Toward an enantioselective total synthesis of sarain A: Construction of an advanced intermediate and rearrangement of the sarain A core under mild conditions

Article abstract of DOI:10.1021/ol050038m

(Chemical Equation Presented) A high-yielding N-sulfonyliminium ion-enoxysilane cyclization and a ring-closing metathesis are key steps in the enantioselective synthesis of late-stage intermediates en route to sarain A. Also revealed is an unprecedented rearrangement of the tetracyclic sarain A core under mildly acidic conditions.

Full text of DOI:10.1021/ol050038m

ORGANIC
LETTERS
2005
Vol. 7, No. 5
933-936
Toward an Enantioselective Total
Synthesis of Sarain A: Construction of
an Advanced Intermediate and
Rearrangement of the Sarain A Core
under Mild Conditions
Christopher J. Douglas, Sheldon Hiebert, and Larry E. Overman*
Department of Chemistry, UniVersity of California-IrVine, 516 Rowland Hall,
IrVine, California 92697-2025
leoVerma@uci.edu
Received January 9, 2005
ABSTRACT
A high-yielding N-sulfonyliminium ion−enoxysilane cyclization and a ring-closing metathesis are key steps in the enantioselective synthesis
of late-stage intermediates en route to sarain A. Also revealed is an unprecedented rearrangement of the tetracyclic sarain A core under mildly
acidic conditions.
The structurally unique sarains A-C (1-3) were isolated
originally by Cimino and co-workers from the sponge
Reniera sarai, collected in the Bay of Naples.1 A distinctive
diazatricycloundecane core with a proximity interaction
between the C2 aldehyde and the N1 tertiary amine defines
these alkaloids. Surrounding this heterocyclic core are two
macrocyclic rings, one saturated and one containing a vicinal
diol and a skipped triene. Sarains A-C display antibacterial,
insecticidal, and antitumor activities,2 although interest in
these molecules derives largely from their unprecedented
structures. Syntheses of the diazatricycloundecane core of
sarains A-C have been reported by the groups of Weinreb,3
Heathcock,4 Cha,5 and our laboratory.6
In the most advanced progress disclosed to date, Weinreb
and Cha described potential intermediates that contain the
heterocyclic core, the C3 all-carbon quaternary stereocenter,
and the saturated macrocyclic ring.3a,b,5a,b
(1) (a) Cimino, G.; De Stefano, S.; Scognamiglio, G.; Trivellone, E. Bull.
Soc. Chim. Belg. 1986, 95, 783-800. (b) Cimino, G.; Mattia, C. A.;
Mazzarella, L.; Puliti, R.; Scognamiglio, G.; Spinella, A.; Trivellone, E.
Tetrahedron 1989, 45, 3863-3872. (c) Cimino, G.; Scognamiglio, G.;
Spinella, A.; Trivellone, E. J. Nat. Prod. 1990, 53, 1519-1525. (d) Guo,
Y.; Madaio, A.; Trivellone, E.; Scognamiglio, G.; Cimino, G. Tetrahedron
1996, 52, 8341-8348.
(3) (a) Hong, S.; Weinreb, S. M. Presented at the 226th National Meeting
of the American Chemical Society, New York, Sept 2003; ORGN 202. (b)
Irie, O.; Samizu, K.; Henry, J. R.; Weinreb, S. M. J. Org. Chem. 1999, 64,
587-595. (c) Sisko, J.; Henry, J. R.; Weinreb, S. M. J. Org. Chem. 1993,
58, 4945-4951. (d) Sisko, J.; Weinreb, S. M. J. Org. Chem. 1991, 56,
3210-3211.
(2) Caprioli, B.; Cimino, G.; DeGuilio, A.; Madaio, A.; Scognamiglio,
G.; Trivellone, E. Comp. Biochem. Physiol. 1992, 103B, 293-296.
10.1021/ol050038m CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/01/2005

A distinctive feature of our approach to sarains A-C is
generation of a highly functionalized diazatricycloundecane
core that incorporates the C3 quaternary center and a C3′
side chain containing the C7′ alcohol stereocenter by an
N-sulfonyliminium ion-enoxysilane cyclization.6-8 Herein,
we report construction of an enantiopure, advanced tetracy-
clic intermediate and an unanticipated late-stage rearrange-
ment of the sarain core under mild conditions.
ylphosphonium chloride and potassium hexamethyldisilazane
provided 2-trimethylsilylethyl (TMSE) enol ether 6 in 98%
yield as a 3:2 mixture of double-bond stereoisomers.
