An enantioselective total synthesis and stereochemical revision of (+)-citrinadin B

Article abstract of DOI:10.1021/ja405548b

This manuscript describes an enantioselective synthesis of the naturally occurring alkaloid citrinadin B. The synthetic effort revealed an anomaly in the original structural assignment that has led to the proposal of a stereochemical revision. This revision is consistent with the structures previously reported for a closely related family of alkaloids, PF1270A-C. The synthesis is convergent and employs a stereoselective intermolecular nitrone cyloaddition reaction as a key step.

Full text of DOI:10.1021/ja405548b

Communication
pubs.acs.org/JACS
An Enantioselective Total Synthesis and Stereochemical Revision of
(+)-Citrinadin B
Ke Kong, John A. Enquist, Jr., Monica E. McCallum, Genessa M. Smith, Takanori Matsumaru,
Elnaz Menhaji-Klotz, and John L. Wood*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80532-1872, United States
S
* Supporting Information
ity, and interesting stereochemical discrepancies found within
ABSTRACT: This manuscript describes an enantioselec-
tive synthesis of the naturally occurring alkaloid citrinadin
B. The synthetic effort revealed an anomaly in the original
structural assignment that has led to the proposal of a
stereochemical revision. This revision is consistent with
the structures previously reported for a closely related
family of alkaloids, PF1270A−C. The synthesis is
convergent and employs a stereoselective intermolecular
nitrone cyloaddition reaction as a key step.
this group of alkaloids, we endeavored to complete their total
synthesis.4 Our initial efforts focused upon the preparation of
citrinadin B (1), and our strategy was designed with the
synthesis of alkaloids 2−5 in mind. Herein we report the initial
phase of our efforts.
Mindful of the versatility that would be required of a
synthesis designed to deliver the citrinadin and the PF1270
compounds, we developed a convergent approach toward
citrinadin B (1) wherein the epoxyketone, spirooxindole, and
methylpiperidine moieties would be introduced as independent
components (Scheme 1). This strategy enables the preparation
itrinadin B (1) is the structurally least complex member in
a family of related alkaloids that includes citrinadin A (2)
and PF1270A−C (3−5, respectively, Figure 1). Isolated from
C
Scheme 1. Retrosynthetic Analysis of ent-Citrinadin B
Figure 1. Reported structures for citrinadins A, B and PF1270A−C.
Penicillium citrinum N059 by Kobayashi, the citrinadins display
modest cytotoxicity against murine leukemia L1210 cells and
were assigned the structures illustrated above, including relative
and absolute stereochemistry, via a combination of spectro-
scopic and chemical correlation studies.1 In contrast, the related
PF1270 compounds (3−5), isolated from Penicillium waksmanii
by Kushida, were found to display a high affinity for the
histamine H3 receptor.2 In this latter series, the assignment of
structural and relative stereochemical features was based upon
an X-ray crystallographic analysis of 3. Although the absolute
stereochemistry of PF1270A was not formally assigned by
Kushida, the structures of alkaloids 3−5 as illustrated in Figure
1 reflect what was proposed in the isolation paper. Notably,
comparison of the published structures of the citrinadins (1 and
2) and the PF1270 compounds (3−5) reveals a critical
difference in the proposed relative stereochemistry between the
spirooxindole core of the molecule and the epoxyketone side
chain.3 Intrigued by the biological activity, structural complex-
of various structurally and stereochemically diverse products.5
As illustrated, the aryl bromide 6 was envisioned to engage in a
late stage coupling, which would allow for incorporation of
either antipode of an intact and potentially labile epoxyketone.
Likewise, to allow the construction of either spirooxindole
antipode we planned to employ enone 8, which was envisioned
as serving as the dipolarophile in an intermolecular [3 + 2]
cycloaddition that would deliver the pertinent stereochemical
features of the polycyclic core (8 + 9 → 7). A particularly
intriguing aspect of this cycloaddition approach would be that it
would leverage asymmetric induction from the stereochemistry
resident in nitrone 9. Given that either antipode of 9 is readily
available from either D- or L-alanine (10) and both stereo-
Received: June 7, 2013
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
chemistries were potentially present in the natural products
(vide supra), we opted to initially prepare the spirooxindole
component (8) as a racemate and explore the ability of 9 to act
as a resolving agent.6 We anticipated that enone ( )-8 would
be available from dibromoaniline 11.
