Total synthesis of potent antifungal marine bisoxazole natural products bengazoles A and B

Article abstract of DOI:10.1002/chem.200700033

The bengazoles are a family of marine natural products that display potent antifungal activity and a unique structure, containing two oxazole rings flanking a single carbon atom. Total syntheses of bengazole A and B are described, which contain a sensitive stereogenic centre at this position between the two oxazolcs. Additionally, the synthesis of 10-epi-bengazole A is reported. Two parallel synthetic routes were investigated, relying on construction of the 2,4-disubstituted oxazole under mild conditions and a diastereoselective 1,3-dipolar cycloaddition. Our successful route is high yielding, provides rapid access to single stereoisomers of the complex natural products and allows the synthesis of analogues for biological evaluation.

Full text of DOI:10.1002/chem.200700033

FULL PAPER
DOI: 10.1002/chem.200700033
Total Synthesis of Potent Antifungal Marine Bisoxazole Natural Products
Bengazoles A and B
James A. Bull, Emily P. Balskus, Richard A. J. Horan, Martin Langner, and
Steven V. Ley*[a]
Abstract: The bengazoles are a family
of marine natural products that display
potent antifungal activity and a unique
structure, containing two oxazole rings
flanking a single carbon atom. Total
syntheses of bengazole A and B are de-
scribed, which contain a sensitive ste-
reogenic centre at this position be-
tween the two oxazoles. Additionally,
the synthesis of 10-epi-bengazole A is
reported. Two parallel synthetic routes
were investigated, relying on construc-
tion of the 2,4-disubstituted oxazole
under mild conditions and a diastereo-
selective 1,3-dipolar cycloaddition. Our
successful route is high yielding, pro-
vides rapid access to single stereoiso-
mers of the complex natural products
and allows the synthesis of analogues
for biological evaluation.
Keywords:
cycloaddition
antifungal agents
heterocycles
·
·
·
natural products · total synthesis
Introduction
The synthesis of oxazole con-
taining natural products has
been driven by their fascinat-
ing structures and biological
activities.[1,2] However, the syn-
thesis of oxazole rings in com-
plex structures remains a chal-
lenge, in particular their con-
struction adjacent to stereo-
genic centres, which are prone
to racemisation. For example,
in the synthesis of the calycu-
lins the C30 stereogenic centre
is readily racemised during for-
Figure 1. Oxazole natural products.
mation of the oxazole ring
(Figure 1).[3]
others into the use of Burgess reagent and DAST to cyclise
serine and threonine amides, followed by oxazoline oxida-
tion, have enabled the formation of oxazoles under mild
conditions tolerant of complex functionality and sensitive
stereochemical features.[4,5] In addition, Wipf has reported a
Robinson–Gabriel oxazole synthesis under mild conditions
using a Dess–Martin periodinane (DMP) oxidation I2/PPh3
protocol for 5-substituted oxazoles, which has also been
modified for 5-unsubstituted examples.[6] These approaches
have found extensive use in complex molecule synthesis.[2,7]
Bisoxazoles make up a significant subsection of oxazole
natural products, with the oxazole rings either well separat-
These challenging structural motifs have stimulated the
discovery of milder reagents for oxazole synthesis, particu-
larly frompeptide precursors. Extensive work by Wipf and
[a] J. A. Bull, E. P. Balskus, Dr. R. A. J. Horan, Dr. M. Langner,
Prof. Dr. S. V. Ley
Department of Chemistry, University of Cambridge
Lensfield Road, Cambridge, CB2 1EW (UK)
Fax : (+44)1223-336-442
E-mail: svl1000@cam.ac.uk
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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ed (for example in the phorboxazoles)[8] or directly linked
(as found in the hennoxazoles,[9] Figure 1). The bengazoles
are a unique family of bisoxazoles in that the two oxazole
rings flank a single carbon atom. In bengazole A (1), this
C10 position carries a myristate ester unit creating an isolat-
ed stereogenic centre adjacent to two oxazole rings suggest-
ing it could be particularly prone to racemisation (Figure 2).
Furthermore, the left hand oxazole is a biogenically unusual
5-monosubstituted oxazole while the central 2,4-disubstitut-
ed oxazole links to a stereochemically dense tetraol side-
chain.
stereogenic centre. With the challenging structural compo-
nents and interesting biological profile, a synthetic route to
bengazole A was devised that would both provide a single
stereoisomer of the natural product and also allow for ana-
logues to be prepared for further biological evaluation.
Our somewhat risky strategy was to install the sensitive
C10 stereogenic centre prior to construction of the bisoxa-
zole unit. This would require retention of stereochemical in-
tegrity at the C10 centre through formation of the central
oxazole and on to the end of the synthesis. However, Molin-
ski and Shioiri had found separation of the C10 epimers to
be impossible once both oxazoles were in place and intro-
duction of the stereochemistry after this point to be relative-
ly poor, which dictated our approach towards the natural
product that was ultimately successful.
It was expected that bengazole A could be synthesised
fromeither advanced intermediate
2 with the myristate
ester already in place, or 3 carrying a TBDPS protecting
group (Scheme 1). The key strategic disconnections from
this intermediate were then logically across the central oxa-
zole ring and across the tetraol side chain, masked as an iso-
xazoline. These operations could be performed in either
order imparting a degree of flexibility to the synthesis. The
resultant three fragments would then be assembled by an
oxazole formation under mild conditions and a diastereose-
lective 1,3-dipolar cycloaddition. This disconnection route
was designed to avoid the use of strong bases and forcing
conditions due to the propensity of the C10 position to race-
mise.
Figure 2. Bengazole A.
To date the bengazole family consists of 22 members from
several isolation sources.[10–12] The parent molecule, benga-
zole A was originally isolated in 1988 and displays potent er-
gosterol dependant antifungal activity against Candida albi-
cans, comparable to that of amphotericin B,[13,14] and is
active against fluconazole-resistant Candida strains.[15] Fur-
thermore, bengazole A shows full anthelminthic activity
against nematode Nippostrongylus braziliensis at just
50 mgmLꢀ1.[10] The structure and absolute stereochemistry of
this highly functionalised molecule was determined by NMR
studies, analysis of degradation products and circular dichro-
ism.[10,12] Other members of the bengazole family differ in
the nature of the fatty acid side chain (bengazoles A to G)
or lack the C10 oxygenation entirely and carry a fatty acid
on one of the tetraol hydroxyl groups.
A previous synthesis of bengazole A by Molinski and co-
workers used a regioselective metallation/addition strategy
to graft the side chains on to the central oxazole.[15–17] How-
ever, this resulted in a 1:1 mixture of C10 epimers and once
the resulting bisoxazole unit was in place the C10 epimers
could not be separated at any stage during the synthesis. In
addition, Shioiri and co-workers achieved a synthesis of de-
acylbengazole[18] that was stereochemically enriched at the
C10 position by an enantioselective reduction of a bisoxa-
zole ketone, resulting in ee values up to 68%.[19] We recently
published a total synthesis of bengazole A, which provided
a single stereoisomer of the natural product.[20] Here we
report our full investigations into the synthesis of bengazole
A and also 10-epi-bengazole A, both as single stereoisomers.
Furthermore, the first total synthesis of bengazole B is also
described.
Scheme 1. Strategic disconnections of bengazole A.
Route A—Initial strategy: The initial approach was to per-
formthe 1,3-dipolar cycloaddition to construct the tetraol
side chain in advance of formation of the central oxazole, as
this allowed the introduction of the C10 stereocentre later
in the synthesis (Scheme 2). Intermediate 2 could then be
constructed fromcarboxylic acid 4 and isoxazoline-contain-
ing amine 5 via amide coupling and oxazole formation.
Amine 5 could be formed by a diastereoselective 1,3-dipolar
cycloaddition between Butane-2,3-diacetal (BDA)-protected
allylic diol 7 and the nitrile oxide derived fromCbz-protect-
ed Garner aldehyde oxime 6, followed by amine deprotec-
tion.
Synthesis plan: Our major objective was the synthesis of
bengazole A as a single stereoisomer and hence to examine
methods of oxazole synthesis adjacent to the activated C10
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Total Synthesis of Bengazoles A and B
FULL PAPER
stereochemistry already in
place. Therefore, acetonide 14
was transformed to the same
mixture of the BDA esters 10/
11 under the previously devel-
oped conditions (Scheme 4).
This mixture could be convert-
ed to exclusively the desired
diastereoisomer using catalytic
BF3·THF in CH2Cl2 in good
yield.[29] To formalkene 7 from
ester 10 it was most convenient
to reduce the ester directly to
Scheme 2. Initial disconnection route.
aldehyde 15 with DIBAL fol-
lowed by Wittig methylenation,
Results and Discussion
which proceeded in 86% yield over the two steps. This
route was readily scaled to rapidly provide large quantities
of alkene 7.
Alkene fragment 7: BDA-protected diols have been used
extensively in our group as stable chiral building blocks.[21]
The BDA group offers greater stability and lower volatility
compared to traditional acetonides and its structural rigidity
often leads to high levels of stereoinduction during addition
reactions and confers crystallinity on many of the products.
In the synthesis of alkene 7, the stereochemistry was ini-
tially introduced by Sharpless dihydroxylation of ethyl crot-
onate 8 to give diol 9 with >95% ee (Scheme 3).[22–25] Treat-
ment of 9 with camphorsulfonic acid and 2,3-butanedione in
methanol under reflux introduced the BDA-protecting
group as a 6:1 mixture of anomerically (10) and non-anom-
erically (11) stabilised products. Reduction of the mixture to
the corresponding alcohols allowed themto be separated by
flash chromatography and NOE analysis gave proof of struc-
ture.[26] Alcohol 12 was then converted to alkene 7 via a se-
quential TPAP oxidation–Wittig methylenation without pu-
rification or isolation of the intermediate aldehyde, which
gave higher yields than the stepwise process (67% vs
49%).[27,28]
Scheme 4. Synthesis of alkene 7. a) 1) 2,3-butanedione, CSA, trimethylor-
thoformate, MeOH, reflux; 2) BF3·THF, CH2Cl2, RT, 83% over two
steps; b) DIBAL-H, CH2Cl2, ꢀ788C, 86%; c) Ph3PCH3Br, KHMDS,
THF, ꢀ788C to RT, quant. DIBAL-H=diisobutylaluminium hydride.
Aldehyde 15 was initially isolated as the hydrate, which
dehydrated during flash chromatography to provide a crys-
talline solid. Following recrystallisation, this material could
be stored at ambient temperature under an inert atmos-
phere for over 12 months with minimal (<5%) degradation.
This is in stark contrast to the equivalent acetonide-protect-
ed compound which is an unstable volatile oil.[30]
However, with acetonide 14 commercially available, it
was deemed more cost-effective to start with the C2 and C3
Cycloaddition and synthesis of amine fragment: The nitrile
oxide precursor, Garner aldehyde-derived oxime 6, had
been previously reported and was prepared according to the
literature procedure.[31] A diastereoselective 1,3-dipolar cy-
cloaddition was then required to couple the nitrile oxide de-
rived fromoxime 6 with BDA-alkene 7 and to install the C4
stereochemistry (Scheme 5). The slow addition of oxime 6
to three equivalents of alkene 7 and three equivalents of
NaOCl, in the presence of NEt3, gave cycloadduct 16 with
4.1:1 diastereoselectivity in favour of the desired anti
isomer. These conditions were important to minimise the
formation of the nitrile oxide dimer 17[32] and of the excess
alkene employed in the reaction, 98% could be recovered.
The major cycloadduct was readily separated by flash chro-
matography and deprotection under hydrogenolysis condi-
Scheme 3. Synthesis of alkene 7. a) AD-mix-b, MeSO2NH2, H2O/tBuOH,
08C, 96% >95% ee; b) 2,3-butanedione, CSA, trimethylorthoformate,
MeOH, reflux, 89% (dr 6:1 10/11); c) LiAlH4, Et2O, 0 8C, 79% (of clean
major isomer 12); d) from 12: TPAP, NMO, 4 Š MS, CH2Cl2 then addi-
tion of Ph3PCH3Br, KHMDS, THF, ꢀ788C to RT, 67%. CSA=camphor-
sulphonic acid, TPAP=tetrapropylammonium perruthenate, NMO=N-
methylmorphonline-N-oxide, KHMDS=potassiumhexamethyldisilazide,
THF=tetrahydrofuran.
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S. V. Ley et al.
Scheme 5. Synthesis of amine 5. a) NaOCl aq., NEt3, CH2Cl2, slow addi-
tion of oxime 6, 08C, 86% (dr 4.1:1); b) H2, Pd(OH)2/C, AcOH, MeOH,
RT, 77 %.
Scheme 6. Synthesis of carboxylic acids 4 and 24. a) TosMIC, K2CO3,
MeOH, reflux, 82%; b) 1) TFA, H2O, RT; 2) TESCl, iPr2NEt, CH2Cl2,
ꢀ788C, 94% over two steps; For R1 =COC13H27: c) myristic acid, DCC,
DMAP, CH2Cl2, 08C to RT, 97%; d) Jones’ reagent, KF, acetone, 08C,
76%; e) TBTU, H-l-Ser-OMe·HCl, iPr2NEt, DMSO, RT (13:1 dr); For
R1 =TBDPS: c) TBDPSCl, Et3N, DMAP, CH2Cl2, RT; f) PPTS MeOH,
RT, 96% over two steps; d) From 23: Jones reagent, acetone, 08C, 49%;
e) TBTU, H-l-Ser-OMe·HCl, iPr2NEt, DMSO, RT, 64%, single diaste-
reoisomer. TosMIC=tosylmethylisocyanide, TFA=trifluoroacetic acid,
TES=triethylsilyl, PPTS=pyridinium para-toluenesulfonate, DCC=
tions in the presence of mild acid smoothly afforded amine
5 ready for coupling with the carboxylic acid fragment.
The configuration of the newly formed stereocentres at
C4 in the cycloadduct diastereoisomers were assigned by
1
correlating H NMR data with literature examples whereby
the anti isomer has a larger coupling constant between pro-
tons at the allylic ether stereocentre and the newly-formed
isoxazoline stereocentre.[33] The anti disposition of the major
N,N’-dicyclohexylcarbodiimide,
DMAP=4-dimethylaminopyridine,
TBTU=2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoro-
borate, DMSO=dimethylsulfoxide.
3
diastereoisomer is supported by comparison of the JH3,H4
coupling constants with those predicted by Macromodel
MMFF calculations (major: J
lated)=5.4 Hz; minor: J
C
racemisation; using TBTU in DMSO gave the best diaste-
reomeric ratio, but epimerisation still occurred (dr 13:1).
Subsequent attempts to couple carboxylic acid 4 with isoxa-
zoline containing amine 5 under these optimised conditions
gave variable yields and levels of racemisation.
We therefore decided to exchange the myristic ester for a
bulky TBDPS group on the C10 hydroxyl in an attempt to
protect the sensitive stereochemistry at this position
(Scheme 6). The primary alcohol 23 was synthesised in two
steps fromalcohol 19, without the previously observed mi-
gration problems, however, oxidation of this substrate also
proved to be extremely difficult and was only achieved
using Jones’ reagent. Subsequent amide coupling performed
in dimethylsulfoxide with serine methyl ester gave the de-
sired amide 25 as a single diastereomer showing there was
no loss of stereochemical integrity during the preceding
steps.
AHCTREUNG
Synthesis of acid fragment—Part 1: The synthesis of acid
fragment 4 relied upon stereocontrol derived fromour
BDA-protected glyceraldehyde derivative 17[21d] as a sub-
strate for a Schçllkopf-type oxazole synthesis.[37] The desired
5-substituted oxazole 18 was obtained in excellent yield by
treatment of aldehyde 17 with tosylmethylisocyanide
(TosMIC) and potassiumcarbonate (Scheme 6). Oxazole 18
was isolated exclusively as the equatorially substituted dia-
stereoisomer hence efficiently setting the desired C10 ste-
reochemistry for the natural product. The BDA group was
then removed using TFA/water, the primary alcohol was
protected as TES-ether 19 and esterification with myristic
acid and DCC gave 20 in excellent yield.[38] Removal of the
TES group from 20 gave a primary alcohol that was prone
to ester migration, which occurred on standing. However, all
attempts to oxidise the silyl ether directly, or in a one-pot
deprotection–oxidation, resulted in no reaction or ester mi-
gration. The only exception was Jones’ reagent, which gave
acid 4 in yields ranging from27 to 76%. To test the condi-
tions for the amide coupling, acid 4 was coupled with serine
methyl ester. However, using coupling reagent 2-(1H-benzo-
triazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate
(TBTU) in CH2Cl2 caused epimerisation at C10 (dr 5.5:1 to
1:1). More polar chelating solvents appeared to suppress the
Attempted synthesis of the central oxazole ring: Gratifying-
ly, under these conditions the coupling between acid 24 and
amine 5 proceeded smoothly, providing amide 26 in 65%
yield as a single diastereomer (Scheme 7). We envisaged
that this substrate would be a suitable precursor for forma-
tion of the central 2,4-substituted oxazole. Cyclisation of
amide 26 to oxazoline 27 was achieved in excellent yield by
treatment with DAST at ꢀ788C. Oxazoline oxidation is
known to be most efficient when the oxazoline is 4-substi-
tuted with an amide or ester group and it was believed that
the oxime-like functionality at this centre would provide the
requisite activation. However, despite investigating a variety
of conditions (BrCCl3, DBU; CuBr2, HMTA, DBU or
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Total Synthesis of Bengazoles A and B
FULL PAPER
tion to the unstable aldehyde 31 under Swern[42] or Dess–
Martin[43] conditions gave the precursor for the Robinson–
Gabriel synthesis. However, when the crude aldehyde was
subjected to a variety of cyclisation conditions (I2, Ph3P,
Et3N, CH3CN, CH2Cl2; C2Cl6, Ph3P, Et3N, CH3CN or
BrCl2CCCl2Br, Ph3Ph, CH2Cl2 then DBU, CH3CN),[6,44] none
of the attempts provided desired oxazole 32. Clearly, the for-
mation of the central 2,4-disubstituted oxazole would be a
critical step in the synthesis and we therefore decided to in-
vestigate an alternative strategy whereby this oxazole could
be introduced at an earlier stage.
Scheme 7. Synthesis of oxazoline 27 and attempted oxidation. a) TBTU,
amine 5, DMSO, RT, 65%; b) DAST, CH2Cl2, ꢀ788C, 91%.
Route B—Revised strategy: Our original disconnection
strategy offered the potential for the building blocks to be
assembled in the reverse order, forming the 2,4-disubstituted
oxazole prior to the dipolar cycloaddition with alkene 7
(Scheme 9). This now provided a more appealing route to
the bisoxazole unit but the C10 stereochemistry would need
to be retained through a larger number of steps to the natu-
ral product. Bisoxazole-oxime 33 would be formed by cou-
pling carboxylic acid 24 with serine ester 34 followed by ox-
azole formation. This would allow formation of the oxazole
ring on a less functionalised substrate and a cyclisation/oxa-
zoline oxidation process could be facilitated by the presence
of an ester in the 4-position. The dipolar cycloaddition be-
tween alkene 7 and the nitrile oxide derived fromoxime 33
would then provide isoxazoline 3, which could be elaborated
to bengazole A.
IBX)[5] oxidation of oxazoline 27 to oxazole 3 could not be
achieved.
To attempt a Robinson–Gabriel oxazole synthesis, the
product fromthe nitrile oxide cycloaddition ( 16) had to be
further elaborated before deprotection and amide coupling
(Scheme 8). Isoxazoline cleavage could be achieved using
molybdenum hexacarbonyl in wet acetonitrile under reflux
to give the b-hydroxyketone in 64% yield,[39] or with tris-
acetonitrile molybdenum tricarbonyl (believed to be the
active species in the reaction) at room temperature in an im-
proved 78% yield. The secondary alcohol proved to be very
difficult to protect with a MOM or TBS group and so the
ketone was reduced to give 1,3-diol 28 using sodiumborohy-
dride to give a 9:1 ratio of 1,3-diols, which were then be sep-
arated by flash chromatography.[40]
After protection of diol 28
as the acetonide, the stereo-
chemistry of the major product
was confirmed using Rychnov-
skyꢁs
method.[41] Removal of the
amino alcohol protecting
[13C]
acetonide
groups under hydrogenation
conditions gave amine 29
which could be coupled with
acid 24 under the previously
identified conditions to give
the desired amide 30 as
single diastereoisomer. Oxida-
a
Scheme 9. Revised retrosynthesis through bisoxazole oxime 33.
Scheme 8. Attempted Robinson-Gabriel oxazole formation. a) 1) [Mo
9:1); b) 1) 2,2-dimethoxypropane, acetone, TsOH, 88%; 2) H2, Pd/C, EtOH, RT, 83%; c) TBTU, acid 24, DMSO, RT, 47%; d) Dess–Martin periodinane,
NaHCO3, CH2Cl2, 08C.
A
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S. V. Ley et al.
Synthesis of acid fragment—Part 2: This revised strategy re-
quired much larger amounts of acid 24 than could be pro-
vided by the BDA route described above (Scheme 6) due to
the low-yielding Jones oxidation step. Therefore, alternative
routes to this important fragment were investigated starting
frompre-formed oxazole-5-carboxaldehyde 37 with the ad-
dition of a suitable masked carboxylic acid group. This alde-
hyde is known and was used in the syntheses of both Molin-
ski and Shioiri,[15a,19,45] but was previously prepared in two
steps frommethyl isocyanide which is highly toxic and not
commercially available. However, the reaction of TosMIC
and potassiumcarbonate with glyoxal-1,1-dimethyl acetal 35
(available as a 45% solution in tert-butyl methyl ether) gave
oxazole 36 in 58% yield using up to 100 grams (500 mmol)
of TosMIC (Scheme 10) and hydrolysis of the resultant
acetal provided oxazole-5-carboxaldehyde 37 in quantitative
yield.[46,25]
in good yield. Hydrolysis of rac-43 using LiOH gave the un-
stable carboxylic acid rac-24, which was immediately cou-
pled with serine methyl ester to give amides 25 and 44 as a
1:1 mixture, in 66% yield over the two steps. The two amide
diastereoisomers were stable to storage could be readily sep-
arated by flash chromatography hence providing a cheap
and efficient resolution of the racemic acid and allowing
access to large quantities of diastereomerically pure material
with which to continue the synthesis.
Scheme 11. Synthesis of amide 25. Racemic synthesis a) TMSCN, Et3N,
CH2Cl2, 08C, then 2m HCl aq, 92%; b) 2m HCl in MeOH, reflux, 89%;
c) TBDPSCl, Et3N, DMAP, DMF, RT, 85%; d) LiOH, H2O, THF, 08C to
RT; e) TBTU, H-l-Ser-OMe·HCl, iPr2NEt, DMF, RT, 66% over two
steps. Enantioselective synthesis: a) TMSCN, thiourea catalyst 45
(5 mol%), CF3CH2OH, CH2Cl2, ꢀ788C, then 2m HCl aq, 90%, 71% ee;
b) 1.25m HCl in MeOH, RT, 70%, 66% ee; c) TBDPSCl, Et3N, DMAP,
DMF, RT, 67%; d) LiOH, H2O, THF, 08C to RT; e) TBTU, H-l-Ser-
OMe·HCl, iPr2NEt, DMSO, RT, 42% over two steps, de 58%. TMS=tri-
methylsilyl, DMF=N,N-dimethylformamide.
Scheme 10. Synthesis of oxazole-5-carbaldehyde. a) TosMIC, K2CO3,
MeOH, reflux, 58%; b) Amberlyst-15, acetone, H2O, RT, quant; c)
TosMIC, DBU, CH2Cl2, 08C, 80%; d) NaBH4, LiCl, THF, MeOH, 08C to
RT, 65%; e) (COCl2), DMSO, NEt3, CH2Cl2, ꢀ78 to 08C, 56%. DBU=
1,8-diazabicyclo[5.4.0]undec-7-ene.
A
Unfortunately, during the course of these studies glyoxal
dimethyl acetal became unavailable commercially so we de-
cided to develop an alternative route to the aldehyde. By
the slow addition of ethyl glyoxylate 38 and DBU to a solu-
tion of TosMIC in CH2Cl2 at 08C, known oxazole 39[25,47,48]
was obtained in good yields, on scales up to 250 mmol. Ester
39 was then converted into aldehyde 37 via a reduction–oxi-
dation sequence. The best results for the reduction of ester
39 were obtained using NaBH4 and LiCl which gave alcohol
40 in 65% yield on a 50 mmol scale.[25] Several oxidation
conditions were attempted with Swern giving the best re-
sults, providing aldehyde 37 in moderate yields (56%), also
on a 24 mmol scale. [During the course of this work a simi-
lar route to 5-oxazole compounds from ethyl glyoxylate and
This approach had the potential to be rendered asymmet-
ric by using an enantioselective cyanide addition. A range of
catalysts were screened for the addition of TMSCN to alde-
hyde 37, however, initially the heterocyclic nature of the al-
dehyde led to poor ee values in all cases.[50] Careful re-opti-
misation of the reported reaction conditions using Jacob-
senꢁs thiourea catalyst 45,[51] involving the slow addition of a
solution of the TMSCN in CH2Cl2 to aldehyde 37 in pres-
ence of catalyst 45 over five minutes, gave (S)-cyanohydrin
41 with up to 78% ee in 89% yield.[52,53] Enantioenriched cy-
anohydrin 41 (71% ee) was converted into amide 25 with
minimal racemisation (58% de, Scheme 11). Conditions for
acidic methanolysis to form ester 42 had to be modified
(room temperature, 20 equivalents of HCl) to minimise the
loss of ee because heating the reaction to reflux or using a
higher concentration of acid resulted in completely racemic
material.[52] Protection as TBDPS-ether 43 and ester hydrol-
ysis under the conditions used above followed by amide cou-
pling in DMSO provided the desired amide 25 and the
minor diastereomer 44 was easily removed by flash chroma-
tography.
TosMIC was reported by Taylor.[48]
]
It was envisaged that the addition of cyanide to aldehyde
37, followed by hydrolysis would provide a facile route to
the desired acid. This was initially investigated under race-
mic conditions with the addition of trimethylsilylcyanide
under Lewis basic catalysis,[49] to afford cyanohydrin rac-41
in 92% yield (Scheme 11). Treating the cyanohydrin with
anhydrous HCl in methanol gave b-hydroxy ketone rac-42,
followed by TBDPS protection provided methyl ester rac-43
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Total Synthesis of Bengazoles A and B
FULL PAPER
Additionally, the C10-hydroxyl functionality was intro-
duced asymmetrically by an enantioselective oxidation of a-
unfunctionalised ester 47 (Scheme 12). The required sub-
strate was prepared by reacting alcohol 40 with thionyl chlo-
ride to provide oxazolyl methyl chloride 46 in good yield[54]
Scheme 13. Synthesis of bisoxazole 51 by oxazoline oxidation. a) DAST,
CH2Cl2, ꢀ788C; b) DBU, BrCCl3, CH2Cl2, ꢀ15 to 08C, 22% over two
steps, 59% ee.
Williams to give oxazole 51.[5a] The yields for this oxidation
were low, up to 40%, and in some cases the only isolated
product was TBDPS-OH. In addition, analysis of the isolat-
ed bisoxazole by chiral HPLC revealed a loss of enantiopur-
ity during this oxidation procedure (ee 80–86%).[60] Apply-
ing a sequential DAST cyclisation/oxidation from 25 gave
the desired bisoxazole 51 but in only 22% yield and 59%
ee.
A synthetic route to bisoxazole 51 that proceeded via en-
amide 52 would exploit the propensity of amide 25 to elimi-
nate water. Conditions to convert enamides to oxazole rings
have been reported by Shin,[61] involving NBS activation and
addition of methanol followed by cyclisation to the me-
thoxy-substituted oxazoline and elimination of methanol.
With this aim in mind, amide 44 was treated with mesyl
chloride, which, in the presence of triethylamine, rapidly
formed enamide ent-52 cleanly as a single enantiomer in ex-
cellent yield (Scheme 14).[60,62] Following Shinꢁs procedures,
treatment of enamide ent-52 with N-bromosuccinimide and
methanol, gave the desired bromide 53 in good yield. Cycli-
sation to give methoxy-substituted oxazoline 54 was per-
formed using caesium carbonate, however attempts to elimi-
nate methanol by heating ent-54 with CSA in toluene as re-
ported by Shin resulted only in decomposition. A range of
other conditions were investigated and methanol could be
successfully eliminated using DBU/TMSOTf, however, dis-
appointingly the resultant bisoxazole was found to be race-
mic.[60]
The advantage to the cyclisation in having the C7 position
fully substituted encouraged further investigation into this
route. Alternative hydroxyl nucleophiles were added in the
NBS step (iPrOH, BnOH, H2O).[63] Surprisingly, warming
bromide 56 (R=Bn) with caesiumcarbonate to performthe
cyclisation, resulted in the formation of the bisoxazole di-
rectly, in a one-pot cyclisation and elimination. However,
the isolated bisoxazole was again racemic rac-51; hence, less
harsh cyclisation/elimination conditions were required.
Given that racemisation was observed following heating
56 with caesiumcarbonate the cyclisation of methanol and
isopropanol derivatives was attempted under novel non-
basic conditions using silver oxide in DMF. Pleasingly, this
gave excellent yields of the cyclised products for both exam-
ples (53/55) at roomtemperature. Water was also added di-
rectly to give 57 in 57% yield, but the attempted cyclisation
in this case gave multiple by-products. Elimination occurred
Scheme 12. Approach to a-hydroxy ester 48 via an enantioselective oxi-
dation. a) SOCl2, hexane/CH2Cl2, reflux; b) NaCN, DMF, 708C, 75%,
over two steps; c) 2m HCl in MeOH, reflux, 73%; d) LHMDS, THF, ox-
aziridine 49, 64%.[56]
and reaction of the crude chloride with sodiumcyanide in
DMF gave nitrile 47 which was converted to the required
ester 48 by methanolysis. It was envisaged that the stereo-
chemistry could then be introduced by oxidation with a
chiral oxidant, such as Davis’ chiral oxaziridines.[55] Deproto-
nation of ester 48 with LiHMDS and exposure of the eno-
late to oxaziridine 49 gave hydroxy ester ent-42 in moderate
yield (64%) with a selectivity of 70% ee.[56] Variation of the
oxaziridine and base resulted in poorer selectivities, howev-
er, enhancement of the stereoinduction (82% ee, 33%
yield) was achieved when four equivalents of anhydrous
LiCl were added to the reaction mixture, possibly due to im-
proved control of the enolate geometry.[57,58]
Successful synthesis of central oxazole ring: With large
quantities of amide 25 in hand, the key challenge in this syn-
thesis was the mild construction of the central 2,4-substitut-
ed oxazole ring in the presence of the sensitive C10 stereo-
genic centre, and initial attempts involved cyclisation to oxa-
zoline 50 followed by oxidation (Scheme 13).
Synthesis of oxazoline 50 was originally attempted with
DAST, which was successful in the more functionalised
system. However, despite performing the cyclisation under a
variety of reaction conditions, only poor yields (up to 50%)
were obtained. Using Burgess reagent also resulted in poor
yields of oxazoline 50, with the dehydration product enam-
ide 52 being preferred. Furthermore, Mitsunobu conditions
resulted in epimerisation at the C10 position and heating
with molybdenum(IV) oxide gave no reaction.[59] Despite
extensive investigation, a scalable route to oxazoline 50 was
not established, however, the isolated oxazolines were sub-
jected to oxidation using the mild conditions reported by
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S. V. Ley et al.
Scheme 14. Attempts to form bisoxazole ent-51 fromenamide ent-52. a) MsCl, NEt3, CH2Cl2, 08C, 95%; b) NBS, ROH, THF, RT, R=Me, 89%; R=iPr,
51%; R=Bn, 36%; R=H, 57%; c) Ag2O, DMF, RT, R=Me, 97%; R=iPr, 95%; d) For R=Me, DBU, TMSOTf, 2,6-lutidine, CH2Cl2, RT, 42%; for
R=iPr, Cs2CO3, dioxane, 608C, 57% e) For R=Bn, Cs2CO3, dioxane, 608C, 47%; f) Br2, CH2Cl2, ꢀ788C, then NEt3, 75%. Ms=methanesulfonyl,
NBS=N-bromosuccinimide.
under the TMSOTf/DBU conditions for the methanol deriv-
ative but for the isopropanol example elimination could
only be achieved with Cs2CO3. However, in both cases the
bisoxazole product was again racemic!
In an attempt to form the bisbromide, which could result
in a one pot cyclisation and easier elimination, enamide ent-
52 was reacted with bromine (Scheme 14).[64] However, fol-
lowing the addition of triethylamine no cyclisation was ob-
served, instead, (E)-vinyl bromide 59 was formed in good
yield. Unfortunately, no cyclisation was observed on heating
vinyl bromide 59 with caesiumcarbonate, or silver oxide
and therefore another change of strategy was required to
obtain the bisoxazole unit as a single enantiomer.
Therefore, although a Robinson–Gabriel approach failed
on the more advanced amide 30, it was attempted on this re-
vised disconnection route (Scheme 15). Serine amide 25 was
converted to primary alcohol 60 in two steps and oxidation
using buffered Dess–Martin periodinane provided aldehyde
61 which was subjected to Robinson–Gabriel-type oxazole
formation under conditions reported by Panek and Bere-
sis,[65] similar to those described previously by Wipf et al.[6b]
Treating crude aldehyde 61 with triphenylphosphine, 2,6-di-
tert-butylpyridine and dibromotetrachloroethane in CH2Cl2
formed the intermediate bromooxazoline, from which HBr
was eliminated by the addition of DBU. This process provid-
ed the desired 2,4-disubstituted oxazole 62 in 72% yield
over the two steps. However, the product still displayed sig-
nificant racemisation (33–66% ee) at the crucial C10
centre.[60] With quantities of non-racemic material now avail-
able, the stability of the C10 stereochemistry could be tested
to the conditions employed in the oxazole formation. The
cause of the racemisation was identified as DBU, used to
eliminate the proposed bromooxazoline intermediate. How-
ever, it was found that treating bisoxazole 62 with triethyla-
mine did not result in any degradation of the stereochemis-
try.
Replacing DBU with triethylamine for the second stage
of the oxazole formation therefore completely prevented
this racemisation and in addition improved the yield over
the two steps fromalcohol 60 to an excellent 89%. Bisoxa-
zole 62 was thus obtained with >98% ee and the process
was amenable to scale-up.[66] We believe this to be a poten-
tially useful general modification for oxazole formation ad-
jacent to highly epimerisable stereogenic centres. Interest-
ingly, using NEt3 fromthe start of the reaction in place of
2,6-di-tert-butylpyridine again provided bisoxazole 62 as a
single enantiomer. However, these conditions gave a yield
of only 47%, which together with a reduced reaction time
and the fact that the bromooxazoline intermediate could not
be observed by TLC, suggests a different reaction pathway
could be operating.
In readiness for the 1,3-dipolar cycloaddition with alkene
7, enantiopure bisoxazole 62 was converted to oxime 33 as a
suitable precursor fromwhich to generate a nitrile oxide
(Scheme 15). Following TBS deprotection, treating alcohol
63 with Dess–Martin periodinane gave the aldehyde, which
was used crude to prevent any racemisation of the activated
system on silica gel. Oxime formation then gave the desired
bisoxazole-oxime 33 in excellent yield over the two steps as
a single enantiomer.[67]
Scheme 15. Synthesis of bisoxazole-oxime 33. a) 1) TBSCl, imidazole,
DMAP, DMF, RT, 90%; 2) NaBH4, LiCl, THF, MeOH, 08C to RT, 80%;
b) Dess–Martin periodinane, NaHCO3, CH2Cl2, 08C; c) PPh3, C2Br2Cl4,
CH2Cl2, 2,6-di-tert-butylpyridine, 08C, then Et3N, MeCN, 08C to RT,
89% over two steps, >98% ee; d) PPTS, MeOH, RT, 93%; e) 1) Dess–
Martin periodinane, NaHCO3, CH2Cl2, 08C; 2) NH2OH·HCl, K2CO3,
MeOH, H2O, RT, 93% over two steps; TBS=tert-butyldimethylsilyl.
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Total Synthesis of Bengazoles A and B
FULL PAPER
Nitrile oxide cycloaddition and synthesis of bengazole A:
Attempts to couple bisoxazole oxime 33 to alkene 7 using
the previously optimised conditions (using sodium hypo-
chlorite as the oxidant), resulted in a complex mixture of
diastereoisomers and by-products. Instead, the required ni-
trile oxide was generated fromoxime 33 in two stages to
allow for easier optimisation of the reaction conditions
(Scheme 16). Firstly, the oxime was chlorinated using N-
with boric acid (about 1m) gave b-hydroxy ketone 65 with
reproducible yields in the range 53–61%.
To formthe protected tetraol side chain, b-hydroxy
ketone 65 was reduced to the syn-diol using diethylmethoxy-
borane and sodiumborohydride (dr 14:1 by 1H NMR).[72]
Protection as isopropylidene acetal 32 gave an 89% yield of
the major diastereomer over the two steps and TBDPS de-
protection using TBAF in THF at 08C gave secondary alco-
hol 66 in quantitative yield.
Subsequent acylation using
myristoyl chloride with trie-
thylamine afforded acetal-pro-
tected bengazole A 67 in good
yield. The removal of residual
myristic acid (formed by an
aqueous quench of the excess
acid chloride) fromthe desired
product was extremely diffi-
cult, therefore, the reaction
was quenched with methanol
before an aqueous work-up
and the resulting ester was
easily separated by flash chro-
matography.
To complete the total syn-
thesis the BDA and acetonide
protecting groups were re-
Scheme 16. Synthesis of isoxazoline 3 and completion of the synthesis of bengazole A (1). a) 1) NCS, CH2Cl2,
pyridine, RT; 2) alkene 7, Cs2CO3, DME, RT, 77% over two steps (dr 7:2); b) TBAF, THF, 08C, 78%; c) myr-
istoyl chloride, NEt3, CH2Cl2, 08C, 73%; d) from 3: Raney Nickel, H2, B(OH)3, EtOH, H2O, 61%; e) 1)
Et2BOMe, NaBH4, THF, ꢀ788C (dr 14:1); 2) 2,2-dimethoxypropane, TsOH, 89% over two steps; f) TBAF,
THF, 08C, quant; g) From 66: myristoyl chloride, NEt3, CH2Cl2, 08C, 85%; h) TFA, H2O, RT, 95 %. NCS =N-
chlorosuccinimide, DME=1,2-dimethoxyethane, TsOH=toluene-4-sulfonic acid, TBAF=tetrabutylammoni-
umfluoride.
moved
simultaneously
by
treating 67 with TFA/water 2:1
for 10 minutes then adding
extra water to give a 1:1 TFA/
chlorosuccinimide with a catalytic amount of pyridine to
formthe chlorooxamic acid, which could then be converted
to the nitrile oxide in a separate step in the presence of
alkene 7.[68] The best results were obtained by adding caesi-
umcarbonate to a solution of the chlorooxamic acid in di-
methoxyethane in the presence of 10 equivalents of alkene
7. The resulting 1,3-dipolar cycloaddition provided isoxazo-
line 3 in a 60% yield of the major diastereoisomer. The
minor diastereoisomer (isolated in 17%) was easily separat-
ed by column chromatography and could be used in ana-
logue studies.[69]
Fromisoxazoline 3, the most rapid route to the natural
product would have involved installation of the myristate
ester to give 2, followed by unmasking of the tetraol side
chain (Scheme 16). Indeed, treatment of TBDPS-ether 3
with TBAF gave alcohol 64, which was acylated with myris-
toyl chloride to provide myristate ester 2 as a single stereo-
isomer but the cleavage of the isoxazoline was unsuccessful
at this stage. Several conditions were therefore tested for
the reductive cleavage of isoxazoline 3 with the TBDPS pro-
water mixture. Within one hour, complete conversion had
occurred and bengazole A 1 could be isolated cleanly and in
excellent yield by an aqueous workup followed by flash
chromatography. The data for our synthetic material was
consistent with those reported for the natural product and
NMR analysis confirmed our product to be a single C10
epimer.[10,15]
Synthesis of 10-epi-bengazole A: The ability to synthesise a
single stereoisomer of bengazole A will allow the impor-
tance of the C10 stereochemistry to the antifungal activity
to be investigated. To this end, amide 44, which contains un-
natural 10R stereochemistry and was available in large
quantities, was used as the starting point for the synthesis of
10-epi-bengazole A (Scheme 17). Amide 44 was converted
to alcohol 68 and the oxidation/Robinson–Gabriel proce-
dure provided bisoxazole ent-62 as a single stereoisomer,
which was then elaborated to the required oxime ent-33
under similar conditions to those employed for the natural
diastereomer.
tecting group still in place. All attempts to cleave isoxazo-
To formisoxazoline 69, the previously developed condi-
tions were again found to be optimal (Scheme 18). Using
oxime ent-33 a mixture of C4 epimers was obtained in good
yield (72%, dr 2.5:1), which were separated using flash
chromatography.[73] Performing the reductive cleavage of
isoxazoline 69 using Raney nickel gave yields of the b-hy-
[70]
line 3 using molybdenum complexes or SmI2
led to de-
composition of the substrate, however, reductive cleavage
using Raney-nickel and boric acid in ethanol/water gave b-
hydroxy ketone 65. The yield was strongly dependent on the
concentration of boric acid,[71] but using a solution saturated
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5523

