Asymmetric synthesis of phorboxazole B - Part II: Synthesis of the C1-C19 subunit and fragment assembly

Full text of DOI:10.1002/1521-3773(20000717)39:14<2536::AID-ANIE2536>3.0.CO;2-U

COMMUNICATIONS
Tetrahedron Lett. 1998, 39, 183 ± 186; s) R. D. Cink, C. J. Forsyth, J.
Org. Chem. 1997, 62, 5672 ± 5673; t) C. S. Lee, C. J. Forsyth, Tetrahe-
dron Lett. 1996, 37, 6449 ± 6452; u) total synthesis of phorboxazole A:
C. J. Forsyth, F. Ahmed, R. D. Cink, C. S. Lee, J. Am. Chem. Soc. 1998,
120, 5597± 5598.
[27] We are aware of few examples of this type of selective lithium ± hal-
ogen exchange reaction. For a report involving bishalogenated arenes,
see M. Kihara, M. Kashimoto, Y. Kobayashi, Tetrahedron 1992, 48,
67± 78.
[28] For an example of a chelation-controlled zincate addition, see D. R.
Williams, W. S. Kissel, J. Am. Chem. Soc. 1998, 120, 11198 ± 11199.
[29] For an example of a chelation-controlled aluminate addition, see H.
Imogai, Y. Petit, M. Larcheveque, Tetrahedron Lett. 1996, 37, 2573 ±
2576.
[30] A similar solvent effect has been noted in additions of alkenyl
Grignard reagents to a-alkoxyaldehydes: G. E. Keck, M. A. Andrus,
D. R. Romer, J. Org. Chem. 1991, 56, 417± 420.
[31] For the preparation of MgBr2 as a solution in Et2O/benzene, see M.
Nakatsuka, J. A. Ragan, T. Sammakia, D. B. Smith, D. E. Uehling,
S. L. Schreiber, J. Am. Chem. Soc. 1990, 112, 5583 ± 5601.
[4] D. A. Evans, D. M. Fitch, Angew. Chem. 2000, 112, 2636 ± 2640;
Angew. Chem. Int. Ed. 2000, 39, 2536 ± 2540.
[5] Abbreviations: drˆ diastereomer ratio; TES ˆ triethylsilyl; TPS ˆ
triphenylsilyl; TIPS ˆ triisopropylsilyl; Ms ˆ methanesulfonyl; Bn ˆ
benzyl; TMS ˆ trimethylsilyl; DBU ˆ 1,8-diazabicyclo[5.4.0]undec-7-
ene; DMF ˆ N,N-dimethylformamide; DMAP ˆ N,N-dimethylami-
nopyridine; LDA ˆ lithium diisopropylamide; TMP ˆ 2,2,6,6-tetra-
methylpiperidide; NBS ˆ N-bromosuccinimide; Trˆ trityl ˆ triphe-
nylmethyl; Ts ˆ para-toluenesulfonyl; DIAD ˆ diisopropylazodicar-
boxylate; THF ˆ tetrahydrofuran; HMDS ˆ hexamethyldisilazide;
pyrˆ pyridine; TEA ˆ triethylamine; DMSO ˆ dimethyl sulfoxide;
Tf ˆ triflate ˆ trifluoromethanesulfonyl.
[6] D. A. Evans, M. C. Kozlowski, J. A. Murry, C. S. Burgey, K. R. Campos,
B. T. Connell, R. J. Staples, J. Am. Chem. Soc. 1999, 121, 669 ± 685.
[7] D. A. Evans, M. D. Ennis, T. Le, N. Mandel, G. Mandel, J. Am. Chem.
Soc. 1984, 106, 1154 ± 1156.
[8] a) D. L. Boger, T. T. Curran, J. Org. Chem. 1992, 57, 2235 ± 2244;
b) D. P. Provencal, C. Gardelli, J. A. Lafontaine, J. W. Leahy, Tetrahe-
dron Lett. 1995, 36, 6033 ± 6036.
Asymmetric Synthesis of Phorboxazole BÐ
Part II: Synthesis of the C1 ± C19 Subunit and
Fragment Assembly**
[9] The product ratio was determined by HPLC analysis (Zorbax, 4.6 Â
150 mm, 5 mm silica gel; 3% iPrOH in CH2Cl2, flow rate ˆ
1 mLminÀ1; Tr minorˆ 12.5 min; Tr majorˆ 14.9 min).
