Total synthesis of the originally assigned structure of vannusal B

Article abstract of DOI:10.1002/anie.200804228

(Chemical Equation Presented) The truth is out there: The chase for the originally assigned structure of vannusal B (see structural formula) by total synthesis ended successfully, but created a new puzzle, that of the true structure of this intriguing marine natural product.

Full text of DOI:10.1002/anie.200804228

Angewandte
Chemie
DOI: 10.1002/anie.200804228
Natural Products
Total Synthesis of the Originally Assigned Structure of Vannusal B**
K. C. Nicolaou,* Hongjun Zhang, Adrian Ortiz, and Philippe Dagneau
Vannusals A (1a, Figure 1) and B (1b) are two marine natural
products notable for their unusual molecular architectures.
Isolated from the tropical interstitial ciliate Euplotes vannus
Figure 2. Retrosynthetic analysis of vannusal B (1b). BOM=benzyl-
oxymethyl, SEM=trimethylsilylethoxymethyl, TIPS=triisopropylsilyl.
Figure 1. Originally assigned structures of vannusals A (1a) and B
(1b).
Scheme 1 summarizes the construction of vinyl iodide 2
from the commercially available meso diol 4. Thus, dehydra-
tion of 4 through the action of POCl3 (py, 908C) furnished
strains Si121 and BUN3, these intriguing molecules include in
their C30 molecular framework seven rings and thirteen
stereogenic centers, three of which are quaternary. Their
structures have been assigned on the basis of mass spectro-
metric and NMR spectroscopic data and chemical trans-
formations.[1,2] Herein we report the total synthesis of
structure 1b that proved that it does not represent the true
structure of vannusal B.
Our retrosynthetic analysis of the vannusal molecule
dissected it as shown in Figure 2, revealing vinyl iodide 2 and
aldehyde 3 as the key building blocks required for the
projected total synthesis. The devised strategy anticipated
their fusion through two carbon–carbon bond-forming reac-
tions, namely lithiation of 2 followed by addition of 3 to join
them, and a samarium-induced ring closure of a subsequent
intermediate to forge the final ring of the target molecule.
conjugated diene 5 (97% yield),[3] which was regio- and
stereoselectively converted into the new meso diol 6 by a
hydroboration–oxidation process (CyBH2; H2O2, NaOH,
51% yield). The latter compound was then desymmetrized
through the enantioselective hydrolytic action of Lipase
Amano PS[4] on its bis-acetate (prepared in quantitative
yield by reaction of 6 with Ac2O in the presence of 4-DMAP),
leading to the monoacetate 7 in 100% yield and 99% ee
(determined by Mosher ester analysis). Silylation of 7
(TBDPSCl, imid, 93% yield) followed by acetate cleavage
(DIBAL-H, 98% yield) and treatment of the resulting
alcohol with Martinꢀs sulfurane (Et3N, CH2Cl2, 91% yield)
afforded enantiomerically pure cyclopentene derivative 8.
The planned stereoselective epoxidation of 8 was achieved
through a two-step procedure that involved first iodohydrin
formation (NIS, H2O), and then ring closure (K2CO3, MeOH)
to give b-epoxide 9 in 91% overall yield. This epoxide was
then regio- and stereoselectively opened with 2-lithiopropene
(generated from the corresponding bromide and tBuLi) in the
presence of BF3·Et2O to afford hydroxy compound 10 (83%
yield), whose stereochemistry was inverted through applica-
tion of a Mitsunobu (pNO2C6H4CO2H, Ph3P, DEAD)[5]/ester
cleavage (DIBAL-H) protocol, leading to the desired hy-
droxy compound 11 in 90% overall yield. With the proper
stereochemistry now installed on 11, a BOM group was
placed on the free hydroxy group (BOMCl, iPr2NEt) and the
TBDPS group was removed (TBAF, 97% overall yield) to
furnish compound 12. The newly generated hydroxy group
within 12 was then oxidized [NMO, TPAP (cat.), 96% yield],
and the resulting ketone was converted into its tris-hydrazone
13 (TrisNHNH2, 80% yield). Finally, the targeted vinyl iodide
2 emerged in 90% yield through a Shapiro reaction[6] of
hydrazone 13 (nBuLi, I2). The relative and absolute stereo-
chemistry of this series of compounds was confirmed by X-ray
crystallographic analysis (see ORTEP drawing, Figure 3)[7] of
[*] Prof. Dr. K. C. Nicolaou, Dr. H. Zhang, A. Ortiz, Dr. P. Dagneau
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-2469
E-mail: kcn@scripps.edu
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92037 (USA)
[**] We thank Dr. D. H. Huang, Dr. G. Siuzdak, and Dr. R. Chadha for
NMRspectroscopic, mass spectrometric, and X-ray crystallographic
assistance, respectively. Financial support for this work was
provided by the NSF (fellowship to A. Ortiz), the Skaggs Institute for
ResearchS, and a grant from the National Institutes of Health
(USA).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804228.
