Enantioselective total synthesis of (-)-citrinadin A and revision of its stereochemical structure

Article abstract of DOI:10.1021/ja405547f

The first enantioselective total synthesis of (-)-citrinadin A has been accomplished in 20 steps from commercially available materials via an approach that minimizes refunctionalization and protection/deprotection operations. The cornerstone of this synthesis features an asymmetric vinylogous Mannich addition of a dienolate to a chiral pyridinium salt to set the initial chiral center. A sequence of substrate-controlled reactions, including a highly stereoselective epoxidation/ring-opening sequence and an oxidative rearrangement of an indole to furnish a spirooxindole, are then used to establish the remaining stereocenters in the pentacyclic core of (-)-citrinadin A. The successful synthesis of citrinadin A led to a revision of the stereochemical structure of the core substructure of the citrinadins.

Full text of DOI:10.1021/ja405547f

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Communication
Enantioselective Total Synthesis of (–)-Citrinadin
A and Revision of its Stereochemical Structure
Zhiguo Bian, Christopher C. Marvin, and Stephen F. Martin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja405547f • Publication Date (Web): 09 Jul 2013
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Journal of the American Chemical Society
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Enantioselective Total Synthesis of (–)-Citrinadin A and Revision of its Ste-
reochemical Structure
Zhiguo Bian, Christopher C. Marvin†, Stephen F. Martin*
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Department of Chemistry and Biochemistry, The University of Texas, Austin, Texas 78712
Supporting Information Placeholder
structure comprising a spirooxindole motif with two contigu-
ous stereogenic centers (BC ring), a densely functionalized
ABSTRACT: The first enantioselective total synthesis of (–)-
citrinadin A has been accomplished in 20 steps from com-
quinolizidine (DE rings), and an α,β-epoxycarbonyl moiety on
mercially available materials via an approach that minimizes
the A ring. The most notable difference in the assigned struc-
refunctionalization and protection/deprotection operations.
tures of citrinadins A and B and PF1270A–C is the relative
The cornerstone of this synthesis features an asymmetric
stereochemistry of the α,β-epoxy ketone and the pentacyclic
vinylogous Mannich addition of a dienolate to a chiral pyri-
core. The complex molecular architecture of these alkaloids
dinium salt to set the initial chiral center. A sequence of sub-
coupled with their important biological activities have in-
strate-controlled reactions, including a highly stereoselective
spired several synthetic investigations, especially toward the
epoxidation/ring opening sequence and an oxidative rear-
citrinadins, but none of these alkaloids have yet been pre-
rangement of an indole to furnish a spirooxindole, are then
used to establish the remaining stereocenters in the pentacy-
clic core of (–)-citrinadin A. The successful synthesis of
citrinadin A led to a revision of the stereochemical structure
of the core substructure of the citrinadins.
3
pared by total synthesis. In this communication, we report
the first enantioselective total synthesis of citrinadin A (1),
and in the accompanying communication Wood and cowork-
ers report the first total synthesis of citrinadin B (2). These
investigations have also led to a revision in the structures of 1
and 2, and the reassignment of the absolute stereochemistry
of the pentacyclic core to correspond to that of PF1270 A–C.
In light of this discovery, the structures in the schemes that
follow will depict what we now know to be the correct stere-
ochemical structure of citrinadin A (1*).4
Citrinadin A (1), citrinadin B (2), and PF1270 A-C (3-5) are
members of a small family of novel spirooxindole alkaloids
,
that exhibit potentially useful biological activities (Figure 1).1 2
Citrinadins A and B, which were isolated by Kobayashi from a
culture broth of Penicillium citrinum, are active against mu-
rine leukemia L1210 and human epidermoid carcinoma KB
We have been interested in the synthesis of indole and
oxindole alkaloids for a number of years, and in 2007, we
5
developed a method for the enantioselective synthesis of the
spiro oxindole ring system (ABC ring) present in citrinadin A
(1*) via a process in which (–)-8-phenylmenthol was utilized
as chiral auxiliary to promote the diastereoselective, oxida-
tive rearrangement of an indole to generate an oxindole.3a
However, further investigations exploring the feasibility of
elaborating such intermediates toward the citrinadins by
introducing the requisite D and E rings were not successful.
