The development of a convergent and efficient enantioselective synthesis of the bengamides via a common polyol intermediate

Article abstract of DOI:10.1002/hlca.200290026

An efficient, general synthetic route to the bengamide family of antitumor agents from a common polyol thioester is described. Consecutive aldol condensations afford the protected polyol thioester side chain suitable for coupling to the bengamides. A novel chiral-phase-transfer-catalyzed enantioselective alkylation affords the properly functionalized caprolactams required for the synthesis of more-complex members of the bengamide family. Use of the methyl 2-naphthyl ether protecting group, compatible with the boron Lewis acids required for enantioselective aldol condensation, allows direct access to all the bengamides.

Full text of DOI:10.1002/hlca.200290026

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Helvetica Chimica Acta Vol. 85 (2002)
The Development of a Convergent and Efficient Enantioselective Synthesis of
the Bengamides via a Common Polyol Intermediate
by Robert K. Boeckman Jr.*, Tammy J. Clark, and Brian C. Shook
Department of Chemistry, University of Rochester, Rochester, New York, 14627-0216
(phone: ‡1(585)275-4229; fax: ‡1(585)756-0210; e-mail: rkb@rkbmac.chem.rochester.edu)
Dedicated to Professor Dieter Seebach on the occasion of his 65th birthday
An efficient, general synthetic route to the bengamide family of antitumor agents from a common polyol
thioester is described. Consecutive aldol condensations afford the protected polyol thioester side chain suitable
for coupling to the bengamides. A novel chiral-phase-transfer-catalyzed enantioselective alkylation affords the
properly functionalized caprolactams required for the synthesis of more-complex members of the bengamide
family. Use of the methyl 2-naphthyl ether protecting group, compatible with the boron Lewis acids required for
enantioselective aldol condensation, allows direct access to all the bengamides.
1. Introduction. Marine organisms have proven rich sources of novel, small-to-
medium-size organic molecules [1]. Natural products of marine origin possess a broad
array of biological activities, many of which are unique relative to materials isolated
from terrestrial organisms, including plant, animal, and microbial sources [1].
Particularly noteworthy is a structurally diverse array of substances exhibiting
antitumor activity, including, to name a few, bryostatin 1, halichonrin B, discodermo-
lide, and the bengamides [1]. Some of these substances possess macrocyclic rings with
complex functional arrays capable of binding to cellular proteins and interfering with
critical processes, such as mitosis. Even acyclic structures, e.g., discodermolide and the
bengamides, a family of N-acyl-a-aminocaprolactams derived from a common polyol
acid (certain representatives bearing an additional OH group esterified with a fatty
acid), are also capable of interfering with mitosis [2][3].
OH OMe
O
H
N
R1
N
OH OH
O
R2
1 R1 = Me, R2 = O2C(CH2)12Me
2 R1 = CH3, R2 = OH
3 R1 = H, R2 = H
Some 24 natural bengamides have now been isolated, principally from Jaspis
sponges found in coral reefs near the Fiji Islands and Australia, and their preliminary
biological activites have been reported [3][4]. Among this group, bengamide B (1)
exhibits a unique profile in the NCI (National Cancer Institute) panel of 60 cell lines

Helvetica Chimica Acta Vol. 85 (2002)
4533
compared to standard antitumor agents, arresting growth at both G1/S and G2/M
restriction points [2]. The antiproliferative activity of a number of the natural
bengamides and synthetic analogues have now been carefully evaluated and compared
to standard antiproliferative agents [3][5]. Several bengamides display activities with
IC50 values for in vitro growth inhibition of 10 100 nm, bengamide B (1) appearing the
most promising of this group [3][5]. Notably, bengamides bearing myristate esters on
the caprolactam subunit are >100 times more potent in vitro than, e.g., bengamide Z
(2). This difference probably arises from the poor cellular uptake of 2, since it has been
demonstrated that 1 is converted to 2 intracellularly, which may suggest that the latter is
the agent actually responsible for the antiproliferative effects [2][3][5]. Recent work
has been reported toward identification of the biological target(s) of the bengamides
[6]. Furthermore, an analogue of bengamide B (1) is currently undergoing clinical trials
as a therapeutic agent against drug-resistant solid tumors [7].
The continuing interest in bengamide analogues as clinical candidates for cancer
chemotherapy has led to a substantial amount of effort being devoted to the
development of methods for their synthesis. A number of total syntheses of the
bengamides have been reported, especially of the structurally fairly simple bengamide
E (3) [8]. These studies are based on methods for the assembly of the polyol acid side-
chain common to all the bengamides. Several interesting approaches based on
carbohydrates and other starting materials from the chiral pool have been recorded,
along with novel approaches by methods for acyclic stereocontrol. Among the most
efficient of these routes, those reported by Mukai et al. require a lengthy route from
tartaric acid or optical resolution leading to enantiomerically enriched bengamide E
[9], while that of Marshall and Luke requires the construction of an enantiomerically
pure allylstannane via an asymmetric reduction and subsequent condensation with a
derivative of (R)-glyceraldehyde [10].
Two of the three existing syntheses of bengamide B (2) are quite lengthy [11]. The
most efficient route to date is that reported recently by Kinder et al., which employs a
sensitive carbohydrate-derived g-lactone aldehyde from which the required olefin is
elaborated in modest yield by a Takai olefination [12]. This route is especially efficient,
since coupling to the amino caprolactam subunit can be accomplished directly with the
g-lactone playing the active ester component. Most prior syntheses had taken
advantage of standard peptide-bond-forming methods that require multiple steps or
amination of esters with dimethylaluminum amides [11][12].
2. Results and Discussion. Herein, we report a full account of our studies towards
the development of an efficient, enantioselective, general route to the bengamide
family of polyol amides [13]. Since all the bengamides share a common polyol acid, we
sought to develop a single short sequence to access the major structural subtypes of the
bengamides, which differ only in the nature of the lactam coupling partner. In common
with all of the previous syntheses, our retrosynthesis begins by disconnecting the side
chain 4 and caprolactam 5 subunits (Scheme 1). Construction of the polyol side chain
was envisaged through an initial syn asymmetric aldol reaction starting from (E)-4-
methylpent-2-enal (6) and the a-functionalized acetimide 7, bearing the chiral auxiliary
8 (4,5,5-trimethyl-2-azabicyclo[2.2.1]heptan-3-one) derived from camphoric acid [14],
followed by either an asymmetric acylation/reduction sequence or an anti aldol

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Helvetica Chimica Acta Vol. 85 (2002)
reaction. Surprisingly, none of the previous syntheses involved the readily available
synthon 6 as a potential starting material, except for that of Marshall and Luke who
employed it for the construction of their enantiomerically enriched allyl stannane unit
[10]. The a-amino e-caprolactam present in bengamide E is commercially available,
however, the functionalized caprolactams present in, e.g., bengamides B and Z had to
be synthesized. Installation of the two stereogenic C-atoms of 5 was envisioned via an
enantioselective alkylation of 9 with the functionalized oxirane 10. An alternative
synthesis of the caprolactam moiety 5, starting from hydroxylysine, was recently
reported [12].
Scheme 1
OPG OMe
SPh
O
H
RO
+
OPG OH
O
NXC
O
4
6
9
7
+
O
O
Ph
Ph
H2N
R1
+
I
N
N
O
O(t-Bu)
10
R2
5
O
PG = Protecting group,
=
NXc
N
R (H)
8
2.1. Synthesis of the Polyol Side Chain. Because the aldehyde 6 is commercially
available only in small quantities and since we required access to larger amounts of this
material, we developed an economical and efficient large-scale synthesis of this
compound (Scheme 2). Condensation of isobutyraldehyde with an excess of acetylene
in N-methylpyrrolidinone (NMP)1) in the presence of KOH according to Chodkiewicz
[15] afforded the propargyl alcohol 11 in 81% yield. Rearrangement of 11 at 1408 in
dioctyl phthalate (DOP), by means of a catalytic system based on TiIV and CuI
originally described by Chabardes [16], provided 6 in 86% yield in an (E)/(Z) ratio
of > 98 :2 (Scheme 2). A variety of high-boiling solvents could be used, but DOP
facilitates the isolation of 6 by fractional distillation at reduced pressure. The residual
mixture (containing the catalyst) could be repeatedly re-used by recharging with
alcohol 11, which makes the process amenable to the development of a continuous process.
We initially investigated the use of a 4-methoxybenzyl (PMB) ether for the
protection of the OH group in 7. However, preliminary experiments demonstrated that
PMB ethers are too labile under the conditions of the boron aldol reaction. Thus, we
chose the more robust benzyl (Bn) ether as the protecting group. Our preparation of
1
)
For abbreviations, see Exper. Part.

Helvetica Chimica Acta Vol. 85 (2002)
4535
Scheme 2
O
OH
Ti(OBu)4, CuCl
H
H
H
KOH
NMP
4-MePhCOOH
DOP
H
H
O
11
6
For abbreviations, see text and Exper. Part
the required polyol sidechain 4 began with acylation of the Li salt of 8 [14] (prepared
by treatment of 8 with BuLi) with benzyloxyacetyl chloride at À 788 ! 08 to give the
desired imide 12 in 89% yield (Scheme 3). The latter was treated with Et2BOTf (Tf ˆ
trifluoromethylsulfonyl) in the presence of (i-Pr)2NEt at À 788 in CH2Cl2 under
standard conditions. This furnished the (Z)-configured boron enolate, which was
condensed with 6 via the chair-like six-membered transition state A to afford the
desired syn aldol product 13 in a diastereoisomer ratio (dr) >24 :1 [14]. Without
purification, 13 was immediately silylated with (t-Bu)Me2SiCl (TBSCl) under standard
conditions, providing 14 in 80% overall yield from 12.
Scheme 3
Bn
H
H
O
O
O
B
O
6
O
BnO
NXc
N
Et2BOTf
(i-Pr)2NEt
O
12
CH2Cl2, –78°
A
OBn
NXc
OBn
TBSCl
imidazole
NXc
CH2Cl2
OH
13
O
TBSO
14
O
The syn configuration of the aldol adduct 13 arises from control over rotamer
population about the enolate CÀN bond in the transition state A. Calculations of
possible transition-state structures employing low-order semi-empirical molecular-
orbital theory were consistant with the observed stereochemical outcome. The lowest-
energy transition-state structure had the BÀO bond of the enolate anti to that of the
lactam CˆO group, thereby minimizing dipole interactions, with subsequent approach
of the aldehyde to the sterically less-encumbered face of the enolate, i.e., syn to the CH2
bridge, affording the (2S,3R)-diastereoisomer in very high stereoselectivity [13][17].
The steric bulk and rigidity of the camphor-derived auxiliary 8 and the aforementioned
dipole/dipole interactions result in a highly organized transition state with excellent
control over bond-rotamer populations.

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Helvetica Chimica Acta Vol. 85 (2002)
According to our original concept (Scheme 4) for the creation of the 2,3-anti-3,4-syn
stereotriad present in 4, we sought to employ an auxiliary-directed asymmetric
acylation followed by a chelation-controlled reduction. Conversion of the syn-adduct
14 to the corresponding acyl halide or mixed anhydride 15 followed by reaction with
the enolate 16 was expected to afford the b-keto imide 17, which could be transformed
to the desired polyol sidechain 19 by two additional steps. Before committing major
effort to this route, we decided to first look at a model system.
Scheme 4
OBn
OBn
NXc
O
X
M
O
+
TBSO
14
O
TBSO
15 X = Cl, OC(O)R
OMe
O
N
16
MeO
BnO
Et2BOMe
NX'c
NaBH4
TBSO
O
O
17
BnO
OMe
BnO
OMe
NX'c
NX'c
TBSOTf
DIPEA
TBSO TBSO
18
O
OH OH
O
19
O
X'c
=
N
Camphor-derived auxiliaries are effective chiral controllers, as seen in the boron-
mediated syn aldol reaction 12 ! 13. Selective formation of the (Z)-enolate 16 by
deprotonation and metallation of 20, was anticipated based on our prior studies
regarding the alkylation of glycolates [18]. The (Z)-enolate 22 is favored kinetically
over the corresponding (E)-enolate 23 owing to −allylic strain× in the latter. Electro-
philes approach the less-hindered a-face (Si-face) of the enolate, avoiding C(7) with its
two Me groups (see Figure) [18].
Figure

Helvetica Chimica Acta Vol. 85 (2002)
4537
We chose (1R,4S)-2-(2-methoxyacetyl)-1,7,7-trimethyl-2-azabicyclo[2.2.1]heptan-3-
one (20) as a model for asymmetric acylation (Table). Initial attempts with pivaloyl
chloride resulted in exclusive O-acylation and formation of the enol ester 24 in 87%
yield (Table, Entry 1). Often, with less-reactive electrophiles, C-acylation is favored
over O-acylation (matching the softness of the enolate). However, when a thioester
was used at À 788, the starting material was recovered (Table, Entry 2). Upon warming
to À 308, 20 decomposed to 21 via ketene formation. Keeping the temperature below
À 408 was, therefore, essential to avoid decomposition. We next explored various other
acyl electrophiles like activated thioesters [19], acyl imidazolides, and mixed
anhydrides (Table, Entry 4), however, each of these experiments resulted in the
recovery of the starting material. Changing the counterion from Li to Na did not
improve the reactivity, in contrast to alkylation [18], suggesting that the Me group
adjacent to the N-atom of 20 is, perhaps, bulky enough to hinder the approach of
electrophiles.
Next, we tested the isomeric camphor-derived auxiliary 25, where the Me group is
adjacent to the CˆO rather than to the N-atom. Reaction of 26 with electrophiles led
to a more-reactive (Z)-enolate, resulting in a 3 :2 mixture of C- versus O-acylation.
However, no stereoselectivity was observed under these conditions, and the two C-
acylation products 27 and 28 were formed in equal amounts (Table, Entry 5). When one
equiv. of Et2Zn was added prior to the acid chloride to, hopefully, create a more-
covalent enolate ÀO bond, stereoselectivity increased to 3 :1, but, surprisingly, the
regioselectivity decreased, resulting in a 3 :2 ratio in favor of O-acylation, which could
be the result of facile ligand exchange in the ate complex (Table, Entry 6). It is known
that Li enolate aggregation is favored in nonpolar solvents [21]. We, therefore,
conducted the reaction in a 6 :1 mixture of toluene/THF. Use of the less-polar medium
had a dramatic effect on the product ratio. In toluene/THF, nearly exclusive C-acylation
was observed. A concommitant increase in stereoselectivity with a ratio of 27/28 to 4 :1
(Table, Entry 7) also occurred. Presumably, aggregation effectively blocks the enolate
O-atom, resulting in a highly regioselective reaction. Various mixed anhydrides gave
similar results when toluene was used as the solvent (Table, Entries 8 and 9). Although
we were able to obtain the desired C-acylation products 27 and 28 with moderate
stereoinduction, the dr could not be further increased.
We then chose to explore the even more direct anti aldol route (Scheme 5).
Beginning with 14, cleavage of the auxiliary NXc group with EtSLi at À 408 provided
the corresponding thioester 29 (95%) along with recovered 8 (93%). Compound 29 was
selectively reduced at À 788 with (i-Bu)2AlH (DIBAL) to afford a mixture of the
monothiohemiacetal 30 and the desired aldehyde 31. No overreduction of 30 was
observed, not even in the presence of excess DIBAL. More surprisingly, 30 was
sufficiently stable to partly survive aqueous workup and chromatography. The origin of
this phenomenon lies in the tendency of aldehydes bearing electron-withdrawing a-
substituents to exist as stable hydrates. Fortunately, conversion of 30 to the required
aldehyde 31 was conveniently achieved by briefly warming the mixture to 858 at ca.
20 torr on a rotary evaporator. The resulting, somewhat sensitive aldehyde 31 was then
immediately subjected to a variant of the chelation-controlled GennariÀMukaiyama
aldol reaction with the phenylthioketene acetal 32 [22], which can be obtained as ca.
10 :1 mixture of the corresponding (E)-and ( Z)-isomers by treatment of S-phenyl 2-

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Helvetica Chimica Acta Vol. 85 (2002)
Table
O
O
O
O
O
O
MeCOCl
XcN
XcN
NH
N
+
+
O
MeO
MeO
21
20
26
LDA
E
27
28
OMe
OMe
or
MeCOCl
O
O
NH
N
O
OMe
XcN
O
O
25
24
Entry Imide Electrophile (E)
Solvent(s)/Additives T [8] Product Ratioa)
27/28/24
Yield
[%]
O
1
2
3
20
20
20
THF
THF
THF
À 78 0 : 0 : 100
87
Cl
O
O
À 78 no reaction
PhS
enolate decomposition
to 21
À 30
PhS
O
X
4
20
THF
À 60 no reaction
N
X = OC(O)R, SPh(NO2),
N
O
5
6
7
26
26
26
THF
À 78 30 : 30 : 40
À 78 33 : 11 : 56
À 78 77: 19 : 4
90
88
94
Cl
O
THF/Et2Zn
THF :PhCH3 (1 : 6)
Cl
O
Cl
O
O
O
O
O
8
9
26
26
PhCH3
PhCH3
À 45 71 : 29 : 0
À 45 77: 23 : 0
94
77
CF3
O
a) The abs. configurations of 27 and 28 were determined by chelation-controlled ZnBH4 reduction and
esterification to syn-oriented methyl 3-hydroxy-2-methoxy-4-methylpentanoate followed by chemical correla-
tion [20].

