Total synthesis of (-)-8-deoxyserratinine via an efficient helquist annulation and double N-alkylation reaction

Article abstract of DOI:10.1021/ol1012444

(Equation Presented). The first enantioselective total synthesis of (-)-8-deoxyserratinine has been achieved in 15 steps from enone 4 with 7% overall yield. The key features include a highly efficient Helquist annulation to furnish the cis-fused 6/5 bicycle, facile construction of the aza nine-membered ring system employing double N-alkylation strategy, as well as asymmetric Shi epoxidation, delivering the desired β-epoxide stereospecifically.

Full text of DOI:10.1021/ol1012444

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3430-3433
Total Synthesis of
(-)-8-Deoxyserratinine via an Efficient
Helquist Annulation and Double
N-Alkylation Reaction
Yu-Rong Yang,*,† Zeng-Wei Lai,†,‡ Liang Shen,† Jiu-Zhong Huang,†,‡
Xing-De Wu,† Jun-Lin Yin,† and Kun Wei†
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming
Institute of Botany, Chinese Academy of Sciences, Kunming, 650204, China, and Key
Laboratory of Medicinal Chemistry for Natural Resource (Yunnan UniVersity),
Ministry of Education, Kunming, 650091, China
yangyurong@mail.kib.ac.cn
Received May 31, 2010
ABSTRACT
The first enantioselective total synthesis of (-)-8-deoxyserratinine has been achieved in 15 steps from enone 4 with 7% overall yield. The key
features include a highly efficient Helquist annulation to furnish the cis-fused 6/5 bicycle, facile construction of the aza nine-membered ring
system employing double N-alkylation strategy, as well as asymmetric Shi epoxidation, delivering the desired ꢀ-epoxide stereospecifically.
The Lycopodium alkaloids are a diverse group of structurally
complex natural products.1 Owing to both their appealing,
synthetically challenging polycyclic systems with dense
stereochemical array and wide-ranging biological activities,
a wealth of total synthesis of Lycopodium alkaloids have been
reported.2 Among the known Lycopodium alkaloids, serra-
tinine 23 and 8-deoxyserratinine 14 are noteworthy due to
their unique tetracyclic structures containing two contiguous
quaternary stereocenters and the interesting biogenetic con-
nection with serratezomine A 35 via fascinating rearrange-
ments (Figure 1). The first, and to date only, total syntheses
of serratinine 2 and 8-deoxyserratinine 1 were accomplished
in racemic forms by the Inubushi group at 1974 and 1979.6
Herein, we wish to report the first asymmetric total synthesis
of (-)-8-deoxyserratinine 1 via a novel efficient route, in
particular, hoping to address the issues of efficiency and
selectivity of the synthesis.
In Inubushi’s pioneering synthesis,6f,g as shown in Scheme
1, they recognized the possibility to control the stereochem-
† Kunming Institute of Botany.
‡ Yunnan University.
(1) For recent reviews of the Lycopodium alkaloids, see: (a) Hirasawa,
Y.; Kobayashi, J.; Morita, H. Heterocycles 2009, 77, 679–729. (b) Ma, X.;
Gang, D. R. Nat. Prod. Rep. 2004, 21, 752–772.
(3) (a) Inubushi, Y.; Ishii, H.; Yasui, B.; Hashimoto, M.; Harayama, T.
Chem. Pharm. Bull. 1968, 16, 82–91. (b) Inubushi, Y.; Ishii, H.; Yasui, B.;
Hashimoto, M.; Harayama, T. Chem. Pharm. Bull. 1968, 16, 92–100.
(4) Inubushi, Y.; Ishii, H.; Yasui, B.; Harayama, T.; Hosokawa, M.;
Nishino, R.; Nakahara, Y. Yakugaku Zasshi 1967, 87, 1394–1404.
(5) (a) Morita, H.; Arisaka, M.; Yoshida, N.; Kobayashi, J. J. Org. Chem.
2000, 65, 6241–6245. (b) Morita, H.; Kobayashi, J. J. Org. Chem. 2002,
67, 5378–5381.
(2) For selected recent total syntheses of Lycopodium alkaloids, see:
(a) Chandra, A.; Pigza, J. A.; Han, J.-S.; Mutnick, D.; Johnston, J. N. J. Am.
Chem. Soc. 2009, 131, 3470–3471. (b) Nilsson, B. L.; Overman, L. E.;
Alaniz, J. R.; Rohde, J. M. J. Am. Chem. Soc. 2008, 130, 11297–11299.
(c) Kozak, J. A.; Dake, G. R. Angew. Chem., Int. Ed. 2008, 47, 4221–
4223. (d) Bisai, A.; West, S. P.; Sarpong, R. J. Am. Chem. Soc. 2008, 130,
7222–7223.
10.1021/ol1012444  2010 American Chemical Society
Published on Web 06/29/2010