David A. Evans* and Duke M. Fitch
[10] For examples of b-ketoimide aldol reactions, see a) D. A. Evans, H. P.
Ng, J. S. Clark, D. L. Rieger, Tetrahedron 1992, 48, 2127± 2142;
b) D. A. Evans, H. P. Ng, D. L. Rieger, J. Am. Chem. Soc. 1993, 115,
11446 ± 11459.
In the preceding communication the syntheses of the C20 ±
C38 and C39 ± C46 phorboxazole B subunits were presented.[1]
Herein we focus on the synthesis of the final C1 ± C19 bispyran
subunit 1 and the successful assembly of these fragments into
phorboxazole B.
[11] D. A. Evans, K. T. Chapman, E. M. Carreira, J. Am. Chem. Soc. 1988,
110, 3560 ± 3578.
1
[12] Product ratio determined by H NMR analysis (500 MHz).
[13] M. D. Lewis, J. K. Cha, Y. Kishi, J. Am. Chem. Soc. 1982, 104, 4976± 4978.
[14] For similar conditions employing ethylene glycol in place of methanol,
see a) T. H. Chan, M. A. Brook, T. Chaly, Synthesis 1983, 203 ± 205;
b) ref. [4].
The retrosynthesis of the C1 ± C19 region (Scheme 1)[2]
began with disconnection of the peripheral functionality at
C4 and C19, and the masking of leaving groups at these
positions as differentially protected primary hydroxyl groups.
The C7 exocyclic olefin was masked as a protected ketone and
the C11 stereocenter was envisioned to arrive through
reduction of hemiketal 2. Ring-chain tautomerization of 2
À
[15] For a related reduction with Raney-Ni, see R. Bacardit, M. Moreno-
Ä
Manas, Tetrahedron Lett. 1980, 21, 551 ± 554.
[16] For reports of oxazole lithiation, see ref. [3h], and references therein.
[17] A. B. Smith III, S. M. Condon, J. A. McCauley, J. L. Leazer, Jr., J. W.
Leahy, R. E. Maleczka, Jr., J. Am. Chem. Soc. 1997, 119, 962 ± 973;
A. B. Smith III, S. M. Condon, J. A. McCauley, J. L. Leazer, Jr., J. W.
Leahy, R. E. Maleczka, Jr., J. Am. Chem. Soc. 1995, 117, 5407± 5408.
[18] Conditions were adapted from: C. H. Heathcock, S. D. Young, J. P.
Hagen, R. Pilli, U. Badertscher, J. Org. Chem. 1985, 50, 2095 ± 2105.
[19] D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277 ± 7287.
[20] (R)-3-(triphenylmethyl)-1,2-epoxypropane is commercially available
from Aldrich Chemical Co. and may also be prepared in 95% ee by
Sharpless asymmetric epoxidation of allyl alcohol and in situ
tritylation. Recrystallization provides the enantiomerically enriched
compound: H. S. Hendrickson, E. K. Hendrickson, Chem. Phys.
Lipids 1990, 53, 115 ± 120.
[21] (E)-bis(tributylstannyl)ethylene was prepared by the following meth-
od: a) E. J. Corey, R. H. Wollenberg, J. Am. Chem. Soc. 1974, 96,
5581 ± 5583; see also b) A. N. Nesmeyanov, A. E. Borisov, Dokl.
Akad. Nauk SSSR 1967, 174, 96 ± 99; For BF3 ´ OEt2-promoted
organolithium additions to epoxides, see c) M. J. Eis, J. E. Wrobel,
B. Ganem, J. Am. Chem. Soc. 1984, 106, 3693 ± 3694.
and aldol disconnection of the C12
C13 bond affords the trans
pyran methylketone fragment 3 and the oxazole aldehyde
fragment 4.
Construction of the C4 ± C12 methylketone 3 began from the
d-hydroxy-b-ketoester 5 previously employed in the construc-
tion of the C33 ± C38 lactone (Scheme 2).[1, 3] Treatment of 5
with ethylene glycol and trimethylsilyl chloride[4] resulted in a
simultaneous cyclization and protection of the ketone to
deliver lactone 6 in good yield. Reduction (DIBAlH) and
acetylation (Ac2O, pyr, DMAP) provided 7 in quantitative
[22] Conditions were adapted from: R. Bellingham, K. Jarowicki, P.
