β); 1.98 s, 3 H (CH3CO); 2.06 dq, 1 H, J(4,4a) = J(4a,5β) =
J(4a,7a) = 10.7, J(4a,5α) = 7.0 (H-4a); 2.16 m , 1 H (H-7a); 2.55 d, 1 H, J(9α,9β) = 13.9 (H-9β);
2.69 d, 1 H, J(9α,9β) = 13.9 (H-9α); 4.51 d, 1 H, J(2′,3′) = 3.8 (H-2′); 5.45 d, 1 H, J(2′,3′) = ___
(H-3′); 5.74 dd, 1 H, J(4,3) = 1.5 J(4,4a) = 10.7 (H-4); 6.98 t, 1 H, J(1,3) = 1.6 (H-3); 7.24 t,
1 H, J(1,3) = 1.6 (H-1); 7.27–7.42 m , 5 H (arom . H). 13C NMR (CD3OD): 20.2 (CH3-6); 22.7
(CH3CO); 31.6 (CH3-6); 31.8 (CH3-8); 35.2 (C-6); 41.1 (C-9); 44.7 (C-7); 47.4 (C-5); 48.0
(C-4a); 56.3 (C-7a); 56.9 (C-3′); 73.8 (C-8); 75.1 (C-2′); 76.8 (C-4); 120.6 (C-9a); 126.2 (C-3a);
128.4, 128.6, 129.5 (arom . C); 139.8 (C-3); 140.7 (arom . C); 142.0 (C-1); 172.9 (C-1′ an d
CH3CO). LSIMS, m/z: 478 (M + Na)+. HR-MS: for C26H33NNaO6 calculated 478.22056, foun d
506.22301.
(4R,4aR,7aS,8S)-4,8-Dihydroxy-6,6,8-trimethyl-1,3,4,4a,5,6,7,7a,8,9-octahydrocyclopenta[4,5]-
cyclohepta[1,2-c]furan-1-one 4-(N-acetyl-(2R,3S)-3-phenylisoserinate) (9c). Ch rom atograph y
dich lorom eth an e–2-propan ol 97 : 3. Yield 70%, m .p. 141–143 °C, [α]D +12.6 (c 0.98, CHCl3).
IR (CHCl3), νm ax: 1 743 (C=O), 1 677 (C=O). 1H NMR (CDCl3): 0.94 s, 3 H (CH3-6); 1.03 s,
3 H (CH3-6); 1.07 t, 1 H, J(7α,7a) = J(7β,7a) = 11.9 (H-7α); 1.21 t, 1 H, J(5α,5β) = J(5α,4a) =
13.5 (H-5); 1.27 s, 3 H (CH3-8); 1.48 m , 1 H (H-5β); 1.56 m , 1 H (H-7β); 1.95 s, 3 H
(CH3CO); 2.05 bs, 1 H (OH-8); 2.48 d, 1 H, J(9α,4β) = 19.1 (H-9α); 2.55–2.67 m , 2 H (H-7a,
H-9β); 2.91 m , 1 H (H-4a); 3.93 bs, 1 H (OH-2′); 4.50 bs, 1 H (H-2′); 4.75 bd, 1 H, J(3α,3β) =
18.0 (H-3α); 4.88 d, 1 H, J(3α,3β) = 18.0 (H-3β); 5.41 dd, 1 H, J(3′,NH) = 9.1, J(3′,2′) = 1.9
(H-3′); 6.64 bs, 1 H (NH); 6.90 bs, 1 H (H-4); 7.28–7.41 m , 5 H (arom . H). 13C NMR: 23.0
(CH3CO); 26.3 (CH3-6); 29.0 (CH3-6); 32.4 (CH3-8); 34.9 (C-9); 37.8 (C-6); 42.4 (C-5); 43.9
(C-4a); 44.6 (C-7); 48.9 (C-7a); 54.9 (C-3′); 70.8 (C-3); 73.2 (C-2′); 73.7 (C-8); 74.8 (C-4);
122.2 (C-3a); 127.0, 128.1, 128.8, 138.5 (arom . C); 158.7 (C-9a); 170.3 (CH3CO); 171.8
(C-1′); 174.9 (C-1). LSIMS, m/z: 472 (M + H)+. HR-MS: for C26H34NO7 calculated 472.23353,
foun d 472.23449.
