First regiospecific, enantiospecific total synthesis of gardnerine and gardnutine

Article abstract of DOI:10.1016/j.tetlet.2005.04.051

The first enantiospecific total synthesis of gardnerine and gardnutine has been achieved from 6-methoxy-d-tryptophan via the asymmetric Pictet-Spengler reaction, a stereocontrolled intramolecular enolate driven palladium-mediated cross-coupling reaction a

Full text of DOI:10.1016/j.tetlet.2005.04.051

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4219–4224
First regiospecific, enantiospecific total synthesis
of gardnerine and gardnutine
Hao Zhou, Dongmei Han, Xuebin Liao and James M. Cook*
Department of Chemistry, University of Wisconsin—Milwaukee, Milwaukee, WI 53201, USA
Received 18 March 2005; revised 12 April 2005; accepted 12 April 2005
Available online 3 May 2005
Abstract—The first enantiospecific total synthesis of gardnerine and gardnutine has been achieved from 6-methoxy-D-tryptophan
via the asymmetric Pictet–Spengler reaction, a stereocontrolled intramolecular enolate driven palladium-mediated cross-coupling
reaction and a chemospecific, regiospecific hydroboration/oxidation sequence as key steps.
Ó 2005 Elsevier Ltd. All rights reserved.
Gardnerine and gardnutine are 11-methoxy substituted
sarpagine indole alkaloids isolated from the dry roots
and stems of Gardneria nutans. The structures of these
alkaloids were determined by analysis of their 1H
NMR spectra,1 by chemical correlation with the known
indole alkaloid ajmaline,2 as well as by nuclear Over-
hauser effects (NOE).3 Important structural features of
these natural products include the 11-methoxy group
in ring A, the asymmetric centers at C-3(S), C-5(R),
C-6(R), C-15(S), and C-16(S), as well as the E-configur-
ation of the olefinic bond at C(19)–C(20), as illustrated
in Figure 1. Gardnutine also contains the unique cyclic
ether at C(6). Both gardnerine and gardnutine exhibit
interesting pharmacological activity.4–6 For instance,
gardnerine exhibited central nervous system depressant
activity in mice,4 and gardnerine showed 25% of the
activity of hexamethonium on ganglionic transmission
in the rabbit and rat superior cervical ganglion in situ.5
In addition, gardnerine was found to augment both con-
tractions elicited by nerve and muscle stimulation when
it was examined on neuromuscular transmission in a rat
limb (in situ), while gardnutine, in contrast, exhibited a
long-lasting depressive effect on both types of contrac-
tion.6 Gardnerine, a sarpagine alkaloid, was believed
to represent the biogenetic precursor of some
Gelsemium alkaloids including 11-methoxykoumine,
des-Na-methoxyhumantenirine,
11-methoxygelsem-
amide, gelsemicine, and 11-methoxy-19(R)-hydroxygel-
selegine (see Fig. 2). The partial syntheses of these
alkaloids were successfully achieved by Sakai and co-
workers in biomimetic fashion from gardnerine.7–11
For example, gardnerine was transformed into 11-meth-
oxykoumine by C–C intramolecular bond formation be-
tween the indole p electrons and allyl palladium species
at C(20), followed by other steps. Gardnerine was also
stereoselectively converted into 11-methoxy-19(R)-
hydroxygelselegine via a biogenetically hypothetical azi-
ridine intermediate. The conversion of gardnerine into
des-Na-methoxyhumantenirine and gelsemicine involved
stereoselective skeletal rearrangements, which included
the indole to oxindole transformations. Although gard-
nerine has been transformed into a variety of alkaloid
natural products, no total synthesis of this indole has
been achieved. Herein we report the first enantiospecific
total synthesis of gardnerine and gardnutine. Bond
constructions critical to the synthesis of these two
alkaloids include the E-ethylidene stereochemistry at
C(19)–C(20) and the S stereochemistry of the hydroxy-
methyl function at C(16). In addition, regiospecific
OH
O
17
H
H
5
N
9
6
7
H
8
H
10
11
16
21
20
4
N
1
3
13
MeO
N
H
2
H
MeO
N
12
H
H
15
19
14
H
H
18
gardnerine
gardnutine
Figure 1. Structures of gardnerine and gardnutine.
