Enantioselective synthesis of schulzeines B and C via a β-lactone-derived surrogate for bishomoserine aldehyde

Article abstract of DOI:10.1021/ol802992m

Enantioselective syntheses of the glucosidase inhibitors schulzeines B and C were achieved by employing a Pictet-Spengler reaction of a β-lactone-derived, masked bishomoserine aldehyde. Subsequent Corey-Link reaction unveiled an α-azido acid enabling cycl

Full text of DOI:10.1021/ol802992m

ORGANIC
LETTERS
2009
Vol. 11, No. 5
1143-1146
Enantioselective Synthesis of
Schulzeines B and C via a
ꢀ-Lactone-Derived Surrogate for
Bishomoserine Aldehyde
Gang Liu and Daniel Romo*
Department of Chemistry, Texas A&M UniVersity, P.O. Box 30012, College Station,
Texas 77842-3012
romo@tamu.edu
Received December 31, 2008
ABSTRACT
Enantioselective syntheses of the glucosidase inhibitors schulzeines B and C were achieved by employing a Pictet-Spengler reaction of a
ꢀ-lactone-derived, masked bishomoserine aldehyde. Subsequent Corey-Link reaction unveiled an r-azido acid enabling cyclization to the
δ-lactam fused tetrahydroisoquinoline. An efficient synthesis of the trisulfate-bearing side chain featured a Noyori hydrogenation and a Sharpless
dihydroxylation. An unexpected reaction of a pendant amine during a Corey-Link process opens avenues for the synthesis of proline and
related amino acid derivatives.
Schulzeines B and C (1/1′) are potent R-glucosidase inhibitors
(IC50 48-170 nM) and viral neuraminidase inhibitors (IC50 60
µM) recently isolated by Fusetani and co-workers from the
marine sponge Penares schulzei.1 The structure of these marine
alkaloids was determined by chemical degradation and extensive
NMR analysis, while the absolute configuration was based on
Mosher ester analysis of fragments from chemical degradation
of the natural product.1 The intriguing bioactivity combined with
the unique structure of schulzeines aroused several synthetic
efforts toward these targets.2 Notably, all of the reported
syntheses of the tricyclic isoquinoline core began with glutamic
acid derivatives. Our interest in the schulzeines was sparked
by their biological activity including their potential as antidia-
betic agents3 and an interest in exploiting the versatility of
ꢀ-lactones and in particular the commercially available, optically
active trichloromethyl-ꢀ-lactone 8,4 which we previously dem-
onstrated serves as a useful masked R-azido acid via the
Corey-Link process.5
Our synthetic strategy toward schulzeines B and C (1/1′)
entailed a late stage trisulfation following amide coupling of
the δ-lactam-fused tetrahydroisoquinolines 2/2′ and the 28-
carbon side chain 3 (Figure 1). The δ-lactam would be derived
from cyclization of R-azido acids derived from trichloromethyl
carbinols 4/4′ via the Corey-Link modified Jocic reaction.6 The
diastereomeric tetrahydroisoquinolines 4/4′ would be formed
(3) For a review of glycosidase inhibitors, see: Jung, M.; Park, M.; Lee,
H. C.; Kang, Y.-H.; Kang, E. S.; Kim, S. K. Curr. Med. Chem. 2006, 13,
1203.
(1) Takada, K.; Uehara, T.; Nakao, Y.; Matsunaga, S.; Van Soest,
R. W. M.; Fusetani, N. J. Am. Chem. Soc. 2004, 126, 187.
(2) (a) Kuntiyong, P.; Akkarasamiyo, S.; Eksinitkun, G. Chem. Lett.
2006, 35, 1008. (b) Gurjar, M. K.; Pramanik, C.; Bhattasali, D.; Ramana,
C. V.; Mohapatra, D. K. J. Org. Chem. 2007, 72, 6591. (c) Wardrop, D. J.;
Bowen, E. G. Abstracts of Papers, 233rd ACS National Meeting, Chicago,
March 25-29, 2007.
(4) This δ-lactone available from Aldrich ($104/25 g, 99% ee, 2008) is
prepared by the method of Wynberg. See: (a) Wynberg, H.; Staring, E. G. J.
J. Am. Chem. Soc. 1982, 104, 166. For preparation using in situ ketene
generation, see: (b) Tennyson, R.; Romo, D. J. Org. Chem. 2000, 65, 7248.
(5) Tennyson, R.; Cortez, G. C.; Galicia, H. J.; Kreiman, C. R.;
Thompson, C. M.; Romo, D. Org. Lett. 2002, 4, 533.
10.1021/ol802992m CCC: $40.75
Published on Web 02/11/2009
2009 American Chemical Society