With enol ether 6 in hand, we examined the pivotal intra-
molecular N-sulfonyliminium ion cyclization to forge the C3
all-carbon quaternary stereocenter and complete the diaza-
tricycloundecane core of sarains A-C (Scheme 2). Following
The present studies began by preparing multigram quanti-
ties of enantiopure tetracyclic aminal 4 in 17 steps from
D-diethyl tartrate (Scheme 1).9 A side chain, which eventually
Scheme 2 a
Scheme 1a
a Reaction conditions: (a) HF (aq), MeCN, rt; (b) TIPSOTf, Et3N,
CH2Cl2, -78 °C to room temperature (87%, two steps); (c) BCl3
(4 equiv), 2,6-di-tert-butyl-4-methylpyridine, 0 °C to room tem-
perature (92%, R ) TIPS; 55%, R ) TMSE).
precedent from earlier studies,6b,10,11 aminal enol ether 6 was
exposed to a large excess of BCl3 and 2,6-di-tert-butyl-4-
methylpyridine at -78 °C in CH2Cl2. These conditions
provided the desired product 8 in poor (<10%) yield, with
the remainder of the recovered mass being an intractable
mixture. Decreasing the amount of BCl3 to 4 equiv and
raising the reaction temperature first to 0 °C and then to room
temperature increased the yield of the tetracyclic aldehyde
product 8 to 55%. Of primary importance, this product was
produced as a single stereoisomer having the required
configuration at the all-carbon quaternary center C3.12,13
In an attempt to improve the yield of this pivotal cy-
clization, the enol ether nucleophile of cyclization precursor
6 was converted to a more reactive enoxysilane. This trans-
formation was accomplished by reaction of 6 with 5%
aqueous HF in MeCN, followed by treatment of the re-
sulting mixture of epimeric aldehydes with triisopropylsilyl
triflate and Et3N to provide enoxysilane 7, a 3:2 mixture of
a Reaction conditions: (a) (i) O3, NaHCO3, CH2Cl2/MeOH, -78
°C; (ii) Me2S, -78 °C to room temperature (90%). (b) H2CdCH-
(CH2)3MgBr, THF/Et2O, -78 to -10 °C. (c) Swern oxidation (81%,
two steps). (d) KHMDS, TMSEOCH2PPh3Cl, THF, -78 to 0 °C
(98%, 3:2 mixture of isomers); TMSE ) 2-(trimethylsilyl)ethyl.
will be employed to form the saturated macrocyclic ring,
was installed next. This four-step sequence began by ozo-
nolysis of 4 to provide the corresponding aldehyde. Addition
of 4-pentenylmagnesium bromide to this intermediate, fol-
lowed by Swern oxidation of the resulting inconsequential
mixture of epimeric alcohols, provided ketone 5 in 72% yield
over the three steps. Wittig reaction of ketone 5 with the
ylide derived from trimethylsilylethoxymethylene triphen-
(4) (a) Denhart, D. J.; Griffith, D. A.; Heathcock, C. H. J. Org. Chem.
1998, 63, 9616-9617. (b) Griffith, D. A.; Heathcock, C. H. Tetrahedron
Lett. 1995, 36, 2381-2384. (c) Heathcock, C. H.; Clasby, M.; Griffith, D.
A.; Henke, B. R.; Sharp, M. J. Synlett 1995, 467-474. (d) Henke, B. R.;
Kouklis, A. J.; Heathcock, C. H. J. Org. Chem. 1992, 57, 7056-7066.
(5) (a) Lee, H. I.; Sung, M. J.; Lee, H. B.; Cha, J. K. Heterocycles 2004,
62, 407-422. (b) Sung, M. J.; Lee, H. I.; Lee, H. B.; Cha, J. K. J. Org.
Chem. 2003, 68, 2205-2008. (c) Sung, M. J.; Lee, H. I.; Chong, Y.; Cha,
J. K. Org. Lett. 1999, 1, 2017-2019.
(6) (a) Jaroch, S.; Matsuoka, R. T.; Overman, L. E. Tetrahedron Lett.