Keywords: Pictet–Spengler reaction; Intramolecular enolate driven
palladium-mediated cross-coupling; Hydroboration.
*
Corresponding author. Tel.: +1 414 229 5856; fax: +1 414 229
5530; e-mail: capncook@uwm.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.051

4220
H. Zhou et al. / Tetrahedron Letters 46 (2005) 4219–4224
H
O
O
Et
N
NH
H
MeO
N
O
O
MeO
N
H
OMe
des-Na-methoxyhumantenirine
gelsemicine
HO
H
H
N
MeO
N
H
H
gardnerine
H
O
H
O
H
OH
CH3
N
N
H
OH
MeO
N
CH3
H
MeO
N
O
H
OMe
11-methoxykoumine
11-methoxy-19(R)-hydroxygelselegine
Figure 2. Examples of partial synthesis of gelsemium alkaloids from gardnerine.
HO
H
O
H
oxidative
H
H
N
N
MeO
N
H
MeO
N
H
cyclization
H
H
H
H
gardnutine
gardnerine
O
H
H
O
cross coupling
N
I
N
MeO
N
H
MeO
N
H
H
H
H
H
CO2Et
NH2
O
asymmetric
Pictet-Spengler
N
MeO
N
MeO
N
H
reaction/Dieckmann
cyclization
H
H
Ph
6-methoxy-(D)-tryptophan
ethyl ester
Scheme 1. Retrosynthetic analysis.

H. Zhou et al. / Tetrahedron Letters 46 (2005) 4219–4224
4221
incorporation of the 11-methoxy group into the indole
was of paramount importance to success.
amine in 3 was converted into the Nb-benzyl tryptophan
4 by reductive amination. The Pictet–Spengler conden-
sation between the Nb-benzylamine 4 and the aldehyde
afforded a mixture (at C-1) of trans- and cis-diester 5
in a ratio of 5:1 in high yield. Addition of 1 equiv of
TFA into the mixture rapidly epimerized the cis-diester
into the trans-diester presumably through a carbocat-
ionic intermediate via the scission of the C(1)–N(2)
bond.15 It is important to note, the epimerization of this
7-methoxy substituted Na-H cis isomer 5a into the trans
diastereomer 5b was completed in 30 min. In the parent
system devoid of the methoxy group in ring A, the epi-
merization was slower and took several days to go to
completion. The epimerization of this 7-methoxy substi-
tuted Na-H cis diastereomer 5a was also completed
faster than that of the related 7-methoxy substituted
Na-CH3 system, which took 7 h. The faster rate for 5a
to 5b could be explained by stabilization of the carbocat-
ionic intermediate via resonance. The latter phenomena
was recently investigated by study of the stable conform-
ations of both the trans and cis diastereomers in the
Based on the previous work on the total synthesis of
indole alkaloids via the asymmetric Pictet–Spengler
reaction,12 the synthesis of gardnerine required 6-meth-
oxy-(D)-tryptophan as the chiral transfer agent and
starting material (Scheme 1). The 6-methoxy-(D)-trypto-
phan ethyl ester 3 was prepared from Larock heteroann-
ulation between iodoaniline 1 and the propargyl unit 2
in the presence of Pd(OAc)2, LiCl, and Na2CO3 at
100 °C on large scale (300 g) in 77% yield.13 Hydrolysis
of the Scho¨llkopf chiral auxiliary, accompanied by
concomitant loss of the indole-2-silyl group during
treatment with aqueous 2 N HCl in THF provided
optically active 6-methoxy-D-tryptophan ethyl ester in
a single step in 90% yield. This approach had also been
employed for the regiospecific preparation of the
7-methoxy-(D)-tryptophan on large scale as well.14 Ester
3 was then employed to construct the Na-H-11-methoxy-
tetracyclic ketone, as shown in Scheme 2. The primary
EtO
N
I
(1)
(2)
+
N
MeO
NH2
OEt
TES
2
1
CO2Et
CO2Et
Ph
(3)
NH2
HN
MeO
N
H
MeO
N
H
3
4
(4)
CO2Et
CO2Et
HN
Ph
N
Ph
(cis
trans)
MeO
N
H
MeO
N
H
CO2Me
CO2Me
5 (cis/trans 1:5)
5a, cis
5b, trans
CO2Et
H
O
(5)
(6)
N
Ph
N
N
MeO
N
H
MeO
H
CO2Me
H
Ph
6
5b, trans
Scheme 2. Reagents and conditions: (1) Pd(OAc)2, Na2CO3, LiCl, DMF, 100 °C, 77%; (2) aq HCl, THF 90% (3) PhCHO, EtOH, rt; NaBH4, À5 °C,
90%; (4) HCOCH2CH2CO2Me, CH2Cl2, HOAc, rt, overnight, then 1% TFA/CH2Cl2 (1 equiv TFA), rt, 30 min, 92%; (5) NaH (60%, 8 equiv), MeOH
(4 equiv), toluene, reflux; (6)33% KOH, dioxane, reflux, two steps, 60%.