Kocienski, V. Martin, Synthesis 1996, 285 ± 296.
[23] Conditions were adapted from: ref. [3p]. For the synthesis of (E)-3-
iodo-2-methylprop-2-enal, see R. Baker, J. L. Castro, J. Chem. Soc.
Perkin Trans. 1 1990, 47± 65.
[*] Prof. D. A. Evans, D. M. Fitch
Department of Chemistry & Chemical Biology
Harvard University
Cambridge, MA 02138 (USA)
Fax : (‡1)617-495-1460
[24] J. R. Parikh, W. E. von Doering, J. Am. Chem. Soc. 1967, 89, 5505 ±
5507.
E-mail: evans@chemistry.harvard.edu
[25] M. T. Reetz, Angew. Chem. 1984, 96, 542 ± 555; Angew. Chem. Int. Ed.
Engl. 1984, 23, 556 ± 569.
[26] After quenching the alkenyllithium with H2O, the selectivity of the
lithium ± halogen exchange was determined to be 20:1 (C39I:C46Br) by
1H NMR spectroscopy.
[**] Financial support has been provided by the National Institutes of
Health (GM-33328) and the National Science Foundation. The
NIH BRS Shared Instrumentation Grant Program 1-S10-RR04870
and the NSF (CHE 88-14019) are acknowledged for providing NMR
facilities.
2536
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1433-7851/00/3914-2536 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2000, 39, No. 14

COMMUNICATIONS
HO
13
O
O
Phorboxazole B
Br
OTIPS
OTIPS
9
N
H
O
H
H
O
O
H
13
H
H
13
19
19
19
H
H
46
4
CH2
H
N
N
H
O
O
H
H
O
O
OH
Bu3P+
MsO–
TIPSO
11
9
MeO
O
1
O
Me
Me
H
H
Me
9
4
2
OH
H
O
N
Me
4
H
7
38
H
BnO
H
O
O
33
O
CH2
HO
O
1
MeO
Br
PhHN
C1–C19
O
O
1
OBn
4
H
OMe
20
46
H
TESO
Me
MeO
O
H
OTES O
O
O
H
38
+
H
O
7
H
Me
I
33
O
TESO
N
TIPSO
N
OTPS
H
Me
13
11
9
O
Me
Me
19
39
O
O
4
3
C39–C46
C20–C38
Scheme 1. Retrosynthetic analysis of the C1 ± C19 fragment (See reference [2] for abbreviations.)
is viewed as an extension of analogous aldol reactions with
chelating aldehydes that we have reported previously,[14] and
the high level of asymmetric induction noted in this trans-
formation provides circumstantial evidence that aldehyde 8 is
indeed chelating to the SnII catalyst. Silylation (TESCl,
imidazole), osmium-mediated dihydroxylation,[15] and oxida-
tive cleavage of the derived diol (Pb(OAc)4) provided
aldehyde 10 in excellent overall yield. Concomitant DIBAlH
reduction of both the C19 aldehyde and the C13 tert-butyl
thioester substituents was then accomplished in a single step,
while subsequent silylation (TIPSOTf, lut) completed the
synthesis of the C13 ± C19 oxazole aldehyde 4 in six steps and
85% overall yield from 8.
OBn
OBn
4
O
O
OH
H
H
b,c
a
O
O
tBuO
5
9
O
O
75%
100%
O
AcO
OBn
9
O
O
5
7
6
d
89%
OBn
H
4
H
4
H
H
9
H
H
BnO
O
H
OR
O
O
H
O
RO
Me
11
9
Nu:
O
TS
3
For the important C12 ± C13 aldol fragment coupling, we
relied upon methodology developed during our synthesis of
altohyrtin C (spongistatin 2),[16] in which boron enolates of b-
alkoxy methylketones were added to aldehydes with high
89:11 Diastereoselection
Scheme 2. Synthesis of the C4 ± C12 trans-pyran 3. a) HO(CH2)2OH,
TMSCl, CH2Cl2, RT; 75%; b) DIBAlH, tol, À788C; 100%; c) Ac2O, pyr,
cat. DMAP, CH2Cl2, RT; 100% (92:8 b:a); d) TMSOTf, 2-(trimethylsilyl-
oxy)propene, cat. pyr, CH2Cl2, À788C; 89%. (See ref. [2] for abbrevia-
tions.)