In the forward sense, exposure of dibromoaniline 11 to
trimethylaluminum followed by lactone 127 furnished an
intermediate alcohol that was protected as the corresponding
silyl ether 13 (Scheme 2).8 Cyclization of amide 13 to oxindole
configuration at the spirooxindole center (C(3)).12 Moreover,
the relative stereochemistry resident in the minor product
((+)-7) was as needed for the conversion to the natural
product.
Although establishing the viability of the critical [3 + 2]
cycloaddition was an important milestone, many challenges
remained in advancing cycloadduct (+)-7 to citrinadin B (1). In
particular, completion of the natural product would require the
addition of a carbon atom, as well as closure of the central fused
D ring of the citrinadin core. In order to address both of these
concerns, we reasoned that a Corey−Chaykovsky epoxidation
would allow for introduction of a single carbon and set the
stage for subsequent ring closure via an intramolecular
nucleophilic attack of the proximal nitrogen onto the derived
epoxide. In the event, exposure of oxindole (+)-7 to
dimethylsulfoxonium methylide furnished the corresponding
spiroepoxide (+)-19 as a single diastereomer (Scheme 4).13
While initial attempts to promote intramolecular opening of the
epoxide were unsuccessful, we eventually found that exposure
of epoxide (+)-19 to in situ generated TMSI furnished
ammonium salt (+)-21 in good yield, presumably via the
intermediacy of iodide 20.14 Moreover, ammonium salt (+)-21
proved to be an excellent substrate for a Zn mediated N−O
bond cleavage reaction that delivered diol (+)-22. Importantly,
diol (+)-22 furnished crystals suitable for an X-ray analysis that
confirmed our previous structural assignment, as well as the
stereochemical fidelity in the steps leading to this key polycyclic
intermediate.
Scheme 2. Synthesis of Enone ( )-8
With the carbocyclic core completed, our attention next
turned to installation of the methylamine group and oxindole
deprotection. Unfortunately, we quickly found the benzyl
protecting group to be intransigent to removal. After an
exhaustive screening of conditions the most reliable combina-
tion of reagents was found to be t-BuLi and O2.15 Unfortunately
these harsh conditions were not compatible with the aryl
bromide moiety of diol (+)-22 (Scheme 4).
In light of this fact, we planned to make use of the aryl
bromide to install a side chain surrogate prior to benzyl
deprotection. To this end, diol (+)-22 was converted to the
corresponding epoxide (+)-6, which was subsequently coupled
with 3-methyl-1-butyne under Sonogashira conditions to give
alkyne (+)-24 (Scheme 5).16 Importantly the alkyne moiety in
the derived product ((+)-24) proved very resilient to the harsh
benzyl deprotection conditions and tolerated a subsequent
epoxide opening reaction with MgCl2/NaN3 to furnish azide
(+)-25. Thereafter, exposure of azide (+)-25 to gold mediated
oxidation conditions reported by Zhang allowed conversion of
the alkyne moiety to an enone, thus delivering azido alcohol
(+)-26.17
( )-14 under Heck conditions9 was followed by benzyl
protection, silyl group cleavage, and alcohol oxidation to
furnish aldehyde ( )-15. At this point we began setting the
stage for an eventual reductive ene-yne cyclization by treating
oxindole ( )-15 with ethynyl Grignard. Addition of the
Grignard was immediately followed by protection of the
resulting diastereomeric alcohols as their corresponding silyl
ethers ( )-16. Cyclization of ( )-16 was thereafter accom-
plished under conditions developed by Trost,10 which was then
followed by TBAF mediated deprotection to afford a
diastereomeric mixture of alcohols (( )-17). Oxidation of the
latter under Swern conditions provided the dipolar cyclo-
addition substrate, enone ( )-8.
With both enone ( )-8 and nitrone (−)-911 in hand we
began exploring the critical [3 + 2] cycloaddition (Scheme 3).