4222
H. Zhou et al. / Tetrahedron Letters 46 (2005) 4219–4224
MeO
Since the cis isomer 5a existed in a half boat-like conform-
MeO
ation in which the d* orbital of the C(1)–N(2) bond
was approximately parallel with the p electrons of the
indole ring, this stabilized the scission of the C(1)–
N(2) bond by p orbital overlap with the indole. In the
half-chair conformation, the d* orbital would be
perpendicular to the p electrons of the indole system,
consequently generation of the carbocationic intermedi-
ate would be more difficult. Furthermore, epimerization
of the cis-Na-H diester with the boat-like conformation
took place more rapidly than the related cis-Na-methyl
case which existed in the half-chair conformation. After
complete conversion of 4 into the trans-diester 5b via the
asymmetric Pictet–Spengler reaction, the Dieckmann
cyclization, decarboxylation process under basic condi-
tions, provided 11-methoxy ketone 6 in good yield.
Bn
H3C
N
H
Bn
COOEt
N
H
N
H
N
H
H
COOEt
H3COOC
COOCH3
(half chair)
(boat-like)
Figure 3. Proposed electronic orbital alignment in the cis Na-CH3 (left)
and Na-H (right) diesters.
Na-H and Na-CH3 series by analysis of the conform-
ations by NMR spectroscopy and X-ray analysis.16 It
was found, the Na-H trans diastereomer 5b as well as
the Na-methyl cis and trans diastereomers existed with
a half-chair C-ring in the preferred conformer in solu-
tion, while the Na-H cis diastereomer 5a adopted a
boat-like C-ring (Fig. 3) in the preferred conformer.
The tetracyclic ketone 6 was then converted into gard-
nerine and gardnutine, as illustrated in Scheme 3. The
H
H
O
O
(1)
NH
N
H3CO
N
H
H3CO
N
H
H
Ph
H
7
6
(2)
O
H
H
N
I
O
(3)
N
H3CO
N
H
H3CO
N
H
H
H
H
9
8
(4)
H
BR2
H
(5)
H
N
N
H3CO
N
H3CO
N
H
H
H
H
H
H
10
O
HO
H
H
H
H
(6)
N
N
H3CO
N
H3CO
N
H
H
H
H
H
H
gardnerine
gardnutine
[α]26D -29.2 o (c 0.34, MeOH)
lit. -29.4o (MeOH)28
Scheme 3. Reagents and conditions: (1) Pd/C, EtOH/HCl, 90%; (2) (Z)-1-bromo-2-iodo-2-butene, THF, K2CO3, reflux, 95%; (3) 5% Pd(OAc)2, 20%
PPh3, 1 equiv Bu4NBr, 4 equiv K2CO3, DMF/H2O (9:1), 65 °C, 80%; (4) CH3PPh3Br, KOtBu, benzene, rt, 2 h, 85%; (5) 9-BBN; NaOH/H2O2, rt, 1 h,
70%; (6) DDQ, THF, reflux, 1 h, 92%.