OTMS
StBu
OH
O
O
a
+
N
N
O
91%
H
19
StBu
13
yield as a 92:8 mixture of b:a anomers.[5, 6] Treatment of the
anomeric acetates with trimethylsilyl trifluoromethanesulfo-
nate[7] and 2-(trimethylsilyloxy)propene resulted in an 89:11
mixture of diastereomeric tetrahydropyrans,[8] with the de-
sired trans isomer favored.[9] Axial attack of the nucleophile
from the bottom face of the oxocarbenium ion (as depicted in
TS) via a chairlike transition structure rationalizes the
formation of the major product.[10] This diastereoface is
partially hindered by the axial portion of the C7 ketal, and
thus, a minor amount of the undesired cis isomer is observed.
The synthesis of the C13 ± C19 oxazole-containing aldehyde
began with a SnII-catalyzed enantioselective aldol addition of
the silylketene acetal derived from tert-butyl thioacetate to
aldehyde 8[11] (10 mol% [Sn((S,S)-Ph-box)](OTf)2; box ˆ
bisoxazoline) to afford adduct 9 in excellent yield (91%)
and enantioselectivity (94% ee; Scheme 3).[12, 13] This reaction
O
Ph
Ph
94% ee
Me
N
Me
N
9
8
O
O
b–d 98%
Sn
Ph
Ph
TfO
OTf
TESO
TESO
O
O
e,f
TIPSO
O
H
N
O
N
StBu
H
13
13
95%
19
19
O
4
10
Scheme 3. Synthesis of the C13 ± C19 oxazole aldehyde 4. a) 10 mol%
[Sn((S,S)-Ph-box)](OTf)2 catalyst, CH2Cl2, À788C; 91%; b) TESCl,
imidazole, cat. DMAP, DMF; 100%; c) cat. K2OsO4(H2O)2, cat. quinucli-
dine, K3Fe(CN)6, K2CO3, methanesulfonamide, tBuOH:H2O (1:1);
d) Pb(OAc)4, K2CO3, CH2Cl2, 08C; 98% (2 steps); e) DIBAlH, CH2Cl2,
À788C; 95%; f) TIPSOTf, lut, CH2Cl2, 08C; 100%. (See ref. [2] for
abbreviations.)
Angew. Chem. Int. Ed. 2000, 39, No. 14
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1433-7851/00/3914-2537 $ 17.50+.50/0
2537

COMMUNICATIONS
levels of 1,5-anti asymmetric induction, regardless of the
stereochemistry of the protected b-alkoxyaldehyde substitu-
ent.[17] While the methylketones employed in the original
study contained either para-methoxybenzyl protected b-
hydroxyl groups or b-benzylidene acetals, it was unclear
whether a methylketone containing a b-tetrahydropyran ring,
as in 3, would exert the same directing effect.[18] In the event
(Scheme 4), treatment of the dibutylboron enolate derived
from ketone 3 with aldehyde 4 in diethyl ether at À1058C
afforded the aldol adduct 11 in good yield as a single
diastereomer.[5, 19] Silylation (TIPSOTf, lut) of the resultant
free C13 hydroxyl group followed by selective deprotection of
the C15 triethylsilyl ether provided hemiketal 2.[20] Axial
hydride reduction of the C11 hemiketal (BF3 ´ OEt2, Et3SiH)[8]
afforded bistetrahydropyran 12 in excellent yield (96%) and
diastereoselectivity (>95:5).[5]
With the requisite stereochemistry incorporated into 12,
some refunctionalization was required to complete the syn-
thesis of this subunit. Ketal hydrolysis (FeCl3 ´ SiO2)[21] and
debenzylation were followed by a Wittig olefination to install
the C7 exocyclic olefin. The C1 ± C3 fragment was incorporated
by displacement of the C4 primary trifluoromethanesulfonate
14 with the dianion of N-phenylpropynamide (15).[22] Selec-
tive deprotection of the C19 triisopropylsilyl ether (TBAF,
À508C) followed by formation of the primary mesylate
completed the subunit 17 in 17steps (longest linear sequence
from aldehyde 8) and 40% overall yield.
the C38 triethylsilyl and C24 triphenylsilyl ethers. At this point
an effort was made to execute a selective macrolactonization
of diol acid 20 in the hope that conformational and entropic
effects might favor cyclization onto the desired C24 hydroxyl
moiety. Unfortunately, cyclization occurred exclusively at the
less hindered C38 primary hydroxyl group under standard
Yamaguchi conditions (2,4,6-trichlorobenzoyl chloride, Et3N,
THF; then DMAP, benzene)[25] to provide the undesired 31-
membered macrocycle 21.[26]
Attempts to selectively silylate the C38 primary hydroxyl
group under standard conditions (TESCl, imidazole, CH2Cl2)
were complicated by competitive silylation of both the C1
carboxyl group and the C24 secondary hydroxyl moieties.