Helvetica Chimica Acta Vol. 85 (2002)
4539
methoxythioacetate with Me3SiOTf and Et3N [23][24]. The (E)/(Z) ratio of 32 is
somewhat variable. However, fortunately, the stereoselectivity of the aldol condensa-
tion with 31 is independent of the isomer ratio of 32 [22]. Addition of 31 at À 788 to the
preformed SnIV enolate (prepared by treatment of freshly distilled 32 in CH2Cl2 with a
1.0m solution of SnCl4 in heptane for 40 min and followed by stirring at À 788 for 4 h)
afforded, after workup and purification, the desired 2,3-anti-3,4-syn aldol product 33 in
73% yield with a dr of 11.5 :1.
Scheme 5
OBn
OBn
DIBAL
NXc EtSLi
SEt
TBSO
O
TBSO
29
O
14
OBn
SEt
TBSO
OH
85°
20 torr
30
SPh
OTMS
+
OBn
BnO
OMe
O
MeO
32
H
SPh
SnCl4
CH2Cl2, –78°
TBSO
O
TBSO
OH
31
33
It is important to note that similar condensations reported by Mukai et al. [9], who
used the related S-(tert-butyl) hemithioacetal, afforded significantly lower dr values of
ca. 7:1. We, by the way, observed this phenomenon in the GennariÀMukaiyama aldol
reaction performed with a variety of chiral aldehydes.
Verification of both the relative and absolute configuration of the polyol sidechain
was easily accomplished by conversion to (‡)-bengamide E (3, 3-aminohexahydro-
benzazepin-3-one). Treatment of 33 with the commercially available (À)-a-amino-e-
caprolactam 34 in dioxane at reflux provided 35 in 98% yield (Scheme 6). Conversion
to 3 was then accomplished by cleavage of the benzyl ether with Li/NH3 under Birch
conditions followed by cleavage of the silyl ether with tetrabutylammonium fluoride
(TBAF) in THF, affording pure (‡)-bengamide E (3) in 67% overall yield for both
steps. Synthetic (‡)-bengamide E was identical in all respects to an authentic natural
sample [12].
2.2. Synthesis of the Substituted e-CaprolactamSubunits . Having confirmed the
relative and absolute configuration of the key intermediate 33, we then turned our
attention to the development of a general route to the functionalized a-amino-e-
caprolactam units present in the more-complex bengamides B (1) and Z (2). Several
routes to these intermediates have been described, but none are ideal [11][12]. The
most practical to date is that of Kinder et al. [12], which affords the required lactam(s)
in seven steps starting from commercial, albeit expensive, (5R)-5-hydroxy-l-lysine. We
sought to develop a route that could be readily adapted to the synthesis of all naturally

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Helvetica Chimica Acta Vol. 85 (2002)
Scheme 6
O
OBn OMe
H2N
SPh
NH
Dioxane
+
∆
TBSO
TBSO
OH
O
33
OBn OMe
34
OH OMe
O
O
H
N
H
1) Li, NH3
N
NH
NH
2) TBAF
OH
O
OH OH
O
3
35
occurring lactam subunits (and synthetic analogues thereof) from a common reaction
sequence. We chose to disconnect the caprolactam to the commercial iminoglycine
ester 9 and the chiral epoxide 10 (Scheme 1) and to control the sense of asymmetry at
the a-amino acid center by using an appropriate chiral phase-transfer catalyst (PTC)
and either of the enantiomers of 10. This should, in principle, allow one to access all
four diastereoisomers of 5 with or without an alkyl group at the lactam N-atom. Corey
et al. described a useful cinchonidine-derived catalyst for this purpose [25]. However,
the use of only a few bifunctional electrophiles, such as 1-chloro-4-iodobutane, has been
described in this context [26].
The epoxide 10 is obtained from (2R)-2-bromobutane-1,4-diol (36), which is
readily available in two steps and 70% overall yield from d-aspartic acid (Scheme 7)
[27]. Treatment of 36 with excess NaH in THF followed by in situ tosylation afforded
37 in 89% yield. The OTs function of 37 was replaced then by a iodo group under
standard Finkelstein conditions, providing 10 in 93% yield.
With 10 in our hands, we then examined the key asymmetric alkylation of 9 by
means of PTC. The key step consists of treating 9 with an appropriate bifunctional
electrophile and CsOH ¥ H2O in the presence of 10 mol-% of the 9-anthracenylmethyl-
substituted cinchonidinium bromide derivative 38 in CH2Cl2 at À 608 [25][26]. We
initially examined the coupling with 39, however, surprisingly, both 39 and 37 were
unreactive. Fortunately, the iodoethyloxirane 10 reacted smoothly under the above
conditions to afford the desired ester 40. Essential for this transformation was to finely
pulverize CsOH ¥ H2O under Ar gas and to use an efficient overhead stirrer to achieve
acceptable reaction rates. Under near-optimal conditions, we found that 9 undergoes
complete conversion to 40 in the presence of as little as 1.3 equiv. of the substrate 10,
5 equiv. of finely powdered CsOH ¥ H2O, and 10 mol-% of the phase-transfer catalyst 38
in CH2Cl2 at À 608 for 18 h, 40 being formed in 83% yield as a single diastereoisomer
1
(dr >96% according to 400 MHz H-NMR analysis). After aqueous workup, the
residual epoxide 10 was removed in vacuo with a Kugelrohr apparatus. The chiral
catalyst was recovered from the aqueous phase (as the chloride salt) by extraction with
CH2Cl2 (85%) and re-used. Compound 40, which proved unstable to chromatography,
did not require further purification and was used as obtained. This application of the
Corey phase-transfer alkylation constitutes a significant extension of the scope of this

Helvetica Chimica Acta Vol. 85 (2002)
4541
Scheme 7
1) NaH, THF
2) TsCl
NaI
HO
TsO
I
OH
O
O
Acetone
Br
36
37
10
Br
O
N
Ph
Ph
N
O
O(t-Bu)
H
N
9
38
I
no reaction
+
O
CsOH • H2O
CH2Cl2, –60o
O
37 or
39
O
Ph
Ph
N
O(t-Bu)
O
Ph
Ph
38
9
N
O(t-Bu)
+
CsOH • H2O
CH2Cl2, –60o
I
O
O
10
40
methodology and highlights its versatility and potential with respect to other
bifunctional electrophiles.
The introduction of a terminal N-function by nucleophilic cleavage of the oxirane
ring in 40 was not expected to be problematic. Unfortunately, primary amines,
including methanolic MeNH2, were insufficiently nucleophilic to this end. Also, the use
of even very mild Lewis acids to activate the oxirane resulted in the bicyclic proline
ester 41, presumably by cyclization of the iminium ion 42 (Scheme 8).
Scheme 8
O
O
Ph Ph
Ph
N
Ph
Ph
O
Ph
N
O(t-Bu)
O(t-Bu)
O(t-Bu)
O
N
O
O
41
42
40
We overcame this limitation by using more-nucleophilic secondary amines.
Treatment of 40 with N-benzyl-N-methylamine (8 equiv.) in MeOH at room temper-
ature for 13 h provided 43 in 98% yield (Scheme 9). Hydrolysis of the imino function of
43 was effected with 10% aqueous citric acid/THF 1:1 [28], and debenzylation by
hydrogenation (1 atm) over 5 mol-% of Pearlman×s catalyst in EtOH [29], affording 44
in 86% overall yield. Treatment of 44 with MeONa in MeOH at 858 (sealed tube)

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Helvetica Chimica Acta Vol. 85 (2002)
Scheme 9
O
O
Ph
Ph
Ph
1) 10% aq.
Citric acid
N
N
Bn(Me)NH
O(t-Bu)
O(t-Bu)
Me
Ph
2) H2/Pd(OH)2
MeOH
N
O
Bn
OH
40
43
O
O
NaOMe, MeOH
80°, sealed tube
H2N
Me
H2N
N
O(t-Bu)
N
H
OR
OH
44
1) TFA, acetyl or
myristoyl chloride
45 R = H
46 R = Ac or
47 R = C(O)C13H27
2) Amberlist IR-409 or
phosphate buffer pH 8.5
provided the desired caprolactam 45, presumably via initial intramolecular cyclization
to the corresponding six-membered lactone followed by ring expansion (O ! N acyl
migration) via a bicyclic ortho amide intermediate [30][31]. The resulting hydroxy
lactam 45 was selectively O-acylated by treatment with either acetyl or myristoyl
chloride in the presence of excess trifluoroacetic acid (TFA) as solvent, affording the
key lactam subunits 46 and 47 after liberation of the free base by treatment with
Amberlyst IR-400 resin or pH 8.5 phosphate buffer [32]. The selective O-acylation was
achieved by irreversible protonation of the a-amino group in the strongly acidic
medium [32].
The synthetic route presented to the lactam subunits 46 and 47 features several
noteworthy elements: 1) complete stereoselectivity and high overall yield, requiring
purification at only three stages (37, 43, and 46 or 47); 2) the possibility for structural
variation at several stages, e.g., through the use of different bifunctional electrophiles
(instead of 10) or alkyl groups on the lactam N-atom and the acyl group on the
secondary alcohol; and 3) the economy of our method, which is based on inexpensive
starting materials and reagents.
2.3. Synthesis of (‡)-Bengamide Z (2). Another attractive feature of the above
sequence is the possibility to directly use the side-chain synthon, the phenyl thioester 33
in the fragment coupling with the lactams 46 or 47 without further activation. Only the
route developed by Kinder et al. is also based on direct coupling by cleavage of a g-
lactone [12]. To prevent side reactions upon condensing 33 with the unprotected
caprolactam 45, the corresponding acetate 46 was used instead. Condensation of 33 and
46 (1.05 equiv.) in refluxing dioxane afforded the desired coupled product 48 in 94%
yield (Scheme 10). Deblocking was then conducted in two steps. First, 48 was reduced
with Na/NH3, resulting in concommitant removal of both the benzyl and the acetate
groups, the latter presumably by aminolysis, affording the corresponding silyl-protected
intermediate in 73% yield. Second, without purification, desilylation with Bu4NF

Helvetica Chimica Acta Vol. 85 (2002)
4543
Scheme 10
O
H2N
Me
O
OBn OMe
N
O
Dioxane
SPh
+
∆
TBSO
OH
33
O
R
46 R = Me
47 R = C13H27
OBn OMe
O
OH OMe
O
H
H
1) Na/NH3
2) TBAF
N
Me
O
N
Me
N
N
TBSO
OH
O
OH OH
O
O
OH
48 R = Me
49 R = C13H27
2
R
(TBAF) afforded (‡)-bengamide Z (2) in 74% yield. This compound was identical in
all respects to natural (‡)-bengamide Z [12].
2.4. Synthesis of (‡)-Bengamide B (1). The coupling of 33 with 47 (1.05 equiv.) in
refluxing dioxane was highly efficient, affording 49, a protected bengamide B
derivative, in 98% yield. Regrettably, in spite of considerable effort, the selective
removal of the benzyl ether in the presence of the myristoyl ester could be effected
under neither reductive nor oxidative conditions. For example, with diethanolamine as
a sodium amide scavenger during Na/NH3 reduction, cleavage was successful for
branched esters but failed for the less-hindered myristoyl ester, affording 50
(Scheme 11). Also, attempts at selective re-esterification of 50 were, surprisingly, not
successful [3][5][12]. Attempts to remove the benzyl group in 49 with 2,3-dichloro-5,6-
dicyanobenzoquinone (DDQ) resulted in a mixture of the regioisomeric benzoates 51
and 52, respectively, largely independent of the amount of DDQ employed. This result
can be explained by a more-rapid oxidation of the hemiacetal intermediate than
oxidation of the starting benzyl ether or hydrolysis of the hemiacetal to the desired
alcohol. Unfortunately, selective cleavage of the benzoyl group in 51 and 52 in the
presence of the myristoyl ester also proved unfeasible, as expected based upon a
literature precedent [33].
These disappointing results led us to consider using a more labile OH protecting
group, namely the para-methoxybenzyl (PMB) function. However, based on prelimi-
nary experiments, PMB ethers are not stable to the Lewis acid conditions of the boron-
enolate aldol reaction. A careful evaluation of the options uncovered during a
literature survey led us to select the 2-naphthylmethyl ether protecting group [34],
since it is stable to Lewis acids (particularly in the a-position of a CˆO group) and can
be readily removed under mild oxidative conditions, e.g., DDQ in aqueous MeOH [34].
The key-2-naphthylmethyl-protected phenyl thioester 53 was prepared in analo-
gous fashion to 33 (Scheme 12). The chiral imide 56 was prepared from ethyl glycolate
(54) in three steps. Treatment of 54 with NaH and 2-(bromomethyl)naphthaline in the
presence of a catalytic amount of Bu4NI afforded the corresponding ether in 80% yield.

4544
Helvetica Chimica Acta Vol. 85 (2002)
Scheme 11
OH OMe
O
H
Me
N
N
Na/NH3
TBSO
OH
50
O
H
N
OBn OMe
OH
O
H
MeO
OMe
Me
N
N
O
OBz OMe
O
H
TBSO
OH
49
O
Me
N
N
TBSO
OH
O
(H27C13)
O
O
51
DDQ
(H27C13)
+
MeOH
O
OH OMe
O
H
Me
N
N
O
TBSO
OBz O
(H27C13)
52
O
Scheme 12
O
1) NaH, Bu4NI, THF
O
O
O
Cl
1)
Br
HO
Np
O
55
Np
O
OEt
ONa
NXc
2) Li-NXc
-78° → r.t.
2) NaOH, MeOH
54
6
56
Np = 2-naphthyl
H
Np
O
O
Np
O
EtSLi
Z
NXc
1) Et2BOTf, CH2Cl2
(i-Pr)2NEt
TBSO
O
TBSO
O
2) TBSCl, imidazole
CH2Cl2
57
58 Z = SEt
59 Z = H
DIBAL
dr 55:1
SPh
OTMS
Np
O
OMe
O
OMe
32
SPh
SnCl4, CH2Cl2
–78°
TBSO
OH
53
Exposure of this material to NaOH in anhydrous MeOH led to the solid Na salt 55 in
97% yield, which was activated with pivaloyl chloride in THFand reacted with the N-Li
salt of 8 to afford 56 in 71% yield (55% for three steps, unoptimized). We were pleased

Helvetica Chimica Acta Vol. 85 (2002)
4545
to observe that generation of the Z-configured boron enolate from 56 upon exposure to
Et2BOTf and (i-Pr)2NEt proceeded smoothly with no evidence of cleavage of the
naphthylmethyl protecting group. Condensation with the unsaturated aldehyde 6
afforded the expected b-hydroxy imide, which was in situ protected as the TBS ether by
treatment with (t-Bu)Me2SiCl and imidazole to afford the protected syn-product 57 in
75% overall yield (dr 55 :1). The bulkier 2-naphthylmethyl group apparently enhances
the stereoselectivity of the aldol reaction compared to the benzyl group. The chiral
auxiliary of 57 was then cleaved with EtSLi to the intermediate thioester 58, which was
directly reduced with DIBAL to the sensitive aldehyde 59 in 91% overall yield. Finally,
59 was treated with the preformed SnIV enolate derived from 32 to give predominantly
the expected anti-configured aldol product 53 (dr >8 :1) in 62% yield (unoptimized).
As expected, coupling of an equimolar mixture of 56 and 47 in dioxane afforded the
corresponding amide 60 in 69% yield (Scheme 13).
Scheme 13
Np
O
OMe
SPh
Np
O
OMe
O
TBSO
OH
O
H
N
Me
53
Dioxane
N
O
(1:1)
+
O
TBSO
OH
60
O
∆, 30 h
H2N
Me
N
O
(H27C13
)
O
O
(C13H27
)
1) DDQ, H2O
47
MeOH/CH2Cl2 1:4
2) PPTS, 45°
MeOH/CH2Cl2 1:1
OH OMe
O
N
H
N
Me
OH OMe
O
TBSO
OH
O
H
PPTS
45°
N
Me
DDQ
MeOH/CH2Cl2 4:1
N
O
O
61
(H27C13
)
+
OH OH
O
MeOH/CH2Cl2 1:1
O
Np
(H27C13
)
O
OMe
O
H
N
Me
1
O
N
TBSO
O
O
O
(H27C13
)
O
62
Unlike benzyl ethers, 2-naphthylmethyl ethers are readily oxidized by DDQ
[33][34]. Thus, we were very pleased to find that treatment of 60 with DDQ in aqueous
MeOH/CH2Cl2 4 :1 produced a 1:1 mixture of the dihydroxy compound 61 and the
corresponding acetal 62. The latter arises from trapping of the intermediate oxonium