(4R,4aS,7aS,8S)-4,8-Dihydroxy-6,6,8-trimethyl-1,3,4,4a,5,6,7,7a,8,9-octahydrocyclopenta[4,5]-
cyclohepta[1,2-c]furan-1-one 4-(N-acetyl-(2R,3S)-3-phenylisoserinate) (9d ). Ch rom atograph y di-
ch lorom eth an e–2-propan ol 48 : 2. Yield 40%, m .p. 112–114 °C, [α]D +33.1 (c 1.04, CHCl3).
IR (CHCl3), νm ax: 3 435 (OH), 1 754 (C=O), 1 676 (C=O). 1H NMR: 1.01 s, 3 H (CH3-6);
1.06 s, 3 H (CH3-6); 1.10 s, 3 H (CH3-8); 1.31 dd, 1 H, J(5α,5β) = 12.7, J(4a,5β) = 11.0 (H-5β);
1.54 dd, 1 H, J(7α,7β) = 13.2, J(7α,7a) = 10.3 (H-7α); 1.60 dd, 1 H, J(5α,5β) = 12.7, J(5α,4a) =
6.7 (H-5α); 1.86 dd, 1 H, J(7β,7α) = 13.2, J(7β,7a) = 8.2 (H-7β); 2.00 s, 3 H (CH3CO);
2.12–2.28 m , 2 H (H-4a, H-7a); 2.33 dd, 1 H, J(9α,9β) = 15.0, J(9α,1) = 1.3 (H-9α); 2.79 d,
1 H, J(9α,9β) = 15.0 (H-9β); 4.54 d, 1 H, J(2′,3′) = 2.5 (H-2′); 4.66 dd, 1 H, J(3α,3β) = 18.2,
J(3α,9β) = 1.9 (H-3α); 4.74 dd, 1 H, J(3α,3β) = 18.2, J(3β,4) = 1.1 (H-3β); 5.46 dd, 1 H,
J(3′,NH) = 9.0, J(2′,3′) = 2.4 (H-3′); 5.82 bd, 1 H, J(4,4a) = 9.8 (H-4); 6.58 d, 1 H, J(NH,3′) =
9.0 (NH); 7.32–7.42 m , 5 H (arom . H). 13C NMR (CDCl3): 20.7 (CH3-3); 23.1 (CH3CO); 30.9
(CH3-6); 31.1 (CH3-6); 34.3 (C-6); 39.4 (C-9); 43.4 (C-5); 44.1 (C-4a); 46.3 (C-5); 54.5 (C-7a);
54.8 (C-3′); 69.2 (C-3); 72.1 (C-8); 73.4 (C-2′); 77.4 (C-4); 124.2 (C-3a); 127.0, 128.3, 128.8,
138.4 (arom . C); 159.8 (C-9a); 170.3 (CH3CO); 172.1 (C-1′); 174.1 (C-1). LSIMS, m/z: 494
(M + Na)+. HR-MS: for C26H33NNaO7 calculated 494.21547, foun d 494.21496.