we employed the commercially available dimethyl catechol
amine 10 to identify suitable Pictet-Spengler conditions.
While several acids in aprotic solvents were unsuccessful
(e.g., AcOH or TFA in CH2Cl2 or CHCl3), the Pictet-Spengler
process including in situ hydrolysis of the vinyl ether 7 was
possible in glacial acetic acid with heating to give the
tetrahydroisoquinolines 11/11′ in excellent yield and as a
1
∼1:1 mixture of diastereomers by H NMR of the crude
product. The diastereomers were readily separated by flash
column chromatography and could be carried on separately
in subsequent transformations.
In our initial strategy, we envisoned a one-pot conversion
of the trichloromethyl carbinol to the δ-lactam 20 (Scheme
2). While several substrates have been utilized in the
Scheme 2
. Attempted One-Pot Strategy to the Tricyclic Core
Leading to a Proline Derivative Synthesis
Figure 1. Retrosynthetic analysis of schulzeines B and C.
via an expected nondiastereoselective Pictet-Spengler conden-
sation of aryl amine 6 and the masked R-amino acid aldehyde
7 ultimately derived from (R)-trichloromethyl-ꢀ-lactone 8.
Access to both diastereomers was desirable as it would enable
synthesis of diastereomeric schulzeines B and C.1 The three
alcohol-bearing stereocenters would be introduced via sequential
Noyori hydrogenation and a reagent-controlled Sharpless asym-
metric dihydroxylation of ꢀ-ketoester 5 derived from methy-
lacetoacetate dienolate alkylation.
Synthesis of the tetrahydroisoquinoline core began with
conversion of commercially available ꢀ-lactone 8 to the vinyl
ether 7 which serves as a masked aldehyde/R-amino acid
for the Pictet-Spengler reaction (Scheme 1). One-carbon,
Corey-Link process, amine-containing substrates have rarely
been studied. Treatment of the trichloromethylcarbinol 11
was expected to provide dichlorooxirane intermediate 13 as
previously proposed for this process,6c which upon epoxide
cleavage by azide with inversion would provide acid chloride
14 that could be trapped by the pendant piperidine nitrogen
to provide δ-lactam 20. However, despite extensive experi-
mentation, this strategy was unsuccessful.7
Scheme 1
.
Synthesis of the Masked Bishomoserine Aldehdye
Tetrahydroisoquinolines 11/12
Under one set of conditions employing DBU as base,
pyrrolidines 16/16′ were isolated as a ∼6:1 mixture of
separable diastereomers (68%, combined yield). These
products presumably arise from attack of the piperidine
(6) (a) Jocic, Z. Z. Zh. Russ. Fiz. Khim. OVa. 1897, 29, 97. (b) Corey,
E. J.; Link, J. O. J. Am. Chem. Soc. 1992, 114, 1906 For mechanistic studies
of the Jocic reaction, see: (c) Reeve, W.; Wood, C. W. Can. J. Chem. 1980,
58, 485 For recent applications of Jocic-type reactions, see: (d) Shamshina,
J. L.; Snowden, T. S. Org. Lett. 2006, 8, 5881.
(7) Solubility issues with the N-unprotected isoquinoline 11 under typical
Corey-Link conditions (0.1 M, H2O/DME) which only gave recovered
starting material led us to study high dilution conditions (0.008 M).
However, this gave multiple polar products which were not readily identified.
IR analysis of the crude reaction mixture showed no azide-containing
products. Other unsuccessful conditions studied include nonprotic solvents
(THF, DMF) with strong bases (NaH, NaHMDS, KOtBu) which mainly
led to recovered starting material.
Wittig homologation of the known aldehyde 9,5 gave vinyl
ether 7 as an inconsequential 3:2 mixture of E/Z olefin
isomers. In our initial studies of the Pictet-Spengler process,
1144
Org. Lett., Vol. 11, No. 5, 2009