4546
Helvetica Chimica Acta Vol. 85 (2002)
ion by the proximal OH group (Scheme 13). Upon use of higher ratios of MeOH/
CH2Cl2 or more H2O, the reaction rate decreased without affecting the product ratio.
When the reaction was performed in MeCN, acetal 62 was obtained exclusively in 79%
yield. Fortunately, treatment of the above mixture with 5 equiv. of pyridinium toluene-
4-sulfonate (PPTS) in MeOH/CH2Cl2 1:1 at 458 cleaved both the acetal and the silyl
ether, affording (‡)-bengamide B (1) in 76% overall yield. Indeed, subsequent
experiments demonstrated that both steps could be conducted in one pot. Thus,
treatment of 60 with DDQ in CH2Cl2/MeOH 4 :1 for 2 h, followed by adjustment to
CH2Cl2/MeOH 1:1, addition of PPTS (5 equiv.), and heating to 458 for 10 h, afforded
(‡)-bengamide B (1) in 89% yield.
3. Conclusions. The efforts described herein have resulted in the development of a
highly efficient and flexible synthetic route to the bengamide family of marine polyol
amide antiproliferative agents. The optimal sequence affords enantiomerically pure
(‡)-bengamide B (1) from d-aspartic acid and 4-methylpent-2-enal (6), with a longest
linear sequence of 12 steps (18 total steps). The same basic route affords bengamide Z
(2) with a longest linear sequence of 13 steps (19 total steps) from the same starting
materials, and also bengamide E (3) in 9 steps.
We thank Dr. Kenneth W. Bair, Dr. Frederick R. Kinder, and Richard W. Versace for their assistance and the
Novartis Institute for Biomedical Research and the NIH (GM-30345) for generous financial support.
Experimental Part
General. Abbreviations: Bn: benzyl (ˆ phenylmethyl), Bz: benzoyl (ˆ phenylcarbonyl), DDQ: 2,3-
dichloro-4,5-dicyanobenzo-1,4-quinone, DIBAL: diisobutylaluminium hydride, DIPEA: diisopropylethyla-
mine, DMF: dimethylformamide, DOP: dioctylphthalate, dr: diastereoisomer ratio, HMPA: hexamethylphos-
phortriamide, HPLC: high-performance liquid chromatography, LDA: lithium diisopropylamide, LHMDS:
lithium hexamethyldisilazane, NMP: N-methylpyrrolidinone, NP: 2-naphthyl, NXc: 4,5,5-trimethyl-3-oxo-2-
azabicyclo[2.2.1]heptan-2-yl (chiral auxiliary 1), NXc' : 1,7,7-trimethyl-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl
(chiral auxiliary 2), PMB: 4-methoxybenzyl, PPTS: pyridinium toluene-4-sulfonate, PTC: phase-transfer
catalysis, TBAF: tetrabutylammonium fluoride, TBS: (tert-butyl)dimethylsilyl, Tf: trifluoromethanesulfonyl,
THF: tetrahydrofuran, TMS: trimethylsilyl, Ts: tosyl (ˆ(4-methylphenyl)sulfonyl).
All reactions performed in org. solvents were conducted in flame-dried glassware under Ar gas atmosphere
and with magnetic stirring, unless otherwise noted. Air-sensitive reagents and solns. were transferred via syringe
(unless otherwise noted) and introduced through rubber septa. Solids were introduced under positive pressure
of Ar gas. Temp. refer to the heating bath, unless otherwise noted. The term −in vacuo× refers to removal of
solvents with a B¸chi rotary evaporator attached to a water aspirator (15 30 Torr) followed by pumping to
constant weight (at <1 Torr). Flash chromatography (FC) was performed with the indicated solvent system on
EM Reagents silica gel 60 (230 400) mesh, or on basic alumina (Baker). Analytical thin-layer chromatography
(TLC) was performed with glass plates (0.25 mm) precoated with silica gel 60 F-254 (EM Reagents).
Visualization was effected by either short-wavelength UV, exposure to I2 vapor, or dipping in the indicated stain
followed by heating on a hot plate for ca. 10 s. Reagent-grade solvents were used without purification for all
extractions and workup procedures. Deionized H2O was used for all extractions and for preparing aq. solns.
Commercial solid reagents were used as received (unless otherwise indicated). Solvents and commercial liquid
reagents for reactions were dried and/or purified according to published procedures by distillation: THF and
Et2O from Na/benzophenone ketyl; (i-Pr)2NH, Et3N, (i-Pr)2EtN, DMF, HMPA, CH2Cl2, and toluene from
CaH2. FT-IR Spectra are reported in cmÀ1, with polystyrene as a standard. 1H-and 13C-NMR Spectra were
recorded at 300 or 400 MHz; chemical shifts d are reported in ppm downfield relative to Me4Si (solvent
calibration); coupling constants J are expressed in Hz. Low- and high-resolution (HR-)mass spectra (MS) are
expressed in m/z.

Helvetica Chimica Acta Vol. 85 (2002)
4547
4-Methylpent-1-yn-3-ol (11). A three-necked 250-ml round-bottom flask was equipped with a mechanical
stirrer, a septum with outlet to an oil bubbler, and a stopper with a glass tube for addition of acetylene. The flask
was charged with powdered KOH (45.7 g, 0.82 mol) and dry NMP (90 ml). The mixture was cooled to À 408,
stirring was initiated, and scrubbed acetylene (passed through conc. H2SO4 and through a drying tube of KOH)
was rapidly bubbled into the suspension until saturated. The inlet tube was removed, adequate outlets were
provided for relief of pressure, and isobutyraldehyde (18.5 ml, 0.20 mol) was added in one portion. The mixture
was allowed to warm to r.t. over 2 h and was quenched by slowly pouring it on ice (175 g). The flask was rinsed
with 60 ml of Et2O. The phases were separated, and the aq. phase was extracted 3 Â with 40 ml portions of Et2O.
The combined org. phases were washed successively with 90 ml of H2O (3Â) and 120 ml of sat. brine, dried
(MgSO4), and carefully concentrated in vacuo to afford 17.4 g (87%) of 11 of a colorless oil, which provided
spectral data identical to those reported in [15]. 1H-NMR (400 MHz, CDCl3): 4.20 (m, 1 H); 2.48 (d, J ˆ 2.3,
1 H); 1.91 (sept., J ˆ 5.7, 1 H); 1.81 (br. s, 1 H); 1.03 (dt, J1 ˆ 7.1, J2 ˆ 2.3, 6 H).
(E)-4-Methylpent-2-enal (6). A 50 ml round-bottom flask was charged with 11 (16.5 g, 0.168 mol), 3.9 g of
p-toluic acid (0.0290 mol), 0.33 g of CuCl (0.0034 mol), 0.81 ml of (BuO)4Ti (0.0023 mol), and 20 ml of dioctyl
phthalate (DOP) under Ar. The flask was equipped with a reflux condenser and heated to 1508. The progress of
the reaction was monitored by GC2), and complete disappearance of 11 was observed after 5 h. The mixture was
cooled to r.t. and purified by Kugelrohr distillation (1008 at 4 torr) to afford 13.4 g (81%) of 6 ((E)/(Z) >98 :2).
1
The spectral data were identical to those reported in [35]. H-NMR (400 MHz, CDCl3): 9.51 (d, J ˆ 7.8, 1 H);
6.81 (d, J1 ˆ 15.7, J2 ˆ 6.4, 1 H); 6.07 (ddd, J1 ˆ 15.7, J2 ˆ 7.8, J3 ˆ 1.3, 1 H); 2.60 (sept., J ˆ 6.7, 1 H); 1.11 (d, J ˆ
6.7, 6 H).
(1S,4S)-4,5,5-Trimethyl-2-{[(phenyl)methoxy]acetyl}-2-azabicyclo[2.2.1]heptan-3-one (12). A soln. of 6.5 g
of (1R,4S)-2-aza-4,5,5-trimethylbicyclo[2.2.1]heptan-3-one (8) [14] (42 mmol) in 60 ml of THF was cooled to À
208, and 30.2 ml of a 1.53m soln. of BuLi in hexanes (46 mmol) was added. The mixture was warmed to 08 and
stirred for 45 min, then cooled to À 788. A soln. of 10.15 g (8.7 ml, 55 mmol) of (benzyloxy)acetyl chloride in
40 ml of THF was added, and the mixture was allowed to warm to À 208. After 14 h, the mixture was quenched
with 15 ml of sat. aq. NH4Cl soln. and diluted with 30 ml of AcOEt and 40 ml of H2O. The phases were
separated, and the aq. layer was extracted twice with 30 ml of AcOEt. The combined org. phases were washed
successively with 40 ml of H2O (2Â), 40 ml of sat. brine, dried (MgSO4), and concentrated to afford a white
25
solid, which was recrystallized from hexanes to provide 11.3 g (89%) of 12. M.p. 66 688. ‰aŠ ˆ ‡6.7 (c ˆ 0.70,
D
1
CH2Cl2). IR (neat): 1743, 1704. H-NMR (400 MHz, CDCl3): 7.43 7.28 (m, 5 H); 4.71 (s, 1 H); 4.69 (s, 2 H);
4.58 (s, 3 H); 1.91 (dd, J1 ˆ 10.4, J2 ˆ 0.8, 1 H); 1.80 1.65 (m, 3 H); 1.14 (s, 3 H); 1.09 (s, 3 H); 0.91 (s, 3 H).
13C-NMR (100 MHz, CDCl3): 178.1; 169.3; 128.4; 128.1; 127.9; 73.4; 70.5; 57.4; 54.0; 44.7; 42.1; 38.1; 26.3; 25.7;
‡
9.7. HR-MS: 302.1744 ([M ‡ 1] , C18H23NO3 ; calc. 302.1756).
Diethylboron Trifluoromethanesulfonate. A 50-ml 3-necked round-bottom flask suited for short path
distillation (vented by a 3-way stopcock to Ar and aspirator vacuum with drying tube) was charged with 48 ml of
a 1.0m soln. of Et3B (4.71 g, 48 mmol) in hexane, and the contents were cooled to 08. Dropwise, with stirring, was
added 4.1 ml of neat trifluoromethanesulfonic acid (6.90 g, 46 mmol) at 08 over 20 min, and stirring of the
resulting orange soln. was continued at 08 for 1 h. The hexane was distilled off at 08, and the residual
diethylboron trifluoromethanesulfonate was purified by distillation at 14 Torr (b.p. 55 608) [36]. Caution: this
reagent is extremely pyrophoric. Upon completion of the distillation, the apparatus was carefully vented with Ar,
and the product was stored neat in a flask bearing a 3-way Teflon stopcock (to allow for removal of material via
gas-tight syringe under Ar). The compound is stable under Ar for several weeks at À 58.
(1S,4S)-2-{(2S,3R,4E)-3-Hydroxy-6-methyl-2-[(phenyl)methoxy]hept-4-enoyl}-4,5,5-trimethyl-2-azabicy-
clo[2.2.1]heptan-3-one (13). A soln. of 3.8 g of 12 (13 mmol) in 75 ml of CH2Cl2 was cooled to À 788 and treated
with 4.4 ml of DIPEA (3.27 g, 25 mmol). Then, 2.61 ml of diethylboron triflate (2.92 g, 13.4 mmol) was added
dropwise3). The mixture was warmed to 08 and stirred for 1 h, and then cooled to À 788 again. Aldehyde 6 (7.0 g,
62 mmol) was added dropwise, and the mixture was warmed to À 508 and stirred for 9 h. The mixture was
quenched at À 508 by addition of 17 ml of a 3 :1 mixture of pH 7 phosphate buffer and MeOH, followed by slow
addition of 17 ml of a 3 :1 mixture of MeOH and 30% aq. H2O2. The biphasic system was warmed to 08 and
stirred for 1 h, the phases were separated, and the aq. phase was extracted three times with 15 ml of CH2Cl2. The
combined org. phases were washed successively with 40 ml each of H2O and sat. brine, dried (MgSO4), filtered
2
)
Parameters: HP-5-crosslinked 5% PHME siloxane column; 30 m  0.32 mm  0.25 mm film thickness;
column pressure: 108 kPa, initial temp.: 508, initial time: 2 min, rate: 38/min.; 11: tR 3.92 min.; 6: tR 4.90 min.
It is likely that Bu2BOTf, which is easier to handle, could also be used.
3
)

4548
Helvetica Chimica Acta Vol. 85 (2002)
and concentrated to afford 4.3 g (85%) of 13 as a white solid, which was used without further purification. IR
(neat): 3477, 2960, 2871, 1744, 1696, 1345. 1H-NMR (400 MHz, CDCl3): 7.27 (m, 5 H); 5.78 (ddd, J1 ˆ 15.6, J2 ˆ
6.1, J3 ˆ 1.0, 1 H); 5.55 (ddd, J1 ˆ 15.6, J2 ˆ 6.3, J3 ˆ 1.4, 1 H); 4.95 (d, J ˆ 3.4, 1 H); 4.70 (d, J ˆ 11.8, 1 H); 4.50
(d, J ˆ 11.8, 1 H); 4.37 (br. s, 1 H); 2.52 (br. s, 1 H); 2.32 (m, J ˆ 6.8, 1 H); 1.89 (d, J ˆ 10.4, 1 H); 1.78 (dd, J1 ˆ
13.0, J2 ˆ 2.8, 1 H); 1.68 (d, J ˆ 10.5, 1 H); 1.63 (d, J ˆ 2.7, 1 H); 1.14 (s, 3 H); 1.08 (s, 3 H); 1.01 (dd, J1 ˆ 6.8, J2 ˆ
2.7, 6 H); 0.83 (s, 3 H). 13C-NMR (100 MHz, CDCl3): 177.7; 169.8; 140.1; 137.1; 128.4; 128.2; 128.0; 125.5; 81.1;
‡
73.7; 72.8; 57.5; 54.7; 44.8; 41.5; 38.1; 30.6; 26.3; 25.8; 22.2; 21.9; 9.9. HR-MS: 400.2474 ([M ‡ 1] , C24H34NO4;
calc. 400.2488).
(1S,4S)-2-{(2S,3R,4E)-3-{[(tert-Butyl)dimethylsilyl]oxy}-6-methyl-2-[(phenyl)methoxy]hept-4-enoyl}-
4,5,5-trimethyl-2-azabicyclo[2.2.1]heptan-3-one (14). A 100 ml round-bottom flask was charged with 3.5 g of 13
(8.8 mmol), 1.8 g of 1H-imidazole (26 mmol), 2.0 g of TBSCl (13 mmol), and 12 ml of DMF (just enough to
dissolve all the reagents)4). The resulting soln. was stirred at r.t. for 13 h, by which time consumption of 13 was
complete (TLC analysis). The mixture was diluted with 80 ml of CH2Cl2 and quenched with 15 ml of sat. aq.
NH4Cl soln. The resulting mixture was diluted with an additional 6 ml of H2O, the phases were separated, and
the aq. phase was extracted with 15 ml of CH2Cl2 (3Â). The combined org. phases were washed successively
with 20 ml of aq. 0.5m HCl soln., 20 ml of H2O (2Â), 20 ml of sat. aq. NaHCO3 soln., and 20 ml of sat. brine.
After drying (MgSO4), the org. phase was filtered and concentrated to a soft white solid. The volatile Si-
containing impurities were removed via Kugelrohr distillation (808, 4.5 torr), and the crude product was purified
25
D
by FC (SiO2; AcOEt/hexanes 1 :15) to afford 3.6 g (94%) of 14 as a white solid. M.p. 98 1008. ‰aŠ ˆ À1.6 (c ˆ
3.1, CH2Cl2). IR (neat): 2959, 1745, 1696. 1H-NMR (400 MHz, CDCl3): 7.35 7.23 (m, 5 H); 5.64 (dd, J1 ˆ 16.0,
J2 ˆ 6.5, 1 H); 5.52 (ddd, J1 ˆ 15.6, J2 ˆ 7.2, J3 ˆ 1.0, 1 H); 5.02 (d, J ˆ 4.9, 1 H); 4.67 (d, J ˆ 12.4, 1 H); 4.58
(s, 1 H); 4.57 (d, J ˆ 12.4, 1 H); 4.52 (d, J ˆ 4.9, 1 H); 4.42 (d, J ˆ 4.9, 1 H); 2.28 (m, J ˆ 6.7, 1 H); 1.84 (d, J ˆ
12.1, 1 H); 1.72 1.70 (m, 1 H); 1.60 1.58 (m, 1 H); 1.29 1.26 (m, 1 H); 1.12 (s, 3 H); 1.06 (s, 3 H); 0.99 (d, J ˆ
6.7, 3 H); 0.98 (d, J ˆ 6.7, 3 H); 0.87 (s, 9 H); 0.75 (s, 3 H); 0.02 (s, 6 H). 13C-NMR (100 MHz, CDCl3): 177.3;
170.0; 139.8; 138.0; 128.2; 128.0; 127.6; 126.2; 82.5; 75.6; 73.1; 57.5; 54.6; 44.7; 41.3; 38.1; 30.6; 26.3; 25.8; 25.7;
‡
22.2; 21.9; 10.0; À 4.2; À 4.8. HR-MS: 514.3343 ([M ‡ 1] , C30H48NO4Si; calc. 514.3353).
(1R,4S)-2-(2-Methoxyacetyl)-1,7,7-trimethyl-2-azabicyclo[2.2.1]heptan-3-one (20). A 37.4 ml portion of a
1.53m soln. of BuLi in hexanes (57 mmol) was added to a soln. of 8.0 g (52 mmol) of 21 [18] in 100 ml of THFat
À 208. The mixture was stirred at 08 for 45 min and cooled to À 788. A 6.2 ml portion of 2-methoxyacetyl
chloride (7.38 g, 68 mmol) was added neat, and the mixture was allowed to warm to À 208. After 13 h, the
mixture was quenched with 15 ml of sat. aq. NH4Cl soln. and diluted with 100 ml of AcOEt and 100 ml of H2O.
The layers were separated, and the aq. phase was extracted with 30 ml of AcOEt (2Â). The combined org.
phases were washed (2Â) with 40 ml of H2O and sat. brine, each dried over MgSO4, and concentrated to afford a
yellow solid, which was purified by FC (SiO2; hexanes/AcOEt 5 :1) to provide 8.8 g (76%) of 20. M.p. 44 458.
25
‰aŠ ˆ À25.4 (c ˆ 1.7, CH2Cl2). IR (neat): 2968, 1745, 1702. 1H-NMR (400 MHz, CDCl3): 4.49 (d, J ˆ 16, 1 H);
D
4.35 (d, J ˆ 16, 1 H); 3.45 (s, 3 H); 2.35 (d, J ˆ 4.4, 1 H); 2.05 2.02 (m, 1 H); 1.96 1.93 (m, 1 H); 1.88 1.85
(m, 1 H); 1.61 1.57 (m, 1 H); 1.53 (s, 3 H); 1.04 (s, 3 H); 0.98 (s, 3 H). 13C-NMR (400 MHz, CDCl3): 178.3;
‡
171.6; 74.0; 73.5; 59.3; 54.8; 32.3; 23.4; 18.6; 17.5; 13.4. HR-MS: 226.1436 ([M ‡ 1] , C12H19NO3; calc. 225.1365).
(Z)-2-Methoxy-1-[(1S,4S)-4,5,5-trimethyl-3-oxo-2-azabicyclo[2.2.1]hept-2-yl]ethen-1-yl 2-Methylpropio-
nate (24). A 1.3 ml portion of an 0.23m soln. of LDA in THF (0.29 mmol) was added to a soln. of 50 mg of
20 (0.22 mmol) in 1.5 ml of THFat À 788, and the mixture was stirred at that temp. for 45 min. A 50-ml portion of
neat isobutyryl chloride (0.49 mmol) was added dropwise over 7 min, the mixture was stirred at À 788 for
15 min, and quenched at that temp. by addition of 2 ml of sat. aq. NH4Cl soln. The layers were separated, the aq.
layer was extracted with 5 ml of Et2O (2Â), and the combined org. phases were washed successively with 5 ml of
H2O and 5 ml of sat. brine, dried (MgSO4), and concentrated in vacuo to afford 62 mg (87%) of 24 as a clear oil.
25
‰aŠ ˆ ‡20 (c ˆ 0.24, CH2Cl2). IR (neat): 2969, 1758, 1725. 1H-NMR (400 MHz, CDCl3): 5.89 (s, 1 H); 3.69
D
(s, 3 H); 2.68 (m, J ˆ 7.0, 1 H); 2.37 (d, J ˆ 4.4, 1 H); 2.02 1.98 (m, 1 H); 1.85 1.79 (m, 1 H); 1.65 1.57
(m, 2 H); 1.27 (d, J ˆ 7.0, 6 H); 1.22 (s, 3 H); 1.00 (s, 3 H); 0.91 (s, 3 H). 13C-NMR (400 MHz, CDCl3): 178.5;
‡
173.5; 138.6; 121.0; 77.3; 72.7; 60.5; 54.9; 49.4; 33.8; 33.6; 23.0; 18.9; 18.5; 18.1; 12.1. HR-MS: 296.1859 ([M ‡ 1] ,
C16H24NO4; calc. 296.1862).
Attempted Reaction of 23 with S-Phenyl Thioisobutyrate. A 0.73 ml aliquot of an 0.22m soln. of LDA in THF
(0.16 mmol) was added to a soln. of 30 mg of 20 (0.13 mmol) in 1.0 ml of THF at À 788, and the resulting
mixture was stirred at À 788 for 75 min. A 48 mg portion of S-phenyl thioisobutyrate (0.27 mmol) [19] in 0.3 ml
4
)
The soln. turns cloudy upon addition of TBSCl, but this does not affect the reaction.