S. V. Ley et al.
Indeed the most significant difference was the C1 protons,
which were marginally different for the two diastereoiso-
mers (dH 1.13/1.14 natural/10-epi). Molinski also reported a
difference for the C15 protons (dH =2.43/2.25 natural/10-
epi).[74] However, we observed that this signal in 10-epi-ben-
gazole A overlayed perfectly with that frombengazole A
(dH =2.43) and we propose that the signal at 2.25 ppmcould
be due to excess myristic acid inseparable from the benga-
zole products. This would fit with the apparent peak sizes in
Molinskiꢁs spectra. It is also worth noting that when benga-
zole A and 10-epi-bengazole A were both characterised by
NMR in CD3OD, a spontaneous loss of the myristate ester
was observed. Extra peaks that corresponded to deacylben-
gazole appeared,[18] as did a peak at 2.31 ppm, presumably
due to the methanolysis of the ester to give methyl myris-
tate.
Scheme 17. Synthesis of bisoxazole oxime ent-33. a) 1) TBSCl, imidazole,
DMAP, DMF, RT, 95%; 2) NaBH4, LiCl, THF, MeOH, 08C to RT, 77%;
b) 1) Dess–Martin periodinane, NaHCO3, CH2Cl2, 08C; 2) PPh3,
C2Br2Cl4, CH2Cl2, 2,6-di-tert-butylpyridine, 08C, then Et3N, MeCN, 08C
to RT, 75% over two steps, >98% ee; c) 1) PPTS, MeOH, RT, 96%; 2)
Dess–Martin periodinane, NaHCO3, CH2Cl2, 08C; 3) NH2OH·HCl,
K2CO3, MeOH, H2O, RT, 87% over two steps.
Synthesis of bengazole B: We
are also interested in the syn-
thesis of analogues containing
variations of the fatty acid at
the C10 position and the relat-
ed natural product, bengazole
B
(76)
was
prepared
(Scheme 19).[10] The required
acid chloride 74 was synthes-
ised fromknown fatty acid
73,[75] with quantitative conver-
1
sion (by H NMR) and used as
Scheme 18. Synthesis of 10-epi-bengazole A (72). a) 1) NCS, CH2Cl2, pyridine, RT; 2) alkene 7, Cs2CO3, DME,
RT, 72% over two steps (dr 2.4:1); b) 1) Raney Nickel, H2, B(OH)3, EtOH, H2O, 49–61%; 2) Et2BOMe,
NaBH4, THF, ꢀ788C, 93% (dr 17:1); 3) 2,2-dimethoxypropane, TsOH, 97%; c) 1) TBAF, THF, 08C, 96%; 2)
myristoyl chloride, NEt3, CH2Cl2, 08C, 90%; d) TFA, H2O, RT, 85 %.
a stock solution in CH2Cl2.
Treatment of secondary alco-
hol 66 with the acid chloride
solution gave acetal-protected
bengazole B 75 in good yield.
droxy ketone in the range 49–61% and syn-reduction to the
diol proceeded with good yield and diastereoselectivity. The
diol was protected as acetonide 70 in excellent yield, but the
minor C6 diastereoisomer could not be fully separated at
this stage. However, this minor product could be completely
removed over the subsequent two steps. Removal of the
TBPDS protecting group from 70 using TBAF gave the sec-
ondary alcohol and installation of the myristate ester gave
71. Removal of the BDA and acetonide protecting groups
using TFA/water afforded 10-epi-bengazole A 72 in excel-
lent yield and as a single stereoisomer.
The first synthesis of bengazole B 76 was completed in ex-
cellent yield by treatment of 75 with TFA/water under the
previously optimised conditions. Thus, it was demonstrated
that fromalcohol 66 alternative side chains could be readily
introduced and that this synthetic route could potentially be
used to synthesise bengazoles A to G or as a starting point
for analogue synthesis.
Conclusion
The NMR spectra of bengazole A and 10-epi-bengazole
Stereocontrolled total syntheses of bengazole A, 10-epi-ben-
gazole A and bengazole B have been successfully complet-
A are remarkably similar, as reported by Molinski.[15a]
Scheme 19. Synthesis of bengazole B 76. a) (COCl)2, CH2Cl2, DMF, RT, quant; b) acid chloride 74 in CH2Cl2, NEt3, CH2Cl2, 08C, 85%; c) TFA, H2O,
RT, 98 %.
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Total Synthesis of Bengazoles A and B
FULL PAPER
CH3), 16.7 (C1); IR (film): nmax = 2952, 1747, 1115s, 1036s cmꢀ1; HRMS
(ESI+): m/z: calcd for C11H20O6Na: 271.1158; found: 271.1151 [M+Na]+
; elemental analysis calcd (%) for C11H20O6 (248.3): C 53.21, H 8.12;
found: C 53.08, H 7.99.
ed. Our route was the first to provide to single stereoiso-
mers of the natural products whereby the sensitive C10 ste-
reochemistry was formed early in the synthesis and was pre-
served through formation of the central oxazole ring and on
to the natural product. Moreover our route reports a useful
modification for the Robinson–Gabriel oxazole synthesis
and features extensive use of the butane-2,3-diacetal (BDA)
to control various oxidation patterns within the natural
product. Biological testing of the natural products and rele-
vant intermediates is underway and will be reported in due
course.
BDA-aldehyde 15: DIBAL (1m in hexanes, 60 mL, 60 mmol) was added
dropwise to a solution of ester 10 (10.54 g, 42.09 mmol) in CH2Cl2
(350 mL) at ꢀ788C, via syringe pump over 2.5 h. The mixture was stirred
for a further 1.5h, then methanol (10 mL) was added dropwise at ꢀ788C.
The reaction mixture was warmed to RT then saturated aqueous Ro-
chelleꢁs salt (100 mL) and Et2O (80 mL) were added and the mixture
stirred overnight. Water (100 mL) was added and the layers separated.
The aqueous layer was extracted with Et2O (2”150 mL) and the com-
bined organic extracts were dried (MgSO4) and the solvent removed in
vacuo. Purification by flash chromatography (10 ! 20 ! 40% ethyl ace-
tate/PE) afforded aldehyde 15 as a white crystalline solid (7.89 g, 86%).
Rf = 0.63 (50% ethyl acetate/PE); m.p. 72–748C; [a]2D5 =+107.2 (c=1.6,
1
CHCl3); H NMR (400 MHz, CDCl3): d=9.64 (s, 1H; 4-H), 3.87 (m, 2H;
Experimental Section
2-H, 3-H), 3.29, 3.27 (2s, 2”3H; 2”OCH3), 1.38, 1.30 (2s, 2”3H; 2”
BDA CH3), 1.26 (d, J=5.8 Hz, 3H; 1-H3); 13C NMR (100 MHz, CDCl3):
d=199.8 (C4), 98.9, 98.6 (BDA Cq), 77.7 (C3), 63.1 (C2), 48.2, 48.1
(OCH3), 17.7, 17.3 (BDA CH3), 16.4 (C1); IR (film): nmax = 2951, 1738,
General methods: Solvents were freshly distilled before use. All non-
aqueous reactions were performed under an atmosphere of argon and
carried out using oven-dried glassware. PE = petroleumether (PE) b.p.
40–608C.
1120s, 1036, 908s, 727s cmꢀ1
; HRMS (ESI+): m/z: calcd for
C10H18O5Na: 241.1046; found: 241.1048 [M+Na]+; elemental analysis
Optical rotations were measured using a Perkin–Elmer Polarimeter 343
over a path length of 10 cm with the sample temperature maintained at
258C in the solvent indicated. Infrared spectra were recorded as thin
films on a Perkin–Elmer Spectrum One FT-IR spectrometer. 1H NMR
spectra were recorded at 278C (unless stated otherwise) on Bruker DPX-
400, Bruker DRX-500 (VT or Cryoprobe) and Bruker DPX-600 spec-
trometers. Residual protic solvent was used as the internal reference
(CHCl3 dH =7.27 ppm). 13C NMR spectra were recorded at 100 MHz,
125 MHz and 150 MHz on Bruker DPX-400, Bruker DRX-500 Cryop-
robe and Bruker DPX-600 spectrometers respectively. The resonance
CDCl3 (dc =77.0 ppm, t) was used as the internal reference. Assignments
were made using a range of NMR experiments and these assignments are
made according to the natural product numbering of bengazole A.[10]
Mass spectra were recorded on Waters LCT Premier, Bruker Daltronics
Bioapex II or Kratos Concept spectrometers. Melting points were per-
formed on a Reichert hot stage apparatus and are uncorrected. Flash
column chromatography was carried out using silica gel [Merck or Breck-
land (230–400 mesh)] under pressure. Biotage flash chromatography
refers to the use of an automated Biotage SP1 system. Collection was
monitored by UV absorption at 220 and 254 nm. All intermediates and
final compounds were stored under argon at ꢀ208C.
BDA-ester10 : A solution of methyl-(4S)-trans-2,2,5-trimethyl-1,3-dioxo-
lane-4-carboxylate (14; 10.0 g, 57.4 mmol), trimethyl orthoformate
(18.8 mL, 172 mmol), 2,3-butanedione (6 mL, 69 mmol) and camphorsul-
fonic acid (1.3 g, 5.7 mmol) in methanol (220 mL) was heated under
reflux for 21 h. On cooling to RT solid NaHCO3 (10 g, 120 mmol) was
added and the mixture stirred for 2 h then filtered. The filtrate was con-
centrated in vacuo, adsorbed onto silica gel (ꢁ150 mL) then loaded onto
a plug of silica gel and the crude product was eluted with ethyl acetate.
The solvent was removed in vacuo to leave an orange oil, as a 6:1 ratio
of fully anomerically stabilised to non-anomerically stabilised isomers 10/
11.
calcd (%) for C10H18O5 (218.3): C 55.03, H 8.31; found: C 54.89, H 8.24.
BDA-alkene 7: KHMDS (0.5m in toluene, 65 mL, 33.3 mmol) was added
to
34.5 mmol) in Et2O (200 mL) at RT. The solution was stirred at RT for
1.5 h then cooled to ꢀ788C. solution of aldehyde 15 (4.70 g,
a suspension of methyl triphenylphosphonium bromide (12.4 g,
A
21.6 mmol) in Et2O (30 mL) was added dropwise and the reaction mix-
ture was stirred at ꢀ788C for 2.5 h then allowed to warmto RT and
stirred for 3 h. The reaction mixture was filtered through a plug of silica
gel, eluting with Et2O (300 mL) and concentrated in vacuo. Purification
by flash chromatography (PE ! 10% Et2O/PE) afforded alkene 7 as a
colourless oil (4.66 g, quant.). Rf = 0.59 (50% Et2O/PE); [a]2D5 =+197.0
(c=0.75, CHCl3); 1H NMR (400 MHz, CDCl3): d=5.78 (ddd, J=17.3,
10.3, 7.4 Hz, 1H; 4-H), 5.38 (d, J=17.3 Hz, 1H; 5-Htrans), 5.26 (d, J=
10.3 Hz, 1H; 5-Hcis), 3.90 (dd, J=9.5, 7.4 Hz, 1H; 3-H), 3.69 (dq, J=9.5,
6.4 Hz, 1H; 2-H), 3.28, 3.27 (2s, 2”3H; 2”OCH3), 1.32, 1.31 (2s, 2”3H;
2”BDA CH3), 1.11 (d, J=6.4 Hz, 3H; 1-H3); 13C NMR (100 MHz,
CDCl3): d=134.4 (C4), 119.3 (C5), 98.8 (2”BDA Cq), 75.4 (C3), 67.0
(C2), 47.88, 47.84 (OCH3), 17.8, 17.7 (BDA CH3), 16.7 (C1); IR (film):
nmax = 2951, 1376, 1122s, 1039s cmꢀ1; HRMS (ESI+): m/z: calcd for
C11H20O4Na: 239.1259; found: 239.1258 [M+Na]+; elemental analysis
calcd (%) for C11H20O4 (216.3): C 61.09, H 9.32; found: C 61.01, H 9.28.
Cycloadduct 16: A solution of oxime 6 (37 mg, 0.133 mmol) in CH2Cl2
(3 mL) was added over 6 h to a mixture of alkene 7 (86 mg, 0.398 mmol),
triethylamine (2 mL, 0.013 mmol), and aqueous NaOCl (0.48 mL,
0.398 mmol) in CH2Cl2 (0.3 mL) at 08C. After the addition was complete,
the reaction mixture was stirred at 08C for 45 min before warming to RT.
The suspension was poured into a mixture of water (20 mL) and CH2Cl2
(20 mL). The aqueous layer was extracted with CH2Cl2 (2”20 mL) and
the combined organics were dried over Na2SO4, filtered, and concentrat-
ed in vacuo. The residue was purified by flash chromatography on silica
gel (10 ! 15 ! 20% ethyl acetate/PE) to afford the major cycloadduct
16 (45 mg, 69%) and minor cycloadduct 16a (11 mg, 17%). Major
isomer 16: [a]2D5 =ꢀ62.4 (c=0.5, CHCl3); 1H NMR (400 MHz,
[D8]toluene, 608C): d=7.18–6.95 (m, Cbz Ph-H, 5H; buried under tolu-
ene peaks), 5.08 (d, J=12.2, 1H; Cbz PhCH2), 4.89 (d, J=12.4 Hz, 1H;
Cbz PhCH2), 4.62 (dd, J=2.3, 6.5 Hz, 1H; 7-H), 4.16 (ddd, J=4.5, 6.3,
9.0 Hz, 1H; 4-H), 3.77 (m, 1H; 8-H), 3.67 (dd, J=6.7, 9.1 Hz, 1H; 8-H),
3.58 (dd, J=4.5, 9.7 Hz, 1H; 3-H), 3.48 (dq, J=6.3, 9.7 Hz, 1H; 2-H),
3.06 (s, 3H; BDA OCH3), 3.06–2.98 (m, 1H; 5-H), 2.98 (s, 3H; BDA
OCH3), 2.51 (m, 1H; 5-H), 1.60, 1.39 (2s, 2”3H; 2”acetal CH3), 1.18,
1.16 (2s, 2”3H; 2”BDA CH3), 1.04 (d, J=6.3 Hz, 3H; 1-H3); 13C NMR
(100 MHz, [D8]toluene, 608C): d=157.1 (Cbz C=O), 151.9 (C6), 136.7
(Ph Cq), Ph-H obscured by toluene peaks, 98.5, 98.4 (BDA Cq), 94.6
(acetal Cq), 79.5 (C4), 73.5 (C3), 66.6 (C8), 66.5 (PhCH2), 65.5 (C2), 54.7
(C7), 47.2, 47.0 (BDA OCH3), 34.7 (C5), 25.7, 23.3 (acetal CH3), 17.2,
The crude product was dissolved in CH2Cl2 (125 mL) and BF3·THF
(1.26 mL, 11.4 mmol) was added dropwise at RT. The brown solution was
stirred for a total of 10 d adding further aliquots of BF3·THF (1.26 mL,
11.4 mmol) after 2 and 6 d. The reaction was quenched by the dropwise
addition of triethylamine (8 mL) and the mixture was concentrated under
reduced pressure. The residue was filtered through a plug of silica gel
(50% Et2O/PE) and the solvent removed in vacuo. Purification by flash
chromatography (35% Et2O/PE) afforded ester 10 as an orange oil
(11.77 g, 83%). Rf = 0.34 (30% ethyl acetate/PE); [a]2D5 =+140.7 (c=
1
1.25, CHCl3); H NMR (400 MHz, CDCl3): d=4.10 (d, J=9.8 Hz, 1H; 3-
H), 3.99 (dq, J=9.8, 6.3 Hz, 1H; 2-H), 3.77 (s, 3H; OCH3), 3.29, 3.26,
1.35, 1.29 (4s, 4”3H; 4”BDA CH3), 1.18 (d, J=6.3 Hz, 3H; 1-H3);
13C NMR (100 MHz, CDCl3): d=169.4 (C4), 98.9, 98.7 (BDA Cq), 73.8
(C3), 64.9 (C2), 52.2 (OCH3), 48.2, 47.9 (BDA OCH3), 17.7, 17.3 (BDA
Chem. Eur. J. 2007, 13, 5515 – 5538
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5525