(4S,4aR,7aS,8S)-8-Ethoxy-4-hydroxy-6,6,8-trimethyl-1,3,4,4a,5,6,7,7a,8,9-octahydrocyclopenta-
[4,5]cyclohepta[1,2-c]furan-1-one 4-(N-acetyl-(2R,3S)-3-phenylisoserinate) (9e). Ch rom atograph y
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

N-Acetyl-3-phenylisoserinates
81
dich lorom eth an e–2-propan ol 49 : 1. Yield 43%, oil, [α ]2D0 +2.4 (c 0.93, CHCl3). IR (CHCl3),
m ax: 3 433 (OH), 1 754 (C=O), 1 683 (C=O). 1H NMR: 1.03 s, 3 H (CH3-6); 1.04 t, 3 H, J =
ν
7.0 (OCH2CH3); 1.07 s, 3 H (CH3-6); 1.19 dd, 1 H, J(4a,5β) = 4.3, J(5α,5β) = 13.7 (H-5β);
1.20 s, 3 H (CH3-8); 1.49 dd, 1 H, J(4a,5α) = 7.0, J(5α,5β) = 13.7 (H-5α); 1.54 dd, 1 H,
J(7α,7β) = 13.0, J(7α,7a) = 12.9 (H-7α); 1.63 dd, 1 H, J(7β,7a) = 6.7, J(7α,7β) = 13.0 (H-7β);
1.99 s, 3 H (CH3CO); 2.51 m , 2 H (H-7a, H-9α); 2.67 m , 1 H (H-4a); 2.70 d, 1 H, J(9α,9β) =
16.2 (H-9β); 3.24 m , 1 H an d 3.41 m , 1 H (OCH2CH3); 3.83 bs, 1 H (OH-2′); 4.39 m , 1 H
(H-3α); 4.54 d, 1 H, J(2′,3′) = 3.0 (H-2′); 4.65 m , 1 H (H-3β); 5.47 dd, 1 H, J(3′,NH) = 8.8,
J(2′,3′) = 3.0 (H-3′); 5.94 d, 1 H, J(4,4a) = 10.5 (H-4); 6.59 d, 1 H, J(3′,NH) = 8.8 (NH);
7.28–7.38 m , 5 H (arom . H). 13C NMR: 15.8 (OCH2CH3); 23.1 (CH3CO); 25.2 (CH3-8); 29.7
(C-9); 30.6 (CH3-6); 31.1 (CH3-6); 35.1 (C-6); 41.7 (C-4a); 42.1 (C-7); 43.5 (C-5); 51.0 (C-7a);
54.8 (C-3′); 56.1 (OCH2CH3); 69.2 (C-3); 72.9 (C-4); 73.6 (C-2′); 74.8 (C-8); 124.7 (C-3a);
126.8, 128.0, 128.6, 138.3 (arom . C); 158.2 (C-9a); 169.6 (CH3CO); 172.0 (C-1′); 174.0 (C-1).
LSIMS, m/z: 522 (M + Na)+. HR-MS: for C28H37NNaO7 calculated 522.24677, foun d 22.24622.
(4R,4aR,7aS,8S)-8-Ethoxy-4-hydroxy-6,6,8-trimethyl-1,3,4,4a,5,6,7,7a,8,9-octahydrocyclopenta-
[4,5]cyclohepta[1,2-c]furan-1-one 4-(N-acetyl-(2R,3S)-3-phenylisoserinate) (9f). Ch rom atograph y
dich lorom eth an e–2-propan ol 49 : 1. Yield 26%, oil, [α ]2D0 +44.9 (c 0.92, CHCl3). IR (CHCl3),
ν
m ax: 3 435 (OH), 1 753 (C=O), 1 677 (C=O). 1H NMR: 1.00 s, 3 H (CH3-6); 1.05 s, 6 H
(CH3-6, CH3-8); 1.13 t, 3 H, J = 6.9 (OCH2CH3); 1.29 dd, 1 H, J(4a,5α) = 10.5, J(5α,5β) = 12.6
(H-5α); 1.53 dd, 1 H, J(7α,7β) = 12.6, J(7α,7a) = 10.3 (H-7α); 1.58 dd, 1 H, J(4a,5β) = 6.7,
J(5α,5β) = 12.6 (H-5β); 1.79 dd, 1 H, J(7a,7β) = 8.2, J(7α,7β) = 12.6 (H-7β); 1.99 s, 3 H