Ultimately, a change in the base from imidazole to 2,6-lutidine
led to exclusive silylation of the desired C38 primary hydroxyl
group (Scheme 6).[27] With the C38 hydroxyl group now
protected, macrolactonization proceeded smoothly to provide
the desired 21-membered macrocycle 23 in excellent yield.[25]
Lindlar reduction of the alkynoate (>95:5 Z:E)[5] led to the
formation of the complete C1 ± C38 macrocyclic region of
phorboxazole B.[28] Selective deprotection of the C38 primary
triethylsilyl ether was followed by Parikh ± Doering oxida-
tion[29] to provide the requisite a-alkoxyaldehyde 25.
For the final fragment coupling, chelate-controlled addition
of a fully functionalized C39 ± C46 alkenylmetal species was
required. Under the previously optimized conditions,[1] site-
selective lithium ± halogen exchange of vinyl iodide 26, trans-
metalation (MgBr2), and solvent exchange (Et2O !CH2Cl2),
followed by the addition of a-alkoxyaldehyde 25 to the
alkenylmagnesium intermediate provided the protected nat-
ural product 27 in excellent yield as a single isomer.[5]
Deprotection of 27 (TBAF, THF) afforded phorboxazole B
in 27steps (longest linear sequence from aldehyde 8) and
12.6% overall yield. The synthetic phorboxazole B was
identical to the natural material as judged by 1H NMR
spectroscopy (600 MHz, CDCl3), HPLC, TLC Rf values,
With the three phorboxazole subunits 17, 18, and 26 in
hand,[1] fragment coupling experiments were initiated. After
some experimentation it was found that in situ formation of
the phosphonium salt of mesylate 17 followed by addition of
aldehyde 18 and DBU resulted in the exclusive[5] formation of
the desired E olefin 19 (Scheme 5).[23] Pursuant to revealing
the terminal carboxylic acid residue, N-phenylamide 19 was
activated through its N-Boc imide and hydrolyzed with
LiOH.[24] These conditions also resulted in the cleavage of
OBn
OBn
4
4
H
H
TESO
O
O
O
OTES OH
O
O
+
a
H
H
O
O
TIPSO
TIPSO
N
O
N
O
13
Me
H
13
9
9
82%
O
O
19
19
4
3
>95:5 Diastereoselection
11
O
b,c
98%
OTIPS
PhHN
OTIPS
OTIPS
O
O
O
13
13
H
H
13
H
H
H
15
19
19
19
N
N
N
O
H
H
O
O
O
O
X
H
e–g
81%
i
RO
TIPSO
TIPSO
9
9
7
9
7
78%
O
4
4
4
7
H
RO
H
BnO
H
O
CH2
CH2
O
1
>95:5 Diastereoselection
PhHN
16 R = TIPS
17 R = Ms
13 R = H
14 R = Tf
2 X = OH
12 X = H
j,k
O
d
96%
h
100%
98%
Scheme 4. Synthesis of the C1 ± C19 bispyran 17. a) nBu2BOTf, iPr2NEt, Et2O, À1058C; 82%; b) TIPSOTf, lut, CH2Cl2, 08C; 99%, c) HF ´ pyr, pyr, THF,
H2O, 0 8C; 99%; d) BF3 ´ OEt2, Et3SiH, CH2Cl2, À78 ! À 508C; 96%; e) FeCl3 ´ SiO2, CHCl3, acetone, RT; 90%; f) 1 atm H2, Pd/C, iPrOH; 100%;
g) Ph3PCH3Br, PhLi, THF, 08C; 90%; h) Tf2O, pyr, CH2Cl2, À58C; 100%; i) 15, nBuLi, THF, À208C; then 14; 78%; j) TBAF, THF, À508C; 99%; k) MsCl,
iPr2NEt, CH2Cl2, À58C; 99%. (See ref. [2] for abbreviations.)