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Figure 3. X-ray derived ORTEP drawing of 14 (thermal ellipsoids at
30% probability); gray C, green H, blue N, red O.
the crystalline p-bromophenyl carbamate 14 (m.p. 136–
1388C, EtOAc/hexanes) prepared from hydroxy compound
10 through reaction with p-bromophenyl isocyanate, followed
by TBAF-induced desilylation, in 74% overall yield as shown
in Scheme 1.
Scheme 2 outlines the construction of building block 3
starting from intermediate 15 (racemic)[8,9] or 15a (enantio-
pure).[9] Thus, exposure of dihydroxy methyl ether 15 to B-
bromocatecholborane, followed by selective monosilylation
of the resulting triol (TIPSCl, imid) led to the corresponding
primary TIPS ether (70% yield for the two steps), which was
oxidized with IBX to afford diketone 16 (90% yield).
Generation of the titanium enolate from 16 followed by
addition of acetone (ꢀ928C) furnished the expected tertiary
alcohol (d.r. ca. 9:1), which was silylated (TESOTf, 2,6-lut.,
ꢀ78!ꢀ408C) to afford bis(silyl) ether 17 (chromatograph-
ically separated) in 81% overall yield of the desired
diastereomer for the two steps. The very low temperature
(ꢀ928C) was necessary for the good stereoselectivity
observed in this aldol reaction. The next step required
stereoselective reduction of the two carbonyl groups within
17 to afford the desired 25a,26b dihydroxy compound, a
prospect that, upon inspection of molecular models, looked
good by virtue of the steric environment of these moieties.
Indeed, exposure of 17 to NaBH4 resulted in the formation of
a single diol, from which the TES group was removed under
mild desilylation conditions (PPTS, EtOH) to afford triol 18
in 85% overall yield from diketone 17. Based on intelligence
gathering from other experiments that will be revealed later,
and in preparation for the samarium ring closure we had in
mind, a SEM group was installed at C-26, a choice that left the
acetonide moiety as the obvious guardian for the other two
hydroxy groups. To this end, triol 18 was exposed to Ac2O and
4-DMAP in CH2Cl2, conditions that acetylated selectively the
C-26 hydroxy group (that turned out to be the most reactive
of the three in our experience with these series of com-
pounds), resulting in crystalline monoacetate 19 in 79% yield
(m.p. 131–1338C, hexanes). X-ray crystallographic analysis[10]
of 19 (see ORTEP drawing, Figure 4) confirmed the relative
stereochemistry of this intermediate as expected from its
NMR spectroscopic data. Exposure of 19 to 2-methoxy-
propene in the presence of CSA afforded the corresponding
Scheme 1. Enantioselective construction of vinyl iodide 2. Reagents
and conditions: a) POCl3 (2.2 equiv), py, 908C, 2 h, 97%; b) BH3·THF
(2.5 equiv), cyclohexene (2.5 equiv), ꢀ40!08C, 2 h; then 5, ꢀ40!