Scheme 2. Retrosynthetic Analysis of 8-Deoxyserratinine (1)
Figure 1. 8-Deoxyserratinine, serratinine, and serratezomine A.
Scheme 1
.
Key Points of Inubushi’s Pioneering Synthesis of
8-Deoxyserratinine (1)
via cascade removal of N-protective group and epoxide ring
opening, a maneuver that had been utilized by Inubushi.
Thus, the ꢀ-epoxide 9 became our subgoal of total synthesis
of 8-deoxyserratinine 1. First, the ꢀ-epoxide 9 could, in
principle, be prepared from a selective epoxidation of the
olefin 10. However, as demonstrated in Inubushi’s synthesis,
this manipulation posed a problem as the standard m-CPBA
procedure provided only minor amounts of ꢀ-epoxide 9
accompanied by its R-isomer as the predominant product
(vide supra). This stereochemical outcome can be attributed
to approach of the reagent from the convex face of the
tricyclic system. Next, the key aza nine-membered ring of
10 was expected to be constructed by double N-alkylations
of the bisiodide compound 11 with a nitrogen atom.7 Finally,
the cis-fused 6/5 bicyclic ring system 12 was envisioned to
arise from Helquist annulation8 of 2-allyl-5-methyl-cyclohex-
2-en-1-one 4. To our knowledge, Helquist annulation was
still an underutilized approach for the synthesis of the
polycyclic system,9 and prior to us there had been no one
who enlisted it to construct the framework of Lycopodium
alkaloids.10 Its uniqueness will be evident by virtue of the
synthetic conciseness and efficiency in rapid construction of
the key 6/5 bicycle, which stands in sharp contrast to those
of Inubushi’s Diels-Alder approach.
istry of the challenging quaternary stereocenter of 5 by using
a Diels-Alder addition between butadiene and racemic
2-allyl-5-methyl-cyclohex-2-en-1-one 4 (29% yield). Scission
of the double bond of the newly formed six-membered ring
of 5 followed by reclosure of the five-membered ring via
aldol and Wadsworth-Emmons reaction afforded substituted
6/5 bicycle 6, which was further elaborated to the tricyclic
lactam 7. Unfortunately, in the subsequent critical stage of
setting the second quaternary stereocenter, i.e., stereoselective
epoxidation of the double bond of the five-membered ring,
a mixture of isomers were obtained, with the undesired
R-epoxide predominating. The precursor of tetracyclic ser-
ratinine framework 8 was eventually synthesized in ca. 0.5%
overall yield over 15 steps. At this point, a more efficient
alternative route is still needed.
Our synthesis commenced with (-)-2-allyl-5-methyl-
cyclohex-2-en-1-one 4, which could be prepared in multi-
gram quantities according to the Caine chiral pool strategy
from R-pulegone.11 With this enone in hand, we then tried
Our retrosynthetic analysis was outlined in Scheme 2. We
proposed to install the second quaternary stereocenter and
the tetracyclic system of 8-deoxyserratinine 1 at the late stage
(7) Fukuyama’s chemistry about 2-nitrobenzenesulfonamide (NsNH2)
as an efficient nitrogen nucleophile for synthesis of medium- or large-sized
cyclic amines is appreciated widely in this regard, see: (a) Kan, T.; Fujiwara,
A.; Kobayashi, H.; Fukuyama, T. Tetrahedron 2002, 58, 6267–6276. (b)
Fujiwara, A.; Kan, T.; Fukuyama, T. Synlett 2000, 11, 1667–1669. (c) Kan,
T.; Kobayashi, H.; Fukuyama, T. Synlett 2002, 5, 697–699, and references
therein. We thank one of the reviewers for bringing these references to our
attention.
(6) For related research from the Inubushi group, see: (a) Inubushi, Y.;
Yasui, H.; Yasui, B.; Hashimoto, M.; Harayama, T. Tetrahedron Lett. 1966,
7, 1537–1549. (b) Inubushi, Y.; Ishii, H.; Yasui, B.; Harayama, T.
Tetrahedron Lett. 1966, 7, 1551–1559. (c) Ishii, H.; Yasui, B.; Harayama,
T.; Inubushi, Y. Tetrahedron Lett. 1966, 7, 6215–6219. (d) Inubushi, Y.;
Ishii, H.; Harayama, T.; Burnell, R. H.; Ayer, W. A.; Altenkirk, B.
Tetrahedron Lett. 1967, 8, 1069–1072. (e) Harayama, T.; Ohtani, M.; Oki,
M.; Inubushi, Y. J. Chem. Soc., Chem. Commun. 1974, 827–828. (f)
Harayama, T.; Takatani, M.; Inubushi, Y. Tetrahedron Lett. 1979, 20, 4307–
4310. (g) Harayama, T.; Takatani, M.; Inubushi, Y. Chem. Pharm. Bull.
1980, 28, 2394–2402. For other synthetic efforts towards serratinine
alkaloids, see: (h) Mehta, G.; Reddy, M. S.; Radhakrishnan, R.; Manjula,
M. V.; Viswamitra, M. A. Tetrahedron Lett. 1991, 32, 6219–6222. (i)
Cassayre, J.; Gagosz, F.; Zard, S. Z. Angew. Chem., Int. Ed. 2002, 41, 1783–
1785.
(8) Bal, S. A.; Marfat, A.; Helquist, P. J. Org. Chem. 1982, 47, 5045–
5050.
(9) For application of the Helquist annulation in natural product
synthesis, see: (a) Johansson, M.; Sterner, O. Org. Lett. 2001, 3, 2843–
2845. (b) Li, S.; Yamamura, S. Tetrahedron 1998, 54, 8691–8710.
(10) Yang, Y.-R.; Shen, L.; Wei, K.; Zhao, Q.-S. J. Org. Chem. 2010,
75, 1317–1320.
(11) Caine, D.; Procter, K.; Cassell, R. A. J. Org. Chem. 1984, 49, 2647–
2648.
Org. Lett., Vol. 12, No. 15, 2010
3431