H. Zhou et al. / Tetrahedron Letters 46 (2005) 4219–4224
4223
Nb-benzyl group of 6 was removed via catalytic hydro-
genation, and this was followed by alkylation with (Z)-
1-bromo-2-iodo-2-butene to provide ketone 8. When
this ketone 8 was heated in DMF/H2O (9/1) with
Pd(OAc)2, PPh3, K2CO3, and Bu4NBr at 65 °C, the
pentacyclic ketone 9 was obtained in 80% yield.
The C(19)–C(20) E-ethylidene function in ketone 9
had been established in stereospecific fashion with this
enolate-driven palladium-catalyzed intramolecular
cyclization.17–23 Recently, we reported the C(19)–
C(20) Z-ethylidene function of (À)-koumidine could
be introduced in a similar fashion, when PCy3 was em-
ployed as the ligand instead of PPh3.24 The Wittig reac-
much of the interest in this endeavor. The authors wish
to thank the NIMH for support (in part) of this work.
References and notes
1. Sakai, S.; Kubo, A.; Haginiwa, J. Tetrahedron Lett. 1969,
19, 1485.
2. Sakai, S.; Kubo, A.; Hamamoto, T.; Wakabayashi, M.;
Takahashi, K.; Ohtani, Y.; Haginiwa, J. Tetrahedron Lett.
1969, 19, 1489.
3. Sakai, S.; Kubo, A.; Hamamoto, T.; Wakabayashi, M.;
Takahashi, K.; Ohtani, H.; Haginiwa, J. Chem. Pharm.
Bull. 1973, 21, 1783.
tion of ketone
9
was then carried out with
4. Harada, M.; Ozaki, Y.; Murayama, S.; Sakai, S.; Hag-
iniwa, J. Yakugaku Zasshi 1971, 91, 997.
5. Harada, M.; Ozaki, Y. Chem. Pharm. Bull. 1978, 26, 48.
6. Harada, M.; Ozaki, Y. Chem. Pharm. Bull. 1976, 24,
211.
7. Sakai, S.; Yamanaka, E.; Kitajima, M.; Yokota, M.; Aimi,
N.; Wongseripatana, S.; Ponglux, D. Tetrahedron Lett.
1986, 27, 4585.
8. Takayama, H.; Masubuchi, K.; Kitajima, M.; Aimi, N.;
Sakai, S. Tetrahedron 1989, 45, 1327.
9. Takayama, H.; Kitajima, M.; Sakai, S. Tetrahedron 1994,
50, 5363.
10. Kitajima, M.; Takayama, H.; Sakai, S. J. Chem. Soc.,
Perkin Trans. 1 1994, 1573.
11. Takayama, H.; Kitajima, M.; Sakai, S. Tetrahedron 1994,
50, 11813.
12. Li, J.; Wang, T.; Yu, P.; Peterson, A.; Weber, R.; Soerens,
D.; Grubisha, D.; Bennett, D.; Cook, J. M. J. Am. Chem.
Soc. 1999, 121, 6998.
methyltriphenylphosphonium bromide in benzene in
the presence of potassium tert-butoxide to afford diene
10 in high yield. The 9-BBN reagent was chosen as the
hydroborating agent to maximize the chemoselectivity
of the process. The use of bulky hydroborating agents
permits differentiation between the disubstituted and
hindered trisubstituted olefinic moieties in diene 10.
The C(19)–C(20) double bond in the related sapargine
indole alkaloids reacted with both BH3ÆDMS and
BH3ÆTHF, however, they did not react with thexyl bor-
ane or 9-BBN.25 In addition, carbon atom (16) of the
C(16)–C(17) olefinic site had been selectively hydrobo-
rated to provide the 16(S) alcohol during the synthesis
of (+)-koumine,26 (E)16-epinormacusine B and (E)16-
epiaffinisine.27 Gardnerine was obtained as the only
detectable diastereomer when 9-BBN was employed
as the hydroborating agent, followed by the usual oxi-
1
dative work up. The H NMR spectrum, 13C spectrum,
13. Liu, X.; Deschamps, J. R.; Cook, J. M. Org. Lett. 2002, 4,
3339.
and optical rotation of synthetic gardnerine (see Ref.