258C, 12 h; then 508C, 30 min; then 30% H2O2/3n NaOH (2:1 v/v),
ꢀ50!508C, 12 h, 51%; c) Ac2O (3.0 equiv), 4-DMAP (0.02 equiv), py,
08C, 8 h, 100%; d) Lipase Amano PS (100 wt%), acetone/phosphate
buffer (pH 7) (2:1), 258C, 48 h, 100%, 99% ee; e) TBDPSCl
(1.2 equiv), imid (3.0 equiv), CH2Cl2, 258C, 12 h, 93%; f) DIBAL-H
(1.0m in hexanes, 2.5 equiv), CH2Cl2, ꢀ788C, 30 min, 98%; g) Martin’s
sulfurane (1.3 equiv), Et3N (3.0 equiv), CH2Cl2, 258C, 12 h, 91%;
h) NIS (1.5 equiv), THF/H2O (4:1), 0!258C, 1.5 h; then K2CO3
(2.5 equiv), MeOH, 258C, 18 h, 91%; i) 2-bromopropene (4.4 equiv),
tBuLi (1.7m in pentane, 8.0 equiv), THF, ꢀ788C, 5 min; then BF3·Et2O,
2 min; 9, ꢀ78!ꢀ408C, 30 min, 83%; j) pNO2C6H4CO2H (1.5 equiv),
DEAD (1.5 equiv), Ph3P (1.8 equiv), benzene, 0!258C, 18 h, 94%;
k) DIBAL-H (1.0m in hexanes, 2.5 equiv), CH2Cl2, ꢀ788C, 30 min,
96%; l) BOMCl (3.0 equiv), iPr2NEt (10 equiv), PhMe, 908C, 12 h;
m) TBAF (1.0m in THF, 15 equiv), 708C, 97% for two steps; n) NMO
(1.5 equiv), TPAP (0.03 equiv), CH2Cl2/CH3CN (9:1), 12 h, 96%;
o) TrisNHNH2 (1.8 equiv), THF, 5 h, 80%; p) nBuLi (2.5m in hexanes,
2.1 equiv) THF, ꢀ78!ꢀ258C, 20 min; then I2 (2.0 equiv), ꢀ78!
ꢀ258C, 20 min, 90%; q) pBrC6H4NCO (4.0 equiv), Et3N (6.0 equiv),
258C; r) TBAF, THF, 258C, 74% for two steps. 4-DMAP=4-dimethyl-
aminopyridine, py=pyridine, TBDPS=tert-butyldiphenylsilyl, imid=
imidazole, DIBAL-H=diisobutylaluminum hydride, NIS=N-iodo-
succinimide, DEAD=diethylazodicarboxylate, TBAF=tetra-n-butyl-
ammonium fluoride, NMO=N-methylmorpholine-N-oxide, TPAP=te-
tra-n-propylammoniumperuthenate, Tris=triisopropylsulfonyl.
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acetoxy acetonide (82% yield) which, after cleavage of the
acetate group (MeMgBr, 508C, 94% yield), was converted
Figure 4. X-ray derived ORTEP drawing of 19 (thermal ellipsoids at
30% probability); gray C, green H, light blue Si, red O.
into its SEM derivative 20 (SEMCl, iPr2NEt, 96% yield).
Having installed the appropriate functionalities, and in their
proper configurations on our growing tricyclic system, we
then turned our attention to the construction of the remaining
quaternary center at C-13. To this end, a Claisen rearrange-
ment was called upon, with allyl enol ether 21 as the substrate.
This substrate was expediently prepared from 20 by ozonol-
ysis (O3; Ph3P, 96% yield), followed by O-allylation of the
resulting aldehyde (KH, allyl chloride, 92% yield). Pleasantly,
the anticipated Claisen rearrangement of 21 proceeded
smoothly upon microwave irradiation at 2008C, furnishing
the desired skeleton, which was swiftly reduced with NaBH4
to afford alcohol 22, in 88% yield for the two steps. The latter
compound was then protected as the BOM ether (BOMCl,
iPr2NEt) and subjected to ozonolysis (O3, Ph3P) to give
aldehyde 23 in 85% yield for the two steps. Finally, truncation
by one carbon atom was accomplished by silyl enol ether
formation (TBSCl, DBU) followed by a second ozonolysis
(O3, Ph3P) to furnish the targeted aldehyde 3 in 97% overall
yield for the two steps.