S. V. Ley et al.
17.1 (BDA CH3), 16.6 (C1); IR (film): nmax = 2942, 1708s, 1125s cmꢀ1
HRMS (ESI+): m/z: calcd for C25H36N2O8Na: 515.2369; found: 515.2346
[M+Na]+.
;
by flash chromatography on silica (10% ethyl acetate in hexanes) to give
ester 20 (653 mg, 97%) as a colourless oil. [a]2D5 =+40.7 (c=1.6, CHCl3);
1H NMR (400 MHz, CHCl3): d=7.83 (s, 1H; 13-H), 7.11 (s, 1H; 12-H),
5.98 (dd, J=6.0, 6.0 Hz, 1H; 10-H), 3.99 (dd, J=6.5, 10.8 Hz, 1H; 9-H),
3.95 (dd, J=5.6, 10.8 Hz, 1H; 9-H), 2.33 (t, J=7.5, 2H; 15-H2), 1.63–1.60
(m, 2H; 16-H2), 1.25 (m, 20H; 17-H to 26-H), 0.93 (t, J=7.9 Hz, 9H,
TES CH3), 0.88 (t, J=7.0, 3H; 27-H), 0.59 (q, J=7.9 Hz, 6H; TES CH2);
13C NMR (100 MHz, CHCl3): d=173.1 (C14), 151.3 (C11), 148.7 (C13),
126.1 (C12), 67.5 (C10), 63.0 (C9), 34.5, 32.3, 30.5–25.2, 23.1 (myristoyl
C14 to C26), 14.5 (C27), 7.0 (TES CH3), 4.7 (TES CH2); IR (film): nmax
Amine 5: Pd(OH)2/C (5 mg of 20% by wt Pd, 9 mmol) was added to a so-
lution of isoxazoline 16 (24.0 mg, 49 mmol) in methanol (1 mL) and acetic
acid (1 drop). The mixture was stirred at RT under a hydrogen atmos-
phere for 15 min then filtered through Celite, eluting with methanol and
the solvent removed in vacuo. Purification by flash chromatography
(CHCl3/methanol/aq. NH4OH 30:1:0.1) afforded amine 5 (12 mg, 77%)
as a colourless oil. [a]D25 =+17.5 (c=0.6, CHCl3); 1H NMR (400 MHz,
CHCl3): d=4.54 (ddd, J=4.5, 6.9, 10.7 Hz, 1H; 4-H), 3.78–3.58 (m, 5H;
2-H, 3-H, 7-H, 8-H2), 3.25 (s, 3H; BDA OCH3), 3.23 (s, 3H; OCH3), 3.23
(dd, J=6.9, 17.0 Hz, 1H; 5-H), 2.97 (dd, J=10.8, 17.0 Hz, 1H; 5-H), 1.27,
1.25 (2s, 2”3H; 2”BDA CH3), 1.21 (d, J=5.8, 3H; 1-H3); 13C NMR
(100 MHz, CHCl3): d=160.3 (C6), 98.6, 98.6 (BDA Cq), 94.6 (acetal Cq),
79.5 (C4), 73.4 (C3), 65.8 (C2), 65.2 (C8), 51.3 (C7), 48.0, 47.9 (BDA
OCH3), 35.8 (C5), 17.6, 17.4 (BDA CH3), 17.0 (C1); IR (film): nmax
=
2923, 1744s, 1108s cmꢀ1
;
HRMS (ESI+): m/z: calcd for
C25H47NO4Na: 476.3172; found: 476.3160 [M+Na]+.
Acid 4: KF (13 mg, 0.225 mmol) and 8n Jonesꢁ reagent (78 mL, 700 mL
per mmol alcohol) were added at 08C to a solution of TES-ether 20
(51 mg, 0.112 mmol) in acetone (0.8 mL). The reaction mixture was
stirred at 08C for 4 h. The crude mixture was purified by loading the neat
reaction mixture onto a silica gel column and chromatographing (ethyl
acetate/methanol/acetone/water 17:1:1:1 ! 12:1:1:1) to give the unstable
acid 4 (30 mg, 76%) as a waxy white solid. [a]2D5 =+30 (c=0.6, CHCl3);
1H NMR (400 MHz, [D6]DMSO): d=8.26 (s, 1H; 13-H), 7.09 (s, 1H; 12-
H), 5.80 (s, 1H; 10-H), 2.23 (t, J=7.3, 2H; 15-H2), 1.52–1.47 (m, 2H; 16-
H2), 1.22 (m, 20H; 17-H to 26-H), 0.84 (t, J=6.4, 3H; 27-H); 13C NMR
(100 MHz, [D6]DMSO): d=172.3 (C14), 167.0 (C9), 158.3 (C11), 152.2
(C13), 125.6 (C12), 67.7 (C10), 31.7, 29.5, 30.5, 29.5, 29.5, 29.4, 29.3, 29.2,
29.1, 28.9, 25.2, 23.1 (C15 to C26), 14.4 (C27); IR (film): nmax = 3443sbr,
=3361wbr, 2948, 1123s cmꢀ1
; HRMS (ESI+): m/z: calcd for
C14H26N2O6Na: 341.1689; found: 341.1689 [M+Na]+.
Compound 18: K2CO3 (7.60 g, 55.1 mmol) and tosylmethyl isocyanide
(3.79 g, 19.4 mmol) were added portionwise to a solution of BDA-pro-
tected glyderaldehyde 17 (3.30 g, 16.2 mmol) in anhydrous methanol
(30 mL). The suspension was heated to reflux for 2 h then cooled to RT
and water (150 mL) was added. The mixture was extracted with CH2Cl2
(3”100 mL) and the combined organics were dried (Na2SO4) and con-
centrated in vacuo. The residue was purified by flash chromatography on
silica (5% acetone in CH2Cl2) to give the oxazole 18 (3.94 g, 82%) as a
white solid. [a]2D5 =ꢀ155.0 (c=1.2, CHCl3); m.p. 928C; 1H NMR
(400 MHz, CDCl3): d=7.85 (s, 1H; 13-H), 7.08 (s, 1H; 12-H), 5.06 (dd,
J=3.2, 11.3 Hz, 1H; 10-H), 4.03 (dd, J=11.3, 11.3 Hz, 1H; 9-Hax), 3.61
(dd, J=3.3, 11.2 Hz, 1H; 9-Heq), 3.35, 3.32, 1.35, 1.33 (4s, 4”3H; 4”
BDA OCH3); 13C NMR (100 MHz, CDCl3): d=151.2 (C11), 148.4 (C13),
124.6 (C12), 99.7, 98.1 (BDA Cq), 62.0 (C10), 60.9 (C9), 48.3, 48.2 (BDA
2923, 1684s, 1640s, 1209s, 1140s cmꢀ1
.
Compound 23: Triethylamine (0.78 mL, 5.6 mmol), TBDPSCl (1.3 mL,
5.15 mmol) and DMAP (630 mg, 5.15 mmol) were added under argon to
a solution of alcohol 19 (1.14 g, 4.68 mmol) in anhydrous DMF (15 mL).
The reaction mixture was stirred at RT for 24 h. Water (5 mL) was added
to quench, and the crude mixture was poured into water (50 mL) and
CH2Cl2 (50 mL). The aqueous layer was extracted with CH2Cl2 (3”
50 mL. The combined organics were dried over Na2SO4, filtered, and con-
centrated in vacuo. The residue was filtered through a plug of silica
(10% ethyl acetate/hexanes) to give the crude silylated-diol 22.
OCH3), 17.7, 17.5 (BDA CH3); IR (film): nmax
= 2950, 1375, 1142s,
1119s, 1037 cmꢀ1
; HRMS (ESI+): m/z: calcd for C11H17NO5Na:
266.1004; found: 266.1001 [M+Na]+.
PPTS (590 mg, 2.34 mmol) was added under argon to a solution of 22 in
anhydrous methanol (20 mL). The reaction mixture was stirred at RT for
15 minutes and quenched by pouring into water (100 mL). This was ex-
tracted with CH2Cl2 (3”100 mL). The combined organics were dried
over Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
fied by flash chromatography on silica (40 ! 50% ethyl acetate/PE) to
give alcohol 23 (1.66 g, 97% over 2 steps) as a colourless oil. [a]2D5 =+
73.6 (c=0.5, CHCl3); 1H NMR (400 MHz, CDCl3): d=7.69 (s, 1H; 13-
H), 7.69–7.67 (m, 2H; Ph-H), 7.54–7.52 (m, 2H; Ph-H), 7.48–7.30 (m,
6H; Ph-H), 6.78 (s, 1H; 12-H), 4.86 (dd, J=5.2, 5.2 Hz, 1H; 10-H), 3.85
(ddd, J=6.1, 6.1, 11.4 Hz, 1H; 9-H), 3.74 (ddd, J=4.7, 6.7, 11.3 Hz, 1H;
9-H), 1.99 (dd, J=6.6, 6.6 Hz, 1H; OH), 1.07 (s, 9H, TBDPS CH3);
13C NMR (100 MHz, CDCl3): d=151.0 (C11), 150.5 (C13), 135.7, 135.6
(Ph-C), 130.1 (Ph-H C), 130.9 (Ph Cq), 127.9, 127.7 (Ph-C), 124.4 (C12),
68.1 (C10), 65.4 (C9), 26.8 (TBDPS CH3), 19.3 (TBDPS tBu Cq); IR
(film): nmax = 3339br, 2858, 1104s cmꢀ1; HRMS (ESI+): m/z: calcd for
C21H25NO3SiNa; 390.1501; found: 390.1494.
Compound 19: A solution of oxazole 18 (160 mg, 0.66 mmol) in TFA/
water 4:1 (16 mL) was stirred at room temperature for 20 min. The sol-
vent was removed in vacuo and the residue redissolved in methanol. To
this solution was added triethylamine dropwise until the solution reached
basic pH, and the solvent was removed in vacuo. The residue was dis-
solved in anhydrous CH2Cl2 (10 mL) and placed under an atmosphere of
argon. To this solution was added Hünigꢁs base (228 mL, 1.32 mmol) and
DMAP (5 mg, cat.). The reaction mixture was cooled to ꢀ788C and
chlorotriethylsilane (110 mL, 0.66 mmol) was added dropwise. After 15
minutes, another 10 mL of chlorotriethylsilane was added. The reaction
mixture was quenched at ꢀ788C with saturated aqueous ammoniom
chloride (15 mL) and was warmed to room temperature. The aqueous
layer was extracted with CH2Cl2 (3”20 mL), dried (Na2SO4), and concen-
trated in vacuo. The residue was purified by flash chromatography on
silica (5 ! 10% acetone in CH2Cl2) to give TES-ether 19 (151 mg, 94%)
as a colourless oil. [a]D25 =+16.0 (c=1.0, CHCl3); 1H NMR (400 MHz,
CHCl3): d=7.82 (s, 1H; 13-H), 7.05 (s, 1H; 12-H), 4.85–4.81 (m, 1H; 10-
H), 3.89 (dd, J=4.1, 10.1 Hz, 1H; 9-H), 3.83 (dd, J=4.1, 10.1 Hz, 1H; 9-
H), 3.03 (brs, 1H; OH), 0.95 (t, J=7.9 Hz, 9H, TES CH3), 0.35 (q, J=
7.8 Hz, 6H; TES CH2); 13C NMR (100 MHz, CHCl3): d=151.2 (C11),
150.6 (C13), 123.8 (C12), 66.7 (C10), 64.9 (C9), 6.6 (TES CH3), 4.3 (TES
CH2); IR (film): nmax = 3311br, 2876, 1113s cmꢀ1; HRMS (ESI+): m/z:
calcd for C11H21NO3Na: 266.1188; found: 266.1177 [M+Na]+.
Acid 24: 8n Jones’ reagent (0.61 mL, 0.7 mL per mmol) was added at
08C under argon to a solution of alcohol 23 (320 mg, 0.872 mmol) in re-
agent-grade acetone (5 mL). The resulting bright red solution was stirred
at 08C for 1 h then warmed to RT and stirred for another 2 h. The crude
reaction mixture was then filtered through a pad of Celite, rinsing with
acetone (100 mL). The filtrate was concentrated in vacuo, and the residue
was purified by flash chromatography on silica gel (ethyl acetate/acetone/
methanol/water 97:1:1:1 ! 47:1:1:1 ! 17:1:1:1) to give unstable acid 24
Ester20 : DCC (1.64 mL of a 1m solution in CH2Cl2, 1.64 mmol), DMAP
(5 mg, cat.) and myristic acid (375 mg, 1.64 mmol) were added to a solu-
tion of alcohol 19 (363 mg, 1.49 mmol) in anhydrous CH2Cl2 (15 mL).
The reaction mixture was stirred at room temperature for 3 h. To precipi-
tate out DCC residue, hexanes (50 mL) was added and the reaction mix-
ture was filtered. The filtrate was extracted with saturated aqueous am-
monium chloride (50 mL), and the aqueous layer was back extracted
with ethyl acetate (2”50 mL). The combined organics were dried
(Na2SO4), filtered, and concentrated in vacuo. The residue was purified
1
(163 mg, 49%) as a colourless oil. H NMR (400 MHz, CD3OD): d=8.02
(s, 1H; 13-H), 7.75–7.73 (m, 2H; Ph-H), 7.57–7.55 (m, 2H; Ph-H), 7.43–
7.29 (m, 6H; Ph-H), 6.70 (s, 1H; 12-H), 5.11 (s, 1H; 10-H), 1.06 (s, 9H,
TBDPS tBu CH3); 13C NMR (125 MHz, CD3OD): d=175.2 (C9), 152.2
(C11), 151.1 (C13), 135.6, 135.4 (Ph-C), 133.1, 132.9 (Ph Cq), 129.6, 129.5,
127.3 and 127.2 (Ph-C), 123.0 (C12), 68.6 (C10), 25.9 (TBDPS CH3), 18.8
(TBDPS Cq); IR (film): nmax =2932, 1744s, 1112s cmꢀ1; HRMS (ESI+):
m/z: calcd for C21H23NO4SiNa: 404.1294; found: 404.1286 [M+Na]+.
5526
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 5515 – 5538

Total Synthesis of Bengazoles A and B
FULL PAPER
Isoxazoline-containing amide 26: Amine 5 (12 mg, 0.038 mmol) as a solu-
tion in DMSO (1 mL) was added under argon to a solution of acid 24
(13 mg, 0.034 mmol) in anhydrous DMSO (1 mL). To this solution was
added TBTU (12 mg, 0.038 mmol), and the reaction mixture was stirred
at RT for 4 h. Another portion of TBTU (2 mg, 0.006 mmol) was added,
and the reaction mixture was stirred for an additional 12 h. Water (1 mL)
was added to the reaction mixture to quench, and the resulting suspen-
sion was poured into ethyl acetate (10 mL) and water (10 mL). The aque-
ous layer was extracted with ethyl acetate (2”10 mL). The combined or-
ganics were dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel (60% ethyl
acetate/PE ! 100% ethyl acetate) to afford amide 26 (15 mg, 65%) as a
colourless oil. [a]2D5 =+7.9 (c=0.8, CHCl3); 1H NMR (600 MHz, CDCl3):
d=8.02 (d, J=7.5 Hz, 1H; amide NH), 7.70 (s, 1H; 13-H), 7.64–7.63 (m,
2H; Ph-H), 7.49–7.40 (m, 6H; Ph-H), 7.31 (dd, J=7.7, 7.3 Hz, 2H, Ph-
H), 6.61 (s, 1H; 12-H), 5.20 (s, 1H; 10-H), 4.81 (ddd, 3.5, 3.5, 7.6 Hz, 1H;
7-H), 4.57 (ddd, J=4.3, 7.7, 10.8 Hz, 1H; 4-H), 4.02 (ddd, J=3.4, 4.9,
11.7 Hz, 1H; 8-H), 3.90 (ddd, J=3.6, 8.4, 11.7 Hz, 1H; 8-H), 3.68–3.62
(m, 1H; 2-H), 3.68–3.62 (m, 1H; 3-H), 3.25, 3.22 (2s, 2”3H; 2”BDA
OCH3), 3.14 (dd, J=7.2, 17.0 Hz, 1H; 5-H), 2.93 (dd, J=10.7, 17.1 Hz,
1H; 5-H), 2.67 (dd, J=5.0, 8.4 Hz, 1H; OH), 1.29, 1.26 (2s, 2”3H; 2”
BDA CH3), 1.23 (d, J=5.9 Hz, 3H; 1-H3), 1.09 (s, 9H, TBDPS CH3);
13C NMR (150 MHz, CDCl3): d=169.0 (C9), 157.1 (C6), 150.9 (C13),
148.5 (C11), 135.6, 135.4 (Ph-C), 131.5, 131.4 (Ph Cq), 130.5, 130.3, 128.1
and 127.8 (Ph-C), 126.0 (C12), 98.7, 98.6 (BDA Cq), 80.0 (C4), 73.3 (C2),
68.1 (C10), 65.7 (C3), 64.1 (C8), 49.9 (C7), 48.0, 47.9 (BDA OCH3), 36.5
(C5), 26.7 (TBDPS CH3), 19.2 (TBDPS tBu Cq), 17.6, 17.4 (BDA CH3),
17.0 (C1); IR (film): nmax = 3486, 2947, 1691, 1507, 1122s cmꢀ1; HRMS
(ESI+): m/z: calcd for C35H47N3O9SiNa: 704.2979; found: 704.2988
[M+Na]+.
3-H), 3.25, 3.23 (2s, 2”3H; 2”BDA OCH3), 2.87–2.77 (m, 2H; 5-H2),
1.69, 1.55 (2s, 2”3H; 2”acetal CH3), 1.27, 1.24 (2s, 2”3H; 2”BDA
CH3), 1.15 (d, J=6.0 Hz, 3H; 1-H3); 13C NMR (125 MHz, CD3NO2,
808C): d=207.7 (C6), 152.5 (Cbz C=O), 136.9 (Ph Cq), 128.4, 127.9 (Cbz
Ph-H), 127.7 (Ph-C), 98.8, 98.6 (BDA Cq), 95.2 (acetal Cq), 75.8 (C3),
67.3 (C4), 66.8 (PhCH2), 65.7 (C2), 65.7 (C7), 65.1 (C8), 46.9, 46.8 (BDA
OCH3), 41.5 (C5), 24.7, 23.3 (acetal CH3), 16.8, 16.6 (BDA CH3), 16.3
(C1); IR (film): nmax = 3526wbr, 2941, 1711s, 1127s cmꢀ1; HRMS (ESI+):
m/z: calcd for C25H37NO9Na: 518.2366; found: 518.2339 [M+Na]+.
NaBH4 (13 mg, 0.345 mmol) was added under argon at 08C to a solution
of the b-hydroxy ketone (34 mg, 0.069 mmol) in methanol (2 mL). The
reaction mixture was stirred at 08C for 1 h before quenching with saturat-
ed aqueous NH4Cl (1 mL). This suspension was warmed to RT, poured
into water (10 mL), and then extracted with Et2O (3”10 mL). The com-
bined organics were dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by flash chromatography on silica gel
(40% ethyl acetate/PE) to afford diol 28 (29.5 mg, 88%), the major dia-
stereomer, as a colourless oil. [a]2D5 =+55.5 (c=1.4, CHCl3); 1H NMR
(500 MHz, CD3NO2, 808C): d=7.46–7.32 (m, 5H; Cbz Ph-H), 5.19 (m,
2H; Cbz PhCH2), 4.21–4.15 (m, 1H; 6-H), 4.12–4.08 (m, 1H; 8-H), 4.12–
4.06 (m, 1H; 7-H), 4.02 (dd, J=6.3, 9.1 Hz, 1H; 8-H), 3.86–3.80 (m, 1H;
4-H), 3.75 (dq, J=6.6, 10.5 Hz, 1H; 2-H), 3.49 (dd, J=4.1, 9.5 Hz, 1H; 3-
H), 3.26, 3.23 (2s, 2”3H; 2”BDA OCH3), 2.00–1.94 (m, 1H; 5-H), 1.65–
1.60 (m, 1H; 5-H), 1.63, 1.52 (2s, 2”3H; 2”acetal CH3), 1.27, 1.23 (2s,
2”3H; 2”BDA CH3), 1.14 (d, J=6.6 Hz, 3H; 1-H3); 13C NMR
(125 MHz, CD3NO2, 808C): d=153.8 (Cbz C=O), 137.2 (Ph Cq), 128.4
(Cbz Ph-H), 127.8 (Cbz Ph-H), 127.7 (Ph-C), 98.8, 98.6 (BDA Cq), 94.5
(acetal Cq), 76.2 (C3), 71.8 (C4), 71.6 (C6), 70.3 (PhCH2), 66.6 (C2), 65.6
(C8), 59.8 (C7), 46.9, 46.7 (BDA OCH3), 33.5 (C5), 25.6, 22.6 (acetal
CH3), 16.7, 16.6 (BDA CH3), 16.2 (C1); IR (film):nmax = 3424wbr, 2938,
Oxazoline 27: DAST (2 mL, 11 mmol) was added at ꢀ788C under argon
to a solution of amide 26 (6.7 mg, 9.8 mmol) in anhydrous CH2Cl2 (1 mL).
The reaction mixture was stirred at ꢀ788C for 30 min. Anhydrous K2CO3
(2 mg) was added to quench, and the mixture was allowed to warm to
RT with stirring. The reaction mixture was poured into aqueous NaHCO3
(5 mL) and extracted with CH2Cl2 (3”10 mL). The combined organics
were dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by flash chromatography on silica gel (40 ! 50% ethyl ace-
tate/PE) to give oxazoline 27 (5.9 mg, 91%) as a colourless oil. [a]2D5 =+
29.0 (c=0.1, CHCl3); 1H NMR (600 MHz, CDCl3): d=7.80 (s, 1H; 13-
H), 7.68 (d, J=6.8 Hz, 2H; Ph-H), 7.56 (d, J=7.0 Hz, 2H; Ph-H), 7.49–
7.38 (m, 4H; Ph-H), 7.35 (dd, J=7.4, 7.5 Hz, 2H; Ph-H), 6.93 (s, 1H; 12-
H), 5.50 (s, 1H; 10-H), 4.95 (dd, J=9.4, 9.4 Hz, 1H; 7-H), 4.53 (ddd, J=
5.4, 7.8, 10.8 Hz, 1H; 4-H), 4.40 (d, J=9.4 Hz, 1H; 8-H), 4.40 (d, J=
9.4 Hz, 1H; 8-H), 3.64 (dq, J=6.1, 9.7 Hz, 1H; 2-H), 3.55 (dd, J=5.3,
9.7 Hz, 1H; 3-H), 3.24, 3.17 (2s, 2”3H; 2”BDA OCH3), 3.10 (dd, J=
7.7, 17.2 Hz, 1H; 5-H), 2.81 (dd, J=10.8, 17.3 Hz, 1H; 5-H), 1.29 (s, 3H;
BDA CH3), 1.24 (d, J=6.5 Hz, 3H; 1-H3), 1.22 (s, 3H; BDA CH3), 1.07
(s, 9H; TBDPS CH3); 13C NMR (150 MHz, CDCl3): d=166.6 (C9), 157.7
(C6), 151.1 (C13), 149.0 (C11), 135.5 (Ph-C), 135.6 (TBPDS Ph-H),
132.127, 132.0 (Ph Cq), 130.2, 130.1, 127.8 and 127.8 (Ph-C), 125.0 (C12),
98.6, 98.6 (BDA Cq), 80.2 (C4), 73.1 (C3), 70.0 (C8), 66.1 (C2), 63.7
(C10), 63.5 (C7), 48.0, 47.9 (BDA OCH3), 35.4 (C5), 26.6 (TBDPS CH3),
1704s, 1128s cmꢀ1
; HRMS (ESI+): m/z: calcd for C25H39NO9Na:
520.2523; found: 520.2536 [M+Na]+.
Amine 29: 2,2-Dimethoxypropane (57 mL, 0.46 mmol) and a catalytic
amount of p-toluenesulfonic acid (<1 mg) was added under argon at RT
to a solution of diol 28 (23 mg, 0.046 mmol) in acetone (0.5 mL). The re-
action mixture was stirred at RT for 15 min before quenching with satu-
rated aqueous NaHCO3 (1 mL). This mixture was diluted with Et2O
(10 mL) and poured into saturated aqueous NaHCO3 (10 mL). The aque-
ous layer was extracted with Et2O (2”10 mL). The combined organics
were dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by flash chromatography on silica gel (10% ethyl acetate/
hexanes) to afford acetonide protected diol (21.7 mg, 88%) as a colour-
less oil. [a]2D5 =+30.8 (c=1.3, CHCl3); 1H NMR (500 MHz, CD3NO2,
808C): d=7.44–7.33 (m, 5H; Cbz Ph-H), 5.19 (d, J=12.5 Hz, 1H; Cbz
PhCH2), 5.12 (d, J=12.5 Hz, 1H; Cbz PhCH2), 4.35 (m, 1H; 6-H), 4.13
(dd, J=1.2, 9.4 Hz, 1H; 8-H), 4.06–4.04 (m, 1H; 7-H), 3.96 (dd, J=6.5,
9.3 Hz, 1H; 8-H), 3.85–3.82 (m, 1H; 4-H), 3.72 (dq, J=6.4, 9.4 Hz, 1H;
2-H), 3.32 (dd, J=6.4, 9.5 Hz, 1H; 3-H), 3.24, 3.23 (2s, 2”3H; 2”BDA
OCH3), 1.72 (ddd, J=2.5, 2.5, 13.1 Hz, 1H, 5-Heq), 1.61, 1.49 (2s, 2”3H;
2”NO acetal CH3), 1.44–1.40 (m, 1H; 5-Hax), 1.42 (s, 3H; acetonide
CH3), 1.33 (s, 3H; acetonide CH3), 1.24, 1.22 (2s, 2”3H; 2”BDA CH3),
1.16 (d, J=6.4 Hz, 3H; 1-H3); 13C NMR (125 MHz, CD3NO2, 808C): d=
153.8 (Cbz C=O), 137.3 (Ph Cq), 128.4, 127.6 (Cbz Ph-H), 127.7 (Ph-C),
98.6, 98.5 (BDA Cq), 98.4 (acetonide Cq), 94.3 (NO acetal Cq), 75.0 (C3),
69.9 (C4), 68.2 (C6), 67.2 (C2), 66.4 (PhCH2), 63.4 (C8), 59.6 (C7), 46.8,
46.6 (BDA OCH3), 29.0 (acetonide CH3), 27.3 (C5), 25.1, 22.4 (NO acetal
CH3), 18.8 (acetonide CH3), 16.8, 16.7 (BDA CH3), 16.6 (C1); IR (film):
19.3 (TBDPS tBu Cq), 17.6, 17.4 (BDA CH3), 17.0 (C1); IR (film): nmax
=
2931s, 1120s cmꢀ1; HRMS (ESI+): m/z: calcd for C35H45N3O8SiNa:
686.2874; found: 686.2870 [M+Na]+.
Diol 28: [Mo(CO)3(MeCN)3] (443 mg, 1.46 mmol) was added to a solu-
G
tion of isoxazoline 16 (360 mg, 0.73 mmol) in acetonitrile/water 3:1
(20 mL) and the resulting orange/brown slurry stirred for 1 h. Silica gel
(ca. 30 mL) was added and the solvent removed in vacuo. The residue
was loaded onto a pad of silica and eluted with EtOAc (500 mL). The
solvent was removed under reduced pressure to give a brown gum which
was purified by flash chromatography on silica gel (Biotage, 40M car-
tridge, PhMe/EtOAc 9:1 ! 4:6) to afford the b-hydroxy ketone as a col-
ourless gum (272 mg, 0.55 mmol, 75%). [a]2D5 =+64.0 (c=0.2, CHCl3);
1H NMR (500 MHz, CD3NO2, 808C): d=7.44–7.32 (m, 5H; Cbz Ph-H),
5.15 (m, 2H; Cbz PhCH2), 4.60 (dd, J=2.8, 7.5 Hz, 1H; 7-H), 4.25 (dd,
J=9.1, 8.2 Hz, 1H; 8-H), 4.09–4.02 (m, 1H; 4-H), 4.06 (dd, J=2.8,
9.1 Hz, 1H; 8-H), 3.69–3.61 (m, 1H; 2-H), 3.49 (dd, J=4.4, 9.8 Hz, 1H;
nmax
= ; HRMS (ESI+): m/z: calcd for
2990, 1707s, 1123s cmꢀ1
C28H43NO9Na: 560.2836; found: 560.2822 [M+Na]+.
Pd/C (1.0 mg of 10% by wt Pd, 1 mmol) was added under an argon at-
mosphere to a solution of the acetonide (7.0 mg, 13 mmol) in ethanol
(0.5 mL). This mixture was then stirred under an atmosphere of hydrogen
vigorously for 15 min, then filtered through a pad of Celite, rinsing with
ethanol (15 mL). Concentration in vacuo and purification of the residue
by flash chromatography on silica gel (CHCl3/methanol/aq. NH4OH
30:1:0.1) afforded amine 29 (12 mg, 77%) as a colourless oil. [a]2D5 =+108
(c=0.5, CHCl3); 1H NMR (600 MHz, CDCl3): d=3.91–3.86 (m, 1H; 4-
H), 3.79–3.77 (m, 1H; 6-H), 3.70 (dq, J=6.3, 9.4 Hz, 1H; 2-H), 3.59 (dd,
Chem. Eur. J. 2007, 13, 5515 – 5538
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5527