32) were in excellent agreement with those of natural
gardnerine.1,28 Further oxidative cyclization of gardn-
erine with DDQ in THF afforded gardnutine in 92%
yield. The use of DDQ to form 6-oxygen substituted
tetrahydro b-carbolines was reported from our labora-
tory several years ago,29 following the earlier work of
Oikawa and Yonemitsu.30,31 Thus, a concise, stereospe-
cific total synthesis of gardnerine and gardnutine has
been completed from 6-methoxy-(D)-tryptophan 3 in
9 (20% overall yield) and 10 steps (18% overall yield),
respectively.
14. Zhou, H.; Liao, X.; Cook, J. M. Org. Lett. 2004, 6, 249.
15. (a) Zhang, L. H.; Gupta, A. K.; Cook, J. M. J. Org. Chem.
1989, 54, 4708; (b) Cox, E. D.; Hamaker, L. K.; Li, J.; Yu,
P.; Czerwinski, K. M.; Deng, L.; Bennett, D. W.; Cook, J.
M.; Watson, W. H.; Krawiec, M. J. Org. Chem. 1997, 62,
44; (c) Cox, E. D.; Li, J.; Hamaker, K.; Yu, P.; Cook, J.
M. Chem. Commun. 1996, 2478; (d) Cox, E. D.; Cook, J.
M. Chem. Rev. 1995, 95, 1797.
16. Han, D; Liu, X; Cook, J. M. Mechanistic Study on the
Asymmetric Pictet–Spengler Reaction: Evidence Support-
ing the Carbocationic Pathway, 227th ACS National
Meeting, Anaheim, CA, United States, March 28–April 1,
2004.
17. Piers, E.; Marais, P. C. J. Org. Chem. 1990, 55, 3454.
18. Piers, E.; Renaud, J. J. Org. Chem. 1993, 58, 11.
19. Birman, V. B.; Rawal, V. H. Tetrahedron Lett. 1998, 39,
7219.
In conclusion, the first regiospecific, enantiospecific
total synthesis of gardnerine and gardnutine has been
achieved from 6-methoxy-D-tryptophan 3 via the asym-
metric Pictet–Spengler reaction. A stereocontrolled
intramolecular enolate driven palladium-mediated
cross-coupling reaction and a chemospecific, regiospeci-
fic hydroboration/oxidation were also key steps in this
route. Since Sakai et al. had earlier converted gardnerine
into 11-methoxykoumine,7 des-Na-methoxyhumanteni-
rine,8 11-methoxygelsemamide,9 gelsemicine,10 and
11-methoxy-19(R)-hydroxygelselegine,11 this work also
constituted a formal total synthesis of these alkaloids.
20. Wang, T.; Cook, J. M. Org. Lett. 2000, 2, 2057.
´
21. Sole, D.; Peidro, E.; Bonjoch, J. Org. Lett. 2000, 2, 2225.
´
22. Sole, D.; Vallverdu, L.; Solans, X.; Font-Bardia, M.;
Bonjoch, J. J. Am. Chem. Soc. 2003, 125, 1587.
´
23. Sole, D.; Diab, F.; Bonjoch, J. J. Org. Chem. 2003, 68,
5749.
24. Cao, H.; Yu, J.; Wearing, X. Z.; Zhang, C.; Liu, X.;
Deschamps, J.; Cook, J. M. Tetrahedron Lett. 2003, 44,
8013.
25. Liu, X. Ph.D Thesis., University of Wisconsin—Milwau-
kee, Milwaukee, WI, 2002.
26. Magnus, P.; Mugrage, B.; Deluca, M.; Cain, G. A. J. Am.
Chem. Soc. 1989, 111, 786.