Scheme 3. Cycloaddition of Enone ( )-8 and Nitrone (−)-9
Given the necessity of incorporating an epoxyketone
precursor, a diastereoselective enone epoxidation was now
required to complete citrinadin B. Although many different
epoxidation conditions were attempted, a protocol developed
by Enders proved most effective.18 At the outset of our
epoxidation studies we explored the intrinsic stereochemical
bias of (+)-26 under the Enders conditions and, thus, ran the
reaction in the absence of any chiral additive. As illustrated in
Scheme 5, this resulted in a mixture (1:1) of the corresponding
epoxides, which proved to be inseparable until converted to the
corresponding Boc-protected variants (+)-27 and (−)-28. In
further experiments with the Enders system we discovered that
the ratio of epoxide diastereomers could be increased in favor
of (−)-28 when (S,S)-N-methylpseudoephedrine was used as
Given the potential for formation of numerous diastereo- and
regioisomeric products, we were delighted to find that under a
variety of conditions only two diastereomeric cycloaddition
products, (+)-7 and (−)-18, were observed. After considerable
experimentation, we found that addition of L-proline to this
reaction had a beneficial effect on both rate and the observed
dr. Extensive studies into the resultant stereochemistry revealed
that cycloadducts (+)-7 and (−)-18 differed only by their
B
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Journal of the American Chemical Society
Communication
Scheme 4. Completion of the Citrinadin Carbocyclic Core
Scheme 5. Epoxyketone Installation and Elaboration
Scheme 6. Completion and Structural Revision of
(+)-Citrinadin B
1
expected to be 1 and (+)-29, respectively. To our surprise, H
and 13C NMR data obtained for 1, the material deriving from
(+)-27 and anticipated to be enantiomeric to citrinadin B, did
not match those reported for the natural product.20 However,
we found that the spectral data obtained for (+)-29 was a much
closer match to Kobayashi’s reported data. Moreover,
scrutinizing the circular dichroism spectra of both 1 and
(+)-29 yielded an unanticipated result. While the CD spectra of
1 appeared mismatched to those of citrinadin B, the CD spectra
of (+)-29 were an excellent match. In light of the chiroptical
data obtained, as well as the use of L-alanine as our nitrone
starting material, we conclude that a structural reassignment of
citrinadin B is necessary. We propose that the absolute
stereochemistry of the spirooxindole and stereogenic centers
residing in the fused tricyclic region are opposite to that
originally assigned by Kobayashi, and thus the structure of
citrinadin B is in fact (+)-29. In addition to being consistent
with the data we have obtained to date, this reassignment
brings the structure of citrinadin B in line with that determined
crystallographically for PF1270A (vide supra). Similar con-
clusions were reached by Martin in the course of his elegant
synthesis of citrinadin A.21
the additive; thus, in accord with the predictive models put
forth by Enders, we assigned (−)-28 as possessing the (S)-
configuration at the epoxide stereocenter.19 The Enders model,
coupled with the fact that our synthesis relied upon L-alanine,
meant that advancement of the (R)-configured epoxide
((+)-27) would be expected to deliver enantiomeric citrinadin
B, in accord with Kobayashi’s structural assignment.
At this point, the final transformation required was the
conversion of the azide moiety to the corresponding methyl-
amine. Given that we had access to (+)-27 and (−)-28, we
decided to subject both to a final three-step sequence that
involved azide reduction, monomethylation, and deprotection
(Scheme 6). To our delight, both (+)-27 and (−)-28 were
readily advanced through this sequence and furnished what we
In conclusion, we have developed a convergent synthetic
strategy that can be used to provide stereocontrolled access to
citrinadin B ((+)-29). Completion of this stereoselective
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Journal of the American Chemical Society
Communication
(11) This material was prepared from L-alanine in accord with the
procedure reported by Chackalamannil (see ref 6). However, in our
hands the ee of 9 varied between 85% and 95%. We illustrate here the
worst-case scenario.
synthesis resulted in a stereochemical revision that more closely
aligns the stereostucture of citrinadin B to the PF1270A−C
alkaloids (3−5). Based on these studies, efforts in our
laboratories are focused on adapting this synthetic strategy to
the preparation of citrinadin A (2), as well as PF1270A−C (3−
5).