1999, 40, 1273-1276. (b) Downham, R.; Ng, F. W.; Overman, L. E. J.
Org. Chem. 1998, 63, 8096-8097.
(7) Weinreb was the first to employ an N-sulfonyliminium ion cyclization
to form the diazatricycloundecane core of the sarain alkaloid;3d in the Sisko-
Weinreb cyclization, the C3 quaternary stereocenter is not formed.
(8) For a review of N-sulfonyliminium ion chemistry, see: Weinreb, S.
M. Topics in Current Chemistry; Springer-Verlag: Berlin, 1997; Vol. 190,
pp 131-184.
(10) Cyclization of related intermediates in which the (CH2)3CHdCH2
group of 7 was replaced with a (CH2)7OBn group had shown that the correct
stereochemistry at the C3 center could be obtained (dr ) 6:1) under these
conditions.11
(11) Dr. Peter Chua, unpublished studies, University of California-Irvine,
Irvine, CA, 1999.
(12) Assigned by NOESY; see Supporting Information for details.
(13) Enol ether stereoisomers either interconvert under the reaction
conditions or react similarly, as subjecting the minor isomer to identical
cyclization conditions provided a product distribution identical to that
obtained using the mixture of enol ether stereoisomers.
(14) (a) Stereoselection in forming the C3 stereocenter under these
conditions is >20:1. Trace amounts of several side-products resulting from
chloride-terminated Prins cyclization of the newly unmasked aldehyde with
the tethered alkene accounted for the remainder of the mass balance. (b) In
our earlier model study wherein the C3 substituent was a methyl group
rather than a 4-pentenyl side chain, the major product had the undesired
configuration at C3.6b High stereoselection in the present case is believed
to be the result of thermodynamic equilibration prior to loss of the
triisopropylsilyl group.
(9) A slight modification of our previously reported sequence was
employed.6b Modifications include beginning the synthesis with D-diethyl
tartrate rather than L-diethyl tartrate and substituting allyl bromide for
3-bromo-2-methylpropene in an early alkylation step. Compound 4 was
prepared originally by Dr. Michael Becker.
934
Org. Lett., Vol. 7, No. 5, 2005

stereoisomers, in 87% yield for the two steps. To our delight,
this TIPS enoxysilane cyclized to provide advanced inter-
mediate 8 in 92% yield.14
As preliminary survey experiments had indicated that
macrolactamization was not a viable strategy for closing the
saturated macrocyclic ring,11 we turned to ring-closing
metathesis (RCM),15 a tactic first verified in this context by
the Weinreb group (Scheme 3).3b Elaboration of aldehyde 8
reflux using 15 mol % of the “second generation” Grubbs
ruthenium catalyst17 provided the desired 13-membered ring
macrocycle as a mixture of (E)- and (Z)-isomers, albeit in
only 17% yield. The major products produced under these
conditions, which were isolated in 61% combined yield,
incorporated two units of the starting material. These major
“dimer products” resulted from thermodynamic control, as
resubmitting them individually to the reaction conditions
returned a 3:1 mixture of 13- and 26-membered ring
products. To minimize secondary metathesis reactions that
were converting the 13-membered RCM product to 26-
membered ring macrocyclic dimers, the less active (PCy3)2-
Cl2RudCHPh catalyst18,19 was employed. Cyclization of 10
under optimal conditions (5 mol % catalyst, 0.25 mM in
refluxing CH2Cl2) produced the desired 13-membered ring
metathesis product in 75-80% yield. Hydrogenation of this
inconsequential 2:1 mixture of pentacyclic alkene stereoi-
somers provided the saturated macrocycle 11 in 95% yield.
We turned our attention to construction of the more com-
plex macrocyclic ring containing the skipped triene unit. The
TBDMS and oxazolidinone protecting groups of 11 could
be removed under basic conditions to provide the corre-
sponding amino diol; however, this intermediate could not
be functionalized on nitrogen by either reductive amination
or acylation. Hypothesizing that the lack of reactivity resulted
from steric hindrance by the neighboring TIPS ether func-
tionality, we adjusted the protecting groups of 11. Exposure
of 11 to aqueous HCl selectively cleaved the TBDMS group.