Acknowledgements
27. Yu, J.; Liao, X.; Cook, J. M. Org. Lett. 2002, 4, 4681.
28. Takayama, H.; Nitta, W.; Kitajima, M.; Aimi, N.; Sakai,
S. J. Nat. Prod. 1994, 57, 521.
This letter is dedicated to Professors Hino and Sakai
whose pioneering work in the indole area stimulated

4224
H. Zhou et al. / Tetrahedron Letters 46 (2005) 4219–4224
29. (a) Cain, M.; Mantei, R.; Cook, J. M. J. Org. Chem. 1982,
47, 4933; (b) Wang, T.; Xu, Q.; Yu, P.; Liu, X.; Cook, J.
M. Org. Lett. 2001, 3, 345.
30. Oikawa, Y.; Yonemitsu, O. J. Org. Chem. 1977, 42, 1213.
31. Oikawa, Y.; Yoshioka, T.; Mohri, K.; Yonemitsu, O.
Heterocycles 1979, 12, 1457.
117.6, 121.6, 135.7, 136.2, 137.4, 151.8, 155.9. EIMS (m/e,
relative intensity): 306 (M+, 72), 305 (100), 199 (39), 198
(60). This material was used directly in the next step.
Gardnerine: [a]D À29.2° (c 0.31, MeOH), lit. [a]D À29.4°
(MeOH). 1H NMR (500 MHz, CDCl3): d 1.66 (dt, 3H,
J = 6.8, 1.8 Hz), 1.84 (dd, 2H, J = 8.5, 2.5 Hz), 2.17–2.23
(m, 1H), 2.89–2.99 (m, 3H), 3.30 (dd, 1H, J = 10.5,
2.0 Hz), 3.58 (dd, 2H, J = 10.5, 6.5 Hz), 3.61 (d, 1H,
J = 3.3 Hz), 3.69 (dt, 1H, J = 16.8, 1.7 Hz), 3.85 (s, 3H),
4.12 (dd, 1H, J = 7.8, 5.2 Hz), 5.25 (q, 1H, J = 6.8 Hz),
6.78 (dd, 1H, J = 8.5, 2.2 Hz), 6.85 (d, 1H, J = 2.2 Hz),
7.36 (d, 1H, J = 8.5 Hz), 8.10 (br s, 1H). 13C NMR
(125 MHz, CDCl3): d 13.2, 23.1, 26.9, 27.6, 42.7, 50.5,
52.9, 56.1, 56.7, 61.8, 95.6, 106.4, 109.2, 114.4, 119.1,
121.2, 135.9, 137.6, 139.9, 156.6.
32. Compound 3: [a] À5.07° (c 0.71, CHCl3); IR (NaCl) 3365,
1
1730, 1625 cmÀ1. H NMR (300 MHz, CDCl3): d 1.23 (t,
3H, J = 7.1 Hz), 1.60 (br s, 2H), 3.0 (dd, 1H, J = 14.3,
7.7 Hz), 3.22 (dd, 1H, J = 14.4, 4.8 Hz), 3.78 (m, 1H), 3.81
(s, 3H), 4.15 (q, 2H, J = 7.2 Hz), 6.80 (m, 2H), 6.90 (d, 1H,
J = 2.0 Hz), 7.45 (d, 1H, J = 8.5 Hz), 8.15 (br s, 1H). 13C
NMR (75 MHz, CDCl3): d 14.0, 30.7, 54.5, 54.9, 60.8,
94.7, 109.2, 111.0, 119.1, 121.8, 121.9, 136.5, 156.1, 175.2;
MS (CI) (m/e): 263 (M++1, 100). Anal. Calcd for
C14H18N2O3: C, 64.12; H, 6.87; N, 10.69. Found: C,
63.96; H, 6.98; N, 10.54.
1H NMR (500 MHz, acetone-d6): d 1.63 (dt, 3H, J = 6.8,
2.2 Hz), 1.73–1.85 (m, 2H), 2.14–2.15 (m, 1H), 2.80–2.96
(m, 3H), 3.17 (dd, 1H, J = 11.0, 9.0 Hz), 3.48–3.54 (m,
2H), 3.56–3.59 (m, 2H), 3.78 (s, 3H), 4.10 (dd, 1H, J = 9.8,
2.7 Hz), 5.21 (q, 1H, J = 6.8 Hz), 6.67 (dd, 1H, J = 8.5,
2.3 Hz), 6.89 (d, 1H, J = 2.3 Hz), 7.28 (d, 1H, J = 8.5 Hz),
9.82 (br s, 1H). 13C NMR (125 MHz, acetone-d6) 12.4,
22.8, 26.8, 27.4, 43.2, 50.2, 52.9, 55.2, 56.6, 60.2, 95.2,
105.7, 108.5, 112.5, 118.5, 121.3, 136.9, 137.8, 142.2, 156.3.