Consequent to these findings, we formulated a new plan that
is outlined in retrosynthetic format in Scheme 1. We envi-
sioned that the spirocenter in 1* could be introduced by a
late-stage, stereoselective oxidative rearrangement of 6,
which would be assembled via
1
cells. The absolute and relative stereochemistry of citrinadin
A (1) was assigned based upon a combination of 1D and 2D
NMR experiments, including ROESY, and CD studies. The
related alkaloids PF1270 A-C, which were isolated from Peni-
2
cillium waksmanii strain PF1270 by Kushida, show submi-
cromolar affinities for the human H3 histamine receptor, with
3 being the most active (Ki = 0.07 μM, EC50 = 0.12 μM). The
structure and relative stereochemistry of 3–5 were assigned
based upon crystallographic analysis of 3.
Figure 1. Citrinadin A, B and PF1270A-C
O
O
CHO
OH
H
N
H
N
A
R
O
R
Scheme 1. Retrosynthetic Analysis of Citrinadin A
B
D
E
C
H
O
O
HN
HN
O
NHMe
NHMe
O
O
NMe2
PF1270A (3): R = (CH2)2CH3
PF1270B (4): R = CH2CH3
PF1270C (5): R = CH3
O
Citrinadin A (1): R =
Citrinadin B (2): R = H
O
The alkaloids 1–5 share a number of structural features, but
there are also some significant differences. For example,
both citrinadins and the PF1270s possess a pentacyclic core
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Page 2 of 5
5
1) Ethylene glycol, CSA,
OH
O
H
N
H
NMe2
1
(EtO)3CH, CH2Cl2
OH
i. LDA, THF, –78 °C
7
H
OH
18
N
Br
O
21
14
O
O
O
2) (MeO)2CO, NaH, THF
ii. ZnCl2, THF, –78 °C
2
3
4
19
16
12
3
O
O
9
HN
1
N
O
3) NaH, ether, then Tf2O
4) CuCN, MeLi, ether
64%
NHMe
CO2Me
NHMe
Citrinadin A (1*)
O
12
10
Fischer Indole
Synthesis
6
5
6
7
OH
O
H
N
O
O
H
N
OMe
TIPS
iii.
OH
O
TIPS
O
O
(+)-TCC
N
O
8
9
16
MeHN
Cl
N
H
TCC-(+)
O
O
O
O
O
14
7
8
O
OMe
OZnCl
iv. 0.5 M aq HCl
66% (92:8 dr)
O
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TIPS
TIPS
CO2Me
MeO
O
13
MeO
15
O
H
N
R*
Cl
O
+
N
OR*
OH
O
H
N
O
CO2Me
O
O
Cs2CO3
O
O
Ph
Vinylogous
Mannich
Reaction
10
11
CO2Me
THF/MeOH (1:1), Δ
TIPS
9
(+)-TCC
80%
O
16
a Fisher indole synthesis of the ketal 7. Introduction of the
trans amino-alcohol moiety in 7 would then be achieved via
substrate-controlled epoxidation/ring opening, whereas the
methyl and hydroxyl groups in 7 would be accessible from 8
by a diastereoselective Michael addition and reduction of the
carbonyl group. The sole stereocenter in 8, which was des-
tined to control the creation of all of the remaining chirality
in the pentacyclic core, would then be established by a dia-
Having established a reliable procedure to access 16 with
high enantioselectivity, we turned our attention to the prepa-
ration of aminoalcohol 7 (Scheme 3). Protiodesilylation of 16
employing excess TBAF and microwave heating afforded
enone 8. The stereoselective 1,4-addition of a methyl group
to 8 proved to be problematic, presumably owing to the rela-
tively planar nature of the tricyclic ring system of 8. Indeed,
conjugate additions of different methyl nucleophiles under a
variety of conditions were examined, and we eventually dis-
covered that the copper-mediated addition of (chlorome-
6
stereoselective, vinylogous Mannich reaction of the dieno-
late derived from 10 to the chiral pyridinium salt 11 to give 9.