Helvetica Chimica Acta Vol. 85 (2002)
4549
of THF was added, and the mixture was warmed slowly and monitored by TLC to detect product formation or
acyl cleavage. When the temp. had reached À 308, deacylation was observed. The mixture was stirred for an
addition 9 h at À 308 and quenched with 2 ml of sat. aq. NH4Cl soln. and warmed to r.t. The layers were
separated, the aq. layer was extracted with 5 ml of Et2O (2Â), and the combined org. phases were washed
successively with 5 ml of H2O and 5 ml of brine, dried (MgSO4), and concentrated in vacuo to afford a yellow
oil. Hexane (2 ml) was added, and the resulting white precipitate was collected by suction to afford 16 mg (80%)
of the auxiliary 21. The filtrate contained a complex mixture, including unreacted S-phenyl thioisobutyrate.
(1R,4S)-2-(2-Methoxyacetyl)-4,7,7-trimethyl-2-azabicyclo[2.2.1]heptan-3-one (26). A 29.4 ml portion of a
1.53m soln. of BuLi in hexanes (45 mmol) was added to a soln. of 6.3 g of 25 (41 mmol) in 80 ml of THFat À 208.
The mixture was stirred at 08 for 1 h, and then cooled to À 788. A 4.8 ml portion of neat 2-methoxyacetyl
chloride (5.75 g, 53 mmol) was added dropwise, and the mixture was allowed to warm to À 208. After 13 h, the
mixture was quenched with 15 ml of sat. aq. NH4Cl soln. and diluted with 25 ml of AcOEt and 20 ml of H2O. The
phases were separated, and the aq. phase was extracted with 30 ml of AcOEt (2Â). The combined org. phases
were washed with 35 ml of H2O and 35 ml of brine (2 Â each), dried (MgSO4), and concentrated in vacuo to
25
D
afford a yellow solid, which was purified by FC (SiO2; hexanes/AcOEt 4 :1) to provide 7.4 g (80%) of 26. ‰aŠ
ˆ
‡818 (c ˆ 0.55, CH2Cl2). IR (neat): 2964, 1744, 1705. 1H-NMR (400 MHz, CDCl3): 4.50 (s, 2 H); 4.33 (d, J ˆ 2.3,
1 H); 3.49 (s, 3 H); 2.02 1.99 (m, 1 H); 1.86 1.83 (m, 1 H); 1.64 1.57 (m, 2 H); 1.06 (s, 3 H); 0.94 (s, 3 H); 0.93
(s, 3 H). 13C-NMR (400 MHz, CDCl3): 178.7; 169.7; 73.1; 63.4; 59.4; 56.1; 48.1; 30.3; 26.7; 18.5; 17.7; 9.3. HR-MS:
‡
226.1439 ([M ‡ 1] , C12H20NO3; calc. 226.1443).
Isobutyric Pivalic Anhydride. A 10-ml round-bottomed flask was charged with 10 mg of 95% NaH
(0.37 mmol) and 2.0 ml of anh. Et2O, and the resulting mixture was cooled to 08. A 38 ml portion of pivalic acid
(0.33 mmol) was added dropwise, and the mixture was vigorously stirred at r.t. until H2 evolution ceased. The
white suspension was cooled to 08, and 39 ml (40 mg, 0.37 mmol) of neat isobutryl chloride was added. The
mixture was warmed to r.t. and stirred for 3 h. The resulting soln. of crude product was diluted with 2 ml of anh.
toluene and used directly in the acylation reaction.
Trifluoroacetic Pivalic Anhydride. A 10-ml round-bottomed flask was charged with 10 mg of 95% NaH
(0.37 mmol) and 2.0 ml of anh. Et2O, and the resulting mixture was cooled to 08. A 26-ml portion of CF3COOH
(39 mg, 0.33 mmol) was added dropwise, and the mixture was vigorously stirred at r.t. until H2 evolution ceased.
The resulting white suspension was cooled to 08, and 39 ml (40 mg, 0.37 mmol) of neat isobutryl chloride was
added. The mixture was warmed to r.t. and stirred for 2.5 h. The crude product was diluted with 2 ml of anh.
toluene and used directly in the acylation reaction.
(1S,4S)-2-[(2S)-2-Methoxy-4-methyl-3-oxopentanoyl]-4,5,5-trimethyl-2-azabicyclo[2.2.1]heptan-3-one
(27), (1S,4S)-2-[(2R)-2-Methoxy-4-methyl-3-oxopentanoyl]-4,5,5-trimethyl-2-azabicyclo[2.2.1]heptan-3-one
(28), and (Z)-2-Methoxy-1-((1S,4S)-4,5,5-trimethyl-3-oxo-2-azabicyclo[2.2.1]hept-2-yl)ethen-1-yl 2-Methylpro-
pionate (24). A 3.35-ml portion of an 0.23m soln. of LDA in THF (0.76 mmol) was added to a soln. of 0.14 g of
26 (0.63 mmol) in 2 ml of THF at À 788, and the resulting mixture was stirred at À 788 for 1 h. This soln. was
added via cannula to a soln. of 74 ml of isobutryl chloride (81 mg, 0.76 mmol) in 1.0 ml of THF at À 788. The
resulting mixture was stirred at À 788 for 30 min, quenched with 5 ml of sat. aq. NH4Cl soln., and warmed to r.t.
The phases were separated, and the aq. phase was extracted with 5 ml of Et2O (2Â). The combined org. phases
were washed successively with 5 ml of H2O and 5 ml of brine, dried (MgSO4), and concentrated in vacuo to
afford 167 mg (90%,) of a yellow oil, which consisted of 27 (30%), 28 (30%), and 24 (40%), as determined by
NMR. Rapid FC (SiO2; hexanes/AcOEt 4 :1) afforded pure 27 and 28 as colorless oils.
25
Data of 27. ‰aŠ ˆ ‡55 (c ˆ 1.5, CH2Cl2). IR (neat): 2968, 1746, 1704. 1H-NMR (400 MHz, CDCl3): 5.54
D
(s, 1 H); 4.36 (d, J ˆ 2.2, 1 H); 3.51 (s, 3 H); 3.08 (m, J ˆ 6.9, 1 H); 2.00 1.96 (m, 1 H); 1.84 1.76 (m, 2 H);
1.69 1.65 (m, 1 H); 1.19 (d, J ˆ 7.1, 3 H); 1.08 (d, J ˆ 6.9, 3 H); 1.02 (s, 3 H); 0.95 (s, 3 H); 0.94 (s, 3 H).
13C-NMR (400 MHz, CDCl3): 208.1; 197.1; 167.9; 84.5; 63.8; 59.4; 56.1; 47.4; 37.6; 30.0; 26.5; 18.5; 18.4; 17.6; 17.4;
‡
9.2. HR-MS: 296.1866 ([M ‡ 1] , C16H26NO4; calc. 296.1862).
25
Data of 28: ‰aŠ ˆ ‡71 (c ˆ 0.52, CH2Cl2). IR (neat): 2968, 1744, 1700. 1H-NMR (400 MHz, CDCl3): 5.40
D
(s, 1 H); 4.36 (d, J ˆ 2.3, 1 H); 3.51 (s, 3 H); 3.12 (m, J ˆ 7.0, 1 H); 2.03 2.00 (m, 1 H); 1.85 1.79 (m, 1 H);
1.65 1.55 (m, 2 H); 1.20 (d, J ˆ 7.0, 3 H); 1.10 (d, J ˆ 7.0, 3 H); 1.03 (s, 3 H); 1.02 (s, 3 H); 0.94 (s, 3 H).
13C-NMR (400 MHz, CDCl3): 207.7; 178.6; 167.4; 85.7; 64.0; 59.4; 56.1; 48.1; 37.5; 30.4; 27.0; 18.5; 18.3; 17.8; 17.4;
‡
9.4. HR-MS: 296.1862 ([M ‡ 1] , C16H26NO4; calc. 296.1862).
Acylation of 26 in the Presence of Et2Zn. A soln. of 1.6 ml of a 0.33m soln. of LDA (0.51 mmol) in THF was
added to a soln. of 96 mg of 26 (0.43 mmol) in 2 ml of THF at À 788, and the resulting mixture was stirred at
À 788 for 1 h. A 0.51 ml portion of a 1.0m soln. of Et2Zn in hexane (0.51 mmol) was added dropwise at À 788, and
the mixture was stirred for an additional 15 min at À 788. This soln. was added via cannula to a soln. of 50 ml

4550
Helvetica Chimica Acta Vol. 85 (2002)
(54 mg, 0.51 mmol) of isobutyryl chloride in 1.5 ml of anh. THF at À 788. The resulting mixture was stirred at
À 788 for 30 min, quenched with 3 ml of sat. aq. NH4Cl soln. and warmed to r.t. The layers were separated, and
the aq. phase was extracted with 5 ml of Et2O (2Â). The combined org. phases were washed with 5 ml of H2O
and 5 ml of brine, dried (MgSO4), and concentrated in vacuo to afford 109 mg (88%) of a yellow oil, which
consisted of 27 (33%), 28 (11%), and 24 (56%).
Acylation of 26 in Toluene/THF. A soln. of 1.4 ml of a 0.33m soln. of LDA in anh. THF (0.47 mmol) was
added to a soln. of 89 mg of 26 (0.40 mmol) in 3 ml of anh. toluene at À 788, and the resulting mixture was
stirred at that temp. for 1 h. This soln. was added via cannula to a soln. of 46 ml of isobutryl chloride (50 mg,
0.47 mmol) in 2.0 ml of anh. toluene at À 788. The resulting mixture was stirred at À 788 for 15 min, quenched
with 5 ml of sat. aq. NH4Cl soln., and warmed to r.t. The phases were separated, and the aq. phase was extracted
with 5 ml of Et2O (2Â). The combined org. phases were washed with 15 ml of H2O and 15 ml of brine, dried
(MgSO4), and concentrated in vacuo to afford 109 mg (94%) of a yellow oil, which consisted of 27 (77%), 28
(19%), and 24 (4%).
Acylation of 26 in Hexane/Toluene with LHMDS. A 0.76 ml portion of a 1.0m soln. of lithium
hexamethyldisilazane in hexane (0.76 mmol) was added to a soln. of 0.14 g of 26 (0.63 mmol) in 2 ml of anh.
toluene at À 788, and the resulting mixture was stirred at À 788 for 1 h. This soln. was added via cannula to a
soln. of 74 ml of isobutryl chloride (81 mg, 0.76 mmol) in 1.0 ml of anh. toluene at À 788 . The resulting mixture
was stirred at À 788 for 10 min, then quenched with 5 ml of sat. aq. NH4Cl soln., and warmed to r.t. The phases
were separated, and the aq. phase was extracted with 5 ml of CH2Cl2 (2Â). The combined org. phases were
washed successively with 15 ml of H2O and 15 ml of sat. brine, dried (MgSO4), and concentrated in vacuo to
afford 169 mg (91%) of a pale yellow oil, which consisted of 27 (75%) and 28 (25%).
Acylation of 26 with Isobutyric Pivalic Anhydride in Toluene/Et2O. A 1.62 ml portion of a 0.23m soln. of
LDA in anh. toluene (0.36 mmol) was added to a soln. of 75 mg of 26 (0.33 mmol) in 1.8 ml of toluene at À 788,
and the resulting mixture was stirred at À 788 for 1 h. This soln. was then added via cannula to a À 788 cold soln.
of 57 mg of isobutyric pivalic anhydride (0.32 mmol) in 4.0 ml of toluene/Et2O 1:1. The resulting mixture was
stirred at À 458 for 10 h, quenched with 5 ml of sat. aq. NH4Cl soln., and warmed to r.t. The phases were
separated, and the aq. phase was extracted with 5 ml of CH2Cl2 (2Â). The combined org. phases were washed
successively with 15 ml of H2O and 15 ml of sat. brine, dried (MgSO4), and concentrated in vacuo to afford
88 mg (94%) of a yellow oil, which consisted of 27 (71%) and 28 (29%).
Acylation of 26 with Trifluoroacetic Isobutyric Anhydride in Toluene/Et2O. A 1.62-ml portion of a 0.23m
soln. of LDA in anh. toluene (0.36 mmol) was added to a soln. of 75 mg of 26 (0.33 mmol) in 1.8 ml of toluene at
À 788, and the resulting mixture was stirred at that temp. for 1 h. This soln. was added via cannula to a soln. of
59 mg of trifluoroacetic isobutyric anhydride (0.32 mmol) in 4.0 ml of anh. toluene/Et2O 1:1 at À 788. The
resulting mixture was stirred at À 458 for 8 h, quenched with 5 ml of sat. aq. NH4Cl soln., and warmed to r.t. The
phases were separated, and the aq. phase was extracted with 5 ml of CH2Cl2 (2Â). The combined org. phases
were washed successively with 15 ml of H2O and 15 ml of sat. brine, dried over MgSO4, and concentrated in
vacuo to afford 71 mg (75%) of a yellow oil, which consisted of 27 (77%) and 28 (23%).
S-Ethyl (2S,3R,4E)-3-{[(tert-Butyl)dimethylsilyl]oxy}-6-methyl-2-[(phenyl)methoxy]hept-4-enethioate
(29). A 250-ml round-bottom flask was charged with 0.44 g of ethanethiol (7.1 mmol) and 17 ml of anh. THF,
and the contents were cooled to À 788. By syringe, 3.2 ml (5.0 mmol) of a 1.53m soln. of BuLi in hexanes was
added over 15 min with magnetic stirring, and stirring was continued at À 788 for 20 min. A À 788 cold soln. of
1.8 g of 14 (3.6 mmol) in 70 ml of THF was added via cannula over 15 min, the mixture was warmed to À 408
and the reaction monitored by TLC (AcOEt/hexanes 1:5, visualized by dipping in p-anisaldehyde and UV).
Consumption of 14 was complete within 5 h. After quenching at À 408 by addition of 13 ml of sat. aq. NH4Cl
soln., the mixture was diluted with 25 ml of H2O and 8 ml of Et2O. The phases were separated, and the aq. phase
was extracted with 20 ml of Et2O (3Â). The combined org. phases were washed successively with 50 ml each of
H2O and sat. brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting viscous oil was triturated
with hexanes, cooled to 08, and 0.51 g of the precipitated auxiliary 8 (93%) was recovered by filtration. The
25
D
filtrate was concentrated in vacuo to afford 1.4 g (95%) of 29 as a pale yellow oil. ‰aŠ ˆ À10 (c ˆ 0.70, CH2Cl2).
IR (neat): 2958, 1681. 1H-NMR (400 MHz, CDCl3): 7.42 7.30 (m, 5 H); 5.55 (dd, J1 ˆ 15.6, J2 ˆ 6.5, 1 H); 5.39
(dd, J1 ˆ 15.6, J2 ˆ 7.4, 1 H); 4.81 (d, J ˆ 11.9, 1 H); 4.47 (d, J ˆ 11.9, 1 H); 4.35 (dd, J1 ˆ 4.6, J2 ˆ 2.7, 1 H); 3.80
(d, J ˆ 4.6, 1 H); 2.85 (q, J ˆ 7.4, 2 H); 2.22 (m, 1 H); 1.25 (t, J ˆ 7.4, 3 H); 0.97 (d, J ˆ 6.8, 3 H); 0.95 (d, J ˆ 6.8,
3 H); 0.87 (s, 9 H); 0.03 (s, 6 H). 13C-NMR (100 MHz, CDCl3): 201.7; 140.0; 137.2; 128.3; 127.8; 126.6; 125.9; 887;
‡
75.4; 73.7; 30.6; 25.8; 22.4; 22.0; 21.9; 18.2; 14.5; À 4.29; À 4.86. HR-MS: 440.2638 ([M ‡ NH4] , C23H42NO3SSi,
calc. 440.2655).