2538
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1433-7851/00/3914-2538 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2000, 39, No. 14

COMMUNICATIONS
OTIPS
OTIPS
O
O
20
H
H
19
O
OMe
N
N
O
O
H
H
O
O
H
H
TESO
Me
MsO
20
OMe
H
O
H
H
38
a
TESO
38 H
Me
17
H
O
TESO
N
O
+
O
H
24
OTPS
81%
>95:5 E:Z
CH2
H
O
Me
Me
N
O
H
H
OTPS
24
TESO
CH2
1
Me
Me
1
PhHN
PhHN
b,c
18
O
O
19
79%
OTIPS
OTIPS
OTIPS
O
O
O
H
H
H
N
N
N
O
H
H
O
O
H
H
O
O
H
H
Me
Me
OH
Me
OH
O
H
O
H
O
H
H
H
O
Me
Me
Me
24
24
d
O
O
24
H
X
1
Me
Me
H
H
H
Me
85%
1
CH2
CH2
CH2
HO
O
O
N
N
1
O
N
O
O
OTES
O
OTES
O
H
H
OTES
O
H
O
38
Phorboxazole skeleton
38
38
OH
OH
20
21
OMe
OMe
OMe
Scheme 5. Wittig coupling and hydrolysis. a) PBu3, DMF; DBU, RT; 81%; b) Boc2O, DMAP, CH3CN; 99%; c) LiOH, THF, H2O, RT; 80%; d) 2,4,6-
trichlorobenzoyl chloride, Et3N, THF; then DMAP, benzene; 85%. (See ref. [2] for abbreviations.)
OTIPS
H
OTIPS
OTIPS
O
O
O
O
H
H
H
N
N
N
O
O
O
O
H
H
O
O
H
H
Me
OH
Me
Me
O
H
O
H
O
H
H
H
H
H
b
Me
Me
Me
a
c
24
24
O
O
20
1
1
Me
Me
Me
97%
86%
97%
H
H
H
1
CH2
CH2
CH2
HO
O
O
O
O
N
N
N
>95:5 Z:E
OTES
O
OTES
O
OTES
O
OTES
O
H
H
H
38
38
38
OTES
OTES
22
23
24
d,e
95%
OMe
OMe
OMe
OH
OTIPS
OTIPS
O
O
O
H
H
H
N
N
N
O
O
H
H
O
H
H
O
H
H
Me
Me
Me
O
H
O
H
O
H
H
H
O
O
O
O
O
Me
Me
Me
g
f
O
O
O
H
1
1
Me
Me
Me
H
H
H
88%
72%
CH2
Br
CH2
CH2
O
O
O
N
N
N
OH
OH
O
Me
Me
Me
OH
OTES
O
46
OTES
O
H
H
H
O
I
38
38
H
Br
39
OMe
OMe
Phorboxazole B
OMe
46
27
>95:5 Diastereoselection
25
26
Br
OMe
OMe
OMe
Scheme 6. Completion of the synthesis of phorboxazole B. a) TESCl, lut, CH2Cl2, À788C; 97%; b)2,4,6-trichlorobenzoyl chloride, Et3N, THF; then DMAP,
benzene; 86%; c) 1 atm H2, Lindlar cat., quinoline, 1-hexene, acetone; 97%; d) HF ´ pyr, pyr, THF, 0 8C; 95%; e) SO3 ´ pyr, Et3N, DMSO, CH2Cl2; 100%; f) 26,
tBuLi, Et2O, À1058C; then MgBr2, À788C; then CH2Cl2, 25; 7 2%; g) TBAF, THF, 08C; 88%. (See ref. [2] for abbreviations.)
Angew. Chem. Int. Ed. 2000, 39, No. 14
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1433-7851/00/3914-2539 $ 17.50+.50/0
2539

COMMUNICATIONS
(À788C) and decomposed upon warming, see M. M. Midland, A.
Tramontano, J. R. Cable, J. Org. Chem. 1980, 45, 28 ± 29. Displacement
of this model trifluoromethanesulfonate with the dianion of propiolic
acid was complicated by O alkylation and double alkylation, which
was surpressed through use of the alternative nucleophile 15. For a
complex example of the use of an N-phenylamide as a carboxyl
surrogate with attenuated nucleophilicity, see D. A. Evans, P. H.