Scheme 3
.
Enantioselective Synthesis of Triene 17
Scheme 4
.
Completion of the Total Synthesis of
8-Deoxyserratinine 1
the Helquist annulation and were gratified to find it was very
successful. Conjugate addition of the acetal-containing
Grignard reagent derived from 2-(2-bromoethyl)-1,3-diox-
olane to enone 4 performed well to provide trans-silyl enol
ether 13 diastereoselectively (93%) (Scheme 3). This enol
ether, upon treatment with warm 2 N HCl, successfully
underwent cascade desilylation, acetal hydrolysis, and in-
tramolecular aldol cyclization to give a separable 2.5:1
mixture of cis-fused 6/5 bicycle 14 (75%) having the correct
configuration of the quaternary stereocenter. Oxidation of a
mixture of the Helquist annulation products with PCC
followed by brief treatment with ethylene glycol via azeo-
tropic distillation afforded selectively protected cyclic acetal
15, in which the carbonyl group within the cyclopentanone
ring was untouched (88%, 2 steps).12 The allyl bromide
Grignard reagent attacked the cyclopentanone 15 providing
the carbinol 16 quantitatively, which was subsequently
exposed to thionyl chloride/pyridine conditions and was
dehydrated readily with complete regioselectivity furnishing
the endocyclic olefin 17 as the only product (80%). At this
juncture, the full complement of 16 carbon atoms of
8-deoxyserratinine 1 have been installed in 49% yield over
6 steps.
refluxing benzene, a smooth double N-alkylative ring closure
was realized in a respectable 60% yield.13 Removal of the
tosyl group of 18 was effected by the use of sodium
naphthalenide as reducing agent providing amine 19 nearly
quantitatively.14 Trifluoroacetylation of this amine and
subsequent cleavage of the cyclic acetal could be carried out
in one pot and afforded keto trifluoroacetyl amide 10 in 70%
yield. With this keto trifluoroacetyl amide in hand, the stage
was now set for the challenging selective epoxidation. After
considerable efforts, it was found that this issue could be
addressed satisfactorily through Shi asymmetric epoxidation
with Shi D-fructose derived catalyst 20.15 A complete
stereoselective epoxidation took place to provide the desired
ꢀ-epoxide 9 as the sole product in 60% yield along with the
recovered starting material 10 (96% yield, brsm). The
Prior to closure of the critical aza nine-membered ring,
the key intermediate bisiodide 11 was prepared through
iodination of the two corresponding terminal hydroxyl
groups, which were obtained via selective hydroboration of
the triene 17 with 9-BBN (70%, 2 steps) (Scheme 4). By
treatment of this bisiodide with TsNH2 as the nucleophilic
nitrogen source in the presence of Bu4NI and NaOH in
(13) Other nitrogen sources such as BnNH2 and PMBNH2 were also
tried, but TsNH2 was finally chosen not only because it can give the best
yield but also because it can be readily deprotected into the free amine 19,
leaving the other functionalities of the substrate untouched.
(14) Similar conditions used by the Heathcock group in their fawcet-
timine total synthesis. Heathcock, C. H.; Blumenkopf, T. A.; Smith, K. M.
J. Org. Chem. 1989, 54, 1548-1562.
(12) Compound 15 was more readily accessible by this selective
ketalization of 1,3-diketone 12 than by what we previously reported in ref
(15) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem.
Soc. 1997, 119, 11224–11235.
10.
3432
Org. Lett., Vol. 12, No. 15, 2010