Reaction of the resulting primary alcohol with sodium
hexamethyldisilazane and p-methoxybenzyl chloride in DMF
resulted in rearrangement of the 5-(hydroxymethyl)-[1,3]-
oxazolidin-2-one fragment to generate the corresponding
5-hydroxy-[1,3]oxazinan-2-one with concurrent protection of
the secondary hydroxyl group to provide 12 in 74% yield
from 11.20 After some experimentation, it was found that
the hindered TIPS group of 12 could be removed by reac-
tion with tris(dimethylamino)sulfur (trimethylsilyl)difluoride
(TAS-F) in N,N-dimethylacetamide (DMA) at 100 °C to
provide the corresponding neopentylic alcohol in 85% yield.21
Cleavage of the oxazinanone functionality of this product
with KOH in EtOH at 90 °C then provided amino diol 13 in
90% yield.
Scheme 3a
a Reaction conditions: (a) TBDMSCl, imidazole, MeCN; (b)
NaBH4, MeOH; (c) TIPSOTf, Et3N, CH2Cl2 (75%, three steps);
(d) Na, naphthalene, DME/THF, -78 °C; (e) 6-hepten-1-al,
NaBH3CN, AcOH, 4 Å mol sieves, MeCN, rt (78%, two steps);
(f) 5 mol % (PCy3)2Cl2RudCHPh, CH2Cl2, reflux, 0.25 mM (75-
80%); (g) H2, Pd/C, EtOAc, rt (95%); (h) HCl (aq), THF, rt, (83%);
(i) PMBCl, NaHMDS, DMF, rt (89%); (j) TAS-F, DMA, 100 °C
(85%); (k) KOH, EtOH, 90 °C (90%).
With amino alcohol 13 in hand, we reexamined function-
alization of the pyrrolidine nitrogen (Scheme 4). Heating a
was initiated by protection of the primary alcohol as a tert-
butyldimethylsilyl ether, reduction of the aldehyde with
NaBH4, and protection of the resulting alcohol to give TIPS
ether 9 in 75% yield over the three steps. Removal of the
tosyl group with sodium naphthalenide,16 followed by
reductive amination with 6-hepten-1-al and NaBH3CN,
provided diene 10 in 78% yield over the two steps.
(17) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(18) (a) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc.
2001, 123, 6543-6554. (b) Sanford, M. S.; Ulman, M.; Grubbs, R. H. J.
Am. Chem. Soc. 2001, 123, 749-750.
(19) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100-110.
(20) To our knowledge, base-promoted rearrangement of an N-alkyl-5-
(hydroxymethyl)-[1,3]oxazolidin-2-one to N-alkyl-5-hydroxy-[1,3]oxazinan-
2-one with concurrent protection of the secondary alcohol is unprecedented.
Examples of this rearrangement with substrates in which nitrogen is
substituted with a hydrogen, allowing the reaction to proceed through the
corresponding isocyanate, are known; see, for example: (a) Tadanier, J.;
Martin, J. R.; Hallas, R.; Rasmussen, R.; Grampovnik, D.; Rosenbrook,
W., Jr.; Arnold, W.; Schuber, E. Carbohydr. Res. 1981, 98, 11-23. (b)
Sadybakasov, B. K.; Ashirmatov, M. A.; Afanas’ev, V. A.; Struchkov, Y.
T. Zh. Strukt. Khim. 1989, 30, 135-140.
With tetracyclic diene 10 in hand, we examined closure
of the macrocyclic ring. Heating 10 in CH2Cl2 (at 1 mM) at
(15) For reviews of the use of RCM reactions in alkaloid synthesis, see:
(a) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199-2238. (b) Felpin,
F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693-3712. (c) Pandit, U.
K.; Overkleeft, H. S.; Borer, B. C.; Biera¨ugel, H. Eur. J. Org. Chem. 1999,
959-968.
(16) Sungchul, J.; Gortler, L. B.; Waring, A.; Battisti, A.; Bank, S.;
Closson, W. D.; Wriede, P. J. Am. Chem. Soc. 1967, 89, 5311-5312.