Carter, E. M. Carreira, A. B. Charette, J. A. Prunet, M. Lautens, J.
Am. Chem. Soc. 1999, 121, 7540 ± 7552. For the synthesis of 15, see
G. M. Coppola, R. E. Damon, Synth. Commun. 1993, 23, 2003 ± 2010.
For the alkylation of carbonyl compounds with the dianion of N-
benzylpropynamide, see G. M. Coppola, R. E. Damon, J. Heterocycl.
Chem. 1995, 32, 1133 ± 1139.
electrospray mass spectrometry, ultraviolet spectroscopy,
infrared spectroscopy, and optical rotation values.[30]
Received: April 25, 2000 [Z15025]
[1] D. A. Evans, V. J. Cee, T. E. Smith, D. M. Fitch, P. S. Cho, Angew.
Chem. 2000, 112, 2633 ± 2636; Angew. Chem. Int. Ed. 2000, 39, 2533 ±
2536.
[2] Abbreviations: Ac ˆ acetyl; Ms ˆ methanesulfonyl; TIPS ˆ tiisopro-
pylsilyl; TES ˆ triethylsilyl; TMS ˆ trimethylsilyl; DIBAlH ˆ diiso-
butylaluminum hydride; Tf ˆ trifluoromethanesulfonyl; Bn ˆ benzyl;
DMAP ˆ 4-dimethylaminopyridine; pyr ˆ pyridine; tol ˆ toluene;
TBAF ˆ tetra-n-butylammonium fluoride; DBU ˆ 1,8-diazabicy-
clo[5.4.0]undec-7-ene; lut ˆ 2,6-lutidine; Boc ˆ tert-butyloxycarbonyl.
[3] D. A. Evans, M. C. Kozlowski, J. A. Murry, C. S. Burgey, K. R.
Campos, B. T. Connell, R. J. Staples, J. Am. Chem. Soc. 1999, 121,
669 ± 685.
[4] T. H. Chan, M. A. Brook, T. Chaly, Synthesis 1983, 203 ± 205.
[5] The product ratio was determined by 1H NMR analysis (500 MHz) of
the unpurified reaction mixture.
[6] Although the anomers were separable by chromatography on silica
gel, the mixture was generally taken on without purification.
[7] Use of stronger Lewis acids such as BF3 ´ OEt2 or TiCl4 led to high
levels of decomposition.
[23] Similar conditions have recently appeared in the literature for an
oxazole-stablized Wittig coupling, see P. Liu, J. S. Panek, J. Am. Chem.
Soc. 2000, 122, 1235 ± 1236.
[24] For the hydrolysis of the N-Boc derivatives of secondary amides and
lactams with LiOH, see D. L. Flynn, R. E. Zelle, P. A. Grieco, J. Org.
Chem. 1983, 48, 2424 ± 2426.
[25] J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull.
Chem. Soc. Jpn. 1979, 52, 1989 ± 1993.
[26] The regioselectivity of the cyclization was determined by 1D 1H NMR
and 2D COSY experiments.
[27] The difference in the selectivity between the two bases is perhaps a
result of the formation of a more active silylating agent derived from
the reaction of imidazole with the silyl chloride. Presumably there is
no reaction between the silyl chloride and 2,6-lutidine, which simply
acts as a base.
[8] For an early example of nucleophilic addition to oxocarbenium ions in
the synthesis of C-glycosides, see M. D. Lewis, J. K. Cha, Y. Kishi, J.
Am. Chem. Soc. 1982, 104, 4976 ± 4978.
[28] The use of 1-hexene as a co-solvent was found to effectively surpress
any overreduction. For related conditions, see T.-L. Ho, S.-H. Liu,
Synth. Commun. 1987, 17, 969 ± 973.
[29] J. R. Parikh, W. von E. Doering, J. Am. Chem. Soc. 1967, 89, 5505 ±
5507.
[9] Optimal results were obtained when buffering the reaction with
20 mol% of pyridine. The diastereoselectivity was determined by
HPLC analysis of the unpurified reaction mixture (Zorbax silica gel,
20% EtOAc in hexanes, flow rate ˆ 1.0 mLminÀ1, 254 nm UV cutoff,
major isomer (trans) Tr ˆ 11 min, minor isomer (cis) Tr ˆ 13 min).
[10] E. L. Eliel, S. H. Wilen, L. N. Mander, Stereochemistry of Organic
Compounds, Wiley, New York, 1994, chap. 11.