Helvetica Chimica Acta Vol. 85 (2002)
4551
(2S,3R,4E)-3-{[(tert-Butyl)dimethylsilyl]oxy}-6-methyl-2-[(phenyl)methoxy]hept-4-enal (31). A 100-ml
round-bottom flask was charged with a soln. of 1.3 g of 29 (3.0 mmol) in 35 ml of toluene5) and the contents
were cooled to À 788. With vigorous stirring, 6.0 ml of a 1.0m soln. of DIBAL in hexanes (6.0 mmol) was added
over 30 min (down the side of the flask to effect precooling). Within 10 min after completion of the addition, 29
was consumed, and the reaction was quenched by addition of 0.3 ml of H2O. The mixture was warmed to r.t.,
stirred for 2 h, and anh. Na2CO3 was added until the salts became granular. After filtration of the solids and
concentration in vacuo (bath temp. >758 to complete the conversion of residual 30), 0.99 g of the sensitive
aldehyde 31 (91%) was obtained. The product was immediately used without further purification. IR (neat):
3642, 2957, 1735. 1H-NMR (400 MHz, CDCl3): 9.67 (d, J ˆ 5.1, 1 H); 7.35 7.26 (m, 5 H); 5.64 (ddd, J1 ˆ 15.5,
J2 ˆ 6.6, J3 ˆ 0.8, 1 H); 5.50 (ddd, J1 ˆ 15.5, J2 ˆ 6.6, J3 ˆ 1.0, 1 H); 4.75 (d, J ˆ 12.2, 1 H); 4.57 (d, J ˆ 12.2, 1 H);
4.41 (t, J ˆ 5.7, 1 H); 3.73 (dd, J1 ˆ 5.0, J2 ˆ 1.7, 1 H); 2.29 (m, J ˆ 6.7, 1 H); 1.00 (d, J ˆ 6.7, 3 H); 0.99 (d, J ˆ 6.7,
3 H); 0.88 (s, 9 H); 0.02 (s, 6 H). 13C-NMR (100 MHz, CDCl3): 202.8; 140.4; 137.4; 128.4; 127.9; 125.3; 86.3; 74.0;
72.9; 30.7; 25.8; 22.1; 18.1; À 4.3; À 5.0.
(E/Z)-[2-Methoxy-1-(phenylsulfanyl)ethenyl]trimethylsilane (32). A 100-ml round-bottom flask was
charged with a soln. of 4.0 g of S-phenyl 2-methoxyethanethioate (22 mmol) in 27 ml of CH2Cl2, and the
contents were cooled to À 788 under Ar. At À 788, 4.0 ml of TMSOTf (4.91 g, 22 mmol) was added dropwise via
syringe, followed by addition of 9.3 ml of Et3N (6.75 g, 67 mmol) over 25 min. The resulting mixture was stirred
at À 108 for 17 h, diluted with 40 ml of hexanes, and the biphasic mixture was cooled to À 788. The higher-
density phase containing amine salts was removed by syringe, and the resulting pale yellow soln. was
concentrated in vacuo and vented to Ar. A short-path-distillation head with cow receiver was attached, and the
product was distilled at reduced pressure (b.p. 1108, 2 torr) to afford 4.3 g (76%) of 32 as a pale yellow,
moisture-sensitive liquid that can be stored at r.t. under Ar. Inevitably, over time, some hydrolysis does occur,
1
therefore, it is recommended to redistill 32 before use. H-NMR (400 MHz, CDCl3): 7.37(d, J ˆ 8.1, 2 H); 7.29
(dd, J1 ˆ 8.1, J2 ˆ 7.4, 2 H); 7.20 (t, J ˆ 7.4, 1 H); 6.16 (s, 1 H); 3.70 (s, 3 H); 0.15 (s, 9 H).
S-Phenyl (2R,3R,4R,5R,6E)-5-{[(tert-Butyl)dimethylsilyl]oxy}-3-hydroxy-2-methoxy-8-methyl-4-[(phen-
yl)methoxy]non-6-enethioate (33). A 100-ml round-bottom flask was charged with 1.6 g (6.1 mmol) of 32 and
40 ml of anh. CH2Cl2, and the contents were cooled to À 788 under Ar. Over 10 min, 5.6 ml of a 1.0m soln. of
SnCl4 in heptane (1.46 g, 5.6 mmol) was added dropwise, during which time the mixture turned bright yellow.
The resulting mixture was stirred at À 788 for 30 min. A À 788 cold soln. of 1.7 g of 31 (4.7 mmol) in 30 ml of
CH2Cl2 was added dropwise via cannula over 35 min, during which time the soln. turned pale yellow. The
resulting mixture was stirred at À 788, and the reaction was monitored by TLC (AcOEt/hexanes 1:2, visualized
with p-anisaldehyde and UV). Aldehyde 31 was consumed after 4 h, at which time the mixture was quenched at
À 788 by addition of 5 ml of sat. aq. NH4Cl soln. The mixture was diluted with 15 ml of H2O and 15 ml of
CH2Cl2, the phases were separated, and the aq. phase was extracted with 10 ml of CH2Cl2 (3Â). The combined
org. phases were washed with 20 ml of 1m aq. HCl soln., 20 ml of H2O, 20 ml of sat. aq. NaHCO3 soln., and 20 ml
of sat. brine, dried (MgSO4), filtered, and concentrated in vacuo to afford a mixture of the desired anti-adduct 33
and residual S-phenyl methoxyethanethioate. The volatile thioester was removed in vacuo (1258, 3.5 torr) by
Kugelrohr distillation, and the residue was purified by FC (SiO2; AcOEt/hexanes 1 :20) to afford 1.8 g (73%) of
25
D
1
33 (d.r. 11.5 :1). ‰aŠ ˆ ‡49 (c ˆ 1.3, CH2Cl2). IR (neat): 3582, 2956, 1705, 1253. H-NMR (400 MHz, CDCl3):
7.30 7.41 (m, 10 H); 5.67 (dd, J1 ˆ 15.6, J2 ˆ 6.7, 1 H); 5.45 (dd, J1 ˆ 15.6, J2 ˆ 7.5, 1 H); 4.95 (d, J ˆ 11.5, 1 H);
4.69 (d, J ˆ 11.6, 1 H); 4.35 (t, J ˆ 7.4, 1 H); 3.95 (t, J ˆ 7.9, 1 H); 3.75 (d, J ˆ 7.2, 1 H); 3.61 (d, J ˆ 7.1, 1 H); 3.35
(s, 3 H); 2.68 (d, J ˆ 9.0, 1 H); 2.33 (m, J ˆ 6.7, 1 H); 1.01 (d, J ˆ 6.7, 6 H); 0.92 (s, 9 H); 0.06 (d, J ˆ 4.5, 6 H).
13C-NMR (100 MHz, CDCl3): 199.5; 140.9; 138.4; 134.7; 129.2; 128.4; 128.1; 127.8; 127.2; 126.7; 88.0; 79.6; 75.2;
‡
74.4; 71.1; 59.0; 30.9; 25.9; 22.2; 22.0; 18.2; À 4.1; À 4.6. HR-MS: 567.2584 ([M ‡ Na] , C30H44O3SSi; calc.
567.2576).
(2R,3R,4R,5R,6E)-5-{[(tert-Butyl)dimethylsilyl]oxy}-N-[(3S)-2,3,4,5,6,7-hexahydro-2-oxoazepin-3-yl]-3-
hydroxy-2-methoxy-8-methyl-4-[(phenyl)methoxy]non-6-enamide (35). To a soln. of 1.0 g (2.2 mmol) of 33 in
1.0 ml of 1,4-dioxane was added 0.3 g (2.2 mmol) of 3-amino-2,3,4,5,6,7-hexahydroazepin-2-one (34). The
resulting mixture was heated to reflux for 15 h. The mixture was cooled to r.t., diluted with 10 ml each of AcOEt
and H2O. The phases were separated, and the aq. layer was extracted with 5 ml of AcOEt (2Â). The combined
org. phases were washed with 10 ml each of H2O and sat. brine, dried (MgSO4), and concentrated to afford
25
D
1.21 g (98%) of 35 as a colorless, viscous oil. ‰aŠ ˆ ‡8.7 (c ˆ 0.30, MeOH). IR (film): 3346, 3061, 3030, 1660.
1H-NMR (400 MHz, CDCl3): 7.76 (d, J ˆ 5.8, 1 H); 7.45 7.25 (m, 5 H); 6.15 6.10 (m, 1 H); 5.66 (dd, J1 ˆ 16,
5
)
CH2Cl2 can also be used.

4552
Helvetica Chimica Acta Vol. 85 (2002)
J2 ˆ 6, 1 H); 5.42 (dd, J1 ˆ 15.4, J2 ˆ 7, 1 H); 4.95 (d, J ˆ 11.3, 1 H); 4.64 (d, J ˆ 11.4, 1 H); 4.53 4.49 (m, 1 H);
4.38 (t, J ˆ 7, 1 H); 3.85 3.79 (m, 1 H); 3.74 (d, J ˆ 7.2, 1 H); 3.59 (d, J ˆ 6.9, 1 H); 3.27 (s, 3 H); 3.30 3.22
(m, 1 H); 3.21 3.10 (m, 2 H); 2.35 2.25 (m, 1 H); 2.15 1.94 (m, 2 H); 1.85 1.25 (m, 3 H); 0.99 (d, J1 ˆ 7.6,
J2 ˆ 3.8, 6 H); 0.90 (s, 9 H); 0.04 (s, 3 H); 0.03 (s, 3 H). 13C-NMR (100 MHz, CDCl3): 175.1; 170.5; 140.5; 138.7;
128.3; 127.9; 127.5; 126.8; 82.1; 80.7; 75.3; 74.5; 71.2; 58.4; 51.9; 42.0; 31.3; 30.7; 28.8; 27.9; 26.0; 22.2; 21.9; 18.2;
‡
‡
À 4.0; À 4.5. MS: 563 ([M ‡ 1] ). HR-MS: 585.3362 (M ‡ Na] , C30H50N2NaO6Si; calc. 585.3336).
(2R,3R,4S,5R,6E)-N-(2,3,4,5,6,7-Hexahydro-2-oxoazepin-3-yl)-3,4,5-trihydroxy-2-methoxy-8-methylnon-
6-enamide ( ˆ Bengamide E; 3). A 50 ml round-bottom flask was charged with a soln. of 0.30 g of 35
(0.54 mmol) in 10 ml of THF, and 0.67 ml of anh. t-BuOH (7.1 mmol) was added. The flask was equipped with a
dissolving −metal addition× funnel containing freshly cut Na metal (0.6 g, 35 mmol) and a dry ice condenser, and
the contents of the flask were cooled to À 788 with stirring. Anh. NH3 was condensed into the flask through the
addition funnel, thereby adding the Na metal as a dark blue soln. As soon as the mixture had retained its blue
color for 1 min, addition was stopped, and the resulting dark blue mixture was stirred at À 788 for 20 min. The
mixture was slowly quenched at À 788 by portionwise addition of solid anh. NH4Cl (ca. 1 g) until the blue color
disappeared. The cooling bath was removed, and the ammonia was allowed to evaporate slowly. The residue was
diluted with 10 ml each of AcOEt and H2O, and the phases were separated. The aq. phase was extracted with
5 ml of AcOEt (2Â). The combined org. phases were washed with 20 ml of sat. brine and dried (MgSO4).
Concentration afforded 0.18 g (70%) of (2R,3R,4R,5R,6E)-5-{[(tert-Butyl)dimethylsilyl]oxy}-N-((3S)-
2,3,4,5,6,7-hexahydro-2-oxoazepin-3-yl)-3,4-dihydroxy-2-methoxy-8-methylnon-6-enamide, which was utilized
without further purification. For anal. purposes, a small sample was purified by FC (SiO2). Colorless, viscous oil.
25
D
1
‰aŠ ˆ ‡11.2 (c ˆ 0.25, MeOH). IR (film): 3313, 1657, 1575. H-NMR (400 MHz, CDCl3): 7.98 7.94 (m, 1 H);
6.28 6.24 (m, 1 H); 5.69 (dd, J1 ˆ 15.5, J2 ˆ 7, 1 H); 5.37 (dd, J1 ˆ 16, J2 ˆ 8, 1 H); 4.60 4.52 (m, 1 H); 4.24
(t, J ˆ 7.5, 1 H); 3.82 3.74 (m, 3 H); 3.58 (d, J ˆ 7.2, 1 H); 3.52 (s, 3 H); 3.31 3.24 (m, 2 H); 2.35 2.25
(m, 1 H); 2.15 2.05 (m, 2 H); 1.95 1.80 (m, 2 H); 1.60 1.20 (m, 3 H); 0.99 (d, J1 ˆ 7.0, J2 ˆ 3.5, 6 H); 0.90
(s, 9 H); 0.09 (s, 3 H); 0.06 (s, 3 H). 13C-NMR (100 MHz, CDCl3): 175.1; 171.6; 141.5; 126.2; 81.6; 75.5; 73.0;
‡
70.6; 59.7; 51.9; 42.1; 31.2; 30.7; 28.8; 27.9; 25.9; 22.2; 21.8; 18.1; À 3.7; À 4.7. MS: 473 ([M ‡ 1] ). HR-MS:
‡
495.2856 ([M ‡ Na] , C23H44N2NaO6Si; calc. 495.2866).
Then, a soln. of 50 mg (0.10 mmol) of the above intermediate in 1.5 ml of anh. THF was cooled to 08. A
0.30 ml portion of a 1.0m soln. of TBAF in THF (0.30 mmol) was added dropwise, and the resulting mixture was
stirred at 08 for 2 h. The mixture was quenched by addition of 1 ml of sat. aq. NH4Cl soln. and warmed to r.t. The
phases were separated, and the aq. phase was extracted with 2 ml of AcOEt (2Â). The combined org. phases
were washed with 5 ml each of H2O and sat. brine, and dried (MgSO4). Concentration and purification by FC
(SiO2; AcOEt/hexanes 5 :1) afforded 34 mg of 3 (95%) as a viscous, colorless oil that was indistinguishable from
25
D
an authentic sample [12]. ‰aŠ ˆ ‡27.3 (c ˆ 0.11, MeOH); lit. ‡ 36.9 (c ˆ 0.043, MeOH) [12]. IR (film): 3332,
1650. 1H-NMR (400 MHz, CDCl3): 8.01(d, J ˆ 5.9, 1 H); 5.99 5.95 (m, 1 H); 5.80 (dd, J1 ˆ 15.5, J2 ˆ 6.4, 1 H);
5.46 (dd, J1 ˆ 16.0, J2 ˆ 7.0, 1 H); 4.58 4.52 (m, 1 H); 4.40 (br. s, 1 H); 4.26 4.21 (m, 1 H); 3.84 3.77 (m, 2 H);
3.67 3.59 (m, 1 H); 3.56 (s, 3 H); 3.36 3.20 (m, 2 H); 3.19 3.00 (m, 2 H); 2.36 2.25 (m, 1 H); 2.13 1.98
(m, 2 H); 1.95 1.74 (m, 2 H); 1.73 1.30 (m, 4 H); 1.01 (d, J ˆ 6.8, 3 H); 1.01 (d, J ˆ 6.7, 3 H). 13C-NMR
(100 MHz, CDCl3): 174.4; 172.0; 141.7; 125.2; 80.6; 74.0; 72.6; 72.1; 59.9; 51.8; 41.9; 30.9; 30.7; 28.7; 27.8; 22.1;
‡
22.0. MS: 381 ([M ‡ Na] ).
2-(Oxiran-2-yl)ethyl 4-Methylphenylsulfonate (37). A 2.8-g portion NaH (60% in oil, 1.75 g, 73 mmol) was
washed free of oil with three 5 ml portions of hexanes, the residual hexanes were evaporated, and the residue
was diluted with 25 ml of anh. THF. The resulting suspension was cooled to À 108, and a soln. of 4.0 g (24 mmol)
of (R)-2-bromo-1,4 butanediol (36) [27] in 25 ml of anh. THF was added dropwise over 15 min. The resulting
mixture was stirred for 30 min at À 108, and 5.0 g of solid p-toluenesulfonyl chloride (26 mmol) was added.
After 4 h at À 108, consumption of 36 was complete according to TLC. The mixture was diluted with 100 ml
Et2O and filtered through a pad of SiO2. Concentration of the filtrate in vacuo and purification by FC (SiO2;
25
D
AcOEt/hexanes 1 :5) afforded 4.52 g (89%) of 37 as a colorless oil. ‰aŠ ˆ À17 (c ˆ 0.57, CH2Cl2). IR (neat):
2995, 1358, 1177. 1H-NMR (400 MHz, CDCl3): 7.82 (d, J ˆ 8, 2 H); 7.35 (d, J ˆ 8, 2 H); 4.15 (t, J ˆ 9, 2 H); 2.97
(m, J ˆ 2, 1 H); 2.76 (t, J ˆ 5, 1 H); 2.48 (dd, J1 ˆ 4.9, J2 ˆ 2.7, 1 H); 2.46 (s, 3 H); 2.05 1.97 (m, 1 H); 1.81 1.77
(m, 1 H). 13C-NMR (400 MHz, CDCl3): 144.9; 132.7; 129.8; 127.8; 67.1; 48.6; 46.8; 32.0; 21.5. HR-MS: 243.0693
‡
([M ‡ 1] , C11H15O4S; calc. 243.0691).
(S)-2-(2-Iodoethyl)oxirane (10). A soln. of 5.95 g (24.6 mmol) of 37 in 65 ml of acetone was combined with
3.68 g of solid NaI (24.6 mmol), and the mixture was heated at reflux for 2 h. After cooling to r.t., the mixture
was diluted with 100 ml of Et2O and filtered through a pad of Celite. The filtrate was concentrated in vacuo to
25
D
afford 4.5 g (93%) of 10 as a colorless oil, which was used without further purification. ‰aŠ ˆ À14 (c ˆ 3.4,