7
The total synthesis of citrinadin A thus commenced with
the preparation of 10 from commercially available 2,2-
dimethylcyclohexane-1,3-dione (12) in 64% overall yield for
the four steps (Scheme 2). With 10 in hand, the stage was set
for the key, diastereoselective, vinylogous Mannich reaction
involving the chiral pyridinium salt 14 to give 15. Although
we are not aware of any examples of the addition of dieno-
lates to chiral acyl pyridinium salts, we were cognizant of the
seminal work of Comins and Sahn, who added the zinc eno-
8
thyl)dimethylphenylsilylmethyl magnesium chloride provid-
ed a mixture of 1,4-addition products. This mixture was di-
rectly reduced with high stereoselectivity using L-Selectride
to give the desired isomer 17 in 71% yield over the two steps;
19% of the C(12) epimer of 17 was also isolated. Heating 17
with TBAF in a microwave oven furnished the unsaturated
lactam 18. Epoxidation of 18 with peroxytrifluoroacetic acid
in the presence of sodium carbonate gave a single epoxide
9
10
late of acetone to 14. b After evaluating different vinylogous
7
19. Although the epoxidation could be performed in un-
buffered media, the ketal moiety was cleaved. The diastere-
oselectivity of this epoxidation was apparently directed by
steric effects associated with the adjacent quaternary center
at C(19) in which the axial methyl group blocked the top face
of the alkene. Treatment of 19 with aqueous methylamine in
enolates, solvents, and reaction temperatures, we discovered
that the addition of the zinc dienolate 13 to the pyridinium
salt 14, which was generated in situ by the reaction of 3-TIPS-
4-methoxypyridine and the chloroformate derivative of (+)-
trans-2-(α-cumyl)cyclohexanol [(+)-TCC], provided the ad-
duct 15 in 66% yield with a dr of 92/8. The absolute stereo-
chemistry at the newly created stereocenter at C(16) was
assigned at this point by analogy with the findings of
Comins. Base-induced cleavage of the chiral auxiliary and
spontaneous cyclization afforded the tricyclic intermediate
16 in 84% ee together with about 70% of recovered (+)-TCC.
Gratifyingly, the optical purity of 16 was readily improved to
98% ee upon recrystallization.
,
11 12
sealed tube furnished the amino-alcohol 7.
Scheme 3. Preparation of Tricyclic Aminoalcohol 7
1) PhSiMe2CH2MgCl,
O
H
a
7
O
CuBr•DMS, BF3•OEt2
TBAF•3H2O
16
O
N
dioxane, 100 °C
2) L-Selectride, THF
71%
73%
O
8
O
H
N
O
H
OH
OH
19
O
O
TBAF•3H2O
Scheme 2. Vinylogous Mannich Reaction
N
12
DMF, 150 °C
O
O
81%
SiMe2Ph
18
17
O
H
OH
MeNH2, 100 °C
CF3CO3H, Na2CO3
O
7
O
N
CH2Cl2, 0 °C
95%
O
76%
19
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The next stage of the synthesis involved creation of the
pentacyclic core of citrinadin A (Scheme 4). In the event,
Enders for the enantioselective synthesis of (S)-epoxides
from α,β-unsaturated ketones delivered a separable mixture
(5:1) of 1* and 26 in 81% yield. The CD spectrum of the syn-
1
2
3
4
5
6
7
8
21
when 7 was heated with o-bromophenyl hydrazine hydro-
13
chloride in aqueous acid, the desired indole 20 was ob-
thetic 1* thus obtained as the free base is identical with that
a
1
tained. Although reduction of the lactam moiety using only
reported for (–)-citrinadin A, whereas the CD spectrum for
26 is different (see Supporting Information). The 1H and 13C
22
alane provided the desired product 6, the procedure with
14
alane followed by NaBCNH3 gave superior yields of 6. The
NMR data of the free base forms of 1* and 26 are wholly con-
1
moment was now at hand to test the feasibility of creating
the critical spirocenter at C(3) by the substrate-controlled
oxidative rearrangement of 6. Although oxidative rear-
rangements of indoles to give spirooxindoles have been well
sistent with their assigned structures, and the H and 13C
NMR data of 1* as its putative bis-hydrochloride salt, which
was formed
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Scheme 5. Endgame: Completing the Total Synthesis of
1*
,
15
documented, inducing such a transformation on 6 proved
to be more challenging than
Scheme 4. Preparation of Pentacyclic Core 22 of Citrina-
NMe2
HO
O
din A
3-Methylbut-1-yne,
Pd(PPh3)2Cl2, CuI
OH