S. V. Ley et al.
J=4.2, 10.6 Hz, 1H; 8-H), 3.49 (dd, J=6.5, 10.7 Hz, 1H; 8-H), 3.31 (dd,
J=7.5, 9.3 Hz, 1H; 3-H), 3.25, 3.25 (2s, 2”3H; 2”BDA OCH3), 2.78–
2.73 (m, 1H; 7-H), 1.79 (m, 1H; 5-H), 1.41 (s, 3H; acetonide CH3), 1.37–
1.35 (m, 1H; 5-H), 1.35 (s, 3H; acetonide CH3), 1.28, 1.28 (2s, 2”3H; 2”
BDA CH3), 1.20 (d, J=6.4 Hz, 3H; 1-H3); 13C NMR (150 MHz, CDCl3):
d=98.4 (acetonide Cq), 98.4, 98.3 (BDA Cq), 74.6 (C3), 70.6 (C6), 69.5
(C4), 67.7 (C2), 63.5 (C8), 56.5 (C7), 47.9, 47.8 (BDA OCH3), 29.9 (aceto-
nide CH3), 29.4 (C5), 19.9 (acetonide CH3), 17.8 (C1), 17.6, 17.5 (BDA
CH3); IR (film): nmax = 3360wbr, 2933, 1123s cmꢀ1; HRMS (ESI+):
m/z: calcd for C17H33NO7Na: 386.2155; found: 386.2152 [M+Na]+.
Enantioselective route: Aldehyde 37 (36 mg, 0.37 mmol), thiourea catalyst
45 (7.2 mg, 18.5 mmol) and 2,2,2-trifluoroethanol (27 mL, 0.37 mmol) were
dissolved in dry CH2Cl2 (2.0 mL) under an argon atmosphere. At ꢀ788C,
a solution of trimethylsilyl cyanide (99 mL, 0.74 mmol) in 1.5 mL dry
CH2Cl2 was added over a period of 5 min and the solution allowed to stir
for 2.5 h. It was warmed to RT and quenched with aqueous 3n HCl
(2 mL). After stirring for further 30 min, the mixture was partitioned be-
tween water (10 mL) and ethyl acetate (10 mL). The aqueous layer was
extracted with ethyl acetate (4”10 mL), the combined organic layers
were dried (MgSO4) and the solvent removed under reduced pressure.
The crude material (78% ee by Mosher ester analysis) is purified by flash
chromatography (PE/ethyl acetate 1:1) to give (S)-41 (41 mg, 0.33 mmol,
89%) as a white solid. M.p. 106–1078C; [a]2D5 =ꢀ15.5 (c=0.9, MeOH).
1H NMR (400 MHz, CD3OD): d=8.30 (s, 1H; 13-H), 7.31 (s, 1H; 12-H),
5.87 (s, 1H; 10-H); 13C NMR (100 MHz, CD3OD): d=154.8 (C13), 149.4
Amide 30: TBTU (10 mg, 31 mmol) was added under argon to a solution
of acid 24 (11 mg, 29 mmol) and amine 29 (4 mg, 11 mmol) in DMSO
(0.25 mL). The reaction mixture was stirred at RT for 16 h. Water (1 mL)
was added to quench, and the crude reaction mixture was poured into
water (10 mL) and ethyl acetate (10 mL). The aqueous layer was extract-
ed with ethyl acetate (3”10 mL). The combined organics were washed
once with brine (10 mL), dried over Na2SO4, filtered, and concentrated
in vacuo. The residue was purified by flash chromatography on silica gel
(70 ! 80% ethyl acetate/hexanes) to afford amide 30 (3.7 mg, 47%) as a
(C11), 126.1 (C12), 118.6 (CN), 56.2 (C10); IR (film): nmax
= 3134,
3043br, 2839, 2716, 1507, 1123s, 1056s, 971s cmꢀ1; HRMS (EI+): m/z:
calcd for C5H4N2O2: 124.0273; found: 124.0271 [M]+.
Preparation of 2m HCl in MeOH: Anhydrous methanol (400 mL) was
cooled to 08C under argon. Acetyl chloride (62.8 mL, 800 mmol) was
added dropwise (dropping funnel) to the rapidly stirring MeOH. After
complete addition, the solution was warmed to RT and used immediately.
colourless oil. Rf
= 0.11 (20% ethyl acetate/2% methanol/CH2Cl2);
[a]2D5 =+104.0 (c=0.5, CHCl3); 1H NMR (600 MHz, CDCl3): d=7.85 (d,
J=8.5 Hz, 1H; N-H), 7.67 (s, 1H; 13-H), 7.64 (d, J=7.4 Hz, 2H; Ph-H),
7.50–7.40 (m, 6H; Ph-H), 7.31 (t, J=7.3 Hz, 2H; Ph-H), 6.52 (s, 1H; 12-
H), 5.19 (s, 1H; 10-H), 4.28 (d, J=11.6 Hz, 1H; 6-H), 4.00–3.97 (m, 2H;
4-H, 7-H), 3.86 (dd, J=11.1, 4.3 Hz, 1H; 8-H), 3.78 (dd, J=11.1, 6.0,
5.1 Hz, 1H; 8-H’), 3.73 (dq, J=9.7, 6.3 Hz, 1H; 2-H), 3.37 (dd, J=9.7,
7.0 Hz, 1H; 3-H), 3.27, 3.18 (2s, 2”3H; 2”OCH3), 2.05 (br, 1H; OH),
1.91 (d, J=13.2 Hz, 1H; 5-Heq), 1.91 (ddd, J=13.2, 12.5, 11.6 Hz, 1H; 5-
Hax), 1.48, 1.36 (2s, 2”3H; 2”acetal CH3), 1.30 (2s, 2”3H; 2”BDA
Hydroxy-ester rac-42: Racemic route: Cyanohydrin rac-41 (11.4 g,
91.9 mmol) was dissolved in 2m HCl/methanol (400 mL, prepared as
above) and heated under reflux for 15 h. After cooling to RT, water
(300 mL) was added and stirred for 1 h before the solution was neutral-
ised to pH 7–8 by the slow addition of saturated aqueous NaHCO3.
Methanol (approx 250 mL) was removed under reduced pressure and the
aqueous solution was extracted with CHCl3 (3”100 mL) and then
CHCl3/iPrOH 3:1 (8”150 mL). The combined organic extracts were
dried (MgSO4) and the solvent removed in vacuo to give methyl ester
rac-42 as a brown oil (12.85 g, 89%).
CH3), 1.25 (d, J=6.3 Hz, 3H; 1-H3), 1.12 (s, 9H, C
(CH3)3); 13C NMR
G
(150 MHz, CDCl3): d=169.5 (C9), 150.7 (C13), 148.1 (C11), 135.7, 135.4
(Ph-C), 132.7, 131.2 (Ph Cq), 130.6, 130.2, 128.2 and 127.7 (Ph-C), 125.9
(C12), 99.0 (acetonide Cq), 98.4, 98.3 (BDA Cq), 74.5 (C3), 70.0 (C6), 69.8
(C4), 67.9 (C2), 67.9 (C10), 64.2 (C8), 54.1 (C7), 44.1, 47.9 (BDA OCH3),
Methanolysis of enantiomerically enriched (R)-41: (S)-Cyanohydrin 41
(116 mg, 0.93 mmol, 71% ee) was treated with 1.25m HCl in MeOH
(18.6 mmol, 14.8 mL). The mixture was allowed to stir for 48 h at RT. It
was then hydrolysed with H2O (10 mL), the pH adjusted to 8 with sat.
aqueous NaHCO3 and the mixture extracted with ethyl acetate (5”
20 mL). The combined organic extracts were dried with MgSO4 and the
solvent was removed under reduced pressure. After drying in vacuo, (S)-
configured ester 42 (102 mg, 70%, 66% ee by Moshers ester analysis)
was obtained as yellow oil which could be directly used in the next step
without further purification.
30.1 (C5), 29.7 (acetal CH3), 27.0 (C(CH3)3), 19.9 (acetal CH3), 19.4 (C-
G
A
3418, 2933, 2859, 1683s, 1512s, 1125s cmꢀ1; HRMS (ESI+): m/z: calcd
for C38H54N2O10SiNa: 749.3445; found: 749.3437 [M+Na]+.
5-Dimethoxymethyloxazole 36: TosMIC (100 g, 0.513 mol) and anhy-
drous K2CO3 (208 g, 1.53 mol) were suspended in methanol (750 mL) at
RT. Glyoxal-1,1-dimethyl acetal (45% solution in tBuOMe, 145 mL,
0.564 mol) was added slowly to the stirred suspension at RT. The reaction
mixture was stirred at RT for 1 h 30 min then heated under reflux for 3 h
before cooling to RT. The volume of the reaction mixture was reduced
by about half under reduced pressure. Water (600 mL) was added, and
the resulting aqueous solution was extracted with CH2Cl2 (6”200 mL).
The combined organics were dried (MgSO4) and the solvent was re-
moved in vacuo and the residue purified by flash chromatography (50%
Enantioselective a-oxidation of ester 48: Under an argon atmosphere,
LiHMDS (275 mL, 0.275 mmol, 1m in THF) is diluted with dry THF
(1.5 mL). To this, a solution of ester 48 (35.3 mg, 0.25 mmol) in dry THF
(1.5 mL) was added dropwise at ꢀ788C. Stirring was continued for
30 min at ꢀ788C and a solution of oxaziridine 49 (79.6 mg, 0.275 mmol)
in dry THF (2.0 mL) was added over 2 min. The mixture was allowed to
stir for further 30 min at ꢀ788C, then quenched with sat. aqueous NH4Cl
(3.0 mL) and partitioned between water (15 mL) and ethyl acetate
(20 mL). The aqueous layer was extracted with ethyl acetate (3”20 mL),
the combined organic extracts were dried with MgSO4 and the solvent
was evaporated under reduced pressure. The crude material was purified
by flash chromatography (PE/ethyl acetate 2:1 ! 1:1; ! ethyl acetate)
to give the (R)-configured a-hydroxy ester ent-42 (25.0 mg, 0.159 mmol,
64%, 70% ee by Moshers ester analysis) as a yellow oil. The reduced
Et2O/PE) to afford oxazole 36 as a colourless oil (42.6 g, 58%). Rf
=
0.22 (50% Et2O/PE); 1H NMR (400 MHz, CDCl3): d=7.89 (s, 1H; 13-
H), 7.14 (s, 1H; 12-H), 5.51 (s, 1H; 10-H), 3.36 (s, 6H; 2”OCH3);
13C NMR (100 MHz, CDCl3): d=151.4 (C13), 148.6 (C11), 125.7 (C12),
97.1 (C10), 53.3 (OCH3); IR (film): nmax = 3133w, 2940, 2834, 1506, 1446,
1103s, 1052s cmꢀ1; HRMS (EI+): m/z: calcd for C6H9NO3: 143.0582;
found: 143.0575 [M]+.
Cyanohydrin rac-41/(R)-41: Racemic route: Triethylamine (1.41 mL,
10.1 mmol) was added to a solution of aldehyde 37 (9.78 g, 100.8 mmol)
in CH2Cl2 (400 mL) at 08C. Trimethylsilyl cyanide (10 g, 100.8 mmol) was
added and the reaction mixture was stirred at 08C for 2.5 h. Aqueous 2m
HCl (100 mL) was added dropwise to the vented flask with vigorous stir-
ring. After 30 min further aqueous 2m HCl (100 mL) was added, stirred
for 30 min and the layers separated. The organic layer was washed with
aqueous 2m HCl (100 mL) and the combined aqueous layers extracted
with ethyl acetate (7”200 mL). The combined organic extracts were
dried (MgSO4) and the solvent removed in vacuo to give cyanohydrin
rac-41 as a yellow solid (11.54 g, 92%). Rf = 0.40 (80% ethyl acetate/
PE).
camphor precursor of 49 can be recovered (57 mg, 83%). Rf
= 0.31
(80% ethyl acetate/PE); 1H NMR (400 MHz, CD3OD): d=8.21 (s, 1H;
13-H), 7.19 (s, 1H; 12-H), 5.42 (s, 1H; 10-H), 3.80 (s, 3H; OCH3);
13C NMR (100 MHz, CD3OD): d=172.3 (C9), 153.9 (C13), 151.6 (C11),
125.7 (C12), 66.6 (C10), 53.6 (OCH3); IR (film): nmax = 3255br, 3136,
1746s, 1646, 1507, 1439 cmꢀ1; HRMS (EI+): m/z: calcd for C6H7NO4:
157.0375; found: 157.0376 [M]+.
Compound 43: Imidazole (10.8 g, 159 mmol) was added to a solution of
methyl ester rac-42 (12.5 g, 79.6 mmol) in DMF (67 mL) at RT, followed
by the addition of TBDPSCl (26 mL, 100 mmol) and DMAP (122 mg,
1 mmol) at RT. After 1 h 45 min, water (400 mL) was added to the stirred
solution and the aqueous mixture extracted with Et2O (3”300 mL). The
5528
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 5515 – 5538

Total Synthesis of Bengazoles A and B
FULL PAPER
combined organic extracts were washed with brine, dried (MgSO4) and
the solvent removed in vacuo. Purification by flash chromatography
(25% Et2O/PE) afforded silyl-protected 43 as a colourless oil (27.0 g,
85%). Rf = 0.58 (50% ethyl acetate/PE); 1H NMR (400 MHz, CDCl3):
d=7.79 (s, 1H; 13-H), 7.71 (d, J=7.2 Hz, 2H; Ph-H), 7.65 (d, J=6.8 Hz,
2H; Ph-H), 7.47–7.33 (m, 6H; Ph-H), 6.88 (s, 1H; 12-H), 5.25 (s, 1H; 10-
(ESI+): m/z: calcd for C25H30N2O6SiNa: 505.1771; found: 505.1786
[M+Na]+.
5-Oxazolylmethyl cyanide (47): Alcohol 40 (3.80 g, 38.3 mmol) was dis-
solved in a mixture of CH2Cl2 (12 mL) and n-hexane (12 mL). At 08C,
thionyl chloride (4.20 mL, 57.2 mmol) was added dropwise. Subsequently,
the mixture was refluxed for 2.5 h whilst bubbling the exhaust gas (HCl,
SO2) through sat. aqueous NaHCO3. After cooling to RT, the mixture
was quenched with ice-cold water (30 mL), neutralised with sat. aqueous
NaHCO3 (20 mL) and extracted into Et2O (3”30 mL). The combined or-
ganic layers were dried (MgSO4), and the solvent was removed under re-
duced pressure (T < 358C, p > 300 mbar) to give crude chloride 46
(4.9 g), which was directly used in the next step without further purifica-
H), 3.63 (s, 3H; OCH3), 1.10 (s, 9H, C
(CH3)3); 13C NMR (100 MHz,
A
CDCl3): d=169.2 (C9), 151.0 (C13), 148.8 (C11), 135.9, 135.6 (Ph-C),
132.3, 132.2 (Ph Cq), 130.13, 130.06, 127.75 and 127.72 (Ph-C), 125.1
(C12), 67.0 (C10), 52.4 (OCH3), 26.6 (C
N
N
(film): nmax = 2955, 2859, 1764s, 1112s cmꢀ1; HRMS (ESI+): m/z: calcd
for C22H26NO4Si: 396.1624; found: 396.1624 [M+H]+. Identical condi-
tions were used when enantioenriched 42 was employed.
1
tion. H NMR (400 MHz, CDCl3): d=7.88 (s, 1H, Ar-H), 7.10 (s, 1H, Ar-
H), 4.62 (s, 2H, CH2).
Amide 25 and amide 44: Ice cooled aqueous LiOH (0.5m, 53 m L,
26.4 mmol) was added dropwise to a rapidly stirred solution of methyl
ester 43 (5.98 g, 15.1 mmol) in THF (60 mL) at 08C. The reaction mixture
was stirred at 08C for 5 min then warmed to RT. The loss of starting ma-
terial was monitored by TLC (80% ethyl acetate/PE) and when all start-
ing material was consumed (30 min) the solution was cooled to 08C and
ice cooled aqueous HCl (0.5m, 20 mL) was added dropwise to the rapidly
stirred solution causing the solution to become cloudy. The reaction mix-
ture was partitioned between brine (175 mL) and ethyl acetate (200 mL)
and the layers separated. The aqueous layer was extracted with ethyl ace-
tate (2”150 mL) and the combined organic extracts were dried (MgSO4),
and the solvent removed in vacuo to give carboxylic acid rac-24 as a
white foam which was used immediately.
Chloride 46 (550 mg, 4.68 mmol) was dissolved in dry DMF (4.0 mL)
under an argon atmosphere. Sodium cyanide (783 mg, 16.0 mmol) was
added and the suspension heated to 708C for 2.5 h. After cooling to RT,
the mixture was diluted with brine (10 mL) and water (15 mL) and ex-
tracted with Et2O (4”15 mL). The combined organic layers were dried
(MgSO4), and the solvent was removed under reduced pressure (T <
308C, p > 550 mbar). The crude material was purified by flash chroma-
tography (PE(30–408C)/Et2O 1:1) to provide cyanide 47 (380 mg, 75%
G
over two steps) as a brown liquid. 1H NMR (400 MHz, CDCl3): d=7.88
(s, 1H; Ar-H), 7.09 (s, 1H; Ar-H), 3.83 (s, 2H; CH2); 13C NMR
(100 MHz, CDCl3): d=151.9, 141.5, 125.5, 114.6, 15.7; IR (film): nmax
=2260, 1607, 1509, 1408, 1099, 971, 919, 837 cmꢀ1
.
Methyl ester48 : A solution of cyanide 27 (188 mg, 1.74 mmol) in 2m
HCl in MeOH heated under reflux for 13 h. After cooling to RT, water
was added and stirring continued for further 75 min. Saturated aqueous
Na2CO3 (20 mL) was added to give pH 8 and the aqueous layer was ex-
tracted with Et2O (5”10 mL). The combined organic extracts were dried
with MgSO4 and the solvent evaporated under reduced pressure (T <
308C, p < 550 mbar). The crude material (178 mg, 1.26 mmol, 73%) was
sufficiently clean by NMR but can be further purified by flash chroma-
Crude carboxylic acid rac-24 was dissolved in DMF (50 mL) then TBTU
(7.29 g, 22.7 mmol) was added and stirred for 10 min at RT. Serine
methyl ester hydrochloride (3.77 g, 24.2 mmol) was suspended in DMF
(40 mL) and Hünigs base (3.95 mL, 22.7 mmol) was added to the stirred
mixture. The amine solution was transferred to the activated acid by can-
nula and the mixture stirred overnight. The reaction mixture was parti-
tioned between 10% w/v aqueous LiCl solution (400 mL) and ethyl ace-
tate (300 mL) and the layers separated. The organic layer was washed
with 1m aqueous HCl (3”100 mL) and the combined HCl washings ex-
tracted with ethyl acetate (150 mL). The combined organic extracts were
washed with saturated aqueous NaHCO3 (150 mL), dried (MgSO4) and
the solvent removed in vacuo. Purification by flash chromatography (1%
MeOH/10% ethyl acetate/89% CH2Cl2 ! 1% MeOH/20% ethyl ace-
tate/79% CH2Cl2) afforded amide 44 as a colourless gum(2.47 g, 34%)
followed by amide 25 as a colourless gum(2.31 g, 32%). Identical condi-
tions were used when enantioenriched 24 was employed.
tography (PE(30–408C)/Et2O 2:1) to give a brown liquid which slowly
A
solidifies in the freezer. M.p. 35–378C; 1H NMR (400 MHz, CDCl3): d=
7.82 (s, 1H, Ar-H), 7.00 (s, 1H, Ar-H), 3.75 (s, 2H, CH2), 3.74 (s, 3H,
OCH3); 13C NMR (100 MHz, CDCl3): d=169.2, 151.3, 145.5, 125. 2, 52.9,
31.7; IR (film): nmax = 1737, 1509, 1230, 1102, 970 cmꢀ1
.
Oxazoline 50: DAST (41 mL, 0.34 mmol) was added dropwise to a stirred
solution of amide 25 (150 mg, 0.311 mmol) in CH2Cl2 (2.5 mL) at ꢀ788C.
After 1 h, K2CO3 (65 mg, 0.467 mmol) was added and the mixture was
warmed to 08C and poured into saturated aqueous NaHCO3 (20 mL).
The mixture was extracted with CH2Cl2 (3”20 mL) and the combined or-
ganic extracts were dried (MgSO4) and the solvent removed in vacuo to
afford crude oxazoline 50. A sample was purified by flash chromatogra-
phy (50% Et2O/PE) afforded oxazoline 50 as a colourless oil (212 mg,
Amide 25: Rf = 0.20 (40% ethyl acetate/2% methanol/CH2Cl2); [a]D25
=
+54.6 (c=1.1, CHCl3); 1H NMR (400 MHz, CDCl3): d=8.07 (d, J=
7.3 Hz, 1H; N-H), 7.70 (s, 1H; 13-H), 7.67 (d, J=7.3 Hz, 2H; Ph-H),
7.50–7.40 (m, 6H; Ph-H), 7.32 (t, J=7.3 Hz, 2H; Ph-H), 6.60 (s, 1H; 12-
H), 5.21 (s, 1H; 10-H), 4.67 (ddd, J=7.3, 3.7, 3.5 Hz, 1H; 7-H), 4.06
(ddd, J=11.2, 6.0, 3.7 Hz, 1H; 8-H), 4.00 (ddd, J=11.2, 6.0, 3.5 Hz, 1H;
8-H’), 3.98 (s, 3H; OCH3), 2.26 (t, J=6.0 Hz, 1H; OH), 1.13 (s, 9H; C-
1
57%). Rf = 0.50 (100% ethyl acetate); [a]2D5 =+45 (c=0.58, CHCl3); H
NMR (400 MHz, CDCl3): d=7.79 (s, 1H; 13-H), 7.68 (d, J=7.2 Hz, 2H;
Ph-H), 7.58 (d, J=7.3 Hz, 2H; Ph-H), 7.49–7.33 (m, 6H; Ph-H), 6.96 (s,
1H; 12-H), 5.56 (s, 1H; 10-H), 4.70 (dd, J=10.6, 8.3 Hz, 1H; 7-H), 4.50
(dd, J=8.8, 8.3 Hz, 1H; 8-H), 4.39 (dd, J=10.6, 8.8 Hz, 1H; 8-H’), 3.76
A
(C13), 149.1 (C11), 136.2, 135.9, 132.1 and 131.7 (Ph-C), 130.9, 130.7 (Ph
Cq), 128.5, 128.2 (Ph-C), 126.3 (C12), 68.5 (C10), 63.5 (C8), 55.0 (C7),
(s, 3H; OCH3), 1.08 (s, 9H, C
(CH3)3); 13C NMR (100 MHz, CDCl3): d=
R
53.2 (OCH3), 27.2 (C
C
G
170.8 (C6), 166.9 (C9), 151.1 (C13), 149.0 (C11), 135.8, 135.7 (Ph-C),
132.2, 132.1 (Ph Cq), 130.1, 130.1, 127.7 and 127.7 (Ph-C), 125.1 (C12),
(ESI+): m/z: calcd for C25H31N2O6Si: 483.1946; found: 483.1950 [M+H]+.
69.9 (C8), 68.0 (C7), 63.8 (C10), 52.6 (OCH3), 26.7 (C(CH3)3), 19.3 (C-
C
Amide 44: Rf = 0.31 (40% ethyl acetate/2% methanol/CH2Cl2); [a]D25
=
A
(ESI+): m/z: calcd for C25H29N2O5Si: 465.1846; found: 465.1852 [M+H]+.
ꢀ35.4 (c=1.33, CHCl3); 1H NMR (400 MHz, CDCl3): d=8.03 (d, J=
7.3 Hz, 1H; N-H), 7.75 (s, 1H; 13-H), 7.68 (d, J=7.3 Hz, 2H; Ph-H),
7.48 (d, J=7.3 Hz, 3H; Ph-H), 7.42 (t, J=7.3 Hz, 3H; Ph-H), 7.33 (t, J=
7.3 Hz, 2H; Ph-H), 6.75 (s, 1H; 12-H), 5.26 (s, 1H; 10-H), 4.63 (ddd, J=
7.3, 3.7, 3.4 Hz, 1H; 7-H), 3.99 (dd, J=11.2, 3.7 Hz, 1H; 8-H), 3.86 (dd,
J=11.2, 3.4 Hz, 1H; 8-H’), 3.82 (s, 3H; OCH3), 2.68 (brs, 1H; OH), 1.13
Bisoxazole 51: DBU (93 mL, 0.622 mmol) was added to a solution of
crude oxazoline 50 in CH2Cl2 (3 mL) at ꢀ158C, followed by the addition
of BrCCl3 (46 mL, 0.467 mmol). The reaction mixture was warmed to 08C
over 30 min then stirred for 1 h. Further DBU (46 mL, 0.311 mmol) was
added and the mixture stirred at RT for 3 h. The reaction mixture was
then diluted with CH2Cl2 and washed with saturated aqueous ammonium
chloride (2”15 mL). The combined aqueous layers were extracted with
ethyl acetate (20 mL) and the combined organic extracts were dried
(MgSO4) and the solvent removed in vacuo. Purification by flash chroma-
tography (20 ! 30% ethyl acetate/PE) afforded bisoxazole 51 as a col-
(s, 9H, C
(CH3)3); 13C NMR (100 MHz, CDCl3): d=170.2 (C6), 168.9
G
(C9), 151.0 (C13), 148.8 (C11), 135.7, 135.5 (Ph-C), 131.6, 131.5 (Ph Cq),
130.5, 130.3, 128.1 and 127.8 (Ph-C), 125.6 (C12), 68.1 (C10), 63.1 (C8),
54.7 (C7), 52.8 (OCH3), 26.7 (C
N
G
Chem. Eur. J. 2007, 13, 5515 – 5538
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5529