Helvetica Chimica Acta Vol. 85 (2002)
4553
CH2Cl2). IR (neat): 2988, 1423. 1H-NMR (400 MHz, CDCl3): 3.30 3.26 (m, 2 H); 3.05 3.03 (m, 1 H); 2.84
(t, J ˆ 5, 1 H); 2.60 (dd, J1 ˆ 5.0, J2 ˆ 3.0, 1 H); 2.19 2.15 (m, 1 H); 2.09 2.05 (m, 1 H). 13C-NMR (100 MHz,
‡
CDCl3): 52.3; 46.9; 36.3; 0.13. HR-MS: 197.9541 (M , C4H7IO; calc. 197.9542).
tert-Butyl (2S)-2-[(1,1-Diphenylmethylidene)amino]-4-[(2S)-oxiran-2-yl]butanoate (40). A 100 ml round-
bottom flask was charged with 7.56 g of CsOH ¥ H2O (50 mmol), which had been finely pulverized under Ar, and
with 15 ml of anh. CH2Cl2, and the contents were cooled to À 788. To the resulting suspension, 2.97 g (10 mmol)
of commercial neat tert-butyl diphenyliminoacetate (9) was added followed by 0.59 g of the phase-transfer
catalyst 38 (1.0 mmol) [25]. The mixture was gently swirled, and 2.6 g of neat 2-(2-iodoethyl)oxirane (10)
(13 mmol) was added. A mechanical stirrer was attached, and the slurry was vigorously stirred at À 608 for 18 h
under Ar. The reaction mixture was diluted with 65 ml of Et2O, quenched with 40 ml of H2O, and warmed to r.t.
After separation of the layers, the aq. phase was extracted three times with 20 ml of Et2O. The combined org.
phases were washed successively with 30 ml each of H2O and sat. brine, dried (Na2CO3), filtered, and
concentrated in vacuo to afford a mixture of the desired alkylation product 40 and excess iodide 10. Volatiles
(including 10) were removed under high vacuum (1008, 0.5 torr) via a Kugelrohr apparatus to afford 3.04 g
(83%) of 40 as an orange solid. The product was established to be a single detectable diastereoisomer (400-MHz
1H-NMR) and was used without further purification, since it is unstable on SiO2 or basic alumina. Extraction of
the aq. phase with CH2Cl2 allowed recovery of 85% of the catalyst 38 as the chloride salt, which was successfully
used again with similar results.
Data for 40: IR (neat): 2976, 1732, 1149. 1H-NMR (400 MHz, CDCl3): 7.80 7.16 (m, 10 H); 3.95 (dd, J1 ˆ
7.8, J2 ˆ 5.0, 1 H); 2.88 2.86 (m, 1 H); 2.70 (t, J ˆ 4.5, 1 H); 2.43 (dd, J1 ˆ 4.8, J2 ˆ 2.7, 1 H); 2.07 1.99 (m, 2 H);
1.62 1.40 (m, 2 H); 1.44 (s, 9 H). 13C-NMR (100 MHz, CDCl3): 171.1; 170.3; 139.5; 136.6; 130.3; 128.8; 128.6;
‡
128.3; 128.0; 127.8; 81.1; 65.5; 51.9; 47.0; 29.7; 29.0; 28.0. HR-MS: 366.2083 ([M ‡ 1] , C23H28NO3; calc.
366.2069).
tert-Butyl (2S,5S)-2-[(1,1-Diphenylmethylidene)amino]-5-hydroxy-6-[methyl(phenylmethyl)amino]hexa-
noate (43). To a soln. of 2.5 g of 40 (6.8 mmol) in 5.0 ml of anh. MeOH at r.t. was added 7.0 ml of N-benzyl-
N-methylamine (6.67 g, 55 mmol). The soln. was stirred at r.t. for 13 h, at which time consumption of 40 was
complete (as analyzed by ESI-MS). The MeOH was removed at aspirator pressure, and the remainder (excess
benzyl(methyl)amine) was removed under high vacuum (758 at 7 torr) with a Kugelrohr apparatus to afford
crude 43 in quant. yield. After purification by FC (SiO2; AcOEt/hexanes 1:15), 3.2 g (98%) of pure 43 was
25
obtained as a colorless oil. ‰aŠ ˆ À35 (c ˆ 0.66, CH2Cl2). IR (neat): 3579, 2930, 1732, 1500. 1H-NMR (400 MHz,
D
CD3OD): 7.57 7.15 (m, 15 H); 3.93 (dd, J1 ˆ 8.0, J2 ˆ 5.2, 1 H); 3.66 3.59 (m, 1 H); 3.51 (dd, J1 ˆ 17.7, J2 ˆ 13.0,
2 H); 2.40 2.30 (m, 2 H); 2.19 (s, 3 H); 2.00 1.93 (m, 2 H); 1.45 (s, 9 H); 1.23 1.37 (m, 2 H). 13C-NMR
(100 MHz, CD3OD): 173.2; 173.1; 140.8; 139.8; 137.8; 131.7; 130.4; 130.1; 129.9; 129.8; 129.3; 129.2; 128.9; 128.2;
‡
82.5; 69.0; 67.1; 64.5; 63.8; 43.1; 32.8; 30.7; 28.3. HR-MS: 487.2974 ([M ‡ 1] , C31H39N2O3; calc. 487.2961).
tert-Butyl 2-Amino-5-hydroxy-6-(methylamino)hexanoate (44). To a soln. of 0.59 g of 43 (1.2 mmol) in
4.4 ml of THF at r.t. was added 4.0 ml of 10% aq. citric acid. The soln. was stirred at r.t. for 30 min at which time
ESI-MS analysis indicated that consumption of 43 was complete. The mixture was diluted with 20 ml each of
H2O and hexanes, and the phases were separated. The aq. phase was extracted with 10 ml of hexanes (2Â),
rendered basic with pH 8.5 phosphate buffer, and extracted with 15 ml of AcOEt (3Â). The combined AcOEt
extracts were dried (Na2CO3), filtered, and concentrated in vacuo to afford 0.33 g (86%) of tert-Butyl (2S,5S)-2-
Amino-5-hydroxy-6-[methyl(phenylmethyl)amino]hexanoate as a colorless oil, which was utilized without
further purification: 1H-NMR (400 MHz, CD3OD): 7.33 7.23 (m, 5 H); 3.79 3.59 (m, 1 H); 3.55 (dd, J ˆ 17.3,
13.0, 2 H); 3.30 3.26 (m, 1 H); 2.40 2.32 (m, 2 H); 2.24 (s, 3 H); 1.74 1.67 (m, 2 H); 1.67 1.58 (m, 1 H); 1.47
(s, 9 H); 1.38 1.32 (m, 1 H). 13C-NMR (100 MHz, CD3OD): 176.0; 139.7; 130.4; 129.3; 128.2; 82.3; 64.9; 64.4;
‡
63.8; 55.8; 43.1; 32.5; 32.1; 28.3. HR-MS: 323.2340 ([M ‡ 1] , C18H31N2O3; calc. 323.2335).
A 100-ml round-bottom flask was charged with a soln. of 0.55 g (1.7 mmol) of the above intermediate in
40 ml of EtOH and 0.24 g of wet Pearlman×s catalyst (0.17 mmol). The flask was purged with H2 gas, and the
mixture was vigorously stirred under H2 (balloon pressure) for 11 h, at which time ESI-MS analysis indicated
completion of the reaction. The mixture was filtered through Celite, the Celite was rinsed with MeOH, and the
25
D
filtrate was concentrated in vacuo to afford 0.39 g of 44 (86% overall yield from 40) as a colorless oil. ‰aŠ
ˆ
‡8.7 (c ˆ 0.23, MeCN). IR (neat): 3382, 2921, 1727, 1367, 1155. 1H-NMR (400 MHz, CD3OD): 3.71 3.65
(m, 1 H); 3.53 3.48 (m, 1 H); 2.60 2.54 (m, 2 H); 2.43 (s, 3 H); 1.75 1.71 (m, 2 H); 1.57 1.52 (m, 2 H); 1.50
(s, 9 H); 1.49 1.41 (m, 2 H). 13C-NMR (100 MHz, CD3OD): 176.0; 82.2; 70.5; 58.4; 5.7; 36.1; 32.7; 32.1; 28.3.
‡
HR-MS: 233.1876 ([M ‡ 1] , C11H25N2O3; calc. 233.1865).
(3S,6S)-3-Amino-2,3,4,5,6,7-hexahydro-6-hydroxy-1-methylazepin-2-one (45). A 30 ml screw-cap vial was
charged with a soln. of 0.20 g of 44 (0.86 mmol) in 15 ml of MeOH, and 0.39 ml of a 3.3m soln. of MeONa

4554
Helvetica Chimica Acta Vol. 85 (2002)
(70.24 mg, 1.3 mmol) in MeOH was added. The vial was sealed and heated to 858 (bath temp.) for 1.5 h. The
mixture was cooled to r.t., quenched with 0.11 g of solid NaHCO3 (1.3 mmol), and the MeOH was removed in
vacuo. The remainder was dissolved in 10 ml of AcOEt/MeOH 15 :1, filtered through basic alumina to remove
inorg. salts, and the filtrate was concentrated in vacuo to afford 0.12 g (88%) of 45 as a white solid. M.p. 119
25
1228. ‰aŠ ˆ ‡14.1 (c ˆ 0.22, MeOH). IR (neat): 3360, 2924, 1646. 1H-NMR (400 MHz, CD3OD): 3.73 (dd, J1 ˆ
D
11.0, J2 ˆ 1.8, 1 H); 3.61 (dd, J1 ˆ 14.5, J2 ˆ 10.1, 1 H); 3.54 (m, 1 H); 3.17 (br. d, J ˆ 14.5, 1 H); 3.02 (s, 3 H); 2.11
(br. d, 1 H); 1.82 (br. d, 1 H); 1.70 1.46 (m, 2 H). 13C-NMR (100 MHz, CD3OD): 177.6; 68.5; 57.3; 53.9; 37.5;
‡
36.8; 32.6. HR-MS: 159.1126 ([M ‡ 1] , C7H15N2O2; calc. 159.1134).
(3S,6S)-6-Amino-2,3,4,5,6,7-hexahydro-1-methyl-7-oxoazepin-3-yl Acetate (46). A soln. of 17 mg of 45
(0.11 mmol) in 0.3 ml of anh. TFA was stirred at r.t. for 10 min. Over 5 min, 15 ml of AcCl (17.3 mg, 0.22 mmol)
was added dropwise to the mixture at r.t., and stirring was continued for 30 min, at which time ESI-MS analysis
showed that the reaction was complete. The mixture was concentrated in vacuo to a viscous oil, which was
dissolved in MeOH and treated with Amberlyst IR-400 resin for 10 min at r.t.. After filtration of the resin,
concentration in vacuo afforded a yellow oil, which was filtered through basic alumina (AcOEt/MeOH 5 :1) to
provide 18 mg (82%) of 46 as a pale yellow oil used without further purification: 1H-NMR (400 MHz, CD3OD):
4.61 4.56 (m, 1 H); 3.79 (d, J ˆ 10.2, 1 H); 3.71 (dd, J1 ˆ 14.9, J2 ˆ 10.0, 1 H); 3.30 3.26 (d, J ˆ 14.6, 2 H); 3.04
(s, 3 H); 2.11 2.05 (m, 1 H); 2.03 (s, 3 H); 1.90 1.84 (m, 2 H); 1.61 1.55 (m, 1 H). 13C-NMR (100 MHz,
CD3OD): 177.5; 171.8; 71.0; 53.9; 53.6; 36.6; 33.7; 32.2; 21.0.
(3S,6S)-6-Amino-2,3,4,5,6,7-hexahydro-1-methyl-7-oxoazepin-3-yl Tetradecanoate (47). A soln. of 61 mg of
45 (0.38 mmol) in 0.8 ml of TFA was stirred at r.t. for 10 min. Dropwise over 5 min, 0.208 ml of myristoyl
chloride (189 mg, 0.77 mmol) was added to the mixture at r.t., and stirring was continued at r.t. for 30 min at
which time ESI-MS analysis indicated completion of the reaction. The mixture was quenched by careful addition
of 2 ml of H2O, diluted with 10 ml of CH2Cl2, and rendered basic with pH 8.5 phosphate buffer. The phases were
separated, and the aq. phase was extracted with 10 ml of CH2Cl2 (3Â). The combined org. phases were washed
with 15 ml of a 1:1 mixture of phosphate buffer pH 8.5 and H2O, dried (Na2CO3), and filtered through a pad of
25
D
Celite to afford 0.12 g (90%) of 47 as a white solid. M.p. 90 928. ‰aŠ ˆ ‡69 (c ˆ 0.85, CH2Cl2). IR (neat): 3487,
2914, 2849, 1732. 1H-NMR (400 MHz, CDCl3): 4.62 (tt, J1 ˆ 2.7, J2 ˆ 0.9, 1 H); 3.8 (br. d, 1 H); 3.61 (dd, J1 ˆ 14.7,
J2 ˆ 10.0, 1 H); 3.22 (dt, J1 ˆ 14.9, J2 ˆ 2.2, 1 H); 3.10 (s, 3 H); 2.31 (t, J ˆ 7.4, 2 H); 2.21 2.07 (m, 1 H); 2.00
1.88 (m, 1 H); 1.87 1.67 (m, 3 H); 1.65 1.53 (m, 3 H); 1.35 1.16 (m, 20 H); 0.89 (t, J ˆ 6.7, 3 H). 13C-NMR
(100 MHz, CDCl3): 176.2; 173.0; 69.6; 453.3; 53.1; 36.5; 34.4; 33.0; 31.9; 31.5; 29.7; 29.6; 29.6; 29.4; 29.3; 29.2;
‡
29.1; 24.9; 22.7; 14.1. HR-MS: 369.3106 ([M ‡ 1] , C21H41N2O3; calc. 369.3117).
(3S,6S)-6-[((2R,3R,4R,5R,6E)-5-{[(tert-Butyl)dimethylsilyl]oxy}-3-hydroxy-2-methoxy-8-methyl-4-(phe-
nylmethoxy)non-6-enoyl)amino]-2,3,4,5,6,7-hexahydro-1-methyl-7-oxoazepin-3-yl Acetate (48). A 5-ml round-
bottom flask equipped with a cold finger was charged with 35 mg of 33 (0.065 mmol), 14 mg of 46
(0.068 mmol), and 0.14 ml of anh. dioxane. The resulting soln. was heated to reflux and was monitored by TLC
(hexane/AcOEt 2 :1, visualization with p-anisaldehyde and UV). Within 18 h, consumption of 33 was complete.
The mixture was cooled to r.t., diluted with 5 ml of AcOEt and 3 ml of H2O. The phases were separated, and the
aq. phase was extracted with 2 ml of AcOEt (3Â). The combined org. phases were washed successively with
3 ml of H2O (2Â) and 5 ml of sat. brine (2Â), dried (MgSO4), and concentrated in vacuo. The resulting oil was
dissolved in hexanes/AcOEt 5 :1 and filtered through a plug of SiO2 to remove the phenylthiol. Then, the
column was flushed with AcOEt/hexanes 3 :1, and the filtrate was concentrated to afford 38 mg (94%) of 48 as a
25
glassy white solid. ‰aŠ ˆ ‡40 (c ˆ 0.9, CH2Cl2). IR (neat): 3483, 2956, 1736, 1655. 1H-NMR (400 MHz, CDCl3):
D
7.78 (d, J ˆ 6.2, 1 H); 7.40 7.26 (m, 5 H); 5.66 (dd, J1 ˆ 15.4, J2 ˆ 6.4, 1 H); 5.44 (ddd, J1 ˆ 15.4, J2 ˆ 7.4, J3 ˆ 1.0,
1 H); 4.96 (d, J ˆ 11.6, 1 H); 4.64 (d, J ˆ 11.6, 1 H); 4.64 4.60 (m, 2 H); 4.37 (t, J ˆ 7.2, 1 H); 3.85 (dt, J1 ˆ 7.0,
J2 ˆ 1.8, 1 H); 3.65 (d, J ˆ 6.9, 1 H); 3.63 3.56 (m, 1 H); 3.54 (dd, J1 ˆ 7.1, J2 ˆ 1.8, 1 H); 3.25 (s, 3 H); 3.26 3.22
(m, 1 H); 3.10 (s, 1 H); 3.04 (d, J ˆ 7.1, 1 H); 2.30 (sept., J ˆ 6.8, 1 H); 2.18 2.08 (m, 1 H); 2.06 (s, 3 H); 2.04
1.89 (m, 1 H); 1.72 1.58 (m, 2 H); 1.00 (dd, J1 ˆ 6.7, J2 ˆ 3.4, 6 H); 0.90 (s, 9 H); 0.10 (s, 3 H); 0.06 (s, 3 H).
13C-NMR (400 MHz, CDCl3): 172.0; 170.5; 170.1; 140.5; 138.8; 128.3; 127.8; 127.4; 126.7; 82.5; 80.4; 75.2; 74.3;
71.1; 69.5; 60.4; 58.5; 53.3; 51.2; 36.2; 32.6; 30.7; 29.2; 25.9; 22.2; 22.0; 21.1; 18.1; 14.2; À 4.04; À 4.58. HR-MS:
‡
635.3700 ([M ‡ 1] , C33H55N2O8Si; calc. 635.3728).
(2R,3R,4S,5R,6E)-N-((3S,6S)-2,3,4,5,6,7-Hexahydro-6-hydroxy-1-methyl-2-oxoazepin-3-yl)-3,4,5-trihy-
droxy-2-methoxy-8-methylnon-6-enamide (ˆ Bengamide Z; 2). A 25-ml two-necked round-bottom flask
equipped with a dry-ice condenser was charged with a soln. of 15 mg of 48 (0.024 mmol) in 0.5 ml of anh.
THF and 23 ml of anh. t-BuOH (0.24 mmol), and the contents were cooled to À 788. Approximately 15 ml of
anh. NH3 was condensed into the flask, and three 5 mg pieces (0.7 mmol) of Na metal (freshly cut and rinsed
with anh. EtOH) were added until a blue color persisted. After stirring for 15 min at À 788, the reaction was