ꢀ-epoxide 9 converted into tetracyclic diketone 21 via
Inubushi’s protocol, that is, tandem cleavage of trifluoroac-
etamide and intramolecular epoxide ring-opening reaction
to furnish tetracyclic amino alcohol (not shown) in a refluxing
methanolic KOH solution and subsequent Jones oxidation
of the amino alcohol intermediate. At this stage, we were
pleased to find our diketone 21 was identical with the
literature compound which was obtained from the natural
(-)-serratinine degradation (see Supporting Information).16
Selective reduction of the carbonyl functionality of the six-
membered ring through careful addition of 2 equiv of NaBH4
at 0 °C was realized, providing 8-deoxyserratinine 1 nearly
quantitatively. The synthetic 1 exhibited a rotation of -14.2
(c 0.38, EtOH), essentially identical to that of the natural
substance,17 and its structure was again secured by single-
crystal X-ray analysis (see Supporting Information). There-
fore, the absolute configuration of 8-deoxyserratinine 1 has
been established as shown in Scheme 4.
enone 4 with 7% overall yield. The key features include a
highly efficient Helquist annulation to furnish the cis-fused
6/5 bicycle, facile construction of the aza nine-membered
ring system employing double N-alkylation strategy, as well
as asymmetric Shi epoxidation, delivering the desired ꢀ-ep-
oxide stereospecifically. The synthetic efficiency and selec-
tivity control of this new approach have been significantly
enhanced. This strategy is sufficiently general to allow the
synthesis of many other complex members of the Lycopo-
dium alkaloids. Studies in this regard are currently underway
and will be reported in due course.
Acknowledgment. We thank the National Natural Science
of China (No.20802084), National Basic Research Program
of China (973 Program, No. 2009 CB522300), Programs of
“One Hundred Talented People” and “Western Light” Joint
Scholar of Chinese Academy of Sciences, and State Key
Laboratory of Phytochemistry and Plant Resources in West
China for financial support. We are also indebted to Prof.
Hongbin Zhang of Yunnan University for helpful discussion.
In summary, the first enantioselective total synthesis of
(-)-8-deoxyserratinine 1 has been achieved in 15 steps from
Supporting Information Available: Experimental pro-
cedures, copies of all spectral data, and full characterization
and CIF file for compound 1. This material is available free
of charge via the Internet at http://pubs.acs.org.
(16) Katakawa, K.; Kitajima, M.; Aimi, N.; Seki, H.; Yamaguchi, K.;
Furihata, K.; Harayama, T.; Takayama, H. J. Org. Chem. 2005, 70, 658–
663.
(17) The reported optical rotation for natural (-)-8-deoxyserratinine is
[R]D-15.6 (c 1.0, EtOH). Ishii, H.; Yasui, B.; Nishino, R.; Harayama, T.;
Inubushi, Y. Chem. Pharm. Bull 1970, 18, 1880–1888.
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