S. V. Ley et al.
ourless oil (30 mg, 22% over two steps, 59% ee by chiral HPLC); Rf
=
RT. The mixture was stirred in the dark for 22 h then filtered through
Celite eluting with Et2O (150 mL). The filtrate was washed with 10% w/
v aqueous LiCl solution (3”70 mL) and the combined aqueous washings
were extracted with Et2O (2”100 mL). The combined organic extracts
were dried (MgSO4) and the solvent removed in vacuo. Purification by
flash chromatography (80% Et2O/PE) oxazoline ent-54 as a yellow oil
(166 mg, 97%, dr 1:1). The absolute stereochemistry at C7 was unas-
signed and the diastereomers are denoted a or b. Rf = 0.27 (90% Et2O/
0.40 (50% ethyl acetate/PE); [a]2D5 =ꢀ15.0 (c=0.15, CHCl3); 1H NMR
(600 MHz, CDCl3): d=8.17 (s, 1H; 8-H), 7.78 (s, 1H; 13-H), 7.57 (m,
4H; Ph-H), 7.45–7.40 (m, 2H; Ph-H), 7.38–7.32 (m, 4H; Ph-H), 6.92 (s,
1H; 12-H), 6.01 (s, 1H; 10-H), 3.90 (s, 3H; OCH3), 1.07 (s, 9H, C-
(CH3)3); 13C NMR (125 MHz, CDCl3): d=161.5 (C9), 161.2 (C6), 151.2
(C13), 148.7 (C11), 144.4 (C8), 135.62, 135.56 (Ph-C), 133.3 (C7), 131.76,
131.72 (Ph Cq), 130.20, 130.16, 127.83 and 127.83 (Ph-C), 125.1 (C12),
1
PE); [a]2D5 =+5.0 (c=0.55, CHCl3); H NMR (400 MHz, CDCl3): d=7.80
63.6 (C10), 52.2 (OCH3), 26.6 (C
N
N
= 2932, 2859, 1747, 1723, 1581, 1428, 1105s cmꢀ1; HRMS (ESI+): m/z:
calcd for C25H27N2O5Si: 463.1689; found: 463.1683 [M+H]+. HPLC on
chiral stationary phase: Agilent 1100 series, Chiralcel AS column,
hexane/2-propanol 95:5, flow rate=1.0 mLminꢀ1, 248C, l=215 nm, re-
tention times: (S)-C10 isomer 17.60 min, (R)-C10 isomer 21.62 min.
(s, 1H; 13-H), 7.71–7.68 (m, 2H; Ph-H), 7.61–7.57 (m, 2H; Ph-H), 7.45–
7.33 (m, 6H; Ph-H), 6.98 (s, 1Ha; 12-Ha), 6.97 (s, 1Hb; 12-Hb), 5.60 (s,
1H; 10-H), 4.49 (d, J=10.3 Hz, 1Hb; 8-Hb), 4.43 (d, J=10.4 Hz, 1Ha; 8-
Ha), 4.28 (d, J=10.4 Hz, 1Ha; 8-H’a), 4.27 (d, J=10.3 Hz, 1Hb; 8-H’b),
a
a
3.80 (s, 3Hb; CO2CH3b), 3.79 (s, 3Ha, CO2CH3 ), 3.32 (s, 3Ha; OCH3 ),
3.29 (s, 3Hb; OCH3b), 1.09 (s, 9H; C(CH3)3); 13C NMR (100 MHz,
G
Enamide ent-52: Serine amide 44 (537 mg, 1.114 mmol) in dry CH2Cl2
(11 mL) was cooled to 08C and triethylamine (777 mL, 5.57 mmol) was
added. Mesylchloride (173 mL, 2.23 mmol) was added dropwise and the
solution was stirred for 20 min before quenching with saturated aqueous
NaHCO3 (50 mL). The mixture was extracted with CH2Cl2 (2”30 mL)
and the combined organic extracts were washed with saturated aqueous
ammonium chloride (50 mL) and brine (40 mL), then dried (MgSO4) and
the solvent removed in vacuo. Purification by flash chromatography
(50% Et2O/PE) afforded enamide ent-52 as a colourless oil (490 mg,
95%, single enantiomer). Rf = 0.35 (90% Et2O/PE); [a]2D5 =ꢀ40.9 (c=
0.9, CHCl3); 1H NMR (400 MHz, CDCl3): d=9.54 (brs, 1H; N-H), 7.68
(s, 1H; 13-H), 7.64 (d, J=7.3 Hz, 2H; Ph-H), 7.48 (d, J=7.4 Hz, 3H; Ph-
H), 7.42 (t, J=7.3 Hz, 3H; Ph-H), 7.32 (t, J=7.4 Hz, 2H; Ph-H), 6.65 (s,
1H; 8-H), 6.58 (s, 1H; 12-H), 6.00 (s, 1H; 8-H’), 5.23 (s, 1H; 10-H), 3.90
CDCl3): d = 169.6 (C9a), 169.4 (C6b), 168.24 (C9b), 169.21 (C6a), 151.18
(C13a), 151.16 (C13b), 148.9 (C11a), 148.7 (C11b), 135.83, 135.81, 135.67
and 135.65 (Ph-Ca/b), 132.07 and 132.04 (Ph Cqa/b), 130.2, 130.1, 127.78
and 127.76 (Ph-Ca/b), 125.2 (C12), 101.6 (C7), 75.1 (C10), 63.9 (C8), 52.9
a
(CO2CH3), 51.9 (OCH3b), 51.8 (OCH3 ), 26.7 (C
A
G
IR (film): nmax = 2954, 2859, 1754s, 1662, 1105s cmꢀ1; HRMS (ESI+):
m/z: calcd for C26H30N2O6SiNa: 517.1771; found: 517.1779 [M+Na]+.
Benzoxy-bromide 56: Benzyl alcohol (20 mL, 0.194) was added to a solu-
tion of enamide ent-52 (45 mg, 0.097 mmol) in THF (0.2 mL), followed
by the addition of N-bromosuccinimide (17 mg, 0.97 mmol) at RT. The
mixture was stirred for 3 h quenched by the addition of saturated aque-
ous NaHCO3 (5 mL) and extracted with ethyl acetate (2”10 mL). The
combined organic extracts were washed with brine, dried (MgSO4) and
the solvent removed in vacuo. Purification by flash chromatography (4%
Et2O/CH2Cl2) afforded bromide 56 as a colourless oil (23 mg, 36%, dr
1:1), followed by 38 alcohol 57 (19 mg, 41%). The absolute stereochemis-
(s, 3H; OCH3), 1.15 (s, 9H, C
(CH3)3); 13C NMR (100 MHz, CDCl3): d=
G
167.2 (C9), 163.9 (C6), 150.8 (C13), 148.3 (C11), 135.7, 135.4, 131.5,
131.1, 130.52 (Ph-C), 130.50 (C7), 130.2, 128.1, 127.7 (Ph-C), 126.1 (C12),
try at C7 was unassigned and the diastereomers are denoted a or b. Rf
=
109.7 (C8), 68.3 (C10), 52.9 (OCH3), 26.7 (C
C
G
0.63 (15% Et2O/CH2Cl2); [a]2D5 =ꢀ45.0 (c=0.15, CHCl3); 1H NMR
(400 MHz, CDCl3): d=8.91 (s, 1Hb; N-Hb), 8.70 (s, 1Ha; N-Ha), 7.71–7.67
(m, 2H; TBDPS Ph-H), 7.68 (s, 1Ha; 13-Ha), 7.59 (s, 1Hb; 13-Hb), 7.51–
7.39 (m, 6H; TBDPS Ph-H), 7.38–7.27 (m, 7H; 2”TBDPS Ph-H and 5”
Bn Ph-H), 6.73 (s, 1Ha; 12-Ha), 6.44 (s, 1Hb; 12-Hb), 5.24 (s, 1Ha; 10-Ha),
5.22 (s, 1Hb; 10-Hb), 4.75 (d, J=10.2 Hz, 1Hb; 8-Hb), 4.71 (d, J=11.0 Hz,
1Hb; PhCHH’b), 4.57 (d, J=10.3 Hz, 1Ha; 8-Ha), 4.53 (d, J=11.1 Hz,
1Ha; PhCHH’a), 4.40 (d, J=11.0 Hz, 1Hb; PhCHH’b), 4.35 (d, J=
11.1 Hz, 1H; PhCH’Ha), 3.87 (d, J=10.2 Hz, 1Hb; 8-H’b), 3.85 (s, 3H;
(film): nmax
=
(ESI+): m/z: calcd for C25H28N2O5SiNa: 487.1660; found: 487.1641
[M+Na]+; HPLC on chiral stationary phase: Agilent 1100 series, Chiral-
cel AS column, hexane/2-propanol 95:5, flow rate=1.0 mLminꢀ1, 248C,
l=215 nm, retention times: (S)-C10 isomer 11.38 min, (R)-C10 isomer
21.88 min.
Methoxy-bromide ent-53: N-Bromosuccinimide (94 mg, 0.528 mmol) was
added to a solution of enamide ent-52 (245 mg, 0.528 mmol) in methanol
(1 mL) and THF (0.5 mL) at RT. The mixture was stirred for 30 min,
then quenched by the addition of saturated aqueous NaHCO3 (30 mL)
and extracted with Et2O (2”25 mL). The organic extracts were washed
with saturated aqueous NaHCO3 (20 mL) and the combined aqueous
layers extracted with Et2O (25 mL). Combined organic extracts were
washed with brine, dried (MgSO4) and the solvent removed in vacuo to
afford bromide ent-53 as a colourless oil (270 mg, 89%, dr 1:1). The abso-
lute stereochemistry at C7 was unassigned and the diastereomers are de-
noted a or b (assignment as a or b determined by partial separation). Rf
CO2CH3), 3.82 (d, J=10.3 Hz, 1Ha; 8-H’a), 1.16 (s, 9H, C(CH3)3); 13C
G
NMR (100 MHz, CDCl3): d=168.4 (C6a), 168.3 (C9b), 168.2 (C9a), 168.3
(C6b), 150.8 (C13a), 150.6 (C13b), 148.5 (C11a), 148.4 (C11b), 136.5 and
136.3 (Bn Ph-Ca/b), 135.8, 135.6, 135.50 and 135.49 (TBDPS Ph-Ca/b),
131.7, 131.5, 131.4 and 131.0 (TBDPS Ph Cq), 130.5, 130.5, 130.3 and
130.3 (TBDPS Ph-Ca/b), 128.39 and 128.37 (Bn Ph-Ca/b), 128.17, 128.14,
128.13 and 128.12 (TBDPS Ph-Ca/b), 127.88, 127.75, 127.74 and 127.65
(Bn Ph-Ca/b), 126.2 (C12a), 126.0 (C12b), 87.1 (C7b), 86.7 (C7a), 68.5
a
b
(C10a), 68.2 (C10b), 67.7 (PhCH2 ), 67.6 (PhCH2 ), 53.7 (CO2CH3), 31.9
=
0.29/0.41 (90% Et2O/PE); [a]2D5 =ꢀ52.4 (c=1.3, CHCl3); 1H NMR
(C8), 26.7 (C
N
N
(400 MHz, CDCl3): d=8.76 (s, 1Hb; N-Hb), 8.56 (s, 1Ha; N-Ha), 7.70–7.67
(m, 2H; Ph-H), 7.68 (s, 1H; 13-H), 7.51–7.40 (m, 6H; Ph-H), 7.34–7.29
(m, 2H; Ph-H), 6.73 (s, 1Ha; 12-Ha), 6.46 (s, 1Hb; 12-Hb), 5.21 (s, 1Ha;
10-Ha), 5.19 (s, 1Hb; 10-Hb), 4.64 (d, J=10.2 Hz, 1Hb; 8-Hb), 4.48 (d, J=
1746s, 1707s, 1499s, 1428, 1309, 1205, 1106s, 1069s cmꢀ1; HRMS (ESI+):
m/z: calcd for C32H36N2O6SiBr: 651.1526; found: 651.1544 [M+H]+. The
data for 38 alcohol 57 is detailed later.
Isopropoxy-bromide 55: N-Bromosuccinimide (94 mg, 0.528 mmol) was
added to a solution of enamide ent-52 (245 mg, 0.528 mmol) in iPrOH
(0.5 mL) and THF (0.5 mL) at RT. The mixture was stirred for 3 h then
further iPrOH (1 mL) was added and the mixture stirred for 1 h. Saturat-
ed aqueous NaHCO3 (30 mL) was added and the mixture was extracted
with Et2O (3”30 mL). The combined organic extracts were washed with
brine, dried (MgSO4) and the solvent removed in vacuo. Purification by
flash chromatography (4% Et2O/CH2Cl2) afforded bromide 55 as a col-
ourless oil (162 mg, 51%, dr 1.3:1). The absolute stereochemistry at C7
was unassigned and the diastereomers are denoted maj or min. Rf = 0.39
(90% Et2O/PE); [a]2D5 =ꢀ43.0 (c=1.4, CHCl3); 1H NMR (400 MHz,
CDCl3): d=8.86 (s, 1Hmaj; N-Hmaj), 8.71 (s, 1Hmin; N-Hmin), 7.70–7.66 (m,
2H; Ph-H), 7.66 (s, 1H; 13-H), 7.50–7.39 (m, 6H; Ph-H), 7.33–7.28 (m,
2H; Ph-H), 6.70 (s, 1Hmin; 12-Hmin), 6.47 (s, 1Hmaj; 12-Hmaj), 5.18 (s, 1H;
10-H), 4.69 (d, J=10.0 Hz, 1Hmaj; 8-Hmaj), 4.53 (d, J=10.2 Hz, 1Hmin; 8-
10.3 Hz, 1Ha; 8-Ha), 3.94 (s, 3Hb, CO2CH3b), 3.92 (s, 3Ha, CO2CH3 ), 3.81
a
(d, J=10.2 Hz, 1Hb; 8-H’b), 3.77 (d, J=10.3 Hz, 1Ha; 8-H’a), 3.32 (s, 3Hb;
OCH3b), 3.24 (s, 3Ha; OCH3 ), 1.15 (s, 9H;
C
(CH3)3); 13C NMR
A
a
(100 MHz, CDCl3): d=168.72 (C6b), 168.69 (C9b), 168.6 (C6a), 168.4
(C9a), 151.2 (C13a), 151.1 (C13b), 148.94 (C11b), 148.85 (C11a), 136.2,
136.1, and 135.9 (Ph-Ca/b), 132.1, 131.9, 131.83 and 131.43 (Ph Cqa/b),
130.94, 130.90, 130.69, 128.5, 128.2 and 128.1 (Ph-Ca/b), 126.5 (C12a), 126.4
b
(C12b), 88.2 (C7a), 87.7 (C7b), 68.8 (C10a), 68.6 (C10b), 54.2 (CO2CH3 ),
a
a
54.1 (CO2CH3 ), 53.3 (OCH3b), 53.2 (OCH3 ), 32.0 (C8), 27.1 (C
(CH3)3),
A
19.6 (C(CH3)3); IR (film): nmax = 3386, 2934, 2860, 1746s, 1706s, 1500s,
C
1105s, 1077s cmꢀ1; HRMS (ESI+): m/z: calcd for C26H32BrN2O6Si:
575.1213; found: 575.1211 [M+H]+.
Methoxy-oxazoline 54: Silver oxide (121 mg, 0.522) was added to a solu-
tion of bromides ent-53 (200 mg, 0.348 mmol, dr=1:1) in DMF (2 mL) at
5530
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 5515 – 5538

Total Synthesis of Bengazoles A and B
FULL PAPER
Hmin), 3.97 (septet, J=6.2 Hz, 1Hmaj
;
OiPr CHmaj), 3.92 (s, 3Hmaj
;
;
Vinyl bromide 59: Bromine (3 mL, 0.059 mmol) was added to a solution
of enamide ent-52 (25 mg, 0.054 mmol) in CH2Cl2 (0.25 mL) at ꢀ788C.
The solution was stirred for 10 min then triethylamine (23 mL,
0.647 mmol) was added and after 15 min quenched with saturated aque-
ous NaHCO3 (10 mL). The mixture was warmed to RT, then extracted
with CH2Cl2 (2”10 mL). The combined organic extracts were washed
with brine, dried (MgSO4) and the solvent removed in vacuo. Purification
by flash chromatography (50% Et2O/PE) afforded E-vinyl bromide 59 as
CO2CH3maj), 3.91 (s, 3Hmin; CO2CH3min), 3.88 (septet, J=6.2 Hz, 1Hmin
OiPr CHmin), 3.79 (d, J=10.0 Hz, 1Hmaj; 8-H’maj), 3.74 (d, J=10.2 Hz,
1Hmin; 8-H’min), 1.16 (s, 9H, C
(CH3)2maj), 1.04 (d, J=6.2 Hz, 6Hmin
ACHTREUNG
,
(100 MHz, CDCl3): d=169.3 (C6), 168.2 (C9min), 168.1 (C9maj), 150.7
(C13min), 150.5 (C13maj), 148.6 (C11min), 148.5 (C11maj), 135.8, 135.7, 135.5
and 135.4 (Ph-Cmaj/min), 131.7, 131.5, 131.4 and 131.0 (Ph Cqmaj/min), 130.5,
130.4, 130.24, 130.22, 128.10, 128.08, 127.71 and 127.69 (Ph-Cmaj/min), 126.0
(C12min), 125.9 (C12maj), 86.7 (C7maj), 86.3 (C7min), 69.13 (OiPr CHmaj),
69.06 (OiPr CHmin), 68.46 (C10maj), 68.43 (C10min), 53.5 (CO2CH3), 32.10
a colourless oil (22 mg, 75%). Rf = 0.58 (70% ethyl acetate/PE); [a]D25
=
ꢀ20.5 (c=1.1, CHCl3); 1H NMR (400 MHz, CDCl3): d=8.63 (brs, 1H;
N-H), 7.69 (s, 1H; 13-H), 7.69 (m, 2H; Ph-H), 7.50 (t, J=7.3 Hz, 3H;
Ph-H), 7.43 (t, J=7.3 Hz, 3H; Ph-H), 7.33 (t, J=7.3 Hz, 2H; Ph-H), 7.26
(s, 1H; 8-H), 6.68 (s, 1H; 12-H), 5.29 (s, 1H; 10-H), 3.82 (s, 3H; OCH3),
(C8min), 32.09 (C8maj), 26.7 (C
CH3maj), 22.60 (OiPr CH3’maj), 22.59 (OiPr CH3’min), 19.23 (C
19.22 (C 3385, 2933, 2861, 1744s, 1706s,
(CH3)3maj); IR (film): nmax
ACHTREUNG
AHCTREUNG
1.14 (s, 9H, C
(CH3)3); 13C NMR (100 MHz, CDCl3): d=166.3 (C9), 162.0
G
A
=
1501s, 1106s, 1063s cmꢀ1
;
HRMS (ESI+): m/z: calcd for
(C6), 150.9 (C13), 148.1 (C11), 135.7, 135.5 (Ph-C), 131.4 (Ph Cq), 131.22
(C7), 131.18 (Ph Cq), 130.6, 130.4, 128.2 and 127.8 (Ph-C), 126.2 (C12),
C28H36N2O6SiBr: 603.1526; found: 603.1526 [M+H]+.
Isopropoxy-oxazoline 58: Silver oxide (76 mg, 0.326 mmol) was added to
a solution of bromide 55 (131 mg, 0.217 mmol, dr 1.3:1) in DMF (1.3 mL)
at RT. The mixture was stirred in the dark for 20 h, then filtered through
Celite eluting with Et2O (120 mL). The filtrate was washed with 10% w/
v aqueous LiCl solution (3”50 mL) and the combined aqueous washings
were extracted with Et2O (2”50 mL). The combined organic extracts
were dried (MgSO4) and the solvent removed in vacuo. Purification by
flash chromatography (70% Et2O/PE) afforded oxazoline 58 as a yellow
oil (108 mg, 95%, dr 1.3:1). The absolute stereochemistry at C7 was un-
assigned and the diastereomers are denoted maj or min. Rf = 0.39 (90%
Et2O/PE); [a]2D5 =+4.2 (c=0.65, CHCl3); 1H NMR (400 MHz, CDCl3):
d=7.78 (s, 1H; 13-H), 7.71–7.66 (m, 2H; Ph-H), 7.60–7.56 (m, 2H; Ph-
H), 7.48–7.33 (m, 6H; Ph-H), 6.96 (s, 1Hmin; 12-Hmin), 6.95 (s, 1Hmaj; 12-
Hmaj), 5.64 (s, 1Hmin; 10-Hmin), 5.58 (s, 1Hmaj; 10-Hmaj), 4.46 (d, J=
10.1 Hz, 1Hmaj; 8-Hmaj), 4.38 (d, J=10.2 Hz, 1Hmin; 8-Hmin), 4.25 (d, J=
10.2 Hz, 1Hmin; 8-H’min), 4.23 (d, J=10.1 Hz, 1Hmaj; 8-H’maj), 4.00 (septet,
J=6.2 Hz, 1H; OiPr CH), 3.78 (s, 3H; CO2CH3), 1.17 (d, J=6.2 Hz,
3Hmaj; OiPr CH3maj), 1.12 (d, J=6.2 Hz, 3Hmin; OiPr CH3min), 1.09 (d, J=
114.0 (C8), 68.3 (C10), 52.9 (OCH3), 26.8, 19.3 (C(CH3)3); IR (film): nmax
U
Alcohol 60: Imidazole (0.86 g, 12.57 mmol) was added to a solution of
serine amide 25 (3.03 g, 6.28 mmol) in DMF (18 mL), followed by the ad-
dition of TBSCl (1.14 g, 7.54 mmol) and a catalytic amount of DMAP
(20 mg) at RT. The mixture was stirred for 45 min and then quenched by
the addition of saturated aqueous NaHCO3 (50 mL) and water (25 mL).
The aqueous solution was extracted with Et2O (2”75 mL) and the com-
bined organic extracts washed with 10% w/v aqueous LiCl (50 mL),
dried (MgSO4) and the solvent removed in vacuo. Purification by flash
chromatography (40 ! 50% ethyl acetate/PE) afforded the TBS ether as
a colourless gum(4.0 g, 90%). Rf = 0.30 (50% ethyl acetate/PE); [a]D25
=
+63.7 (c=1.3, CHCl3); 1H NMR (400 MHz, CDCl3): d=8.06 (d, J=
8.8 Hz, 1H; N-H), 7.69 (d, J=7.3 Hz, 2H; Ph-H), 7.65 (s, 1H; 13-H),
7.48 (m, 3H; Ph-H), 7.41 (t, J=7.4 Hz, 3H; Ph-H), 7.30 (t, J=7.4 Hz,
2H; Ph-H), 6.53 (s, 1H; 12-H), 5.21 (s, 1H; 10-H), 4.76 (ddd, J=8.8, 2.8,
2.4 Hz, 1H; 7-H), 4.17 (dd, J=10.1, 2.4 Hz, 1H; 8-H), 3.89 (dd, J=10.1,
6.2 Hz, 3Hmaj; OiPr CH3’maj), 1.09 (s, 9H, C
(CH3)3), 1.03 (d, J=6.2 Hz,
A
2.8 Hz, 1H; 8-H’), 3.80 (s, 3H; OCH3), 1.13 (s, 9H, TBDPS C
ACHTREUNG
3Hmin; OiPr CH3’min); 13C NMR (100 MHz, CDCl3): d=170.3 (C6maj),
170.0 (C6min), 169.0 (C9min), 168.6 (C9maj), 151.1 (C13), 148.9 (C11min),
148.8 (C11maj), 135.8, 135.7 and 135.6 (Ph-Cmaj/min), 132.1 (Ph Cqmaj/min),
130.10, 130.09, 127.8 and 127.7 (Ph-Cmaj/min), 125.1 (C12), 101.7 (C7maj),
101.5 (C7min), 76.6 (C10), 69.1 (C8maj), 68.9 (C8min), 64.1 (iPr CHmin), 63.9
0.91 (s, 9H, TBS C
ACHTREUNG
CH3); 13C NMR (100 MHz, CDCl3: d=170.2 (C6), 168.2 (C9), 150.6
(C13), 148.8 (C11), 135.8, 135.4 (Ph-C), 131.8, 131.8 (Ph Cq), 131.2, 130.4,
128.1 and 127.7 (Ph-C), 125.8 (C12), 68.1 (C10), 63.8 (C8), 54.2 (C7), 52.4
(OCH3), 26.8 (TBDPS C
(CH3)3), 18.2 (TBS C
C
G
(iPr CHmaj), 52.7 (CO2CH3), 26.6 (C
(CH3)3), 24.5 (iPr CH3), 23.6 (iPr
N
U
A
=
CH3’), 19.3 (C(CH3)3); IR (film): nmax = 2933, 2860, 1754s, 1661, 1106s,
G
1087s cmꢀ1; HRMS (ESI+): m/z: calcd for C28H35N2O6Si: 523.2264;
found: 523.2276 [M+H]+.
Alcohol 57: N-Bromosuccinimide (8 mg, 0.045 mmol) was added to a so-
lution of enamide ent-52 (20 mg, 0.043 mmol) in THF (0.5 mL) and water
(0.2 mL) at RT. The mixture was stirred for 1 h, then saturated aqueous
NaHCO3 (30 mL) was added and the mixture was extracted with ethyl
acetate (2”10 mL). The combined organic extracts were washed with
brine, dried (MgSO4) and the solvent removed in vacuo. Purification by
flash chromatography (90% Et2O/PE) afforded bromide 57 as a colour-
less oil (13 mg, 57%, dr 1:1). The absolute stereochemistry at C7 was un-
assigned and the diastereomers are denoted a or b. Rf = 0.14 (90%
Et2O/PE); [a]2D5 =ꢀ32 (c=0.2, CHCl3); 1H NMR (400 MHz, CDCl3): d=
8.58 (s, 1Ha, N-Ha), 8.49 (s, 1Hb, N-Hb), 7.71 (s, 1Hb, 13-Hb), 7.69 (s, 1Ha,
13-Ha), 7.67 (m, 2H; Ph-H), 7.52–7.40 (m, 6H; Ph-H), 7.36–7.29 (m, 2H;
Ph-H), 6.65 (s, 1Hb, 12-Hb), 6.60 (s, 1Ha, 12-Ha), 5.16 (s, 1H; 10-H), 3.93
(d, J=10.2 Hz, 1Ha, 8-Ha), 3.83 (d, J=10.4 Hz, 1Hb, 8-Hb), 3.79 (d, J=
LiCl (1.04 g, 24.5 mmol) was added portionwise to a stirred solution of
the TBS-ether methyl ester (5.84 g, 9.79 mmol) in dry MeOH (36 mL)
and THF (20 mL) at 08C, followed by the portionwise addition of
NaBH4 (0.926 g, 24.5 mmol). The mixture was allowed to warm slowly to
RT and after 19 h, the suspension was quenched with saturated aqueous
NaHCO3 (50 mL) and water (50 mL). The aqueous layer was extracted
with CH2Cl2 (4”100 mL) and the combined organic extracts were dried
(MgSO4) and the solvent was removed in vacuo. Purification by flash
chromatography (40% ethyl acetate/PE) afforded primary alcohol 60 as
colourless oil (4.46 g, 80%). Rf = 0.22 (60% ethyl acetate/PE); [a]2D5 =+
1
61.7 (c=1.0, CHCl3); H NMR (400 MHz, CDCl3): d=7.79 (d, J=8.1 Hz,
1H; N-H), 7.70 (s, 1H; 13-H), 7.65 (d, J=6.8 Hz, 2H; Ph-H), 7.47 (d, J=
6.8 Hz, 3H; Ph-H), 7.41 (m, 3H; Ph-H), 7.31 (t, J=7.4 Hz, 2H; Ph-H),
6.62 (s, 1H; 12-H), 5.21 (s, 1H; 10-H), 4.02 (m, 1H; 7-H), 3.92–3.80 (m,
3H; 6-H2, 8-H), 3.69 (dd, J=11.1, 4.8 Hz, 1H; 8-H’), 2.59 (brs, 1H; OH),
10.2 Hz, 1Ha, 8-H’a), 3.74 (d, J=10.4 Hz, 1Hb, 8-H’b), 3.90 (s, 3Hb,
a
OCH3b), 3.89 (s, 3Ha, OCH3 ), 1.13 (s, 9H,
C
(CH3)3); 13C NMR
G
(100 MHz, CDCl3): d=171.2 (C6a), 170.25 (C9a), 170.19 (C6b), 170.0
(C9b), 151.1 (C13b), 150.9 (C13a), 148.4 (C11a), 148.0 (C11b), 135.75,
135.69, 135.48 and 135.47 (Ph-Ca/b), 131.46, 131.35, 131.26 and 131.20 (Ph
Cqa/b), 130.60, 130.58, 130.39, 128.20, 128.18 and 127.83 (Ph-Ca/b), 126.1
1.11 (s, 9H, TBDPS C
N
N
TBS CH3), 0.12 (s, 3H; TBS CH3); 13C NMR (100 MHz, CDCl3): d=
168.6 (C9), 150.7 (C13), 149.0 (C11), 135.7, 135.4 (Ph-C), 131.6, 131.4 (Ph
Cq), 130.5, 130.2, 128.1 and 127.7 (Ph-C), 125.6 (C12), 68.2 (C10), 64.1
(C12), 82.1 (C7a), 81.8 (C7b), 67.9 (C10b), 67.8 (C10a), 54.0 (OCH3b), 54.1
(C8), 63.5 (C6), 51.4 (C7), 26.8 (TBDPS C
19.2 (TBDPS C(CH3)3), 18.2 (TBS C
(CH3)3), ꢀ5.58 (TBS CH3), ꢀ5.61
(TBS CH3); IR (film): nmax 3419, 3400br, 2954, 2858, 683s, 1516,
A
N
a
(OCH3 ), 30.3 (C8b), 29.56 (C8a), 26.7 (C
G
G
A
ACHTREUNG
=
(film): nmax
= 3388, 3300, 2957, 2860, 1751, 1704s, 1504, 1112s, 702s
1106s, 835s, 702s cmꢀ1; HRMS (ESI+): m/z: calcd for C30H45N2O5Si2:
cmꢀ1; HRMS (ESI+): m/z: calcd for C25H30BrN2O6Si: 561.1057; found:
561.1066 [M+H]+.
569.2867; found: 569.2883 [M+H]+.
Chem. Eur. J. 2007, 13, 5515 – 5538
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5531