nitrogen onto the intermediate dichloroepoxide 13 as shown
(Scheme 2). In the presence of MeOH, the methyl ester is
generated from the presumed acid chloride intermediate 15.
This unexpected intramolecular capture of the presumed
dichloroepoxide 13 with the pendant amine suggests a
potential new strategy for the synthesis of proline, pipecolinic
acid, and other cyclic amino acid derivatives.
To avoid the observed premature cyclization, the amine
11 was protected as the corresponding t-butyl carbamate
(Boc) and then subjected to standard Corey-Link conditions
which now proceeded smoothly to give the R-azido acid 17
(R ) Me; Scheme 3). Direct Boc deprotection and cycliza-
separable and could be processed separately to schulzeines
B and C.
Following the same process developed in the dimethyl
series, amine protection of trichloromethyl carbinol 12 was
followed by subjection of Boc-protected isoquinoline 4 to
the previously employed Corey-Link conditions (Scheme
3). However, with this dibenzyl substrate, no reaction was
observed under these reaction conditions. We reasoned that
this was likely due to a solubility issue of this more
hydrophobic substrate in the DME/H2O reaction medium.
Thus, the concentration of reagents (NaOH/NaN3) was
maintained (0.4 M/0.2 M), while substrate concentration was
significantly lowered (0.008 M). Under these conditions, the
Corey-Link reaction proceeded efficiently to give the desired
azido acid 18 (R ) Bn) which was directly transformed to
the tricyclic structure 21 by Boc deprotection and lactam-
ization. Hydrogenolysis of the benzyl ethers with concomitant
reduction of the azide enabled correlation to the previously
prepared amino catechol 22 and confirmed relative and
absolute stereochemistry identical to the previous sequence.
Selective azide reduction of tricycle 21 with PPh3 gave the
primary amine 2 readied for coupling to the side chain.
The synthesis of the side chain began with alkylation of
the dienolate of methylacetoacetate with allyl bromide 25
prepared by bromination of the commercially available allylic
alcohol 24 (Scheme 4). The derived ꢀ-ketoester 5 was
Scheme 3. Synthesis of Core Structures 20/21 from a Dimethyl
and a Dibenzyl Catechol Substrate (Inset: ORTEP of Azide 20)
Scheme 4. Synthesis of the Side Chain Carboxylic Acid 3
tion to the δ-lactam with diphenylphosphoryl azide (DPPA)8
in DMF gave the azido tricycle 20, and the relative
stereochemistry of this intermediate was confirmed by X-ray
crystallography (inset, Scheme 3). Following azide reduction
and demethylation of the protected catechol, the known
amino tricycle 22 was obtained, and all spectroscopic data
matched those previously reported for the same compound
derived from schulzeine degradation.1
In a second-generation strategy to the isoquinoline core
with an eye toward simplifying final deprotection of the
catechol, we employed a dibenzyl-protected catechol 6 in
the Pictet-Spengler reaction to enable a late stage hydro-
genation (Scheme 1). The required phenethyl amine 6 was
prepared by reduction of a known cyanide precursor using
aslightmodificationofaliteratureprocedure.9,10 Pictet-Spengler
condensation of vinyl ether 7 and ꢀ-aryl amine 6 gave the
tetrahydroisoquinolines 12/12′ (dr ∼1:1) which were readily
subjected to Noyori hydrogenation11 to give optically active
ꢀ-hydroxy ester in good yield and excellent enantioselectivity
(er > 95:5, Mosher ester10,12 ). To avoid reduction of the
olefin, the hydrogenation was terminated prior to reaching
completion, and the starting material was readily separated
and recycled. The C17′, C18′ diol was then introduced via
(8) Qian, L.; Sun, Z.; Deffo, T.; Mertes, K. B. Tetrahedron Lett. 1990,
31, 6469.
(11) (a) Noyori, R.; Ohkuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.;
Kumobayashi, H.; Akutagawa, S. J. Am. Chem. Soc. 1987, 109, 5856. (b)
Taber, D. F.; Silverberg, L. J. Tetrahedron Lett. 1991, 32, 4227.
(12) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
(9) The addition of 1 equiv of sulfuric acid to the LiAlH4 reduction led
to greatly improved yields versus LiAlH4. See: Brown, H. C; Yoon, N. M.
J. Am. Chem. Soc. 1966, 88, 1464
.
(10) See Supporting Information for details
.
2543.
Org. Lett., Vol. 11, No. 5, 2009
1145