H
N
OH
NHNH3Cl
O
HN
14
i. AlEt3, THF, –78 °C
22
OH
H
N
H
N
OH
Br
DMF, i-Pr2NH, 80 °C
ii. AlH3•EtNMe2, PhMe
EDCI, DMAP
CH2Cl2
Br
NHMe
7
86%
aq. H2SO4, reflux
23
iii. MeOH, AcOH,
NaCNBH3
97%
97%
MeHN
O
81%
20
O
O
OH
H
N
OH
H
N
R
R
N
O
Br
HN
HN
OH
H
N
OH
H
H
N
H
N
PPTS, CH2Cl2
O
OH
OH
Br
Br
then
O
Au(PPh3)NTf2,
THF
NHMe
NHMe
N
Davis oxaziridine
NHMe
NHMe
NMe2
NMe2
6
75%
21
O
O
24: R =
25: R =
O
+
O
O
OH
H
N
Bu
OH
HN
AcOH, CH2Cl2
O
3
NMe2
O
OH
OH
H
N
N
Br
47%
O
S
S
NMe2
S
O2
HN
NHMe
O
O
22
Davis oxaziridine
s
NHMe
Et2Zn, O2, PhMe
O
citrinadin A (1*)
81%, (dr = 5:1)
NMe2
anticipated. Indeed, all attempts utilizing a variety of stand-
ard oxidants including tert-BuOCl, OsO4 and NBS failed to
give 22. We eventually discovered that Davis’ oxaziridine,
which had been used by Williams to prepare spirooxindole
O
OH
H
N
O
HN
O
O
NHMe
O
16
alkaloids, was effective. The indole 6 was first treated with
26
24
pyridinium p-toluenesulfonate (PPTS) to protect the amino
groups from oxidation, and an excess of Davis’ oxaziridine
was added to afford a moderately stable epoxide, which was
tentatively assigned the structure 21.16b When 21 was treated
with acetic acid, the anticipated semi-pinacol rearrangement
ensued to provide the spirooxindole 22.
upon standing in CDCl3, are in good agreement with those
reported for a bis-salt of (–)-citrinadin A (see Supporting In-
formation). Because we were unable to obtain an authentic
sample of (–)-citrinadin A or its bis-salt, a direct comparison
with the synthetic sample was not possible. Nevertheless,
the CD spectra of synthetic 1* coupled with the crystallo-
graphic data for 24 strongly suggest that the correct stereo-
chemical structure of (–)-citrinadin A is represented by 1*,
At this juncture, it remained to install the requisite side
chains on the A and E rings (Scheme 5). In initial experiments,
we examined the possibility of directly converting the aryl
bromide moiety into an α,β-unsaturated ketone by a car-
bonylative cross-coupling reaction in analogy with prior work
1
not 1 as originally assigned by Kobayashi. This revised struc-
ture, in which the stereocenters in the pentacyclic core are
opposite those depicted in 1, is in agreement with the find-
ings of Wood and coworkers, who completed the first total
17
in our laboratories. However, these efforts were to no avail,
and we resorted to a stepwise process that commenced with
23
synthesis of (+)-citrinadin B.
the Sonogashira coupling between 22 and 3-methylbut-1-yne
18
to furnish the alkyne 23. O-Acylation of the hydroxyl group
In summary, we completed the first total synthesis of (–)-
citrinadin A and revised its stereochemical structure to be
that depicted in 1*. The synthesis, which requires only 20
steps from commercially available starting material, features
a highly diastereoselective vinylogous Mannich reaction of a
dienolate with a chiral pyridinium salt to establish the first
stereogenic center. The chirality at this critical center was
then used to control the introduction of the remaining stere-
at C(14) with N,N-dimethyl-L-valine in the presence of EDCI
19
and DMAP provided 24, the absolute and relative stereo-
chemistry of which were unambiguously proven by X-ray
crystallography. The gold-promoted oxidation of 24 using 2-
bromopyridine N-oxide according to a method reported by
20
Zhang gave the enone 25. Finally, the diastereoselective
epoxidation of the enone moiety using a method reported by
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ocenters in the pentacyclic core by substrate control. Further
Page 4 of 5
1
2
3
4
5
6
7
8
applications of this strategy to the syntheses of citrinadin B
(2) and the related alkaloids PF1270 A–C (3–5) are in pro-
gress, and the results of these investigations will be reported
in due course.
Hillier, M. C. J. Am. Chem. Soc. 1999, 121, 866-867. (f) Ito, M.; Clark, C.
W.; Mortimore, M.; Goh, J. B.; Martin, S. F. J. Am. Chem. Soc. 2001, 123,
8003-8010. (g) Liras, S.; Lynch, C. L.; Fryer, A. M.; Vu, B. T.; Martin, S. F.
J. Am. Chem. Soc. 2001, 123, 5918-5924. (h) Humphrey, J. M.; Liao, Y.;
Ali, A.; Rein, T.; Wong, Y.-L.; Chen, H.-J.; Courtney, A. K.; Martin, S. F. J.