Helvetica Chimica Acta Vol. 85 (2002)
4555
quenched by addition of solid anh. NH4Cl, and the mixture was diluted slowly with 5 ml of AcOEt, resulting in a
cloudy white soln. The NH3 was allowed to evaporate upon warming to r.t., and the resulting mixture was
filtered through Celite and concentrated to afford 9 mg (73%) of 5-{[(tert-butyl)dimethylsilyl]oxy}-N-
(2,3,4,5,6,7-hexahydro-6-hydroxy-1-methyl-2-ox oazepin-3-yl)-3,4-dihydroxy-2-methoxy-8-methylnon-6-enam-
ide, which was used without further purification. 1H-NMR (400 MHz, CDCl3): 8.02 (br. d, J ˆ 7, 1 H); 5.68
(dd, J1 ˆ 15.6, J2 ˆ 6.5, 1 H); 5.36 (dd, J1 ˆ 15.6, J2 ˆ 6.7, 1 H); 4.68 4.52 (m, 2 H); 4.22 (t, J ˆ 7.4, 1 H); 3.77
(dd, J1 ˆ 7.4, J2 ˆ 5.5, 1 H); 3.70 3.34 (m, 3 H); 3.51 (s, 3 H); 3.23 (d, J ˆ 14.9, 1 H); 3.10 (s, 3 H); 2.28
(sept., J ˆ 6.7, 1 H); 2.25 2.16 (m, 2 H); 2.12 (s, 3 H); 2.11 2.04 (m, 1 H); 1.64 1.54 (m, 2 H); 1.31 1.25
(m, 1 H); 0.99 (d, J ˆ 6.7, 3 H); 0.98 (d, J ˆ 6.7, 3 H); 0.89 (s, 9 H); 0.09 (s, 3 H); 0.05 (s, 3 H).
To a soln. of 7.3 mg (0.015 mmol) of the above intermediate in 0.8 ml of anh. THFat r.t. was added dropwise
30 ml of a 1.0m soln. of TBAF in THF (0.03 mmol). The soln. was stirred at r.t. for 15 min and quenched with 3 ml
of H2O. The phases were separated, and the aq. phase was washed with 1 ml of CH2Cl2, treated with 5 mg of
solid NaHCO3, and lyophilized. The residue was purified by FC (C18 reversed-phase SiO2; MeOH/H2O 1 :10 !
2 :1) to afford 4.3 mg (74%) of bengamide Z (1) as a colorless, viscous oil, which was spectroscopically
25
D
indistinguishable from an authentic sample [3]. ‰aŠ ˆ ‡44 (c ˆ 0.9, MeOH); lit.: ‡ 45 (c ˆ 0.11, MeOH)
[3][4]. IR (neat): 3380, 2928, 1644. 1H-NMR (400 MHz, CD3OD): 5.72 (dd, J1 ˆ 15.5, J2 ˆ 6.6, 1 H); 5.43
(dd, J1 ˆ 15.5, J2 ˆ 7.5, 1 H); 4.71 (d, J ˆ 10.9, 1 H); 4.69 (t, J ˆ 7.2, 1 H); 3.82 3.65 (m, 3 H); 3.55 (dd, J1 ˆ 7.0,
J2 ˆ 2.0, 2 H); 3.39 (s, 3 H); 3.21 (br. d, J ˆ 14.8, 1 H); 3.04 (s, 3 H); 2.28 (sept., J ˆ 6.7, 1 H); 2.21 2.09 (m, 1 H);
1.99 (br. d, J ˆ 14.1, 1 H); 1.79 1.52 (m, 2 H); 1.00 (d, J ˆ 6.7, 6 H). 13C-NMR (400 MHz, CDCl3): 174.2; 173.0;
142.1; 127.6; 83.5; 75.0; 74.3; 68.4; 58.7; 57.5; 52.9; 37.2; 36.7; 32.2; 30.1; 22.7; 22.6.
(3S,6S)-6-[((2R,3R,4R,5R,6E)-5-{[(tert-Butyl)dimethylsilyl]oxy}-3-hydroxy-2-methoxy-8-methyl-4-[(phen-
yl)methoxy]non-6-enoyl)amino]-2,3,4,5,6,7-hexahydro-1-methyl-7-oxoazepin-3-yl Tetradecanoate (49). A 25-ml
round-bottom flask, equipped with a cold finger, was charged with 0.322 g of 33 (0.61 mmol), 0.209 g of 47
(0.61 mmol), and 1.5 ml of anh. dioxane. The soln. was heated to reflux under Ar, and the reaction was
monitored by TLC (hexanes/AcOEt 2 :1, visualization by p-anisaldehyde and UV). After 23 h, the reaction was
complete according to TLC. The mixture was cooled to r.t. and diluted with 30 ml of AcOEt and 20 ml of H2O.
The phases were separated, and the aq. phase was extracted with 10 ml of AcOEt (3Â). The combined org.
phases were washed with 20 ml of H2O (2Â) and 30 ml of sat. brine (2Â), dried (MgSO4), and concentrated in
vacuo. The resulting oil was dissolved in hexanes/AcOEt 5 :1 and filtered through a plug of SiO2 to remove the
phenylthiol. The column was then flushed with AcOEt/hexanes 3 :1, and the eluate was concentrated in vacuo to
25
D
afford 0.48 g (98%) of 49 as a clear, glassy solid. ‰aŠ ˆ ‡28 (c ˆ 0.76, CH2Cl2). IR (neat): 3405, 2925, 1737,
1659. 1H-NMR (400 MHz, CDCl3): 7.76 (d, J ˆ 6.2, 1 H); 7.38 7.24 (m, 5 H); 5.64 (dd, J1 ˆ 15.6, J2 ˆ 6.5, 1 H);
5.42 (dd, J1 ˆ 15.6, J2 ˆ 7.4, 1 H); 4.93 (d, J ˆ 11.6, 1 H); 4.65 4.56 (m, 2 H); 4.62 (d, J ˆ 11.6, 1 H); 4.35 (t, J ˆ
7.2, 1 H); 3.83 (br. d, J ˆ 5.8, 1 H); 3.64 3.50 (m, 3 H); 3.23 (s, 3 H); 3.22 3.15 (m, 1 H); 3.07 (s, 3 H); 3.08
3.00 (m, 1 H); 2.3 (t, J ˆ 7.5, 2 H); 2.32 2.26 (m, 1 H); 2.18 2.10 (m, 1 H); 2.05 1.84 (m, 1 H); 1.63 1.55
(m, 4 H); 1.25 1.29 (m, 18 H); 0.97 (d, J ˆ 6.7, 6 H); 0.88 (t, J ˆ 5.6, 3 H); 0.86 (s, 9 H); 0.03 (s, 3 H); 0.01
(s, 3 H). 13C-NMR (400 MHz, CDCl3): 173.0; 172.0; 170.5; 140.5; 138.8; 128.3; 127.8; 127.4; 126.8; 82.5; 80.4;
75.2; 74.3; 71.1; 69.3; 58.5; 53.3; 51.2; 36.2; 34.3; 32.7; 31.9; 30.7; 29.6; 29.6; 29.4; 29.3; 29.2; 29.1; 25.9; 24.8; 22.7;
‡
22.2; 22.0; 18.1; 14.1; À 4.0; À 4.6. HR-MS: 803.5622 ([M ‡ 1] , C45H79N2O8Si; calc. 803.5606).
Sodium2-[(2-Naphthyl)methoxy]acetate (55). To a slurry of 4.06 g of NaH (169 mmol) in 150 ml of anh.
THFat 08 was slowly added 14.8 ml (16.03 g, 154 mmol) of neat ethyl 2-hydroxyacetate (54) over 15 min, and the
cooling bath was removed. After 30 min, a soln. of 34.0 g of 2-(bromomethyl)naphthalene (154 mmol) in
100 ml of THF was added via cannula at r.t. followed by the addition of a catalytic amount (ca. 300 mg) of
Bu4NI. After 18 h at r.t., 100 ml of sat. aq. NH4Cl soln. was added, and the layers were separated. The aq. phase
was extracted with 100 ml of AcOEt (3Â), and the combined org. extracts were washed successively with 150 ml
each of H2O and sat. brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by FC (SiO2;
hexanes/AcOEt 9 :1) to afford 35.0 g (80%) of ethyl 2-[(2-naphthyl)methoxy]acetate as a yellow oil. IR (film):
3055, 1748, 1602. 1H-NMR (400 MHz, CDCl3): 7.90 7.77 (m, 4 H); 7.57 7.45 (m, 3 H); 4.82 (s, 2 H); 4.26
(q, J ˆ 7.1, 2 H); 4.16 (s, 2 H); 1.31 (t, J ˆ 7.1, 3 H ) . 13C-NMR (100 MHz, CDCl3): 170.2; 134.5; 133.1; 133.0;
‡
‡
128.2; 127.8; 127.6; 126.8; 126.1; 126.0; 125.8; 73.3; 67.1; 30.8; 14.1. MS: 243 ([M À 1] ). HR-MS: 244.1107 (M ,
C15H16O3; calc. 244.1099).
A 7.28-g sample of solid NaOH pellets (182 mmol) was added to a magnetically stirred soln. of 12.21 g
(50 mmol) of the above intermediate in 90 ml of MeOH. After 10 h at r.t., the resulting precipitate was collected
by suction and dried in vacuo overnight to afford 11.55 g (97%) of 55 as a white solid used without further
purification.

4556
Helvetica Chimica Acta Vol. 85 (2002)
(1S,4S)-2-{2-[(2-Naphthyl)methoxy]acetyl}-4,5,5-trimethyl-2-azabicyclo[2.2.1]heptan-3-one (56). To a sus-
pension of 11.55 g (48.5 mmol) of 55 in 100 ml of THF was added dropwise 5.848 g of neat pivaloyl chloride
(48.5 mmol) at r.t. After 30 min stirring at r.t., the resulting mixture was cooled to À 788, and 200 ml of a À 788
cold 0.27m soln. of the lithiated chiral auxiliary (obtained by treatment of a soln. of 8.38 g of 8 (54.7 mmol) in ca.
175 ml of anh. THF with 36.5 ml of a 1.5m soln. of BuLi in hexanes) was added via cannula. The soln. was
allowed to warm slowly to r.t. in the cold bath for ca. 4 5 h. After an additional 12 h at r.t., the mixture was
diluted with 100 ml of sat. aq. NH4Cl soln. and mixed well. After separation of the phases, the aq. phase was
extracted with 50 ml of AcOEt (3Â), the org. phases were combined, washed successively with 100 ml each of
H2O and sat. brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by FC (SiO2; hexanes/
25
AcOEt 3 :2) to afford 11.9 g (71%, two steps) of 56 as a white solid. M.p. 80 828. ‰aŠ ˆ ‡2.3 (c ˆ 2.9, AcOEt).
D
1
IR (film): 3054, 3013, 1746, 1704, 1602. H-NMR (400 MHz, CDCl3): 7.85 7.80 (m, 4 H); 7.58 7.43 (m, 3 H);
4.84 (s, 2 H); 4.69 (s, 1 H); 4.61 (s, 2 H); 1.86 (d, J ˆ 10.3, 1 H); 1.78 1.60 (m, 3 H); 1.10 (s, 3 H); 1.05 (s, 3 H);
0.86 (s, 3 H). 13C-NMR (100 MHz, CDCl3): 177.9; 169.2; 134.7; 133.1; 133.0; 128.1; 127.8; 127.5; 126.8; 125.9;
‡
125.8; 125.8; 109.3; 73.4; 70.4; 57.2; 53.9; 44.6; 42.0; 38.0; 26.2; 25.6; 9.6. MS: 352 ([M ‡ 1] ). HR-MS: 352.1914
‡
([M ‡ 1] , C22H26NO3; calc. 352.1913).
(1S,4S)-2-((2S,3R,4E)-3-{[(tert-Butyl)dimethylsilyl]oxy}-6-methyl-2-[(2-naphthyl)methoxy]hept-4-enoyl)-
4,5,5-trimethyl-2-azabicyclo[2.2.1]heptan-3-one (57). A soln. of 50 mg of 56 (0.14 mmol) in 0.75 ml of anh.
CH2Cl2 was cooled to À 788, and 49 ml of neat (i-Pr)NEt (0.28 mmol) was added. The resulting mixture was
treated dropwise with 29 ml of neat Et2BOTf (0.15 mmol)3) and the À 788 cooling bath was replaced with a 08
cold bath. After 1 h, the mixture was cooled again to À 788, 18 mg of neat aldehyde 6 (0.18 mmol) was added
slowly over several min and rinsed in with a small amount of THF, and the resulting mixture was warmed to À
408. After 23 h at that temp., 0.5 ml of a mixture of pH 7.5 buffer/MeOH 3 :1 was added, followed by the cautious
addition of 0.5 ml of a mixture of MeOH/30% aq. H2O2 3 :1 with vigorous stirring at 08. After 1 h, the layers
were separated, and the aq. phase was extracted thoroughly with 2 ml portions of CH2Cl2 (3Â). The combined
org. phases were washed with 5 ml each of H2O and sat. brine, dried (MgSO4), and concentrated in vacuo to
afford 60 66 mg of the expected aldol adduct as a light yellow solid used without further purification.
A soln. of the above intermediate (ca. 0.14 mmol) in 1.0 ml of CH2Cl2 was treated with 38 mg of solid
imidazole (0.57 mmol) and 42 mg (0.28 mmol) of solid TBSCl3). After stirring for 11 h at r.t., 2 ml of sat. aq.
NaHCO3 soln. was added, and the phases were separated. The aq. phase was extracted thoroughly with 2 ml of
CH2Cl2 (3Â), and the org. extracts were combined, washed with 5 ml H2O and sat. brine, dried (MgSO4),
concentrated, and purified by FC (SiO2; hexanes/AcOEt 9 :1) to afford 56 mg (70%, two steps) of 57 (d.r.
25
55 :1)6) as a clear oil. ‰aŠ ˆ ‡1.3 (c ˆ 2.9, AcOEt). IR (film): 3051, 3012, 1746, 1698. 1H-NMR (400 MHz,
D
CDCl3): 7.82 7.71 (m, 4 H); 7.50 7.40 (m, 3 H); 5.65 (dd, J1 ˆ 15.7, J2 ˆ 6, 1 H); 5.54 (dd, J1 ˆ 16.0, J2 ˆ 7.0,
1 H); 5.04 (d, J ˆ 4.9, 1 H); 4.78 (s, 2 H); 4.55 (br. s, 1 H); 4.48 (dd, J1 ˆ 7.2, J2 ˆ 5.1, 1 H); 2.35 2.20 (sept., J ˆ
7.0, 1 H); 1.80 (d, J ˆ 10.4, 1 H); 1.67 1.62 (m, 1 H); 1.57 1.53 (m, 1 H); 1.47 1.42 (m, 1 H); 1.27 (t, J ˆ 7.1,
1 H); 1.05 (s, 3 H); 1.00 0.76 (m, 23 H); 0.43 (s, 2 H); 0.02 (s, 3 H); 0.01 (s, 3 H). 13C-NMR (100 MHz, CDCl3):
177.1; 169.8; 139.8; 135.4; 133.0; 132.9; 127.8; 127.4; 126.6; 126.0; 125.7; 125.6; 109.3; 82.4; 75.5; 73.2; 57.3; 54.4;
‡
44.4; 41.1; 37.8; 30.5; 26.1; 25.9; 25.7; 25.0; 22.1; 21.8; 18.1; 9.8; À 4.3; À 4.9. MS: 587 ([M ‡ Na] . HR-MS:
‡
586.3310 (C34H49NNaO4Si ; calc. 586.3329).
Preparation of 57 on Larger Scale. A soln. of 1.16 g of 56 (3.31 mmol) in 20 ml of anh. CH2Cl2 was cooled to
À 788, and 1.15 ml of neat (i-Pr)NEt (6.61 mmol) was added. The resulting mixture was treated dropwise with
0.68 ml of neat Et2BOTf (3.47 mmol)3), and the À 788 cooling bath was replaced with a 08 cold bath. After 1 h,
the resulting mixture was cooled again to À 788, 421 mg of neat aldehyde 6 (4.30 mmol) was added slowly over
several min and rinsed in with a small amount of THF, and the reaction mixture was warmed to À 408. After 20 h
at that temp., 8 ml of a mixture of pH 7.5 buffer/MeOH 3 :1 was added, followed by the cautious addition of 8 ml
of a mixture of MeOH/30% aq. H2O2 3 :1 with vigorous stirring at 08. After 1 h, the layers were separated, and
the aq. phase was extracted thoroughly with 20 ml of CH2Cl2 (3Â). The combined org. phases were washed
successively with H2O and sat. brine, dried (MgSO4), and concentrated in vacuo to afford 1.45 1.57 g of the
expected aldol adduct as a light yellow solid used without further purification.
A soln. of the above intermediate (ca. 3.31 mmol) in 12 ml of CH2Cl2 was treated with 788 mg of solid
imidazole (11.58 mmol) followed by the addition of 871 mg (5.78 mmol) of solid TBSCl4). After stirring for 15 h
at r.t., 12 ml of a sat. aq. NaHCO3 soln. was added, and the phases were separated. The aq. phase was extracted
thoroughly with 12 ml of CH2Cl2 (3Â), and the org. extracts were combined, washed successively with 10 ml of
6
)
Determined by HPLC.