EIMS (m/e, relative intensity): 324 (M+, 66), 323 (70), 293
(39), 199 (100), 198 (100).
1
Compound 10: H NMR (300 MHz, CDCl3): d 1.66 (dt,
3H, J = 6.8, 1.9 Hz), 1.89 (ddd, 1H, J = 12.0, 3.9, 2.4 Hz),
2.12 (ddd, 1H, J = 11.7, 9.6, 1.8 Hz), 2.95 (dd, 1H,
J = 15.5, 1.5 Hz), 3.14 (dd, 1H, J = 15.6, 5.0 Hz), 3.32
(dd, 1H, J = 3.9, 1.4 Hz), 3.68 (d, 2H, J = 1.5 Hz), 3.81 (s,
3H), 3.83–3.85 (m, 1H), 4.14 (dd, 1H, J = 9.3, 1.7 Hz),
4.84 (d, 2H, J = 2.4 Hz), 5.26 (q, 1H, J = 6.8 Hz), 6.76 (dd,
1H, J = 8.4, 2.2 Hz), 6.80 (d, 1H, J = 1.9 Hz), 7.35 (d, 1H,
J = 8.4 Hz), 7.93 (br s, 1H). 1H NMR (300 MHz,
CD3OD): d 1.67 (dt, 3H, J = 6.8, 1.8 Hz), 1.90 (ddd, 1H,
J = 12.3, 4.2, 2.6 Hz), 2.20 (td, 1H, J = 11.4, 2.1 Hz), 3.00
(dd, 1H, J = 16.8, 2.1 Hz), 3.11 (dd, 1H, J = 16.5, 4.8 Hz),
3.42 (dd, 1H, J = 4.2, 1.7Hz), 3.65 (d, 1H, J = 16.5 Hz),
3.76 (dt, J = 13.0, 3.1 Hz), 3.81 (s, 3H), 3.87 (dd, 1H,
J = 4.6, 2.2 Hz), 4.21 (d, 1H, J = 10.1 Hz), 4.88 (d, 2H,
J = 2.7 Hz), 5.32 (q, 1H, J = 6.9 Hz), 6.66 (dd, 1H, J = 8.6,
2.2 Hz), 6.84 (d, 1H, J = 2.1 Hz), 7.28 (d, 1H, J = 8.5 Hz).
13C NMR (75 MHz, CD3OD): d 11.0, 25.5, 35.5, 36.3,
50.5, 54.6, 54.9, 56.7, 94.4, 103.0, 104.2, 107.9, 114.9,
1
Gardnutine: H NMR (500 MHz, CDCl3): d 1.67 (d, 3H,
J = 6.8 Hz), 1.84 (t, 1H, J = 11.5 Hz), 2.02 (dt, 1H,
J = 13.5, 3.3 Hz), 2.32 (qd, 1H, J = 11.5, 3.5 Hz), 2.85
(q, 1H, J = 3.0 Hz), 3.50 (t, 1H, J = 9.6 Hz), 3.74 (br s,
2H), 3.82 (dd, 1H, J = 11.5, 7.5 Hz), 3.87 (s, 3H), 3.87 (t,
1H, J = 9.0 Hz), 4.00 (dd, 1H, J = 10.3, 2.4 Hz), 5.33 (q,
1H, J = 6.9 Hz), 5.63 (d, 1H, J = 7.5 Hz), 6.84 (dd, 1H,
J = 8.6, 2.2 Hz), 6.87 (d, 1H, J = 2.1 Hz), 7.59 (d, 1H,
J = 8.6 Hz), 7.91 (br s, 1H). EIMS (m/e, relative intensity):
322 (M+, 48), 212 (31), 199 (75), 198 (100).