reagent-controlled Sharpless dihydroxylation in excellent
yield and diastereoselectivity (>19:1 dr, H NMR). To
led to schulzeine B (1) of high purity that was identical in
all respects to the natural product including optical rotation
(lit. [R]D22 -23 (c 0.1, MeOH);1 syn. [R]D23 -23.5 (c 0.68,
MeOH). Following the same sequence, schulzeine C (1′, not
shown)10 was also synthesized from the diastereomeric core
structure 12′, and data for the synthetic material matched
those previously reported for the diastereomeric natural
1
confirm the relative stereochemistry, the triol 29 was
peracylated with p-bromobenzoyl chloride to give a crystal-
line tribenzoate (not shown)10 enabling confirmation of the
relative and absolute stereochemistry by X-ray crystal-
lographic analysis to be as shown based on heavy atom (Br)
anomalous dispersion. Protection of the triol ester 29 as the
corresponding tris-triethylsilyl ether 30 and half-reduction
gave an intermediate aldehyde that was directly subjected
to olefination with the Wittig reagent derived from phos-
phonium salt 31. Simultaneous alkene hydrogenation and
benzyl hydrogenolysis in the presence of 2,6-lutidine, to
avoid TES deprotection, gave the carboxylic acid side chain
3.
22
product including optical rotation (lit. [R]D +33 (c 0.1,
MeOH);1 syn. [R]D +38.0 (c 0.42, MeOH).
23
In summary, we have accomplished the total synthesis of
the naturally occurring, R-glucosidase inhibitors schulzeines
B and C in a highly convergent manner employing a masked,
R-amino acid aldehyde synthon derived from a ꢀ-lactone.
Key features of the synthesis include a tetrahydroisoquinoline
synthesis via a Pictet-Spengler reaction of a masked
bishomoserine aldehyde, a Corey-Link process to unmask
the R-amino acid, and a highly efficient synthesis of the
required optically active, sulfated triol side chain employing
a Noyori hydrogenation and Sharpless dihydroxylation
sequence. An unexpected pyrrolidine product was obtained
under modified Corey-Link conditions with a substrate
bearing a pendant amine and suggests the possiblity of
capturing the dichloroepoxide intermediate by other tethered
nucleophiles leading to proline and other amino acid deriva-
tives. This synthesis further demonstrates the utility of
ꢀ-lactones as intermediates in natural product total synthesis,
and in particular application of the readily available trichlo-
romethyl ꢀ-lactone 8 which, in this instance, leads to a
versatile masked surrogate for bishomoserine aldehyde.
Under typical carbodiimide coupling conditions, the car-
boxylic acid side chain 3 and the amino tetrahydroisoquino-
line core 2 were joined to give amide 32 (Scheme 5).
Scheme 5. Completion of the Synthesis of Schulzeine B
Acknowledgment. We thank the Welch Foundation (A-
1208) for generous support of this work. We thank Dr.
Nattamai Bhuvanesh (TAMU) for obtaining X-ray crystal-
lographic data for azide 20 and the tribenzoate ester derived
from triol 29.
Cleavage of the TES ethers under mild acidic conditions gave
triol 33 which was subjected to sulfation with the
SO3·pyridine complex13 to provide the trisulfate 34. This
material was of sufficient purity following rapid purification
through silica gel to carry on to the final step. Hydrogenolysis
of the benzyl groups and filtration to remove the Pd catalyst
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 1-7, 9,
11, 12, 16, 17, 20-22, 25, 28-30, 32-33 (and the
diastereomeric series leading to schulzeine C), X-ray crystal-
lographic data including cif files for tricyclic azides 20 and
20′, and the tribenzoate derived from triol 29. This material
is available free of charge via the Internet at http://pubs.acs.org.
(13) For a lead reference to sulfation methods, see: Simpson, L. S.;
Widlanski, T. S. J. Am. Chem. Soc. 2006, 128, 1605.
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