(12) The stereochemistry present at C(3) of spirooxindoles 7 and 18
was assigned via NOESY studies, as well as a correlation to X-ray
structures of analogues lacking the bromo group. The relative and
absolute stereochemical assignment of (+)-7 was verified via X-ray
crystallography of a later intermediate (see (+)-22, Scheme 4).
(13) (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87,
1353−1364. (b) Aggarwal, V. K.; Winn, C. L. Acc. Chem. Res. 2004, 37,
611−620.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental and characterization details (PDF, CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
(14) Caputo, R.; Mangoni, L.; Neri, O.; Palumbo, G. Tetrahedron
Lett. 1981, 22, 3551−3552.
(15) Williams, R. M.; Kwast, E. Tetrahedron Lett. 1989, 30, 451−454.
(16) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467−4470.
(17) Lu, B.; Li, C.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 14070−
14072.
AUTHOR INFORMATION
■
Corresponding Author
john.l.wood@colostate.edu
Notes
(18) Enders, D.; Zhu, J.; Raabe, G. Angew. Chem., Int. Ed. Engl. 1996,
35, 1725−1728.
The authors declare no competing financial interest.
(19) This stereochemical assignment was also consistent with a
comparison of chiroptical properties akin to that employed by
Kobayashi in his original isolation paper.
ACKNOWLEDGMENTS
■
Financial support was provided by Amgen, Bristol-Myers
Squibb, and the NSF (CHE-1058292). J.E. thanks the NIH
(GM095076) for a postdoctoral fellowship. T.M. thanks the
Uehara Foundation, Professor Toshiaki Sunazuka, Professor
(20) The original isolation paper reports NMR data as being
obtained on an unpsecified salt. In our hands the greatest
spectroscopic similarities were seen upon conversion to the
corresponding TFA salt form. Identical NMR spectra were not
obtainable, which we attribute to the presence of an unknown salt
form in the natural sample. Unfortunately, authentic samples, original
NMR data, and even the producing fungal strain were not available.
Efforts to reisolate the citrinadins from a related penicillium are
currently underway and will be reported in due course.
(21) See the accompanying manuscript in this issue.
Satoshi Omura, and the Kitasato Institute, for postdoctoral
̅
support. In addition, Dr. Chris Rithner, Don Heyse, and Don
Dick are acknowledged for their assistance in obtaining
crystallographic and spectroscopic data. We also thank Scott
A. Kalbach for assistance in obtaining circular dichroism
spectra. Finally, we thank Professor Stephen Martin for the
collegial exchange of information regarding his work on
citrinadin A.
REFERENCES
■
(1) (a) Tsuda, M.; Kasai, Y.; Komatsu, K.; Sone, T.; Tanaka, M.;
Mikami, Y.; Kobayashi, J. Org. Lett. 2004, 6, 3087−3089.
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Kawabata, J.; Watanabe, M.; Akao, K.; Kobayashi, J. J. Org. Chem.
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(2) Kushida, N.; Watanabe, N.; Okuda, T.; Yokoyama, F.; Gyobu, Y.;
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(3) If Kushida had illustrated the antipode, one might have attributed
the difference to the epoxide stereochemistry. Based on the current
study (vide infra) we believe Kushida’s depiction of absolute
stereochemistry to be correct.
(4) For previously reported synthetic approaches to the citrinadins,
see: (a) Pettersson, M.; Knueppel, D.; Martin, S. F. Org. Lett. 2007, 9,
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(5) It is important to note that the retrosynthetic analysis illustrated
in Scheme 1 reflects the fact that our synthetic studies to date have
been performed using L-alanine, the natural and least expensive
antipode. Based on Kobayashi’s stereochemical assignment we
expected our synthesis to furnish enantiomeric citrinadin B.
(6) For the enantioselective preparation of 9, see: Chackalamannil,
S.; Wang, Y. Tetrahedron 1997, 53, 11203−11210.
(7) Murphy, J. A.; Rasheed, F.; Roome, S. J.; Scott, K. A.; Lewis, N. J.
Chem. Soc., Perkin Trans. 1 1998, 2331−2339.
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D
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