With both building blocks 2 and 3 readily available, their
union and further elaboration to the reported vannusal B
structure 1b became the next task. As shown in Scheme 3,
lithiation of the vinyl iodide 2 (tBuLi, ꢀ78!ꢀ408C) followed
by addition of racemic aldehyde 3 (ꢀ40!08C) furnished a 1:1
diastereomeric mixture of products (24 and its diastereoiso-
mer, not shown) in 80% total yield. The two diastereoisomers
were chromatographically separated and compared to the
Scheme 2. Construction of aldehyde 3. Reagents and conditions:
a) B-Br-catecholborane (3.5 equiv), CH2Cl2, 25!508C, 3 h; b) TIPSCl
(1.5 equiv), imid (6.0 equiv), DMF, 24 h, 70% for two steps; c) IBX
(3.0 equiv), DMSO, 508C, 4 h, 90%; d) TiCl4 (1.0m in CH2Cl2,
1.2 equiv), Et3N (3.0 equiv), CH2Cl2, ꢀ78!ꢀ308C, 30 min; then ace-
tone, ꢀ928C, 12 h (d.r. 9:1); e) TESOTf (3.0 equiv), 2,6-lut. (5.0 equiv),
ꢀ78!ꢀ408C, 1 h, 81% for two steps; f) NaBH4 (10 equiv), THF/
MeOH (1:1), ꢀ10!258C, 5 h; g) PPTS (0.2 equiv), EtOH, 258C, 2 h,
85% for two steps; h) Ac2O (20 equiv), 4-DMAP (0.1 equiv), Et3N
(40 equiv), CH2Cl2, 258C, 18 h, 79%; i) 2-methoxypropene (20 equiv),
CSA (1.0 equiv), CH2Cl2, ꢀ78!ꢀ308C, 3 h, 82%; j) MeMgBr
(50 equiv), PhMe, 508C, 8 h, 94%; k) SEMCl (10 equiv), iPr2NEt
(30 equiv), TBAI (1.0 equiv), CH2Cl2, 508C, 48 h, 96%; l) O3, py
(1.0 equiv), CH2Cl2/MeOH (1:1), ꢀ788C; then Ph3P (5.0 equiv), ꢀ78!
258C, 1 h, 96%; m) KH (10 equiv), allyl chloride (20 equiv), HMPA
(5.0 equiv), DME, ꢀ10!258C, 3 h, 92%; n) iPr2NEt (1.0 equiv), 1,2-
dichlorobenzene, 2008C (microwave), 20 min; then NaBH4 (20 equiv),
MeOH, 1 h, 258C, 88% for two steps; o) BOMCl (6.0 equiv), iPr2NEt
(15 equiv), CH2Cl2, 508C, 12 h; p) O3, py (1.0 equiv), CH2Cl2/MeOH
(1:1), ꢀ788C; then Ph3P (5.0 equiv), ꢀ78!258C, 1 h, 85% for two
steps; q) TBSCl (10 equiv), DBU (20 equiv), CH2Cl2, 258C, 36 h; r) O3,
py (1.0 equiv), CH2Cl2/MeOH (1:1), ꢀ788C; then Ph3P (5.0 equiv),
ꢀ78!258C, 1 h, 97% for two steps. TES=triethylsilyl, 2,6-lut.=2,6-
dimethylpyridine, PPTS=pyridinium p-toluenesulfonate, CSA=cam-
phorsulfonic acid, HMPA=hexamethylphosphoramide, DBU=1,8-
diazabicyclo[5.4.0]undec-7-ene, DME=1,2-dimethoxyethane, IBX=
o-iodoxybenzoic acid, OTf=trifluoromethanesulfonate, TBAI=
tetra-n-butylammonium iodide, TBSCl=tert-butyldimethylsilyl chloride.
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single (and diastereomerically desired) product obtained
and their structures unambiguously assigned indirectly by X-
ray crystallographic analysis of a crystalline derivative (see
below). This identification was important since (ꢁ )-3 was
easier to obtain than its enantiopure counterpart, and was,
therefore, employed at this juncture for practical reasons. The
b stereochemistry of the newly generated stereocenter in 24
(C-12) was expected on steric grounds (addition of the lithio
reagent to the less hindered face of the chelated aldehyde)
and was confirmed by nuclear Overhauser effect (NOE)
studies. At this stage, our designed strategy called for a SmI2-
induced ring closure involving radical anion generation at the
aldehyde site, followed by attack on the adjacent olefinic
bond and expulsion of a leaving group at C-12 with
concomitant migration of the double bond to the C-11–C-12
position.[11]
from the coupling reaction in which enantiopure aldehyde
(+)-31 (closely related to aldehyde 3 having only the SEM
and acetonide groups flipped, Scheme 4) was used to reveal
the identity of the desired diastereoisomer within the above
mixture. The coupling products derived from the two
aldehydes [(ꢁ )-3 and (+)-31] were correlated downstream,
It was to this end that the following four-step sequence
was carried out from hydroxy compound 24 to the aldehyde
carbonate 25: 1) exchange of the TIPS moiety (TBAF, 258C,
98% yield) for the more labile TES group (TESCl, imid, 99%
yield); 2) carbonate formation at C-12 (KHMDS, ClCO2Me);
3) selective removal of the TES group (HF·py, 92% for the
two steps); and 4) oxidation of the liberated primary hydroxy
group to the aldehyde (TEMPO, PhI(OAc)2, 98% yield). The
final ring of the desired polycyclic skeleton was then forged by
treatment of substrate 25 with a solution of SmI2 in THF in the
presence HMPA at ꢀ10!258C, yielding a mixture of two
diastereomeric alcohols (differing at C-28), 26 (28% yield)
and 27 (52% yield), which were chromatographically sepa-
rated. The stereochemical assignments for these two com-
pounds were based on NMR spectroscopic analysis, partic-
ularly NOE studies. Faced with the unpleasant stereochemical
outcome of this reaction, which otherwise performed admir-
ably, we decided to eradicate the two newly generated
stereocenters (at C-10 and C-28) through dehydration, and
reconstruct them in their proper configurations by exploiting
the reactivity preferences of the resulting diene system.