S. V. Ley et al.
Bisoxazole 62: NaHCO3 (2.24 g, 26.6 mmol) was suspended in CH2Cl2
(8.5 mL) and Dess–Martin periodinane (1.13 g, 2.66 mmol) was added at
RT. The mixture was stirred for 5 min, cooled to 08C and then a solution
of alcohol 60 (1.01 g, 1.78 mmol) in CH2Cl2 (11.0 mL) was added drop-
wise to the DMP suspension. The reaction mixture was stirred at 08C for
2 h before adding a 1:1 mixture of saturated aqueous NaHCO3 and
sodium thiosulphate solutions (80 mL). This was stirred for 10 min then
partitioned between water (100 mL) and ethyl acetate (100 mL) and the
layers separated. The aqueous layer was extracted with ethyl acetate (2”
100 mL). The combined organic extracts were washed with brine, dried
(MgSO4) and evaporated to give crude aldehyde 61.
sodium thiosulphate solutions (100 mL). This was stirred for 10 min then
partitioned between water (50 mL) and ethyl acetate (50 mL) and sepa-
rated. The aqueous layer was extracted with ethyl acetate (2”50 mL)
and the combined organic extracts were washed with brine, dried
(Na2SO4) and the solvent removed in vacuo to give the crude aldehyde,
which was used without purification.
A solution of hydroxylamine hydrochloride (391 mg, 5.68 mmol) and
Na2CO3 (300 mg, 2.84 mmol) in water (2 mL) was added to a solution of
the crude aldehyde in methanol (25 mL) at 08C. After 1 h the solution
was poured into brine (50 mL) and water (50 mL). The mixture was ex-
tracted with ethyl acetate (3”50 mL) and the combined organic extracts
were dried (Na2SO4) and the solvent removed in vacuo. Purification by
flash chromatography (35% ethyl acetate/PE) afforded oxime 33 as a
white foam(1.18 g, 93% over 2 steps, cis/trans 1:5). Rf = 0.25 (50%
ethyl acetate/PE); [a]D25 =ꢀ34.3 (c=1.0, CHCl3); 1H NMR (400 MHz,
CDCl3): d=9.56 (brs, 1Htrans; OHtrans), 8.52 (brs, 1Hcis; OHcis), 8.39 (s,
1Htrans; 8-Htrans), 7.99 (s, 1Hcis; 8-Hcis), 7.82 (s, 1Hcis; 13-Hcis), 7.81 (s,
1Htrans; 13-Htrans), 7.79 (s, 1Htrans; 6-Htrans), 7.61–7.57 (m, 4H; Ph-H), 7.46
(s, 1Hcis; 6-Hcis), 7.45–7.32 (m, 6H; Ph-H), 6.97 (s, 1Hcis; 12-Hcis), 6.95 (s,
1Htrans; 12-Htrans), 5.99 (s, 1Htrans; 10-Htrans), 5.96 (s, 1Hcis; 10-Hcis), 1.09 (s,
Crude aldehyde 61 was dissolved in CH2Cl2 (80 mL) and cooled to 08C.
2,6-Di-tert-butylpyridine (9.73 mL, 44.5 mmol) was added, followed by
PPh3 (2.33 g, 8.9 mmol), then dibromotetrachloroethane (2.90 g,
8.90 mmol) was added portionwise to the stirred solution. The reaction
mixture was stirred at 08C for 3 h. Triethylamine (6.19 mL, 44.5 mmol) in
MeCN (20 mL) was added and the mixture was allowed to warm to RT,
then stirred for a further 36 h before filtering through a pad of silica elut-
ing with CH2Cl2. The solvent was removed in vacuo and purification by
flash chromatography (20 ! 40% Et2O/PE) afforded a single enantio-
9Hcis; TBDPS C
N
N
mer of bisoxazole 62 as a yellow oil (870 mg, 89% over 2 steps). Rf
=
NMR (100 MHz, CDCl3): d=161.6 (C9trans), 160.2 (C9cis), 151.30 (C13cis),
151.27 (C13trans), 149.1 (C11cis), 149.0 (C11trans), 143.7 (C8cis), 141.1
(C8trans), 139.8 (C6cis), 137.9 (C6trans), 135.65 (Ph-C), 135.60 (Ph-C), 134.7
(C7trans), 131.9, 131.8 (Ph Cq), 130.8 (C7cis), 130.2, 130.1, 127.81 and 127.79
(Ph-C), 124.92 (C12trans), 124.89 (C12cis), 63.59 (C10trans), 63.54 (C10cis),
0.29 (50% Et2O/PE); [a]D25 =ꢀ24.0 (c=0.5, CHCl3); 1H NMR (400 MHz,
CDCl3): d=7.78 (s, 1H; 13-H), 7.61 (d, J=7.2 Hz, 2H; Ph-H), 7.58 (d,
J=7.2 Hz, 2H; Ph-H), 7.49 (s, 1H; 8-H), 7.45–7.33 (m, 6H; Ph-H), 6.93
(s, 1H; 12-H), 5.90 (s, 1H; 10-H), 4.61 (d, J=14.2 Hz, 1H; 6-H), 4.58 (d,
J=14.2 Hz, 1H; 6-H’), 1.07 (s, 9H, TBDPS C
N
26.7 (TBDPS
C
N
C(CH3)3); IR (film): nmax =
G
C
G
ACHTREUNG
160.6 (C9), 151.1 (C13), 149.5 (C11), 141.7 (C7), 135.7, 135.63 (Ph-C),
135.58 (C8), 132.2, 132.1 (Ph Cq), 130.0, 130.0, 127.7 and 127.7 (Ph-C),
124.8 (C12), 63.7 (C10), 58.6 (C6), 26.6 (TBDPS C
(CH3)3), 19.3 (TBDPS C(CH3)3), 18.3 (TBS C
(CH3)3), ꢀ5.4, ꢀ5.4 (TBS
CH3); IR (film): nmax = 2954, 2858, 1472, 1428, 1105s, 873s, 701s cmꢀ1
HRMS (ESI+): m/z: calcd for C30H41N2O4Si2: 549.2605; found: 549.2595
[M+H]+; HPLC on chiral stationary phase: Agilent 1100 series, Chiralcel
AS column, hexane/2-propanol 99:1, flow rate=0.5 mLminꢀ1, 248C, l=
215 nm, retention times: (S)-C10 isomer 10.35 min, (R)-C10 isomer
11.85 min.
A
Isoxazoline 3: N-Chlorosuccinimide (52 mg, 0.388 mmol) was added in
one portion to a solution of oxime 33 (158 mg, 0.353 mmol) and pyridine
(2 mL) in CH2Cl2 (5 mL) at RT. The reaction mixture was stirred in the
dark for 1 h and the solvent was removed in vacuo to provide the crude
chlorooxamic acid.
G
G
ACHTREUNG
A solution of alkene 7 (764 mg, 3.53 mmol) in DME (16 mL) was added
to the crude chlorooxamic acid and cooled to 08C, then Cs2CO3 (126 mg,
0.388 mmol) was added in one portion and the mixture was stirred vigo-
rously for 18 h at 08C. Saturated aqueous NaHCO3 (50 mL) and water
(20 mL) were added, then the mixture was extracted with ethyl acetate
(4”50 mL). The combined organic extracts were dried (MgSO4) and the
solvent removed in vacuo. Purification by Biotage flash chromatography
(gradient from10% Et 2O/PE ! 90% Et2O/PE in 3 stages) afforded the
nitrile-oxide dimer 3b as a yellow oil (10 mg, 6%), major cycloadduct 3
as a white foam (141 mg, 60%), followed by minor cycloadduct 3a as a
white foam(40 mg, 17%).
Bisoxazole alcohol 63: PPTS (0.73 g, 2.90 mmol) was added to a solution
of TBS-ether 62 (2.27 g, 4.13 mmol) in methanol (32 mL) at RT. The so-
lution was stirred for 4 h, then quenched by the addition of saturated
aqueous NaHCO3 (150 mL) and water (50 mL). The mixture was extract-
ed with ethyl acetate (3”150 mL) and the combined organic extracts
were washed with brine, dried (MgSO4) and the solvent removed in
vacuo. Purification by flash chromatography (50 ! 70% ethyl acetate/
PE) afforded primary alcohol 63 as a pale yellow oil (1.67 g, 93%,
>98% ee by chiral SFC). Rf = 0.33 (80% ethyl acetate/PE); [a]D25
=
Major cycloadduct isoxazoline 3: Rf
= 0.38 (50% ethyl acetate/PE);
1
[a]2D5 =ꢀ36.0 (c=1.6, CHCl3); 1H NMR (400 MHz, CDCl3): d=7.93 (s,
1H; 8-H), 7.80 (s, 1H; 13-H), 7.58 (t, J=7.4 Hz, 4H; Ph-H), 7.47–7.30
(m, 6H; Ph-H), 6.97 (s, 1H; 12-H), 5.98 (s, 1H; 10-H), 4.63 (ddd, J=
11.0, 8.8, 5.1 Hz, 1H; 4-H), 3.74–3.65 (m, 2H; 2-H and 3-H), 3.41 (dd, J=
17.2, 8.9 Hz, 1H; 5-H), 3.27, 3.25 (2s, 2”3H; 2”OCH3), 3.19 (dd, J=
17.2, 11.0 Hz, 1H; 5-H’), 1.30, 1.28 (2s, 2”3H; 2”BDA CH3), 1.26 (d,
ꢀ10.0 (c=0.55, CHCl3); H NMR (400 MHz, CDCl3): d=7.80 (s, 1H; 13-
H), 7.60 (d, J=7.1 Hz, 2H; Ph-H), 7.57 (d, J=7.1 Hz, 2H; Ph-H), 7.52 (s,
1H; 8-H), 7.45–7.40 (m, 2H; Ph-H), 7.38–7.33 (m, 4H; Ph-H), 6.94 (s,
1H; 12-H), 5.92 (s, 1H; 10-H), 4.50 (s, 2H; 6-H), 2.13 (brs, 1H; OH),
1.07 (s, 9H, TBDPS C
(CH3)3); 13C NMR (100 MHz, CDCl3): d=161.1
G
(C9), 151.2 (C13), 149.3 (C11), 140.6 (C7), 135.7, 135.64 (Ph-C), 135.57
(C8), 132.1, 132.0 (Ph Cq), 130.1, 130.0, 127.8 and 127.7 (Ph-C), 124.8
J=5.9 Hz, 3H; 1-H3), 1.08 (s, 9H,
C
(CH3)3); 13C NMR (100 MHz,
A
(C12), 63.7 (C10), 56.8 (C6), 26.7 (TBDPS C
A
CDCl3): d=161.3 (C9), 151.2 (C13), 150.1 (C6), 149.0 (C11), 137.5 (C8),
135.64, 135.58 (Ph-C), 132.0 (C7), 131.9, 131.9 (Ph Cq), 130.2, 130.1, 127.8
and 127.7 (Ph-C), 125.0 (C12), 98.7, 98.6 (BDA Cq), 80.3 (C4), 72.7 (C3),
66.4 (C2), 63.6 (C10), 48.0 (OCH3), 47.9 (OCH3), 36.3 (C5), 26.6 (C-
A
HRMS (ESI+): m/z: calcd for C24H27N2O4Si: 435.1740; found: 435.1745
[M+H]+. HPLC on chiral stationary phase: Agilent 1100 series, Chiralcel
AS column, hexane/2-propanol 97:3, flow rate=1 m Lm in , 248C, l=
A
ACHTREUNG
215 nm, retention times: (S)-C10 isomer 40.85 min, (R)-C10 isomer
44.69 min; Chiral SFC (supercritical fluid chromatography): (Berger
Minigram, Chiralcel AS column with 7% MeOH/CO2, flow rate=
3 m Lm in at 100 bar, 358C, l=210 nm, retention times: (S)-C10 isomer
8.66 min, (R)-C10 isomer 9.08 min).
=
;
C35H43N3O8SiNa: 684.2717; found: 684.2718 [M+Na]+. Biotage condi-
tions: Cartridge FLASH 40M, flow rate 40 mLminꢀ1, monitor by UV
(254 nm), Et2O/PE (5% Et2O 100 mL, 5 ! 70% Et2O 400 mL, 70%
Et2O 300 mL, 70 ! 90% Et2O 400 mL, 90% Et2O 450 mL), 33”50 mL
fractions (fractions: 7–10 recovered 7, 16–19 3b, 21–25 3, 26–30 3a).
ꢀ1
Oxime 33: Dess–Martin periodinane (1.81 g, 4.26 mmol) and NaHCO3
(3.58 g, 42.6 mmol) were suspended in CH2Cl2 (10 mL) and cooled to
08C. A solution of primary alcohol 63 (1.24 g, 2.84 mmol) in CH2Cl2
(10 mL) was added dropwise and the mixture was stirred at 08C for 2 h
30 min before adding a 1:1 mixture of saturated aqueous NaHCO3 and
Compound 64: TBAF (1m in THF, 0.15 mL, 0.15 mmol) was added to a
solution of TBDPS-ether 3 (67 mg, 0.10 mmol) in THF (3 mL) at 08C.
After 10 min saturated aqueous ammonium chloride (20 mL) was added
and the mixture was extracted with ethyl acetate (3”20 mL). The com-
5532
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 5515 – 5538

Total Synthesis of Bengazoles A and B
FULL PAPER
bined organic extracts were dried (MgSO4) and the solvent removed in
vacuo. Purification by flash chromatography (100% Et2O) afforded bi-
soxazole alcohol 64 as a colourless oil (33 mg, 78%). Rf = 0.20 (80%
ethyl acetate/PE); [a]D25 =+3.2 (c=1.5, CHCl3); 1H NMR (400 MHz,
CDCl3): d=7.99 (s, 1H; 8-H), 7.89 (s, 1H; 13-H), 7.16 (s, 1H; 12-H), 6.10
(s, 1H; 10-H), 4.63 (ddd, J=10.7, 8.8, 4.8 Hz, 1H; 4-H), 3.74–3.65 (m,
2H; 2-H, 3-H), 3.48 (dd, J=17.0, 8.6 Hz, 1H; 5-H), 3.25 (s, 3H; OCH3),
3.24 (s, 3H; OCH3), 3.24 (dd, J=17.0, 10.7 Hz, 1H; 5-H’), 1.29, 1.27 (2s,
2”3H; 2”BDA CH3), 1.26 (d, J=5.9 Hz, 3H; 1-H3); 13C NMR
(100 MHz, CDCl3): d=162.2 (C9), 151.6 (C13), 149.7 (C6), 148.8 (C11),
138.2 (C8), 132.2 (C7), 125.1 (C12), 98.72, 98.67 (BDA Cq), 80.6 (C4),
72.7 (C3), 66.3 (C2), 62.1 (C10), 48.0, 47.9 (OCH3), 36.0 (C5), 17.6, 17.4
(BDA CH3), 17.0 (C1); IR (film): nmax = 3200br, 3134, 2951, 1432, 1375,
1121s cmꢀ1; HRMS (ESI+): m/z: calcd for C19H26N3O8: 424.1720; found:
424.1711 [M+H]+.
(MgSO4) and the solvent removed in vacuo. The residue was dissolved in
methanol and stirred at RT for 10 min then evaporated (repeated”5) to
provide the crude diol. Purification by flash chromatography (80% ethyl
acetate/PE) afforded the syn-diol as a colourless oil (112 mg, quant., dr
14:1). Rf = 0.22 (80% ethyl acetate/PE); [a]2D5 =+66.0 (c=1.15, CHCl3);
only peaks for the major diastereoisomer are quoted: 1H NMR
(400 MHz, CDCl3): d=7.79 (s, 1H; 13-H), 7.60–7.54 (m, 4H; Ph-H), 7.53
(s, 1H; 8-H), 7.45–7.31 (m, 6H; Ph-H), 6.94 (s, 1H; 12-H), 5.91 (s, 1H;
10-H), 4.87 (dd, J=9.0, 3.0 Hz, 1H; 6-H), 3.88 (m, 1H; 4-H), 3.78 (dq,
J=9.9, 6.4 Hz, 1H; 2-H), 3.60 (dd, J=9.8, 3.5 Hz, 1H; 3-H), 3.25 (s, 3H;
OCH3), 3.23 (s, 3H; OCH3), 2.02 (m, 1H; 5-H), 1.88 (m, 1H; 5-H’), 1.30,
1.28 (2s, 2”3H; 2”BDA CH3), 1.13 (d, J=6.4 Hz, 3H; 1-H3), 1.06 (s,
9H, C
(CH3)3); 13C NMR (100 MHz, CDCl3): d=160.6 (C9), 151.1 (C13),
A
149.4 (C11), 143.9 (C7), 135.58, 135.57 (Ph-C), 135.1 (C8), 132.0, 132.0
(Ph Cq), 130.1, 130.0, 127.72 and 127.66 (Ph-C), 124.6 (C12), 98.9, 98.7
(BDA Cq), 75.5 (C3), 70.9 (C4), 67.0 (C6), 64.9 (C2), 63.7 (C10), 47.87,
Compound 2: Triethylamine (434 mL, 3.12 mmol) was added to a solution
of 64 (33 mg, 0.078 mmol) in CH2Cl2 (3 mL) at 08C. Myristoyl chloride
(39 mL, 0.156 mmol) was added dropwise to the stirred solution and after
10 min at 08C, saturated aqueous ammonium chloride (10 mL) was
added. The mixture was extracted with ethyl acetate (3”20 mL) and the
combined organic extracts were dried (MgSO4) and the solvent removed
in vacuo. Purification by flash chromatography (20% to 40% ethyl ace-
tate/PE) afforded myristate ester 2 as a colourless oil (36 mg, 73%). Rf
= 0.28 (50% ethyl acetate/PE); [a]2D5 =ꢀ1.9 (c=0.8, CHCl3); 1H NMR
(400 MHz, CDCl3): d=8.05 (s, 1H; 8-H), 7.91 (s, 1H; 13-H), 7.27 (s, 1H;
12-H), 7.11 (s, 1H; 10-H), 4.63 (ddd, J=10.5, 9.0, 5.1 Hz, 1H; 4-H), 3.75–
3.65 (m, 2H; 2-H, 3-H), 3.50 (dd, J=17.3, 9.0 Hz, 1H; 5-H), 3.27 (dd, J=
17.3, 9.0 Hz, 1H; 5-H’), 3.26, 3.25 (2s, 2”3H; 2”OCH3), 2.43 (t, J=
7.5 Hz, 2H; 15-H2), 1.66 (m, 2H; 16-H2), 1.29, 1.27 (2s, 2”3H; 2”BDA
CH3), 1.26 (m, 20H; 17-H2 to 26-H2), 1.26 (d, J=5.9 Hz, 3H; 1-H3), 0.88
(t, J=7.0 Hz, 3H; 27-H3); 13C NMR (100 MHz, CDCl3): d=172.0 (C14),
158.5 (C9), 151.9 (C13), 150.0 (C6), 145.5 (C11), 138.1 (C8), 132.7 (C7),
127.2 (C12), 98.73, 98.67 (BDA Cq), 80.6 (C4), 72.7 (C3), 66.8 (C2), 61.3
(C10), 48.1, 47.9 (OCH3), 36.3 (C5), 33.8 (C15), 31.9, 29.65, 29.62, 29.61,
29.55, 29.40, 29.32, 29.15, 29.0 (C17 to C25), 24.7 (C16), 22.7 (C26), 17.6,
17.4 (BDA CH3), 17.0 (C1), 14.1 (C27); IR (film): nmax = 2925s, 2854,
1752, 1464, 1375, 1122 cmꢀ1; HRMS (ESI+): m/z: calcd for C33H52N3O9:
634.3704; found: 634.3728 [M+H]+.
47.82 (OCH3), 38.0 (C5), 26.6 (C
N
A
16.9 (BDA CH3); IR (film): nmax
=
1038s, 824s, 754s, 702s cmꢀ1
;
C35H47N2O9Si: 667.3051; found: 667.3065 [M+H]+.
para-Toluenesulfonic acid (3 mg) was added to a solution of the diol
(100 mg, 0.15 mmol) in 2,2-dimethoxypropane (2 mL) and stirred at RT
for 2 h. The reaction was quenched by the addition of saturated aqueous
NaHCO3 (30 mL) and extracted with ethyl acetate (3”25 mL). The com-
bined organic extracts were washed with brine, dried (MgSO4) and the
solvent removed in vacuo. Purification by flash chromatography (30%
ethyl acetate/PE) afforded acetonide 32 as a colourless oil (94 mg, 89%).
Rf = 0.41 (60% ethyl acetate/PE); [a]2D5 =+38.3 (c=0.85, CHCl3); 1H
NMR (600 MHz, CDCl3): d=7.78 (s, 1H; 13-H), 7.60–7.54 (m, 4H; Ph-
H), 7.53 (s, 1H; 8-H), 7.45–7.40 (m, 2H; Ph-H), 7.37–7.32 (m, 4H; Ph-
H), 6.93 (s, 1H; 12-H), 5.92 (s, 1H; 10-H), 4.84 (dd, J=11.8, 1.9 Hz, 1H;
6-H), 3.98 (ddd, J=11.4, 7.0, 2.1 Hz, 1H; 4-H), 3.75 (dq, J=9.4, 6.4 Hz,
1H; 2-H), 3.41 (dd, J=9.4, 7.0 Hz, 1H; 3-H), 3.27 (s, 3H; OCH3), 3.24 (s,
3H; OCH3), 2.11 (ddd, J=13.1, 2.1, 1.9 Hz, 1H; 5-Heq), 1.54 (ddd, J=
13.1, 11.8, 11.4 Hz, 1H; 5-Hax), 1.49 (s, 3H; acetonide CH3eq), 1.43 (s,
3H; acetonide CH3ax), 1.30 (s, 6H; 2”BDA CH3), 1.23 (d, J=6.4 Hz,
3H; 1-H3), 1.06 (s, 9H, C
(CH3)3); 13C NMR (150 MHz, CDCl3): d=160.5
A
(C9), 151.1 (C13), 149.4 (C11), 142.5 (C7), 135.68, 135.64 (Ph-C), 135.5
(C8), 132.2, 132.1 (Ph Cq), 130.1, 130.0, 127.75 and 127.69 (Ph-C), 124.8
(C12), 98.9 (acetonide Cq), 98.5, 98.4 (BDA Cq), 74.7 (C3), 69.5 (C4), 67.5
(C2), 65.7 (C6), 63.7 (C10), 47.9, 47.9 (OCH3), 32.7 (C5), 29.9 (acetonide
b-Hydroxy ketone 65: Boric acid (240 mg, 3.87 mmol) was added to a so-
lution of isoxazoline 3 (50 mg, 0.076 mmol) in ethanol (5 mL) and water
(0.5 mL) at RT. Raney nickel (ꢁ1 mL as an aqueous slurry) was added
and the mixture stirred under an atmosphere of hydrogen. After 3 h the
mixture was filtered through a plug of Celite and the solvent removed in
vacuo, azetroping with toluene. The crude product was purified by flash
chromatography (stepped gradient from 20 ! 80% ethyl acetate/PE) to
afford b-hydroxy ketone 65 as a colourless oil (31 mg, 61%). Rf = 0.26
(60% ethyl acetate/PE); [a]2D5 =+56.6 (c=0.6, CHCl3); 1H NMR
(400 MHz, CDCl3): d=8.14 (s, 1H; 8-H), 7.80 (s, 1H; 13-H), 7.59 (t, J=
7.8 Hz, 4H; Ph-H), 7.48–7.41 (m, 2H; Ph-H), 7.39–7.32 (m, 4H; Ph-H),
6.97 (s, 1H; 12-H), 5.97 (s, 1H; 10-H), 4.19 (m, 1H; 4-H), 3.70 (m, 1H;
2-H), 3.62 (dd, J=9.6, 4.6 Hz, 1H; 3-H), 3.23 (s, 3H; OCH3), 3.23 (s, 3H;
OCH3), 3.10 (m, 2H; 5-H2), 1.28, 1.26 (2s, 2”3H; 2”BDA CH3), 1.22 (d,
CH3ax), 26.7 (C
A
17.7, 17.5 (BDA CH3); IR (film): nmax = 2939, 1428, 1380, 1105s, 730s
cmꢀ1; HRMS (ESI+): m/z: calcd for C38H50N2O9SiNa: 729.3183; found:
729.3188 [M+Na]+.
Alcohol 66: TBAF (1m in THF, 0.16 mL, 0.16 mmol) was added to a so-
lution of TBDPS-ether 32 (73 mg, 0.103 mmol) in THF (2 mL) at 08C.
After 15 min water (30 mL) was added and the mixture was extracted
with ethyl acetate (5”20 mL). The combined organic extracts were dried
(MgSO4) and the solvent removed in vacuo. Purification by flash chroma-
tography (40 ! 60% ethyl acetate/PE) afforded the bisoxazole alcohol
66 (48 mg, quant.) as a colourless oil. Rf = 0.14 (60% ethyl acetate/PE);
[a]2D5 =+79.9 (c=0.55, CHCl3); 1H NMR (600 MHz, CDCl3): d=7.89 (s,
1H; 13-H), 7.62 (s, 1H; 8-H), 7.14 (s, 1H; 12-H), 5.99 (d, J=6.3 Hz, 1H;
10-H), 4.95 (dd, J=11.8, 1.4 Hz, 1H; 6-H), 4.03 (ddd, J=11.4, 7.6,
1.8 Hz, 1H; 4-H), 3.75 (dq, J=9.4, 6.4 Hz, 1H; 2-H), 3.55 (d, J=6.3 Hz,
1H; OH), 3.43 (dd, J=9.4, 7.6 Hz, 1H; 3-H), 3.27 (s, 3H; OCH3), 3.24 (s,
3H; OCH3), 2.19 (ddd, J=13.0, 1.8, 1.4 Hz, 1H; 5-Heq), 1.66 (ddd, J=
13.0, 11.8, 11.4 Hz, 1H; 5-Hax), 1.53 (s, 3H; acetonide CH3eq), 1.44 (s,
3H; acetonide CH3ax), 1.29, 1.28 (2s, 2”3H; 2”BDA CH3), 1.24 (d, J=
6.4 Hz, 3H; 1-H3); 13C NMR (150 MHz, CDCl3): d=161.0 (C9), 151.5
(C13), 148.9 (C11), 142.4 (C7), 136.2 (C8), 125.1 (C12), 99.0 (acetonide
Cq), 98.5, 98.4 (BDA Cq), 74.6 (C3), 69.5 (C4), 67.6 (C2), 65.4 (C6), 62.3
(C10), 48.0, 47.9 (OCH3), 32.4 (C5), 29.9 (acetonide CH3eq), 19.7 (aceto-
nide CH3ax), 17.9 (C1), 17.7, 17.5 (BDA CH3); IR (film): nmax = 3240br,
J=6.2 Hz, 3H; 1-H3), 1.08 (s, 9H,
C
(CH3)3); 13C NMR (100 MHz,
A
CDCl3): d = 194.8 (C6), 161.0 (C9), 151.3 (C13), 148.7 (C11), 142.7 (C8),
140.6 (C7), 135.67, 135.61 (Ph-C), 131.8, 131.8 (Ph Cq), 130.25, 130.23,
127.86 and 127.82 (Ph-C), 125.2 (C12), 98.8, 98.6 (BDA Cq), 75.1 (C3),
68.0 (C4), 65.9 (C2), 63.7 (C10), 47.9, 47.8 (OCH3), 42.1 (C5), 26.6 (C-
A
N
= 3420br, 2935, 2860, 1691, 1127s cmꢀ1; HRMS (ESI+): m/z: calcd for
C35H44N2O9SiNa: 687.2714; found: 687.2710 [M+Na]+.
Compound 32: Diethylmethoxyborane (1m in THF, 0.51 mL,
0.505 mmol) was added to a stirred solution of b-hydroxy ketone 65
(112 mg, 0.168 mmol) in THF (3 mL) at ꢀ788C. After 2 h NaBH4 (22 mg,
0.57 mmol) was added and the mixture stirred at ꢀ788C for 16 h. Water
(2 mL) was added and the reaction was warmed to RT, partitioned be-
tween water (20 mL) and ethyl acetate (30 mL) and the layers were sepa-
rated. The aqueous layer was extracted with ethyl acetate (2”20 mL)
and the combined organic extracts were washed with brine, dried
2993, 2936, 1381, 1125s cmꢀ1
C22H32N2O9Na: 491.2006; found: 491.2022 [M+Na]+.
Chem. Eur. J. 2007, 13, 5515 – 5538
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5533