[30] We thank Professor T. F. Molinski for kindly providing a sample and
copies of 1H NMR spectra of natural phorboxazole B for comparison.
[11] Aldehyde 8 was obtained from reduction (DIBAlH, CH2Cl2, À918C,
95% yield) of the known ethyl ester. See J. S. Panek, R. T. Beresis, J.
Org. Chem. 1996, 61, 6496 ± 6497.
[12] Dr. David MacMillan is gratefully acknowledged for the development
of this reaction.
[13] Reported results for the reaction run on >60 mmol scale (18.5 g
isolated product). Enantiomeric excess values were determined by
chiral HPLC analysis (Chiralcel OD-H column, 4% EtOH in hexanes,
flow rate ˆ 1.0 mLminÀ1, R enantiomer Tr ˆ 34.2 min, S enantiomer
Tr ˆ 36.8 min).
Asymmetric, StereocontrolledTotal Synthesis
of Paraherquamide A**
Robert M. Williams,* Jeffrey Cao, and
Hidekazu Tsujishima
[14] D. A. Evans, D. W. C. MacMillan, K. R. Campos, J. Am. Chem. Soc.
1997, 119, 10859 ± 10860.
[15] Dihydroxylation was performed using the achiral ligand, quinuclidine.
For a review of asymmetric dihydroxylation under these conditions,
see H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless, Chem. Rev.
1994, 94, 2483 ± 2547.
The paraherquamides (1, 2, 5, 6),[1±4] marcfortines (3, 4),[5]
brevianamides,[6] VM55599 (9),[3b] and, most recently, the
sclerotamides (10)[7] and aspergimides (8)[8] are indolic
secondary metabolites isolated from various fungi
(Scheme 1). The parent and most potent member, paraher-
à Â
[16] D. A. Evans, B. W. Trotter, P. J. Coleman, B. Cote, L. C. Dias, H. A.
Rajapakse, A. N. Tyler, Tetrahedron 1999, 55, 8671 ± 8726.
à Â
[17] D. A. Evans, P. J. Coleman, B. Cote, J. Org. Chem. 1997, 62, 788 ± 789.
See also I. Paterson, K. R. Gibson, R. M. Oballa, Tetrahedron Lett.
1996, 37, 8585 ± 8588.
[*] Prof. Dr. R. M. Williams, J. Cao, H. Tsujishima
Department of Chemistry
[18] A model aldol reaction with ketone 3 and dihydrocinnamaldehyde
under unoptimized conditions (nBu2BOTf, iPr2NEt, Et2O, À788C)
resulted in a 72% yield of the desired anti adduct with >95:5
diastereoselectivity as determined by 1H NMR analysis (500 MHz) of
the unpurified reaction mixture. The relative stereochemistry of this
product was determined by X-ray crystallography.
Colorado State University
Fort Collins, CO 80523 (USA)
Fax : (‡1)970-491-3944
E-mail: rmw@chem.colostate.edu
[19] The remainder of the material was comprised of cleanly recovered 3
and 4.
[20] Hemiketal 2 existed as a 92:8 mixture of the closed hemiketal and
open hydroxy ketone. This mixture was taken on together in the
subsequent reduction.
[21] K. S. Kim, Y. H. Song, B. H. Lee, C. S. Hahn, J. Org. Chem. 1986, 51,
404 ± 407.
[22] The lithium anions of methyl and ethyl propiolate failed to alkylate a
model primary trifluoromethanesulfonate derived from the commer-
cial available tetrahydropyran-2-methanol at low temperature
[**] This work was supported by the NIH (Grant CA 70375). The Japanese
Society for the Promotion of Science (JSPS) is acknowledged for
providing support to H.T. Mass spectra were obtained on instruments
supported by the NIH Shared Instrumentation Grant (GM 49631). We
also wish to thank Dr. Timothy Blizzard (Merck & Co.) for providing
an authentic sample of natural paraherquamide A. We also wish to
acknowledge Dr. Byung H. Lee (Pharmacia ± Upjohn Co.) for provid-
ing NMR spectra and an authentic specimen of 14-oxoparaherqua-
mide B. We also wish to thank Dr. Alfredo Vazquez for assistance with
purification and characterization of synthetic paraherquamide A.
2540
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1433-7851/00/3914-2540 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2000, 39, No. 14