Am. Chem. Soc. 2002, 124, 8584-8592. (i) Neipp, C. E.; Martin, S. F. J. Org.
Chem. 2003, 68, 8867-8878. (j) Deiters, A.; Chen, K.; Eary, C. T.; Martin,
S. F. J. Am. Chem. Soc. 2003, 125, 4541-4550. (k) Deiters, A.; Pettersson,
M.; Martin, S. F. J. Org. Chem. 2006, 71, 6547-6561. (l) Miller, K. A.; Mar-
tin, S. F. Org. Lett. 2007, 9, 1113-1116. (m) Cheng, B.; Sunderhaus, J. D.
and Martin, S. F. Org. Lett. 2010, 12, 3622-3625. (n) Fu, T.-H; McElroy, W.
T.; Shamszad, M. and Martin, S. F. Org. Lett. 2012, 14, 3834-3837.
(6) For reviews of the vinylogous Mannich reaction, see: (a) Martin, S. F.
Acc. Chem. Res. 2002, 35, 895-904. (b) Casiraghi, G.; Battistini, L.; Curti,
C.; Rassu, G.; Zanardi, F. Chem. Rev. 2011, 111, 3076-3154.
(7) (a) Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am. Chem. Soc.
1994, 116, 4719-4728. (b) Comins, D. L.; Sahn, J. J. Org. Lett. 2005, 7,
5227-5228.
(8) Comins, D. L.; Al-awar, R. S. J. Org. Chem. 1995, 60, 711-716.
(9) Heitzman, C. L.; Lambert, W. T.; Mertz, E.; Shotwell, J. B.; Tinsley, J.
M.; Va, P.; Roush, W. R. Org. Lett. 2005, 7, 2405-2408.
ASSOCIATED CONTENT
Supporting Information.
Complete experimental procedures, full characterization of new
compounds, X-ray crystallographic data for 24, comparison of
CD spectra of 1*and 26 with those published for (–)-citrinadin A,
and a comparison of 1H and 13C NMR data for 1*, both as its free
base and bis-salt forms, with those published for a bis-salt of (–)-
citrinadin A. This material is available free of charge via the In-
ternet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
sfmartin@mail.utexas.edu
Present Addresses
†Department of Chemistry, Hendrix College, 1600 Washington
Ave. Conway, AR 72032
(10) Fehr, C. Angew. Chem. Int. Ed. 1998, 37, 2407-2409.
(11) Sarabia, F.; Chammaa, S.; Garcia-Castro, M. and Martin-Galvez, F.
Chem. Commun. 2009, 5763-5765.
(12) The relative and absolute stereochemistry shown in 7 was later
confirmed by X-ray crystallographic analysis of 24.
ACKNOWLEDGMENT
We thank the National Institutes of Health and the Robert A.
Welch Foundation for generous support of this research. We are
also grateful to Dr. Vincent Lynch (The University of Texas, Aus-
tin) for X-ray crystallography and Dr. John Wood (Colorado State
University) for helpful discussions regarding the structure of the
citrinadins and suggestions for introducing the epoxy ketone
moiety. We also thank Dr. James Sahn (The University of Texas,
Austin) for helpful suggestions and Professor Daniel Comins
(North Carolina State University) for a generous gift of (–)-TCC
that was used in initial synthetic studies. We also thank Dr. Eun
Jeong Cho (The University of Texas, Austin) for assistance with
obtaining the CD spectra.
(13) For some examples see: (a) Danishefsky, S.; Chackalamannil, S.;
Harrison, P.; Silvestri, M. J. Am. Chem. Soc. 1985, 107, 2474-2484. (b)
Chen, C.-Y.; Senanayake, C. H.; Bill, T. J.; Larsen, R. D.; Verhoeven, T. R.;
Reider, P. J. J. Org. Chem. 1994, 59, 3738-3741. (c) Blair, J. B.; Kurrasch-
Orbaugh, D.; Marona-Lewicka, D.; Cumbay, M. G.; Watts, V. J.; Barker,
E. L.; Nichols, D. E. J. Med. Chem. 2000, 43, 4701-4710. (d) Roberson, C.
W.; Woerpel, K. A. J. Am. Chem. Soc. 2002, 124, 11342-11348.
(14) (a) Martin, S. F.; Benage, B.; Geraci, L. S.; Hunter, J. E., Mortimore,
M. J. Am. Chem. Soc. 1991, 113, 6161-6171. (b) Cushing, T. D.; Sanz-
Cervera, J. F. and Williams, R. M. J. Am. Chem. Soc. 1996, 118, 557-579.