S. V. Ley et al.
Ester67 : Triethylamine (196 mL, 1.41 mmol) was added to a solution of
the bisoxazole alcohol 66 (22 mg, 0.047 mmol) in CH2Cl2 (2.5 mL) at
08C. Myristoyl chloride (19 mL, 0.07 mmol) was added dropwise to the
stirred solution and after 20 min methanol (0.05 mL) was added and the
mixture stirred for a further 5 min. Saturated aqueous NaHCO3 (20 mL)
was added and the mixture extracted with Et2O (5”20 mL). The com-
bined organic extracts were washed with saturated aqueous ammonium
chloride (20 mL), then dried (Na2SO4) and the solvent removed in vacuo.
Purification by flash chromatography (20 ! 40% ethyl acetate/PE) af-
forded acetal-protected bengazole A 67 as a colourless oil (27 mg, 85%).
OCH3), 1.12 (s, 9H, TBDPS C
C
N
(C10), 63.4 (C8), 54.3 (C7), 52.4 (OCH3), 26.8 (TBDPS C
(TBS C(CH3)3), 19.2 (TBDPS C(CH3)3), 18.1 (TBS C
ACHTREUNG
T
G
ACHTREUNG
(TBS CH3); IR (film): nmax = 3427, 2954, 2858, 1750, 1691, 1507, 1104s,
832s, 701s cmꢀ1; HRMS (ESI+): m/z: calcd for C31H45N2O6Si2: 597.2816;
found: 597.2809 [M+H]+.
LiCl (1.20 g, 28.2 mmol) was added portionwise to a stirred solution of
the TBS-ether methyl ester (6.73 g, 11.3 mmol) in dry MeOH (40 mL)
and THF (25 mL) at 08C, followed by the portionwise addition of
NaBH4 (1.07 g, 28.2 mmol). The mixture was allowed to warm slowly to
RT and after 14 h the suspension was quenched with saturated aqueous
NaHCO3 (100 mL) and water (100 mL). The aqueous layer was extracted
with ethyl acetate (3”75 mL) and the combined organic extracts were
dried (MgSO4) and the solvent was removed in vacuo. Purification by
flash chromatography (50% ethyl acetate/PE) afforded primary alcohol
68 as colourless oil (4.96 g, 77%). Rf = 0.28 (60% ethyl acetate/PE);
[a]2D5 =ꢀ27.7 (c=1.3, CHCl3); 1H NMR (600 MHz, CDCl3): d=7.77 (d,
J=7.8 Hz, 1H; N-H), 7.69 (s, 1H; 13-H), 7.63 (d, J=7.1 Hz, 2H; Ph-H),
7.47 (m, 3H; Ph-H), 7.41 (m, 3H; Ph-H), 7.31 (t, J=7.5 Hz, 2H; Ph-H),
6.60 (s, 1H; 12-H), 5.20 (s, 1H; 10-H), 4.00 (m, 1H; 7-H), 3.93 (dd, J=
11.1, 4.0 Hz, 1H; 8-H CHH’OH), 3.99 (dd, J=10.3, 3.3 Hz, 1H; 6-H
CHH’OTBS), 3.81 (dd, J=10.3, 4.2 Hz, 1H; 6-H’ CHH’OTBS), 3.77 (dd,
J=11.1, 4.7 Hz, 1H; 8-H’ CHH’OH), 2.66 (brs, 1H; OH), 1.09 (s, 9H,
Rf
=
0.13 (60% Et2O/PE); [a]2D5 =+47.7 (c=0.35, CHCl3); 1H NMR
(500 MHz, CDCl3): d=7.90 (s, 1H; 13-H), 7.63 (s, 1H; 8-H), 7.24 (s, 1H;
12-H), 7.10 (s, 1H; 10-H), 4.94 (dd, J=11.9, 1.9 Hz, 1H; 6-H), 4.03 (ddd,
J=11.4, 7.3, 2.3 Hz, 1H; 4-H), 3.74 (dq, J=9.5, 6.4 Hz, 1H; 2-H), 3.42
(dd, J=9.5, 7.3 Hz, 1H; 3-H), 3.26, 3.24 (2s, 2”3H; 2”OCH3), 2.41 (t,
7.5 Hz, 2H; 15-H2), 2.19 (ddd, J=13.2, 2.3, 1.9 Hz, 1H; 5-Heq), 1.63 (m,
3H; 16-H2, 5-Hax), 1.51 (s, 3H; acetonide CH3eq), 1.43 (s, 3H; acetonide
CH3ax), 1.29, 1.28 (2s, 2”3H; 2”BDA CH3), 1.26 (m, 20H; 17-H2 to 26-
H2), 1.23 (d, J=6.4 Hz, 3H; 1-H3), 0.89 (t, J=7.2 Hz, 3H; 27-H3); 13C
NMR (125 MHz, CDCl3): d=172.0 (C14), 157.5 (C9), 151.8 (C13), 146.0
(C11), 142.9 (C7), 136.2 (C8), 127.1 (C12), 99.0 (acetonide Cq), 98.4, 98.3
(BDA Cq), 74.6 (C3), 69.6 (C4), 67.5 (C2), 65.6 (C6), 61.3 (C10), 47.95,
47.89 (OCH3), 33.8 (C15), 32.6 (C5), 31.9 (C17), 29.9 (acetonide CH3eq),
29.7, 29.63, 29.62, 29.56, 29.41, 29.33, 29.16, 28.97 (C18 to C25), 24.7
(C16), 22.7 (C26), 19.7 (acetonide CH3ax), 17.9 (C1), 17.7, 17.5 (BDA
CH3), 14.1 (C27); IR (film): nmax = 2925s, 2854, 1753, 1464, 1380, 1126s
cmꢀ1; HRMS (ESI+): m/z: calcd for C36H58N2O10Na: 701.3989; found:
701.3992 [M+Na]+.
TBDPS C
A
G
TBS CH3); 13C NMR (150 MHz, CDCl3): d=168.9 (C9), 150.8 (C13),
148.9 (C11), 135.7, 135.4 (Ph-C), 131.7, 131.4 (Ph Cq), 130.5, 130.2, 128.1
and 127.7 (Ph-C), 125.9 (C12), 68.2 (C10), 63.6 (C8), 63.2 (C6), 52.0 (C7),
Bengazole A (1): Acetal protected bengazole A 67 (22 mg, 0.032 mmol)
was dissolved in TFA/water 1:1 (1 mL) and stirred for 10 min at RT, then
water was added (0.5 mL, to give a 1:2 TFA/water mixture). The reaction
mixture was stirred for 30 min at RT then stirred under reduced pressure
for 15 min (reducing the reaction volume by about half). Saturated aque-
ous NaHCO3 (25 mL) was added dropwise and the mixture extracted
with ethyl acetate (4”25 mL). The combined organic extracts were dried
(Na2SO4) and the solvent removed in vacuo. Purification by flash chro-
matography (5% methanol/CH2Cl2) afforded bengazole A 1 as a colour-
less oil (16 mg, 95%). Rf = 0.24 (10% methanol/ CH2Cl2); [a]2D5 =+6
(c=0.18, MeOH); 1H NMR (600 MHz, CD3OD): d=8.25 (s, 1H; 13-H),
7.85 (s, 1H; 8-H), 7.31 (s, 1H; 12-H), 7.11 (s, 1H; 10-H), 4.91 (dd, J=7.1,
6.9 Hz, 1H; 6-H), 3.92 (dq, J=6.4, 3.4 Hz, 1H; 2-H), 3.67 (ddd, J=9.2,
6.8, 2.5 Hz, 1H; 4-H), 3.18 (dd, J=6.8, 3.4 Hz, 1H; 3-H), 2.43 (t, J=
7.3 Hz, 2H; 15-H2), 2.23 (ddd, J=14.1, 6.9, 2.5 Hz, 1H; 5-H), 1.90 (ddd,
J=14.1, 9.2, 7.1 Hz, 1H; 5-H’), 1.63 (t, J=7.0 Hz, 2H; 16-H2), 1.28 (brm,
20H; 17-H2 to 26-H2), 1.15 (d, J=6.4 Hz, 3H; 1-H3), 0.89 (t, J=7.4 Hz,
3H; 27-H3); 13C NMR (150 MHz, CD3OD): d=173.4 (C14), 159.7 (C9),
154.4 (C13), 147.7 (C11), 145.7 (C7), 138.0 (C8), 127.5 (C12), 78.8 (C3),
71.2 (C4), 67.8 (C2), 66.3 (C6), 62.9 (C10), 40.5 (C5), 34.5 (C15), 33.1,
30.77, 30.73, 30.73, 30.67, 30.55, 30.45, 30.3, 30.0 (C17 to C25), 25.8 (C16),
23.7 (C26), 19.9 (C1), 14.4 (C27); IR (film): nmax = 3360br, 2923, 2854,
1751 cmꢀ1; HRMS (ESI+): m/z: calcd for C27H45N2O8: 525.3176; found:
525.3163 [M+H]+.
26.8 (TBDPS C
18.3 (TBS C
N
A
ACHTREUNG
A
=
Bisoxazole ent-62: NaHCO3 (6.78 g, 80.7 mmol) was suspended in
CH2Cl2 (22 mL) and Dess–Martin periodinane (2.97 g, 6.99 mmol) was
added at RT. The mixture was stirred for 5 min, cooled to 08C and then
a solution of alcohol 68 (3.06 g, 5.38 mmol) in CH2Cl2 (30 mL) was added
dropwise to the DMP suspension. The reaction mixture was stirred at
08C for 2 h before adding a 1:1 mixture of saturated aqueous NaHCO3
and sodium thiosulphate solutions (120 mL). This was stirred for 5 min
then partitioned between water (100 mL) and ethyl acetate (100 mL) and
the layers separated. The aqueous layer was extracted with ethyl acetate
(2”100 mL). The combined organic extracts were washed with brine,
dried (MgSO4) and the solvent removed in vacuo to give the crude alde-
hyde. The crude aldehyde was dissolved in CH2Cl2 (240 mL) and cooled
to 08C. Di-tert-butylpyridine (20.6 g, 107.6 mmol) was added, followed by
PPh3 (7.06 g, 26.9 mmol) then dibromotetrachloroethane (20.6 g,
107.6 mmol) was added portionwise to the stirred solution. The reaction
mixture was stirred at 08C for 3 h 30 min. Triethylamine (6.19 mL,
44.5 mmol) in MeCN (20 mL) was added and the mixture was allowed to
warmto RT, then stirred for a further 42 h before filtering through a pad
of silica gel eluting with CH2Cl2. The solvent was removed in vacuo and
purification by flash chromatography (20 ! 40% Et2O/PE) afforded a
single enantiomer of bisoxazole ent-62 as a yellow oil (2.21 g, 75% over 2
steps). [a]2D5 =+13.4 (c=0.65, CHCl3); Rf, IR and NMR data identical to
62 above; chiral HPLC retention times as quoted above; HRMS (ESI+):
m/z: calcd for C30H41N2O4Si2: 549.2605; found: 549.2592 [M+H]+.
Alcohol 68: Imidazole (1.65 g, 2.08 mmol) and DMAP (15 mg) were
added to a solution of serine-amide 44 (5.84 g, 12.1 mmol) in DMF
(35 mL), followed by the addition of TBSCl (2.19 g, 14.5 mmol) at RT.
The mixture was stirred for 90 min, then quenched by the addition of sa-
turated aqueous NaHCO3 (100 mL) and water (50 mL). The aqueous so-
lution was extracted with Et2O (2”75 mL) and the combined organic ex-
tracts were washed with 10% w/v aqueous LiCl (10 mL). The combined
aqueous washes were extracted with Et2O (75 mL) and the combined or-
ganic extracts dried (MgSO4) and the solvent removed in vacuo. Purifica-
tion by flash chromatography (30 ! 40 ! 50% ethyl acetate/PE) afford-
ed the TBS ether as a colourless gum(6.85 g, 95%). Rf = 0.54 (80%
ethyl acetate/PE); [a]D25 =ꢀ26.4 (c=1.6, CHCl3); 1H NMR (400 MHz,
CDCl3): d=8.00 (d, J=8.2 Hz, 1H; N-H), 7.66 (s, 1H; 13-H), 7.65 (d, J=
6.7 Hz, 2H; Ph-H), 7.47 (d, J=6.7 Hz, 3H; Ph-H), 7.40 (t, J=7.5 Hz,
3H; Ph-H), 7.30 (t, J=7.5 Hz, 2H; Ph-H), 6.69 (s, 1H; 12-H), 5.24 (s,
1H; 10-H), 4.68 (ddd, J=8.2, 2.7, 2.4 Hz, 1H; 7-H), 4.18 (dd, J=10.2,
2.4 Hz, 1H; 8-H), 3.91 (dd, J=10.2, 2.7 Hz, 1H; 8-H’), 3.79 (s, 3H;
Alcohol ent-63: PPTS (680 mg, 2.70 mmol) was added to a solution of
TBS-ether ent-62 (2.12 g, 3.86 mmol) in methanol (30 mL) at RT. The so-
lution was stirred for 3 h, then extra PPTS (340 mg, 1.35 mmol) was
added. After a total of 8 h the reaction was quenched by the addition of
saturated aqueous NaHCO3 (150 mL) and water (50 mL). The mixture
was extracted with ethyl acetate (3”150 mL) and the combined organic
extracts were dried (MgSO4) and the solvent removed in vacuo. Purifica-
tion by flash chromatography (50 ! 70% ethyl acetate/PE) afforded pri-
mary alcohol ent-63 as a pale yellow oil (1.47 g, 96%, >98% ee by chiral
SFC). [a]2D5 =+10.6 (c=0.65, CHCl3); Rf, IR and NMR data identical to
5534
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 5515 – 5538