(CH3CO); 2.25 m , 1 H (H-4a); 2.32 m , 1 H (H-7a); 2.39 dd, 1 H, J(9α,9β) = 14.9, J(9α,3α) =
2.0 (H-9α); 2.80 d, 1 H, J(9α,9β) = 14.8 (H-9β); 3.33 m , 2 H (OCH2CH3); 4.54 d, 1 H,
J(2′,3′) = 2.5 (H-2′); 4.69 ABq, JAB = 18.0 (H-3); 5.46 dd, 1 H, J(3′,NH) = 9.0, J(2′,3′) = 2.5
(H-3′); 5.79 dd, 1 H, J(4,4a) = 10.5, J(3,4) = 1.3 (H-4); 6.59 d, 1 H, J(3′,NH) = 9.0 (NH);
7.28–7.38 m , 5 H (arom . H). 13C NMR: 16.0 (OCH2CH3); 18.0 (CH3-6); 23.1 (CH3CO); 30.9
(CH3-6); 31.1 (CH3-8); 33.8 (C-9); 34.3 (C-6); 43.3 (C-7); 44.2 (C-4a); 46.1 (C-5); 52.5 (C-7a);
54.8 (C-3′); 56.3 (OCH2CH3); 69.3 (C-3); 73.4 (C-2′); 75.9 (C-8); 77.3 (C-4); 124.4 (C-3a);
127.0, 128.3, 128.8, 138.5 (arom . C); 159.4 (C-9a); 170.2 (CH3CO); 172.1 (C-1′); 174.2 (C-1).
LSIMS, m/z: 522 (M
+
Na)+. HR-MS: for C28H37NNaO7 calculated 522.24677, foun d
522.24736.
(4S,4aR,7aS,8S)-4,8-Dihydroxy-6,6,8-trimethyl-1,3,4,4a,5,6,7,7a,8,9-octahydrocyclopenta[4,5]-
cyclohepta[1,2-c]furan-3-one 4-(N-acetyl-(2R,3S)-3-phenylisoserinate) (9g). Ch rom atograph y
dich lorom eth an e–2-propan ol 49 : 1. Yield 38%, m .p. 98–101 °C, [α ]2D0 +9.6 (c 0.94, CHCl3).
IR (CHCl3), νm ax: 3 444 (OH), 1 750 (C=O), 1 654 (C=O). 1H NMR: 0.98 s, 3 H (CH3-6);
1.04 s, 3 H (CH3-6); 1.06 m , 1 H (H-7α); 1.14 t, 1 H, J(4a,5α) = J(5α,5β) = 11.2 (H-5α); 1.29 s,
3 H (CH3-8); 1.64–172 m , 2 H (H-7β, H-5β); 2.03 s, 3 H (CH3CO); 2.58 d, 1 H, J(9α,9β) =
19.4 (H-9α); 2.64–2.73 m , 2 H (H-7a, H-9a); 2.78 d, 1 H, J(9α,9β) = 19.4 (H-9β); 4.60 d, 1 H,
J(2′,3′) = 1.9 (H-2′); 4.69 bs, 2 H (H-1); 5.61 dd, 1 H, J(3′,NH) = 10.0, J(2′,3′) = 1.9 (H-3′);
5.82 d, 1 H, J(4,4a) = 2.1 (H-4); 6.69 d, 1 H, J(NH,3′) = 10.0 (NH); 7.23–7.38 m , 5 H
(arom . H). 13C NMR: 23.4 (CH3CO); 26.0 (CH3-6); 29.0 (CH3-6); 32.1 (CH3-8); 36.4 (C-6);
37.1 (C-9); 42.3 (C-4a); 45.8 (C-5); 46.2 (C-7); 49.0 (C-7a); 53.8 (C-3′); 69.9 (C-4); 72.3 (C-1);
72.6 (C-2′); 73.0 (C-8); 122.6 (C-9a); 126.9, 127.7, 128.5, 138.2 (arom . C); 164.2 (C-3a);
170.1 (CH3CO); 172.3 (C-1′); 174.0 (C-3). LSIMS, m/z: 494 (M
26H33NNaO7 calculated 494.21547, foun d 494.21582.
+
Na)+. HR-MS: for
C
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82
Barycki et al.:
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