(15) For a review, see: (a) Marti, C. and Carreira, E. M. Eur. J. Org. Chem.
2003, 2209-2219. See also: (b) Peterson, A. C.; Cook, J. M. J. Org. Chem.
1995, 60, 120-129. (c) Cushing, T. D.; Sanz-Cervera, J. F. and Williams, R.
M. J. Am. Chem. Soc. 1996, 118, 557-579. (d) Wearing, X. Z.; Cook, J. M.
Org. Lett. 2002, 4, 4237-4240.
REFERENCES
(16) (a) Greshock, T. J.; Grubbs, A. W.; Tsukamoto, S.; Williams, R. M.
Angew. Chem. Int. Ed. 2007, 46, 2262-2265. (b) Greshock, T. J.; Grubbs,
A. W.; Williams, R. M. Tetrahedron, 2007, 63, 6124-6130. (c) Greshock, T.
J.; Grubbs, A. W.; Jiao, P.; Wicklow, D. T.; Gloer, J. B.; Williams, R. M.
Angew. Chem. Int. Ed. 2008, 47, 3573-3577.
(17) (a) O’Keefe, B. M.; Simmons, N.; Martin, S. F. Org. Lett. 2008, 10,
5301-5304. (b) O’Keefe, B. M.; Simmons, N.; Martin, S. F. Tetrahedron
2011, 67, 4344-4351.
(18) (a) Sonogashira, K., Tohda, Y., Hagihara, N. Tetrahedron Lett. 1975,
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(19) Neises, B. and Steglich, W. Angew. Chem. Int. Ed. 1978, 17, 522-524
(20) Lu, B.; Li, C. and Zhang, L. J. Am. Chem. Soc. 2010, 132, 14070-
14072.
(21) Enders, D.; Zhu, J. and Raabe, G. Angew. Chem. Int. Ed. 1996, 35,
1725-1728.
(1) (a) Tsuda, M.; Kasai, Y.; Komatsu, K.; Sone, T.; Tanaka, M.; Mikami,
Y.; Kobayashi, J. Org. Lett. 2004, 6, 3087-3089. (b) Mugishima, T.; Tsuda,
M.; Kasai, Y.; Ishiyama, H.; Fukushi, E.; Kawabata, J.; Watanabe, M.;
Akao, K.; Kobayashi, J. J. Org. Chem. 2005, 70, 9430-9435.
(2) Kushida, N.; Watanabe, N.; Okuda, T.; Yokoyama, F.; Gyobu, Y.;
Yaguchi, T. J. Antibiotics, 2007, 60, 667-673.
(3) (a) Pettersson, M.; Knueppel, D.; Martin, S. F. Org. Lett. 2007, 9, 4623-
4626. (b) McIver, A. L.; Deiters, A. Org. Lett. 2010, 12, 1288-1291. (c)
Chandler, B. D.; Roland, J. T.; Li, Y.; Sorensen, E. J. Org. Lett. 2010, 12,
2746-2749. (d) Guerrero, C. A. and Sorensen, E. J. Org. Lett. 2011, 13,
5164-5167.
(4) The originally proposed structures of citrinadins A and B are those
given by 1 and 2, respectively, whereas the corresponding revised struc-
ture for citrinadin A is given by 1*.
(5) For some examples see: (a) Martin, S. F.; Rüeger, H.; Williamson, S.
A.; Grzejszczak, S. J. Am. Chem. Soc. 1987, 109, 6124-6131. (b) Martin, S.
F.; Mortimore, M. Tetrahedron Lett. 1990, 31, 4557-4560. (c) Martin, S. F.;
Benage, B.; Geraci, L. S.; Hunter, J. E.; Mortimore, M. J. Am. Chem. Soc.
1991, 113, 6161-6171. (d) Martin, S. F.; Clark, C. W.; Corbett, J. W. J. Org.
Chem. 1995, 60, 3236-3242. (e) Martin, S. F.; Humphrey, J. M.; Ali, A.;
(22) We have also prepared the enantiomers of 1* and 26, but their CD
spectra spectra are not consistent with the CD spectrum reported by
Kobayashi for (–)-citrinadin A in reference 1a.
(23) See accompanying manuscript in this issue.
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TIPS
NMe2
O
O
OH
H
N
O
OH
H
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O
OH
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O
N
H
TCC-(+)
O
O
Br
O
NHMe
NHMe
O
O
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CO2Me
citrinadin A
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