(21) Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.; Coffey,
D. S.; Roush, W. R. J. Org. Chem. 1998, 63, 6436-6437.
Org. Lett., Vol. 7, No. 5, 2005
935

product 17 was obtained in good overall yield when [1,3]-
oxazocane 15 was reduced with (i-Bu)2AlH at -78 °C in
toluene.
Scheme 4
Insight into how the structural reorganization to form 16
takes place was gained when we discovered that tetracyclic
diol 17 was converted to tetracyclic amino ether 16 when
exposed at room temperature to acetic acid in MeCN/
CH2Cl2. As summarized in Scheme 4, we hypothesize that
protonation of 17 triggers displacement of the pyrrolidine
nitrogen by the piperdine nitrogen to form aziridinium ion
intermediate 19. Opening of this latter intermediate by attack
of the primary alcohol on the aziridinium ion then provides
16. To our knowledge, this is the first example of an
aziridinium ion rearrangement in which the leaving group
is a tertiary amine.22
In summary, an enantioselective synthesis of an advanced
intermediate en route to sarain A has been developed. Our
strategy employs a high-yielding and highly stereoselective
intramolecular N-tosyliminium ion-enoxysilane condensa-
tion to generate the diazatricycloundecane core, install the
C3 all-carbon quaternary stereocenter, and reveal a C3′ side
chain containing the C7′ alcohol stereocenter. An efficient
reductive amination/RCM sequence was used to install the
saturated macrocycle. An unanticipated rearrangement of the
sarain core structure under mild acidic conditions was
discovered, which is believed to occur by an aziridinium ion
rearrangement in which a tertiary amine serves as the leaving
group. Efforts to construct the second macrocyclic ring from
advanced intermediate 17 to complete an enantioselective
total synthesis of sarain A are ongoing.
Acknowledgment. This research was supported by the
National Heart, Lung, and Blood Institute (HL-25854).
Fellowship support to C.J.D. from Bristol-Myers Squibb and
the Achievement Rewards for College Scientists Foundation
and to S.H. from the Natural Science and Engineering
Research Council of Canada is gratefully acknowledged.
NMR and mass spectra were determined at UC Irvine with
instruments purchased with the assistance of the NSF and
NIH shared instrumentation programs.
benzene solution of tetracyclic amino diol 13 and iododienal
14, available in five steps from 4-pentynoic acid, resulted
in dehydration to provide a pentacyclic product 15 as a single
stereoisomer. To our surprise, the HMBC correlation depicted
in Scheme 4 established that the pyrrolidine nitrogen and
the neopentylic primary alcohol had combined with the
aldehyde to generate a [1,3]oxazocane ring. A second
surprise ensued when this eight-membered ring aminal was
treated at room temperature with NaBH3CN and acetic acid
in MeCN/CH2Cl2 to provided a tetracyclic reduction product
16 in 80% yield. Initially, this product appeared to have
spectral characteristics (1H NMR, 13C NMR, IR, COSY,
HMQC, ESI-MS) consistent with the desired reductive
amination product. However, our inability to oxidize 16 to
a dialdehyde led us to question the initial structural assign-
ment. Finally, additional NMR studies established that 16
contained a CH-O-CH2 fragment (HMBC correlation),
leading us to conclude that extensive rearrangement of the
sarain core structure had taken place to produce tetracyclic
product 16. Fortunately, the desired reductive amination
Supporting Information Available: Experimental pro-
cedures for the preparation of 8, 11, and 15-17; copies of
1H and 13C NMR spectra for all new compounds; copies of
COSY, HMQC, and HMBC spectra of 15-17; and a copy
of the NOESY spectrum of 8. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL050038M
(22) (a) Fragmentation of protonated 1,2-ethylenediamine to an aziri-
dinium ion has been observed in the gas phase; see: Bouchoux, G.; Choret,
N.; Penaud-Berruyer, P.; Flammang, R. J. Phys. Chem. A 2001, 105, 9166-
9177. (b) N,N′-Dimethyl-1,3-propanediamine exchanges methyl groups
slowly in water in the presence of acid; see: Callahan, B. P.; Wolfenden,
R. J. Am. Chem. Soc. 2003, 125, 310-311.
936
Org. Lett., Vol. 7, No. 5, 2005