Triene 28 was secured from either isomer 26 or 27, each
precursor, however, requiring its own path. Thus, treatment of
isomer 26 (in which the OH group resides anti to H-10) with
POCl3 (py, 608C) led directly to 28 (81% yield), whereas
isomer 27 (in which the OH group is syn to H-10) required
conversion into its xanthate first (NaH, CS2, MeI, 0!258C),
and then syn elimination, a process that proceeded smoothly
upon microwave irradiation at 1858C (92% overall yield).[12]
The next hurdle to be overcome was the regio- and
stereoselective hydration of the C-10–C-28 olefinic bond in
Scheme 3. Completion of the synthesis of structure 1b. Reagents and
conditions: a) 2 (1.3 equiv), tBuLi (2.6 equiv), THF, ꢀ78!ꢀ408C,
30 min; then 3 (1.0 equiv), ꢀ40!08C, 20 min, 80%; b) TBAF (1.0m in
THF, 5.0 equiv), THF, 258C, 1 h, 98%; c) TESCl (1.5 equiv), imid
(5.0 equiv), CH2Cl2, 258C, 1 h, 99%; d) KHMDS (0.5m in PhMe,
3.0 equiv), ClCO2Me (5.0 equiv), Et3N (5.0 equiv), THF, ꢀ78!258C,
2 h; e) HF·py/py (1:4), 0!258C, 12 h, 88% for two steps; f) TEMPO
(1.0 equiv), PhI(OAc)2 (3.0 equiv), CH2Cl2, 258C, 24 h, 98%; g) SmI2
(0.1m in THF, 5.0 equiv), HMPA (15 equiv), THF, ꢀ10!258C, 30 min,
80% (26: 28%, 27: 52%); h) POCl3 (60.0 equiv), py, 608C, 3 h, 81%;
i) CS2 (8.0 equiv), NaH (6.0 equiv), THF, 0!258C, 30 min; then CH3I
(12 equiv), 0!258C, 3 h; then 1858C (microwave), 1,2-dichloroben-
zene, 15 min, 92%; j) ThexBH2 (5.0 equiv), THF, ꢀ10!258C, 1 h;
then BH3·THF (15 equiv), 0!258C, 30 min; then 30% H2O2/3n
NaOH (1:1), 25!408C, 1 h; 65% (1:1.3 mix); k) oNO2C6H4SeCN
(2.0 equiv), nBu3P (6.0 equiv), py (12 equiv), THF, 258C; then 30%
H2O2, 0!258C, 67%; l) KHMDS (0.5m in PhMe, 5.0 equiv), TESCl
(5.0 equiv), Et3N (8.0 equiv), THF, ꢀ78!258C, 30 min, 94%;
m) LiDBB (excess), THF, ꢀ78!ꢀ508C, 30 min, 84%; n) TEMPO
(1.0 equiv), PhI(OAc)2 (3.0 equiv), CH2Cl2, 258C, 24 h, 88%; o) Ac2O
(30 equiv), Et3N (30 equiv), 4-DMAP (1.0 equiv), CH2Cl2, 258C, 12 h,
100%; p) HF·py/THF (1:4), 258C, 3 h; then 3n aq HCl/THF (1:3),
258C, 6 h, 80%. KHMDS=potassium hexamethyldisilazide,
TEMPO=2,2,6,6-tetramethyl-1-piperidinyloxy free radical,
LiDBB=lithium di-tert-butylbiphenyl, ThexBH2 =2,3-dimethyl-2-butyl-
borane.