Total Synthesis of Bengazoles A and B
FULL PAPER
63 above; HPLC and SFC retention times as quoted above; HRMS
(ESI+): m/z: calcd for C24H27N2O4Si: 435.1740; found: 435.1741 [M+H]+.
(2s, 2”3H; 2”OCH3), 3.09 (m, 2H; 5-H2), 1.28, 1.25 (2s, 2”3H; 2”
BDA CH3), 1.21 (d, J=6.3 Hz, 3H; 1-H3), 1.08 (s, 9H, C
(CH3)3); 13C
A
NMR (100 MHz, CDCl3): d=194.9 (C6), 161.0 (C9), 151.3 (C13), 148.8
(C11), 142.7 (C8), 140.6 (C7), 135.65, 135.62 (Ph-C), 131.84, 131.78 (Ph
Cq), 130.3, 130.2, 127.87 and 127.81 (Ph-C), 125.2 (C12), 98.8, 98.6 (BDA
Cq), 75.2 (C3), 68.0 (C4), 65.9 (C2), 63.6 (C10), 47.9, 47.8 (OCH3), 42.0
Oxime ent-33: Dess–Martin periodinane (2.11 g, 4.97 mmol) and
NaHCO3 (4.17 g, 49.7 mmol) were suspended in CH2Cl2 (10 mL) and
cooled to 08C. A solution of primary alcohol ent-63 (1.44 g, 3.31 mmol)
in CH2Cl2 (12 mL) was added dropwise and the mixture was stirred at
08C for 2 h. Further NaHCO3 (2.1 g, 25 mmol) and Dess–Martin periodi-
nane (1.05 g, 2.5 mmol) were added and the mixture was stirred for a fur-
ther 2h; before adding a 1:1 mixture of saturated aqueous NaHCO3 and
sodium thiosulphate solutions (150 mL). The mixture was stirred for
10 min then partitioned between water (100 mL) and ethyl acetate
(150 mL) and the layers separated. The aqueous layer was extracted with
ethyl acetate (2”50 mL) and the combined organic extracts were washed
with brine, dried (Na2SO4) and the solvent removed in vacuo to give the
crude aldehyde, which was used without purification.
(C5), 26.6 (C
N
N
IR (film): nmax = 3440br, 2933, 2859, 1692, 1126s cmꢀ1; HRMS (ESI+):
m/z: calcd for C35H44N2O9SiNa: 687.2714; found: 687.2690 [M+Na]+.
Diethylmethoxyborane (1m in THF, 0.43 mL, 0.43 mmol) was added to a
solution of the b-hydroxy ketone (96 mg, 0.144 mmol) in THF (2.5 mL)
at ꢀ788C. After 2 h, NaBH4 (20 mg, 0.50 mmol) was added and the mix-
ture stirred at ꢀ788C for 15 h. Water (2 mL) was added and the reaction
was warmed to RT, partitioned between water (30 mL) and ethyl acetate
(30 mL) then the layers were separated. The aqueous layer was extracted
with ethyl acetate (2”20 mL) then the combined organic extracts were
washed with brine, dried (MgSO4) and the solvent removed in vacuo.
The residue was dissolved in methanol and stirred at RT for 10 min then
evaporated (repeated”5), to provide the crude diol. Purification by flash
chromatography (30% ethyl acetate/PE) afforded the syn-diol as a col-
ourless oil (89 mg, 93%, C6 dr 17:1 by 1H NMR). Rf = 0.22 (80% ethyl
acetate/PE); [a]2D5 =+120.6 (c=1.1, CHCl3); only NMR peaks for the
major diastereoisomer are quoted; 1H NMR (400 MHz, CDCl3): d=7.79
(s, 1H; 13-H), 7.61–7.54 (m, 4H; Ph-H), 7.52 (s, 1H; 8-H), 7.45–7.31 (m,
6H; Ph-H), 6.93 (s, 1H; 12-H), 5.90 (s, 1H; 10-H), 4.89 (dd, J=8.8,
3.0 Hz, 1H; 6-H), 3.90 (m, 1H; 4-H), 3.77 (dq, J=9.6, 6.3 Hz, 1H; 2-H),
3.61 (dd, J=9.7, 3.5 Hz, 1H; 3-H), 3.26, 3.20 (2s, 2”3H; 2”OCH3), 2.03
(m, 1H; 5-H), 1.94 (m, 1H; 5-H’), 1.30, 1.28 (2s, 2”3H; 2”BDA CH3),
A solution of hydroxylamine hydrochloride (457 mg, 6.62 mmol) and
Na2CO3 (350 mg, 3.31 mmol) in water (2 mL) was added to a solution of
the crude aldehyde in methanol (25 mL) at 08C. After 1 h the solution
was poured into brine (60 mL) and water was added (60 mL). The aque-
ous mixture was extracted with ethyl acetate (3”150 mL) and the com-
bined organic extracts were dried (Na2SO4) and the solvent removed in
vacuo. Purification by flash chromatography (35% ethyl acetate/PE) af-
forded oxime ent-33 as a white foam(1.29 g, 87% over 2 steps, cis/trans
4:5). [a]2D5 =+37.7 (c=1.0, CHCl3); Rf, IR and NMR data identical to 33
above. HRMS (ESI+): m/z: calcd for C24H25N3O4SiNa: 470.1512; found:
470.1505 [M+Na]+.
Isoxazoline 69: N-Chlorosuccinimide (95 mg, 0.713 mmol) was added in
one portion to a solution of oxime ent-33 (290 mg, 0.648 mmol) in
CH2Cl2 (9 mL) and pyridine (3 mL) at RT. The reaction mixture was
stirred in the dark for 1 h and the solvent removed in vacuo to provide
the crude chlorooxamic acid.
1.13 (d, J=6.3 Hz, 3H; 1-H3), 1.06 (s, 9H,
C
(CH3)3); 13C NMR
A
(100 MHz, CDCl3): d=160.7 (C9), 151.1 (C13), 149.4 (C11), 143.9 (C7),
135.6, 135.6 (Ph-C), 135.0 (C8), 132.0, 132.0 (Ph Cq), 130.1, 130.0, 127.74
and 127.68 (Ph-C), 124.7 (C12), 98.9, 98.6 (BDA Cq), 75.4 (C3), 70.9
(C4), 66.9 (C6), 64.9 (C2), 63.6 (C10), 47.9, 47.8 (OCH3), 37.9 (C5), 26.6
A solution of alkene 7 (1.40 g, 6.48 mmol) in DME (29 mL) was added to
the crude chlorooxamic acid and cooled to 08C. Cs2CO3 (232 mg,
0.713 mmol) was added in one portion and the mixture was stirred vigo-
rously for 15 h warming slowly to RT. Saturated aqueous NaHCO3
(60 mL) and water (20 mL) were added and the mixture was extracted
with ethyl acetate (4”50 mL). The combined organic extracts were dried
(MgSO4) and the solvent removed in vacuo and purification by Biotage
flash chromatography (gradient from 10% Et2O/PE ! 90% Et2O/PE in
3 stages) provided major cycloadduct 69 as a white foam(218 mg, 51%),
followed by minor cycloadduct 69a as a white foam(90 mg, 21%).
(C
N
N
nmax =3386br, 2934, 1429, 1377, 1113s, 1038s, 824s, 754s cmꢀ1; HRMS
(ESI+): m/z: calcd for C35H47N2O9Si: 667.3051; found: 667.3049 [M+H]+.
para-Toluenesulfonic acid (3 mg) was added to a solution of the diol in
2,2-dimethoxypropane (2 mL) and stirred at RT for 2 h. The reaction was
quenched by the addition of saturated aqueous NaHCO3 (30 mL) and ex-
tracted with ethyl acetate (3”25 mL). The combined organic extracts
were washed with brine, dried (MgSO4) and the solvent removed in
vacuo. Purification by flash chromatography (30% ethyl acetate/PE) af-
forded acetonide 70 as a colourless oil (82 mg, 97%, C6 dr 19.5:1 by
Major cycloadduct isoxazoline 69: Rf = 0.42 (60% ethyl acetate/PE);
[a]2D5 =+27.0 (c=1.1, CHCl3); 1H NMR (400 MHz, CDCl3): d=7.93 (s,
1H; 8-H), 7.80 (s, 1H; 13-H), 7.58 (t, J=7.4 Hz, 4H; Ph-H), 7.46–7.31
(m, 6H; Ph-H), 6.97 (s, 1H; 12-H), 5.98 (s, 1H; 10-H), 4.63 (ddd, J=
10.8, 8.8, 5.5 Hz, 1H; 4-H), 3.70 (dq, J=9.7, 6.1 Hz, 2H; 2-H), 3.64 (dd,
J=9.7, 5.5 Hz, 1H; 3-H), 3.43 (dd, J=17.2, 8.8 Hz, 1H; 5-H), 3.26, 3.23
(2s, 2”3H; 2”OCH3), 3.18 (dd, J=17.2, 10.8 Hz, 1H; 5-H’), 1.29, 1.26
(2s, 2”3H; 2”BDA CH3), 1.27 (d, J=6.1 Hz, 3H; 1-H3), 1.07 (s, 9H, C-
1H NMR); Rf
=
0.20 (30% ethyl acetate/PE); [a]2D5 =+69.5 (c=0.85,
CHCl3); only NMR peaks for the major diastereoisomer are quoted; 1H
NMR (400 MHz, CDCl3): d=7.79 (s, 1H; 13-H), 7.60–7.53 (m, 4H; Ph-
H), 7.51 (s, 1H; 8-H), 7.46–7.40 (m, 2H; Ph-H), 7.38–7.30 (m, 4H; Ph-
H), 6.93 (s, 1H; 12-H), 5.92 (s, 1H; 10-H), 4.84 (dd, J=11.7, 1.9 Hz, 1H;
6-H), 3.99 (ddd, J=11.3, 7.1, 2.1 Hz, 1H; 4-H), 3.74 (dq, J=9.4, 6.4 Hz,
1H; 2-H), 3.41 (dd, J=9.4, 7.1 Hz, 1H; 3-H), 3.26, 3.22 (2s, 2”3H; 2”
OCH3), 2.11 (ddd, J=13.5, 2.1, 1.9 Hz, 1H; 5-Heq), 1.59 (ddd, J=13.5,
11.7, 11.3 Hz, 1H; 5-Hax), 1.50 (s, 3H; acetonide CH3eq), 1.42 (s, 3H; ace-
tonide CH3ax), 1.28 (s, 6H; 2”BDA CH3), 1.23 (d, J=6.4 Hz, 3H; 1-H3),
A
(C6), 149.0 (C11), 137.5 (C8), 135.64, 135.59 (Ph-C), 132.0 (C7), 131.9,
131.9 (Ph Cq), 130.1, 130.0, 127.8 and 127.7 (Ph-C), 125.0 (C12), 98.7, 98.6
(BDA Cq), 80.4 (C4), 72.7 (C3), 66.5 (C2), 63.6 (C10), 48.0, 47.9 (OCH3),
1.06 (s, 9H; C
(CH3)3); 13C NMR (100 MHz, CDCl3): d=160.6 (C9), 151.1
U
36.4 (C5), 26.6 (C
N
N
(C1); IR (film): nmax = 2935, 2859, 1429, 1115s cmꢀ1; HRMS (ESI+): m/
z: calcd for C35H43N3O8SiNa: 684.2717; found: 684.2718 [M+Na]+.
(C13), 149.4 (C11), 142.3 (C7), 135.67, 135.66 (Ph-C), 135.4 (C8), 132.1,
132.1 (Ph Cq), 130.1, 129.9, 127.8 and 127.7 (Ph-C), 124.9 (C12), 98.9
(acetonide Cq), 98.5, 98.4 (BDA Cq), 74.7 (C3), 69.6 (C4), 67.5 (C2), 65.5
(C6), 63.7 (C10), 47.9, 47.9 (OCH3), 32.6 (C5), 29.9 (acetonide CH3ax),
Compound 70: Boric acid (1.48 g, 24 mmol) was added to a solution of
isoxazoline 69 (215 mg, 0.32 mmol) in ethanol (20 mL) and water (4 mL)
at RT. Raney nickel (ꢁ1 mL as an aqueous slurry) was added and the
mixture was stirred under an atmosphere of hydrogen. After 22 h the
mixture was filtered through a plug of Celite eluting with methanol and
evaporated, and azetroped fromtoluene. Purification by flash chromatog-
raphy (35 ! 45% ethyl acetate/PE) afforded the b-hydroxy ketone as a
26.7 (C
U
G
;
HRMS (ESI+): m/z: calcd for C38H50N2O9SiNa: 729.3183; found:
729.3192 [M+Na]+.
Ester71 : TBAF (1m in THF, 0.21 mL, 0.21 mmol) was added to a solu-
tion of TBDPS-ether 70 (99 mg, 0.14 mmol) in THF (2.5 mL) at 08C.
After 15 min, water (20 mL) was added and the mixture was extracted
with ethyl acetate (5”20 mL). The combined organic extracts were dried
(MgSO4) and the solvent removed in vacuo. Purification by flash chroma-
tography (40 ! 60% ethyl acetate/PE) afforded bisoxazole secondary al-
colourless oil (104 mg, 49%). Rf = 0.30 (60% ethyl acetate/PE); [a]D25
=
+76.0 (c=0.75, CHCl3); 1H NMR (400 MHz, CDCl3): d=8.14 (s, 1H; 8-
H), 7.80 (s, 1H; 13-H), 7.61–7.56 (m, 4H; Ph-H), 7.46–7.32 (m, 6H; Ph-
H), 6.97 (s, 1H; 12-H), 5.96 (s, 1H; 10-H), 4.15 (m, 1H; 4-H), 3.70 (dq,
J=9.6, 6.3 Hz, 1H; 2-H), 3.62 (dd, J=9.6, 4.5 Hz, 1H; 3-H), 3.23, 3.22
Chem. Eur. J. 2007, 13, 5515 – 5538
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5535

S. V. Ley et al.
cohol as a colourless oil (63 mg, 96%). Rf = 0.12 (60% ethyl acetate/
Acid chloride 74: Oxalyl chloride (44 mL, 0.51 mmol) was added to a so-
lution of acid 73 in CH2Cl2 (1 mL) followed by one drop of DMF. The
mixture was stirred at RT for 1 h and the solvent was removed in vacuo
to leave a yellow oil. NMR analysis showed complete conversion. The oil
was dissolved in dry CH2Cl2 (1 mL) to give a stock solution of the acid
chloride 74 (0.17m). 1H NMR (400 MHz, CDCl3): d=2.29 (t, J=7.3 Hz,
2H; 15-H2), 1.72 (m, 2H; 16-H2), 1.53 (m, 2H; CH2), 1.27 (brm, 17H;
8”CH2, 26-H), 1.16 (m, 2H; CH2), 0.86 (d, J=6.6 Hz, 6H; 2”CH3); 13C
NMR (100 MHz, CDCl3): d=173.8 (C14), 47.1 (C15), 39.1 (CH2), 29.9
(CH2), 29.7 (CH2), 29.6 (CH2), 29.5 (CH2), 29.3 (CH2), 29.1 (CH2), 28.4
(CH2), 28.0 (C26), 27.4 (CH2), 25.1 (CH2), 22.6 (2”CH3); IR (film): nmax
1
PE); [a]2D5 =+66.3 (c=1.2, CHCl3); H NMR (400 MHz, CDCl3): d=7.88
(s, 1H; 13-H), 7.58 (s, 1H; 8-H), 7.11 (s, 1H; 12-H), 6.02 (d, J=6.3 Hz,
1H; 10-H), 4.89 (dd, J=11.7, 1.8 Hz, 1H; 6-H), 3.89 (ddd, J=11.2, 7.3,
2.0 Hz, 1H; 4-H), 3.73 (dq, J=9.5, 6.3 Hz, 1H; 2-H), 3.39 (dd, J=9.5,
7.3 Hz, 1H; 3-H), 3.24, 3.21 (2s, 2”3H; 2”OCH3), 2.14 (ddd, J=13.2,
2.0, 1.8 Hz, 1H; 5-Heq), 1.63 (ddd, J=13.2, 11.7, 11.2 Hz, 1H; 5-Hax), 1.49
(s, 3H; acetonide CH3eq), 1.41 (s, 3H; acetonide CH3ax), 1.26, 1.25 (2s, 2”
3H; 2”BDA CH3), 1.21 (d, J=6.3 Hz, 3H; 1-H3); 13C NMR (100 MHz,
CDCl3): d=161.5 (C9), 151.5 (C13), 149.2 (C11), 142.2 (C7), 136.0 (C8),
124.9 (C12), 99.0 (acetonide Cq), 98.5, 98.4 (BDA Cq), 74.5 (C3), 69.6
(C4), 67.6 (C2), 65.4 (C6), 62.1 (C10), 47.9, 47.8 (OCH3), 32.4 (C5), 29.9
(acetonide CH3eq), 19.7 (acetonide CH3ax), 17.8 (C1), 17.6, 17.4 (BDA
CH3); IR (film): nmax = 3240br, 2993, 1381, 1124 cmꢀ1; HRMS (ESI+):
m/z: calcd for C22H32N2O9Na: 491.2006; found: 491.2020 [M+Na]+.
= 2926s, 2855, 1803 cmꢀ1
.
Compound 75: Triethylamine (107 mL, 0.767 mmol) was added to a solu-
tion of the bisoxazole alcohol 66 (12 mg, 0.026 mmol) in CH2Cl2 (1 mL)
at 08C. Acid chloride 74 (0.17m in CH2Cl2, 0.23 mL, 0.038 mmol) was
added dropwise to the stirred solution and after 25 min methanol
(0.05 mL) was added and the mixture stirred for a further 5 min. Saturat-
ed aqueous NaHCO3 (20 mL) was added and the mixture extracted with
Et2O (4”20 mL). The combined organic extracts were washed with satu-
rated aqueous ammonium chloride (20 mL) then dried (Na2SO4) and the
solvent removed in vacuo. Purification by flash chromatography (20 !
40% ethyl acetate/PE) afforded acetal-protected bengazole B 75 as a col-
ourless oil (15 mg, 85%). Rf = 0.13 (60% Et2O/PE); [a]2D5 =+73.2 (c=
0.65, CHCl3); 1H NMR (500 MHz, CDCl3): d=7.90 (s, 1H; 13-H), 7.63
(s, 1H; 8-H), 7.24 (s, 1H; 12-H), 7.10 (s, 1H; 10-H), 4.94 (dd, J=11.8,
2.2 Hz, 1H; 6-H), 4.01 (ddd, J=11.4, 7.3, 2.3 Hz, 1H; 4-H), 3.74 (dq, J=
9.4, 6.4 Hz, 1H; 2-H), 3.41 (dd, J=9.4, 7.3 Hz, 1H; 3-H), 3.26, 3.23 (2s,
2”3H; 2”OCH3), 2.40 (t, 7.5 Hz, 2H; 15-H2), 2.19 (ddd, J=13.2, 2.3,
2.2 Hz, 1H; 5-Heq), 1.64 (m, 2H; 16-H2), 1.61 (ddd, J=13.2, 11.8,
11.4 Hz, 1H; 5-Hax), 1.51 (s, 4H; acetonide CH3eq), 1.51 (m, 1H; 26-H),
1.43 (s, 3H; acetonide CH3ax), 1.28, 1.27 (2s, 2”3H; 2”BDA CH3), 1.25
(m, 16H; 8”CH2), 1.23 (d, J=6.4 Hz, 3H; 1-H3), 1.15 (m, 2H; CH2),
0.86 (d, J=7.2 Hz, 6H; 27-H3 and 28-H3); 13C NMR (125 MHz, CDCl3):
d=172.0 (C14), 157.5 (C9), 151.8 (C13), 145.9 (C11), 142.9 (C7), 136.2
(C8), 127.0 (C12), 99.0 (acetonide Cq), 98.4, 98.3 (BDA Cq), 74.5 (C3),
69.6 (C4), 67.5 (C2), 65.6 (C6), 61.3 (C10), 47.93 (OCH3), 47.89 (OCH3),
39.0 (CH2), 33.8 (C15), 32.6 (C5), 29.90 (CH2), 29.88 (acetonide CH3eq),
29.67, 29.61, 29.55, 29.42, 29.39, 29.14, 28.94 (7”CH2), 28.0 (C26), 27.4
(CH2), 24.7 (C16), 22.6 (C27, C28), 19.7 (acetonide CH3ax), 17.9 (C1),
17.7, 17.5 (BDA CH3); IR (film): nmax = 2926s, 2855, 1753, 1464, 1380,
Triethylamine (180 mL, 1.28 mmol) was added to a solution of the bisoxa-
zole secondary alcohol (20 mg, 0.043 mmol) in CH2Cl2 (2 mL) at 08C.
Myristoyl chloride (18 mL, 0.64 mmol) was added dropwise to the stirred
solution and after 20 min methanol (0.05 mL) was added and the mixture
stirred for a further 5 min. The reaction mixture was partitioned between
saturated aqueous NaHCO3 (20 mL) and Et2O (20 mL) and the layers
separated. The aqueous layer was extracted with Et2O (3”20 mL) and
the combined organic extracts were washed with saturated aqueous am-
monium chloride (20 mL) then dried (MgSO4) and the solvent removed
in vacuo. Purification by flash chromatography (20 ! 30 ! 40 ! 50%
Et2O/PE) afforded acetal-protected 10-epi-bengazole A 71 as a colourless
oil (21 mg, 90%). Rf
=
0.13 (60% Et2O/PE); [a]2D5 =+56.4 (c=1.05,
1
CHCl3); H NMR (500 MHz, CDCl3): d=7.90 (s, 1H; 13-H), 7.63 (s, 1H;
8-H), 7.24 (s, 1H; 12-H), 7.09 (s, 1H; 10-H), 4.94 (dd, J=11.9, 2.2 Hz,
1H; 6-H), 4.01 (ddd, J=11.4, 7.2, 2.3 Hz, 1H; 4-H), 3.74 (dq, J=9.5,
6.4 Hz, 1H; 2-H), 3.41 (dd, J=9.5, 7.2 Hz, 1H; 3-H), 3.25, 3.23 (2s, 2”
3H; 2”OCH3), 2.40 (t, 7.8 Hz, 2H; 15-H2), 2.19 (ddd, J=13.2, 2.3,
2.2 Hz, 1H; 5-Heq), 1.64 (m, 2H; 16-H2), 1.61 (ddd, J=13.2, 11.9,
11.4 Hz, 1H; 5-Heq), 1.51 (s, 3H; acetonide CH3eq), 1.43 (s, 3H; acetonide
CH3ax), 1.28, 1.27 (2s, 2”3H; 2”BDA CH3), 1.26 (m, 20H; 17-H2 to 26-
H2), 1.23 (d, J=6.4 Hz, 3H; 1-H3), 0.89 (t, J=7.2 Hz, 3H; 27-H3); 13C
NMR (125 MHz, CDCl3): d=172.0 (C14), 157.5 (C9), 151.8 (C13), 145.9
(C11), 142.9 (C7), 136.5 (C8), 127.0 (C12), 99.0 (acetonide Cq), 98.4, 98.3
(BDA Cq), 74.5 (C3), 69.6 (C4), 67.5 (C2), 65.6 (C6), 61.3 (C10), 47.94,
47.89 (OCH3), 33.8 (C15), 32.6 (C5), 31.9 (C17), 29.9 (acetonide CH3eq),
29.64, 29.61, 29.60, 29.54, 29.38, 29.32, 29.14, 28.94 (C18 to C25), 24.7
(C16), 22.7 (C26), 19.7 (acetonide CH3ax), 17.9 (C1), 17.7, 17.5 (BDA
CH3), 14.1 (C27); IR (film): nmax = 2925s, 2854, 1753, 1463w, 1380, 1125s
cmꢀ1; HRMS (ESI+): m/z: calcd for C36H58N2O10Na: 701.3989; found:
701.4001 [M+Na]+.
1126s cmꢀ1
found: 693.4296 [M+Na]+.
Bengazole (76): Acetal protected bengazole
;
HRMS (ESI+): m/z: calcd for C37H61N2O10
:
693.4326;
B
B
75 (13 mg,
0.0188 mmol) was dissolved in TFA/water 1:1 (1 mL) and stirred for
15 min, then extra water was added (0.5 mL, to give a 1:2 mixture). The
mixture was stirred for 40 min at RT then stirred under reduced pressure
for 15 min, (reducing the reaction volume by about half). Saturated aque-
ous NaHCO3 (25 mL) was added dropwise and the mixture extracted
with ethyl acetate (4”25 mL). The combined organic extracts were dried
(Na2SO4) and the solvent removed in vacuo. Purification by flash chro-
10-epi-Bengazole A 72: Acetal protected 10-epi-bengazole A 71 (20 mg,
0.029 mmol) was dissolved in TFA/water 1:1 (1 mL) and stirred at RT for
5 min, then extra water (0.5 mL, to give a 1:2 mixture) was added. The
mixture was stirred for at RT 30 min, then stirred under reduced pressure
for 10 min, (reducing the reaction volume by about half). Saturated aque-
ous NaHCO3 (15 mL) was added dropwise and the mixture extracted
with ethyl acetate (3”15 mL). The combined organic extracts were dried
(Na2SO4) and the solvent removed in vacuo. Purification by flash chro-
matography (5% methanol/CH2Cl2) afforded 10-epi-bengazole A 72 as a
matography (5% methanol/CH2Cl2) afforded 76 as
a colourless oil
(10 mg, 98%). Rf = 0.24 (10% methanol/CH2Cl2); [a]2D5 =+11 (c=0.045,
MeOH); 1H NMR (600 MHz, CD3OD): d=8.26 (s, 1H; 13-H), 7.86 (s,
1H; 8-H), 7.31 (s, 1H; 12-H), 7.11 (s, 1H; 10-H), 4.91 (dd, J=7.1, 6.9 Hz,
1H; 6-H), 3.92 (dq, J=6.4, 3.3 Hz, 1H; 2-H), 3.67 (ddd, J=9.3, 6.8,
2.5 Hz, 1H; 4-H), 3.18 (dd, J=6.8, 3.3 Hz, 1H; 3-H), 2.43 (t, J=7.3 Hz,
2H; 15-H2), 2.23 (ddd, J=14.1, 6.9, 2.5 Hz, 1H; 5-H), 1.90 (ddd, J=14.1,
9.3, 7.1 Hz, 1H; 5-H’), 1.63 (m, 2H; 16-H2), 1.52 (m, 1H; 26-H), 1.28
(brm, 16H; 8”CH2), 1.16 (m, 2H; CH2), 1.15 (d, J=6.4 Hz, 3H; 1-H3),
0.88 (d, J=6.6 Hz, 6H; 27-H3, 28-H3); 13C NMR (150 MHz, CD3OD): d=
171.9 (C14), 158.2 (C9), 153.0 (C13), 146.3 (C11), 144.2 (C7), 136.6 (C8),
126.1 (C12), 77.3 (C3), 69.8 (C4), 66.3 (C2), 64.8 (C6), 61.4 (C10), 39.0
(C5), 38.8 (C15), 33.1, 29.6, 29.4, 29.3, 29.2, 29.1, 28.9, 28.6, 27.7 (C17 to
C25), 27.1 (C26), 24.4 (C16), 21.6 (C27, C28), 18.4 (C1); 13C NMR
(600 MHz, CDCl3): d=7.92 (s, 1H; 13-H), 7.65 (s, 1H; 8-H), 7.24 (s, 1H;
12-H), 7.06 (s, 1H; 10-H), 5.00 (brd, J=9.3 Hz, 1H; 6-H), 4.08 (brs, 2H;
2-H, 4-H), 4.00 (brs, 2H; 2”OH), 3.33 (brs, 1H; 3-H), 3.00 (brs, 2H; 2”
OH), 2.42 (t, J=7.2 Hz, 2H; 15-H2), 2.13 (brd, J=14.3 Hz, 1H; 5-H),
1.98 (m, 1H; 5-H’), 1.65 (m, 2H; 16-H2), 1.52 (m, 1H; 26-H), 1.28 (brm,
colourless oil (13 mg, 85%). Rf = 0.24 (10% methanol/CH2Cl2); [a]D25
=
ꢀ1.6 (c=0.65, MeOH); 1H NMR (600 MHz, CD3OD): d=8.26 (s, 1H;
13-H), 7.86 (s, 1H; 8-H), 7.31 (s, 1H; 12-H), 7.11 (s, 1H; 10-H), 4.91 (dd,
J=7.1, 6.9 Hz, 1H; 6-H), 3.93 (dq, J=6.4, 3.4 Hz, 1H; 2-H), 3.68 (ddd,
J=9.2, 6.8, 2.5 Hz, 1H; 4-H), 3.19 (dd, J=6.8, 3.4 Hz, 1H; 3-H), 2.43 (t,
J=7.3 Hz, 2H; 15-H2), 2.24 (ddd, J=14.1, 6.9, 2.5 Hz, 1H; 5-H), 1.90
(ddd, J=14.1, 9.2, 7.1 Hz, 1H; 5-H’), 1.63 (t, J=7.0 Hz, 2H; 16-H2), 1.28
(brm, 20H; 17-H2 to 26-H2), 1.16 (d, J=6.4 Hz, 3H; 1-H3), 0.89 (t, J=
7.4 Hz, 3H; 27-H3); 13C NMR (150 MHz, CD3OD): d=173.4 (C14), 159.7
(C9), 154.4 (C13), 147.7 (C11), 145.6 (C7), 138.0 (C8), 127.5 (C12), 78.7
(C3), 71.2 (C4), 67.7 (C2), 66.3 (C6), 62.8 (C10), 40.4 (C5), 34.5 (C15),
33.1, 30.8–30.0 (C17 to C25), 25.8 (C16), 23.7 (C26), 19.9 (C1), 14.4
(C27); IR (film): nmax = 3350br, 2923, 2854, 1751 cmꢀ1; HRMS (ESI+):
m/z: calcd for C27H45N2O8: 525.3176; found: 525.3179 [M+H]+.
5536
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Chem. Eur. J. 2007, 13, 5515 – 5538

Total Synthesis of Bengazoles A and B
FULL PAPER
18H, 17-H2 to 25-H2), 1.15 (d, J=6.3 Hz, 3H; 1-H3), 0.87 (d, J=6.6 Hz,
6H; 27-H3, 28-H3); 13C NMR (150 MHz, CDCl3): d=172.1 (C14), 158.0
(C9), 152.0 (C13), 145.7 (C11), 144.1 (C7), 135.7 (C8), 127.0 (C12), 76.4
(C3), 73.7 (C4), 67.5 (C2), 66.9 (C6), 61.3 (C10), 39.0 (C15), 38.4 (C5),
33.8, 29.9, 29.7, 29.6, 29.5, 29.4, 29.1, 29.0, 27.9, 27.4 (C17 to C26), 24.7
(C16), 22.6 (C27, C28), 19.6 (C1); IR (film): nmax = 3350br, 2924, 2854,
1751 cmꢀ1; HRMS (ESI+): m/z: calcd for C28H47N2O8: 539.3332; found:
539.3344 [M+H]+.
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Acknowledgements
The authors would like to thank Novartis for a Novartis Research Fel-
lowship (S.V.L.), the EPSRC for a studentship (J.A.B.) and a postdoctor-
al fellowship (R.A.J.H.), the Winston Churchill Foundation of the U.S.A.
for a scholarship (E.P.B.) and the DAAD for a postdoctoral fellowship
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1
Mosherꢁs ester showed only a single diastereoisomer by H NMR.
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compounds 9, 37, 39, and 40, see Supporting Information.
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could be monitored by GC of the crude product (Agilent 6890N
GC, Varian Chirasil Dex-CB column (25 m”0.25 mm) using Helium
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630712 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge fromThe Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
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[34] See Supporting Information for further details of the coupling con-
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S. V. Ley et al.
[36] See Supporting Information for full characterisation of the minor cy-
cloadduct diastereomer 16a. CCDC630709 contains the supplemen-
tary crystallographic data for this paper. These data can be obtained
free of charge fromThe Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
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BDA group. See Supporting Information for full procedures and
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ent-52.
[63] Treatment of enamide ent-52 with NBS and benzyl alcohol formed
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the desired product by TLC and was problematic to remove. The
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cis/trans ratio depended on the oxidation method. TPAP oxidation
gave predominantly cis-oxime (up to 5:1 cis/trans) presumably due
to chelation with residual rutheniumsalts promoting a cis-conforma-
tion, whereas following DMP oxidation the trans-oxime was fav-
oured (up to 1:5 cis/trans). The mixture geometries made the assess-
ment of enantiopurity by chiral HPLC very difficult so a number of
batches of bisoxazole 62 (with a range of enantiopurities) were pro-
gressed to the oxime and the optical rotation values were recorded.
Pleasingly, the different batches gave reproducible and consistent aD
values suggesting the stereochemical integrity had been maintained.
This was confirmed following the cycloaddition, from which none of
the C10 epimer was observed.
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[50] See Supporting Information for selected results of the catalyst
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employed in the reaction was recovered in excellent yields. See Sup-
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diastereomer 3a and nitrile oxide dimer 3b.
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experimental procedures and full characterisation of the Mosherꢁs
esters.
[53] Unfortunately, attempts to scale up the enantioselective addition of
TMSCN caused a significant decrease of the ee value (10 mmol:
52% ee, 70% yield). Any attempt to enrich the ee of the cyanohy-
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PE/ethyl acetate 4:1) or completely destroyed the ee (13% ee, from
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lower in the 10-epi-series (ent-33) than with oxime 33 (dr 2.5:1 vs
3.5:1). Notwithstanding the distance of the chirality fromthe react-
ing centre, this was presumed to be due to a chirality match/mis-
match between alkene 7 and the chiral oximes. A similar phenomen-
on was observed for the enantiomer of the nitrile oxide of Garnerꢁs
aldehyde oxime (dr 4.1:1 vs 2.5:1) although in this case the chirality
is closer to the reacting centres.
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unstable, see references [45] and [48].
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[74] See Supporting Information for spectra for bengazole A, 10-epi-ben-
gazole A and bengazole B.
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duction of the a-ketoester formed by the oxidation of rac-48 gave
low yields and ee. See Supporting Information for characterisation
of the ketone intermediate.
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Received: January 9, 2007
Published online: April 17, 2007
5538
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Chem. Eur. J. 2007, 13, 5515 – 5538