Helvetica Chimica Acta Vol. 85 (2002)
4557
H2O and sat. brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by FC (SiO2; hexanes/
25
AcOEt 9 :1) to afford 1.32 g (71%, two steps) of 57 (dr >24 :1)7) as a clear oil. ‰aŠ ˆ ‡1.3 (c ˆ 2.9, AcOEt).
D
For anal. data, see above.
S-Ethyl (2S,3R,4E)-3-{[(tert-Butyl)dimethylsilyl]oxy}-6-methyl-2-[(2-naphthyl)methoxy]hept-4-enethioate
(58). A soln. of 0.82 ml of ethane-1,2-thiol (11.03 mmol) in 50 ml of THF was cooled to À 788, and 6.13 ml of a
1.35m soln. of BuLi in hexanes (8.28 mmol) was added. After 30 min at À 788, a soln. of 3.24 g of 57
(5.52 mmol) in 25 ml of THF (precooled to À 788) was added via cannula, and the resulting mixture was
warmed to À 408. After 10 h at that temp., the mixture was warmed to r.t., quenched with 25 ml of sat. aq.
NH4Cl soln., and the resulting mixture was diluted with 150 ml Et2O. The phases were separated, and the aq.
phase was extracted with 50 ml of Et2O (3Â). The org. phases were combined, washed successively with 50 ml
each of H2O and sat. brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by FC (SiO2;
25
D
hexanes/AcOEt 9 :1) to afford 2.38 g (91%) of 58 as a clear oil. ‰aŠ ˆ À59.7 (c ˆ 2.3, AcOEt). IR (film): 3055,
3030, 1682, 1605. 1H-NMR (400 MHz, CDCl3): 7.84 (d, J ˆ 8, 4 H); 7.55 7.45 (m, 3 H); 5.56 (dd, J1 ˆ 15.5, J2 ˆ
7.4, 1 H); 4.99 (d, J ˆ 12.0, 1 H); 4.65 (d, J ˆ 12.0, 1 H); 4.41 4.36 (m, 1 H); 3.89 (d, J ˆ 4.4, 1 H); 2.89 (dd, J1 ˆ
14.8, J2 ˆ 7.4, 2 H); 2.27 2.14 (m, 1 H); 1.28 (t, J ˆ 7, 4 H); 0.94 (d, J ˆ 6.8, 6 H); 0.88 (s, 9 H); 0.03 (s, 6 H).
13C-NMR (100 MHz, CDCl3): 201.6; 140.0; 134.6; 133.0; 133.0; 127.9; 127.8; 127.5; 127.0; 126.2; 125.9; 125.8; 88.6;
‡
‡
75.4; 73.7; 30.6; 25.7; 22.4; 21.9; 18.1; 14.4; À 4.4; À 4.9. MS: 473 ([M ‡ 1] ). HR-MS: 473.2529 ([M ‡ 1] ,
C27H41O3SSi; calc. 473.2545).
S-Phenyl (2R,3R,4R,5R,6E)-5-{[(tert-Butyl)dimethylsilyl]oxy}-3-hydroxy-2-methoxy-8-methyl-4-[(2-
naphthyl)methoxy]non-6-enethioate (53). A soln. of 2.02 g of 58 (4.28 mmol) in 40 ml of anh. toluene was
cooled to À 788, and 5.3 ml (7.95 mmol) of a 1.0m soln. of DIBAL in hexanes was added dropwise by slow
addition down the side of the flask to effect precooling8). After 45 min at À 788, the mixture was quenched with
8 ml of a 1.0m soln. of aq. HCl, and the cooling bath was removed. After 35 min, excess solid Na2CO3 was added,
and the mixture was filtered and concentrated in vacuo. The contents were permitted to remain on the rotary
evaporator for 20 min at 908 after the bulk of the solvent had been removed (to assure complete decomposition
of the hemithioacetal to the aldehyde) to afford 1.75 g (99%) of (2S,3R,4E)-3-{[(tert-Butyl)dimethylsilyl]oxy}-
25
D
6-methyl-2-[(2-naphthyl)methoxy]hept-4-enal (59) as a clear oil used without further purification. ‰aŠ ˆ À22.8
(c ˆ 0.9, AcOEt). IR (film): 3051, 2711, 1734, 1581. 1H-NMR (400 MHz, CDCl3): 9.71 (d, J ˆ 1.4, 1 H); 7.87 7.76
(m, 4 H); 7.53 7.46 (m, 3 H); 5.66 (dd, J1 ˆ 15.5, J2 ˆ 6.5, 1 H); 5.54 (dd, J1 ˆ 15.6, J2 ˆ 6.6, 1 H); 4.94 (d, J ˆ
12.3, 1 H); 4.74 (d, J ˆ 12.3, 1 H); 4.47 4.42 (m, 1 H); 3.83 3.79 (m, 1 H); 2.31 2.26 (m, 1 H); 0.99 (t, J ˆ 6.0,
6 H); 0.88 (s, 9 H); 0.03 (s, 3 H); 0.02 (s, 3 H). 13C-NMR (100 MHz, CDCl3): 202.8; 140.5; 134.9; 133.1; 133.1;
128.3; 127.9; 127.7; 126.8; 126.2; 126.0; 125.8; 125.4; 86.3; 74.1; 73.0; 30.7; 25.8; 22.1; 22.1; 18.1; À 4.3; À 5.0. MS:
‡
430 ([M ‡ H2O] ).
A soln. of 1.94 g of 32 ((E)/(Z) ca. 10 :1) (7.63 mmol) in 15 ml of anh. CH2Cl2 was cooled to À 788 under
Ar, and 3.8 ml of a 1.0m soln. of SnCl4 in heptane (990 mg, 3.8 mmol) was added dropwise. After 45 min at À
788, a soln. of 1.57 g of 59 (3.82 mmol) in 22 ml of CH2Cl2 (precooled to À 788) was added dropwise via cannula.
After 1.5 h at that temp., 20 ml of sat. aq. NaHCO3 soln. was added. After warming to r.t., the biphasic mixture
was diluted with 20 ml of H2O and shaken vigorously. The phases were separated, and the aq. phase was
extracted with 20 ml of CH2Cl2 (3Â). The org. phases were combined, washed successively with 25 ml each of
sat. aq. NaHCO3 soln. and sat. brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by FC
25
(SiO2; hexanes/AcOEt 9 :1) to afford 1.41 g (62%) of 53 (dr >8 :1)7) as a clear oil. ‰aŠ ˆ ‡55.9 (c ˆ 3.7,
D
AcOEt). IR (film): 3478, 3059, 3025, 1704. 1H-NMR (400 MHz, CDCl3): 7.92 7.85 (m, 4 H); 7.58 7.48
(m, 3 H); 7.42 (s, 5 H); 5.73 (dd, J1 ˆ 15.6, J2 ˆ 6.7, 1 H); 5.52 (dd, J1 ˆ 15.6, J2 ˆ 7.5, 1 H); 5.15 (d, J ˆ 11.8, 1 H);
4.89 (d, J ˆ 11.8, 1 H); 4.22 (t, J ˆ 7.4, 1 H); 4.02 (t, J ˆ 8.0, 1 H); 3.80 (d, J ˆ 7.1, 1 H); 3.72 (d,J ˆ 7.2, 1 H); 3.28
(s, 3 H); 2.80 (d, J ˆ 8.9, 1 H); 2.40 2.32 (m, 1 H); 1.05 (d, J ˆ 6.7, 6 H); 0.95 (s, 9 H); 0.10 (s, 3 H); 0.09 (s, 3 H).
13C-NMR (100 MHz, CDCl3): 199.4; 140.9; 135.8; 134.6; 133.1; 132.9; 129.1; 129.0; 128.1; 127.8; 127.6; 127.1;
126.6; 126.1; 126.0; 125.9; 88.0; 79.6; 75.1; 74.4; 71.1; 58.9; 30.8; 25.9; 22.1; 22.0; 18.1; À 4.2; À 4.7. MS: 617
‡
‡
([M ‡ Na] ). HR-MS: 617.2762 ([M ‡ Na] , C34H46NaO5SSi; calc. 617.2733).
(3S,6S)-6-[((2R,3R,4R,5R,6E)-5-{[(tert-Butyl)dimethylsilyl]oxy}-3-hydroxy-2-methoxy-8-methyl-4-[(2-
naphthyl)methoxy]non-6-enoyl)amino]-2,3,4,5,6,7-hexahydro-7-oxo-1-methylazepin-3-yl Tetradecanoate (60).
To a soln. of 304 mg of 53 (0.51 mmol) in 7.0 ml of anh. dioxane was added 189 mg of 47 (0.51 mmol), and the
resulting soln. was heated at reflux for 30 h under Ar. The mixture was cooled to r.t., 25 ml each of AcOEt and
1
7
8
)
)
Determined by H-NMR.
Less than 1.8 equiv. of DIBAL are insufficient to complete the reaction.

4558
Helvetica Chimica Acta Vol. 85 (2002)
H2O were added and, after thorough mixing, the phases were separated. The aq. phase was extracted with 5 ml
of AcOEt (3Â), and the combined org. phases were washed successively with 20 ml each of H2O and sat. brine,
dried (MgSO4), and concentrated in vacuo. The residue was purified by radial chromatography on a 1 mm silica-
25
D
gel plate (hexanes/AcOEt 3 :2) to afford 296 mg (69%) of 60 as a clear oil. ‰aŠ ˆ ‡37.3 (c ˆ 0.9, AcOEt):
1H-NMR (400 MHz, CDCl3): 7.82 7.77 (m, 5 H); 7.52 7.41 (m, 3 H); 5.67 (dd, J1 ˆ 15.6, J2 ˆ 6.5, 1 H); 5.46
(dd, J1 ˆ 15.6, J2 ˆ 7.4, 1 H); 5.11 (d, J ˆ 11.8, 1 H); 4.79 (d, J ˆ 11.8, 1 H); 4.61 4.52 (m, 2 H); 4.40 (t, J ˆ 7.2,
1 H); 3.91 3.85 (m, 1 H); 3.68 (d, J ˆ 6.6, 1 H); 3.59 (d, J ˆ 7.0, 1 H); 3.43 (dd, J1 ˆ 14.7, J2 ˆ 10.0, 1 H); 3.2
(s, 3 H); 3.07 (br. s, 1 H); 3.03 (s, 3 H); 2.35 2.27 (m, 3 H); 2.20 2.04 (m, 2 H); 1.99 1.82 (m, 1 H); 1.65 1.50
(m, 3 H); 1.30 1.15 (m, 21 H); 0.99 (dd, J1 ˆ 6.6, J2 ˆ 4.0, 1 H); 0.88 (s, 9 H); 0.03 (s, 6 H). 13C-NMR (100 MHz,
CDCl3): 172.9; 171.9; 170.4; 140.4; 136.2; 133.1; 132.7; 132.1; 127.8; 127.5; 126.7; 126.0; 125.8; 125.8; 125.6; 113.5;
82.6; 80.3; 75.1; 74.2; 71.0; 69.1; 58.3; 55.3; 53.0; 51.0; 36.0; 34.2; 32.5; 31.8; 30.6; 29.5; 29.5; 29.3; 29.2; 29.1; 29.0;
‡
‡
25.8; 24.7; 22.5; 22.1; 21.9; 18.0; 14.0; 2.9; À 4.2; À 4.7. MS: 888 ([M ‡ Cl] . HR-MS: 875.5557 ([M ‡ Na] ,
C49H80N2NaO8Si; calc. 875.5581).
(3S,6S)-6-{[(2R,3R,4S,5R,6E)-3,4,5-Trihydroxy-2-methoxy-8-methylnon-6-enoyl]amino}-2,3,4,5,6,7,-hexa-
hydro-7-oxo-1-methylazepin-3-yl Tetradecanoate (ˆ(‡)-Bengamide B; 1). Procedure A: To a soln. of 111 mg of
60 (0.13 mmol) in 3.0 ml of a mixture of CH2Cl2/MeOH 4 :1 at r.t. was added 44 mg of solid DDQ (0.20 mmol).
After 2 h, 1.8 ml of MeOH (resulting in a 1:1 mixture of CH2Cl2/MeOH) and 163 mg of solid PPTS (0.65 mmol)
were added, and the resulting mixture was warmed to 458. After 6 h at that temp., the mixture was cooled to r.t.,
and the solvent was removed in vacuo. The residual oil was taken up in 10 ml of CH2Cl2, and the soln. was
washed with 5 ml of sat. aq. NaHCO3 soln. (2Â), dried over MgSO4, and concentrated in vacuo. The residue was
purified by radial chromatography (1 mm SiO2 plate; CH2Cl2/MeOH 19 :1) to afford 69 mg (89%) of 19) as a
25
D
waxy, white solid. M.p. 27 298. ‰aŠ ˆ ‡42.3 (c ˆ 0.3, MeOH); lit.: ‡ 34.6 (c ˆ 0.11, MeOH) [12]. IR (film):
3368, 1734, 1660, 1639, 1587. 1H-NMR (400 MHz, CDCl3): 8.13 (d, J ˆ 6.1, 1 H); 5.79 (dd, J1 ˆ 15.5, J2 ˆ 6.5,
1 H); 5.46 (dd, J1 ˆ 15.5, J2 ˆ 7.2, 1 H); 4.70 4.55 (m, 2 H); 4.40 4.25 (m, 1 H); 4.24 4.20 (m, 1 H); 3.85 3.77
(m, 2 H); 3.70 3.58 (m, 3 H); 3.55 (s, 3 H); 3.24 (d, J ˆ 14.8, 2 H); 3.11 (s, 3 H); 2.35 2.28 (m, 3 H); 2.20 2.13
(m, 2 H); 2.05 1.90 (m, 2 H); 1.72 1.60 (m, 4 H); 1.40 (t, J ˆ 7.3, 2 H); 1.35 1.20 (m, 24 H); 1.00 (dd, J1 ˆ 7.0,
J2 ˆ 2.0, 6 H); 0.88 (t, J ˆ 7, 3 H ) . 13C-NMR (100 MHz, CDCl3): 172.9; 172.0; 171.6; 141.7; 125.2; 80.6; 74.2; 72.7;
72.2; 69.0; 59.9; 53.2; 51.2; 45.8; 36.2; 34.2; 32.5; 31.8; 30.6; 29.5; 29.5; 29.5; 29.3; 29.2; 29.1; 28.9; 28.8; 24.7; 22.5;
‡
22.1; 22.0; 14.0; 8.5. MS: 634 ([M ‡ Cl] ).
Procedure B: To a soln. of 8.0 mg of 60 (9.37 mmol) and H2O (0.5 ml, 28.11 mmol) in 0.5 ml of CH2Cl2/
MeOH 4 :1 was added 3.2 mg of DDQ (14.06 mmol). After 2 h at r.t., 0.5 ml of sat. aq. NaHCO3 soln. was added,
and the resulting soln. was concentrated to dryness at r.t. in vacuo. The solid residue was diluted with 1.0 ml each
of H2O and CH2Cl2, mixed well, and the phases were separated. The aq. phase was extracted with 1 ml of CH2Cl2
(3Â), and the combined org. phases were washed with 1 ml of sat. aq. NaHCO3 soln. (3Â). The combined aq.
layers were re-extracted with 5 ml of CH2Cl2. The combined org. phases were dried (MgSO4), and concentrated
in vacuo to afford 6.6 mg of a mixture of 61 and 62 (see Scheme 13), which, for anal. purposes, was purified by
radial chromatography (1 mm SiO2 plate; hexanes/AcOEt 19 :1) to afford 3.1 mg (46%) of 61 and 3.5 mg (44%)
of 62 as colorless oils.
Data of 61: 1H-NMR (400 MHz, CDCl3): 8.05 (d, J ˆ 7.2, 1 H); 5.68 (dd, J1 ˆ 15.7, J2 ˆ 6.5, 1 H); 5.36 (dd, J1 ˆ
16.0, J2 ˆ 8.0, 1 H); 4.75 4.55 (m, 2 H); 4.23 (t, J ˆ 7.4, 1 H); 3.78 (t, J ˆ 7, 1 H); 3.73 3.53 (m, 3 H); 3.52 (s, 3 H);
3.22 (d, J ˆ 14.9, 1 H); 3.11 (s, 3 H); 2.36 2.22 (m, 3 H); 2.20 2.10 (m, 2 H); 2.05 1.94 (m, 1 H); 1.68 1.58
(m, 4 H); 1.37 1.20 (m, 25 H); 0.99 (d, J ˆ 6.7, 3 H); 0.98 (d, J ˆ 6.7, 3 H); 0.90 (s, 9 H); 0.09 (s, 3 H); 0.05 (s, 3 H).
Data of 62: 1H-NMR (400 MHz, CDCl3): 8.02 (d, J ˆ 6.0, 1 H); 7.94 (s, 1 H); 7.85 7.79 (m, 3 H); 7.65
(d, J ˆ 8.5, 1 H); 7.50 7.44 (m, 2 H); 6.08 (s, 1 H); 5.66 (dd, J1 ˆ 15.0, J2 ˆ 6.0, 1 H); 5.52 (dd, J1 ˆ 16.2, J2 ˆ 6.8,
1 H); 4.75 4.67 (m, 1 H); 4.65 4.57 (m, 1 H); 4.55 4.49 (m, 1 H); 4.47 4.42 (m, 1 H); 3.98 (d, J ˆ 2.8, 1 H);
3.73 3.63 (m, 1 H); 3.53 (s, 3 H); 3.24 (d, J ˆ 14.6, 1 H); 3.12 (s, 3 H); 2.36 2.29 (m, 3 H); 2.28 2.14 (m, 2 H);
2.08 1.98 (m, 1 H); 1.65 1.56 (m, 4 H); 1.39 1.20 (m, 25 H); 1.00 (d, J ˆ 6.7, 3 H); 0.98 (d, J ˆ 6.7, 3 H); 0.91
(s, 9 H); 0.07 (s, 3 H); 0.04 (s, 3 H).
To a soln. of 5.0 mg of the above mixture of 61 (ca. 3.51 mmol) and 62 (ca. 2.94 mmol) in 0.3 ml of MeOH,
containing 10 equiv. of H2O, was added 14.8 mg of solid PPTS (58.8 mmol), the resulting soln. was warmed to
508. After 12 h10), the mixture was cooled to r.t., 0.2 ml of sat. aq. NaHCO3 soln. was added, and the resulting
9
)
)
Purification also afforded the dimethyl acetal of 2-naphthaldehyde.
The acetal is cleaved first, but the extended reaction time gives rise to partial cleavage of the silyl
protecting group.
10

Helvetica Chimica Acta Vol. 85 (2002)
4559
mixture was concentrated to dryness at r.t. in vacuo. The solid remainder was diluted with 2 ml each of H2O and
CH2Cl2, the resulting biphasic mixture was agitated well, and the phases were separated. The aq. phase was
extracted with 2 ml of CH2Cl2 (2Â), and the combined org. phases were washed with 5 ml of sat. brine, dried
(MgSO4), and concentrated in vacuo. The residue was purified by radial chromatography (1 mm SiO2 plate;
CH2Cl2/MeOH 49 :1) to afford 2.9 mg (74%) of Bengamide B (1) as a white solid identical in all respects to
natural Bengamide B and the sample obtained by Procedure A9).
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Received June 24, 2002