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the presence of the other two within intermediate 28. An
expedient tactic to solve this seemingly thorny problem was
devised based on the unique steric environment of each
olefinic bond within this substrate. Thus, hydroboration of
triene 28, first with ThexBH2 (terminal olefin, two diastereo-
isomers), and then with BH3·THF (C-10–C-28 olefin, single
diastereisomer) afforded, after the usual oxidative work-up, a
mixture of two diastereomeric diols (ca. 1:1.3, 65% yield).
This mixture was then dehydrated through syn elimination
(H2O2, 67% overall yield) of the primary o-nitrophenyl
selenides which were selectively generated from the diol
mixture (oNO2C6H4SeCN, nBu3P).[13] The desired configura-
tions at C-10 and C-28 within the newly obtained hydroxy
compound (29) were confirmed by NOE studies. Having
reached 29 with all stereochemistry in place as required, only
a short path now separated it from the targeted molecule. The
requisite aldehyde and acetate moieties were installed
through a short sequence [1) KHMDS, TESCl, 94% yield;
2) LiDBB, THF, ꢀ78!ꢀ508C, 84% yield; 3) TEMPO, PhI-
(OAc)2, 88% yield; and 4) Ac2O, 4-DMAP, Et3N, 100% yield]
to afford advanced intermediate 30. Global deprotection of 30
through the sequential action of HF·py and aqueous HCl in
the same pot furnished the coveted structure 1b in 80% yield.
The spectroscopic data of the synthesized compound, how-
ever, although similar, did not match those reported[1] for the
naturally occurring vannusal B.
group upon the initially generated reactive intermediate in
each of these reactions. Proximity combined with rigidity
must be responsible for this unusual, but facile process.
Sequential removal of the BOM (LiDBB) and SEM (HF·py)
groups gave the corresponding diol, which reacted with p-
bromophenyl isocyanate to afford p-bromophenyl carbamate
34 in 70% overall yield. The latter compound crystallized in
beautiful needles from EtOAc/hexanes, m.p. 180–1828C. X-
ray crystallographic analysis of these crystals (see ORTEP
drawing, Figure 5)[14] provided unambiguous confirmation of
its structure and those of its precursors.
Figure 5. X-ray derived ORTEP drawing of 34 (thermal ellipsoids at
30% probability); gray C, green H, brown Br, blue N, red O.
Lest there was any doubt about our synthesized structure
1b, a serendipitous discovery allowed further support for its
structural identity. Thus, activation of alcohol 32 [Scheme 4;
obtained from (+)-31 through a similar sequence as that
shown in Scheme 3] under Mitsunobu conditions (attempted
for inversion of configuration) resulted in the formation of the
polycyclic compound 33 (88% yield based on recovered
material). The new, and unexpected, ring within 33 was
apparently formed by intramolecular attack of the OBOM
The described chemistry provides a highly convergent
approach to the vannusal molecular framework, including the
originally proposed structure of vannusal B (1b). It also
proved that this structure (1b) does not represent the true
molecular identities of the vannusals, precipitating a puzzle
that still remains to be solved.
Received: August 26, 2008
Published online: October 10, 2008
Keywords: cyclization · natural products · samarium diiodide ·
.
total synthesis · vannusals A and B
[1] G. Guella, F. Dini, F. Pietra, Angew. Chem. 1999, 111, 1217 –
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[3] D. S. Greidinger, D. Ginsburg, J. Org. Chem. 1957, 22, 1406 –
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[4] For reviews on enzymatic desymmetrization in organic synthesis,
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105, 313 – 354; b) I. V. Hartung, H. M. R. Hoffmann, Angew.
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[5] S. F. Martin, J. F. Dodge, Tetrahedron Lett. 1991, 32, 3017 – 3020.
[6] For use of the Shapiro reaction in organic synthesis, see: a) R. H.
Shapiro, Org. React. 1976, 23, 405 – 506; b) R. H. Shapiro, M. J.
Heath, J. Am. Chem. Soc. 1967, 89, 5734 – 5735; c) R. M.
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d) K. C. Nicolaou, Z. Yang, J.-J. Liu, P. G. Nantermet, C. F.
Scheme 4. Synthesis of crystalline derivative 34. Reagents and condi-
tions: a) DEAD (10 equiv), Ph3P (10 equiv), pNO2C6H4CO2H
(10 equiv), benzene, 608C, 2 h, 88% based on recovered starting
material; b) LiDBB, THF, ꢀ78!ꢀ508C; c) HF·py/THF, 258C, 4 h;
d) pBrC6H4NCO (3 equiv), Et3N, 408C, 70% for three steps.
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Communications
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